(Contemporary Clinical Neuroscience) Giuliana Grimaldi, Mario Manto (auth.), Giuliana Grimaldi, Mario Manto (eds.)-Mechanisms and Emerging Therapies in Tremor Disorders-Springer-Verlag New York (2013).pdf

Contemporary Clinical Neuroscience
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Mario Manto
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Giuliana Grimaldi • Mario Manto
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Mechanisms and Emerging

Therapies in Tremor
Disorders
Editors
Giuliana Grimaldi Mario Manto
Unité d’Etude du Mouvement (UEM) Unité d’Etude du Mouvement (UEM)
Neurologie ULB Erasme Neurologie ULB Erasme
Bruxelles, Belgium Bruxelles, Belgium
ISBN 978-1-4614-4026-0 ISBN 978-1-4614-4027-7 (eBook)

DOI 10.1007/978-1-4614-4027-7
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2012943613
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Preface
Who could claim they’ve never experienced trembling at least some point in their
lifetime? Indeed, everybody has perceived some tremor some time in life. For instance,
the postural tremor observed when using the pointer during one’s first lecture… In
fact, a slight, rapid, and postural physiological tremor is permanently present, as
shown when placing a piece of paper on the hand when the upper limb is extended.
Tremor is thus a very common phenomenon when one looks around carefully.
Medical doctors are aware that the observation of an unexpected tremor in a
given subject can result either from diseases of non-neurological origin (hyperthy-
roidism, drug treatments, etc.) or from an affliction of the nervous system. The most
known of the latter are Parkinson’s disease (PD), although the classical rest tremor
is not always present, and Essential Tremor (ET), characterized by a postural/kinetic
tremor and whose prevalence is six times higher than the prevalence of PD. By
contrast with what is usually believed, the diagnosis of tremor is far from being
easy. When its intensity is minimal, it is often difficult to distinguish ET from physi-
ological tremor (for instance in subjects pertaining to ET families). When tremor is
severe, its large amplitude may wrongly orient towards other disorders such as
repetitive movements observed in PD treated by levodopa. Even more difficult, a
tremor can mimic rhythmic myoclonus as seen in dystonic patients or depressed
patients overtreated with various medications (lithium, etc.). In all these difficult
cases, a polygraphic recording of tremor by an experienced clinical physiologist can
be very helpful. Although tremor is a remarkable sign to perform an accurate diag-
nosis during daily clinical practice, it is often underlooked. There are many biases
and drawbacks, for example, the amalgam between tremor and senility, or the wrong
idea that tremor is often associated with alcoholism (I recall the case of a waiter who
was considered alcoholic, although he had in fact a severe ET that he tried to improve
by drinking several glasses of wine before serving the guests).
When possible, the treatment of tremor depends primarily on the treatment of the
condition causing the tremor (hyperthyroidism for example). However, this is
exceptionally the case in most neurological disorders. In PD patients, tremor is
rarely disabling, except in few forms of the diseases, and it is usually largely attenu-
ated by the administration of levodopa provided the doses of the administrated
v
vi Preface
amino acid are high enough, which is not always possible. In most severe cases of
parkinsonian tremor, the neurosurgical approach (high-frequency stimulation of the
thalamus, thalamotomy) can be extremely helpful. Bilateral stimulation of the sub-
thalamic nucleus has not only the advantage of abolishing the contralateral rest
tremor, but also to markedly improve the most disabling akineto-rigid syndrome. In
patients with ET, one has to clearly distinguish two clinical situations. In benign
cases, when the symptom starts to bother the patient in his daily life, the administra-
tion of drugs such as beta-blockers or primidone is required provided there is no
contraindication. In patients with severe ET, i.e., when the amplitude of the tremor
is interfering with the most elementary gestures of daily life, the medical treatment
becomes ineffective, and the best option, when acceptable, is neurosurgery. High-
frequency stimulation of the Vim of the thalamus is the treatment of choice, but the
destructive approach (thalamotomy) can be considered in fragile, aged, or non-
cooperative patients.
These comments are obviously oversimplified and will be extensively developed
in the book. Whether benign, needing a simple follow-up, or severe, implying a
sophisticated treatment, the clinical aspects of the various types of tremor need to be
perfectly identified as it is the only way to ensure an optimal management of patients.
To become a good semiologist in the field of tremor is necessary, but it is not
sufficient! One needs also to be an excellent physiologist. Nowadays, as the mecha-
nisms of the different categories of tremor start to be understood, this is now pos-
sible. In this field, the practitioner needs to keep in mind three main ideas (1) tremor
can result from the dysfunction of all parts of the nervous system: the cerebral cor-
tex (rhythmic myoclonus), the basal ganglia (PD rest tremor), the brain stem
(Holmes tremor), the cerebellum (ET), the spinal cord (in fact segmental myoclo-
nus), and peripheral nerves (Charcot–Marie–Tooth diseases); (2) several groups of
neurons are tremorogenic, giving rise to various rhythmic oscillations in the brain
(12–14 Hz in the olive; 3–6 Hz in the basal ganglia); (3) there is no unique “center
of tremor” explaining the rhythm, the speed, and the amplitude of tremor, which
also depends on the tension of the implicated muscles. In most cases, even if the
lesions are selectively confined in the brain, tremor results from the dysfunction of
various neuronal circuits, thereby giving rise to different symptomatic aspects of
tremor.
Why this new book then? The reason is that it provides an extensive state of the
art of the available clinical and scientific knowledge related to tremor. The numer-
ous chapters, provided by the best experts in the field, will allow the clinicians to
base their diagnosis, prognosis, and treatment on an updated clinical and pathophys-
iological basis, with bridges between fundamental aspects and clinical approaches.
Institut du Cerveau et de la Moëlle épinière

Paris, France Yves Agid
Introduction
The field of tremor has dramatically widened since the publication of the books of
Findley-Capildeo (1984) and Findley-Koller (1995). The Consensus Statement of the
Movement Disorder Society is another key document for the history of research on
tremor (Deuschl et al. 1998), suggesting a classification based on the distinction
between rest, postural, kinetic, and “intention” tremor (tremor during target-directed
movements). Additional data from a medical history and the results of a neurologic
examination have been combined into one of the following clinical syndromes defined
in the statement: enhanced physiologic tremor, classical essential tremor, primary
orthostatic tremor, task- and position-specific tremors, dystonic tremor, tremor in
Parkinson’s disease, cerebellar tremor, Holmes’ tremor, palatal tremor, drug-induced
and toxic tremor, tremor in peripheral neuropathies, or psychogenic tremor.
A broad range of common neurological disorders manifest with rhythmic oscil-
lations; this area of research has become increasingly productive both at the experi-
mental and clinical level, and as a consequence, much new information has
accumulated over the last years. Therefore, we thought that the quantity of novel
knowledge was worthy of a comprehensive update. An example of the sprouting of
knowledge is related to our current understanding of Essential Tremor. It is now
accepted that this terminology covers several distinct disorders and that the symp-
tomatology is much broader than initially thought. Interestingly, a better under-
standing of tremor mechanisms may bring new insights for fundamental brain
mechanisms such as synchronization of neural networks, coordination and execu-
tion of movement.
Although apparently simple, tremor is a complex physiological and physiopatho-
logical phenomenon. Tremor may occur at any age and is often a cause of social
difficulties, even if patients may not seek medical care, due to impairment of activi-
ties of daily life such as eating or writing. Ad hoc clinical rating scales of tremor are
now complemented by functional evaluations and the use of motion transducers
allow in particular the extraction of the amplitude and the frequency of tremor.
Novel methods of assessment have emerged with their own advantages and limita-
tions. Reliable and unobtrusive wearable sensors are available, so that a detailed
monitoring and an accurate assessment of tremor can be performed. Such evaluation
vii
viii Introduction
can by itself contribute to a correct diagnosis of the underlying neurological disorder.

Novel approaches in signal processing have also been developed. These methods
are shared between several disciplines and research topics. In addition, many labo-
ratories have developed their own tools and approaches to tremor assessment.
Tremor is intimately linked to the numerous interactions of the central and
peripheral nervous system components tuning motor control, from the cerebral cor-
tex up to the peripheral effectors. Activities of central generators, reflex loop delays,
inertia, stiffness, and damping are all factors influencing features of tremor. This
book discusses the pathophysiology of tremor including membrane mechanisms
and rodent models, the advances in genetics and the musculoskeletal models perti-
nent to body oscillations. The main forms of tremor encountered during clinical
practice are considered, taking into account neuroimaging aspects. The book covers
recent advances in methodologies and techniques of assessment and provides prac-
tical information for the daily management. In addition to pharmacological treat-
ments, neurosurgical approaches such as deep brain stimulation (DBS) and
thalamotomy are discussed. Emerging techniques under development are also intro-
duced. Future challenges are also presented.
This overview is intended for a large audience of scientists, clinicians including
neurologists and neurosurgeons, internists, fellows, trainees, biologists, and bio-
medical and electrical engineers. The goal of this book is to provide both basic sci-
ence information and detailed clinical approaches and to make recent developments
accessible to this audience, in order to promote understanding and optimal care of
patients suffering from tremor.
All the experts who have excellently contributed to this book have a direct expe-
rience in tremor. We are indebted to all of them for their efforts. We are also particu-
larly grateful to Ann Avouris and Simina Calin for their commitment, continuous
support, and professionalism.
Unité d’Etude du Mouvement (UEM) Giuliana Grimaldi

ULB Erasme, Bruxelles, Belgium Mario Manto
References
Findley LJ, Capildeo R. Movement disorders: Tremor. Macmillan, London; 1984.

Findley LJ, Koller WC. Handbook of tremor disorders. Marcel Dekker, New York, NY; 1995.
Deuschl G, Bain P, Brin M. Ad Hoc Scientific Committee. Consensus statement of the Movement
Disorder Society on Tremor. Mov Disord. 1998;13(Suppl 3):2–23.
Contents
Part I Fundamental Aspects
1 Definition of Tremor ............................................................................... 3

Giuliana Grimaldi and Mario Manto
2 Membrane Mechanisms of Tremor ....................................................... 11
Aasef G. Shaikh, Lance M. Optican, and David S. Zee
3 Rodent Models of Tremor ...................................................................... 37
Hideto Miwa
4 Advances in the Genetics of Human Tremor........................................ 53
Fabio Coppedè
5 Musculoskeletal Models of Tremor ....................................................... 79
Dingguo Zhang and Wei Tech Ang
Part II The Various Forms of Tremor in Clinical Practice:

Presentation and Mechanisms
6 Physiologic Tremor ................................................................................. 111

Rodger J. Elble
7 Rest Tremor ............................................................................................. 121
8 Postural Tremors..................................................................................... 133
Jean-François Daneault, Benoit Carignan, Fariborz Rahimi,
Abbas F. Sadikot, and Christian Duval
9 Isometric Tremor .................................................................................... 151
Dennis A. Nowak, Hans-Jürgen Gdynia, and Jan Raethjen
ix
x Contents
10 Essential Tremor and Other Forms of Kinetic Tremor ....................... 167

Elan D. Louis
11 Dystonic Tremor ...................................................................................... 203
Stefania Lalli and Alberto Albanese
12 Orthostatic Tremor ................................................................................. 219
Julián Benito-León, Andrés Labiano-Fontcuberta, and Elan D. Louis
13 Vocal Tremor ........................................................................................... 235
Katherine A. Kendall
14 Update in Familial Cortical Myoclonic Tremor
with Epilepsy ........................................................................................... 249
Eloi Magnin, Pierre Labauge, Lucien Rumbach, and Marie Vidailhet
15 Posttraumatic Tremor and Other Posttraumatic
Movement Disorders ............................................................................... 263
Jose Fidel Baizabal-Carvallo and Joseph Jankovic
16 Psychogenic Tremor ................................................................................ 289
Luis Redondo-Vergé and Natividad Carrion-Mellado
17 Tremor in Childhood .............................................................................. 305
Padraic J. Grattan-Smith and Russell C. Dale
Part III Assessment of Tremor: Clinical, Neurophysiological

and Neuroimaging Aspects
18 Assessment of Tremor: Clinical and Functional Scales ....................... 325

19 Instrumentation: Classical and Emerging Techniques........................ 341
Peter H. Kraus
20 Signal Processing ..................................................................................... 371
James McNames
21 Diffusion Imaging in Tremor ................................................................. 391
Johannes C. Klein
22 Metabolic Networks in Parkinson’s Disease ......................................... 403
Michael Pourfar, Martin Niethammer, and David Eidelberg
Part IV Therapies of Tremor
23 Pharmacological Treatments of Tremor ............................................... 419

24 Thalamotomy........................................................................................... 431
Julie J. Berk and Olga S. Klepitskaya
Contents xi
25 Deep Brain Stimulation .......................................................................... 445

Ioannis U. Isaias and Jens Volkmann
26 Dopaminergic Influences on Rest and Action Parkinsonian Tremors
and Emerging Therapies for Tremor .................................................... 463
Quincy J. Almeida, Fariborz Rahimi, David Wang,
and Farrokh Janabi-Sharifi
Index ................................................................................................................. 477

wwwwwwwwwwwww
Contributors
Alberto Albanese, M.D. Fondazione Istituto Neurologico Carlo Besta,

Milano, Italy
Istituto di Neurologia, Università Cattolica del Sacro Cuore, Milano, Italy
Quincy J. Almeida Sun Life Financial Movement Disorders Research and
Rehabilitation Center, Faculty of Science, Wilfrid Laurier University,
Waterloo, ON, Canada
Wei Tech Ang School of Mechanical and Aerospace Engineering, Nanyang
Technological University, Singapore, Singapore
Jose Fidel Baizabal-Carvallo, M.D. Department of Neurology, Parkinson’s
Disease Center and Movement Disorders Clinic, Baylor College of Medicine,
Houston, TX, USA
Julián Benito-León, M.D., Ph.D. Department of Neurology,
University Hospital “12 de Octubre”, Madrid, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Madrid, Spain
Department of Medicine, Faculty of Medicine, Complutense University,
Madrid, Spain
Julie J. Berk Department of Neurology, School of Medicine,
University of Colorado, Aurora, CO, USA
Benoit Carignan, Ph.D. Département des Sciences Biologiques, Université du
Québec à Montréal, Montreal, QC, Canada
Natividad Carrion-Mellado Servicio de Psiquiatría, Hospital de Valme,
Sevilla, Spain
Fabio Coppedè, Ph.D. Faculty of Medicine, Section of Medical Genetics,
University of Pisa, Pisa, Italy
xiii
xiv Contributors
Russell C. Dale Children’s Hospital Westmead, The University of Sydney,

Sydney, NSW, Australia
Jean-François Daneault, Ph.D. Department of Neurology and Neurosurgery,
Montreal Neurological Institute, McGill University, Montreal, QC, Canada
Christian Duval, Ph.D. Département de Kinanthropologie,
Université du Québec à Montréal, Montreal, QC, Canada
David Eidelberg Department of Neurology, North Shore University Hospital,
Manhasset, NY, USA
Center for Neurosciences, The Feinstein Institute for Medical Research,
Manhasset, NY, USA
Rodger J. Elble, M.D., Ph.D. Department of Neurology,
Southern Illinois University School of Medicine,
Springfield, IL, USA
Eloi Magnin, M.D. Department of Neurology, CMRR de Franche-Comté,
CHU Besançon, Besancon, France
Laboratoire de Neuroscience, Université de Franche-Comté (UFC), Besançon,
France
Hans-Jürgen Gdynia Neurologische Klinik Kipfenberg, Kipfenberg, Germany
Padraic J. Grattan-Smith Children’s Hospital Westmead,
The University of Sydney, Sydney, NSW, Australia
Giuliana Grimaldi Unité d’Etude du Mouvement (UEM),
Neurologie ULB Erasme, Bruxelles, Belgium
Ioannis U. Isaias Neurologische Klinik und Poliklinik,
Universitätsklinik Würzburg, Würzburg, Germany
Farrokh Janabi-Sharifi Department of Industrial and Mechanical Engineering,
Ryerson University, Toronto, ON, Canada
Joseph Jankovic, M.D. Department of Neurology, Parkinson’s Disease Center
and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, USA
Katherine A. Kendall, M.D. Associate Professor, Department of Otolaryngology,
University of Minnesota, Minneapolis, MN, USA
Johannes C. Klein, M.D. Department of Neurology, Goethe-University Frankfurt,
Frankfurt am Main, Germany
Olga S. Klepitskaya University of Colorado Denver, Aurora, CO, USA
Peter H. Kraus, M.D. Department of Neurology, Ruhr-University Bochum,
St. Josef-Hospital, Bochum, Germany
Pierre Labauge, M.D., Ph.D. Department of Neurology, CHU de Montpellier,
Montpellier, France
Contributors xv
Andrés Labiano-Fontcuberta, M.D. Department of Neurology,

University Hospital “12 de Octubre”, Madrid, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Madrid, Spain
Department of Medicine, Faculty of Medicine, Complutense University,
Madrid, Spain
Stefania Lalli, M.D., Ph.D. Fondazione Istituto Neurologico Carlo Besta,
Milano, Italy
Elan D. Louis, M.D., M.S. Unit 198, Neurological Institute,
New York, NY, USA
GH Sergievsky Center, College of Physicians and Surgeons, Columbia University,
New York, NY, USA
Department of Neurology, College of Physicians and Surgeons, Columbia
University, New York, NY, USA
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain,
College of Physicians and Surgeons, Columbia University, New York, NY, USA
Department of Epidemiology, Mailman School of Public Health, Columbia
University, New York, NY, USA
Mario Manto FNRS, Unité d’Etude du Mouvement (UEM),
Neurologie – ULB Erasme, Bruxelles, Belgium
James McNames Portland State University, Portland, OR, USA
Hideto Miwa, M.D. Department of Neurology, Wakayama Medical University,
Wakayama-city, Wakayama, Japan
Martin Niethammer Department of Neurology, North Shore University
Hospital, Manhasset, NY, USA
Center for Neurosciences, The Feinstein Institute for Medical Research,
Manhasset, NY, USA
Dennis A. Nowak Neurologische Klinik Kipfenberg, Kipfenberg, Germany
Neurologische Universitätsklinik, Philips-Universität Marburg,
Marburg, Germany
Lance M. Optican, Ph.D. Laboratory of Sensorimotor Research,
National Eye Institute, NIH, DHHS, Bethesda, MD, USA
Michael Pourfar Department of Neurology, North Shore University Hospital,
Manhasset, NY, USA
Jan Raethjen Neurologische Universitätsklinik, Universitätsklinikum
Schleswig-Holstein, Kiel, Germany
xvi Contributors
Fariborz Rahimi, Ph.D. Department of Electrical Engineering, University of

Waterloo, Waterloo, ON, Canada
Department of Clinical Neurological Sciences, London Health Sciences Centre,
University Hospital of Western Ontario, London, ON, Canada
Luis Redondo-Vergé Servicio de Neurología, Hospital Virgen Macarena,
Sevilla, Spain
Lucien Rumbach, M.D., Ph.D. Department of Neurology,
CMRR de Franche-Comté, CHU Besançon, Besancon, France
Laboratoire de Neuroscience, Université de Franche-Comté (UFC),
Besançon, France
Abbas F. Sadikot, M.D., Ph.D., FRCSC Department of Neurology and
Neurosurgery, Montreal Neurological Institute, McGill University,
Montreal, QC, Canada
Aasef G. Shaikh, M.D., Ph.D. Department of Neurology, Case Western Reserve
University, University Hospitals Case Medical Center, Cleveland, OH, USA
Marie Vidailhet, M.D., Ph.D AP-HP, Department of Neurology,
Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière
(CRICM), Paris, France
Jens Volkmann Neurologische Klinik und Poliklinik, Universitätsklinik
Würzburg, Würzburg, Germany
David Wang Department of Electrical Engineering, University of Waterloo,
Waterloo, ON, Canada
David S. Zee, M.D. Department of Neurology, The Johns Hopkins University,
Baltimore, MD, USA
Dingguo Zhang Institute of Robotics, School of Mechanical Engineering,
Shanghai Jiao Tong University, Shanghai, China
Part I
Fundamental Aspects
Chapter 1
Definition of Tremor
Keywords Rhythmic • Rest • Postural • Kinetic • Action • Movement disorders

• Thalamus • Inferior olive • Cerebellum
1.1 Introduction
Tremor is generally defined as a rhythmic shaking of a body part (Deuschl et al.

1998; Findley and Capildeo 1984). Tremor is a non linear and non stationary
phenomenon, often made of a roughly sinusoidal oscillatory movement, usually
non voluntary. Tremor is readily apparent in most cases. The oscillation is com-
posed of a back-and-forth movement (McAuley and Marsden 2000), where
“back-and-forth” means that there is a relatively symmetric velocity profile in both
directions about a midpoint of the movement, with the velocity profile of oscilla-
tions appearing sinusoidal (Sanger et al. 2010).
Tremor is the most common movement disorder encountered during daily prac-
tice (Louis et al. 1995). Its incidence and prevalence increase with aging. The preva-
lence in people over 60 years has been estimated to be 4.6% (Louis and Ferreira
2010). In this sense, and given the aging of the population, tremor disorders are a
matter of interest for the society in general and for the scientific community in
particular.
Tremor causes functional disability and social inconvenience, disturbing daily
life activities and also contaminating other specific motor activities. Nevertheless, a
nonnegligible amount of patients, especially those with a mild tremor, do not ask for
medical advice if tremor does not impede daily life activities.
G. Grimaldi (*) • M. Manto

Unité d’Etude du Mouvement (UEM), Neurologie ULB Erasme,
808 Route de Lennik, 1070 Bruxelles, Belgium
e-mail: giulianagrim@yahoo.it; mmmanto@ulb.ac.be
G. Grimaldi and M. Manto (eds.), Mechanisms and Emerging Therapies in Tremor 3

Disorders, Contemporary Clinical Neuroscience, DOI 10.1007/978-1-4614-4027-7_1,
4 G. Grimaldi and M. Manto
Table 1.1 Main disorders associated with tremor according to the presentation
Clinical presentation Diseases
Rest tremor Parkinson’s disease
Drug-induced Parkinsonism
Stroke
Post-traumatic tremor
Postural tremor Essential tremor
Enhanced physiological tremor
Cerebellar diseases
Multiple sclerosis
Post-traumatic tremor
Metabolic diseases (Wilson’s disease)
Peripheral neuropathy
Drug-induced
Withdrawal syndromes (ethanol, etc.)
Kinetic tremor Cerebellar diseases
Essential tremor
Multiple sclerosis
Adapted from Grimaldi and Manto (2008)
Tremor may present with different clinical features and different parameters.
The different kinds of tremor are usually grouped on the basis of the topographical
distribution, the task or position dependence, the frequency, and the amplitude.
From the clinical point of view, the most commonly used classification is the
following: rest tremor, postural tremor, and kinetic tremor. Indeed, numerous
neurological diseases are associated with a form of tremor falling within these
categories (Table 1.1). The term “action tremor” refers to any tremor produced by
voluntary contraction of muscles. It includes postural, isometric, and kinetic tremor
(Grimaldi and Manto 2008). Task-specific tremor appears while attempting to
perform a specific task such as writing.
1.2 Types of Tremor
A list of the main types of tremor encountered during daily practice with a brief
definition is proposed here. Detailed descriptions are provided along the book’s
chapters. Table 1.2 summarizes their main features for the commonest forms.
Physiologic tremor is an involuntary rhythmical movement of upper limb segments
typically in the frequency range of 8–12 Hz, occurring in healthy subjects. The ampli-
tude is often small and is barely seen with the naked eye (Cathers et al. 2006).
Enhanced Physiologic Tremor is a visible high frequency postural tremor, which
can be associated with several metabolic conditions (mainly thyrotoxicosis or
hypoglycemia), drugs administration, caffeine intake, and muscle fatigue (Grimaldi
and Manto 2008).
Rest tremor occurs while the body segment is maintained at rest and may disap-
pear with action. It is typically asymmetrical, starting distally in the arms, with a
1
Table 1.2 Principal types of tremor

Tremor type Amplitude Frequency (Hz) Distribution Precipitants
Physiologic tremor Small, barely seen 8–12 Proximal and distal
Definition of Tremor
with the naked eye

Enhanced physiologic tremor Visible – mild 8–12 Proximal and distal Any posture
Rest tremor Mild to severe 3–6 Distal/asymmetrical Rest
Mental activities
Postural tremor Mild to severe 4–12 Proximal and distal Any posture
Kinetic tremor Mild to severe 2–7 Proximal > distal Execution of a movement
Isometric tremor Mild to severe Variable Body region in isometric Isometric muscle contraction
contraction
Postural tremor in cerebellar diseases
Asthenic cerebellar tremor Mild to severe Irregular Proximal and distal Fatigue/weakness
Precision cerebellar tremor Mild to severe 2–5 Distal Accurate placements
Cerebellar axial postural tremor Mild to severe 2–10 Proximal > distal Any posture
Cerebellar proximal exertional tremor Mild to severe 3–4 Proximal > distal Prolonged exercise
Midbrain tremor
Rest postural and kinetic Mild to severe 2–5 Proximal > distal Any posture
Orthostatic tremor
Isometric tremor Mild to severe 13–18 Legs and trunk Isometric contraction
of the limb muscles
Dystonic tremor
Postural and kinetic Unsteady 4–9 Asymmetrical May increase with movement
5
frequency range of 3–6 Hz. Usually, rest tremor in the upper limbs reminds a “pill
rolling” movement at the level of the hands.
Postural tremor is triggered by postural tasks. Its frequency is usually between
4 and 12 Hz. Tremor appears immediately and often increases in amplitude after
a few seconds in the line of gravity.
Postural tremor in cerebellar disease can be further described as (a) precision
tremor, with a frequency of 2–5 Hz, occurring during the execution of precision
tasks and involving the distal musculature; (b) asthenic tremor, precipitated by
fatigue; (c) axial postural tremor; (d) midbrain tremor (Brown et al. 1997) (see also
below).
Kinetic tremor appears during the execution of a movement and is usually
maximal as the limb approaches the target (Holmes 1939). It has a frequency
between 2 and 7 Hz in the large majority of cases. Kinetic tremor tends to involve
predominantly the proximal musculature (Gilman et al. 1981; Lechtenberg 1993)
and oscillations are usually perpendicular to the main direction of the intended
movement. It is reduced by addition of inertia (Chase et al. 1965; Hewer et al. 1972).
Cerebellar tremor is a tremor associated with cerebellar disorders. It is mainly
composed of low frequency oscillations. There is usually a kinetic component often
associated with a concomitant postural tremor (Rondot and Bathien 1995). Action
tremor is common in cerebellar disorders. Tremor may be bilateral, but in case of
cerebellar unilateral lesions oscillations are observed ipsilaterally to the cerebellar
lesion.
Isometric tremor occurs when a voluntary muscle contraction is opposed by a
rigid stationary object (Findley and Koller 1995).
Orthostatic tremor is a high frequency tremor (13–18 Hz) predominantly in the
legs and trunk, triggered during isometric contraction of the limb muscles or during
standing (Piboolnurak et al. 2005).
Dystonic tremor is mainly a postural and sometimes kinetic tremor in a body part
affected by dystonia. Its frequency is typically irregular, varying from 4 to 9 Hz.
Amplitude is unsteady. It is usually asymmetrical and often remains localized,
although shaking can extend to other body segments or the entire body (Bhidayasiri
2005). Dystonic tremor may be enhanced by a goal-directed movement. Tremor
may anticipate a genuine dystonia by several years, which can be a source of
diagnostic difficulties (Rivest and Marsden 1990). Dystonic tremor is likely
underdiagnosed.
The most common form of task-specific tremor is primary writing tremor which
occurs during writing. Several authors consider that primary writing tremor is a
dystonic tremor.
Midbrain tremor (also called Holmes tremor) is characterized by a combination
of 2–5 Hz rest, postural, and kinetic tremor (Hopfensperger et al. 1995). It affects
predominantly proximal segments in upper limbs.
Thalamic tremor presents as a postural and kinetic tremor occurring several
weeks or months after a thalamic lesion involving posterior nuclei (Kim 2001).
Dystonic features may be associated.
Rhythmic cortical myoclonus (cortical tremor) presents as an action tremor. It
may be associated with myoclonus and seizures (Ikeda et al. 1990).
1 Definition of Tremor 7
Table 1.3 Differential diagnosis of involuntary movements

Diseases commonly associated
Definition/Features with the movement disorder
Tremor
– Rest See text Parkinson’s disease
– Postural Essential tremor
– Kinetic Cerebellar tremor
Dystonia Prolonged muscle contractions leading to Drug-induced
abnormal postures. May be repetitive. Genetic
Twisting movements Idiopathic
Chorea Irregular; often hidden in voluntary movement; Huntington’s disease
generates a dance-like movement
Athetosis Continuous slow hyperkinesia of distal Stroke
segments of limbs; causes an octopus-like
movement
Ballism Fast and ample movement of proximal Stroke
segments of limbs; gives a “throw Inflammatory diseases
away”-like movement. More severe
in upper limbs
Tics Fast and short hyperkinetic movements Gilles-De-La-Tourette
usually with a facial or head topography Syndrome
Myoclonus Sudden, short (20–150 ms) movement; may Essential myoclonus
cause a pseudo-repetitive muscular Myoclonic epilepsy
contraction Symptomatic myoclonus
From Grimaldi and Manto (2008)
Palatal tremor (also called palatal myoclonus) may be symptomatic or essential.

Symptomatic palatal tremor is due to rhythmic contractions of the levator veli
palatini muscle and is often unilateral. It may persist during sleep. It is usually asso-
ciated with a lesion of the posterior fossa (see also Guillain-Mollaret triangle).
Essential palatal tremor is bilateral. Patients may perceive an ear click due to con-
tractions of the tensor veli palatine muscle (closing Eustachian tube).
Psychogenic tremor has usually a frequency between 4 and 11 Hz, often varying
with time. It may have a sudden onset, with frequent remissions, and may respond
to placebo or suggestion.
Some patients with tremor exhibit subclinical or clinically evident neuropsycho-
logical changes. For instance, patients with essential tremor may show impairments
in executive functions, language, and visuospatial abilities (Higginson et al. 2008).
Very often, the consequences of these deficits are underestimated in clinical settings.
1.2.1 Differential Diagnosis Between Tremor and the Other

Involuntary Disorders
The repetitive and stereotyped feature of oscillations allows to distinguish tremor from
other involuntary movement disorders, such as chorea, athetosis, ballism, tics, and
myoclonus (Table 1.3) (Bhidayasiri 2005). However, comorbidity is not rare. Indeed,
tremor may coexist with other involuntary movements, as for the dystonic tremor.
Fig. 1.1 Motor pathways and main loops involved in tremor genesis. Corticosubcortical loops
including (a) the basal ganglia–thalamocortical motor circuit involving the sensorimotor cortex,
and (b) the Guillain–Mollaret triangle (including red nucleus, inferior olive, and contralateral
cerebellar nuclei; yellow lines). The GPi (internal globus pallidus) and SNr (substantia nigra pars
reticulata) tonically inhibit the thalamocortical neurons. Thalamic neurons have a firing mode
varying with the membrane potential and are prone to oscillations. Cerebellar afferences include
the climbing fibers (cf) from the contralateral inferior olive, the mossy fibers (mf ) from the crossed
ponto-cerebellar tract and the direct spinocerebellar tract (SCT: Flechsig tract or dorsal spino-
cerebellar fasciculus; the crossed spinocerebellar tract is not illustrated) which conveys proprio-
ceptive information. Neurons of the inferior olive are electrotonically coupled via gap junctions
and are endowed with voltage-dependent ionic conductances explaining oscillatory properties.
Cerebellar nuclei (CN; mainly interpositus and dentate nuclei) project contralaterally to red nucleus
and thalamic nuclei, providing an excitatory activity to these targets. Cerebellar nuclei exert an
inhibitory activity on the contralateral inferior olive via the nucleoolivary tract (NOT; not illus-
trated). Segmental spinal loops are not illustrated (see Chapter 5). Abbreviations: STN: subtha-
lamic nucleus; SNc: substantia nigra (pars compacta); VLa: ventrolateral thalamus (anterior);
VLp: ventralateral thalamus (posterior); ML: medial lemniscus
1 Definition of Tremor 9
1.2.2 Sources of Tremor
The sources of tremor can be summarized into three groups: mechanical, reflex,
central oscillations (see also Chap. 6). Tremor may be generated by the central and/
or peripheral nervous system, with complex interactions. In some neurological
disorders, the central generator is obvious, but in other cases, its identification is a
real challenge. Indeed, a myriad of structures are all involved in tremorogenesis:
joints and muscles obeying the laws of physics (inertia, damping, etc.), spinal cord,
segments at the supra-spinal level including the brainstem, basal ganglia, cerebral
cortex, as well as the cerebellum which is considered to be a major site for tremoro-
genesis (Grimaldi and Manto 2008; Fig. 1.1). Rest tremor is believed to be
generated in the basal ganglia loop, whereas the postural and kinetic tremor are
likely generated by the olivo–cerebello–thalamo–cortical loop which includes the
so-called Guillain–Mollaret triangle (cerebello–rubro–olivary projections).
References
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afferent input. Exp Brain Res. 2006;171(2):194–203.
Chase RA, Cullen Jr JK, Sullivan SA, et al. Modification of intention tremor in man. Nature.
1965;206(983):485–7.
Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor.
Ad Hoc Scientific Committee. Mov Disord. 1998;13 suppl 3:2–23.
Findley LJ, Capildeo R. Movement disorders: tremor. London: Macmillan; 1984.
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Claypool; 2008.
Hewer RL, Cooper R, Morgan MH. An investigation into the value of treating intention tremor by
weighting the affected limb. Brain. 1972;95:579–90.
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essential tremor consistent with frontosubcortical dysfunction. J Clin Exp Neuropsychol.
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Chapter 2
Membrane Mechanisms of Tremor
Aasef G. Shaikh, Lance M. Optican, and David S. Zee
Keywords Membrane • Neurons • Oscillations • Loops • Spikes • Coupling

• Synchronization • Thalamus • Inferior olive • Cerebellum
2.1 Background
A number of neurological and psychogenic disorders present with tremor. In some,

there is a known structural abnormality, while in others the pathophysiology is
unknown. For example, the scarcity of a neurotransmitter from presynaptic
neuronal degeneration causes tremor in degenerative cerebellar or basal ganglia
disorders (Jankovic and Tolosa 2007). Instability of the brainstem neural integrators
may cause tremor of the eyes (pendular nystagmus) in patients with demyelinating
disorders (Das et al. 2000). However, the anatomical and pathophysiological
correlates of some tremor disorders, for example essential tremor, are unsettled.
Regardless of the primary etiology (structural deficit or idiopathic) contemporary
literature suggests that oscillations can arise at the level of neuronal membranes.
More recently, it was proposed that membrane hyperexcitability could cause essen-
tial tremor (Shaikh et al. 2008). In support of this hypothesis, commonly used drugs
(e.g., primidone, propranolol, gabapentin, topiramate) also have membrane stabili-
zation effects (O’Suilleabhain and Dewey 2002; Zesiewicz et al. 2005).
A.G. Shaikh, M.D., Ph.D. (*)

Department of Neurology, Case Western Reserve University, University Hospitals
Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106-5040, USA
e-mail: aasefshaikh@gmail.com
L.M. Optican, Ph.D.
Laboratory of Sensorimotor Research, National Eye Institute, NIH, DHHS, Bethesda, MD, USA
D.S. Zee, M.D.
Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA

12 A.G. Shaikh et al.
2.2 Outline
In this chapter we will focus on membrane electrophysiology and its relationship to

tremor. We will review literature on membrane electrophysiology of the central
neurons that are known to cause tremor. We will discuss how intrinsic membrane
properties of these neurons can generate oscillations, and how isolated cellular
oscillations are synchronized to generate tremor. We will also address computa-
tional studies that propose specific hypotheses for the membrane mechanisms of
tremor. Finally we will discuss the pharmacotherapy of tremor that supports the
membrane contribution to tremor generation. In this chapter we emphasize the role
of membrane properties in the generation of tremor, but we do not exclude the role
of anatomical and physiological abnormalities that also serve as a substrate for
tremor. We only suggest that abnormalities in both anatomical circuits and the
properties of membranes of their constituent neurons are important for a complete
understanding of the genesis of tremor.
2.3 Membrane Mechanisms of Essential Tremor
Figure 2.1 shows a simplified diagram of the primate motor system and indicates
possible sources of tremor. The mass and biophysical property of the part of the
body to be moved is a key determinant of the frequency of any tremor (Elble and
Koller 1990). Of course, neurological disorders producing tremor, such as essential
tremor, clearly have a central origin (Timmermann et al. 2003; Volkmann et al.
1996). A strong coherence between the tremor and thalamic oscillations (Hua and
Lenz 2004; Hua et al. 1998) and an influence of thalamic lesions on the tremor
(Koller et al. 2000; Pahwa et al. 2000) support the role of a thalamocortical pathway
in the pathophysiology of essential tremor (blue pathway in Fig. 2.1). Synchronized
activity in a circuit comprised of cerebellar Purkinje neurons, the deep cerebellar
nuclei, and the inferior olive plays a key role in motor learning and motor timing
(Apps and Garwicz 2005; Wolpert et al. 1998). Increased synchronization of the
inferior olive neurons by harmaline is a common way to generate an animal model
of tremor (Lamarre et al. 1971; Lamarre and Mercier 1971; de Montigny and
Lamarre 1973; Llinás and Volkind 1973). Increased activity in the olivocerebellar
pathway has been reported in patients with essential tremor (Louis et al. 2004;
Deuschl and Elble 2000; Jenkins and Frackowiak 1993). The olivocerebellar
pathway is illustrated in a green color in Fig. 2.1.
Here we address two fundamental questions: Why do thalamocortical and olivo-
cerebellar networks oscillate? Which factors predispose them to generate tremor? It
is known that the intrinsic membrane properties of thalamic and inferior olive
neurons facilitate spontaneous rhythmic firing (Jahnsen and Llinás 1984; Park et al.
2010; Llinás and Yarom 1986). These isolated cellular oscillations may become
synchronized to generate sufficient drive causing actual tremor.
2 Membrane Mechanisms of Tremor 13
Fig. 2.1 This figure illustrates a schematic summary simplified diagram of primate motor system
highlighting three possible circuits that are known to cause tremor. The brown circuit illustrates
possible peripheral tremor generator, which include mechanical system comprised of muscle,
tendon, and joint. The afferent pathway of the mechanical system is made of sensory neurons
which synapse at spinal cord, send proprioceptive signals to thalamus, and also influence the
interneuron that project locally to the motor neuron. Blue circuit illustrates thalamocortical circuit
for central tremor generation. The blue box (thalamus) contains reciprocally innervating thalamo-
cortical and thalamoreticular neurons—the reciprocal innervations are fundamental for generation
of tremor. Basal ganglia receives cortical input through striatum and its output nuclei is globus
pallidus. Latter, normally inhibits the oscillations in the circuit of reciprocally innervating thalamic
neurons. Synchronized inferior olive oscillations transmitted in olivocerebellar circuit, shown in
green, is third source of tremor. Normally this circuit has cardinal role in motor learning
2.3.1 Membrane Oscillations in Thalamic Neurons
Thalamic neurons express voltage activated ion conductances such as 4-amin-

opyridine sensitive potassium currents (IA), low threshold calcium currents (IT),
hyperpolarization-activated mixed cation currents (Ih), and calcium-dependent
potassium current (GK[Ca]) (Jahnsen and Llinás 1984). Because of the inherent struc-
ture of the thalamic membrane, when certain electrophysiological conditions are
Fig. 2.2 This caricature illustrates the underlying ion currents responsible to two oscillatory
attributes of the thalamic neurons. (a) Action potential spike is generated by fast acting sodium
currents (GNa). The spike is voltage-sensitive potassium current and calcium-dependent potassium
currents, causing after-hyperpolarization. After hyperpolarization (AHP) typically brings membrane
to threshold for fast spike, but not further negative than −55 mV. The threshold is sufficient for
subsequent, spike in approximately 100 ms, causing 10 Hz spikes. (b) Strong hyperpolarization
simulating inhibitory postsynaptic potential (IPSP) brings membrane potential further negative
than −55 mV, de-inactivating 4-aminopyridine sensitive potassium current (IA) to further prolong
the duration of the hyperpolarized state. Latter then de-inactivates low-threshold calcium current
(IT) and hyperpolarization-activated mixed cation current (Ih) triggering a rebound spike of action
potential (post-inhibitory rebound)
met isolated thalamic neurons generate spontaneous action potentials. Thalamic

neurons have two key properties related to the generation of tremor: (1) partial
depolarization of the membrane potential triggers a “burst” of low-threshold spikes;
and (2) a further depolarized state results in sustained firing (“tonic discharge”)
(Jahnsen and Llinás 1984; McCormick and Pape 1990).
The resting membrane potential of the thalamic neuron determines the frequency
of cellular oscillations. A high frequency (9–11 Hz) oscillatory pattern emerges
when the thalamic neuron is depolarized to around −46 mV (Jahnsen and Llinás
1984; Fig. 2.2a). Such a depolarized state activates a slow sodium conductance
followed by fast sodium current to generate an action potential and subsequent
after-hyperpolarization (Jahnsen and Llinás 1984). The after-hyperpolarization,
caused by the voltage- and calcium-dependent potassium current (Hotson and Prince
1980; Llinás and Sugimori 1980; Llinás and Yarom 1981), brings the membrane
potential to a subthreshold state lasting for about 100 ms. The duration of the sub-
threshold, “refractory,” state determines the frequency (9–11 Hz) of the oscillatory
behavior. Figure 2.2a depicts a schema of the temporal sequence of ion conduc-
tances responsible for 9–11 Hz oscillations. The strength of hyperpolarization that
follows the isolated action potential spike is generally not sufficient to de-inactivate
IT and Ih low-threshold spikes.
In the thalamus approximately 6 Hz oscillations emerge as the membrane is
hyperpolarized beyond −55 mV. This strong hyperpolarization triggers a pro-
longed after-hyperpolarized state due to inhibitory postsynaptic potentials (IPSP)
and relatively prolonged inactivation state of IA (gray zone in Fig. 2.2b). The
hyperpolarized state triggers pacemaker currents (such as Ih and IT currents)
(Jahnsen and Llinás 1984; Pape and McCormick 1989; McCormick and Pape 1990;
see yellow zone in Fig. 2.2b). The cell membrane is then depolarized, resulting in the
burst of action potentials (post-inhibitory rebound, PIR; see light blue zone in
Fig. 2.2b). Each action potential (within the burst) is followed by a voltage-
dependent potassium current and then a successive spike of action potential
(dashed black box in Fig. 2.2b, c). The rate of depolarization of the membrane that
follows hyperpolarization after each single action potential is determined by the
extracellular concentration of potassium ions. A reduced extracellular potassium
concentration favors a rapid rate of membrane depolarization to reach the threshold
for successive action potential, hence, an increased number of action potentials
within the burst (i.e., the “strong” burst). A number of factors, including levels of Ih
and IT, determine the extracellular levels of potassium, the number of action poten-
tials within the burst, and hence, the strength of PIR. Each burst typically lasts
20–30 ms and is followed by a refractory period (Jahnsen and Llinás 1984).
The hyperpolarization, more negative to −55 mV, which follows each burst, again
de-inactivates low-threshold currents and causes a subsequent PIR. In the presence
of a periodic inhibitory stimulus, sustained, 6 Hz bursts of PIR appear. The rela-
tively low frequency of the bursts of PIR is attributed to the longer inactivation
time of the IT current (Jahnsen and Llinás 1984).
2.3.2 Membrane Oscillations in the Inferior Olive Neurons
Neurons within the inferior olive show three types of oscillatory behavior; two are
similar to thalamic neurons. Approximately 9–10 Hz oscillations are seen during
the burst of spontaneous discharge (Llinás and Yarom 1986). These oscillations are
comprised of a sequence of action potentials each of which typically is followed by
a relatively short after-hyperpolarization. However, when the membrane is strongly
hyperpolarized a relatively sustained after-hyperpolarization de-inactivates Ih and IT
currents and results in PIR (Llinás and Yarom 1986). In addition, subthreshold,
3–6 Hz sinusoidal oscillations of the resting membrane potential is a unique prop-
erty of inferior olive neurons (Llinás and Yarom 1986). The amplitude and fre-
quency of these subthreshold sinusoidal oscillations are independent of the amplitude
of the transmembrane voltage during the resting state (Llinás and Yarom 1986).
Attenuation of the fast sodium current has no effect on the subthreshold oscillations;
however, antagonists of IT abolish them. Generally, the depolarizing shift in the
resting membrane potential during subthreshold sinusoidal oscillation does not
cause action potentials. However, when the membrane is hyperpolarized, subthresh-
old oscillations frequently result in low-threshold currents, (such as IT) that are often
followed by a burst of action potentials (Llinás and Yarom 1986). In other words, in
the hyperpolarized state, subthreshold sinusoidal oscillations increase the propen-
sity to rhythmically generate action potential bursts.
Fig. 2.3 (a) Caricatures of repetitive bursts from two thalamic neurons are illustrated. Due to
membrane ion channel profile, the action potential in the given neuron is followed by after-hyper-
polarization. When the strength of after-hyperpolarization is sufficient to bring the membrane
potential more negative than −55 mV, there is de-inactivation of 4-aminopyridine sensitive potas-
sium current, low threshold calcium current (IT), and hyperpolarization-activated cation current
(Ih). As a result there is rebound burst, post-inhibitory rebound. As illustrated in this panel, in
absence of consistent, repetitive burst of inhibition, the bursting oscillatory behavior of these neurons
dissipates. Furthermore, resultant spikes from an isolated neuron are not sufficient to generate
2.3.3 Thalamic and Inferior Olive Oscillation and Relation

to Harmaline Model of Tremor
The mechanisms underlying spontaneous oscillations in the thalamus and inferior

olive relate to the pathophysiology of harmaline-induced tremor, the popular experi-
mental animal model of essential tremor (Lamarre et al. 1971; Lamarre and Mercier
1971; de Montigny and Lamarre 1973; Llinás and Volkind 1973). Local application
of harmaline could enhance the de-inactivation of IT and Ih, and increases the
membrane excitability to cause occasional 3–6 Hz spike trains of action potentials
(Llinás and Yarom 1986). Harmaline also accentuates the subthreshold sinusoidal
oscillations and further increases the propensity to produce action potential in
otherwise “silent” neurons (Llinás and Yarom 1986).
2.3.4 Synchronization of Isolated Neuronal Oscillations
Now that we have described underlying mechanisms for oscillations in isolated

thalamic and inferior olive neurons, we must emphasize that when isolated, these
neurons are unable to sustain their oscillations (Fig. 2.3a). Repetition of an inhibi-
tory stimulus, generating inhibitory postsynaptic potentials, and subsequent PIR is
required to maintain the oscillatory behavior. Furthermore, an ensemble discharge
from a group of neurons is necessary to generate adequate drive to move a body
part. In physiological system, the groups of neurons are coupled or synchronized to
generate a sufficient motor drive and sustain their oscillations causing tremor. The
sections below describe mechanisms of synchronization in thalamic and inferior
olive neurons.
Fig. 2.3 (continued) adequate force generating tremor. These spikes would dissipate over time in
absence of repetitive external impulse. (b) This panel illustrates the circuit of reciprocally inner-
vating neurons controlling movements. As illustrated thalamocortical neurons (TC) and thalamic
reticular neurons (TR) makes a circuit of reciprocally innervating neurons. Unless inhibited or
hyperexcited the reciprocally innervating circuit can oscillate. The oscillations are normally inhib-
ited by the globus pallidus internus (GpI) neurons. This panel is modified from Shaikh et al. (2008).
(c) The thalamic reticular and thalamocortical neurons form reciprocally inhibitory circuit and thus
couple with each other forming multiple synchronized patches. Here, in example of two inhibitory
neurons A and B, due to reciprocal inhibition, a burst in neuron A is followed by a burst in neuron
B (due to inhibition from neuron A). The burst in neuron B then result in burst in neuron A, hence,
train of bursts in two mutually inhibitory neurons start. When these neurons are designated to
innervate agonist and antagonist muscles, respectively, alternating firing of agonist and antagonist
muscle pairs cause tremor
2.3.4.1 Coupling of Neurons in Thalamus
Reciprocal inhibition of agonist and antagonist neurons is necessary to generate

sustained oscillations in the thalamic circuit (Sherrington 1908). This principle is
schematized in Fig. 2.3b. Thalamo-cortical relay (TC) neurons send glutamatergic
excitatory projections to thalamic reticular (TR) neurons, while TR neurons send
GABA-mediated inhibitory projections to TC neurons (Pinault 2004; Guillery and
Harting 2003). In addition, TR neurons mutually inhibit each other via inhibitory
collaterals (Pinault 2004; Guillery and Harting 2003). This interaction amongst TC
and TR neurons makes reciprocal loops, negative feedback from TR to TC, and
mutually inhibitory TR neurons. This organization, reciprocal innervations of
neurons that can generate PIR, could provide adequate drive to generate prompt and
high-speed ballistic movements. However, such reciprocally innervating circuits are
inherently unstable and are prone to generate oscillations (Shaikh et al. 2007, 2008;
Ramat et al. 2005; Fig. 2.3b). Figure 2.3c illustrates a schematic of two reciprocally
inhibitory thalamic neurons with a membrane profile suitable to generate PIR
(neurons A and B). When a small pulse of neural signal, either spontaneous neural
firing or a small voluntary movement, activates neuron A, it in turn would inhibit
neuron B. The latter, having PIR, would have the burst of action potentials at the end
of the inhibitory pulse from neuron A. Furthermore, neuron B would also inhibit
neuron A (reciprocal inhibition), causing it to have PIR at the end of the pulse from
neuron B. As consequence a sustained train of PIR, alternating between agonist and
antagonist neurons (neurons A and B), would emerge and the reciprocally inner-
vated neural circuit would begin to oscillate (Fig. 2.3c). The coupling between
multiple neurons allows synchronization of oscillations in groups of neurons,
allowing sufficient electrical drive to generate and sustain tremor.
2.3.4.2 Experimental and Computational Evidence of Thalamic

Coupling as a Cause of Tremor
It was hypothesized that sufficient external inhibition is nature’s solution to inher-

ently unstable thalamic circuits (Shaikh et al. 2007, 2008). As schematized in
Fig. 2.3b, inhibitory projections to TC and TR neurons from the globus pallidus
internus (GPi) provide a substrate for GABAergic external inhibition to poten-
tially unstable thalamic circuits (Parent and Hazrati 1995; Takada and Hattori
1987). Abolishing GABAergic inhibition in GABA mutant mice caused tremor
phenotype (Kralic et al. 2005). A recent 11C-flumazenil PET study showed an
association between reduced GABA function and increased availability of GABA
receptors in cerebellar and thalamic sites (Boecker et al. 2010). Boecker and
colleagues (2010) interpreted these results in support of the “GABA hypothesis,”
which attributes the thalamic oscillations to the scarcity of GABA function.
However, the “GABA hypothesis” remains controversial in the pathogenesis of
human essential tremor. García-Martín et al. (2011) did not find differences in the
frequencies of allelic variants in the genotypes of GABA receptors from the

essential tremor patients and healthy subjects (García-Martín et al. 2011). Thus,
indirectly, this study found no apparent molecular evidence if impaired
GABAergic inhibition in patients with essential tremor. A different study did not
find any mutation in the GABA receptor genotype in humans with essential tremor
(Deng et al. 2006).
We proposed a novel hypothesis for the pathophysiology of essential tremor
Shaikh et al. (2008). Our hypothesis was based on the idea that increased excit-
ability of TC and TR neurons causes reverberations in the coupled circuits (Shaikh
et al. 2008). It was proposed that the effect of (normal) inhibition is reduced by
increased excitability within a circuit of reciprocally innervated neurons. It is
possible that increased activation kinetics of Ih or IT, due to the alterations in the
intracellular levels of second messengers or other regulators, increase the neural
excitability (McCormick and Pape 1990; Shaikh and Finlayson 2005; Wainger et al.
2001; Lüthi and McCormick 1999). Computational models of the thalamic neurons
with physiologically realistic membrane properties and anatomically realistic
neural connections are compatible with a role for neuronal hyperexcitability in the
pathogenesis of essential tremor (Shaikh et al. 2008). Key features of our model
were (1) increased neural excitability secondary to increase in Ih and/or IT, currents
and (2) inherent circuit instability resulting from reciprocal innervation between
the neurons with PIR. A proposed increase in Ih and/or IT simulated limb oscilla-
tions resembling essential tremor (Shaikh et al. 2008). Indeed NNC55-0396, a
potent blocker of IT, reduced tremor in GABAA receptor null and harmaline-treated
animal models and provided experimental support for our hypothesis (Shaikh et al.
2008; Quesada et al. 2011).
2.3.4.3 Other Causes of Thalamic Neuronal Excitability in Essential Tremor
All patients with essential tremor would not be expected to have the same cause for
their increased excitability. A loss of inhibition due to a structural abnormality in
cerebellar Purkinje neurons has been proposed for the subgroup of essential tremor
patients (Axelrad et al. 2008; Louis and Vonsattel 2008; Louis 2010). Hypothetically
a structural lesion in Purkinje neurons could increase the excitability of thalamic
neurons by reducing inhibition in the dentate–thalamic projection. The gly9 suscep-
tibility variant of the DRD3 gene was reported in some essential tremor families
(Jeanneteau et al. 2006; Lucotte et al. 2006; Sóvágó et al. 2005). Such a mutation
can prolong the intracellular action of mitogen-activated protein kinase (MAPK),
leading to increased intracellular levels of cyclic AMP (cAMP) via excessive inhibi-
tion of phosphodiesterase E4 (Hoffmann et al. 1999; Houslay and Milligan 1997;
Houslay et al. 1998; Jeanneteau et al. 2006). It is known that increased intracellular
cAMP increases Ih and subsequently increases the membrane excitability of central
neurons (Shaikh and Finlayson 2005).
2.3.4.4 Coupling of Neurons in Inferior Olive
Isolated inferior olive neurons generate small amplitude, episodic, subthreshold

oscillations, which are only sustained for a few seconds (Llinás and Yarom 1981,
1986; Leznik and Llinás 2005; Yarom 1991; Placantonakis et al. 2006) . If
sustained and synchronized, these oscillations can also cause tremor. Recent
studies increasingly supported a role for connexin gap junctions to synchronize
and sustain the subthreshold oscillations in the inferior olive (Yarom 1991;
Bleasel and Pettigrew 1992; Manor et al. 1997; Condorelli et al. 1998; Long
et al. 2002; De Zeeuw et al. 2003; Placantonakis et al. 2006). Each inferior olive
neuron is coupled with variable number of neighboring neurons (Hoge et al.
2011). The patches of inferior olive neurons have variable coupling strength
(Hoge et al. 2011). Uncoupling resulting from genetic disruption of connexin 36
or its blockade, in vivo, with local injection of carbenoxolone or 18-glycyrrhetinic
acid degraded the ensemble rhythm of the inferior olive (Leznik and Llinás 2005;
Blenkinsop and Lang 2006; Placantonakis et al. 2006). Hence, it is likely that
electrotonic gap junctions comprised of connexin molecules between adjacent
inferior olive neurons are key elements for facilitating synchronization in the
inferior olive. In the harmaline model of tremor, the role of subthreshold oscilla-
tions and the influence of harmaline on connexin gap junction remain controversial.
Harmaline induced robust oscillations in animal knockout models for con-
nexin36, which are the same as oscillations in wild-type phenotypes (Placantonakis
et al. 2006). Therefore, it has been suggested that there is another ionic mecha-
nism that facilitated synchronization of harmaline-treated connexin36, knockout
animals (Placantonakis et al. 2006).
2.3.4.5 Influence of Cerebellum and Conditional Learning on Synchronized

Inferior Olive Discharge and Tremor
It is hypothesized that cerebellar conditional learning may alter the kinematic prop-
erties (amplitude and regularity) of the inferior olive discharge (Shaikh et al. 2010).
Synchronized activity of the inferior olive is transmitted to the cerebellar Purkinje
cells by two parallel pathways—through climbing fibers and through parallel fibers
via deep cerebellar nuclei. As seen in a classical conditioning paradigm, here
Purkinje cells would learn an irrelevant conjunction from an inferior olive input
arriving directly on climbing fibers, and indirectly, with a delay, on parallel fibers.
The Purkinje cell would therefore pause with each inferior olive pulse, increasing
the output of the inferior olive and making it smoother and larger. In patients with
oculopalatal tremor (OPT), this hypothesis was tested by simulating pendular eye
oscillations with a computational model (Hong and Optican 2008; Shaikh et al.
2010). The model featured the interaction between the inferior olive and the cere-
bellum using (1) high-conductance soma-somatic gap junctions in adjacent inferior
olive neurons, (2) synchronized discharge of a population of inferior olive neurons,

and (3) cerebellar motor learning (Hong and Optican 2008; Shaikh et al. 2010). The
similar process may also alter the characteristics of essential tremor originating
due to hyperactivity of olivocerebellar pathway (Louis et al. 2004; Deuschl and
Elble 2000; Jenkins and Frackowiak 1993).
2.3.5 Membrane Electrophysiology and Essential

Tremor Frequency
Many factors influence the frequency of essential tremor. The mass and physical
property of the mechanical system is one, for example. Tremor of an organ with a
smaller mass (e.g., the fingers) is typically of a higher frequency than one with a
larger mass (e.g., wrist) (Elble and Koller 1990). However, the frequency of essen-
tial tremor of the same organ among different subjects is variable (Deuschl et al.
2001). The conductance-based model of essential tremor predicts that profile of
expression of Ih and IT channels determines inter-subject variability in the fre-
quency of tremor (Shaikh et al. 2008). Increasing the value of Ih in the conduc-
tance-based model of thalamic neurons increases the tremor frequency but decreases
the amplitude (Shaikh et al. 2008). In contrast, increasing the value of IT (while
keeping Ih constant) increases the tremor amplitude but decreases the frequency.
Simulations of the conductance-based model of thalamic neurons correlate well
with the data from essential tremor patients (Shaikh et al. 2008). Although specula-
tive, these simulations speak for the plausibility of a role for ion channel expres-
sion profiles and intrinsic membrane properties in the genesis and variability of
tremor in patients.
As described earlier, thalamic neurons have two oscillatory characteristics,
one with a low frequency (approximately 6 Hz) and the other with a relatively
high frequency (9–11 Hz) (Jahnsen and Llinás 1984). Only the 6 Hz component
is reflected in the frequency of the essential tremor (Elble 2000). We hypothe-
size that it is due to a selective synchronization of low frequency oscillations.
Patch-clamp and computational studies showed that the inhibition of the coupled
neuron has to be strong enough to evoke an IPSP, subsequent low-threshold
spike, and PIR (Jahnsen and Llinás 1984; Shaikh et al. 2008). Therefore only
rebound firing of the inhibitory (presynaptic) neuron could generate an IPSP in
the inhibited (postsynaptic) neuron. Therefore amongst the coupled neurons
only the “low-frequency thalamic oscillations” comprised of low-threshold
spikes and PIR are synchronized. In contrast, individual hyperpolarization
(responsible for “high-frequency thalamic oscillations”) does not evoke a
sufficiently inhibitory postsynaptic potential to synchronize with the coupled
neuron. Therefore high frequency oscillations are typically not seen in the
patients with essential tremor.
2.3.6 Pharmacotherapy of Tremor Supports the Membrane

Hypothesis for Essential Tremor
2.3.6.1 Beta-Blockers and Membrane Physiology of Tremor
Beta-blockers, such as propranolol, are considered a first-line treatment for

essential tremor (Zesiewicz et al. 2005). Atenolol is used when propranolol is
contraindicated, e.g., in patients with asthma (Zesiewicz et al. 2005). Beta-blockers
reduce intracellular levels of cyclic AMP, inhibit signaling through protein kinase
C and extracellular signal-regulated kinase (Sozzani et al. 1992; Pascoli et al. 2005;
Franzellitti et al. 2011). The intracellular level of cyclic AMP is one of the key
determinants of the strength of Ih and IT currents; reduction in the levels of cyclic
AMP reduces Ih and IT and subsequently the membrane excitability (Shaikh and
Finlayson 2003, 2005; Alvarez et al. 1996; Pape and McCormick 1989; Yue and
Huguenard 2001; Jahnsen and Llinás 1984). It is not surprising that reduction in
membrane excitability reduces tremor amplitude and frequency (Shaikh et al. 2008).
2.3.6.2 Antiepileptics and Membrane Physiology of Tremor
Primidone, an antiepileptic, is also considered a standard treatment for essential

tremor (Zesiewicz et al. 2005). Primidone is a desoxybarbiturate with two active
metabolites—phenylethylmalonic acid and phenobarbitone (Baumel et al. 1972).
One of the active metabolites, phenobarbitone has a dual action—it enhances post-
synaptic GABA-mediated inhibition as well as reduces neural excitability (Polc and
Haefely 1976). Reducing excitability and enhancing external (GABAergic) inhibi-
tion on a reciprocally inhibited, unstable, oscillating circuit of thalamic neurons
would promote stabilization and reduce tremor (Shaikh et al. 2008).
Gabapentin is an antiepileptic that is also effective in essential tremor. It reduces
calcium trafficking by blocking the alpha-2-delta subunit of the calcium channel
(Thorpe and Offord 2010). Gabapentin can also block NMDA glutamate receptors
(Kim et al. 2009). As a result gabapentin could reduce membrane excitability in
thalamic neurons and attenuate tremor (Shaikh et al. 2008).
Zonisamide, an antiepileptic and an IT blocker, also may be effective in essential
tremor. This too supports the hypothetical role of increased neural excitability
(secondary to an increase in Ih and/or IT) and subsequently a release of oscillations
in the thalamocortical circuit, in the pathophysiology of essential tremor (Morita
et al. 2005; Song et al. 2008; Handforth et al. 2009).
2.3.6.3 Membrane Physiology of Tremor and Alcohol
At least three membrane mechanisms might account for a reduction of tremor with
the acute consumption of alcohol. Ethanol induces sustained GABAA-mediated
inhibition, decreasing neural excitability and firing rate (Jia et al. 2008). Reduced
thalamic neural excitability can attenuate tremor (Shaikh et al. 2008). Abnormalities
within the NMDA pathway are another proposed mechanisms of essential tremor
(Manto and Laute 2008) and increased glutamatergic stimulation can increase
membrane excitability of thalamic neurons causing tremor (Shaikh et al. 2008).
Ethanol antagonizes this effect by decreasing the glutamate concentration and
NMDA current, which in turn would reduce membrane excitability and diminish
tremor (Manto and Laute 2008; Shaikh et al. 2008).
2.4 Membrane Physiology and Tremor of Parkinson’s Disease
There is increasing evidence that parkinsonism is a complex network disorder

secondary to abnormally increased excitability, oscillatory activity, and synchrony
in the basal ganglia neurons affecting their thalamic and cortical connections
(Obeso et al. 1997; Bergman et al. 1990, 1998; Herrero et al. 1996; Mitchell et al.
1989; Vila et al. 1996, 1997; Galvan and Wichmann 2008; Gittis et al. 2011). The
scarcity of dopamine has a key role in increasing excitability and facilitating the
synchronization of oscillatory behavior in the basal ganglia (Bergman et al. 1998;
Gittis et al. 2011).
One piece of evidence for increased excitability in parkinsonism comes from
intracellular recordings from single, dopamine-deprived striatal neurons. They
showed spontaneous GABA-mediated, depolarizing, postsynaptic potentials
(Calabresi et al. 1993). Lesion of SNPr, which is the source of dopaminergic termi-
nals to the striatum, increases postsynaptic (striatal) sensitivity of D2 dopamine
receptors. This, in turn, enhances the release of glutamate and reduces D1 dopamine
receptor-induced inhibition. Such an increase in striatal excitability could alter the
striatal output to other nuclei in the basal ganglia (Vila et al. 1996, 1997; Wichmann
et al. 1999; Orieux et al. 2000; Galvan and Wichmann 2008). The net response of
enhanced excitability and attenuated inhibition would result in oscillatory activity
which could produce or accentuate tremor.
Neurons within the subthalamic nucleus of patients with Parkinson’s disease
show three patterns of activity—tonic, irregular, and oscillatory (Rodriguez-Oroz
et al. 2001). Neurons with irregular and tonic firing are relatively common and are
equally activated by movement. Rhythmically firing neurons within the subthalamic
nucleus are of two subtypes: those with long-lasting low-frequency bursts and those
with high-frequency bursts. The dominant oscillation frequency of those with the
high-frequency bursts matches that of tremor. Microstimulation or lesion of these
neurons promptly attenuates the tremor (Rodriguez-Oroz et al. 2001; Wichmann
et al. 1994; Baunez et al. 1995; Guridi et al. 1996; Krack et al. 1997; Limousin et al.
1998). The oscillatory behavior in subthalamic circuit further propagates to
thalamic and cortical neurons. The neuronal discharges recorded from the thalamus
and globus pallidus are also phase locked with tremor (Albe-Fessard et al. 1962;
Lenz et al. 1994; Guridi et al. 1999; Vitek et al. 1998). The discharge within two
distinct cerebral cortical networks, temporoparietal-brainstem and frontal, is coherent

with subthalamic oscillations (Litvak et al. 2011). Hence, it is proposed that the
subthalamic nucleus, globus pallidus, thalamus, and cerebral cortex are all part of a
neural circuit generating tremor in Parkinson’s disease (Alexander et al. 1986;
DeLong 1990).
2.5 Membrane Physiology in Drug-Induced Tremor
2.5.1 Valproate-Induced Tremor
Valproate, an anticonvulsant and mood stabilizer, has several known mechanisms of

action. It enhances the effects of GABA by reducing its transamination (Chapman
et al. 1982) and it selectively inhibits IT (Kelly et al. 1990). Given these, valproate
should enhance GABAergic inhibition and decrease the propensity to cause tremor
by reducing membrane excitability and neuronal threshold. In contrast, parkin-
sonism and postural tremor can be side effects of valproate (Zadikoff et al. 2007).
Why is there an increased risk of developing tremor and parkinsonism in patients
exposed to valproic acid? One idea is that enhancement of GABA reduces the
dopamine turnover in the nigrostriatal system (Waldmeier and Maitre 1978). For
example, the GABAB-agonist, baclofen, reduces the release of dopamine in the
striatum (Kabuto et al. 1995). Therefore reduced dopaminergic tone could cause
tremor and extrapyramidal symptoms resembling parkinsonism in patients taking
valproate. Valproate-induced cerebellar atrophy can be associated with tremor in
some patients (Papazian et al. 1995).
2.5.2 Lithium-Induced Tremor
Tremor is a common side effect of lithium, a commonly used mood stabilizer

(Varaflor et al. 1970). Lithium replaces the sodium ions, causing marked depolariza-
tion and alters the configuration of the action potential (Carmeliet 1964). Due to its
similarity to sodium, lithium is transported inside of the cell. However, it cannot
bind with Na–K-ATPase pump and accumulates intracellularly (Carmeliet 1964).
According to the Goldman–Hodgkin–Katz equation, replacement of sodium by
lithium results in a depolarization shift of the resting membrane potential
(Thiruvengadam 2001). A reduced neuronal threshold due to the depolarized state
of the resting membrane potential can increase neuronal excitability and a propen-
sity to develop tremor (Shaikh et al. 2008). In support of this idea, a beta-blocker,
propranol, improves lithium-induced tremor (Kellett et al. 1975). Propranolol non-
selectively reduces Ih and IT and consequently reduces neuronal excitability (Pape
and McCormick 1989; Shaikh and Finlayson 2003).
2.5.3 Neuroleptic-Induced Tremor
Neuroleptics also cause tremor and parkinsonism, and atypical antipsychotics are
more likely to manifest extrapyramidal side effects. These compounds are lipophilic
and strongly block the D2 subtype of dopamine receptors (Susatia and Fernandez
2009). Depletion of dopamine in presynaptic terminals causes increased activity of
the GABAergic system which reduces the turnover of dopamine in the nigrostriatal
system (Susatia and Fernandez 2009; Waldmeier and Maitre 1978; Kabuto et al.
1995). The membrane pathophysiology of neuroleptic-induced tremor is therefore
similar to that induced by experimental models of dopamine depletion as described
in the section of tremor in Parkinson’s disease (section 2.4).
2.5.4 Tremor in Hyperthyroidism
Thyroid hormone has many effects on the electrical activity of the cell membrane.
The effect of hyperthyroidism on cardiac pacemaker membrane is well studied, but
much less is known about the effects on neurons. Thyroid hormone decreases the
duration of the monophasic action potential and effective refractory period in
cardiac pacemakers, predisposing to cardiac arrhythmias (Yu et al. 2009; Childers
2006). One can speculate that an analogous increased excitability in neurons would
increase the propensity of central oscillators to cause tremor. In hippocampal and
cortical neurons, thyroid hormone up-regulates fast-acting sodium currents and
increases the rate of depolarization and the firing rate (Hoffmann and Dietzel 2004).
An increase in the rate of depolarization and reduction of the refractory period in
central neurons would increase their excitability. An increase in neural excitability
of thalamocortical or olivocerebellar circuit could then result in tremor (Shaikh
et al. 2008).
2.5.5 Caffeine-Induced Tremor
Caffeine stimulates the brain in many ways. At high, nonphysiological concentra-

tions, caffeine mobilizes intracellular calcium, inhibits phosphodiesterases,
affecting depolarizing currents including Ih and IT. These changes would increase
membrane excitability of the thalamocortical and olivocerebellar neurons and
could cause tremor. At normal doses, caffeine increases cerebral energy metabo-
lism, decreases cerebral blood flow, decreases pH, and activates noradrenaline
(Nehlig et al. 1992). An increase in noradrenergic tone and decrease in pH favors
an increase in depolarizing currents including Ih and IT, reducing the membrane
threshold, and increasing membrane excitability (Pape and McCormick 1989;
Shaikh and Finlayson 2003, 2005).
2.5.6 Tremor Induced by Adrenergic Agonists
Terbutaline, isoproterenol, epinephrine, amphetamines, selective serotonin reuptake

inhibitors (SSRIs), tricyclic antidepressants, nicotine, and theophylline all increase
adrenergic activity. Adrenergic agonists increase Ih and IT and thus membrane
excitability and so could contribute to tremor (Pape and McCormick 1989; Shaikh
et al. 2008).
2.6 Membrane Mechanisms in Pathogenesis of Acquired

Pendular Nystagmus and Saccadic Oscillations
Acquired pendular nystagmus (APN) is a rhythmic sinusoidal or quasi-sinusoidal

oscillation of the eyes often impairing vision because of excessive motion of images
on the retina (Leigh and Zee 2006). APN can be considered the tremor of the eyes
and in many ways it can be analogous to tremor of the limbs. Two common causes
of APN are multiple sclerosis (MS) and the syndrome of oculopalatal tremor (OPT)
(Lopez et al. 1996; Deuschl et al. 1994). Saccadic oscillations are another tremor-
like disturbance of the eyes in which there are uncalled for back-to-back saccades
which also interferes with vision. They can be unidimensional, pure horizontal, or
multidimensional affecting all three axes of rotation. Unidimensional saccadic
oscillations are called ocular flutter, when multidimensional, they are called opso-
clonus (Leigh and Zee 2006). Paraneoplastic syndromes, postinfectious encephali-
tis, demyelinating disorders, or poisoning commonly causes continuous or transient
saccadic oscillations (Shaikh et al. 2008; Leigh and Zee 2006; Ko et al. 2008).
Physiologically they are present in newborns; even some healthy subjects have an
innate ability to produce saccadic oscillations, which are called voluntary “nystag-
mus” (Shaikh et al. 2007, 2010; Hoyt 1977). Experimental and computational stud-
ies of APN and saccadic oscillations suggest primary disturbances at the levels of
neuronal membranes (Das et al. 2000; Shaikh et al. 2007, 2008, 2010, 2011a, b).
In subsequent sections we will describe membrane mechanisms contributing to the
pathogenesis of APN in MS and OPT.
2.6.1 Membrane Mechanism for APN in MS
The most accepted hypothesis for APN in MS is that the oscillations are generated
because of instability in the neural integrator that normally sends premotor commands
to hold the eyes steady in a given orbital position (Das et al. 2000). Evidence for the
unstable neural integrator hypothesis is that the perturbation of ongoing oscillations
by a velocity signal, e.g., a saccade, resets the oscillation phase (Das et al. 2000).
In this section we will first discuss the membrane mechanisms for neural
integration and then discuss the possible abnormality, at the level of cell membrane,
causing instability in the neural integrator. A pulse of neuronal discharge generated

by the saccadic burst neurons determines the eye velocity; the burst of neural
discharge is then converted to steady-state tonic firing in the motor neurons by a
neural integrator in the mathematical sense. The persistent tonic firing rate after the
saccade is associated with the step-like changes in the inter-spike membrane poten-
tial of velocity-position integrator neurons (Aksay et al. 2001). Amplitude of the
inter-spike membrane potential and thus neuronal firing rate is directly proportional
to the eye position (Aksay et al. 2001). When the membrane is hyperpolarized, brief
intracellular pulses (mimicking the saccade) causes step-like change in inter-spike
membrane potential (which would potentially translate into steady change in the
gaze position) (Aksay et al. 2001). In contrast, when the membrane is depolarized,
there is increasing fluctuations in the inter-spike membrane potential. It is proposed
that sustained change in the inter-spike membrane potential is due to the persistent
synaptic input. There is a mutually excitatory feedback network amongst ipsilateral
neurons and mutually inhibitory feedback between ipsi- and contralateral neurons.
Mutually inhibitory connections serve to yoke the firing rate and inter-spike
membrane potential above (ipsilateral) or below (contralateral) the equilibrium
(Aksay et al. 2007). Within the network of neurons serving as neural integrator, the
persistence of the firing rate and the similarity of the persistence (i.e., evidence of
integration) is also determined by the circuit’s functional architecture; physically
closer neurons have relatively similar persistence of the firing rate (Miri et al. 2011).
Latter underscores the importance of strong network connections (as expected in
closely placed neurons) in efficiency of integration (Miri et al. 2011).
These considerations allow us to predict that a constant hyperpolarization of the
membrane or disruption of the interconnections would prevent changes in inter-
spike membrane potential and subsequently impair the ability of the neural integrator
to maintain a steady state change in the firing rate. Indeed injection of the hyperpo-
larizing agent, muscimol (a selective GABAA receptor agonist), at the putative site
of the neural integrator in monkeys made the integrator unstable, while depolariza-
tion (with glutamate) reversed the effects (Arnold and Robinson 1997; Arnold et al.
1999). In the presence of a visual feedback, the unstable neural integrator would
then oscillate (Das et al. 2000). It is therefore hypothesized that the severity of the
instability of the neural integrator determines the amplitude of APN in MS patients
and the membrane depolarization would reduce the amplitude of APN. Indeed,
gabapentin and memantine, which indirectly depolarize the cells of the nucleus
prepositus hypoglossi, by blocking the alpha-2-delta subunit of calcium channels
and antagonizing NMDA receptors at the cerebellar Purkinje neurons, reduces the
amplitude of APN in MS (Shaikh et al. 2011a; Thurtell et al. 2010).
2.6.2 Membrane Mechanism for Pathogenesis of APN in OPT
In OPT, hypertrophic degeneration of the inferior olive causes APN due to a breach
in the “Guillain-Mollaret triangle” (a circuit from the inferior olive to the deep
cerebellar nuclei and cerebellar cortex, and then projecting from the cerebellum
through the superior cerebellar peduncle, passing through the red nucleus and then
descending through the central tegmental tract back to the inferior olive) (Guillain
and Mollaret 1931). These oscillations are characteristic because they are irregular,
smooth, disconjugate, and have random cycle-by-cycle variability in their shape
(Shaikh et al. 2010). It has been proposed that hypertrophic degeneration of inferior
olive results in development of somatic connexin gap junctions between neighboring
inferior olive neurons, physiologically the gap junctions are restricted to the
dendrites of the inferior olive (de Zeeuw et al. 1990). As a result, local inferior olive
patches begin to fire in synchrony and act as “pacemaker” for maladaptive learning
by the cerebellar cortex (Hong and Optican 2008; Shaikh et al. 2010). Maladaptive
cerebellar learning causes the irregular character of the oscillations in OPT. The
hypothesis was pharmacologically tested in patients with OPT who took gabapentin
or memantine (Shaikh et al. 2011a; Thurtell et al. 2010). Both gabapentin and
memantine reduced the amplitude of OPT and changed the cycle-by-cycle variability
(irregularity) in the frequency. Gabapentin and memantine can reduce the excitability
of the cerebellar Purkinje neurons, and thus would reduce the amplitude and affect
the frequency irregularity of OPT.
2.6.3 Membrane Mechanisms for Pathogenesis of Saccadic

Oscillation
The Intrinsic membrane properties of saccade generating burst neurons and the
reciprocal innervation between the agonist and antagonist burst neurons are
cardinal to generate saccadic oscillations (Shaikh et al. 2007; Ramat et al. 2005).
The concept is analogous to the thalamic mechanism (involving reciprocally inner-
vating thalamocortical and thalamic reticular neurons with PIR and external inhibi-
tion to prevent oscillations) for tremorgenesis. Saccade burst generators, the
excitatory burst neurons (EBN), and the inhibitory burst neurons (IBN) reciprocally
innervate those on the opposite side, forming an inherently unstable circuit that is
prone to oscillate. Physiologically these oscillations are prevented by the inhibitory
projections from the omnipause neurons (OPN). The membrane attributes of these
neurons are also suitable for PIR (Shaikh et al. 2007). We proposed that instability
in the saccadic burst neuron circuit was due to an imbalance between the burst
neuron excitability (e.g., increased excitability due to the increase in strength of PIR)
and the external inhibition (e.g., disinhibition due to acquired antagonism or con-
genital hypofunction of inhibitory glycinergic mechanism) which could cause sac-
cadic oscillations (Shaikh et al. 2007, 2008). Simulations of this model showed that
the amplitude of Ih or IT determined the neural excitability, amplitude of PIR, and
therefore the frequency and amplitude of saccadic oscillations (Shaikh et al. 2007;
Shaikh and Finlayson 2003, 2005; Perez-Reyes 2003). Furthermore, a beta-blocker,
propranolol, decreased the amplitude of saccadic oscillations in a patient with the
syndrome of microsaccadic oscillations and limb tremor (Shaikh et al. 2011b).

Ethosuximide, a selective antagonist of IT, reduced the amplitude and increased the
frequency of saccadic oscillations during eye closure in two healthy subjects (Shaikh
et al. 2011b).
2.7 Summary and Future Directions
Hypothetical disturbances in membrane properties can account for many aspects of

the pathophysiology of tremor of the eyes, head, and limbs. Converging evidence
for these hypotheses comes from multiple sources including the mechanism of
action of drugs used to treat these disorders, animal models, the effects of novel
drug compounds on animal models of tremor, links between the genetic mutations
in tremor patients and their effects on physiological membrane function, and physi-
ologically realistic computational models of tremor. Further validation of abnor-
malities of membrane electrophysiology and their links with genetics in various
tremor disorders will point to the development of specific and more effective treat-
ments including gene-based therapy of inherited tremors. Recent studies have shown
that the principles underlying the mechanisms for tremor of the eyes, head, and
limbs have many features in common. For example, a membrane mechanism for
saccadic oscillations is analogous to a mechanism based on thalamocortical circuits
for the generation of essential tremor. The mechanism for APN in OPT is analogous
to olivo-cerebellar mechanism for essential tremor. Studies comparing and contrasting
the phenotype, natural history, and kinematics of eye and limb tremor would further
enhance understanding of etiology of eyes and limb movement disorders.
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Chapter 3
Rodent Models of Tremor
Hideto Miwa
Keywords Harmaline • Oxotremorine • Inferior olive • 6-Hydroxydopamine

• 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) • Purkinje cell • Basal
ganglia • Cerebellum
3.1 Introduction
Tremor is a rhythmical, involuntary, oscillatory movement of a body part, and it is

one of the most frequently encountered abnormal involuntary movements. Tremor
is a principal symptom of neurological disorders such as essential tremor, Parkinson’s
disease, and related disorders. Unfortunately, the actual pathophysiological mecha-
nisms underlying tremor remain poorly understood, and thus no effective therapeu-
tic strategies have been developed. The creation and analysis of animal models for
tremor (Martin et al. 2005) allow a better understanding of the tremor-generating
mechanisms. This chapter reviews the animal models of tremor, particularly those
induced by pharmacological agents in rodents.
H. Miwa, M.D. (*)

Department of Neurology, Wakayama Medical University, 811-1 Kimiidera,
Wakayama-city, Wakayama 641-8510, Japan
e-mail: h-miwa@wakayama-med.ac.jp

38 H. Miwa
Fig. 3.1 Chemical structure

of harmaline
3.2 Tremor Models
3.2.1 Harmaline and Other b -Carbolines
3.2.1.1 Harmaline-Induced Tremor
Beta-carboline derivatives, such as harmaline, harmine, and ibogaine, are known to

produce generalized tremor in animals (Fig. 3.1), with harmaline-induced tremor
being the most studied model of tremor. Indeed, the rodent model of harmaline-
induced tremor is widely used as an animal model of essential tremor, one of the
most representative tremor disorders in humans (Deuschl and Elble 2000). Harmaline-
induced tremor is an action tremor with both kinetic and postural components.
Electromyographic analysis has demonstrated that tremor activities are synchronous
between agonist and antagonist muscles (Lamarre and Mercier 1971). The tremor
frequencies vary among animals and are likely to be higher in smaller animals than
in larger ones. The tremor frequency in monkeys, rats, and mice is 8–10 Hz, 10–12 Hz,
and 11–14 Hz, respectively (Yamazaki et al. 1979; Milner et al. 1995).
3.2.1.2 Tremor-Generating Mechanisms
Local application of harmaline in the inferior olivary nucleus (ION) is sufficient to

induce rhythmic activity in the ION (De Montigny and Lamarre 1975), demonstrating
that the ION is the primary action site of harmaline for tremor-generating mecha-
nisms. In addition, it has also been shown that the tremor-generating action of harma-
line is lost if ION neurons are destroyed by 3-acetylpyridine (Simantov et al. 1976).
Studies of 14C-deoxyglucose uptake have also revealed that harmaline differentially
increases metabolism in the medial and dorsal accessory olive in the ION (Batini et al.
1979, 1981). In addition, it has been reported that c-Fos, an immunohistochemical
marker of neuronal activation, differentially increases in the ION following systemic
administration of harmaline (Miwa et al. 2000; Fig. 3.2). Together, these findings indi-
cate that differential pharmacological activation of the ION is the initial step for the
mechanisms underlying harmaline-induced tremor. ION neurons are electrically cou-
pled and generate synchronous oscillations of membrane potential. Harmaline modu-
lates their rhythm-generating ionic currents and enhances the rhythmic electronic
coupling of ION neurons, eventually resulting in generation of tremor. The electronic
coupling of ION neurons is mediated through gamma-aminobutyric acid (GABA)
3 Rodent Models of Tremor 39
Fig. 3.2 c-Fos immunohistochemistry of the inferior olivary nucleus (ION) in rats treated with
vehicle (a, b) and harmaline (25 mg/kg) (c, d). Compared with vehicle-treated rats, there is an
increase in c-Fos immunoreactive nuclei in the harmaline-treated rats. c-Fos is a transcription
factor and is regarded as a marker of neuronal activation, suggesting that ION neurons are differ-
entially activated by harmaline. Scale bars: 300 mm (a, b); 50 mm (c, d)
receptor-controlled gap junctions (Llinas et al. 1974). In addition, it has been suggested
that serotonergic innervation of the ION may also have a role in the tremor-generating
mechanism of harmaline (Sugihara et al. 1995). The rhythmic activities generated in
the ION are transmitted to the Purkinje cells in the cerebellar cortex. The massive
excitatory projections from the ION to Purkinje cells are well known as climbing
fibers. Because the tremor-inducing effects of harmaline are lost in mutant mice with
Purkinje cell degeneration (Milner et al. 1995), it has been suggested that Purkinje
cells play a crucial role in harmaline-induced tremor. In addition, it has been recently
reported that harmaline-induced tremor is suppressed in mice with a selective knock-
down of the CaV3.1 gene in the ION, successfully showing that T-type calcium chan-
nels, particularly CaV3.1 channels, are actually involved in the tremor-generating
mechanisms underlying harmaline-induced tremors (Park et al 2010).
3.2.1.3 Tolerance
It is of interest to note that repeated administration of harmaline results in tolerance

in both mice and rats (Lutes et al. 1988). Because this tolerance develops rapidly
40 H. Miwa
and is long-lasting, rodent models of harmaline-induced tremor should be used for

screening and developing anti-tremor drugs only upon first administration of the
drug. The pathophysiological mechanism underlying this tolerance remains uncer-
tain. Because harmaline, as discussed in the following section, may potentially exert
excitotoxic influences on Purkinje cells, it can be speculated that an alteration of
Purkinje cell functions following harmaline administration may be related to the
mechanisms underlying the tolerance. Indeed, in harmaline-tolerant animals, the
rhythmic discharges in Purkinje cells are lost (Lorden et al. 1988). Another specula-
tion about the mechanism underlying tolerance in harmaline-induced tremor is as
follows. Because harmaline-induced tremor appears with voluntary movements and
is aversive in animals, animals may learn to avoid movement while in the harmaline
state. Animals can prevent tremor if they become motionless (Fowler et al. 2005).
Further studies are necessary to determine the exact mechanism of tolerance to
harmaline.
3.2.1.4 Purkinje Cell Damages: A Model of Trans-Synaptic Excitotoxicity
Harmaline selectively induces cerebellar Purkinje cell degeneration in rats

(O’Hearn and Molliver 1993, 1997; Miwa et al. 2006). It has been suggested
that a trans-synaptic mechanism contributes to this neurotoxicity to Purkinje
cells because chemical ablation of olivocerebellar fibers by 3-acetylpyridine
can abolish harmaline-induced Purkinje cell degeneration. Speculatively, har-
maline may excite ION neurons and induce an excessive release of glutamate
from nerve terminals of the olivocerebellar system. As a result, Purkinje cells
are exposed to excessive glutamate, finally resulting in neurodegeneration
(Figs. 3.3 and 3.4).
Fig. 3.3 Cerebellar cortex in rats. Calbindin-28KD immunohistochemistry in rats treated with
vehicle (a) and harmaline (50 mg/kg) (b). Panel (c) demonstrates Iba-1 immunohistochemistry in
rats treated with harmaline (50 mg/kg). Purkinje cell bodies and their dendrites are strongly cal-
bindin-28KD-positive in both vehicle-treated (a) and harmaline-treated (b) rats. However, in
harmaline-treated rats, multiple unstained patches in the continuity of both Purkinje cells and
molecular layers are present (arrows), indicating a loss of Purkinje cells (b). In harmaline-treated
rats, activated microglia are arranged toward the parasagittal stripe. Scale bars, 100 mm
Fig. 3.4 Fluoro-Jade C staining for the cerebellar cortex in a rat treated with harmaline (50 mg/kg).
The Fluoro-Jade C-positive degenerative Purkinje cells are demonstrated. Perikaryon of degenera-
tive Purkinje cells (arrows) and their dendritic branches in the molecular layer (M) are observed
Recognition of species-specific differences in response to harmaline (Miwa et al.

2006) is an important consideration for experimental analysis of rodent models of
tremor. In rats but not in mice, Purkinje cell degeneration is associated with activated
microgliosis in the cerebellar cortex, following administration of harmaline. On the
other hand, in mice but not rats, microgliosis appears in the ION following harma-
line administration. Because numbers of neurons in the mouse ION do not decrease,
it is possible to speculate that microgliosis in the ION might not be a simple neuro-
toxic effect. Presumably, differences in sensitivity of Purkinje cells between rats and
mice may be related to differences in functional alterations in their respective olivo-
cerebellar systems induced by harmaline.
3.2.2 Cholinergic Agents
3.2.2.1 Cholinomimetic-Induced Generalized Tremor
Generalized tremor can be elicited by administration of large doses of cholinergic

agents, and marked parasympathetic symptoms are also induced in cholinomi-
metic-induced tremors. To date, various cholinergic agents have been used for
42 H. Miwa
inducing tremor in animals, such as tremorine, oxotremorine, pilocarpine, and

carbachol. Among them, oxotremorine, an active metabolite of tremorine, is the
most frequently used agent.
3.2.2.2 Tremor-Generating Mechanisms
The pathophysiological mechanism underlying cholinomimetic-induced tremor has

not been fully determined. Only muscarinergic antagonists, and not nicotinergic or
cholinergic antagonists that do not cross the blood–brain barrier, can suppress the
tremor (Stern et al. 1965; Hallberg and Almgren 1987), suggesting that central mus-
carinergic activity is essential for this type of tremor. It was reported that tremors are
producible if cholinergic drugs are injected directly into the striatum (Cox and
Potkonjak 1969). This suggests that muscarinic receptors in the striatum play a prin-
cipal role in the mechanisms underlying cholinomimetic-induced tremor. In addition,
lesions of the entopeduncular nucleus, but not of the globus pallidus (GP) or subtha-
lamic nucleus (STN), have been reported to effectively suppress tremorine-induced
tremor activity (Slater and Dickinson 1982). This may suggest that among striatal
efferent pathways, the “direct” pathway has more prominent roles than the “indirect”
pathways in the background mechanisms underlying this type of tremor. In addition,
based on the neural activation mapping using c-Fos immunohistochemistry, it has
been suggested that not only basal ganglia but also the thalamic reticular nucleus may
also be involved in cholinomimetic-induced tremor (Miwa et al. 2000).
3.2.2.3 Tacrine-Induced Tremulous Jaw Movements
Following systemic administration of acetylcholinesterase inhibitors such as tacrine,

characteristic jaw movements appear in rats (Salamone et al. 1998). This jaw move-
ment has been described as “tremulous or vacuous jaw movements.” Researchers
have proposed that tacrine-induced tremulous jaw movements (TJMs) in rats may
be a pharmacological model of parkinsonian tremor because TJMs share pharmaco-
logical characteristics with human parkinsonian tremor. It has been reported that
dopamine antagonists and dopamine depletion could induce similar TJMs that can
be successfully suppressed by anti-parkinsonian drugs (Salamone et al. 1998, 2005).
Although it remains controversial whether this type of jaw movement is tremor,
tacrine-induced TJMs have been used for assessing the therapeutic potential of
drugs for treatment of parkinsonian tremor. This may be because of the ease of
quantitative assessment of TJMs.
3.2.2.4 Nicotine-Induced Tail Tremor
Repeated administration of nicotine has been shown to cause a tail tremor accompa-
nied by locomotor hyperactivity without rigidity or hypokinesia in rats (Suemaru
et al. 1994). However, this model has not been widely used.
3.2.3 Dopaminergic Neurotoxins
3.2.3.1 MPTP
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a toxin that selectively

destroys dopaminergic neurons (Langston et al. 1983; Ballard et al. 1985). It has been
widely used for experimental analysis of dopaminergic neuron degeneration in vari-
ous animal species including primates, cats, and mice, but not in rats. Systemic admin-
istration of MPTP can induce selective degeneration of dopaminergic neurons in the
substantia nigra and dopamine deficiency-related behavioral disturbances resembling
those of Parkinson’s disease. After enzymatic conversion to 1-methyl-4-phenylpiridium
ions (MPP+) in glial cells, systemically administered MPTP inhibits the activity of
mitochondrial complex I, leading to the production of reactive oxygen species or
decreasing ATP production, finally inducing dopaminergic neuron death. MPP + also
binds to vesicular monoamine trasporter-2 and interacts with synaptic vesicles, lead-
ing to the release of dopamine and resulting in an excess of cytosolic dopamine.
Consequently, auto-oxidation of dopamine occurs, facilitating oxidative stress.
To date, the MPTP model has been regarded as a standard animal model of Parkinson’s
disease.
It was thus expected that analysis of MPTP-induced tremor would provide help-
ful insight into the pathophysiological mechanism underlying rest tremors.
Unfortunately, the pharmacological actions of MPTP are species-specific. Rats, one
of the most prevalently used experimental animals, are known to be completely
resistant (Kalaria et al. 1987). C57BL/6 mice are sensitive to MPTP, but prominent
tremors are usually not observed. Thus, MPTP mice are not regarded as a useful
model for experimental analysis of tremor.
3.2.3.2 6-Hydroxydopamine
Another representative dopaminergic neurotoxin is 6-hydroxydopamine (6-OHDA).

Injection of 6-OHDA into nigrostriatal dopaminergic pathways, such as the sub-
stantia nigra, striatum, and medial forebrain bundle (MFB), can selectively destroy
catecholaminergic fibers that include nigrostriatal dopaminergic projections
(Ungerstedt et al. 1974). Rodent models that employ 6-OHDA are widely used for
experimental analysis of Parkinson’s disease. In particular, it is well known that rats
with unilateral damage of the nigrostriatal dopamine pathway by 6-OHDA exhibit
contralateral circling following systemic administration of dopamine agonists such
as apomorphine. In addition, repeated administration of levodopa induces dyski-
netic movements in the contralateral limbs in rats with unilateral damage of the
nigrostriatal dopamine pathway by 6-OHDA. This model is used as the model of
l-DOPA-induced dyskinesia. However, a few reports have described tremors in
6-OHDA-treated rats. Unilateral lesions of the substantia nigra by 6-OHDA cause
sporadic rest tremor of the head and neck (Buonamici et al. 1986). It has also been
reported that intra-MFB injection of 6-OHDA produces tremor with rigidity and
44 H. Miwa
hypokinesia in rats (Jolicoeur et al. 1991). However, 6-OHDA rat models are usu-
ally not regarded as a model of tremor because tremors associated with dopamine
depletion in rodents (either by MPTP or 6-OHDA) are less remarkable as compared
with the tremors induced by harmaline or oxotremorine.
3.2.4 Other Tremor-Generating Agents
Systemic administration of penitrem A, a fungal neurotoxin, induces long-lasting

tremors in mice (Jortner et al. 1986) and rats (Cavanagh et al. 1998). Ataxia is
also observed. Penitrem A-induced tremor is not abolished if the ION is destroyed,
suggesting that the tremor mechanism differs from that of harmaline.
Neuropathologically, a Purkinje cell degeneration is induced following adminis-
tration of the neurotoxin (Cavanagh et al. 1998; Lu et al. 2008). Because peni-
trem A increases the spontaneous release of endogenous glutamate (Norris et al.
1980), excitotoxicity may also play an important role in the mechanism underly-
ing Purkinje cell neurodegeneration.
3.2.5 Genetic Mutants
Rodents with spontaneous mutations are known to exhibit tremor as a prominent

phenotypic feature, such as trembler (Suter et al. 1992), shiverer (Mikoshiba et al.
1982) and jimpy mice (Billings-Gagliardi et al. 1995), and zitter rats (Rehm et al.
1982). These mutant rodents have accompanying severe pathological findings, such
as demyelination or spongiform degeneration of the peripheral and/or central ner-
vous system. For example, degeneration of the spinocerebellar and motor neuron
system is observed in vibrator (Weimar et al. 1982; Hamilton et al. 1997) and wob-
bler mice (LaVail et al. 1987), respectively. It has been noted that Purkinje cell
degeneration occurs in shaker rats (Tolbert et al. 1995). In general, these models are
not regarded as a specific model of tremors, although analyses of these models
could potentially provide valuable insight into the mechanisms underlying
tremorgenesis.
3.2.5.1 GABA(A) Receptor Alpha-1 Subunit Knockout Mice
GABA is one of the major inhibitory neurotransmitters. Three types of GABA

receptors have been identified: GABA(A), GABA(B), and GABA(C). GABA(A)
and GABA(C) receptors are ion channel receptors, whereas GABA(B) receptors are
metabotropic receptors. Recently, it was reported that GABA(A) receptor alpha-1
subunit knockout mice exhibit postural and kinetic tremors of approximately
16–22 Hz (Kralic et al. 2005). The tremor is observable early in life, and the
amplitude increases in 8-month-old mice as compared with 4-month-old mice. In

these mice, the response to synaptic and exogenous GABA is lost in cerebellar
Purkinje cells, but the brain remains morphologically intact. As with essential trem-
ors, the GABA(A) benzodiazepine-receptor agonist diazepam exacerbates tremor,
while the anti-tremor effect of ethanol is more marked. It is expected that this ani-
mal model of tremor will contribute to a better understanding of the pathophysio-
logical mechanisms underlying essential tremor.
3.3 Rodent Models of Representative Human Tremor

Disorders
3.3.1 Essential Tremor
Essential tremor is the most frequently encountered adult-onset movement disorder.

The prevalence of the disease in the population may be about 1%, reaching up to 4%
in the elderly. The tremor is characterized by 4- to 12-Hz kinetic tremors. Subtle
impairment of cerebellar function may be occasionally seen. Tremor commonly
affects the arm, but it may affect other parts of the body also, particularly the head
and neck, voice, the trunk, lower extremities, tongue, and other facial muscles. It is
well known that a small dose of alcohol effectively suppresses essential tremor in
about half of patients. However, both the etiology and pathophysiology of essential
tremor remains poorly understood to date. Because the etiopathogenesis of essential
tremor remains uncertain, the ideal animal model is not available. Nevertheless, two
models have been regarded as rodent models of essential tremor. One is harmaline-
induced tremor, and the other is a GABA(A) receptor alpha-1 subunit knockout
mouse model (Kralic et al. 2005).
First, harmaline-induced tremor has been proposed as a possible model of essen-
tial tremor (Wilms et al. 1999) because both essential tremor and harmaline-induced
tremor have common characteristics. Symptomatologically, both models are char-
acterized by kinetic tremors. In addition, not only essential tremor but also harma-
line-induced tremor in rodents can be attenuated by ethanol (Rappaport et al. 1984).
But it should be realized that the pathophysiological mechanisms underlying both
tremors differ on two points. First, the generator of tremor may be different. As
described earlier, the primary target of tremor generation in harmaline-induced
tremor is neurons of the ION (Lamarre and Mercier 1971; Llinas et al. 1974)
(Fig. 3.5a, b). On the other hand, it remains undetermined whether the olivocerebel-
lar system also plays a role in tremor-generating mechanisms in essential tremor. To
date, there have been controversies regarding whether a positron emission tomogra-
phy scan in patients with essential tremors exhibits hypermetabolism in the ION
(Hallett and Dubinsky 1993; Wills et al. 1994). The second difference between
essential tremor and harmaline-induced tremor in rodents is the transmission path-
way of the tremor-related neuronal activities in the brain. In harmaline-induced
46 H. Miwa
Fig. 3.5 (a) Harmaline selectively activates the inferior olivary nucleus (ION) neurons. Neurons
of the ION are electrically coupled and likely generate synchronous oscillations of membrane
potential. Harmaline modulates their rhythm-generating ionic currents and enhances the rhythmic
electronic coupling of ION neurons, eventually resulting in generation of tremor. T-type calcium
channels in the ION neurons are involved in the formation of tremor-related rhythmical discharges
by harmaline. (b) The rhythmic activities generated in the ION are transmitted to the Purkinje cells
in the cerebellar cortex. The excitatory projections originating from the ION are known as climb-
ing fibers. (c) Purkinje cells receive climbing fiber inputs as well as the synaptic response to
GABA(A) pathway stimulation. In GABA(A) receptor alpha-1 subunit knockout mice, neuronal
response to synaptic GABA is lost in cerebellar Purkinje cells, resulting in rhythmical activities.
T-type Ca channels (CaV3.1) are involved in the tremor-generating mechanisms. Harmaline-
induced tremor is suppressed in mice with a selective knockdown of the CaV3.1 gene in the ION.
(d) In rodents, the tremor-related activities in the cerebellum are transmitted to the deep cerebellar
nuclei (DCN), whereas in humans they are also transmitted to the thalamus. Not only in essential
tremor but also parkinsonian tremor in humans, the thalamo-cortical pathways play an important
role in the tremor-generating mechanisms. It remains undetermined whether these rhythmic activi-
ties are transmitted to the thalamus via cerebello-thalamic pathways, contributing to tremor-
generating mechanisms in rodents. (e) Cholinomimetics act on cholinergic neurons in the striatum,
resulting in the generation of rhythmical activities in the basal ganglia outputs
tremor in rodents, it is speculated that rhythmical activities responsible for the

tremor in the cerebellum are transmitted to motoneurons in the spinal cord, medi-
ated via deep cerebellar nuclei and brainstem. On the other hand, in essential tremor,
it has been suggested that the cerebello-thalamo-cortical pathways play a crucial
role (Fig. 3.5d). This is supported by the fact that stereotaxic thalamotomy or deep
brain stimulation of the thalamus is able to dramatically suppress essential tremor.
Thus, based on the difference in the mechanisms underlying the tremors, it is impor-
tant to note that harmaline-induced tremor in rodents may not be an ideal model of
essential tremor, although, as described later, harmaline-induced tremor in rodents
is a model that has some advantages in screening and/or developing novel drugs for
tremors. Also, harmaline interferes with several neurotransmitters, such as gluta-
mate and serotonin, but the cascade of events leading to changes in neurotransmit-
ters remains poorly defined in essential tremor.
Second, the GABA(A) receptor alpha-1 subunit knockout mouse is another

possible rodent model of essential tremor (Kralic et al. 2005). In this mouse, Purkinje
cells are unresponsive to synaptic or exogenous GABA, suggesting that GABAergic
transmission in Purkinje cells plays an important role in the inhibition of tremor
(Fig. 3.5c). Similarly to harmaline-induced tremor, the tremor in the GABA(A)
receptor alpha-1 subunit knockout mouse is kinetic, which is a principal symptoma-
tological feature of essential tremor. Importantly, patients with essential tremor have
no significant genetic mutation in the GABA(A) receptor alpha-1 gene (Jankovic
and Noebels 2005). In addition, the onset of essential tremor generally occurs in
older individuals and only occasionally during childhood, while tremor appears
early in development in these knockout mice. The tremor frequency clearly differs
between them: tremor frequency in this knockout mouse (16–22 Hz) is higher than
that of essential tremor (4–12 Hz). Moreover, in this knockout mouse, other cerebel-
lar motor deficits are observable, although some patients with advanced essential
tremor show subtle gait disturbances (Stolze et al. 2001). Thus, it should be kept in
mind that the GABA(A) receptor alpha-1 subunit knockout mouse also is not a
model reproducing exactly essential tremor (Jankovic and Noebels 2005), although
this model is a useful model for studying the GABAergic modulation of Purkinje
cells in tremor-generation processes and for screening and/or developing novel
drugs targeting tremors.
3.3.2 Parkinsonian Tremor
The principal pathophysiological mechanism that underlies Parkinson’s disease is a

dopamine deficiency in the striatum. But in rodents, no rest tremor is observable
under conditions of dopamine deficiency. Currently, 6-OHDA-induced damage of
the nigrostriatal dopamine pathway (Ungerstedt et al. 1974) and systemic adminis-
tration of MPTP (Gupta et al. 1986) are commonly used to induce dopaminergic
denervation in the striatum for obtaining a Parkinson’s disease model. It is unfortu-
nate that no rest tremor similar to parkinsonian tremor is induced in either model,
although both models are generally used for experimental analysis of Parkinson’s
disease. Thus, rodent models of dopamine deficiency could not be regarded as a
useful model of parkinsonian tremor.
Another viewpoint regarding parkinsonian tremor is that the tremor may origi-
nate in the basal ganglia. One may speculate that alterations of striatal afferent
activity caused by dopamine deficiency in the striatum may be the primary step for
tremor generation. It has been suggested that basal ganglia neurons, such as pallidal
and subthalamic neurons, have oscillating properties that contribute to rhythmic
activities responsible for parkinsonian tremor. Thus, for experimental analysis of
parkinsonian tremor, tremor originating from the basal ganglia may be useful. In
this regard, a cholinomimetic-induced tremor model may be such candidate that is
pathophysiologically related to the basal ganglia, although cholinomimetic-induced
parkinsonism is not regarded as an animal model of Parkinson’s disease because
48 H. Miwa
dopamine deficiency (a principal biochemical feature of Parkinson’s disease) is

lacking. In cholinomimetic-induced tremor, the primary mechanism of tremorgen-
esis is activation of cholinergic neurons in the striatum, and the striatal efferent
pathway is involved in transmission of tremor-related activity (Cox and Potkonjak
1969; Slater and Dickinson 1982) (Fig. 3.5d). Among cholinomimetic-induced
tremors, TJMs have been frequently used for screening and/or developing drugs for
treatment of parkinsonian tremor (Salamone et al. 1998, 2005; Miwa et al. 2008,
2009, 2011; Miwa and Kondo 2011).
3.4 Conclusions
Animal tremor models are useful for developing our understanding of the pathophys-
iology of human tremor disorders and for developing effective therapeutic strate-
gies. In particular, rodent tremor models are helpful because rodents are easy to
handle as compared with larger animals. These last years, there has been an accu-
mulation of both neurophysiological and neurochemical findings in rodents (Martin
et al. 2005). However, there is an unavoidable gap between rodent tremor models
and human tremor disorders because rodents are four-footed and humans are two-
footed (Miwa 2007). In addition, it is technically difficult to analyze tremors in
rodents because of the smaller size of the animals, the smaller amplitude of tremor,
and the higher frequency of tremor. However, quantitative methods for analysis of
rodent tremor have been proposed (Martin et al. 2005; Fowler et al. 2005; Wang and
Fowler 2001; de Souza da Fonseca et al. 2001). Beyond these limitations, the appli-
cation of rodent models for analysis of tremor will be helpful if an appropriate
translation can be made pathophysiologically.
Acknowledgment We gratefully acknowledge Ms. Tomomi Kubo and Mrs. Ai Suzuki for technical
assistance.
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Chapter 4
Advances in the Genetics of Human Tremor
Fabio Coppedè
Keywords Genetics • Tremor • Genome-wide association (GWAS) • Parkinson’s

disease (PD) • Essential tremor (ET) • LINGO1 gene
4.1 Introduction
This chapter aims at describing the recent advances in the genetics of human tremor.
Several human disorders are characterized by tremor as one of the possible symp-
toms, making it almost impossible to fully describe the genetic basis of each of them
within the context of a single book chapter. Essential tremor (ET) and Parkinsonian
tremor represent the most common forms of human tremor and their genetics is
fully described within the first sections of the chapter. Following the introduction,
the chapter starts with a description of the genetics of Parkinson’s disease (PD)
given the great advances in our understanding during the last two decades. PD is
characterized by resting tremor, rigidity, bradykinesia, and postural instability as
well as several non-motor symptoms. Linkage studies in PD families identified five
well-validated causative genes for the disease and several potential genes/loci
(Nuytemans et al. 2010). Moreover, the recent application of genome-wide associa-
tion (GWAS) approaches is now revealing genetic variants that increase the risk for
the sporadic (idiopathic) forms of the disease (Hardy 2010). However, despite the
continuous advance in our understanding of the genetics of Parkinsonian tremor,
little is still known concerning essential tremor, the most common pathologic tremor
in humans. As discussed in the third section of this chapter three ET loci have been
F. Coppedè, Ph.D. (*)

Faculty of Medicine, Section of Medical Genetics, University of Pisa,
Via S. Giuseppe 22, 56126 Pisa, Italy
e-mail: f.coppede@geog.unipi.it

54 F. Coppedè
linked to the disease, but no causative gene has been so far identified. Interestingly,
a recent GWAS revealed association between ET and the LINGO1 gene, and repli-
cation studies are ongoing in several ET populations (Tan 2010). Tremor is often
observed in other diseases, including ataxias and dystonias, and several examples of
monogenic forms of these disorders are provided within the text. Moreover, the
chapter covers the genetics of familial cortical myoclonic tremor with epilepsy,
Roussy–Lévy syndrome, and Wilson’s tremor.
4.2 Genetics of Parkinson’s Disease
Parkinson’s disease (PD) is the second most common neurodegenerative disorder

after Alzheimer’s disease, affecting 1–2% of the population over the age of
65 years and its prevalence increases to approximately 4% in those above 85 years.
The disease is clinically characterized by resting tremor, rigidity, bradykinesia,
and postural instability as well as non-motor symptoms such as autonomic
insufficiency, cognitive impairment, and sleep disorders. Some improvement can
be achieved with levodopa and dopaminergic therapy, but there is currently no
treatment that arrests the progression of the disease. Pathologically, PD is charac-
terized by progressive and profound loss of neuromelanin containing dopaminer-
gic neurons in the substantia nigra with the presence of eosinophilic,
intracytoplasmic inclusions termed as Lewy bodies (LBs; containing aggregates
of a-synuclein as well as other substances), and Lewy neurites in surviving neu-
rons (Thomas and Beal 2011). The majority of PD cases are sporadic, likely aris-
ing from a combination of polygenic inheritance, environmental exposures, and
complex gene–environment interactions superimposed on slow and sustained
neuronal dysfunction due to aging (Migliore and Coppedè 2009). A familial his-
tory of PD is shown in approximately 20% of the cases, and in a minority of them
the disease is inherited as a Mendelian trait. Studies in PD families have led to the
identification of 15 PD loci (PARK1–15) and 11 genes for PARK loci have so far
been described (Table 4.1). Although follow-up genetic studies are inconsistent
for some of them or conclusive data are still pending, there is evidence that five of
those genes (a-synuclein, parkin, PTEN-induced putative kinase 1, DJ-1, and
leucine-rich repeat kinase 2) cause typical PD (Nuytemans et al. 2010). In addi-
tion, mutations of ATP13A2 (PARK9) cause Kufor-Rakeb disease, an autosomal
recessive parkinsonism with many other features, including pyramidal tract dys-
function, supranuclear gaze paresis and dementia (Ramirez et al. 2006). Sporadic
forms of the disease are likely resulting from three interactive events: an individ-
ual’s inherited genetic susceptibility, subsequent exposure to environmental risk
factors, and aging. A great number of PD association studies have been performed
in recent years by either the candidate gene approach or genome-wide screenings.
The genetic screening has been successful with a common high-risk locus
identified (GBA) and many common low-risk loci (SNCA, MAPT, LRRK2) recently
elucidated (Table 4.2) (Hardy 2010).
4 Advances in the Genetics of Human Tremor 55
Table 4.1 Loci and genes associated with familial PD

Function or probable
Designation Locus Gene Inheritance function
PARK1 PARK4 4q21.3-q22 SNCA AD a-synuclein: presynaptic
protein, component of
Lewy bodies
PARK2 6q25.2-q27 PARK AR Parkin: ubiquitin E3 ligase
PARK3 2p13 Unknown AD Unknown
PARK5 4p14 UCH-L1 AD Ubiquitin hydrolase
PARK6 1p35-36 PINK1 AR Mitochondrial protein
kinase
PARK7 1p36 DJ-1 AR Mitochondrial protein
involved in antioxidant
defense
PARK8 12q12 LRRK2 AD Protein kinase
PARK9 1p36 ATP13A2 AR Lysosomial ATPase
PARK10 1p32 Unknown Not clear Unknown
PARK11 2q36-37 GIGYF2 AD Regulation of signaling at
endosomes
PARK12 Xq21-q25 Unknown X-linked Unknown
PARK13 2p12 OMI/HTRA2 AD Mitochondrial serine
protease
PARK 14 22q13.1 PLA2G6 AR Phospholipase
PARK 15 22q11.2-qter FBXO7 AR Ubiquitin E3 ligase
Table 4.2 Genes frequently Susceptibility gene Protein/Function

associated with idiopathic PD
SNCA a-synuclein: presynaptic protein,
component of Lewy bodies
LRRK2 Protein kinase
MAPT Microtubule-associated protein tau
GBA Glucocerebrosidase, lysosomal enzyme
4.2.1 Autosomal Dominant PD
4.2.1.1 a-Synuclein: PARK1 and PARK4
A mutation in the a-synuclein gene (SNCA) on 4q21 (PARK1), causing an A53T sub-
stitution, was found to segregate with the disease in an Italian kindred and three unre-
lated families of Greek origin (Polymeropoulos et al. 1997). Another mutation in the
SNCA gene, leading to an A30P substitution, was subsequently described in a small
German family with PD (Krüger et al. 1998), and a third mutation resulting in an
E46K substitution, in a Spanish family (Zarranz et al. 2004). A study in a large family
identified a triplication of the a-synuclein gene (PARK4) as causative of PD (Singleton
et al. 2003). PARK4 individuals have four fully functional copies of the a-synuclein
gene. Other PD families have been subsequently described with a-synuclein gene
56 F. Coppedè
duplication and a disease course less severe of that observed in PARK4 carriers,
suggesting the existence of a gene dosage effect (Chartier-Harlin et al. 2004).
Particularly, SNCA triplications and the E46K mutation are more commonly associ-
ated with dementia than the A30P mutation and gene duplications. The A53T muta-
tion has been associated with dementia and the presence of cortical LBs. Although
SNCA has been the first PD gene identified, SNCA missense mutations and multiplica-
tions are both extremely rare causes of familial autosomal dominant parkinsonism
(Nuytemans et al. 2010). a-Synuclein is expressed throughout the mammalian brain
particularly in presynaptic nerve terminals, and mutated a-synuclein has an increased
tendency to form aggregates critical to Lewy body formation. These fibrillar aggre-
gates are the major component of LBs in both familial and idiopathic PD, and
aggregation of a-synuclein is though to be a key event in dopaminergic neuronal cell
death. The function of a-synuclein under normal physiological conditions is not yet
fully elucidated, although there is evidence that implicates SNCA in neurotransmit-
ter release and vesicle turnover at the presynaptic terminals (Abeliovich et al. 2000;
Liu et al. 2004). Genetic polymorphisms in the SNCA gene have been consistently
associated with PD risk, including a dinucleotide repeat sequence (Rep1) within the
promoter region and several single nucleotide polymorphisms (SNPs) at the 3¢ end of
the gene (Maraganore et al. 2006; Kay et al. 2008; Mata et al. 2011). Moreover,
SNCA has been among the genes most significantly associated with PD in GWAS
(Pankratz et al. 2009; Satake et al. 2009; Simón-Sánchez et al. 2009; Edwards et al.
2010). A list of genetic association studies and GWAS linking SNCA variants to PD
risk can be found at the PDGene database (http://www.pdgene.org), a continuously
updated public database containing data on PD association studies. Meta-analyses of
those studies reveal that SNCA is a low-risk locus for idiopathic PD, with odds ratios
(ORs) ranging from 1.2 to 1.4 (http://www.pdgene.org). The mechanism by which
common SNCA variants modify susceptibility for PD is not yet known. However,
there is evidence suggesting that SNCA alleles associated with increased PD risk are
also correlated with higher a-synuclein expression, pointing again to a gene dosage
effect (Fuchs et al. 2008).
4.2.1.2 Leucine-Rich Repeat Kinase 2: PARK 8
The leucine-rich repeat kinase 2 (LRRK2) gene maps on the PARK8 locus in 12q12
and was the second causal gene linked to autosomal dominant PD (Paisán-Ruíz
et al. 2004; Zimprich et al. 2004). Subsequent studies revealed over 100 mutations
in PD families and sporadic cases, though the pathogenic role of many of them has
not yet been proven (a complete list can be found at the PD mutation database:
http://www.molgen.ua.ac.be/PDmutDB). LRRK2 encodes the protein dardarin
which contains several domains including the catalytic domain of a tyrosine kinase,
and whose name is derived from dardara, the Basque word for tremor. The precise
physiological role of dardarin is unknown, but the presence of several domains sug-
gests involvement in a wide variety of functions and, as a kinase, LRRK2 is almost
certainly involved in signaling cascades, probably relating to cytoskeletal dynamics
(Hardy 2010). All of the identified pathogenic mutations occur in predicted

functional domains. The most prevalent LRRK2 mutation is a G2019S missense
mutation occurring in 1–2% of PD patients of European origin, 20% of Ashkenazi
Jewish patients, and approximately 40% of Arab Berbers with PD. Another fre-
quent hotspot of LRRK2 pathogenic mutations is the Arg1441 codon (Nuytemans
et al. 2010). A G2385R mutation, originally identified as a putative pathogenic
mutation in a Taiwanese PD family, was subsequently reported to be a common
polymorphism and, probably, one of the most frequent genetic risk factors for PD in
Asian populations (Farrer et al. 2007). Subsequent studies confirmed that LRRK2
polymorphisms, such as G2385R and R1628P, are well validated PD risk factors in
Asians, and a meta-analysis of published studies revealed an OR of 2.2 associated
with the G2385R variant (http://www.pdgene.org).
4.2.2 Autosomal Recessive PD
4.2.2.1 Parkin: PARK2
Autosomal recessive juvenile parkinsonism (AR-JP) is characterized by early-onset

and a marked response to levodopa treatment. AR-JP differs from idiopathic PD in
that there is usually no LBs formation, although the distribution of neuronal cell loss
is similar to that of conventional PD. The genetic locus for AR-JP was identified in
Japanese families, which led to identification of homozygous deletions in the parkin
gene on chromosome 6q25.2–q27 (PARK2) (Kitada et al. 1998). Subsequently, over
100 mutations in parkin, including missense mutations and exonic deletions and
insertions, have been observed in PD families (Mata et al. 2004). Parkin is an ubiq-
uitin E3 ligase preparing target proteins for their degradation mediated by the ubiq-
uitin–proteosomal system (Leroy et al. 1998). Moreover, parkin is involved in
mitochondrial maintenance, is required for the repair of mitochondrial oxidative
DNA damage, might be involved in mitochondrial cytochrome c release, and induces
subsequent autophagy of dysfunctional mitochondria (Deng et al. 2008; Narendra
et al. 2008; Poole et al. 2008; Rothfuss et al. 2009).
4.2.2.2 PTEN-Induced Putative Kinase 1 Gene: PARK6
Several mutations in the PTEN-induced putative kinase 1 gene (PINK-1) on chro-

mosome 1p35-36 (PARK6), encoding a protein which is mitochondrially located
and whose loss of function is supposed to render neurons more vulnerable to cel-
lular stress, have been linked to autosomal recessive early-onset PD (Valente et al.
2004). PINK1 mutations, primarily missense and nonsense ones, cause mitochon-
drial deficits contributing to PD pathogenesis; several different mutations have been
identified in PD families worldwide (http://www.molgen.ua.ac.be/PDmutDB).
PINK1 is a kinase with an N-terminal mitochondrial targeting sequence, provides
58 F. Coppedè
protection against mitochondrial dysfunction and regulates mitochondrial morphology

via fission/fusion machinery. PINK1 also acts upstream of parkin in a common
pathway. Recent studies have described PINK1/parkin function in the maintenance
of mitochondrial quality via autophagy (Kawajiri et al. 2011).
4.2.2.3 DJ-1: PARK7
Mutations in the DJ-1 gene on 1p36 (PARK7), including exonic deletions and point
mutations, have been associated with a monogenic early-onset autosomal recessive
form of parkinsonism characterized by slow progression and response to levodopa
(van Duijn et al. 2001; Lockhart et al. 2004), see http://www.molgen.ua.ac.be/
PDmutDB for a complete list. DJ-1 is a mitochondrial protein involved in the pro-
tection against oxidative stress, and it was shown that parkin, PINK1, and DJ-1 form
a complex to promote ubiquitination and degradation of parkin substrates, including
parkin itself (Xiong et al. 2009). Recent evidence indicates that DJ-1 works in paral-
lel to the PINK1/parkin pathway to maintain mitochondrial function in the presence
of an oxidative environment (Thomas et al. 2011).
4.2.2.4 ATP13A2 Gene: PARK9
Clinical features similar to those of idiopathic PD and pallidopyramidal syndrome

were observed in a Jordanian family; these included parkinsonism, pyramidal tract
dysfunction, supranuclear gaze paresis, and dementia. The pattern of transmission
was autosomal recessive, and a region of linkage was identified on chromosome
1p36 (PARK9) (Hampshire et al. 2001). The causative gene underlying PARK9 was
then identified as the ATP13A2 gene encoding a lysosomal 5 P-type ATPase
(Ramirez et al. 2006). Recent studies suggest that ATP13A2 plays important roles
in protecting cells against manganese cytotoxicity via regulating intracellular
manganese homeostasis (Tan et al. 2011).
4.2.3 Additional Putative PARK Genes
Additional putative PARK genes include (1) the UCH-L1 gene on 4p14 (PARK5)
coding for a protein that possesses both a hydrolase activity to generate the ubiq-
uitin monomer and a ligase activity to link ubiquitin molecules to tag proteins for
disposal (Leroy et al. 1998; Liu et al. 2002). (2) The GYGYF2 gene on 2q36-37
(PARK11) encoding a protein that could participate in the regulation of signaling at
endosomes (Lautier et al. 2008; Higashi et al. 2010). (3) The OMI/HTRA2 gene on
chromosome 2p12 (PARK 13) coding for a nuclear-encoded serine protease local-
ized in the inter-membrane space of the mitochondria and involved in mediating
caspase-dependent and caspase-independent cellular death (Strauss et al. 2005).
(4) The PLA2G6 gene on chromosome 22q13.1 (PARK14) encoding a calcium-

independent group VI phospholipase A2 (Paisán-Ruiz et al. 2010). (5) The FBXO7
gene on 22q11.2-qter (PARK15) encoding for a member of the F-box family of
proteins, all of which may have a role in the ubiquitin–proteosome protein-degrada-
tion pathway (Shojaee et al. 2008; Di Fonzo et al. 2009).
4.2.4 Susceptibility Genes
Several hundreds of genetic association studies have been performed in the last few
decades by means of the candidate gene approach in order to identify genetic risk
factors for non-Mendelian forms of PD. More recently, GWAS have revolutionized
our efforts to find loci at which common, normal genetic variability contributes to
disease risk. The PDGene database (http://www.pdgene.org) is a continuously
updated database collecting data from PD genetic association studies and GWAS.
Accessed on September 2011 the database contained information on 860 studies for
a total of 909 candidate genes and 3,434 polymorphisms within those genes includ-
ing data from 13 GWAS (http://www.pdgene.org). There is strong consensus from
either GWAS or updated meta-analyses of the literature that variants at four loci
(SNCA, MAPT, GBA, and LRKK2) contribute to disease risk (Table 4.2). In addition,
recent GWAS are revealing novel putative PD risk loci to be confirmed in future
studies (International Parkinson Disease Genomics Consortium 2011). The contri-
bution of SNCA and LRRK2 polymorphisms to sporadic PD have been discussed
earlier in the previous sections of this chapter, therefore other loci will now be
presented further.
4.2.4.1 Microtubule-Associated Protein Tau: MAPT
The microtubule-associated protein tau, encoded by the MAPT gene, binds to micro-
tubules and is primarily involved in the organization and integrity of the cytoskele-
ton. Mutations of MAPT cause frontotemporal dementia with parkinsonism linked
to chromosome 17 (FTDP-17) (Dumanchin et al. 1998; Spillantini and Goedert
2000). Therefore, it is not surprising that MAPT polymorphisms could contribute to
PD risk. Indeed, large case–control studies, meta-analyses of the literature, and
GWAS confirmed a role for the MAPT haplotype H1 to disease risk (Goris et al.
2007; Zabetian et al. 2007; http://www.pdgene.org).
4.2.4.2 Glucocerebrosidase: GBA
Mutations in the GBA gene encoding glucocerebrosidase, the enzyme deficient in

the lysosomal glycolipid storage disorder Gaucher disease (GD: an autosomal reces-
sive disorder with multisystemic manifestations, including involvement of the liver,
60 F. Coppedè
spleen, bone marrow, lungs, and nervous system), are associated with the
development of Parkinson disease and other Lewy body disorders (Velayati et al.
2010). The observation that a small subset of GD patients develop parkinsonism
with brainstem or diffuse Lewy-related pathology (Tayebi et al. 2003), and that rela-
tives of patients with GD have an increased incidence of parkinsonism (Halperin
et al. 2006), led researchers to investigate GBA mutations as a possible risk factor
for PD. A pooled analysis of 5,691 PD subjects and 4,898 controls revealed that
GBA loss of function variants are the most common genetic risk factor associated
with parkinsonism (odds ratio: 5.4) (Sidransky et al. 2009). A recently updated
meta-analysis of published studies including over 9,000 PD subjects and 12,000
controls reveals that the common GBA N370S variant is a high-risk variant for PD
with an odds ratio of 3.4 (http://www.pdgene.org). Although the mechanism for this
association is unknown, several theories have been proposed, including protein
aggregation, prion transmission, lipid accumulation and impaired autophagy,
mitophagy or trafficking (Westbroek et al. 2011).
4.2.4.3 Additional Loci
The application of GWAS to the understanding of the genetics of sporadic PD has

significantly improved our knowledge in the field and several loci have been sug-
gested to be associated with disease risk. A recent meta-analysis of published GWAS
indicates that, in addition to MAPT, SNCA, and LRRK2, eight additional loci (HLA-
DRB5, BST1, GAK, ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/
HIP1R) are significantly associated with disease risk (International Parkinson
Disease Genomics Consortium 2011).
4.3 Genetics of Essential Tremor
Essential tremor (ET) is one of the most common movement disorders in adults and
the most common pathologic tremor in humans. The disease prevalence is estimated
to be 0.4% across all ages. However ET prevalence increases markedly with age and
is reported to be 4.6% in those aged 65 years, reaching more than 20% in nonage-
narians (Louis and Ferreira 2010). ET shows a bimodal age of onset, with a smaller
peak in the second decade of life and a larger peak in the sixth decade (Brin and
Koller 1998). Childhood-onset ET is usually hereditary and three times more fre-
quent in males than in females (Ferrara and Jankovic 2009). The disease is charac-
terized by an action tremor with mixed postural and kinetic elements. The postural
tremor is commonly seen in the hands and the kinetic tremor is brought out by
action, such as writing, eating, or pouring a cup of water (Dalvi and Mercury 2011).
ET is a heterogeneous condition with variable clinical expression in affected
patients. While the hands are most commonly affected, many patients have a head
tremor as well. Approximately 90–95% of the patients have tremor in their upper
Table 4.3 Loci and genes associated with essential tremor

Function or
Designation Locus Gene Inheritance probable function
ETM1 3q13 Unknown AD Unknown
ETM2 2p22-p25 Unknown AD Unknown
ETM3 6p23 Unknown AD Unknown
Susceptibility gene Protein/Function
LINGO1 (rs9652490) LINGO1 is part of a complex called the Nogo-66 receptor
(NgR1). The NgR acts as an inhibitor to axonal
regeneration in adults
extremities, 30–34% have a head tremor, 12–20% a voice tremor, and 5–10% a face
or trunk tremor. Almost 10% of the patients have a lower limb tremor (Whaley et al.
2007; Dalvi and Mercury 2011). Non-motor symptoms including mild cognitive
changes, changes in personality, anxiety, and depression are more frequent in ET
patients than in normal age-matched controls (Zesiewicz et al. 2010). The analysis
of postmortem ET brains revealed that 75% of them are characterized by cerebellar
changes, including loss of Purkinje cells and increase in the number of axonal swell-
ings, termed “torpedoes.” Lewy bodies were observed in the locus ceruleus of the
remaining 25% of the brains (Louis et al. 2007). Overall, ET can be considered a
cerebellar disorder with pathologic changes affecting either the cerebellum itself or
neurons that synapse with Purkinje cells (Dalvi and Mercury 2011). Studies in twins
revealed elevated concordance among monozygotic twins, suggesting that the dis-
ease has a high heritability (Lorenz et al. 2004). Most of the studies indicate that ET
is a familial disorder in 40–50% of the cases, and the disease is often inherited in a
manner suggesting an autosomal dominant genetic pattern with incomplete pene-
trance. A family history of ET appears to correlate with younger age at onset, and
first-degree relatives of ET patients have a fivefold increased risk to develop the
disease than normal controls. Non-familial “sporadic” ET cases are known and
might result from either low-penetrant autosomal dominant loci or from multifacto-
rial inheritance (Deng et al. 2007). Linkage analyses revealed at least three loci for
familial ET (ETM1 on 3q13, ETM2 on 2p24.1, and a locus on 6p23) in Iceland and
North American families (Table 4.3). However, the causative gene has yet to be
unraveled (Dalvi and Mercury 2011). A more recent GWAS study showed an asso-
ciation with the LINGO1 gene (Stefansson et al. 2009) that has been subsequently
replicated by several authors (Clark et al. 2010b; Thier et al. 2010) suggesting that
LINGO1 is a susceptibility gene for ET.
4.3.1 ETM1
In 1997 the first ET locus (ETM1) was mapped to chromosome 3q13 in 75 members
of 16 Icelandic families (Gulcher et al. 1997). A Ser9Gly variant in the dopamine
D3 receptor (DRD3) gene, located in the ETM1 locus, was subsequently associated
62 F. Coppedè
with disease risk and age at onset (Jeanneteau et al. 2006). More recent studies
failed to find a significant association of the DRD3 variant with ET or linkage to the
DRD3 receptor in German, Danish, Italian, and French ET patients and families,
suggesting that it is unlikely to be a causal factor for ET (Lorenz et al. 2009).
4.3.2 ETM2
The ETM2 locus was mapped to a 9.1 cM region on chromosome 2p22-p25 (Higgins
et al. 1997) in a large American family of Czech descent. Subsequent studies
suggested an association between ET and an A265G substitution in the HS1-binding
protein 3 gene (HS1BP3) mapping within the ETM2 locus (Higgins et al. 2005).
However, the association with the HS1BP3 gene was not replicated by other
investigators (Deng et al. 2005; Shatunov et al. 2005).
4.3.3 The 6p23 Locus (ETM3)
Linkage to ETM1 and ETM2 loci was not evident in several ET families suggesting
genetic heterogeneity in ET. A third ET locus was mapped to chromosome 6p23.
Several genes within this locus have been investigated as candidates, but none of
them was found to bear pathogenic mutations (Shatunov et al. 2006).
4.3.4 LINGO1
A GWAS in ET identified a sequence variant (rs9652490 G allele) of the LINGO1

gene to be a risk factor in European and American populations (Stefansson et al.
2009). Clark et al. (2010a, b) conducted a replication study in a North American
cohort and genotyped 15 SNPs in the LINGO1 gene. The authors showed that the
strength of association with rs9652490 was stronger in those with a more definitive
diagnosis of ET. They also observed that three other SNPs (rs177008, rs13313467,
and rs8028808) were associated with ET in younger patients (age at onset
<40 years). Additional replication studies (Tan et al. 2009; Thier et al. 2010;
Vilariño-Güell et al. 2010) provided substantial evidence that LINGO1 rs9652490
is associated with ET. Interestingly, the rs9652490 SNP is located in intron 3 and
there is no evidence that it could alter splicing or affect protein function. Therefore,
this variant may not be the functional variant but may be in linkage disequilibrium
with unknown functional variants in the vicinity (Tan 2010). LINGO1 is part of a
complex called the Nogo-66 receptor (NgR1). NgR1 is expressed mainly on neu-
rons and is usually associated in a trimolecular complex. The second member of
the complex, LINGO-1, is often connected to NgR function and is further found to
function independently as a negative regulator of oligodendrocyte proliferation
and differentiation (Mi et al. 2004). The NgR acts as an inhibitor to axonal
regeneration in adults (Zhang et al. 2008). More recently, a study performed in
Spanish ET families failed to replicate the association with LINGO1 polymor-
phisms (Lorenzo-Betancor et al. 2011).
4.3.5 Additional Loci
Our understanding of the genetics of ET has been so far elusive (Table 4.3). Initial
observations linking DRD3 and HS1-BP3 gene variants to ET have not been consis-
tently replicated, and no gene linked to ET has been so far identified at 6p23. The
LINGO1 gene remains the most replicated gene associated to ET, even if a lack of
association has emerged from a recent study in the Spanish population (Lorenzo-
Betancor et al. 2011). One of the major limits to our understanding of ET genetics is
that ET is essentially a clinical diagnosis and despite proposed diagnostic criteria, we
still do not know for certain whether ET is a single disorder or rather a more hetero-
geneous syndrome with varied aetiologies (see also Chap. 10). Many investigators
observed an overlap between the ET phenotype and other neurological diseases
including Parkinson’s disease, dystonia, myoclonus, hereditary peripheral neuropa-
thy, and other neurological disorders. Therefore, it is estimated that the disease is
misdiagnosed in 30–50% of the cases, mainly as Parkinson’s disease or dystonia
(Hawley et al. 2010; Zesiewicz et al. 2010). Several studies suggest that there may be
a link between ET and PD although this remains controversial (Zesiewicz et al.
2010). Particularly, some people with ET progress to develop Parkinson’s disease
years after the initial ET diagnosis. However, the biologic nature of the association is
not well understood, and it is not clear what factors predict which ET patients later
develop PD and whether patients with PD are more likely to develop ET (Fekete and
Jankovic 2011). Mutations of several PD genes, including SNCA, parkin, LRRK2,
and GBA, have been investigated as possible ET risk factors, but none of them has
been consistently associated with the disease (Clark et al. 2010a; Deng et al. 2007).
Also the analysis of the DYT1 dystonia-associated gene revealed no link to ET
(Illarioshkin et al. 2002). Similarly, the LINGO1 gene has been investigated as a PD
susceptibility locus, but results are conflicting and still inconclusive (Annesi et al.
2011; Białecka et al. 2010; Haubenberger et al. 2009; Klebe et al. 2010). ET-like
tremor or parkinsonian tremor has been observed in several other diseases, including
monogenic ataxias. This point is discussed in the following sections of this chapter.
4.4 Tremor in Ataxias
The ataxias are a heterogeneous group of progressive neurodegenerative disorders

with ataxia as the leading symptom. Cerebellar disorders can be divided into sporadic
forms and inherited diseases. Inherited ataxias include autosomal dominant spinocer-
ebellar ataxias (SCAs), autosomal recessive cerebellar ataxias, episodic ataxias (EA),
64 F. Coppedè
Table 4.4 Some examples of loci and genes associated with inherited ataxias
Designation Locus Gene Inheritance Function or probable function
SCA2 12q24 ATXN2 AD Ataxin-2, RNA processing
SCA3 14q21 ATXN3 AD Ataxin-3, deubiquitinating
enzyme, ubiquitin–proteasome
system
SCA12 5q32 PPP2R2B AD Regulatory subunit of protein
phosphatase 2A
SCA15/SCA16 3p26.1 ITPR1 AD Inositol 1,4,5-triphosphate
receptor 1, mediates calcium
release from endoplasmic
reticulum
SCA20 11q12 Unknown AD Unknown
FXTAS Xq27.3 FMR1 X-linked Fragile X mental retardation 1
gene, development of synapses
CA 19p13.3 ATCAY AR Caytaxin, glutamate synthesis
AOA1 9p13.3 APTX AR DNA repair
AOA2 9q34.13 SETX AR DNA/RNA helicase
AT 11q22-q23 ATM AR DNA repair
and X-linked ataxias (Manto and Marmolino 2009). Almost 30 types of SCAs are
currently known, and over 20 types of autosomal recessive ataxias are counted. The
genes associated with these diseases have been identified for several of them (reviewed
in: Teive 2009, and Embiruçu et al. 2009). Tremor is often observed in ataxias. Aim
of this section of the chapter is the discussion of several of the best known examples
of cerebellar ataxias characterized by tremor as one of the symptoms (Table 4.4).
4.4.1 SCA2 and SCA3
Parkinsonism, dystonia, and postural tremor are particularly prevalent in SCAs

types 2 and 3. SCA2 and SCA3 are caused by abnormal CAG trinucleotide repeat
expansion of ATXN2 and ATXN3 genes, respectively. SCA2 can manifest either
with a cerebellar syndrome or as Parkinson’s syndrome, while later stages involve
mainly brainstem, spinal cord, and thalamus. The disease is caused by a CAG repeat
expansion of ATNX2, which can expand in families over successive generations
resulting in earlier onset age and faster progression. Affected individuals have
alleles with 32 or more CAG trinucleotide repeats, resulting in polyglutamine tract
expansion in the protein (Lastres-Becker et al. 2008). Machado-Joseph disease
(MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common
form of spinocerebellar ataxia worldwide, caused by CAG trinucleotide repeat
expansion in ataxin-3 (ATXN3), coding a conserved and ubiquitous protein known
to bind polyubiquitin chains and to function as a deubiquitinating enzyme. Affected
individuals have alleles with 52 or more trinucleotide repeats (Matos et al. 2011).
The parkinsonian phenotype of SCA2 and SCA3 is often observed in Asians (Lu
et al. 2004; Kim et al. 2007).
4.4.2 SCA12
Spinocerebellar ataxia 12 (SCA12) is a late-onset, autosomal dominant, slowly

progressive disorder. Action tremor is the usual presenting sign, often starting in
the fourth decade. Subsequent development of ataxia and hyperreflexia suggests
spinocerebellar ataxia. Up to 25% of patients develop a peripheral neuropathy
(Manto 2010). The disease is caused by a CAG repeat expansion in PPP2R2B, a
gene that encodes Bb, a regulatory subunit of protein phosphatase 2A (PP2A).
CAG repeats between 55 and 78 are observed in SCA12 patients. The CAG expan-
sion in PPP2R2B correlates with increased Bb expression, and does not result in
polyglutamine production. SCA12 may be considered in patients who present with
action tremor and later develop signs of cerebellar and cortical dysfunction
(O’Hearn et al. 2011).
4.4.3 SCA15 and SCA16
Spinocerebellar ataxia type 15 (SCA15) is a slowly progressive dominantly inher-

ited ataxia. Six pedigrees have been reported to date in Anglo-Celtic and Japanese
populations. Its main distinguishing characteristic is tremor, often affecting the
head, which is seen in about half of the affected individuals and which may be the
presenting feature (Storey and Gardner 2012). The disease is due to various dele-
tions of the inositol 1,4,5-triphosphate receptor 1 gene (ITPR1) on chromosome 3.
“SCA16” has been shown to be due to an ITPR1 mutation, and has now been subsumed
into SCA15 (Iwaki et al. 2008).
4.4.4 SCA20
Spinocerebellar ataxia type 20 (SCA20) is a slowly progressive dominantly inher-

ited disorder so far reported in a single Anglo-Celtic family from Australia. Its dis-
tinguishing clinical features, each present in a majority of affected persons, are
palatal tremor, and a form of dysphonia resembling spasmodic dysphonia. The
responsible locus was mapped in the pericentric region of chromosome 11 (Knight
et al. 2004).
4.4.5 Fragile X-Associated Tremor/Ataxia Syndrome
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurode-

generative disorder affecting mainly men over the age of 50 years. The disease is
caused by a CGG repeat expansion in the premutation range (55–200) in the fragile
66 F. Coppedè
X mental retardation 1 (FMR1) gene whose full mutation causes the fragile
X syndrome (FXS), the most common cause of inherited mental retardation. Major
signs are cerebellar gait ataxia, intention tremor, frontal executive dysfunction, and
global brain atrophy. Other frequent findings are parkinsonism, peripheral neuropa-
thy, psychiatric symptoms, and autonomic dysfunction. Affected females have a
less severe disease, and some symptoms different from that of men, for example,
muscle pain (Leehey 2009).
4.4.6 Others
As discussed in the Introduction of this section tremor is often observed in several

ataxias, including other SCAs and recessive ataxias, and not limited to the above
detailed examples. Early onset hypotonia and nonprogressive axial cerebellar ataxia,
associated to nystagmus, intention tremor, and dysarthria characterize Cayman
ataxia (CA). The name derives from the fact that the disease has only been found in
the Grand Cayman Island. CA is an autosomal recessive disease caused by mutation
of ATCAY, which codes for caytaxin, a protein involved with glutamate synthesis
and also with synaptogenesis of cerebellar granular neurons and Purkinje cells
(Hayakawa et al. 2007). Tremor is also observed in other autosomal recessive atax-
ias, such as those caused by defects of DNA repair genes (Gueven et al. 2007;
Embiruçu et al. 2009). Ataxia with oculomotor apraxia type 1 (AOA1) is a condi-
tion characterized by involuntary movements (chorea and dystonia) and/or progres-
sive global ataxia, with dysarthria associated with hands and head tremor. The
disease is caused by mutation in the aprataxin (APTX) gene, which encodes a
nuclear protein involved in single-strand DNA repair. Ataxia with oculomotor
apraxia type 2 (AOA2) is characterized by global progressive ataxia with onset usu-
ally between 8 and 25 years of age. Dystonia, head and postural tremor, chorea,
dysphagia, pes cavus, and scoliosis are occasionally seen. The disease is caused by
autosomal recessive mutations of senataxin (SETX), encoding a DNA/RNA helicase
involved in RNA processing and DNA repair. Peripheral neuropathy and movement
disorder, as tremor or choreoathetosis, are seen after 5 years of age in ataxia–telang-
iectasia (AT), a recessive disorder caused by mutations of the ATM gene that encodes
for a serine/threonine kinase responsible for DNA repair during the cell cycle
(Gueven et al. 2007).
4.5 Familial Cortical Myoclonic Tremor with Epilepsy
The acronym familial cortical myoclonic tremor with epilepsy (FCMTE) was proposed
to describe a clinical entity observed in 50 Japanese and European families with
irregular postural myoclonic tremor of the distal limbs, familial history of epilepsy,
a rather benign outcome, and autosomal dominant inheritance (Regragui et al. 2006).
Table 4.5 Loci linked to familial cortical myoclonic tremor with epilepsy
Function or
Designation Locus Gene Inheritance probable function
FCMTE1 8q23.3-q24.11 Unknown AD Unknown
FCMTE2 2p11.1-q12.2 Unknown AD Unknown
FCMTE3 5p15.31-p15 Unknown AD Unknown
Two loci, 8q23.3-q24.11 (FCMTE1) and 2p11.1-q12.2 (FCMTE2), have been reported
without an identified gene, and a third locus (FCMTE3) has been recently identified in
a large French family with 16 affected relatives. The third locus maps to 5p15.31-p15,
but the mutated gene is still pending identification (Table 4.5) (Depienne et al. 2010).
4.6 Dystonic Tremor
Dystonia is a movement disorder characterized by sustained muscle contractions,

frequently causing twisting and repetitive movements or abnormal postures.
Idiopathic dystonic tremor is a tremor that occurs in conjunction with dystonia
and has developed spontaneously or due to an unknown cause. Dystonia can be
classified by age at onset, including early onset (<26 years) and late onset
(>26 years), or by distribution (focal, multifocal, unilateral, or generalized).
Dystonic tremor, in a manner similar to dystonia, can occur in two distinct age
groups and appears to occur in families with the disease, even if there are also
cases with no family history of dystonia. Dystonic tremor can also affect multi-
ple body parts, mainly the hands, the head, and occasionally the voice (Zorzi
et al. 2009). The aetiological classification of dystonias includes five main cate-
gories: primary dystonias, dystonia plus, secondary dystonias, heredodegenera-
tive dystonias, and psychogenic dystonia (Edwards 2008; Zorzi et al. 2009). In
primary dystonias patients have dystonia as the only clinical feature with or
without tremor. Dystonia plus syndromes are a group of conditions where dysto-
nia occurs with other symptoms such as myoclonus and parkinsonism, but there
is no neurodegeneration. Secondary dystonia refers to a dystonia occurring sec-
ondary to brain lesions, infections, or drug use. Heredodegenerative dystonias
are dystonic movements occurring in the context of other neurodegenerative
disorders, including autosomal dominant and autosomal recessive conditions
(Huntington’s disease, juvenile parkinsonism, Wilson disease, etc.). Psychogenic
dystonia or pseudodystonias are not a true dystonia but mimics it (Edwards 2008;
Müller 2009; Zorzi et al. 2009). A study performed on 132 cases of primary dys-
tonia and 51 patients with secondary dystonia revealed that dystonic tremor was
present in 60% and 24% of the cases with primary and secondary forms of the
disease, respectively (Svetel et al. 2004). Dystonias show genetic heterogeneity,
including autosomal dominant, autosomal recessive, and X-linked forms
(Table 4.6) (Müller 2009).
68 F. Coppedè
Table 4.6 Some examples of loci and genes associated with inherited dystonias
Designation Locus Gene Inheritance Function or probable function
DYT1 9q34 TOR1A AD ATPase with chaperone functions
DYT3 Xq13.1 TAF1/DYT3 X-linked Unknown
DYT5a 14q22.1-q22.2 GCH1 AD Dopamine synthesis
DYT5b 11p15.5 TH AR Dopamine synthesis
DYT6 8p11.21 THAP1 AD Transcription factor that regulates
the expression of TOR1A
DYT11 7q21.3 SGCE AD Sarcoglycan
DYT12 19q13.31 ATP1A3 AD Na+/K+ ATPase subunit a3
DYT16 2q31.2 PRKRA AR Protein kinase
4.6.1 Autosomal Dominant Dystonias
Autosomal dominant pure dystonias (primary dystonias) include dystonia 1, 4, 6, 7

and 13. Dystonia plus syndromes include dystonia 5a, 11, 12, and 15. A third group
includes dystonia 8, 9, 18, 19, and 20, referred to as paroxysmal dystonias. Several
loci and at least seven genes have been identified to cause these diseases (Table 4.6).
Early-onset primary dystonia (dystonia 1) is caused by mutations in the TOR1A
gene at DYT1 locus on 9q34, and encoding a protein named torsinA (Ozelius et al.
1997). The most frequent mutation is a GAG deletion in exon 5, observed in almost
all dystonia 1 patients, and transmitted in an autosomal dominant fashion with low
penetrance (30%). TorsinA is a member of a superfamily of ATPases with chaper-
one functions. The protein is expressed in the central nervous system, mainly located
in the nuclear envelope and the lumen of the endoplasmic reticulum (ER), suggest-
ing a role in both maintenance of structural integrity and/or normal function of
protein processing and trafficking. TorsinA might also have a role in the secretory
pathway in ER, in neurite outgrowth, and in synaptic vesicle recycling (Zorzi et al.
2009). Dystonia 6 is a slowly progressive frequently generalized dystonia, thought
to be the second most common pure monogenic dystonia after dystonia 1. The dis-
ease is caused by mutations of the transcription factor THAP1 (DYT6) on chromo-
some 8p11.21. TOR1A (DYT1) and the transcription factor THAP1 (DYT6) are the
only genes identified thus far for primary dystonia. A physical interaction between
THAP1 and the TOR1A promoter has been recently observed, and the interaction is
abolished by pathophysiological mutations (Gavarini et al. 2010). Another group
observed that wild type THAP1 represses the expression of TOR1A, whereas dys-
tonia 6-associated mutant THAP1 results in decreased repression of TOR1A (Kaiser
et al. 2010). Overall, these data demonstrate that THAP1 regulates the transcription
of TOR1A, suggesting transcriptional dysregulation as a cause of dystonia (Gavarini
et al. 2010; Kaiser et al. 2010). The rare autosomal dominant dystonia plus syn-
dromes, named dystonia 5a or Sagawa syndrome, is caused by mutations of GCH1,
a gene that codes for GTP-cyclohydrolase I, essential for the synthesis of dopamine.
Very rare autosomal dominant dystonia plus syndromes, dystonia 11 and dystonia
12, are caused by mutations of SGCE and ATP1A3 genes, respectively; the first
coding for a-sarcoglican, and the latter for the Na+/K+ ATPase subunit a3 (for a
detailed review, see Müller 2009).
4.6.2 Recessive Dystonias
Recessive dystonias include autosomal recessive pure dystonia 2 and 17, auto-
somal recessive dystonia plus syndrome 5b and 16, and the X-linked recessive
dystonia plus syndrome or dystonia 3 (Müller 2009). The genes causing dystonia
5b, 16, and 3 have been identified (Table 4.6). Dystonia 5b is phenotypically simi-
lar to the type 5a, it is however less common and recessively inherited. The disease
is caused by mutations of the tyrosine hydroxylase (TH) gene on the short arm of
chromosome 11, resulting in lack of the tyrosine hydroxylase enzyme leading to
impaired conversion of tyrosine into l-dopa (Verbeek et al. 2007). Tyrosine
hydroxylase is a rate limiting enzyme in dopamine biosynthesis and missense
mutations in both alleles of the TH gene cause dopamine-related phenotypes,
including dystonia and infantile Parkinsonism. Recently, a novel deletion of the
entire TH gene was observed in an adult with PD. After screening 635 cases and
642 controls, the deletion was found in one PD case but not in any control. The
patient had an age-at-onset of 54 years, no evidence for dystonia, and was respon-
sive to l-DOPA (Bademci et al. 2010). Dystonia 16 was observed in seven Brazilian
patients and linked to mutations of the gene PRKRA, encoding a protein kinase,
interferon-inducible double-stranded RNA-dependent activator. Parkinsonism was
observed in four of the seven patients (Camargos et al. 2008). The X-linked reces-
sive dystonia plus syndrome or dystonia 3 is an adult-onset dystonia often accom-
panied by parkinsonism, resulting from recessive mutations of TAF1/DYT3 on
chromosome Xq13.1. It is not yet clear how changes within the TAF1/DYT3 sys-
tem cause the disease (Müller 2009).
4.7 Roussy–Lévy Syndrome
Charcot–Marie–Tooth (CMT) disease encompasses a genetically heterogeneous

group of inherited neuropathies, also known as hereditary motor and sensory neu-
ropathies (HSMN). CMT results from mutations in more than 30 genes expressed
in Schwann cells and neurons causing overlapping phenotypes. The classic CMT
phenotype reflects length-dependent axonal degeneration characterized by distal
sensory loss and weakness, deep tendon reflex abnormalities, and skeletal deformi-
ties (Patzkó and Shy 2011). The first cases of CMT associated with ET have been
reported more than 30 years ago (Salisachs 1975, 1976). Subsequently, others
70 F. Coppedè
provided evidence that CMT disease with tremor coincides with the Roussy–Lévy
syndrome (Barbieri et al. 1984). The Roussy–Lévy syndrome was first described in
1926 by Roussy and Lévy as a disorder beginning in infancy or childhood and pre-
senting with pes cavus and tendon areflexia, distal limb weakness, tremor in the
upper limbs, gait ataxia, and distal sensory loss. In 1998 Auer-Grumbach et al.
reported a family with affected members in four generations, showing the clinical
signs of Roussy–Lévy syndrome and a partial duplication at chromosome 17p11.2, a
genetic defect commonly found in CMT1A patients (the duplication of the PMP22
gene), suggesting a close relation with the CMT syndrome. The PMP22 gene encodes
a 22-kDa protein that comprises 2–5% of peripheral nervous system myelin. It is
produced primarily by Schwann cells and expressed in the compact portion of essen-
tially all myelinated fibers in the peripheral nervous system (Auer-Grumbach et al.
1998). In members of the original family studied by Roussy and Lévy, Plante-
Bordeneuve et al. (1999) identified a heterozygous mutation in the myelin protein
zero (MPZ) gene, encoding the major structural protein of peripheral myelin; muta-
tions in this gene are also associated with CMT1B (Plante-Bordeneuve et al. 1999).
4.8 Wilson’s Disease
Wilson’s disease is an inherited autosomal recessive disorder of copper balance

leading to hepatic damage and neurological disturbance of variable degree. The
hepatic and the neurological form can be distinguished, but many patients present
with a mixture of both. An estimate for the disease frequency in most populations
is about 17 per million, suggesting a carrier frequency ranging from 1 in 90 to 1
in 122 (Huster 2010; Lorincz 2010). The disease is caused by mutations of the
ATP7B gene on chromosome 13q14.3, encoding a copper transporting P-type
transmembrane ATPase. Mutations in ATP7B result in abnormal copper metabo-
lism and subsequent toxic accumulation of copper (Thomas et al. 1995). Overall,
over 300 ATP7B mutations have been so far identified (http://www.wilsondisease.
med.ualberta.ca/database.asp), with only a few of them functionally character-
ized. The patient is usually presymptomatic during early life, but the accumula-
tion of copper causes subclinical liver disease. Disease symptoms are highly
variable and can manifest between early childhood and the fifth or sixth decade of
life, with a peak incidence of around 17 years. Hepatic, neurological, and psychi-
atric manifestations are observed. Neurological features include dysarthria, dys-
tonia, tremor, parkinsonism, choreoathetosis, ataxia, and subtle cognitive
impairment. Tremor is reported in 22–55% of the cases, occurring at rest, upon
assumption of a posture, or with action. Clinical signs include asymmetric distal
accentuated tremor of the hands, “wing beating” tremor, intention tremor, and
sometimes tremor of the trunk and head. Parkinsonism has been reported in
19–62% of the cases. Psychiatric symptoms, including attention deficit, depres-
sion, and mood swings, are observed in up to one-third of the patients (Huster
2010; Lorincz 2010).
4.9 Conclusions
Advances have been obtained in recent years in our understanding of the genetics of
PD, with almost half of the genetic risk of developing the disease already identified
(Hardy 2010). Studies on recessive forms of the disease have highlighted a central
role for mitochondrial damage, repair, and turnover in the pathophysiology of the
disease, with parkin, DJ1, PINK1, and FBX07, participating in the same or in simi-
lar/overlapping mitochondrial pathways. In addition, as suggested by J. Hardy, both
glucocerebrosidase and ATP13A2 are lysosomal enzymes, indicating a second PD
pathway involving lysosomes. In contrast, a-synuclein and LRRK2 biology is still
poorly understood, despite both proteins are central to the disease etiology
(Hardy 2010). The application of genome-wide technology has already led to the
identification of several genetic risk factors for the idiopathic forms of the disease,
and additional genes are expected to be unraveled within the next future. Public
databases, such as the PD mutation database (http://www.molgen.ua.ac.be/
PDmutDB) and the PDGene database (http://www.pdgene.org), have been created
where people can find updates on the genetics of either familial or idiopathic forms,
respectively. Less is known concerning the genetics of ET, with no causative gene
already identified, and a genetic risk factor (LINGO1) deserving further investiga-
tion (Tan 2010). Tremor occurs in several other neurological disorders, such as atax-
ias, dystonias, and peripheral neuropathies, among others. I do have provided several
examples of hereditary forms of these disorders and the genes are listed in Tables 4.4,
4.5, and 4.6. Overall, it is clear that the compromising of several pathways can result
in neuronal dysfunction and tremor, and the heterogeneity of the diseases character-
ized by tremor as one of the possible symptoms is reflected by the heterogeneity of
genes and pathways causing such diseases. Similarly, mutations in the same gene
can cause different diseases, depending on the nature of the mutation itself, making
the picture even more complex. Some examples are the MAPT gene, that can cause
frontotemporal dementia with parkinsonism or increase the risk for idiopathic PD,
or mutations of FRM1 that can lead to either fragile X syndrome or fragile
X-associated/tremor ataxia syndrome, depending on the length of the repeated tract.
I hope that this chapter could give a broad overview of the human disorders charac-
terized by tremor and of the genetics beyond them. Additional information on the
specific diseases can be found in the following chapters of this book.
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Chapter 5
Musculoskeletal Models of Tremor
Dingguo Zhang and Wei Tech Ang
Keywords Modeling • Musculoskeletal • Reflex loops • Muscle • Tendon • Neural

drive • Joint dynamics • Torques • Elasticity • Viscosity
5.1 Introduction
Notwithstanding the contribution of many prior works in tremor (Elble and Koller
1990; Findley and Koller 1994), a clear consensus of its origin and pathogenesis
among the scientific community is still lacking. The prevalent opinion supports the
idea that the main source of tremor is from central neural oscillators located in brain
(central tremor), but the peripheral nervous system may also have a significant
contribution in some cases (peripheral tremor) (see also the Chap. 6; Stein and
Oguztoreli 1976; Wenderoth and Bock 1999).
Even if the origin of tremor is inconclusive, its association with the musculosk-
eletal system is indisputable. Therefore, the development of a musculoskeletal
model, or in other words, a description of the association of tremor with the muscu-
loskeletal system in mathematical terms, may be very useful as an investigative tool
to understand tremor and, perhaps, to provide bases for alternative treatments.
Specifically, musculoskeletal models of tremor may be used for two general
purposes: the first is to explore the mechanism of tremor from a neurophysiolog-
ical perspective (Zhang et al. 2009; Dideriksen et al. 2011); the second is to serve as
a plant in a simulation environment to test the control performance of tremor
suppression strategies via assistive engineering techniques (Zhang et al. 2011).
D. Zhang (*)
Institute of Robotics, School of Mechanical Engineering,
Shanghai Jiao Tong University, Shanghai, China
e-mail: dgzhang@sjtu.edu.cn
W.T. Ang
School of Mechanical and Aerospace Engineering,
Nanyang Technological University, Singapore, Singapore

80 D. Zhang and W.T. Ang
In this chapter, the focus will be on the former. A musculoskeletal model in combi-
nation of neural models of some organs or reflex loops in nervous system, i.e., a
neuromusculoskeletal model, will be presented. The second purpose of the muscu-
loskeletal model will be briefly discussed at the end of the chapter.
In general, there are two classes of work in the study of tremor using mathematical
or systematical methods. Some researchers have developed neuronal models to
explore the origin of tremor in central nervous system (CNS), and to investigate
how the central oscillators generate the tremor (Beuter et al. 2003; Smirnov et al.
2008). Others study the origin of tremor based on models of peripheral nervous
system based upon a musculoskeletal system (Bock and Wenderoth 1999; Fukumoto
1986; Oguztoreli and Stein 1976; Santillan et al. 2003; Stein and Oguztoreli 1976;
Wenderoth and Bock 1999). The peripheral nervous system is relatively simple in
nature as compared to the complexity of the CNS. However, previously proposed mod-
els, especially the peripheral mechanism models, are generally oversimplified. One
approach to develop a relatively complete musculoskeletal model would be to com-
bine the central neural oscillator with the peripheral loops, and hence it provides a
powerful method to investigate the inner mechanism of tremor in simulation.
As a complementary method to the direct neurophysiological study in medicine,
musculoskeletal models of tremor may provide theoretical supports for clinical
observations. By comparison with the previous works (Bock and Wenderoth 1999;
Fukumoto 1986; Hidler and Ryme 1999; Wenderoth and Bock 1999), we employ a
mathematical model in which we attempt to represent more precisely the observable
physiological phenomena in relation to the underlying tremor dynamics. It contains
enough details both on the anatomical side and also in terms of dynamic properties
(1) to allow the identification of the structures responsible for the peripheral origin
of tremor from a theoretical point of view and (2) to test the assumptions of the
related research work in neuroscience.
5.2 Methodology of Modeling
5.2.1 Overview
A musculoskeletal model with reflex loops is proposed as depicted in Fig. 5.1.

The muscles represented are the skeletal muscles, which are attached to the bones
by bundles of collagen fibers known as tendons, so sometimes the term “musculo-
tendon” is used to represent the combination of muscle/tendon. Skeletal muscle is a
striated muscle tissue controlled by the somatic nervous system, i.e., it is voluntarily
controlled in healthy subjects. Similarly, for patients suffering from pathological
tremor, the skeletal muscles are controlled by involuntary tremulous stimuli. The
muscle model has activation dynamics and contraction dynamics. The reflex loops
include the following structures: muscle spindle, Golgi tendon organ, and the inhib-
itory Renshaw cell in the spinal cord. In such a lumped model, the neurons of an
identical kind are considered as a neuron pool, which represents the dynamics of a
set of single neurons for a specific muscle. Therefore, a simple transfer function or
5 Musculoskeletal Models of Tremor 81
Fig. 5.1 A lumped model of peripheral nervous system includes musculoskeletal model and reflex
loops (muscle spindle, Renshaw cell, and Golgi tendon organ)
Fig. 5.2 Central oscillator is connected with peripheral nervous system regarding an antagonist
musculoskeletal model
equation may generalize the property of nervous loops or organs of the same kind.
Based on this neuromusculoskeletal system, some hypotheses may be evaluated.
The peripheral system including musculoskeletal model can be connected with
central oscillation as shown in Fig. 5.2. In such a configuration, the contribution of
central oscillation and peripheral oscillation on tremor may be studied.
5.2.2 Musculoskeletal Model
The proposed musculoskeletal model is shown in Fig. 5.3. A Muscle models describe
the mechanism of force generation under a stimulus and may be classified accord-
ing to the level or scale of the structure: microscopic models and macroscopic
Fig. 5.3 Macroscopic musculoskeletal model in detail
(whole muscle) models. The typical microscopic model is the conventional cross-
bridge model, i.e., Huxley-type model (Huxley 1957), and the most famous macro-
scopic model is Hill-type muscle model (Hill 1938). These two kinds of muscle
models are well studied and widely adopted by scientists. The former has superior
comprehensiveness as it captures more physiological details, while the latter is
simpler and more tractable because it generalizes some key features.
Among the many improved Hill-type muscle models, the proposal by Zajac
(1989) is adopted here. It has the attractive feature of “scaling,” which permits the
calculation of the mechanical behavior of many different muscles using some
simple characteristic quantities. The benefit of such simplicity seems to be worth
the cost of some loss of fidelity in the representation of the complex muscle
mechanics. As tremor is most related to the upper extremities, the musculoskeletal
models of elbow or wrist joint are targeted in this work.
The proposed muscle model contains two major components: activation dynamics
and contraction dynamics. These two components work in series. Activation dynam-
ics is an electrical process in response to a stimulus, and its output performs func-
tions on contraction dynamics that is a mechanical process as muscle contraction.
Activation Dynamics: When the muscle tissue is stimulated by neural drives, an
internal muscle tissue state (muscle activation am) is generated. This process is asso-
ciated with two factors, the release of calcium at the neuromuscular junction and then
through the muscle contraction dynamics. This action energizes the cross-bridges, so
that the muscle force is generated. It has two important properties: recruitment curve
and calcium dynamics. Recruitment curve can be defined as the static gain relation-
ship between the stimulus intensity and activation level (or the output force). When
a neural drive is applied to a muscle, it activates or recruits a certain number of motor
units in the muscle fibers. For a lumped model, if a stimulus is injected to the
motoneuron pool, the number of motor units recruited varies when the intensity of
stimulus is changed, and so does the activation level of the muscle. The recruitment
curve is typically nonlinear, and exhibits deadband (neutral zone) and saturation.
This mechanism will be modeled in later part in motoneuron dynamics.
Fig. 5.4 Hill-type muscle model
Muscles cannot be activated or relaxed instantaneously. The delay between

muscle excitation and activation (or the development of muscle force) is mainly due
to the time taken for calcium to pump out of the sarcoplasmic reticulum, to travel
down the T-tubule system and bind to troponin. The relationship between neural
drive u and muscle activation a is usually modeled as a first-order process (Pandy
2000), and it can be written as follows:
a = 1 / τa (um2 − ur a ) + 1 / τd (ur − a ), (5.1)
where τ a is the activation time constant, and τ d is the deactivation time constant.
As the recruitment curve is considered, the recruitment level um instead of neural
drive u is used here.
Contraction dynamics: Muscle contraction dynamics is dependent on the mechani-
cal properties of muscle. According to the Hill-type muscle model shown in Fig. 5.4,
it has three elements: a contractile element (CE), which models the muscle force–
length and force–velocity properties, a series element (SE) related to the muscle
active stiffness, and a parallel element (PE), which models the muscle passive
visco-elasticity.
CE is the key element. It indicates that the muscle active force is dependent on
the muscle length and muscle contraction velocity. Therefore, the force–length and
force–velocity properties should be modeled accordingly.
The muscle active force is dependent on the muscle length lm. When lm changes,
it affects not only the maximum peak force produced by the muscle, but also the
joint angles at which peak force occurs. Due to the cross-bridge structure of CE, it
can be shown that the peak force occurs at the optimal muscle length lopt . There are
various mathematical equations representing the force–length relationship. Three
examples are given below, and (5.2), (5.3), and (5.4) are adopted from He et al.
(2001), Ogihara and Yamazaki (2001), andRiener and Fuhr 1998) respectively.
⎛ l 2.8286 − 1 2.368 ⎞
fl = exp ⎜ ⎟, (5.2)
⎜⎝ 0.6182 ⎟
⎠
fl = 0.32 + 0.71exp[ −1.112( l − 1)]sin[3.772( l − 0.656)], (5.3)
⎡ ⎛ l − 1⎞ 2 ⎤
fl = exp ⎢ − ⎜ ⎟ ⎥, (5.4)
⎢⎣ ⎝ ε ⎠ ⎥⎦
where l is the normalized muscle length with respect to the optimal muscle length
l
lopt , and l = m .
lopt
All the three variations show a parabolic relationship. It is obvious that the rela-
tionship shown in (5.2) and (5.3) is not generalized and only suitable for a specific
muscle type. While a more general representation of the muscle model is desirable,
the parameters identification is not an easy task. Hence, a Gaussian-function-like
equation (5.4) is selected to represent the force–length relationship in this work.
The main advantage of this form is that it is simple with very few parameters and
can be regulated for different muscles by the parameter ε .
The force–velocity relationship is described by the function fv , which also has
various representations. Three examples are given in the following equations (5.5),
(5.6) and (5.7), which are adopted from Happee (1994), He et al. (2001) and Riener
and Fuhr (1998), respectively. None of these models is a generalized model. For
different muscles, the differences of force–velocity relationship are not significant
as compared with force–length relationship. Research publications providing the
full parameter identification for different muscles are very rare. Therefore, the
constant force–velocity relationship was widely used in the previous research. In
fact, the variation of parameter in different muscle is very small, so it has minor
effects on force–velocity representation. In this work, (5.5) is adopted.
fv = 0.54 arctan(5.69v + 0.51) + 0.745, (5.5)
1 + 7.3125v
fv = for v > 0 (muscle stretching ),
1 + 4.0625v
1+ v
fv = for v < 0 (muscle shortening ), (5.6)
1 − 2.25v
fv = 1 + tan(3.0 v ), (5.7)
where v is the normalized muscle velocity with respect to the maximum contraction
vm
(shortening) velocity vmax of the muscle, and v = v .
max
The active force generated by the muscle, Fa , is the final result of co-functions
of activation and contraction dynamics, and it is affected by four factors: the peak
isometric force Fmax, the muscle length lm , the muscle shortening or lengthening
velocity vm , and muscle activation am . The general form is Fm = f ( Fmax , lm , vm , am ) ,
which is a nonlinear function. However, when it is used in specific computation, the
active muscle force often takes the form of the product of Fmax with the three
dimensionless quantities:
Fa = afl fv Fmax . (5.8)
The muscle length (lm ) and shortening/stretching velocity (vm ). are difficult to
measure in reality, while the joint angle ( θ) and angular velocity ( θ ) are relatively
easy to be estimated via noninvasive measurement. In fact, some relationships
between joint angle (angular velocity) and muscle length (shortening/stretching
velocity) have already been found in previous studies, which developed a bridge
crossing from microscopic level to macroscopic level. Such transformation models
may help us in developing a lumped model. For example, the general transformation
may be represented as
lm = Cm + ∑ ∫ rm (θ)dθ, (5.9)
.
vm = ∑ θ rm (θ), (5.10)
where rm is the moment arm and Cm is a constant.

Similarly, the PE component in Hill-type muscle model can also be developed as a
lumped model, which is represented in the form of angular visco-elasticity in a given
joint. The experimental data in literature are available to estimate the parameters. For
example, the PE model developed by Lemay and Crago (1996) is given by:
.
Tp = k0 θ + k1 θ+ k2 (e k3θ − 1), (5.11)
.
where Tp is the passive torque, θ is the wrist angle, θ is the angular velocity, and
k0 , k1 , k2 , k3 are coefficients needing identification for different joints.
Skeletal dynamics: The dynamics of human body is very complex since most human
motions include many degrees-of-freedom (DOF), and many muscles and skeletons
are involved around joints. However, if the muscles and other soft tissues are not
considered or simply viewed as parts of rigid bodies, the skeletal dynamics or body
segmental dynamics can be computed with the methods used widely in robotics, e.g.,
Newton–Euler method, etc. In general, the skeletal dynamics can be described by
.. . .
Fm Rm (Θ) = M (Θ) Θ+ C (Θ) Θ+ G(Θ) + E (Θ, Θ), (5.12)
. ..
where Θ, Θ, Θ are vectors of the generalized coordinates (joint angels),
.. velocities,
and accelerations; M (.Θ) is the system mass matrix and M (Θ) Θ is a vector of
inertial torques; C (Θ) Θ is a vector of centrifugal and Coriolis torques; G(Θ) is a
vector of gravitational torques; Fm is a vector of muscle forces, Rm (Θ) is the matrix
.
of muscle moment arms, and Fm Rm (Θ) is a vector of muscle torques; E (Θ, Θ) is a
vector of external torques applied to the body by the environment.
Specifically, the dynamics of wrist joint with one DOF can be modeled as
follows:
Tm = Ta + Tp ,
⎛1 ⎞ .. 1
Tm = ⎜ mlh2 + I ⎟ θ+ mglh cos θ, (5.13)
⎝4 ⎠ 2
where Tm is the total muscle torque applied on to wrist joint, and it is the sum of
active muscle torque Ta and passive muscle torque Tp . The term m is the hand mass,
I is the moment of inertia with respect to the hand center of mass, lh is the hand
length, and g is the gravitational constant.
5.2.3 Peripheral Nervous System Modeling
In this section, the components in peripheral nervous system are modeled, which
include neuronal pool dynamics, muscle spindles, Golgi tendon organs, and inhibi-
tory Renshaw cells.
5.2.3.1 Neuronal Pool Dynamics
Motoneurons and interneurons are components in charge of connecting functions

in the whole neuromusculoskeletal model. The motoneurons are the intermediate
components receiving signals from central nervous system and sending the signals
to the muscles. They project their axons outside the CNS, and, directly or indirectly,
control the muscles. The motoneuron pool dynamics can be modeled by a bandpass
filter (He et al. 2001). The transfer function from the combined synaptic current i to
the motoneuron output u, the neural drive to the muscle, is given by u(s)
u(s ) km [1 + s / 33 + (s / 33)2 ]
= , (5.14)
i(s ) 1 + 2(s / 58) + (s / 58)2
where km is the static gain.

Since the motoneuron pool is considered as a component of the whole lumped
system, all the motoneurons cannot be fired at the same time under a synaptic
current. Some neurons can fire, while other cannot discharge under the synaptic
current. It should have the recruitment property that is typically nonlinear, exhibiting
deadband and saturation. In our model, a piecewise linear function (Ferrarin et al.
2001) is adopted to match the curves in Heckman and Binder (1991). The threshold
of the synaptic current id , which causes nonzero activation, is 20 nA, and the saturation
current is is 80 nA.
enlarged view of muscle spindle
γ -s motoneuron
: II afferent
spinal cord
extrafusal
(main)
muscle
fascicles
intrafusal
la afferent muscle
fibers
γ -d motoneuron
Fig. 5.5 Physiological structure of muscle spindle
⎧ 0 (im < id )
⎪
⎪i − i
um = ⎨ m d id < im < is . (5.15)
⎪ id − is
⎪⎩ 1 im < is
Interneurons are interconnections between the different components (reflex

loops) and the motoneuron (illustrated in Fig. 5.1). However, the dynamics regard-
ing the firing behavior of interneurons is not fully understood so far. Generally, its
function is simply simulated as to perform the sum of the feedback signals, as con-
sidered in previous works (Prochazka et al. 1997a, b; Song et al. 2008). Experimental
support for this approach is given by Powers and Binder (2000).
5.2.3.2 Muscle Spindle
Muscle spindles are sensory receptors located in the belly of a skeletal muscle,
encapsulated by connective tissue, and aligned parallel to extrafusal muscle fibers.
The physiological structure is shown in Fig. 5.5. Normally, a muscle spindle is
composed of 3–12 intrafusal muscle fibers, which can be classified into three types:
dynamic nuclear bag fibers (bag1 fibers), static nuclear bag fibers (bag2 fibers),
nuclear chain fibers and the axons of sensory neurons.
Muscle spindles primarily detect changes in the muscle length, which play an
important role in regulating the contraction of muscles by activating motoneurons
via the stretch reflex to resist muscle stretch. Axons of gamma motoneurons also
terminate in muscle spindles at either or both of the ends of the intrafusal muscle
fibers and regulate the sensitivity of the sensory afferents, which are located in the
noncontractile central region (Hulliger 1984).
The muscle spindle has both sensory and motor component. Primary and second-
ary sensory nerve fibers spiral around and terminate on the central portions of the
intrafusal muscle fibers, providing the sensory components via stretch-sensitive ion
channels of the axons. The motor component receives signals from many gamma
motoneurons and by one or two beta motoneurons. Gamma and beta motoneurons
are called fusimotor neurons, because they activate the intrafusal muscle fibers.
Gamma motoneurons only innervate intrafusal muscle fibers, whereas beta motoneu-
rons innervate both extrafusal and intrafusal muscle fibers and so are named as
skeletofusimotor neurons. Fusimotor drive causes a contraction and stiffening of the
end portions of the intrafusal muscle fibers.
Fusimotor neurons are classified as static or dynamic according to the type of
intrafusal muscle fibers they innervate and their physiological effects on the
responses of the Ia and II sensory neurons innervating the central, noncontractile
part of the muscle spindle. The static axons innervate the chain or bag2 fibers. They
increase the firing rate of Ia and II afferents at a given muscle length. The dynamic
axons innervate the bag1 intrafusal muscle fibers. They increase the stretch-
sensitivity of the Ia afferents by stiffening the bag1 intrafusal fibers.
According to the anatomical structure, a complete and complex model of the
muscle spindle can be developed (Lin and Crago 2002a). The model contains three
types of intrafusal fibers (bag1, bag2, and chain), two efferents (dynamic gamma
efferent to the bag1 fiber and static gamma efferent to bag2 and chain fibers), and
two afferents (primary Ia and secondary II). As in the real muscle spindle, the
spindle model, under the modulation of gamma efferents, responds to the extrafusal
muscle fiber length. Based on the published data, the credibility of the model is
verified via a series of simulation study. For example, both outputs (Ia and II affer-
ents) of the model were investigated, under both sinusoidal stretch (with different
stretch amplitudes and frequencies) and ramp and hold stretch (with different stretch
amplitudes) and velocities in three different fusimotor activation conditions
(dynamic gamma stimulation, static gamma stimulation, and without gamma stimu-
lation). The detailed model provides a powerful tool for simulation studies of
neuromusculoskeletal systems, and demonstrates the feasibility of using a structural
approach to model complex neurophysiological systems.
Since muscle spindle may be the most important reflex loop in charge of tremor,
we aim to embed such a detailed spindle model into the proposed neuromusculosk-
eletal model at the beginning. However, the complexity will increase when addi-
tional parameters are included, so that the whole model may turn to be unmanageable
in simulation. Therefore, a simplified version of spindle model is used.
In fact, the spindle organ has a similar structure of the extrafusal muscle com-
posed of activation and contraction dynamics. The intrafusal tension (force) is
the output of spindle organ, and it is transferred to motoneuron pools with
encoder dynamics. The activation element of spindle organ is driven by beta and
gamma motoneurons. as is used to represent the activation level, and the activation
process is assumed as a linear first-order dynamics (Lin and Crago 2002a).
as = As (us − as ), (5.16)
where As is the time constant. us is the normalized neural input of spindle organ, it
is assumed to be the sum of beta and gamma efferents, i.e., us = uβ + uγ (Lin and
Crago 2002b). uβ is defined as a fraction of the neural drive to extrafusal muscle um ,
and uβ = wβ um , and wβ gamma is the fraction factor. While gamma signal is inde-
pendent with alpha signal, ur cannot be represented by the portion of um . Currently,
there are no direct data available for the gamma drive in the decerebrate condition,
so uγ is arbitrarily selected, the normalized range is generally about 0.3–0.4
(Lin and Crago 2002b; Song et al. 2008).
Regarding the spindle contraction dynamics, a linear transfer function is available
(Prochazka et al. 1997b). It is also named as Ia transfer function represented by
100 s(s + 0.4)(s + 4)(s + 44) (5.17)

.
(s + 0.04)(s + 0.8)(s + 1000)2
Compared with the above equation (5.17), a nonlinear formulation in Houk et al.
(1981) is more credible and it is adopted here. The identification of the parameters
is provided in Prochazka et al. (1997b). The output is the Ia response as a feedback
to the motoneuron directly. In this version, the spindle dynamics and encoder
dynamics of the interneurons are combined together.
is = Gs [C1 + C2 (ls − ls0 )vs0.3 as ], (5.18)
where is is the output of Ia response that will be fed back to the motoneuron, Gs is
the gain, C1 , C2 are constants, ls is the length of spindle organ, ls0 is the slack length,
and vs is the stretch velocity. The relationship between muscle length and spindle
length is given as ls = 0.05lm + 1 (Prochazka et al. 1997a). A time delay ts is not
shown in the equation, but it has an effect on the whole model. C1 , C2 , ls0 are selected
as 0.5, 1 and 1 mm separately.
5.2.3.3 Golgi Tendon Organ
Golgi tendon organ (GTO) is a proprioceptive sensory receptor which signals

the force developed by the muscle. GTO is located at the insertion of skeletal
muscle fibers into the tendons of skeletal muscle. It provides the sensory component
of the Golgi tendon reflex. GTOs are oriented in series to extrafusal muscle fibers,
unlike the muscle spindles, which are aligned parallel. Each GTO is innervated
by a single afferent type Ib sensory fiber that branches and terminates as spiral
endings around the collagen strands. The sensory endings of the Ib afferent are
entwined amongst the musculotendinous strands of 10 to 20 motor units. The Ib
enlarged view of a tendon organ
muscle
spinal cord
tendon
Fig. 5.6 Physiological structure of Golgi tendon organ
sensory feedback generates spinal reflexes and supraspinal responses which control
muscle contraction. The primary functions of GTO prevent skeletal muscles from
(1) developing too much tension; (2) tearing or breaking tendons. The physiological
structure of GTO is shown in Fig. 5.6.
GTO is generally viewed as a force sensor an engineering perspective. The
feedback loop with regard to Golgi tendon organ is also referred as Ib reflex loop.
Its dynamics can be modeled by a transfer function and confirmed in work of
(Prochazka and Gorassini 1998) as
Gg (1 + s / 0.15)(1 + s / 1.5)(1 + s / 16)

H g (s) = . (5.19)
(1 + s / 0.2)(1 + s / 2)(1 + s / 37)
The Golgi tendon organ feedback is received by motoneurons through a disyn-

aptic pathway. The exact dynamics of the interneuron between the Golgi tendon
organ and motoneuron is still unclear. It is assumed to be a static gain Gg with a time
delay tg in this work.
5.2.3.4 Renshaw Cell
Renshaw cells are inhibitory interneurons found in the gray matter of the spinal
cord, and are associated in two ways with an alpha motor neuron. They receive an
excitatory collateral from the alpha neuron’s axon as they emerge from the motor
root, and are thus “kept informed” of how vigorously that neuron is firing. They also
Fig. 5.7 Physiological representation of Renshaw cell
send an inhibitory axon to synapse with the cell body of the initial alpha neuron
and/or an alpha motor neuron of the same motor pool. The physiological representa-
tion of Renshaw cell is shown in Fig. 5.7.
In this way, Renshaw cell inhibition represents a negative feedback mechanism.
A Renshaw cell may be supplied by more than one alpha motor neuron collateral
and it may synapse on multiple motor neurons. The dynamics of Renshaw cell is
modeled as a nonlinear integrator followed by a linear function (Windhorst 1990).
It can be written by
3.25Gr (1 + s / 7)(1 + s / 0.36)

H r (s) = , (5.20)
[3.25(1 + 0.071Cr ) + s ] (1 + s / 0.48)(1 + s / 120 π)
where Gr is the statistic gain of Renshaw cell feedback, Cr is the motoneuron firing
rate. This loop also has a time delay t r through the interneuron linking to the
motoneuron pool.
5.2.4 Central Neural Oscillator
Neural oscillators play important roles in CNS and a variety of models have been
developed (Ijspeert 2008). Generally, there are three popular types of models widely
used to simulate the neural oscillators: recurrent neural oscillator (Matsuoka 1985),
phase oscillator (Ekeberg 1993), and Van der Pol neural oscillator (Bay and Hemami
1987). Unlike the normal oscillators providing motor patterns for rhythmic move-
ments such as walking, running, swimming, and breathing of animals, the oscillator
in charge of tremor may be viewed as a kind of pathological oscillator, which is a
part (e.g., thalamus) of the brain affected by pathological changes, and generates
involuntary and undesired motor patterns of high frequency to muscles. Among the
Fig. 5.8 Structure of Matsuoka’s neural oscillator model
available neural oscillator models, a kind of recurrent neural oscillator, i.e.,

Matsuoka’s model, is utilized to simulate the pathological neural oscillator, which
serves as the central source and supports the simulation study in this work.
The structure of the model is illustrated in Fig. 5.8, and the mathematical descrip-
tion of Matsuoka’s neural oscillator is given as follows,
K f τ1 x1 = − x1 − b v1 − hf ( x2 ) + Le + R
τ 2 v1 = − v1 + f ( x1 )
K f τ1 x 2 = − x2 − b v2 − hf ( x1 ) − Le + R (5.21)
τ 2 v2 = − v2 + f ( x2 )
y j = f ( x j ) = max( x j ,0), j = 1,2
where x j represents the membrane voltage in a neuron, v j is the membrane current

of the slow recovery component, f ( x j ) is a nonlinear function, which has a unit
gain for xi when the input is nonnegative and zero otherwise, y j is the neuronal
output, h is the gain for the interaction between the two neurons, b is the adaptive
gain for the self-inhibition of the neuron, e is the sensory feedback, R is the tonic
input, and L is the feedback gain, K f is the parameter for frequency regulation.
It seems that this model is composed of only two neurons, but it should be noted
this is also a lumped model and it simulates the function (not the structure) of the
neural oscillator at a macroscopic level. Actually, it is well recognized and used widely.
10
8
6
Kf
4
2
0
0 2 4 6 8 10 12 14 16 18 20
time [s]
output of neural oscillator
0 2 4 6 8 10 12 14 16 18 20
Essential tremor Parkisonian tremor normal fast movement normal slow movement
Cerebellar tremor
Fig. 5.9 Matsuoka’s neural oscillator can generate a wide range of tremors with different frequencies
along the changing of parameter Kf
When connected to the peripheral system, the oscillator output yi may be seen as
the supraspinal input to the motoneuron pool. It can generate a wide range of
motions including tremors with different frequencies as shown in Fig. 5.9, which
satisfies the requirement for study on different types of tremors.
5.3 Simulation Results
Based on the methodology introduced in the previous section, the whole model is
developed in Matlab/Simulink environment, and the factors that may cause the
tremor can now be examined. For a specific case study, the musculoskeletal model
of wrist joint with one degree of freedom in sagittal plane is considered (see
Fig. 5.10), because most tremors encountered in the clinic involve wrist joints. This
model can contain one muscle or a pair of antagonistic muscles upon different
purposes. The values for the parameters of the model have been summarized in the
previous work (Zhang et al. 2009), which are collected from abundant sources in
many literatures. Actually, the model developed is general. Any joints of human
limb may be modeled if the required physiological data sets can be provided for the
parameters. As a supplementary study, some new results are presented here. The
primary study focuses on the effects of reflex loops, which is conducted in a single-
muscle system. Moreover, the results on the relationship between central oscillator
and peripheral system are given.
Fig. 5.10 Musculoskeletal model of wrist joints in drawing contains flexor and extensor. Wrist
angle in sagittal plane is defined
80 20
60 15
joint angle [deg]
gain value
40 10
20 5
0 0
0 2 4 6 8 10 12 14 16 18 20
time [sec]
Fig. 5.11 Gain of spindle organ has significant effects on tremor. Right=>Left axis indicates the
wrist joint angle, and left=>right axis indicates the gain value of muscle spindle
5.3.1 Primary Simulation Results
We target the three reflex loops, and three sets of the key variables are concerned:
(Gs , ts ), (Gr , t r ) , and (Gg , tg ). These variables will be tuned to observe the phenomena
of tremor.
Based on simulation, we find that the muscle spindle contributes more to the
tremor. Both the gain and the time delay of spindle loop can have effects. We test
the tremor generation along with the variation of Gs that increases smoothly
from 0 to 20. The result is shown in Fig. 5.11. We can observe a sharp change
when Gs = 9 , and tremor is generated suddenly at this moment. There is a tran-
sient period Gs = 9 − 14 , after Gs = 14 , a stable tremor occurs and it remains
invariant even if Gs is still increasing. The stable frequency is about 5 Hz, the
amplitude is about 5°, and the resting joint angle is 55°.
1600
1400
wrist joint angluar velocity [deg/sec]
1200
1000
800
600
400
200
-200
-60 -40 -20 0 20 40 60 80
wrist joint angle [deg]
Fig. 5.12 Initial values of wrist joint are different, but the phase plot finally converges to a
limit cycle
From a different point of view, the tremor will converge to a series of cycles if
illustrated in a phase plane (i.e., angle vs. angular velocity). This stable phenome-
non may be explained by the limit cycle theory. Limit cycles are frequently observed
in nonlinear dynamical systems, which can be described as a self-excited, isolated
periodic motion with constant amplitude (Strogatz 2001). A stable limit cycle
plotted in the phase plane will form a closed-loop orbit, and any trajectory initiated
near the attractor will converge onto it. Figure 5.12 verifies the existence of limit
cycle in tremor caused by muscle spindle. Different initial values are set for the
wrist joint angle, (−60°, −30°, 0°, 30°, 60°), however, they all converge to the same
limit cycle in the end.
Poincaré map is a useful method to analyze the property of limit cycle. Poincaré
section is the intersection of a periodic orbit in the state space of a continuous
dynamical system with a certain lower dimensional subspace, transversal to the flow
of the system. More precisely, one considers a periodic orbit with initial conditions
within a section of the space, which leaves that section afterwards, and observes the
point at which this orbit first returns to the section. One then creates a map to send
the first point to the second. The transversality of the Poincaré section means that
periodic orbits starting on the subspace flow through it and not parallel to it. A Poincaré
map can be interpreted as a discrete dynamical system with a state space that is one
dimension smaller than the original continuous dynamical system.
Consider an n-dimensional deterministic dynamical system x = f ( x ) , and let S
be an n-dimensional surface of section that is traverse to the flow, i.e., all trajectories
starting from S flow through it and are not parallel to it. Then a Poincaré map S is a
Fig. 5.13 Limit cycle and Poincare map (zero acceleration) of tremor caused by muscle spindle in
3D phase space. The arrow transverses from the below to the above indicates muscle lengthening;
otherwise, muscle shortening
mapping from S to itself obtained by following trajectories from one intersection of

the surface S to the next. A locally stable limit cycle indicates the intersection points
of Poincaré map S are very close, i.e., the cycle to cycle variation is very small.
In order to check the limit cycle behavior of the tremor caused by muscle spindle,
a 3D plot is shown in the phase space regarding wrist joint angle, angular velocity,
and acceleration (see Fig. 5.13). The Poincaré map is defined as z = 0, and we find
that the intersection points in this plane are very close; it means the tremor plots
converge to a stable limit cycle. This observation is similar with that shown in spas-
ticity (Hidler and Ryme 2000).
5.3.2 Kinetic Tremor and Postural Tremor
It is well known that there are three basic types of tremor: resting tremor, postural
tremor, and kinetic tremor (see also Chap. 1; Elble and Koller 1990). Resting tremor
based on neuromusculoskeletal model is simulated and studied in most of our
previous works. The kinetic tremor is associated with human voluntary movement,
and postural tremor appears when subjects try to keep a stable posture against
gravity. Actually, the postural tremor and kinetic tremor can also be simulated based
on our musculoskeletal model. For kinetic tremor simulation, the voluntary motion
65
overall motion (voluntary motion+tremor)
60
angle [deg]
55
50
45
5
kinetic tremor
angle [deg]
-5
65
voluntary motion
60
angle [deg]
55
50
45
10 12 14 16 18 20 22 24 26 28 30
time [sec]
Fig. 5.14 Simulation results on kinetic tremor. The top plot shows the overall motion of wrist
joint. The middle plot is the tremor (involuntary motion). The lower plot is the voluntary motion
and tremulous should be considered at the same time, and they are mixed. Since
voluntary motion is driven by the signals from the brain in nature, in simulation, a
supraspinal neural signal is assumed to be applied into the motoneuron pool that
activates muscle to generate a voluntary motion. Unlike tremor, the voluntary
motions are often performed during daily life, such as grasping a cup or holding a
book, etc. Voluntary motion is nonrhythmic or exhibits a low frequency. Arbitrarily,
a neural drive of 0.2 Hz is provided to the motoneuron pool in order to generate the
voluntary motions. At the same time, the gain of spindle organ is set as 30 that is the
origin of tremor. The result is shown in Fig. 5.14. We can see the voluntary motion
is mixed with kinetic tremor in the overall motion, and they can be separated via a
filter as shown in the lower two subfigures.
Similarly, for postural tremor, a constant (supraspinal) is sent to the motoneuron
pool to generate a steady force, and then the wrist can hold a posture. Different
intensities of the supraspinal signal can make the wrist joint stay at different posi-
tions, which simulates the wrist posture behavior. The gain of spindle organ is
always set as 30, and it is the origin of tremor along with the posture. The simulation
result is shown in Fig. 5.15. We find that the amplitude of the tremor is different at
three positions. The tremor of highest amplitude appears in a medium position. The
phenomenon should be attributed to the muscle contraction dynamics, especially
62
60
58
56
wrist angle [deg]
position 3
54
52
position 2
50
48
position 1
46
0 1 2 3 4 5 6 7 8 9 10
time [sec]
Fig. 5.15 Simulation results on postural tremor. Three different positions or wrist angle are held,
which are accompanied by tremor
the length–force property of the muscle. This latter can generate the maximum force
at the optimal length as indicated by (5.3). At position 2, muscle length should be
near the optimal length, so the highest tremor force is generated even though the
muscle is under the stimulation of the same intensity from the neural drive as that at
position 1 and 3.
5.3.3 Central Oscillation Versus Peripheral Oscillation
The controversial issue on the origin of tremor focuses on central oscillation or

peripheral oscillation, and perturbation test is often used to identify them. Phase
resetting is an important phenomenon observed in the perturbation test, so it is used
as a key index. The well-established criterion in the perturbation test is (1) if the
type 1 phase resetting (the new phase is the same as the old phase, no phase shift) is
observed, then the origin of the tremor is the central oscillation; (2) if type 0 reset-
ting (the new phase is different from the old phase, phase shift exists) is observed,
then the origin is from the peripheral oscillation (Elble and Koller 1990). In most
conditions, the perturbation is effective. However, because the sensory feedback
make the central oscillation coupled with peripheral oscillation, perturbation test is
inappropriate in such case.
90
85
perturbation
no perturbation
75
angle [deg]
65
55
45
8 9 10 11 12 13
time [sec]
Fig. 5.16 Simulation results on perturbation test. Significant phase shift exists since the tremor is
caused by muscle spindle (i.e., peripheral tremor)
Based on the neuromusculoskeletal model, simulation can be performed to verify

the perturbation test. Two cases are considered separately. In first case, the tremor is
merely generated by the peripheral mechanism, i.e., the gain of muscle spindle is set
as 20, and the neural oscillator is disconnected. At the 10th second, an impulse
torque (2 Nm) is suddenly applied on the musculoskeletal model, which is viewed
as the perturbation. Then we observe the phase shift as shown in Fig. 5.16. In
second case, the tremor is merely generated by the central oscillation, i.e., the gain
of muscle spindle is normal as 0.1, and the neural oscillator is connected. At the
10th second, the same impulse torque (2 Nm) is suddenly applied on the musculo-
skeletal model, which is viewed as the perturbation. Then we observe the phase shift
as shown in Fig. 5.17. The results are in accordance with most of the previous study.
In Fig. 5.16, there is a significant phase shift after perturbation. On the contrary,
there is no phase shift after perturbation in Fig. 5.17. Therefore, the origins can be
well identified.
The limit cycle behavior is investigated in perturbation test and the results are
illustrated in Fig. 5.18. After perturbation, the phase plot will eventually come back
to the same limit cycle as that of the original tremor for both central oscillation and
peripheral oscillation. However, most researchers in previous research often high-
light the robust limit cycle behavior of central oscillation at one side, and it seems
to ignore the peripheral contribution. Our simulation results indicate that the stable
limit cycle existed in peripheral neuromusculoskeletal system is also very robust to
disturbance, which is similar to central oscillation. There is no significant difference
90
85
perturbation
no perturbation
75
angle [deg]
65
55
45
35
8 9 10 11 12 13
time [sec]
Fig. 5.17 Simulation results on perturbation test. No phase shift exists since the tremor is caused
by neural oscillator merely (i.e., central tremor)
400
300 limit cycle

angular velocity [deg/sec]
200
100
Perturbation
-100
-200
-300
50 55 60 65 70 75 80 85 90 95
angle [deg]
Fig. 5.18 Simulation results on perturbation test in phase plane, and a stable limit cycle is
observed. The peripheral tremor is robust to disturbance
100
80 no inertial load
transient period
60 inertial load on
40
20
-20
-40
-60
-80
-100
47 48 49 50 51 52 53 54
angle [deg]
Fig. 5.19 Simulation results on inertial load test on peripheral tremor in phase plane, and two
limit cycles are observed. Center of limit cycle moves after inertial load is put on
on limit cycles using perturbation test between peripheral oscillation and central
oscillation, therefore the limit cycle behavior is not suitable to identify the origin of
tremor in perturbation test. On the contrary, the difference of phase shift is obvious,
so it is understandable why phase resetting is used widely.
Another common method to identify the origin of tremor is the inertial load test.
Although simple, it is really effective in some cases. Generally, an inertial load is
attached to the tremulous limb of a patient in experiments. If the tremor frequency
is changed, then the origin should be from the peripheral oscillation; otherwise, the
origin should be from central oscillation. It supports the idea that central oscillation
is more refractory and robust than peripheral oscillation. This test can be simulated
on the neuromusculoskeletal model. Firstly, peripheral tremor is generated due to
the muscle spindle ( Gs = 20) as shown in Fig. 5.11, and then the inertial load (two
times of the hand mass) is applied to the musculoskeletal model at the 10th second.
We find both amplitude and frequency of the tremor decrease. Furthermore, limit
cycle behavior is presented. It exhibits two limit cycles in phase plane. For central
oscillation, there also exist two different limit cycles (the figure is not shown).
Because the tremor amplitude and velocity are changed for both central oscillation
and peripheral oscillation, it is easy to understand that two limit cycles exist in
phase plane if an inertial load is added. The center of cycle (i.e., rest wrist joint
angle) is moved in Fig. 5.19, while it is unchanged in Fig. 5.20. This is the slight
difference in limit cycle between peripheral oscillation and central oscillation.
300
no inertial load
250
200
transient period
150
inertial load on
100
50
-50
-100
-150
-200
40 42 44 46 48 50 52 54 56 58
time [sec]
Fig. 5.20 Simulation results on inertial load test on central tremor in phase plane, and two limit
cycles are observed. Center of limit cycle does not move after inertial load is put on
While the tremor frequency information cannot be exhibited in phase plane, so limit
cycle behavior cannot identify the origin of tremor in inertial load test.
It should be noted that the sensory feedback to central neural oscillator is not
considered in the above simulation. If the sensory feedback is considered, the
central oscillation is coupled with peripheral oscillation, most results achieved
should be reconsidered (Zhang et al. 2009). This is why there are some different and
even controversial conclusions drawn in previous literature.
5.4 Applications for Tremor Suppression
From the simulation point of view, we find that the musculoskeletal model is a very
useful tool to study the inner mechanism of tremor, especially if it is combined with
some neural models in the nervous system. Nevertheless, it may also provide help
for assistive tremor suppression technology, such as exoskeleton or functional
electrical stimulation (FES). For example, if FES technique is used, the assistive
system can be illustrated by block diagram in Fig. 5.21. The basic idea of such a
FES system is to reciprocally stimulate extensor and flexor around a joint with anti-
phase pattern according to the original tremulous EMG pattern of the antagonist
muscles. It means that FES makes the antagonist muscle generate an appropriate
counteractive force, thus the tremulous motion of concerned joint is suppressed.
Fig. 5.21 Basic idea of pathological tremor suppression via FES
In a case study, a full FES control system for tremor suppression can be
developed as shown in Fig. 5.22, where the musculoskeletal system is a controlled
plant (Zhang et al. 2011). In order to evaluate the performance of the control system,
a musculoskeletal model can be used in simulation study before real clinical experi-
ments on patients. A comprehensive musculoskeletal model can enhance the design
of a better FES controller. For such a musculoskeletal model in this paradigm, there
should be three types of inputs sending to the muscle model (see Fig. 5.23): volun-
tary EMG signal, tremulous EMG signal, and artificial electrical pulses (i.e., FES).
The controlled variables are the intensity and pattern of artificial electrical pulses.
However, the FES assistive technology only treats the symptoms but not the
cause of tremor and the tremorogenic activation still exists. So it is only a palliative
treatment in nature.
It is known that the deep brain stimulation (DBS) technique has achieved
successes in selected cases (see also other chapters dealing with this technique). It
can successfully block some tremors caused by central oscillation. However, if the
tremor is at least partly due to peripheral oscillations, DBS is obviously inadequate.
DBS targets specific areas of the CNS, while FES targets the peripheral nervous
Fig. 5.22 Schematic diagram of a FES control system for pathological tremor attenuation via FES
on wrist joint. Surface EMG from extensor (ECRL) and flexor (FCU) is used as biofeedback to
make the feedback controller have adaptive ability. Feedback controller performs the online tuning
of the stimulation patterns with motion information
Fig. 5.23 The role of a musculoskeletal model in assistive tremor suppression system via FES
system in skeletal muscles. Compared with DBS, we speculate that FES might
reduce peripheral tremor, but this needs to be demonstrated by clinical studies. It is
reported that the mechanical or electrical stimulation to the peripheral system may
change the inner mechanism of tremor (Jobges et al. 2002; Mones and Weiss 1969).
As we know, the reflex loops such as Renshaw cells, Golgi tendon organs and
muscle spindles play important roles in the tremor pathogenesis, and our simulation
study has already confirmed it. If these reflex loops can be stimulated accurately at
a microscopic level, it could be possible to eradicate certain tremors.
Although this idea is possible in theory, it is impractical in reality at present. The
big problem is that the FES technique (especially surface FES) is generally applied
at a macroscopic level. When a muscle is stimulated, not only reflex loops but also
many motoneurons fire as shown in Fig. 5.1. The FES impact on motoneurons is
probably much stronger than that on reflex loops, so the role of reflex loops is totally
overwhelmed. In other words, noninvasive FES cannot provide the stimulation to
the targeted reflex loops in a controlled or quantified way at present. In future, with the
development of nanotechnology and invasive micro-FES technique, this interesting
idea might be realized.
5.5 Conclusion and Future Work
In this chapter, the roles and functions of musculoskeletal models in appraisal of

tremor are presented. Based on a musculoskeletal model, the identification of tremor
origin is illustrated and some previous hypothesis is verified. The musculoskeletal
model is a very useful tool to investigate the inner tremor mechanism. Moreover, it
could also be used to test the performance of tremor suppression strategies and
enhance the assistive system design. However, the musculoskeletal model involved
is only based on single joint of one DOF with one/two muscles. In the future, a
musculoskeletal model based on the joints of multiple DOFs including multiple
muscles and skeletons in three-dimensional space is expected to be developed,
because such a model is closer to the reality.
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Part II
The Various Forms
of Tremor in Clinical Practice:
Presentation and Mechanisms
Chapter 6
Physiologic Tremor
Rodger J. Elble
Keywords Physiologic tremor • Accelerometry • Electromyography • Oscillation

• Stretch reflex • Biomechanics
Physiologic tremor is barely visible to the unaided eye unless it is enhanced by fatigue,
anxiety, or a medication (e.g., thyroxin and beta-adrenergic drugs). Consequently, the
study of physiologic tremor requires the use of sensitive motion transducers such as
miniature accelerometers, gyroscopic angular velocity transducers, or force transducers.
Muscle activity is recorded electromyographically, using skin electrodes for gross
motor activity and needle electrodes for single motor unit activity (Elble and Deuschl
2002). Motion transducer and electromyographic (EMG) signals are usually recorded
digitally with a computer and analyzed using spectral (Fourier) techniques to deter-
mine the amplitude and frequency of tremor and the coherence (linear correlation
squared) between tremor and EMG activity. These electrophysiologic methods are
also used to quantify the effect of mass (inertial) and spring (elastic) loading on tremor
frequency. Using these methods, investigators have demonstrated mechanical-reflex
and central-neurogenic mechanisms of physiologic tremor.
6.1 Mechanical-Reflex Tremor
Normal mechanical-reflex oscillation is the principal component of physiologic

tremor and is invariably present in tremor recordings (Elble and Randall 1978; Fox
and Randall 1970; Stiles 1976). This oscillation is so named because it emerges
R.J. Elble, M.D., Ph.D. (*)

Department of Neurology, Southern Illinois University School of Medicine, P.O. Box 19643,
Springfield, IL 62794-9643, USA
e-mail: relble@siumed.edu
112 R.J. Elble
Fig. 6.1 Fourier power spectra of wrist (hand) tremor and rectified-filtered extensor carpi radialis
brevis EMG with and without a 300-g load attached to the dorsal surface of the horizontally
extended hand. The forearm was supported, so motion was restricted to the wrist. The EMG spec-
tra are statistically flat, indicating no entrainment of motor unit activity at the frequency of tremor.
Tremor frequency decreased with mass (inertial) loading
primarily from the inertial, viscous, and elastic properties of the body. Perturbations
to our musculoskeletal system produce damped oscillations at a frequency w determined
by the equation ω = K / I , where K is the stiffness of the joint and I is the inertia.
Under normal circumstances, the response of somatosensory receptors (e.g., muscle
spindles) to the mechanical oscillations of physiologic tremor is too weak to entrain
motoneurons at the frequency of tremor (Hagbarth and Young 1979; Young et al. 1975).
Consequently, the EMG and muscle force are not modulated at the frequency of tremor,
and the rectified-filtered EMG spectrum is statistically flat (Fig. 6.1).
Normal elbow tremor has a frequency 3–5 Hz that is lower than the 7–10 Hz
frequency of wrist tremor (Fig. 6.1) because the moment of inertia of forearm and
hand, rotating about the elbow, is much greater than that of the hand rotating about
the wrist (Elble and Randall 1978; Fox and Randall 1970; Stiles 1976). Similarly, a
finger has much less mass (inertia) than the entire hand or forearm, so the frequency
of metacarpophalangeal joint tremor is 17–30 Hz. Adding mass to a limb decreases
tremor frequency, and additional stiffness K increases frequency in proportion to
K / I (Takanokura and Sakamoto 2005). Similarly, voluntary co-contraction of
the muscles about a joint produces a slight increase in tremor frequency due to
increased joint stiffness, and gradual relaxation of the joint reduces the frequency of
mechanical-reflex tremor.
6 Physiologic Tremor 113
Fig. 6.2 Recordings of head acceleration in the sagittal plane (upper trace) and the electrocardio-
gram (lower trace). The normal volunteer was seated in a chair with back supported. Following
each QRS complex, there is a sharp perturbation of the head (arrows) and subsequent oscillation
The musculoskeletal system does not oscillate in the absence of exogenous or

endogenous forces or perturbations. Mechanical-reflex tremor occurs in response to
irregularities in muscle contraction, vibrations produced by cardiac systole, and
external perturbations (e.g., someone bumping the limb) (Elble and Randall 1978).
Steady voluntary muscle contractions are generally produced by orderly motor
unit recruitment and little or no motor unit synchronization or entrainment, result-
ing in a fairly smooth EMG interference pattern and muscle force. However, such
muscle contractions are not perfectly smooth, and normal irregularities in motor
unit firing and recruitment provide a broad-frequency forcing to the involved limb
and any load that the limb may carry. These irregularities in force cause low-amplitude
damped mechanical oscillations that are not associated with motor-unit entrainment
at the frequency of tremor unless the oscillations become large enough to induce
stretch-reflex modulation of motor-unit discharge (e.g., resulting from the limb
being bumped) or unless the sensitivity of the reflex arc is increased by such factors
as drugs, fatigue, or anxiety (e.g., adrenaline) (Hagbarth and Young 1979; Logigian
et al. 1988; Young et al. 1975). In the absence of muscle contraction, passive
mechanical oscillation still occurs in response to mechanical vibrations caused by
the ejection of blood at cardiac systole (Elble and Randall 1978; Marsden et al.
1969). This cardioballistic forcing accounts for nearly all of physiologic tremor at
rest and is the principal component of normal head tremor at rest and during steady
posture (Fig. 6.2).
6.2 Central Neurogenic Tremor
In contrast to normal mechanical-reflex tremor, central-neurogenic tremor is always

associated with a modulation of motor unit activity, even when this tremor is much
smaller than the mechanical-reflex oscillation (Fig. 6.3). Central neurogenic tremor
114 R.J. Elble
Fig. 6.3 Fourier power spectral of wrist (hand) tremor and rectified-filtered extensor carpi radialis
extended hand. The forearm was supported, so motion was restricted to the wrist. With no mass
load, there is a single peak in the tremor and EMG spectra. Mass loading reduced the frequency of
the mechanical-reflex (MR) oscillation and produced separation of the mechanical-reflex oscilla-
tion (MR) and 8- to 12-Hz tremor (arrow) into two spectral peaks. Note that the 8- to 12-Hz EMG
peak is much larger than the MR peak even though the 8- to 12-Hz tremor is much smaller than the
MR tremor
in normal people occurs at frequencies of 8–12 Hz and at 15–30 Hz (Baker et al.

1999; Elble and Randall 1976; Halliday et al. 1999). The 8- to 12-Hz tremor is the
stronger of the two oscillations, and the 15–30 Hz is difficult to record except in
finger tremor. The frequency bands of both oscillations are not a function of limb
mechanics (inertia and stiffness) or reflex loop time, hence the belief that these
oscillations emerge from networks within central nervous system.
In most individuals, the 8- to 12-Hz component of physiologic tremor is small
and intermittent unless the tremor is enhanced with fatigue or beta-adrenergic ago-
nists, and even then, some patients do not exhibit 8- to 12-Hz tremor during the
maintenance of a steady posture. However, nearly all people exhibit 8- to 12-Hz
bursts of EMG during slow voluntary movements, particularly in the wrist and
finger extensors during slow wrist or finger flexion (Wessberg and Vallbo 1996).
Thus, there is a tendency for 8- to 12-Hz motor unit entrainment to occur in
everyone, but this tendency is too weak in most healthy adults to produce an EMG
spectral peak during steady horizontal extension of the hand or finger.
Motor units participating in the 8- to 12-Hz tremor are entrained at 8–12 Hz,
regardless of their mean firing frequency (Elble and Randall 1976). The frequency
of this tremor is not reduced by inertial loading and is independent of stretch reflex
loop time. There is now convincing evidence that this component of physiologic
tremor emerges from spinal and supraspinal transcortical pathways (Köster et al.
1998; Raethjen et al. 2002, 2004).
In a study of finger tremor, Halliday and coworkers demonstrated the presence of
15- to 30-Hz motor unit entrainment that was estimated to explain about 20% of
finger tremor in this frequency band (Halliday et al. 1999). The contribution of
15- to 30-Hz motor unit entrainment to tremor in body parts with greater inertia
(e.g., hand, forearm) is much smaller, and the strength of this motor unit entrain-
ment is much weaker than in the 8- to 12-Hz tremor. This component of physiologic
tremor is therefore relatively insignificant and is believed to emerge from cortical
rhythmicity (Baker et al. 1997, 1999; Conway et al. 1995; Halliday et al. 1998;
Salenius et al. 1997).
6.2.1 Enhanced Physiologic Tremor
Limb ischemia sufficient to suppress the stretch reflex causes a slight reduction in
normal mechanical-reflex tremor, so the stretch reflex appears to contribute little to
the control of physiologic postural tremor. As already discussed, there is little or no
reflex modulation of EMG in normal mechanical-reflex tremor.
Reflex-induced modulation of EMG increases when perturbations to the limb
increase the amplitude of mechanical oscillation or when stretch-reflex gain is
enhanced by fatigue, anxiety, thyrotoxicosis (Fig. 6.4), or beta-adrenergic drugs
(Logigian et al. 1988; Stiles 1976; Stiles and Hahs 1991). The amplitude of
tremor may increase by a factor of 5–20, and the mechanical oscillation becomes
associated with an entrainment of motor unit activity, produced by sensory feed-
back (Hagbarth and Young 1979; Stiles 1980). This enhanced physiologic
tremor is primarily an enhanced mechanical-reflex oscillation because the fre-
quency of tremor is proportional to K / I (Fig. 6.4). Enhanced participation
of spinal and long-loop transcortical stretch reflex pathways mediates the
entrainment of motor units.
The frequency of enhanced mechanical-reflex oscillation decreases as the
amplitude increases, possibly due to a reduction in joint stiffness with increasing
amplitude of oscillation (Agarwal and Gottlieb 1984; Gottlieb and Agarwal 1977;
Lakie et al. 1984; Milner and Cloutier 1998; Zahalak and Pramod 1985). The
reduction in tremor frequency with increased amplitude produces a greater phase
advance of sensory feedback on tremor, resulting in greater reflex damping (Stiles
and Hahs 1991).
People with deafferented limbs exhibit broad-frequency arrhythmic fluctuations
in limb position when their tremor is enhanced, but they do not exhibit the very
rhythmic tremor and motor unit entrainment seen in normal people with enhanced
mechanical-reflex tremor (Sanes 1985). Thus, sensory feedback tends to entrain or
concentrate tremor at a particular frequency, resulting in rhythmic oscillation, but
116 R.J. Elble
Fig. 6.4 Fourier power spectral of wrist (hand) tremor and rectified-filtered extensor carpi radialis
extended hand. The forearm was supported, so motion was restricted to the wrist. This is a classic
example of enhanced mechanical-reflex tremor. There is entrainment of EMG activity at the tremor
frequency, which decreased with mass loading
appears to be relatively ineffective in controlling tremor amplitude. In other words,

greater stretch-reflex involvement appears to increase physiologic tremor. The
stretch-reflex seems to destabilize the wrist and similar joints at frequencies of 7 Hz
or greater (Milner and Cloutier 1998).
Central neurogenic tremor is enhanced by the same factors that enhance
mechanical-reflex tremor, but the frequency of enhanced central neurogenic tremor
is not proportional to K / I , nor is it a function of reflex loop time. Without enhance-
ment, the motor unit entrainment of central neurogenic tremor is often very intermit-
tent, and the intermittent bursts of EMG activity do little more that perturb the
mechanical-reflex system, producing damped mechanical oscillations that induce a
reflex modulation of motor unit activity at a frequency that is sensitive to mechanical
loading (Deuschl et al. 1994; Elble 1991). Consequently, the presence of central neu-
rogenic oscillation may be difficult to appreciate in the absence of enhancement.
Table 6.1 Properties of tremor in healthy people

Enhanced
Mechanical reflex Central neurogenic mechanical reflex
Amplitude Invisible or barely visible; Invisible or barely Less than 1 cm; may
not disabling visible; not interfere with fine
disabling motor control
Frequency A function of joint stiffness Frequency does not A function of joint
and inertia. Reduced by vary with limb stiffness and inertia.
adding inertia to the inertia or reflex Reduced by adding
limb. Increased arc length inertia to the limb.
by adding stiffness Increased by adding
stiffness. Influenced
by reflex arc length
Electromyogram No motor unit entrainment Motor unit entrainment Motor unit entrainment
or synchronization at 8–12 Hz and at at the frequency of
15–30 Hz tremor
6.3 Summary
The properties of tremor in healthy adults and adolescents are summarized in

Table 6.1. These components of physiologic tremor and their relative importance
have not been studied adequately in children and infants (Marshall 1959).
In a one-minute recording of hand (wrist) tremor during steady horizontal pos-
ture, about 60% of adults exhibit only a pure mechanical resonant tremor with no
evidence of motor unit entrainment, about 30% exhibit some evidence of motor-unit
entrainment at the mechanical resonant frequency, and about 10% exhibit a central-
neurogenic tremor at 8–12 Hz in addition to mechanical-reflex oscillation (Elble
2003). Motor-unit entrainment at the mechanical resonant frequency and the 8- to
12-Hz central neurogenic tremor become more evident with fatigue, anxiety, and
drugs or hormones that enhance reflex sensitivity. Physiologic tremor at rest (i.e., in
the absence of muscle activation) is primarily a mechanical resonant oscillation in
response to cardioballistic oscillations.
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Chapter 7
Rest Tremor
Keywords Rest • Frequency • Parkinson’s disease • Cortico–subthalamo–pallido–

thalamic loop • Dopamine • Levodopa • Dopamine agonists • Anticholinergic
7.1 Definition and Clinical Description
By definition, rest tremor is an involuntary oscillation occurring while the body seg-
ment is maintained at rest, fully supported against gravity. To look for a rest tremor,
the patient is seated with the upper limbs relaxed and the forearms on the thighs, or
the patient is lying horizontally in complete repose. Rest tremor is typically in the
3–6 Hz frequency range (Fig. 7.1) and may reach high levels of severity. Rest tremor
is usually asymmetrical, in general starting distally in the arms and legs. Typically,
tremor in the upper limbs reminds the “pill rolling” movement. Lips and jaw can be
affected, with a rhythmic clicking of teeth. Head and trunk are usually spared. Rest
tremor may disappear or subside with action (posture, movement, maintaining an
isometric force, exerting a specific task) and is associated with reciprocal activation
in antagonistic muscles. In some cases, patients can reduce the tremor by holding
one hand with the other or crossing the legs. Rest tremor often increases with mental
stress (i.e. counting backwards) or contralateral motion (Froment manoeuvre).
However, this feature is not specific. Rest tremor disappears during sleep, as most
tremulous disorders.
A physiological rest tremor may be present (see Chap. 8), but in this case the
acceleration power spectrum does not show a clear dominant peak in most cases,
and its magnitude is low (the tremor is barely perceptible). The enhanced physio-
logical tremor may worsen with emotions or volitional movements.

REST TREMOR
PARKINSON’S DISEASE
Acc - Right
FCR - Right
0.2 V Alternating EMG pattern
ECR - Right
30 sec
Fig. 7.1 Rest tremor in a patient with idiopathic Parkinson’s disease. Dopamine transporter
SPECT confirmed a decreased uptake in striatum in this patient. Single axis accelerometer (Acc)
fixed on right index. Surface EMG recordings at the level of the right flexor carpi radialis (FCR)
and extensor carpi radialis (ECR) show an alternating EMG pattern in the agonist/antagonist EMG
pair (dotted lines show that bursts of EMG in the FCR muscle occur when the ECR muscle is
electrically silent). Note the fluctuation over time of the intensities of burst of EMG activities
Rest tremor is a cause of social embarrassment, interfering with dexterous hand

movements and causing various degrees of disability. However, because rest tremor
often decreases with action, it causes a greater social embarrassment than a functional
deficit during daily life. The patient may not report tremor himself at the beginning.
Rather a family member may be the first to note the involuntary movement. In other
cases, the patient may feel a “trembling sensation” at the very beginning in the absence
of visible contractions. Anxiety and stress exacerbate rest tremor, and a very mild tremor
may be brought up by stress during the office interview.
7.2 Disorders Associated with Rest Tremor
Rest tremor is mainly associated with Parkinson’s disease (PD) and related disor-
ders. The term “parkinsonism” refers to a symptomatology characterized by rest
tremor, rigidity and bradykinesia that is not in the frame of PD (atypical Parkinson’s
disease). The causes of parkinsonism include extrapyramidal neurodegenerative
diseases such as Progressive supranuclear palsy (PSP), Multiple Systemic Atrophy
(MSA), CorticoBasal Degeneration (CBD) or Lewy Body Disease (LBD), rare
genetic forms of PD, metabolic disorders such as Wilson’s disease (Figs. 7.2 and
7.3), vascular damage, drugs, toxic agents such as neuroleptics or antidepressants
and rarely antibiotics (cotrimoxazole, amphotericin B), brain infections (especially
7 Rest Tremor 123
REST TREMOR –WILSON’S DISEASE
CH1 Y
CH2 Y
CH3 Y
CH4 Y
Z
0.05 a.u.
5 sec
Fig. 7.2 Rest tremor affecting the whole upper limb in a patient with Wilson’s disease. Triaxial
(X,Y,Z) accelerometers affixed along the left upper limb from index (upper traces) to shoulder
(lower traces). A distal and proximal tremor is clearly visible. This patient also exhibited a postural
and kinetic tremor. The patient had very low serum ceruloplasmin levels and increased excretion
of copper in urine
abscesses), and brain trauma (see also dementia pugilistica) (Abbruzzese 2003).
Dystonia may present with an atypical rest tremor, often with a jerky component.
PD is a progressive neurodegenerative disorder originally described by James
Parkinson in 1817 (see also Chaps. 4 and 22). Distal resting tremor (“pill-rolling”)
of 3–6 Hz, rigidity (sustained increase of resistance throughout the range of passive
movement at a joint), bradykinesia, impaired postural reflexes and asymmetrical
onset are cardinal features of PD. The parkinsonian tremor is typically asymmetri-
cal, at least initially, and affects the upper limb before involving the ipsilateral leg
after a period of about 2 years. Tremor of the lips, jaw or tongue may also occur.
Head or voice tremor is rare, unlike in essential tremor (ET). A postural tremor is
also present in most cases, with heterogeneity in terms of severity (Habib-ur-
Rehman 2000). However, kinetic tremor is uncommon in PD (Kraus et al. 2006).
Isolated lower leg rest tremor is an uncommon symptom of neurological disease and
is considered as an unusual presentation of PD. It should raise suspicion for MSA,
psychogenic tremor or drug-induced parkinsonism (Hellmann et al. 2010).
PD presentation is heterogeneous and clinicians often distinguish a “tremor-
dominant” from an “akineto-rigid” form mainly because this phenotypic distinction
might predict the clinical course and the response to medications (Foltynie et al.
2002). The clinical progression is more rapid and the mental status declines more
rapidly in the akineto-rigid form.
TIME - FREQUENCY ANALYSIS - HAND

3.5 3
3
2.5
2.5
2
PSD
1.5
2
1
0.5
1.5
0
0
5 1
10
15 0.5
20
25
time (sec) 30 40
10 20
30
freq (Hz)
TIME - FREQUENCY ANALYSIS - ELBOW

2.5 2
2 1.8
1.5 1.6
PSD
1 1.4
1.2
0.5
1
0
0 0.8
5 0.6
10
0.4
15
20 0.2
25
time (sec) 30 40
10 20
30
freq (Hz)
Fig. 7.3 Time–frequency analysis of the rest tremor illustrated in Fig. 7.2. A 4-Hz tremor is
identified on power spectra. The generator is relatively stable over time. Windows of 1 s duration
are used
7 Rest Tremor 125
Fig. 7.4 Axial flair images show multiple hypersignals in a patient with vascular parkinsonism
exhibiting a rest tremor on the left side. R: right
Other well-known clinical signs of PD include persistence of primitive reflexes

(glabellar reflex, palmar grasp reflex) and micrographia (small handwriting).
Parkinsonian patients often present an abnormal posture called camptocormia (rang-
ing from mild to severe) characterized by an excessive anterior flexion of the spine
(Bonneville et al. 2008).
Response to an adequate therapeutic challenge of levodopa or a dopamine ago-
nist is one of the key features for the diagnosis (Guidelines for the diagnosis of
Parkinson’s disease 2003). However, a positive response to levodopa can also be
observed in MSA patients (Wüllner et al. 2007).
PD also includes non-motor signs and symptoms, involving cognitive and auto-
nomic functions. Decreased scores in cognitive tests are associated with greater
impairment in motor performances (Verbaan et al. 2007). Among the symptoms
autonomic failure, orthostatic dizziness, bladder dysfunction and constipation are
considered to have great impact on daily life (Magerkurth et al. 2005). A decreased
olfactory function has been reported.
Vascular parkinsonism (VP), accounting for 4.4–12% of all cases of parkin-
sonism, is considered as a distinct clinicopathological entity due to cerebrovascular
disease. Parkinsonism tends to be bilaterally symmetrical, affecting the lower limbs
more than the upper limbs in some patients (Thanvi et al. 2005). Patients with VP
are usually older than PD patients, with a shorter duration of illness, often present-
ing with symmetrical gait difficulties. Rest tremor is often mild. VP patients are less
responsive to levodopa, and more prone to postural instability, falls and dementia.
Concomitant pyramidal signs, pseudobulbar palsy and incontinence are not rare.
Structural neuroimaging is abnormal in VP (Kalra et al. 2010; Fig. 7.4).
Rest tremor may also be associated with Essential Tremor (see Chap. 10), espe-
cially in advanced cases (about 15% of advanced ET present a rest tremor), thus
posing challenges in the diagnosis. Nisticò and colleagues proposed that the
electromyographic (EMG) pattern of rest tremor may help to differentiate PD from
ET. In fact, by comparing the electrophysiological parameters of tremor in PD
patients and in ET patients with rest tremor, the authors found that the amplitude of
rest tremor amplitude in PD patients was significantly higher as compared to patients
with ET, whereas burst duration and frequency were significantly higher in the ET
group. All patients with ET had a synchronous EMG pattern (co-contractions
between agonist and antagonist EMG bursts) whereas PD patients showed an alter-
nating pattern between agonist and antagonist muscles (Nisticò et al. 2011; see also
Fig. 7.1). Rest tremor in ET is not associated with Lewy body pathology, indicating
that the pathogenesis differs from a deficit in dopamine (Louis et al. 2011). SPECT
studies show normal striatal dopamine uptake in ET with rest tremor, unlike in PD
(Marshall et al. 2009).
Rest tremor may occur in combination with other presentations of tremor, for
instance in the case of midbrain tremor, also called Holmes’ tremor or rubral tremor.
Midbrain tremor is characterized by a combination of 2–5 Hz rest, postural and
kinetic tremor (Hopfensperger et al. 1995; Findley and Koller 1995), affecting pre-
dominantly proximal segments in upper limbs. Midbrain tremor often results from
a combined lesion of the nigrostriatal and cerebellothalamic pathways around the
contralateral red nucleus (see also Chap. 1).
7.3 Pathophysiology of Rest Tremor
Three main neuronal mechanisms have been hypothesized: a cortico–subthalamo–

pallido–thalamic loop-generating tremor (see also Chap. 1), a pacemaker activity
emerging from the external pallidum and the subthalamic nucleus, and an abnormal
synchronization within the whole striato–pallido–thalamic pathway leading to a
loss of segregation (Deuschl et al. 2000).
The arguments against the hypothesis of a pure peripheral mechanism generating
rest tremor are the following (Llinas and Paré 1995):
– Rest tremor is not abolished by sectioning the dorsal roots, indicating that it does
not reflect the sole action of a pure spinal reflex loop.
– It is very difficult to reset rest tremor by a mechanical perturbation, and the phase
shift lasts for a few cycles only.
– Recordings of Ia afferents show patterns similar to the one found during a volun-
tary alternating movement.
Neurons of the VLa nucleus are rhythmically active at the frequency of tremor,
but are not sensitive to sensory feedback or voluntary movements (Llinas and Paré
1995). Importantly, the main input to the VLa neurons originates from the GPi
(Globus pallidus, internal segment), whose lesions reduce rest tremor, and VLa
neurons project to the premotor cortex. In monkeys, the neurotoxin MPTP
(1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) causes a parkinsonian syndrome
7 Rest Tremor 127
associated with changes in the patterns of neuronal discharges in the GPi and which
is abolished by subthalamic lesions (Bergman et al. 1990). The intrinsic features of
thalamic neurons, in particular the fact that their firing modes change with the
membrane potential, contribute to the genesis of rest tremor. Interactions between
cation current, low-threshold calcium conductance and changes in potassium con-
ductance trigger oscillations between 0.5 and 4 Hz in thalamic nuclei, as demon-
strated by in vitro and in vivo experiments.
Typical PD resting tremor (4–6 Hz) is associated with strong coherence between
the EMG of forearm muscles and activity in the contralateral primary motor cortex
(M1) not only at tremor frequency but also at double tremor frequency. Tremor-
related oscillatory activity within a cerebral network has been demonstrated. There
is an abnormal coupling in a cerebello–diencephalic–cortical loop, including corti-
cal motor (primary motor cortex, cingulated/supplemental motor area, lateral pre-
motor cortex) and sensory (secondary somatosensory cortex, posterior parietal
cortex) areas contralaterally to the tremor hand (Timmermann et al. 2003).
In a study on coherence in 22 subjects affected by PD, no consistent pattern
across patients was found, suggesting that rest tremor is generated by multiple oscil-
latory circuits which tend to operate on similar frequencies (Ben-Pazi et al. 2001;
Raethjen et al. 2000). PD tremor is coupled within but not between limbs. Oscillating
neurons in one or multiple localizations within the basal ganglia–thalamo–cortical
loop may cause rest tremor. The anatomy of basal ganglia loops may explain the
presence of several generators.
Force oscillations share common origins. Christakos et al. have demonstrated
that the motor unit synchrony in PD shares features with the physiological tremor
(Christakos et al. 2009). However, the authors have noted that occurrence of rhyth-
mical doublets and triplets is observed in frequencies between 5 and 7.5 Hz. These
doublets/triplets are very rarely found in healthy subjects. It is suggested that dou-
blets/triplets might be a common behaviour in Parkinson’s disease, and could cor-
respond to responses of motoneurons to a rhythmical synaptic input exhibiting
multiple local peaks per cycle. They might be specific for parkinsonian tremors,
hence the importance of identifying them in the future to test the hypothesis that
they might represent electrophysiological signatures (Christakos et al. 2009).
The analysis of the dynamics of oscillatory activity in the subthalamic nucleus
(STN) during functional neurosurgery in PD patients with rest tremor has revealed
an altered balance between beta and gamma oscillations in the motor circuits of
STN. Ratios of the beta to gamma coherence are significantly lower in periods with
stronger tremor as compared with periods of no/weak tremor. The simultaneous
recording of neuronal firing and local field potential (LFP) activity has shown that
neurons exhibiting oscillatory activity at tremor frequency are located in the dorsal
region of STN (where neurons with beta oscillatory activity are found) and that their
activity is coherent with LFP oscillations in the beta frequency range. Furthermore,
the coherence of two LFPs recorded simultaneously increased in the gamma range
with increased amplitudes of tremor (Weinberger et al. 2009). Coherence analysis
in the STN has revealed a specific topography of “tremor clusters” for rest and
postural tremors in tremor-dominant and akinetic-rigid PD (coherence at single
tremor frequency during rest in both subgroups of DP; coherence at double tremor
frequency during postural tremor only in patients with akinetic-rigid PD), suggest-
ing that symptoms in patients with tremor-dominant and akinetic-rigid PD are
related to different degrees of the same tremor mechanisms (Reck et al. 2010).
The most striking differences between parkinsonian patients and healthy sub-
jects imitating the resting tremor are a reduction of the coupling between primary
sensori-motor cortex and a diencephalic structure—most likely the thalamus—and
an enhancement of the coupling between premotor and primary sensorimotor cortex
(Pollok et al. 2004). These results indicate that the coupling of oscillatory activity
within a cerebello–diencephalic–cortical loop constitutes a basic feature of physio-
logical motor control, sustaining the hypothesis that parkinsonian resting tremor
involves oscillatory cerebro-cerebral coupling in a physiologically pre-existing
network.
The nigrostrial dopamine deficiency correlates with bradykinesia, but the corre-
lation is less clear for rest tremor. A specific pattern of neuronal loss in the substan-
tia nigra of PD patients with rest tremor has been reported (Jellinger 1999). Autopsy
studies in PD and controls have shown that dopamine (DA) levels in the external
globus pallidus (GPe) of normal brains are greater than in the GPi. In PD the mean
loss of DA is marked (−82%) in GPe and moderate (−51%) in Gpi. However, DA
levels are nearly normal in the ventral (rostral and caudal) GPi of PD cases with
prominent tremor. There is a marked loss of DA (−89%) in the caudate and a severe
loss (−98.4%) in the putamen in PD. The pattern of pallidal DA loss does not match
the putaminal DA loss. The possible functional disequilibrium between GABAergic
and DAergic influences the balance in favour of DA in the caudoventral parts of the
Gpi, which may contribute to rest tremor in tremor dominant and classic PD cases
(Rajput et al. 2008).
The involvement of the cerebellum and cerebello–thalamo–cortical circuit in the
pathogenesis of parkinsonian rest tremor has been highlighted during the last decade.
An active contribution of the cerebellum and the cerebello–thalamo–cortical projec-
tions in the pathogenesis of parkinsonian rest tremor has been recently suggested on
the basis of voxel-based morphometry (VBM). This technique has revealed morpho-
logical changes in the cerebellum of PD patients with rest tremor, when compared
with PD patients without rest tremor (Benninger et al. 2009). Grey matter volume is
decreased in the right quadrangular lobe and declive of the cerebellum in PD with
tremor as compared to those without. Interestingly, there is a correlation between rest
tremor and an increased metabolic and oscillatory activity in the cerebellum, thala-
mus and motor cortex (Antonini et al. 1998). Anatomically, the posterior quadrangu-
lar lobule (lobule VI) of the cerebellar cortex projects indirectly into the hand area of
the motor cortex (Kelly and Strick 2003). Vim, a target of cerebellar projections, is
an efficacious target to suppress rest tremor with deep brain stimulation (DBS, see
Chap. 25). This is another argument for a role of cerebellar projections in the patho-
genesis of rest tremor. Still, additional studies are required to clarify the contribution
of the cerebellar circuitry in rest tremor and possible therapeutical interventions.
Alpha-synuclein aggregates in Purkinje neurons and cerebellar glial cells have been
shown, but their clinical correlate remains unclear (Piao et al. 2003).
7 Rest Tremor 129
7.4 Therapy of Rest Tremor
The therapy of rest tremor is often based on anticholinergics (biperiden 2–6 mg/day,
trihexyphenidyl 5–10 mg/day) in the absence of contra-indications. However, the
assumption that anticholinergics exert a selective effect upon rest tremor is not
based on scientific evidence. The efficacy is similar to levodopa (see below), but
safety profile of anticholinergic agents is lower. Therefore, they may be used either
as monotherapy in young patients with predominant PD rest tremor, or as adjunctive
therapy to levodopa (Jiménez and Vingerhoets 2012).
Levodopa-based medications (Levodopa + carbidopa; Levodopa + COMT inhibi-
tors) and dopamine agonists (pramipexole, ropinirole) are beneficial to reduce tremor
intensity. Once a day sustained release preparations and transdermal applications of
dopaminergic therapies are increasingly used. Dopamine agonists are very likely
associated with a significant delay in the rate of decline of nigrostriatal function (The
Parkinson Study Group 2002; Whone et al. 2003). Dopamine agonists reduce levodopa
refractory rest tremor when used as adjunct treatment in fluctuating patients (Fishman
2008). Whereas rest tremor in PD is usually improved by dopaminergic drugs, the
response of the postural component is usually relatively poor (Raethjen et al. 2005).
Although the response of bradykinesia and rigidity to levodopa is excellent in PD, rest
tremor responds less and the interindividual benefits are variable. Responders show a
response up to 50% of tremor reduction (Henderson et al. 1994).
Inhibitors of monoamine oxidase B (selegiline 10 mg/day, rasagiline 0.5–1 mg/
day) as adjunctive therapies of levodopa reduce tremor intensity (Parkinson Study
Group 2005). The effects of amantadine are unclear. The sparing effect upon doses
of levodopa remains doubtful.
Clozapine may be useful in resistant parkinsonian tremor, but requires a close
hematologic follow-up due to the risk of agranulocytosis.
Other therapeutic options include beta-blockers such as propranolol, primidone
and zonizamide. However, the effectiveness of propranolol in parkinsonian tremor
remains a matter of debate (Crosby et al. 2003).
Surgical procedures such as thalamotomy and DBS (targets: Vim, GPi, STN) are
discussed elsewhere in the book. These techniques may decrease substantially rest
tremor, providing a long-lasting alleviation (Jiménez and Vingerhoets 2012). They are
proposed in advanced cases refractory to medications. Rest tremor usually responds
better to surgery than to drugs. Gamma-knife thalamotomy is under evaluation.
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Chapter 8
Postural Tremors
Jean-François Daneault, Benoit Carignan, Fariborz Rahimi,

Abbas F. Sadikot, and Christian Duval
Keywords Posture • Physiological tremor • Enhanced physiological tremor

• Essential tremor • Parkinson tremor
8.1 Introduction
Tremor can be observed in every individual. Its amplitude and frequency is dependent
on mechanical as well as neural components, and can be modified by disease. The
objective of the current chapter is to discuss the specific characteristics of postural
tremor in healthy controls and in different pathologies. We believe that postural
tremor deserves some attention since limbs are rarely completely at rest. Accordingly,
postural tremor may hide important information about the state of the system.
Furthermore, in some pathologies, postural and rest tremor may present different
characteristics. Identifying the origins of postural tremor and its relationship with
rest tremor characteristics may be helpful for diagnostic purposes. We will discuss
J.-F. Daneault, Ph.D. • A.F. Sadikot, M.D., Ph.D., FRCSC

Department of Neurology and Neurosurgery, Montreal Neurological Institute,
McGill University, Montreal, QC, Canada
B. Carignan, Ph.D.
Département des Sciences Biologiques, Université du Québec à Montréal,
Montreal, QC, Canada
F. Rahimi, Ph.D.
Department of Electrical Engineering, University of Waterloo, Waterloo, ON, Canada
Department of Clinical Neurological Sciences, London Health Sciences Centre,
University Hospital of Western Ontario, London, ON, Canada
C. Duval, Ph.D. (*)
Département de Kinanthropologie, Université du Québec à Montréal,
C.P. 8888 Succ. Centre-Ville, Montreal, QC, Canada H3C 3P8
e-mail: duval.christian@uqam.ca
134 J.-F. Daneault et al.
the possible origins of those tremor oscillations, as well as current controversies.

While we acknowledge that tremor, either physiological or pathological, can be
observed in the lower limbs, head and even trunk just as often as in the upper limbs,
the present chapter will focus on finger or hand tremor. More specifically, we will
compare some of the most common postural tremors with their resting tremor
equivalents. Physiological tremor (PT), enhanced physiological tremor (EPT) and
essential tremor (ET) will be discussed. Next, we will consider the possible link
between these different types of postural tremors. Finally, we will discuss postural
tremor in the context of Parkinson’s disease (PD) and its possible relation to ET.
8.2 Postural Physiological Tremor
Postural PT can be described as involuntary oscillations of a limb with sinusoidal

properties (Elble and Koller 1990). These oscillations are present in every limb but
are of such small amplitude that they are difficult to see with the naked eye. In young
healthy adults, postural PT amplitude of the finger normally ranges from 0.1 to
0.2 mm (Duval and Jones 2005; Carignan et al. 2010). Raethjen et al. (2000) demon-
strated that age does not seem to influence postural PT amplitude, but modifies the
median power frequency of postural PT. Indeed, other studies have also demonstrated
that median power frequency of postural PT decreases with advancing age (Marshall
1961; Marsden et al. 1969; Wade et al. 1982; Birmingham et al. 1985; Lakie 1995).
Postural PT comprises oscillations between 1 and 40 Hz (Brumlik 1962; Allum et al.
1978; Isokawa-Akesson and Komisaruk 1985), but when examining the acceleration
power spectrum of postural PT of the finger, one may observe a predominance of
oscillations between 16 and 30 Hz (Carignan et al. 2010), as well as a peak between
8 and 12 Hz (Fig. 8.1). However, the systematic presence of the 8–12 Hz peak is still
controversial. For instance, Raethjen et al. (2004) observed this peak in the majority
of their subjects whereas another study observed the 8–12 Hz peak in less than 20%
of their subjects (Raethjen et al. 2000). Another study from the same group failed to
observe this peak in a majority of subjects and demonstrated that the majority of
power lies within the oscillations located between 16 and 30 Hz in the acceleration
power spectrum (Carignan et al. 2010). On the other hand, when oscillations located
between 8 and 12 Hz are removed from finger tremor acceleration power spectrum,
close to 93% of total power remains (Carignan et al. 2010). This indicates that when
examining the acceleration of postural finger PT, whether a peak between 8 and
12 Hz can be observed or not has little impact on the overall acceleration power.
Rest PT shares many of the characteristics of postural PT, but some differences
exist. The amplitude of rest PT is significantly smaller than of postural PT. When
examining the acceleration power spectrum of rest PT, however, oscillations between
1 and 40 Hz are still present but the relative distribution of power of these oscillations
diverges from postural PT. The acceleration power spectrum of rest PT usually does
not present any dominant oscillations. Thus, a relatively flatter power spectrum can be
observed (Fig. 8.1). The differences between postural and rest PT may
stem largely from the origin of the oscillations that drive those two types of tremor.
8 Postural Tremors 135
Fig. 8.1 Finger tremor was recorded from a 43-year-old female without any known neurological
disorders. A laser displacement sensor was used to measure tremor during a postural condition, a
rest condition and a postural condition while a mechanical load (70g) was added to the finger. Top:
example of finger tremor displacement over a 6 s window within a 60 s trial. Bottom: acceleration
power spectrums of the complete trial from which each of the above examples were taken. Here
the 8–12 Hz peak is identifiable in the postural condition. Note that the y-axis of the power spec-
trum represents the percentage of total power for each frequency; with a resolution of 0.2 Hz. More
details on the analysis can be obtained from Carignan et al. (2010) and Daneault et al. (2010)
While both rest and postural PT probably stem from the same systems, it is reasonable
to suggest that it is the different level of activation within those systems that causes the
inherent differences. The oscillations can be divided into two categories: those stem-
ming from central origins and those that are derived from mechanical reflex sources.
Studies have shown that for index finger tremor, frequencies below 7 Hz are associ-
ated with reflex activities influenced by the mechanical properties of the limb involved
(van Buskirk et al. 1966; Yap and Boshes 1967). Mechanical properties, such as
unfused motor-unit activity (De Luca and Erim 1994) or sensorimotor control pro-
cesses (Morrison et al. 2006), are inherently different while maintaining posture when
compared to rest. This can explain some of the differences observed between postural
and rest PT. The ballistocardiac impulse is also involved in the generation of low-
frequency oscillations (Marsden et al. 1969; Elble and Koller 1990; Wade et al. 1982;
Lakie et al. 1986). However, it has recently been demonstrated that this phenomenon
only accounts minimally for the low-frequency oscillations in rest PT (Morrison and
Newell 2000). Since postural PT stems from higher activation of other systems, the
minimal implication of the ballistocardiac impulse to rest PT is even less significant
in postural PT. As for frequencies between 8 and 12 Hz, they are associated with cen-
trally originating oscillations (Lamarre et al. 1975; Llinas 1984; Koster et al. 1998;
Halliday and Redfearn 1956). The most common method to identify whether oscilla-
tions stem from central structures is to load the limb being examined. Indeed, by load-
ing the limb under study, its mechanical properties are altered. This modifies the
power spectrum (Fig. 8.1). While the frequency of the centrally generated oscillations
is unaffected by loading, their amplitude increases (Halliday and Redfearn 1956;
Marshall and Walsh 1956; Randall and Stiles 1964; Elble 1995; Vaillancourt and
Newell 2000). Thus, these oscillations should be present both during postural PT and
rest PT. Yet, the peak between 8 and 12 Hz is much more prominent in postural PT.
This can be explained by the fact that rest PT requires little activation while postural
PT requires holding the limb against gravity, i.e. there is a muscular activation. This
has previously been observed as coherence between postural PT and EMG occurs in
the 8–12 Hz frequency band (Elble and Randall 1976). The link to the central ner-
vous system is also largely based on the fact that 10 Hz oscillations were detected in
the inferior olive (Llinas and Volkind 1973; Armstrong 1974). It was suggested that
these oscillations could be transmitted directly or indirectly to the periphery by the
olivo-cerebellar (Poirier et al. 1966; Lamarre et al. 1975; Llinas 1984; Llinas and
Paré 1995) and the cerebello–thalamo–cortical tracts (Duval et al. 2000, 2005,
2006). One compelling argument for the central genesis of these oscillations is that,
in patients having undergone a thalamotomy, in addition to the elimination of the
pathological central oscillations, the 8–12 Hz component of postural PT is also
absent when tremor amplitude was normalized (Duval et al. 2000, 2005). The other
component of PT comprises the oscillations in the 16–30 Hz range, which seem to
originate from the mechanical resonance of the finger (Stiles and Randall 1967) as
well as cortical oscillations (Conway et al. 1995; McAuley et al. 1997) modulated
by the mechanical properties of the finger (Vaillancourt and Newell 2000). This
component is also affected by thalamotomy (Duval et al. 2005), which argues for
central involvement in the generation of these oscillations.
The mechanical resonance frequency of a limb (f0) has been demonstrated to be
directly proportional to the square root of its rigidity (K) (Robson 1959) and
inversely proportional to the square root of its inertia (I) (Stiles and Randall 1967):
K
f0 =
I
Since the limb’s inertia remains unchanged when examining postural and rest
PT, some of the observed changes could be due to slight changes in rigidity brought
forward by increased muscular activation. Thus, postural PT oscillations stem from
mechanical as well as central structures and are different from rest PT in terms of
amplitude and spectral characteristics, probably because the relative involvement of
the different mechanical and central components varies depending on whether the
limb is held or not against gravity.
8.3 Postural Enhanced Physiological Tremor
It was previously demonstrated that in some cases, the mechanical component of PT

can be enhanced by reflex activity (Deuschl et al. 2001; Young and Hagbarth 1980).
This phenomenon can be best observed by loading the limb while in a postural position.
Indeed, as for postural PT, the peak observed between 16 and 30 Hz in the tremor
Fig. 8.2 Top: finger tremor from a 41-year-old male presenting with clinically visible tremor was
recorded using a laser displacement sensor during a postural condition, a rest condition and a pos-
tural condition while a mechanical load (70g) was added to the finger. Bottom: acceleration power
spectra of the complete trial from which each of the above examples were taken. Note again that
the y-axis of the power spectrum represents the percentage of total power for each frequency; with
a resolution of 0.2 Hz
power spectrum shifts towards lower frequencies as the load is applied, while the
frequency of the 8–12 Hz peak remains unchanged (Fig. 8.2). Interestingly, young
individuals can present with tremor whose amplitude is slightly above normal when
assuming posture. While there is usually no prominent EMG peak in postural PT,
there is an easily identifiable 8–12 Hz EMG peak that is independent of loading in
enhanced physiological tremor (EPT) (Deuschl et al. 2001; Elble 1986), and which
could be of cortical origin (Koster et al. 1998). Since EPT is not usually a burden to
people, except in situations where precision is required, only few studies have exam-
ined its characteristics. Most studies evaluated EPT during posture (Young and
Hagbarth 1980; Deuschl et al. 2001; Koster et al. 1998; Lauk et al. 1999) and to our
knowledge only one examined it during rest (Lauk et al. 1999). Interestingly, the
prominent peak in the tremor power spectrum fades in the rest condition, resulting in
a relatively flatter curb (Fig. 8.2). Lauk et al. (1999) observed a higher coherence
between bilateral EPT during rest and posture than for PT, essential (ET) or parkin-
sonian (PD) tremor. This may indicate a common or linked central process generat-
ing these dominating oscillations. Although EPT can be induced experimentally
through muscular fatigue (Young and Hagbarth 1980), loading (Young and Hagbarth
1980; Koster et al. 1998; Gironell et al. 2004), manoeuvres influencing the stretch
reflex (Young and Hagbarth 1980), and the injection of various drugs such as adrena-
line (Marsden and Meadows 1968), isopropeterenol (Young and Hagbarth 1980) and
salbutamol (Koster et al. 1998), the pathophysiological basis of its unprovoked pres-
ence in some individuals is yet unknown. Studies using loading (Gironell et al. 2004;
Koster et al. 1998) and transcranial magnetic stimulation (Koster et al. 1998) seem to
suggest that the cortex is not involved in the generation of EPT, but that peripheral
mechanisms do play an important role in generating these oscillations. It was also sug-
gested that EPT could be an intermediate step to progress from physiological tremor to
ET which can be first identified through frequency-invariant motor unit entrainment
below 8 Hz (Elble et al. 2005); this hypothesis will be discussed in Sect. 8.5.
8.4 Postural Essential Tremor
Although Essential tremor (ET) is the most common movement disorder (Louis
2000; Louis et al. 1998b), its pathophysiology is yet to be clearly determined. ET
affects the upper-limbs in 95% of patients (Louis et al. 1998a) and it classically
occurs during posture and movement (Fig. 8.3) (Elble and Deuschl 2009; Bhidayasiri
Fig. 8.3 Graph representing an example of advanced classical ET where postural tremor can be
observed and there is no visible rest tremor. Finger tremor was recorded using a laser displacement
sensor during both a postural and a rest condition. These recordings were made from a 62-year-old
female diagnosed with ET and scheduled to undergo stereotactic neurosurgery to alleviate her
tremor. Top: example of finger tremor displacement over a 6 s window within a 30 s trial. Bottom:
velocity power spectrums of the complete trial from which each of the above examples were taken.
Note again that the y-axis of the power spectrum represents the percentage of total power for each
frequency; with a resolution of 0.2 Hz. The velocity power spectrums are displayed since double
differentiation of the displacement signal amplifies the harmonics as can already be seen from the
postural ET power spectrum (i.e. the second peak is the first upper harmonic of the dominant oscil-
lations located at 5 Hz). Note also that even though there is no visible tremor, a peak is detectable at
the same frequency as postural for rest tremor. This could indicate that although tremor is not clini-
cally detectable, abnormal oscillations can still be detected at rest in this patient with advanced ET
Fig. 8.4 Graph representing an example of advanced ET where postural tremor and rest tremor
can both be observed. Finger tremor was recorded using a laser displacement sensor during both a
postural and a rest condition. These recordings were made from an 85-year-old female diagnosed
with ET and scheduled to undergo stereotactic neurosurgery to alleviate her tremor. Top: example
of finger tremor displacement over a 6 s window within a 30 s trial. Bottom: velocity power spec-
trums of the complete trial from which each of the above examples were taken. Note again that the
y-axis of the power spectrum represents the percentage of total power for each frequency; with a
resolution of 0.2 Hz. The velocity power spectrums are displayed since double differentiation of
the displacement signal amplifies the harmonics as can already be seen from both power spectrums
(i.e. the second peak is the first upper harmonic of the dominant oscillations located at 4 Hz)
2005; Brennan et al. 2002; Louis et al. 1998a; Hubble et al. 1997) but it can also be
observed during rest in as many as 20–30% of the cases (Fig. 8.4) (Louis et al. 2005;
Gironell et al. 2004; Burne et al. 2004; Cohen et al. 2003; Dotchin and Walker
2008). Some argue that rest tremor is merely present in advanced ET and that this
rest tremor is in fact postural tremor that is caused by incomplete muscle relaxation
which would disappear if the patient was lying or seated in a position with complete
body support (Elble and Deuschl 2009). Others (Louis et al. 2005, 2011) propose
that when both rest and postural tremor are present in ET, they stem from a common
process. A possible reason for the prevailing postural tremor in ET is that the load-
dependant component of tremor is dominant (Burne et al. 2004). Thus, holding the
limb against gravity activates load-bearing muscles which in turn activate tremor.
Postural ET amplitude can greatly vary not only between patients but also within
one patient from day to day, and within a given day (Tamas et al. 2004). ET can
be a progressive disease; tremor amplitude tends to increase with advancing age
(Zesiewicz and Hauser 2001) and can become functionally incapacitating for some
patients. When examining the spectral characteristics of postural ET, one can
observe a distinct high amplitude peak located anywhere within a wide range
between 5 and 12 Hz (Deuschl et al. 1998; Panicker and Pal 2003). This is probably
due to the fact that ET frequency has been shown to decrease over time (Hellwig
et al. 2009). Indeed, in early ET, the prominent peak is usually located closer to
10 Hz while in advanced ET this peak shifts closer to 5 Hz. In contrast to PT or EPT,
ET peak frequency does not change when loading the limb while in a postural posi-
tion (Zeuner et al. 2003; Gironell et al. 2004). This can be explained by the fact that
a central generator contributes to setting the dominant tremor frequency in ET. While
loading does not significantly modify postural PT amplitude, interestingly, it
significantly reduces postural tremor amplitude in ET patients (Heroux et al. 2009).
Heroux et al. (2009) suggested that in ET, the centrally generated component
determines tremor frequency whereas the synergistic and/or competitive interaction
between central and mechanical reflex components determines tremor amplitude.
Furthermore, it was demonstrated that the central component itself might stem from
stochastically interacting central structures which cause large intra- and inter-sub-
ject variability in tremor characteristics (Tamas et al. 2004). Some have suggested
that these central structures most likely do not involve primary motor areas (Halliday
et al. 2000; Tamas et al. 2004) but rather lower order regions. Nonetheless, others
have shown that metabolic activation of the contralateral supplementary motor area
and bilateral cerebellum (Colebatch et al. 1990; Jenkins et al. 1993) as well as con-
tralateral thalamus (Jenkins et al. 1993) is observed during postural ET. The senso-
rimotor cortex has also been implicated in the generation of the oscillations observed
in ET (Hellwig et al. 2001). The thalamus also plays an important part in ET cir-
cuitry since lesioning of the posterior portion of the ventral lateral nucleus, which
receives deep proprioceptive input, as well as cerebellar projections, eliminates ET
(Young et al. 2010; Kondziolka et al. 2008; Zesiewicz et al. 2005; Akbostanci et al.
1999). Overactivity of the cerebellum and its projections may be induced by the
abnormal oscillatory activity arising as afferent input from the inferior olive, which
would then be conducted via the thalamus and cortex to the periphery via the corti-
cospinal tract (Jenkins et al. 1993; Hellwig et al. 2001). Note that these activation
patterns were observed in ET patients without rest tremor. Whether this pattern is
also present when rest ET is present is yet to be determined. The relationship
between ET and other forms of tremor is discussed below.
8.5 Relationships Between PT, EPT and ET
While the characteristics of different tremors have been described above, one might
wonder as to whether there is a link between PT, EPT and ET. PT is the normal
behaviour observed in every limb in the absence of any pathological condition. If a
link exists between these tremors, it should start from this normal physiological
process. EPT is thought to stem from similar origins as PT with its increased
amplitude resulting from abnormal central activity as evident on EMG spectra
(Elble 1986; Deuschl et al. 2001). Since only amplitude and the central 8-12 Hz
drive are modified over the tremor signal, it is plausible that EPT is merely the ini-
tial manifestation of abnormal oscillations within the central nervous system. As
mentioned above, it was suggested that EPT could be an intermediate step to prog-
ress from PT to ET (Elble et al. 2005). Much work remains to be done, however, to
confirm this hypothesis. Patients having been diagnosed with ET often present with
mildly asymmetrical symptoms (Louis et al. 1998a). Whereas one side presents
with definite ET characteristics, it is not uncommon to observe some form of EPT
on the contralateral side. This could indicate that EPT is more prevalent in ET
patients, or that EPT could be included as a precursor sign of ET.
8.6 Postural Parkinson’s Disease Tremor
Rest tremor is a cardinal symptom of Parkinson’s disease (PD) (Deuschl et al. 1996;
Jankovic 2008), but postural tremor can also be observed in some patients with PD
(Fig. 8.5) (Duval 2006; Bhidayasiri 2005). In advanced PD, tremor may remain pres-
ent in patients during postural tasks or movement (Forssberg et al. 2000; Wenzelburger
et al. 2000; Lance et al. 1963; Teravainen and Calne 1980; Duval et al. 2000, 2005,
2006). Interestingly, some patients with PD presenting with mild tremor exhibit a
postural component (Duval 2006). When examining rest and postural PD tremor
amplitude, as for ET, much variation exists between patients, as well as within the
same patient from day to day. As the disease progresses, tremor shifts from being
unilateral to bilateral, and its amplitude tends to increase in patients with the tremor-
dominant form of the disease. Conversely, one study reported that tremor eventually
subsides completely in up to 10% of the patients (Hughes et al. 1993). Duval (2006)
demonstrated that the amplitude of postural and rest PD tremor shows a strong posi-
tive correlation in patients with mild PD tremor. A prominent peak between 4 and
8 Hz can be observed when examining the spectral characteristics of postural PD
tremor (Fig. 8.5) (Duval 2006; Duval et al. 2000, 2005, 2006; Henderson et al. 1994).
This same prominent peak is a hallmark of rest PD tremor (Deuschl et al. 1998). This
contrasts with PT and EPT. Indeed, in both PT and EPT, the respective rest and pos-
tural tremor spectral characteristics differ (Raethjen et al. 2000; Homberg et al. 1987).
On the other hand, in PD (Jankovic et al. 1999; Henderson et al. 1994) and ET (Cohen
et al. 2003; Burne et al. 2002), the respective rest and postural tremor (when present)
spectral characteristics are similar. Thus, while the pathophysiology of postural PD
tremor has not yet been definitively defined, it is suggested that the mechanisms
involved in the generation and/or propagation of rest PD tremor may remain active
despite voluntary muscle activation (Duval et al. 2004; Jankovic et al. 1999; Duval
2006). Similar to a change in posture, an application of inertial loads to tremulous
limbs may or may not affect tremor characteristics. Loading the limb lowers the fre-
quency of oscillations markedly in PT and EPT (Raethjen et al. 2004; Elble and
Deuschl 2002), but does not change these tremors’ acceleration amplitude significantly
(Raethjen et al. 2000, 2004; Elble 2003). On the other hand, ET and PD have major
Fig. 8.5 Graph representing an example of advanced PD tremor where postural tremor and rest
tremor can both be observed. Finger tremor was recorded using a laser displacement sensor during
both a postural and a rest condition. These recordings were made from a 62-year-old male diag-
nosed with PD and scheduled to undergo stereotactic neurosurgery to alleviate his tremor. More
details on the analysis can be obtained from Carignan et al. (2010) and Daneault et al. (2010). Top:
example of finger tremor displacement over a 6 s window within a 30 s trial. Bottom: velocity
power spectrums of the complete trial from which each of the above examples were taken. Note
again that the y-axis of the power spectrum represents the percentage of total power for each fre-
quency; with a resolution of 0.2 Hz. The velocity power spectrums are displayed since double
differentiation of the displacement signal amplifies the harmonics as can already be seen from both
power spectrums [i.e. the second peak is the first upper harmonic of the dominant oscillations
located at 5 Hz (Gresty and Buckwell 1990)]
frequency-invariant central tremor components. Loading can affect these tremors

through the interaction of these frequency-invariant components with mechanical
resonance and mechanical reflex components, depending on the relative amplitude of
these components. For instance, loading reduces amplitude of ET postural tremor, and
usually separates central and mechanical components in the power spectrum (Elble
et al. 2005; Heroux et al. 2009). Of course, the magnitude of the inertial load plays an
important role. In PD tremor, inconsistent reports can be found in the literature on the
effect of inertial loading. While some researchers have reported marginal effect on
amplitude and frequency of rest (Homberg et al. 1987; Deuschl et al. 1996) and pos-
tural (Meshack and Norman 2002) PD tremors, significant loading effects have also
been reported (Forssberg et al. 2000; Burne et al. 2004). In fact, it was shown that
there is a large load-independent component in rest PD tremor which remains present
during posture (Burne et al. 2004). In addition to this load-independent component, a

load-dependent component is also present during postural PD tremor, which could
explain the amplitude difference often seen between rest and postural PD tremors
(Burne et al. 2004).
Some imaging studies have suggested that PD tremor is, at least partially,
generated through a network encompassing the supplementary motor area, sen-
sorimotor cortex, cerebellum and thalamus (Fukuda et al. 2004; Deiber et al.
1993; Parker et al. 1992; Tasker et al. 1997; Boecker et al. 1997). Other imaging
studies have also implicated structures such as the subthalamic nucleus. It was
postulated that changes in subthalamic nucleus neuronal firing lead to excitation
of pallidal neurons, which in turn increase inhibitory output from pallidum to
thalamus. The result is a decrease in thalamic excitatory output to cortex, associ-
ated with a decrease in cortical activity (Gold and Lauritzen 2002; Lauritzen
2001). Since a subset of subthalamic nucleus neurons are tuned to the tremor
frequency, it was also suggested that PD tremor is generated by these neurons
(Amtage et al. 2008, 2009). Whether this is the case, or if PD tremor originates
from abnormal activity in other regions of the brain is still debated. Indeed, a
study has also observed that a subset of neurons within the globus pallidus have
oscillatory activity within PD tremor range (Hurtado et al. 1999), suggesting that
this structure could provide abnormal oscillations leading to PD tremor. Other
studies have also observed that some spectral characteristics of tremor were no
longer present after a thalamotomy (Duval et al. 2000, 2005, 2006) indicating
that the thalamus is involved in generating—or at least in relaying—tremor oscilla-
tions. Currently, there is still much debate as whether rest and postural PD tremor
share common neural substrates. Some have suggested that it is indeed the case
(Jankovic et al. 1999; Moore et al. 2000; Henderson et al. 1994) while other studies
(Reck et al. 2010) emphasize the differences between ET and PD tremor. Contrary
to classic PD rest tremor with a single peak on the frequency spectrum (about
4–6 Hz), PD action tremor (which includes postural tremor) exhibits one or two
frequency peaks (Findley et al. 1981; Forssberg et al. 2000; Raethjen et al. 2005) in
a wide reported range of 4.8–12 Hz (Hadar and Rose 1993; Findley et al. 1981;
Forssberg et al. 2000; Lance et al. 1963). However, since amplitude and spectral
characteristics seem to overlap, it is suggested that the neural network involved in
rest PD tremor may simply remain active during posture. Some researchers believe
that PD postural (action) tremor might not be distinguishable from enhanced (or
exaggerated) PT (Forssberg et al. 2000; Raethjen et al. 2005). Others, however, have
instead suggested that some patients may concomitantly exhibit both ET and PD
simultaneously, as discussed below. Thus, several hypotheses may be brought for-
ward. The first is that the neural network responsible for rest PD tremor described
above remains active during posture. In that case, the basal ganglia–thalamo–corti-
cal pathway would be crucial to the generation of this postural PD tremor. Another
possibility is that some patients may also exhibit ET as well as PD. In this case,
however, postural PD tremor would rather involve the olivo–cerebellar–thalamo–
cortical network. Whether this is indeed the case remains to be determined and the
possible relationship between both pathologies will be discussed below.
8.7 Relationships Between ET and PD
Existence of a possible link between ET and PD tremors has been debated for many
years (Adler et al. 2011). This idea of a possible link between both pathologies
could stem from similar clinical features between ET and PD as is evident by the
misdiagnosis rates close to 30% between PD and ET in the early stages of the dis-
ease (Hughes et al. 1992; Poewe and Wenning 2002). In addition, a recent study
considering the overlap in the clinical features of the two pathologies and examin-
ing the literature suggests that the two movement disorders are pathogenically
related (Fekete and Jankovic 2011). As mentioned above, in addition to the typical
rest tremor, a postural tremor resembling ET can be observed in many patients with
PD (Jankovic et al. 1999; Louis et al. 2001). Furthermore, tremor frequency in both
ET and PD decreases with disease progression (Hellwig et al. 2009). Although ET
is characterized by a postural and kinetic tremor of higher frequency, PD tremor,
especially in posture, can occur in a frequency range that overlaps with ET. Moreover,
ET patients can exhibit rest tremor with disease progression (Benito-Leon and Louis
2006). Tremor amplitude is also not a differentiating factor between ET and PD.
These facts pose challenges for differential diagnosis of the two tremor types.
Nevertheless there are promising methods for discriminating the two tremors based
on the harmonic components of the tremor signal (Muthuraman et al. 2011), or
based on the EMG firing pattern of antagonistic muscle groups (Milanov 2001;
Nistico et al. 2011). Some studies have observed a link between both pathologies
(Hornabrook and Nagurney 1976; Geraghty et al. 1985; Tan et al. 2008; Rocca et al.
2007; Louis and Frucht 2007; Koller et al. 1994), while others have not (Cleeves
et al. 1988; Marttila et al. 1984). Indeed, both pathologies can be present in the same
patient (Yahr et al. 2003; Geraghty et al. 1985; Shahed and Jankovic 2007; Minen
and Louis 2008). In this subgroup, of patients with both diseases the side exhibiting
the majority of ET tremor also exhibits most of the PD motor symptoms (Minen and
Louis 2008; Shahed and Jankovic 2007). Furthermore, the dominant motor symp-
tom of these patients was tremor: initially of the ET-type and then later more char-
acteristic of PD (Minen and Louis 2008). While an overall relationship between ET
and PD is yet to be ultimately defined, more evidence is coming to light regarding
an association between ET and distinct subgroups of patients with PD as suggested
by Barbeau and Pourcher (1982). Indeed, Rocca et al. (2007) observed a significantly
increased risk of developing ET in the relatives of young-onset patients with PD.
This risk was further increased for relatives of patients with PD presenting with
tremor-dominant or a mixed form of PD when compared to akinetic-rigid patients.
Similarly, Louis et al. (2003) also observed an increased risk of action tremor in the
relatives of patients with PD having a tremor-dominant form of the disease, but not
in those exhibiting postural instability and gait disorders. Therefore, current data
suggest a significant relationship between ET and PD mainly within the subgroup
of patients with PD exhibiting tremor as their dominant motor manifestation.
Determining if postural PD tremor is the result of activation of neural circuits gen-
erating rest PD tremor (basal ganglia–thalamo–cortical networks), or the results of
the activation of neural networks involved in ET (olivo–cerebellar networks) could
ultimately provide the best avenue to determine whether ET and PD are indeed pres-
ent concomitantly within the same patient. This is important information to deter-
mine the best course of action for treatment.
8.8 Conclusion
As demonstrated above, differential diagnosis of postural tremors remains a formi-

dable challenge. In the future, examination of subclinical aspects of different forms
of postural tremor may provide clues about their respective origins, thus helping
clinicians to better assess these different forms of tremor.
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Chapter 9
Isometric Tremor
Dennis A. Nowak, Hans-Jürgen Gdynia, and Jan Raethjen
Keywords Isometric • Action tremor • Resonance frequency • Loading
9.1 Introduction
Tremor is a rhythmic mechanical oscillation of at least one functional body region

(Deuschl et al. 2007). Tremor is usually considered to be pathologic, but one should
keep in mind that any voluntary movement is accompanied by physiological tremor,
which is believed to be necessary to facilitate fast voluntary motion. The borderline
between pathological and physiological tremors is less strictly delineated than most
clinicians wished to. This is particularly true for isometric tremor, a subtype of
action tremor. Isometric tremor can occur in isolation, but is most frequently associ-
ated with other types of (action) tremor. Isometric tremor is a common symptom in
a variety of clinical tremor syndromes and may vary regarding its frequency and
amplitude depending on the underlying condition.
D.A. Nowak (*)

Neurologische Klinik Kipfenberg, Kindingerstrasse 13, 85110 Kipfenberg, Germany
Neurologische Universitätsklinik, Philipps-Universität Marburg, Marburg, Germany
e-mail: dennis.nowak@neurologie-kipfenberg.de
H.-J. Gdynia
Neurologische Klinik Kipfenberg, Kindingerstrasse 13, 85110 Kipfenberg, Germany
e-mail: dennis.nowak@neurologie-kipfenberg.de
J. Raethjen
Neurologische Universitätsklinik, Universitätsklinikum Schleswig-Holstein,
Campus Kiel, Kiel, Germany
152 D.A. Nowak et al.
12
ON-Stimulation/ OFF-Stimulation/
Grip Force [N]

OFF-Medication OFF-Medication
6
0
1s
Fig. 9.1 Example of an isometric tremor in a subject with Parkinson’s disease off dopaminergic
medication lifting an instrumented object between index finger and thumb under stimulation of the
subthalamic nucleus (on-stimulation) and with subthalamic nucleus stimulation switched off (off-
stimulation). The instrumented object incorporates a grip force to register grip forces exerted nor-
mal to the grip surfaces and linear acceleration sensors to register accelerations in three dimensions.
The isometric tremor is evident only when subthalamic nucleus stimulation is switched off and
occurs after the lifting movement when the object is held stationary in the air. The tremor is directed
normal to the axis of grasping and shows a frequency of 5 Hz
9.2 Definition and Phenomenology of Isometric Tremor
Classification of tremor is based on the clinical condition in which the tremor

appears or is most pronounced (Deuschl et al. 1998). Within this classification the
following types of tremors can be differentiated: resting tremor, action tremor (with
its subtypes postural, isometric, simple kinetic and task-specific kinetic tremor) and
intention tremor. Isometric tremor is defined as involuntary oscillations of one or
more body regions occurring in situations of isometric muscle contraction against a
rigid resistance, e.g. pressing the hand and arm against a heavy table, standing on
the feet or hands (orthostatic tremor), or simply holding an object between thumb
and other fingers in opposition (Fig. 9.1).
9.3 Diagnostic Pathways and Therapeutic

Options in Isometric Tremor
Isometric tremor may be the only tremor variant in a given individual (physiological
tremor, orthostatic tremor) or be combined with other subtypes of action tremor as
well as resting and intention tremor. Isometric tremor may be an isolated symptom
in healthy individuals (physiological tremor) or be part of the syndrome in a variety
of tremor disorders, such as essential tremor (ET) (postural, kinetic and isometric
tremor), Parkinson’s disease (resting, postural, kinetic and isometric tremor), cere-
bellar tremor (intention, postural and isometric), dystonic tremor (postural, kinetic
and isometric tremor), Holmes tremor (resting, intention, postural and isometric
tremor) or psychogenic tremor (all tremor types and combination of tremor types
9 Isometric Tremor 153
Fig. 9.2 Synopsis of frequent movement disorders exhibiting tremors of different types and
sharing the symptom of isometric tremor. In orthostatic tremor, isometric tremor is the only tremor
symptom. Isometric tremor may also be a symptom of (normal) physiological tremor, writing
tremor and other task-specific tremors, drug-induced tremors and tremors in peripheral neuropa-
thies (all not shown)
possible) (Nowak and Fink 2009). Given the fact that isometric tremor may be part
of the syndrome in a variety of movement disorders associated with tremor, its
presence in an affected individual does not allow direct identification of its aetiol-
ogy or underlying pathology. There is a broad overlap between movement disorders
exhibiting isometric tremor (Fig. 9.2).
In order to diagnose the clinical tremor syndrome the clinician cannot rely on the
identification of isometric tremor alone (with the exception of primary orthostatic
tremor where isometric tremor of muscles working against gravity is the major
diagnostic clue), but has to screen for additional signs and symptoms, such as aki-
nesia, muscular rigidity, postural abnormalities, dystonia, muscular spasticity, ataxia
or signs of peripheral neuropathy to fix the diagnosis in an affected individual. As
in other forms of action tremor isometric tremor may occur at different frequencies
within the same patient and during the same (isometric) action. In Parkinson’s dis-
ease isometric tremor may occur as re-emergent postural tremor at the frequency of
the rest tremor of 4–6 Hz (Fig. 9.1) or kinetic action tremor with a frequency of
³6 Hz or both. This characteristic is particularly evident when analysing the tremor
of grip force when holding or moving a hand-held object (see below). To select
appropriate treatment strategies for isometric tremor, it is essential to diagnose the
underlying tremor syndrome.
9.3.1 Isometric Tremor in the Physiological Tremor Syndrome
Almost every movement is accompanied by usually invisible muscle oscillations,

which do not interfere with movement performance or accuracy. The frequency of
physiological tremor ranges between 6 and 12 Hz (Deuschl et al. 2007). There is
definitely a continuum from normal physiological tremor to enhanced physiological
tremor. The later is defined to be a high frequency tremor of larger amplitude and
therefore is clearly visible. Enhanced physiological tremor is short living (less than
2 years duration) and there is a large overlap with drug-induced (toxic) tremors
regarding tremor frequency. The frequency of physiological tremor should be
greater than 6 Hz, lower tremor frequencies should be considered pathological (Elbe
et al. 2005).
9.3.1.1 Pathophysiology
The oscillations of limb segments during movement in physiological tremor result

from mechanical amplification of the muscles’ effect on limb segments in motion at
its resonance frequency (Timmer et al. 1998). This explains why the amplitude of
physiological tremor is commonly quite small. The physiological tremor frequency
depends on the stiffness and inertia of the limb segments involved. This explains why
physiological tremor frequency is smaller in proximal limb segments, e.g. shoulder
and proximal arm, and higher in distal limb segments, e.g. wrist and fingers. The
rhythmic activation of muscle spindles induced by the mechanical dynamics of limb
movement activates spinal or long-loop (transcortical) reflex mechanisms, which can
occasionally enhance the tremor oscillations. In addition, central oscillations may
add to the frequency spectrum of physiological tremor. Loading the limb, e.g. plac-
ing a weight on the palm of the hand while holding the arm in elevation, usually
reduces the frequency in case of mechanical and/or reflex enhanced mechanical
oscillations. In contrast, the frequency of central oscillations in physiological tremor,
which are present in up to 30% of healthy subjects, cannot be reduced by loading
(Raethjen et al. 2000a). Drugs, e.g. amitryptillin (Raethjen et al. 2001), can increase
the amplitude of central oscillations in physiological tremor.
9.3.1.2 Therapeutic Strategies
Isometric tremor in the physiological tremor syndrome is commonly not disabling

and does not need any treatment apart from reassuring the affected individual of the
benign nature of the tremor. In case the tremor amplitude is large enough to cause
disability, e.g. enhanced physiological tremor syndrome, medical treatment should
be initiated. Therapeutic trials have been performed mainly for beta blockers, such
as propanolol, metoprolol, atenolol, acebutolol, nadolol, oxprenolol and timolol
(Deuschl et al. 2007). When the tremor is associated with intake of a specific drug
(valproate, tricyclic antidepressants, lithium, cocaine, alcohol, steroids, thyroid

hormones, cytostatics, etc.), cessation of the drug is the therapy of choice.
9.3.2 Isometric Tremor in the Essential Tremor Syndrome
Classic essential tremor is the most common movement disorder. It is a monosymp-

tomatic, bilateral, postural and kinetic (action) tremor with a frequency in the range
of 4–12 Hz, which is mostly inherited and slowly progresses over the years (Deuschl
et al. 2007). The tremor frequency typically decreases with the duration of the dis-
ease and with age (Elbe et al. 2000). However, for a given patient at a certain point
in time the tremor frequencies during different activation conditions fall within the
same range. Thus the frequency of isometric tremor in ET usually does not differ
from postural or kinetic tremor frequency. Isometric tremor is a common feature in
the classic essential tremor syndrome and may enhance disability particularly when
it affects isometric muscle contraction of distal muscle segments of the forearm and
hand during grasping (Stani et al. 2010).
Primary writing tremor (appearing during writing only, type A, or when the hand
position used for writing is adopted, type B) is a variant of essential tremor. As hold-
ing the pen while writing is an isometric task these, tremors can be partly regarded
as isometric tremors. Primary writing tremor is a task-specific tremor. Task-specific
tremors have also been described during other manual tasks, such as playing a musi-
cal instrument (piano, guitar, etc.) or handling a sports instrument (golf, tennis,
etc.). The relationship between writing tremor and task-specific dystonic tremor is
not clearly defined.
Classic essential tremor does not significantly change its frequency under different
mechanical conditions, which suggests central generators. A network of cortical
and subcortical structures is involved in generating the muscle oscillations and there
are several independent loops triggering oscillations for each extremity involved
(Raethjen et al. 2000b). However, peripheral perturbations (as well as transcranial
magnetic stimulation of the primary motor cortex) can reset tremor frequency. So
both peripheral and central mechanisms can influence the centrally generated oscil-
lations in classic essential tremor. The pathophysiology of primary writing tremor is
controversial.
Isometric tremor in the classic essential tremor syndrome is most disabling when it
affects the hands. About half of subjects with classic essential tremor show at least
some intention tremor during goal-directed hand and grasping movements (Deuschl
et al. 2000). Propanolol and primidone are the medical therapy of choice (Deuschl
et al. 2007). Only 25% of affected individuals maintain a stable response over 2
years. A combination of propanolol and primidone should be tried if a single drug
does not allow sufficient symptom relief. Topiramate and gabapentin have also been
shown to be effective. Deep brain stimulation should be considered for individuals
resistant to medical treatment who suffer profound disability (Limousin et al. 1999).
Deep brain stimulation of the nucleus ventralis intermedius of the thalamus at least
partially improves isometric tremor in classic essential tremor when grasping and
lifting an object (Stani et al. 2010). Management of task-specific tremors comprises
propanolol, local botulinumtoxin injections and abstinence from the tremor-
producing tasks with consecutive behavioural re-training (Deuschl et al. 2007).
9.3.3 Isometric Tremor in Parkinson’s Disease
The majority of subjects with Parkinson’s disease present with tremor. The most
widely accepted tremor in Parkinson’s disease is resting tremor with a frequency of
3–7 Hz, but up to 40% of affected individuals show additional or isolated postural
tremor (often re-emergent postural tremor with a frequency of 3–6 Hz) and kinetic
(action) tremor with a frequency of ³6 Hz. Postural and kinetic tremor syndromes
in Parkinson’s disease may be associated with isometric tremor, which is often most
disabling at the hands and impacts on manual dexterity (Forssberg et al. 2000;
Nowak and Hermsdörfer 2002; Nowak et al. 2005b; Raethjen et al. 2005;
Wenzelburger et al. 2002). Resting tremor hardly influences manual dexterity in
Parkinson’s disease as it ceases as soon as movement is initiated, but slows move-
ment initiation (Wenzelburger et al. 2002).
Isometric tremor associated with kinetic tremor in Parkinson’s disease may inter-
fere with moving an object held between the thumb and other fingers in opposition
(Nowak and Hermsdörfer 2002). Remarkably, isometric kinetic tremor of grip force
(representative of distal muscles of the forearm and hand stabilising the grasp) is not
in phase, but typically shows a lower frequency, than kinetic tremor of proximal arm
muscles (responsible for moving the object) (Figs. 9.3 and 9.4).
The pathophysiological substrate of resting tremor in Parkinson’s disease is a

pathological synchronisation of oscillatory activity within a cortical–subcortical
network (Timmermann et al. 2003). Within this network the primary motor cortex
plays a major role, which shows a strong frequency coupling with the peripheral
muscle oscillations. Interestingly, neural tremor activity in the primary motor cor-
tex occurs at double the tremor frequency (8–12 Hz) and the tremor frequency
itself (4–6 Hz). It has been hypothesised that the main corticomuscular drive is at
Grip Force (N)

10 10 10
8 8 8
6 6 6
4 4 4
2 2 2
0 0 0
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
8 8 8
Acceleration (m/s2) Load Force (N)
6 6 6
4 4 4
2 2 2
0 0 0
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
20 20 20
15 15 15
10 10 10
5 5 5
0 0 0
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
Time (s)
Fig. 9.3 Acceleration in the direction of movement, load force, and grip force profiles from
consecutive upward and downward movements of a subject with Parkinson’s disease on dopamin-
ergic medication during three experimental trials. Acceleration and load force profiles represent
activity of proximal arm muscles, grip force profiles represent activity of distal muscles of the
forearm and hand holding the object. Oscillations of 8–10 Hz are present in the acceleration and
load force profiles towards the end of an upward movement and at the start of a downward move-
ment as well as during the second of stationary holding the object in between the vertical arm
movements. These oscillations correspond to kinetic tremor of proximal arm muscles, responsible
for moving the object and holding it steady in between each movement. The break in between each
movement is too short for a re-emergent postural tremor to be established. Oscillations with a
frequency of 5–7 Hz are shown in the grip force profile during and in between each movement.
These are representative of an isometric kinetic tremor of distal muscles of the forearm and hand.
Modified from Nowak and Hermsdörfer (2002)
double the tremor frequency and that a 2:1 transformation from central to periph-
eral resting tremor activity might be due to a “flip-flop” effect at the level of the
spinal cord leading to an alternating drive of the 8–12 Hz central activity towards
agonistic and antagonistic limb muscles (Timmermann et al. 2003). At the moment
this remains speculation, but the special role of double the tremor frequency in PD
as compared to other tremors becomes increasingly clear. In ET or voluntary
rhythmic hand movements the actual movement frequency is represented in the
same central network and shows similar time courses as the tremor frequency
itself oscillations at these two frequencies seem to be separate in time and space
at least (Raethjen et al. 2009). The pathophysiological basis of this may be the
more widespread central pathology in PD with a wide range of pathological oscil-
latory activities above the tremor frequency (Raethjen et al. 2000a) and might be
related to the higher frequency Parkinsonian tremors encountered in parallel to
the classical low frequency resting tremor, e.g. during isometric muscle activation
Grip Force (N)

15 15 15
10 10 10
5 5 5
0 0 0
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
8 8
Acceleration (m/s2) Load Force (N)
8
6 6 6
4 4 4
2 2 2
0 0 0
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
20 20 20
15 15 15
10 10 10
5 5 5
0 0 0
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
Time (s)
Fig. 9.4 Acceleration, load force, and grip force profiles from consecutive vertical movements
with a hand-held object performed by a subject with Parkinson’s disease under medication during
three successive experimental trials. Oscillations with a frequency of 6–7 Hz are illustrated in the
acceleration and load force profiles most pronounced towards the end of the upward movement and
at the start of the downward movement. These oscillations are attributed to kinetic tremor of proxi-
mal arm muscles. Oscillations of 5–6 Hz are present in the grip force profile both during movement
and when holding the object in between each movement. These oscillations represent isometric
tremor of distal muscles of the forearm and hand grasping the object. Modified from Nowak and
Hermsdörfer (2002)
(see below). This special role of double the tremor frequency in PD is also reflected
in accelerometric recordings of the postural tremor which show higher amplitudes
of the additional peaks at integer multiples of the tremor frequency than in ET and
this may be an easy diagnostic test to separate advanced ET cases from tremulous
PD (Muthuraman et al. 2011).
Next to the primary motor cortex also other brain areas, such as premotor cortex,
supplementary motor area, primary and secondary somatosensory cortices, dien-
cephalic and cerebellar areas are involved in central generation of Parkinsonian
resting tremor (Timmermann et al. 2003). Resting tremor of one limb is primarily
caused by central generators within the contralateral hemisphere, but there is also
cross-talk in between both hemispheres.
Postural tremor in Parkinson’s disease is considered to represent re-emergence of
the resting tremor once a dynamic movement has ceased and only steady isometric
muscle contractions persist (Jankovic et al. 1999; Raethjen et al. 2005). Next to this
re-emergent postural tremor, an additional kinetic (action) tremor may be present
during voluntary movements in Parkinson’s disease (Forssberg et al. 2000;
Wenzelburger et al. 2000). Kinetic tremor is observed towards the (acceleration or)
deceleration phase of a reaching movement or during movements with a handheld
Fig. 9.5 The proportion of subjects with Parkinson’s disease (n = 20) exhibiting kinetic and
re-emergent postural tremors during grasping and lifting an instrumented object between the index
finger and thumb. The incidence of each tremor is shown with (ON) and without (OFF) l-Dopa
treatment and compared to age-matched controls (n = 18). The low frequency re-emergent postural
tremor (4–7 Hz) responds well to l-Dopa, whereas the high frequency kinetic tremor (7–15 Hz)
remains unchanged after l-Dopa administration. Modified from Raethjen et al. (2005)
object (Figs. 9.3 and 9.4) and has a higher frequency (6–10 Hz) than the re-emergent
postural tremor (4–6 Hz) to be found after the reaching movement has ceased for a
while (at least 2–3 s). Thus kinetic and re-emergent resting tremors are clearly dis-
cernable tremor types in the Parkinsonian tremor syndrome.
Medical strategies to improve isometric tremor in Parkinson’s disease have to take

into account that different tremor subtypes may be present. Regarding the effect on
isometric re-emergent postural and kinetic tremors in Parkinson’s disease, it appears
as if l-Dopa develops differential effects. When grasping and lifting an object
between index finger and thumb, both kinetic (lifting the object) and re-emergent
postural (holding the object stationary several seconds after lifting it) tremors can be
discerned. The low frequency re-emergent postural tremor when holding the object
is significantly ameliorated by l-Dopa (as is resting tremor), while the high fre-
quency kinetic tremor when lifting the object is not changed by l-Dopa medication
(Fig. 9.5).
Deep brain stimulation is an effective therapy in subjects not responding to medi-
cal treatment. Electrical stimulation of the nucleus ventralis intermediate thalami
applied bilaterally significantly improves resting tremor, but has no relevant effect
on akinesia (Deuschl et al. 2007). Bilateral subthalamic nucleus stimulation
improves resting tremor along with akinesia and rigidity (Krack et al. 1998) and is
the preferred target for deep brain stimulation. Subthalamic nucleus stimulation
improves primarily resting and re-emergent postural tremor when grasping and lift-
ing an object between index finger and thumb in Parkinson’s disease (Nowak et al.
2005a, b; Wenzelburger et al. 2002, 2003; Fig. 9.6).
PD subjects off stimulation PD subjects on stimulation

110 110
Grip Force Rate [N/s]
Grip Force Rate [N/s]

self-paced lifting
self-paced lifting
35 35
-40 -40
3 3
Acceleration [m/s2]
Acceleration [m/s2]
0 0
-3 -3
18 18
Grip Force [N]
Grip Force [N]
9 9
0 0
1s 1s
Fig. 9.6 Average profiles (±one standard deviation) of the rate of grip force development, accel-
eration and grip force obtained from five subjects with Parkinson’s disease grasping and lifting an
object without dopaminergic medication and subthalamic nucleus stimulation switched either off
or on. It is evident that the low amplitude isometric kinetic tremor to be found in the grip force rate
(and acceleration) profiles is diminished by stimulation of the contralateral subthalamic nucleus.
Modified from Nowak et al. (2006)
9.3.4 Isometric Tremor in Cerebellar Disorders
Cerebellar tremor is often used synonymously with intention tremor, although differ-
ent clinical types of tremor have been described in cerebellar disorders (Fahn 1984).
The following criteria have to be fulfilled to diagnose cerebellar tremor (1) pure or
dominant intention tremor, (2) tremor frequency below 5 Hz and (3) postural tremor
may be present, but not resting tremor (Deuschl et al. 2007). Disorders most com-
monly causing intention tremor are multiple sclerosis, brain trauma and hereditary
ataxias. Postural tremor is only accepted to be of cerebellar origin when additional
cerebellar signs, such as dyscoordination and decomposition of movement, dysmetria,
rebound phenomenon, oculomotor disturbance, ataxia of stance and gait, etc., are
present. Isometric tremor may occur in the cerebellar tremor syndrome (Fig. 9.7).
The cerebellum is generally considered to regulate movement indirectly by adjusting

the output of the descending motor system of the brain. Lesions of the cerebellum
Fig. 9.7 Profiles of grip force, load force and acceleration during single upward and downward
movements performed by a subject with cerebellar degeneration with a hand-held object. Six to
7 Hz oscillations in the profiles of acceleration and load force are evident during and in between
each movement indicative of intention tremor. As can be seen in the acceleration and load force
profile, tremor amplitude decreased following each arm movement. A 5 Hz isometric tremor,
which is out of phase with the intention tremor obvious in the acceleration and load force profiles,
is evident in the grip force profile during each movement and the phase of stationary holding the
object in between each movement
disrupt coordination of limb and eye movements, impair balance and decrease mus-
cle tone (Glickstein et al. 2005). The most widely accepted idea is that the cerebel-
lum acts as a comparator that compensates for errors in movement by comparing
intended movement with actual performance. Through comparison of internal and
external feedback signals, the cerebellum is able to correct ongoing movements when
they deviate from the intended course and to modify central motor commands so that
subsequent movements are performed with less prediction errors.
The cerebellum receives input from the periphery and from all levels of the cen-
tral nervous system. Information entering the cerebellum is initially acting on the
cerebellar cortex and via collaterals on neurons of the cerebellar nuclei (e.g. the
fastigial, interpositus and dentate nuclei) (Colin et al. 2002). Afferent information is
processed within the cerebellar cortex. The cerebellar nuclei receive input from the
Purkinje cells, the only output cells of the cerebellar cortex. The cerebellar nuclei
transmit all output from the cerebellum, primarily to the motor regions of the cere-
bral cortex and brainstem (Hoover and Strick 1999). Cerebellar tremor is believed
to result from abnormal feedforward and feedback mechanisms via long-loop
transcortical processing during voluntary movement.
The treatment of isometric tremor associated with intention tremor is difficult. Cholinergic
drugs (physostigmine) and 5-hydroxythryptophan have been found to be effective in
some affected individuals (Deuschl et al. 2007). Propanolol, clonazepam, carbamaze-
pin, tetrahydrocanabinol and trihexyphenidyl also showed efficiency in small groups of
cerebellar subjects. Also the loading of the affected extremity can reduce the tremor
amplitude for a short period of time, but adaptation to the load increase is frequently
observed. Deep brain stimulation of the ventral intermediate thalamic nucleus can
significantly reduce intention tremor of ³3 Hz frequency (Lozano 2000).
9.3.5 Isometric Tremor in the Dystonic Tremor Syndrome
Dystonic isometric tremor is defined as a postural/kinetic tremor usually not seen

during complete rest, which occurs in an extremity or body part that is affected by
dystonia (Deuschl et al. 2007). Usually dystonic tremor is a focal postural and/or
kinetic tremor with irregular amplitudes and variable frequencies (usually less than
7 Hz). Sometimes focal tremors are observed in the absence of overt dystonia.
Antagonistic gestures often can reduce tremor frequency and amplitude, e.g. in dys-
tonic head tremor. Postural tremor is the typical clinical presentation of dystonic
head tremor. Tremor in task-specific dystonia of the hand, e.g. writer’s cramp, is an
example for an isometric postural/kinetic tremor. Dystonic tremor and tremor asso-
ciated with dystonia are different as unspecific postural tremor often at higher fre-
quencies than the dystonic tremor itself may occur in extremities not involved by
dystonia. Isometric postural/kinetic dystonic tremor in task-specific focal hand dys-
tonia may hamper manual dexterity during a specific task, e.g. writing, playing a
musical instrument or using a sports tool (Nowak et al. 2005a, b).
The pathophysiology of the dystonic tremor syndrome is unknown. Possibly

impaired sensorimotor integration at the level of the basal ganglia with impaired
coupling of feedback and feedforward control mechanisms plays an essential role
(Deuschl et al. 2001).
Medical treatment options for isometric postural/kinetic dystonic limb tremors are
widely ineffective (Deuschl et al. 2007). Dystonic head tremor had been found to
improve with propanolol. Botulinumtoxin is probably the most effective medical
treatment option for postural dystonic head tremor and probably also for many cases
of isometric postural dystonic hand tremor (Brin et al. 2001). In cases who do not
respond, deep brain stimulation of the Globus pallidus internus is meanwhile a well
established advance treatment option (Mueller et al. 2008).
9.3.6 Isometric Tremor in the Holmes Tremor Syndrome
Holmes tremor (synonyms: rubral tremor, midbrain tremor, Benedikt’s syn-

drome) is caused by a lesion of the central nervous system predominantly the
midbrain (Deuschl et al. 1998). Holmes tremor is defined by (1) the presence of
both an irregular resting and intention tremor often giving the impression of
jerky movements, (2) slow frequency (less than 4.5 Hz) and (3) a delay of 2
weeks to 2 years between the acute lesion and the occurrence of tremor. Holmes
tremor is usually unilateral, most frequently affects the arm and hand, and many
subjects with Holmes tremor also exhibit a postural tremor. Holmes tremor is the
most disabling tremor form as it disturbs rest and all kinds of voluntary and
involuntary movements (Deuschl et al. 2007). An isometric kinetic and some-
times postural tremor component may add to the disability of manual dexterity in
affected subjects.
The origin of Holmes tremor is a lesion in the midbrain, cerebellum and/or thalamus
(Deuschl et al. 1998; Nowak et al. 2010). However, also lesions of the involved
fibre tracts in other regions may cause a similar clinical tremor. The pathophysiol-
ogy of Holmes tremor is a combined lesion of the cerebello-thalamic and nigro-
striatal system. Central oscillators cause this kind of tremor. In healthy people, the
rhythm of resting tremor is blocked during voluntary movement by the cerebellum.
If this cerebellar compensation is absent, a kinetic tremor develops.
Reliable clinical study-based therapeutic recommendations for a successful medi-

cal therapy of Holmes tremor do not exist. Dopaminergic substances are effective
in many patients, but its specific effect on isometric tremor components is not
known.
9.3.7 Isometric Tremor in the Orthostatic Tremor Syndrome
Primary orthostatic tremor is a unique tremor syndrome observed only in subjects

older than 40 years of age (Deuschl et al. 2007). Primary orthostatic tremor is char-
acterised by subjective unsteadiness of stance (only in severe cases also of gait). The
symptoms disappear in the supine or sitting position. The neurological examination
is generally unremarkable. Electromyographic recordings from limb or trunk mus-
cles acting against gravity show a typical 13–18 Hz isometric tremor of agonistic
and antagonistic muscles. The tremor oscillations are typically in phase for all limb
and trunk muscles when standing. Isometric tremor is the diagnostic clue in primary
orthostatic tremor. Other tremor types are not present in orthostatic tremor.
Because the tremor oscillations in orthostatic tremor are highly coherent in the
limbs of both body sides and trunk muscles during standing, a central tremor gen-
erator is very likely. However, the anatomical location of this central tremor genera-
tor is unknown. Resetting of the tremor frequency was possible only after electrical
stimulation over the posterior fossa, but not over the cerebral cortex. This suggests
that the tremor generator is sited within the brainstem.
Primary orthostatic tremor has been documented to respond to medical treatment

with clonazepam and primidone (Deuschl et al. 2007). Valproate, l-Dopa and pro-
panolol have variable efficiency. Gabapentin has probably the best therapeutic effect
to reduce the subjective unsteadiness of stance and electromyographic tremor activ-
ity (Evidente et al. 1998). But medical treatment is difficult and ineffective in a large
proportion of patients. First case reports on VIM stimulation in orthostatic tremor
are promising but the response to deep brain stimulation does not seem to be com-
parable to the other tremors.
9.4 Conclusion
Isometric tremor is a subtype of action tremor. Isometric tremor occurs as a result of

muscle contraction against a stationary rigid object, e.g. when holding an object
between the tips of the thumb and other fingers in opposition. Isometric tremor can
occur in isolation, but is most frequently associated with other types of tremor.
Isometric tremor, a common symptom in a variety of clinical tremor syndromes,
varies in frequency and amplitude depending on the underlying condition. Therapy
of the underlying clinical condition also improves isometric tremor.
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Chapter 10
Essential Tremor and Other Forms
of Kinetic Tremor
Elan D. Louis
Keywords Kinetic • Epidemiology • Genetics • Cerebellum • Purkinje cell

• Torpedoes
10.1 Kinetic Tremor. An Introduction
Kinetic tremor is a tremor (i.e., a rhythmic and oscillatory movement) that occurs
during guided voluntary movements like writing or touching finger to nose. As
such, it is a type of action tremor, that is, tremor that occurs during voluntary con-
traction of skeletal muscle. It may be distinguished from rest tremor, which occurs
when a limb is fully relaxed, and intention tremor, which is present with visually
guided movement and increases in amplitude with approach of the target. A broad
range of kinetics tremors occurs and these may be divided into those that are normal
vs. pathological. Physiological or enhanced physiological tremor is the most com-
mon form of normal tremor (Elble 1998a, b, 2003; Louis et al. 1998a, b, c) and
essential tremor (ET) is the most common pathological form of tremor (Louis and
Support: R01 NS39422 and R01 NS42859 (National Institutes of Health, Bethesda, MD).
E.D. Louis, M.D., M.Sc. (*)
Unit 198, Neurological Institute, 710 West 168th Street, New York, NY 10032, USA
New York, NY, USA
Department of Neurology, College of Physicians and Surgeons, Columbia University,
New York, NY, USA
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain,
College of Physicians and Surgeons, Columbia University, New York, NY, USA
Department of Epidemiology, Mailman School of Public Health, Columbia University,
New York, NY, USA
e-mail: EDL2@columbia.edu
168 E.D. Louis
Ferreira 2010). Other pathological tremors include dystonic tremor, orthostatic

tremor, drug-induced tremor, and several other conditions. The focus of this chapter
is the pathological forms of kinetic tremor, and we will begin with ET, which is the
most common of these.
10.2 Essential Tremor
10.2.1 Essential Tremor or Essential Tremors?
ET is not only the most prevalent abnormal tremor but it is also one of the more
prevalent neurological diseases (Louis and Ferreira 2010; Louis et al. 1998a, b, c;
Dogu et al. 2003). Patients with ET receive their treatment from a wide range of
health professionals aside from neurologists; these include internists, geriatricians
and general practitioners. Although ET is often viewed as a condition that is easy to
diagnose, in fact, misdiagnosis is exceedingly common, with an estimated 30–50%
of “ET” patients having other diseases (Schrag et al. 1999, 2000; Jain et al. 2006).
Thus, in addition to being one of the more prevalent neurological diseases, ET may
be one of the most commonly misdiagnosed of these diseases as well.
The traditional paradigm, held for many years, regarded ET as a benign, mono-
symptomatic condition (Elble 2002)—action tremor. Yet, in recent years, this notion
has been challenged (Bermejo-Pareja 2011; Benito-Leon and Louis 2006; Lorenz and
Deuschl 2007; Louis 2009). More recent views of ET hold it as a progressive and
often disabling neurological disease characterized by a core motor feature, action
tremor, yet often accompanied by a number of other motor and nonmotor features
(Bermejo-Pareja 2011; Louis and Okun 2011). Patients often differ with respect to the
presence, evolution, and severity of these features, indicating that there is clinical
heterogeneity beyond what can be explained by disease stage/duration alone.
Furthermore, postmortem studies have identified a range of different structural changes
in the brains of ET patients, indicating the presence of some amount of pathological
heterogeneity. These parallel observations have appropriately given rise to the ques-
tion as to whether ET represents a single disease entity or rather a family of diseases
(Benito-Leon and Louis 2006; Louis 2009). A nomenclatural issue that naturally fol-
lows is whether the more appropriate term is “essential tremor,” which has historical
primacy (Louis et al. 1998a, b, c) and whose continued use inertia would favor, or the
term “essential tremors,” which perhaps better reflects an emerging understanding of
the aforementioned clinical and pathological heterogeneity (Louis 2009). For the time
being, however, “essential tremor” continues to be the favored term.
10.2.2 Etiology: Epidemiology and Genetics
The rate at which new ET cases arise (i.e., disease incidence) has been estimated in
one population-based study, which ascertained cases from central Spain; the adjusted
10 Essential Tremor and Other Forms of Kinetic Tremor 169
incidence was 619 per 100,000 person-years among persons aged 65 and older
(Benito-Leon et al. 2005). In other words, if one were to follow an ET-free cohort of
1,000 persons aged 65 and older for 1 year, one would expect that by the end of that
year that approximately six individuals would have developed new-onset ET, and
following that same cohort for 2 years would yield 12 new ET cases. Although most
cases are older adults, it is nevertheless important to note that ET can begin in child-
hood as well (Louis et al. 2001a, b, c, d, 2005a, b, c; Tan et al. 2006; Ferrara and
Jankovic 2009), with the large majority of these young onset cases being familial
(Bain et al. 1994; Louis and Ottman 2006; Louis and Dogu 2007).
Although ET is quite common, ironically, establishing a precise prevalence has
been challenging; a number of methodological issues have resulted in a wide range
of prevalence estimates in the approximately 30 population-based prevalence stud-
ies from around the world (Louis and Ferreira 2010; Louis et al. 2011a, b, c, d).
These methodological issues include but are not limited to the following: (1) method
of case ascertainment, with studies that examine participants rather than relying on
self-report (screening questionnaires) yielding higher prevalence estimates, and (2)
case definition, with studies that more broadly (i.e., loosely) define ET resulting in
higher prevalence estimates (Louis and Ferreira 2010; Louis et al. 1998a, b, c).
A recent population-based study in Mersin, Turkey that did not rely on screening
questionnaires (i.e., all study participants were examined regardless of whether they
complained of tremor) and that used stringent criteria for ET reported a prevalence
of 4.0% among individuals age ³40 years (Dogu et al. 2003). In another population-
based study in Finland that used a comparable methodology (Rautakorpi et al.
1982), the prevalence in individuals age 40 years and older was 5.6%, and 9.0%
among individuals ³60 years of age. In these and numerous other studies, the preva-
lence of ET increased with advancing age, and ET was highly prevalent in the sixth
through eighth decades of life, with prevalence estimates generally in the range of
6–9% (Louis and Ferreira 2010; Louis et al. 1998a, b, c; Dogu et al. 2003), and
some data suggest that prevalence continues to rise into advanced age groups (i.e.,
90 years and older), where the prevalence may attain values in excess of 20% (Louis
and Ferreira 2010; Louis et al. 2009a, b, c, d, e, f).
What predisposes so many people to this disease? Through epidemiological
studies, several risk factors for ET have been identified. First, age is clearly a risk
factor, with studies having shown an age-associated rise in both the incidence
(Rajput et al. 1984) and prevalence (Louis and Ferreira 2010; Louis et al. 1998a, b, c;
Dogu et al. 2003) of ET. Moreover, as with other neurodegenerative diseases, the
prevalence increases in a nonlinear, exponential manner with advanced age, with
estimates of the prevalence reaching 20% or higher among the oldest old (Louis
and Ferreira 2010; Das et al. 2009; Louis et al. 2009a, b, c, d, e, f). Second, there is
some evidence that ethnicity may be a risk factor for ET. Studies in the United
States have reported differences in the prevalence among whites and African-
Americans (Haerer et al. 1982; Louis et al. 1995, 2009a, b, c, d, e, f). A study in
Israel reported a very low prevalence of ET in Arabic villagers (Inzelberg et al.
2006) and a study in Singapore (Tan et al. 2005a, b) reported marginally different
prevalence estimates for Singaporean Chinese, Malays, and Indians. These ethnic
differences could be the result of differences in the presence of genes that increase
170 E.D. Louis
disease susceptibility. Third, a family history of ET is a strong risk factor for ET, as
the disease is in many cases familial (Louis et al. 2001a, b, c, d; Tanner et al. 2001).
Canonically, genetic factors have been viewed as important in the etiology of ET, as
the disease can aggregate in families, many of which show an autosomal dominant
pattern of inheritance (Gulcher et al. 1997; Higgins et al. 1997; Louis et al. 2001a,
b, c, d; Tanner et al. 2001). Finally, a number of environmental risk factors, and
particularly toxicants that can produce tremor (e.g., lead, harmane), are under active
investigation as etiological agents in ET (Louis et al. 2003a, b, c, d, 2008a, b, c, d,
e, f; Dogu et al. 2007; Louis 2008). The etiological roles of both the genetic and
environmental factors will be discussed more below.
On an etiological level, ET is often considered to be largely a genetic disorder
(Gulcher et al. 1997; Higgins et al. 1997, 1998, 2006; Kovach et al. 2001; Shatunov
et al. 2006; Deng et al. 2007). There are numerous examples of families in which
the proband and multiple relatives have ET (Marshall 1962; Gulcher et al. 1997;
Higgins et al. 1997, 1998, 2003, 2004a, b, 2005, 2006; Kovach et al. 2001) and in
which the pattern of inheritance is most consistent with an autosomal dominant
model. In 1997, linkage was demonstrated to a region on chromosome 2p in a small
number of American families (Higgins et al. 1997) and, in that same year, to a
region on chromosome 3q in 16 Icelandic families (Gulcher et al. 1997). Since then,
a third study has demonstrated linkage to a region on chromosome 6p in several
North American families (Shatunov et al. 2006). Other studies have failed to dem-
onstrate linkage to these three regions, indicating that there is additional genetic
heterogeneity (Kovach et al. 2001; Ma et al. 2006; Aridon et al. 2008; Deng et al.
2007). Despite these advances, ET genes have yet to be identified (Gulcher et al.
1997; Higgins et al. 1997; Shatunov et al. 2006; Deng et al. 2007). A growing number
of studies have explored the role that genetic polymorphisms play in ET (Agundez et al.
1997; Sazci et al. 2004; Higgins et al. 2005; Louis 2005a, b; Alonso-Navarro et al.
2006; Deng et al. 2006; Xiao and Zhang 2006; Martinez et al. 2007, 2008; Blair
et al. 2008), with reports of associations between polymorphisms in each of the fol-
lowing genes and ET: glutathione-S-transferase P1 (involved in metabolism of car-
cinogens) (Martinez et al. 2008), delta-amino-levulinic acid dehydrogenase (involved
in lead kinetics) (Louis 2005a, b), methylenetetrahydrofolate reductase (involved in
folate- and vitamin B12-dependent homocysteine metabolism) (Sazci et al. 2004),
and CYP2C19 (possibly related to primidone metabolism) (Alonso-Navarro et al.
2006). A reported association of the dopamine receptor D3 gene (DRD3) Ser9Gly
variant and ET, while initially promising, has also not been consistently replicated
(Deng et al. 2012). Most recently, a number of studies have reported an association
between ET and variants in the LINGO1 gene (a gene with multiple biological func-
tions, among them central nervous system development and axonal growth) (Clark
et al. 2010; Deng et al. 2012; Vilarino-Guell et al. 2010; Stefansson et al. 2009). The
pathogenic implications of these diverse findings have yet to be sorted out.
Environmental factors are likely to contribute to the etiology of ET as well.
First, environmental factors are believed to play a substantial role in other
progressive and degenerative neurological disorders including Parkinson’s dis-
ease, Alzheimer’s disease, and amyotrophic lateral sclerosis (Perl 1985; Semchuk
et al. 1992; Rybicki et al. 1993; Gorell et al. 1997, 1998, 1999; Ritz and Yu 2000;
Racette et al. 2001; Dick 2006; Baldereschi et al. 2008; Morahan et al. 2007;
Shcherbatykh and Carpenter 2007), so that by extension, it is conceivable that
they could play an etiological role in ET as well. Second, although a common
refrain in the ET literature is that “50%” of ET cases have a genetic basis, the
precise derivation of this estimate is unclear and its validity is also doubtful (Louis
and Ottman 1996). Indeed, some estimates are as low as 17% (Louis and Ottman
1996). There has been one familial aggregation study of ET (Louis et al. 1997a, b),
and in that study, 55% of ET cases had no affected first- or second-degree rela-
tives. This observation was consistent with data from numerous other clinical
series, among whom the majority of ET cases did not report affected relatives
(Critchley 1972; Hornabrook and Nagurney 1976; Aiyesimoju et al. 1984;
Martinelli et al. 1987; Louis and Ottman 1996; Salemi et al. 1998; Dogu et al.
2005). Third, in the ET twin studies (Tanner et al. 2001; Lorenz et al. 2004) con-
cordance in monozygotic twins was far from 100%; it was 60% in one study and
63% in another. Fourth, the well-known existence in ET families of intra-familial
differences in age of onset, tremor location, and tremor severity (Larsson and
Sjogren 1960; Louis et al. 2001a, b, c, d) also suggests that environmental factors
may be serving as modifiers of the putative underlying susceptibility genes in
those families. In terms of environmental factors, recent epidemiological studies
(Louis et al. 2002a, b, 2003a, b, c, d, 2008a, b, c, d, e, f; Dogu et al. 2007; Louis
2008) have implicated several specific toxicants, namely b-carboline alkaloids
(e.g., harmine and harmane, a group of highly tremorogenic dietary chemicals)
and lead, in ET. At least one study has shown that higher levels of baseline ethanol
consumption are associated with increased risk of developing ET, an observation
that is interesting in light of the known cerebellar toxicity of ethanol (Louis et al.
2009a, b, c, d, e, f). Studies of several other toxicants (e.g., manganese, pesti-
cides) have failed to demonstrate associations with ET (Louis et al. 2004, 2006a,
b, c, d; Louis 2008). Other studies have pointed to a possible protective role of
cigarette smoking in ET (Benito-Leon et al. 2008a, b; Louis et al. 2008a, b, c, d,
e, f), parallel with the situation that has been observed in Parkinson’s disease. In
summary, the etiology of ET is likely to be genetic in many instances, environ-
mental in others, and due to the combined influence of these two factors in yet
other cases. This is a research area undergoing active investigation.
10.2.3 Pathophysiology
Despite being one of the more common neurological disorders, little progress was
made during the nineteenth and most of the twentieth century in terms of advancing
the understanding of underlying mechanisms of ET (Louis 2010; Louis and Vonsattel
2007). Curiously, many text book chapters and review articles on this disease did
not include a section devoted to disease pathophysiology. This paralleled the notion
that ET was not really a disease per se, but rather, a relatively benign constitutional
trait; as such, the loose terms “condition” and “disorder” were often preferred rather
than the more definitive term “disease.” Discussion of disease mechanisms, although
172 E.D. Louis
sparse, was also dominated by a focus on tremor physiology (DeLong 1978;

Elble 1998a, b; Deuschl and Elble 2000). The existence of a central tremor
pacemaker or oscillator was posited, with the main support for this idea being the
existence of an animal model of action tremor using the neurotoxin harmaline (simi-
lar to harmine and harmane), which induces a nonspecific action tremor in labora-
tory animals and postmortem changes in the olivocerebellar pathway in these
animals (Llinas and Volkind 1973; Sinton et al. 1989; Handforth and Krahl 2001;
Krahl et al. 2004; Martin et al. 2005; Martin and Handforth 2006). Buoyed by this
observation, some sort of a physiological derangement in the inferior olivary
nucleus, a structure which has inherent oscillatory-pacemaking properties, was
viewed as the possible prime mover in ET, although there was very little actual sup-
port for this theoretical physiological construct. Indeed, rhythm generating networks
(i.e., pacemakers) are a nonspecific finding, located throughout the mammalian
cerebral cortex and brainstem (Li et al. 2010; Buzsaki and Draguhn 2004), and their
role in the generation of ET, although widely discussed, has never been empirically
demonstrated. Based on cortico-muscular coherence studies, other investigators
have suggested the existence of several rather than one central pacemaker in ET
(i.e., a complex cortical and subcortical network that is responsible for tremor)
(Raethjen et al. 2000; Lorenz and Deuschl 2007), although the precise location of
these pacers is not clear and furthermore, although these coherence studies indicate
that the cortex may be play some role in tremor oscillations, these data do not neces-
sarily indicate that the cortex is involved in tremor generation (i.e., that the oscilla-
tory activity is transmitted from cortex to muscle) (Raethjen et al. 2007). With
regard to the inferior olivary nucleus, positron emission tomography studies, which
began to emerge in the 1990s, did not demonstrate involvement of the inferior oli-
vary nucleus in ET nor did later postmortem studies reveal structural changes in that
nucleus (Louis 2010; Wills et al. 1994, 1995), which further casts doubt on any role
that this nucleus could play in the generation of ET.
The olivary hypothesis regarded ET as a functional dysregulation of an electro-
physiological system, that is, no more than a reversible oscillatory disturbance aris-
ing from an electrophysiological system gone awry (i.e., similar to epilepsy)
(Deuschl and Elble 2009). This stands in contrast to the notion that ET, like
Parkinson’s disease, Alzheimer’s disease and other neurodegenerative disorders, is
more than a manifestation of an abnormality in a central electrophysiological cir-
cuit, but represents a clinical–pathological entity that is grounded in a set of molecu-
lar and cellular changes, which give rise to a cascade of both microscopic and
macroscopic structural changes in the brain as well as altered neuronal function and
activity. The olivary hypothesis arose in an environment in which there had been no
substantive attempt to search for such structural brain correlates in ET. Indeed, in
the 100-year period between 1903 (the first reported postmortem on ET) and 2003,
there had only been 15 postmortem examinations (Louis and Vonsattel 2007). Many
of these were published in the earlier part of that time period. Most did not use rig-
orous methodologies, and none used age-matched control brains for comparison
(Louis 2010). Hence, the search for a structural brain correlate had not begun with
any rigor.
While physiological studies were positing the involvement of the inferior olive or
some sort of an olivary-cerebellar network in ET, an emerging clinical literature
gathered increasing support for the notion that the cerebellum itself might be cen-
trally involved in ET. First, cerebellar-like problems, with abnormalities in tandem
gait and balance, have been repeatedly described in ET patients (Louis et al. 2010a,
b; Rao et al. 2011; Singer et al. 1994; Hubble et al. 1997; Stolze et al. 2001; Klebe
et al. 2005; Parisi et al. 2006). Intention (i.e., “cerebellar”) tremor of the arms (in
addition to the more typical kinetic tremor of ET) occurs in 58% of ET patients
(Deuschl et al. 2000; Koster et al. 2002), and in 10% of ET patients, such intention
tremor involves the head (Leegwater-Kim et al. 2006). There are a variety of other
motor abnormalities that point to what is likely to be a more pervasive underlying
abnormality of cerebellar function in ET. These include oculomotor deficits
(Helmchen et al. 2003) as well as abnormalities in limb motor behavior in ET (Bares
et al. 2010; Farkas et al. 2006; Trillenberg et al. 2006; Avanzino et al. 2009). Second,
unilateral cerebellar stroke has been reported to abruptly terminate ipsilateral arm
tremor in patients with ET (Dupuis et al. 1989; Rajput et al. 2008) and cerebellar
outflow (dentato-rubro-thalamic) pathways are the target of deep brain stimulation,
which is highly effective in treating ET (Benabid et al. 1993; Schuurman et al. 2000).
Third, a wide array of neuroimaging methods used in a growing number of studies
now indicate the presence not only of functional and metabolic abnormalities in the
ET cerebellum, but also of structural abnormalities in both the cerebellar gray and
white matter as well. These studies include functional magnetic resonance imaging
(MRI) studies (Bucher et al. 1997), positron emission tomography studies (Colebatch
et al. 1990; Jenkins et al. 1993; Wills et al. 1994), [1H] magnetic resonance spectro-
scopic imaging studies (Louis et al. 2002a, b; Pagan et al. 2003), diffusion tensor
imaging studies (Klein et al. 2011; Nicoletti et al. 2010; Shin et al. 2008), voxel-
based morphometry studies (Quattrone et al. 2008; Benito-Leon et al. 2009), and
studies using other automated volumetric methods (Cerasa et al. 2009).
In tandem with the clinical studies, noted above, which were gathering increas-
ing support for the notion that the cerebellum and cerebellar systems seemed to be
at the root of ET, a growing postmortem literature was for the first time attempting
to quantify microscopic changes in the ET brain and compare these brains to control
brains (Louis and Vonsattel 2007). Three large ET case series have been published
in detail; these comprise 20 cases (Canada, six cases initially published and 14
added later) (Rajput et al. 1991a, b, 2004), 24 cases (Arizona, USA) (Shill et al.
2008), and 78 cases (New York, USA, with data from this continually expanding
case series reported in a sequence of papers spanning 6 years) (Erickson-Davis et al.
2010; Kuo et al. 2011; Louis et al. 2005a, b, c, 2006a, b, 2007a, b, 2009a, b, 2010a,
b; Louis and Vonsattel 2007; Axelrad et al. 2008). In the New York series, which is
the largest series, the large majority of ET cases have demonstrated degenerative
changes present in and restricted to the cerebellum (Louis et al. 2007a, b), and,
based on this simple empiric observation, those brains have been designated as “cer-
ebellar-ET” (Louis et al. 2009a, b, c, d, e, f).
The changes in ET cases with cerebellar ET that have been catalogued to date
include (1) a six- to sevenfold increase in the number of swellings of the Purkinje
174 E.D. Louis
Fig. 10.1 Torpedoes, which are swellings of the proximal portion of the Purkinje cell axon, occur
in abundance in patients with cerebellar ET. Bielschowsky-stained cerebellar cortical section of an
ET case (400× magnification) shows two torpedoes (arrows)
cell axon (i.e., “torpedoes”) (Fig. 10.1), (2) an approximate 40% reduction in the
number of Purkinje cells (Fig. 10.2), (3) an increase in the number of heterotopic
Purkinje cells (i.e., Purkinje cells whose cell body lies outside of the Purkinje cell
layer) (Fig. 10.3), and (4) hypertrophic changes in basket cell axonal processes
(Fig. 10.4) (Louis 2010). It is important to note that each of these changes, noted in
the New York study, occurs relative to normal age-matched controls brains as com-
parators. Although the Canadian study did not examine most of these microscopic
changes or attempt to quantify most of them, they did quantify the number of
Purkinje cells in a small number of ET cases (N = 7), demonstrating between a 5.8%
and 23.7% reduction in the number of Purkinje cells, yet they only compared that
small number of cases to an even smaller number of controls (N = 2) (Rajput et al.
2011), so that the case–control difference could not be effectively assessed due to
insufficient study power (Louis et al. 2011a, b, c, d). Investigators in New York also
quantified the number of Purkinje cells in five of the Canadian brains with adequate
and available tissue and the number was even lower than reported in ET brains in
New York (Louis 2010). The Arizona series (Shill et al. 2008) have remarked quali-
tatively about the presence of Purkinje cell loss in some of their ET brains; however,
those investigators have not yet systematically quantified Purkinje cells, torpedoes,
or other microscopic changes in each brain.
The mechanistic significance of torpedoes is not fully known, although the most
common model is that they indicate an injured and agonal (i.e., dying) Purkinje cell
(Mizushima 1976; Baurle and Grusser-Cornehls 1994). Studies in ET show that it is
Fig. 10.2 Luxol fast blue/ 175
hematoxylin and eosin stained
cerebellar cortical section
(100× magnification) in ET
showing Purkinje cells
(arrows, left) and segmental
loss of Purkinje cells (right)
Fig. 10.3 Three heterotopic

Purkinje cells in the granular
layer (arrows). Calbindin
stained cerebellar cortical
section of an ET case (100×
magnification). Heterotopic
Purkinje cells may also be
found in the molecular layer
in other instances
176 E.D. Louis
Fig. 10.4 Bielschowsky-

stained cerebellar cortical
section (200× magnification)
in ET. Hypertrophic changes
in basket cell axonal processes
are shown by arrows
the brains with more torpedoes that also have greater Purkinje cell loss (Louis et al.
2007a, b), further supporting the notion that torpedoes in ET are likely to be a
marker of Purkinje cell degeneration. A recent finding in a considerable number of
cerebellar ET brains in the New York series is of an unusual dense and tangled
appearance of the basket cell axonal plexuses surrounding the Purkinje cell body on
Bielschowsky-stained cerebellar cortical sections (Erickson-Davis et al. 2010).
Basket cells are gamma-aminobutyric acid (GABA)-ergic inhibitory interneurons
whose axonal collaterals form a pericellular basket around the body of the Purkinje
cell. The hypertrophic basket cell axonal processes were referred to by the authors
as “hairy baskets” (Erickson-Davis et al. 2010). The mechanism by which these
hypertrophic changes occur in cerebellar ET is unknown, although it is conceivable
that the increased plexus density represents an accumulation of converging basket
cell processes recruited from neighboring Purkinje cells that have been damaged or
died. Regardless of the mechanisms, this finding provides initial evidence that the
structural changes in ET are not restricted to the Purkinje cell and its processes but
also involve other cell types and a reorganization of the Purkinje cell functional
network (Erickson-Davis et al. 2010). Along these same lines, the presence of
Bergmann gliosis in some series (Louis et al. 2006a, b, c, d; Shill et al. 2008) sug-
gests that there may also be a set of reactive changes occurring in another cell type,
astroglia, in ET.
As noted above, in the New York series, the majority of ET brains demonstrated
microscopic structural changes in the cerebellum (Louis et al. 2007a, b), and, based
on that simple empiric observation, were designated as “cerebellar-ET” (Louis et al.
2009a, b, c, d, e, f). The bulk of the remaining brains in that series exhibited a dif-
ferent set of degenerative changes, namely, Lewy bodies, and this will now be dis-
cussed. In the New York series (Louis et al. 2007a, b), while 9.5% of control brains
had rare Lewy bodies in the locus ceruleus on alpha synuclein-stained sections,
none had moderate to severe Lewy bodies, as was observed in the 25% of ET brains
even on the less sensitive Luxol fast blue/hematoxylin and eosin (LH&E) stain
(p = 0.017) (Louis 2010). In terms of the distribution of the Lewy bodies in the New
York series (Louis et al. 2007a, b), Lewy bodies were abundant in the locus ceruleus
and either absent or infrequent in other brainstem structures (dorsal vagal nucleus,
substantia nigra pars compacta) and, in some cases, these Lewy bodies were associ-
ated with neuronal loss in the locus ceruleus (Louis et al. 2005a, b, c). Lewy bodies
and Lewy neurites were not present in other brain regions, including the hippocam-
pus, cingulate gyrus, or temporal, prefrontal and motor cortex.
One prior postmortem series had reported the presence of Lewy bodies in some
of their ET brains. Thus, a report published in 2004 in abstract form noted that
brainstem Lewy bodies were more common in the brains of 11 ET cases than 11
controls; in that study, the Braak Lewy body stage was twice as high in the ET cases
(1.3) than the controls (0.6) but, given the small sample size, the numerical doubling
did not reach statistical significance (Ross et al. 2004). The precise distribution of
the Lewy bodies (e.g., dorsal vagal nucleus, locus ceruleus, substantia nigra) was
not reported in that study (Ross et al. 2004). By contrast, in the Canadian series
(Rajput et al. 2004), brainstem Lewy bodies were not detected in any of the 20 ET
cases studied. In the Arizona series, 2 (8.3%) of 24 ET brains had Lewy bodies in
the locus ceruleus vs. 0% of controls; this modest difference was not significant
(Shill et al. 2008). Clearly there is a need for additional studies in order to more
precisely define the prevalence and distribution of Lewy bodies in ET relative to
control brains.
Lewy bodies have been observed in the brainstem in some asymptomatic elderly
people, and this raises the question as to whether the Lewy bodies observed in ET
could merely be incidental (Deuschl and Elble 2009). This explanation is problem-
atic for several reasons. First, it overlooks the important issues of quantity and
methodology. One must be careful to distinguish between a rare Lewy body on an
alpha synuclein stained section, as has been observed in some control brains, and
abundant Lewy bodies seen even on a less sensitive LH&E stained section, as has
been observed in the locus ceruleus in the New York series (Louis 2010). Second,
one must take into consideration not only the presence but also the anatomical dis-
tribution of the Lewy bodies. Although, Lewy bodies were present in a high propor-
tion of 1,241 consecutive autopsy cases of the elderly, in all but one of these 1,241
cases (Saito et al. 2004), Lewy bodies involved the dorsal vagal nucleus and not the
locus ceruleus. In only 1 (0.08%) of 1,241, was there isolated involvement of the
locus ceruleus (Saito et al. 2004).
178 E.D. Louis
While two very different sets of degenerative changes have thus far emerged
from postmortem studies in ET, it is expected that the disease heterogeneity will not
end there, especially as the number of postmortems has been relatively limited.
A recently published ET brain points to what appears to be additional heterogeneity
of degenerative pathology (Louis et al. 2010a, b). On postmortem examination,
there were abundant torpedoes, segmental loss of Purkinje cells and Bergmann glio-
sis (Louis et al. 2010a, b). In addition, Purkinje cells showed prominent ubiquit-
inated, nuclear inclusions.
What are the pathophysiological implications of the postmortem data described
above? Nearly all of the changes in cerebellar ET as well as in the one ET brain
with intranuclear inclusions are centered on and around the Purkinje cell. Purkinje
cells are inhibitory neurons; their dysfunction and death likely result in decreased
inhibitory modulation (i.e., increased activation) from the cerebellum, with possi-
ble resultant diminished motor control and, particularly, problems of dysrhythmia,
including tremor (Louis 2010). In this sense, ET may very well be a structural,
degenerative brain disorder of cerebellar disinhibition. One must also begin to con-
sider the potential significance of Lewy bodies in the locus ceruleus (Louis 2010),
which, as noted above, seems to be a feature of some ET brains. The locus ceruleus
is the principal source of norepinephrine in the central nervous system (Olson and
Fuxe 1971; Hicks et al. 1987; Fritschy and Grzanna 1989). Among its main effer-
ent connections are Purkinje cells (Olson and Fuxe 1971; Hoffer et al. 1973; Moises
and Woodward 1980; Moises et al. 1981; Foote et al. 1983; Hicks et al. 1987;
Fritschy and Grzanna 1989; Wang et al. 1999). Neurons in the locus ceruleus syn-
apse directly with Purkinje cells. Despite the relatively small number of locus
ceruleus neurons, each locus ceruleus neuron is thought to terminally project onto
numerous Purkinje cells (Olson and Fuxe 1971; Hoffer et al. 1973) and these con-
nections are important for the normal function of Purkinje cells and their inhibitory
output (Hoffer et al. 1973; Moises and Woodward 1980; Moises et al. 1981; Rogers
et al. 1981). This locus ceruleus innervation is thought to play an important role in
inducing synthesis of postsynaptic cytoskeletal proteins and neurotrophic factors
(Mavridis et al. 1991). Furthermore, these connections seem to be important for the
physical integrity of Purkinje cells (Sievers et al. 1981; Sievers and Klemm 1982;
Robain et al. 1985; Maier and West 2003). Hence, lesions in the locus ceruleus in
ET could plausibly result in subtle Purkinje cell changes and/or altered Purkinje
cell output (Louis 2010).
In summary, the pathophysiology of ET is far from clear. Dominated for many
years by the notion that the disease was the result of brain circuitry gone awry, and
that the cerebellum was involved in that circuitry disturbance, more recent studies
have been able to identify a set of structural/cellular changes in the ET brain, most
of which are centered on the Purkinje and connected neuronal populations. With
evidence of neuronal loss and protein aggregation in these brains, it is appearing
more and more likely that this progressive, age-associated disease is degenerative in
nature. This then opens the door to further research to identify and elucidate the
primary set of molecular events that sets the cascade of degenerative cellular changes
in motion.
Fig. 10.5 An ET patient’s tremor is apparent while they draw an Archimedes spiral with their
right hand
10.2.4 Clinical Presentation and Natural History
The onset of clinical disease in ET may be at any age, with childhood-onset cases
clearly described in the literature (Louis et al. 2001a, b, c, d, 2005a, b, c; Jankovic
et al. 2004); however, the majority of ET cases who are seen in clinical settings have
an onset that is in the 60s, 70s, and 80s (Brin and Koller 1998). A bimodal distribu-
tion of age of onset has been described, with the two peaks in the second and sixth
decades of life (Lou and Jankovic 1991; Koller et al. 1994; Brin and Koller 1998),
yet that is likely an artifact of ascertainment bias. Thus, a recent study (Louis and
Dogu 2007) assessed age of onset in ET, comparing cases ascertained from a ter-
tiary referral setting to cases from a population. In the population-based sample, the
peak in later life was clearly present but the young-onset peak was barely discern-
able (Louis and Dogu 2007). By contrast, in the sample from the tertiary referral
center, both peaks were clearly present (Louis and Dogu 2007). The young-onset
peak is likely due to the preferential referral to tertiary centers of patients with
young-onset, familial forms of ET (Bain et al. 1994; Louis and Dogu 2007).
The central, clinical disease-defining feature in patients with ET is a kinetic
tremor of the arms. This tremor may be apparent during a variety of common daily
activities, including eating, drinking, writing, and typing (Fig. 10.5). ET patients
often have a postural tremor as well. This type of tremor is elicited by asking them
to hold their arms outstretched in front of their body. The amplitude of kinetic
tremor is generally greater than that of the postural tremor (Brennan et al. 2002).
The opposite pattern (i.e., postural tremor of greater amplitude than kinetic tremor)
180 E.D. Louis
may be a clue that the diagnosis is not ET. The kinetic tremor may also have an
intentional component (Louis et al. 2009a, b, c, d, e, f); thus, during the finger–
nose–finger maneuver, the tremor may worsen when the patient approaches his/her
own nose or the examiner’s finger. There may also be a tendency to overshoot dur-
ing this maneuver, and these features give the movement a quality of cerebellar
dysfunction. Indeed, intention tremor is reported to occur in approximately 58% of
ET patients (Deuschl et al. 2000). The frequency of the kinetic tremor (generally
between 4 and 12 Hz) is inversely related to age, with older patients exhibiting
slower tremors and younger patients, faster tremors (Elble et al. 1992, 1994).
Some patients with ET develop a tremor at rest without other features of parkin-
sonism (Koller and Rubino 1985; Rajput et al. 1993). This is an arm rather than leg
tremor. At one tertiary referral center (Cohen et al. 2003), 18.8% of the ET patients
had a rest tremor. In population-based studies, where one might expect the preva-
lence to be lower, prevalence estimates have ranged from as low as 0% (Louis et al.
1998a, b) to as high as 29.2% (Dotchin and Walker 2008), so the precise prevalence
is unclear. One study demonstrated that the ET patients with rest tremor had disease
of longer duration and of greater severity than did those without rest tremor (Cohen
et al. 2003). The rest tremor in ET may occur in isolation of other features of
parkinsonism (i.e., bradykinesia, rigidity) and, indeed, postmortem studies have
repeatedly indicated that ET patients who develop isolated rest tremor do not have
emerging Lewy body pathology in the substantia nigra (Louis et al. 2011a, b, c, d;
Rajput et al. 1993, 2004).
While the tremor of ET is most commonly seen in the arms, other body regions
may also be involved (Critchley 1949). The most common among these is head (i.e.,
neck), the prevalence of which varies across study samples, but which is generally
in the range of 15–55% (Ashenhurst 1973; Lou and Jankovic 1991; Bain et al. 1994;
Hubble et al. 1997; Louis et al. 2003a, b, c, d). A characteristic feature of ET is the
somatotopic spread of tremor over time. Head tremor (most often as a side-to-side
“no–no” type of head tremor without any dystonic posturing) typically evolves sev-
eral years after the onset of arm tremor and the converse pattern (i.e., spread of
tremor from the head to the arms) is distinctly unusual (Critchley 1949; Larsson and
Sjogren 1960; Louis et al. 2003a, b, c, d; Rajput et al. 2004). The other interesting
feature of the head tremor is that it is strongly associated with female gender, with
women being several-fold more likely to develop head tremor than men (Hubble
et al. 1997; Louis et al. 2003a, b, c, d; Hardesty et al. 2004). Head tremor is not a
common finding in children with ET either (Louis et al. 2001a, b, c, d, 2005a, b, c).
While the head tremor is a postural tremor that is present while sitting across from
the patient, one other feature of the tremor is that it may also have an intentional
component. In one study (Leegwater-Kim et al. 2006), approximately 10% of ET
cases had a postural head tremor that was exacerbated during goal-oriented
movement (e.g., when bending their neck downwards while drinking from a cup or
spoon). While on the one hand, head tremor may be embarrassing for some patients,
one other interesting feature about the head tremor of ET is that patients are often
unaware of it, which helps to distinguish it from dystonic head tremor. In one study
(Louis et al. 2008a, b, c, d, e, f), one-third to one-half of ET cases who exhibited a
head tremor on examination did not report the presence of head tremor. Indeed,
when their tremor was pointed out to them, many of these patients stated that they
were unaware of it. A lack of internal feedback about a movement may lessen self-
awareness of that movement. Whether, from a proprioceptive vantage point, patients
have a subjective experience of head tremor, is not always clear. For example, with
some types of oscillatory cranial movements, perceptual stability may be achieved
through a reduced sensitivity to the motion or the use of other signals to cancel the
effects of the movements (i.e., a spatial constancy feedback loop) (Louis et al.
2008a, b, c, d, e, f). Whether such a mechanism is operative in ET cases is unclear.
Jaw tremor may also occur in patients with ET, with the prevalence estimated to
be lowest in population-based studies (7.5%) and highest in referred samples (10.1–
18.0%) (Louis et al. 2006a, b, c, d). ET patients with jaw tremor tend to have more
clinically severe and more topographically widespread disease. The jaw tremor is
predominantly a postural tremor (occurring while the mouth is held slightly open or
during sustained phonation) or a kinetic tremor (occurring during speech). A small
number of patients may also exhibit mild tremor while their mouth is closed; how-
ever, in these it can be difficult to determine whether the jaw is fully relaxed (Louis
et al. 2006a, b, c, d). Jaw tremor differs from the peri-oral tremor of Parkinson’s
disease, which often manifests as a tremor of the lower lip. Leg tremor also occurs
in ET. In one clinical-based study, while mild kinetic leg tremor occurred in nearly
one-half of ET cases, moderate kinetic leg tremor occurred in 14.3% of cases, and
the severity of leg tremor was correlated modestly with disease duration (i.e., more
marked leg tremor occurred in patients with longer disease duration) (Poston et al.
2009). From a functional and clinical-care standpoint, however, kinetic leg tremor
is not a major clinical feature of ET (Poston et al. 2009).
Despite the fact that ET is a progressive disorder (Critchley 1949; Louis et al.
2003a, b, c, d), longitudinal studies are scant. In general, the amplitude of the kinetic
tremor increases over time (i.e., the tremor in ET progressively worsens) (Critchley
1949; Louis et al. 2003a, b, c, d; Putzke et al. 2006), with recent estimates indicating
a median annual increase in tremor severity of approximately 2.0% (Louis et al.
2011a, b, c, d), although patients differ with respect to rate of change, with some
subgroups (e.g., older onset ET) exhibiting more rapid rates of decline (Louis et al.
2000, 2009a, b, c, d, e, f). Both rest tremor (Cohen et al. 2003) and intention tremor
(Leegwater-Kim et al. 2006) are associated with disease of longer duration, indicat-
ing that both the severity of kinetic tremor and the complexity of tremor phenome-
nology seem to increase with more longstanding disease.
It is well-known that patients with ET can later develop Parkinson’s disease (Yahr
et al. 2003; Chaudhuri et al. 2005; Shahed and Jankovic 2007; Minen and Louis 2008).
Indeed, family studies have shown an increased co-occurrence of the two diseases in
the same families above that expected by chance alone (Louis et al. 2003a, b, c, d;
Rocca et al. 2007), and case–control studies have shown an increased co-occurrence
of the two disorders in the same individuals above that expected by chance alone, with
increased odds being at least five times (Tan et al. 2008). Recent prospective analyses
have similarly indicated that patients with ET have a four- to fivefold increased risk of
developing incident Parkinson’s disease (Benito-Leon et al. 2008a, b).
182 E.D. Louis
The severity of tremor in ET may range from mild and asymptomatic (e.g.,
cases seen in population-settings) to more severe cases seen in treatment settings
(Louis et al. 1998a, b, c, 2001a, b, c, d). More than 90% of the patients who come
to medical attention report disability (Louis et al. 2001a, b, c, d) and severely
affected patients may be unable to feed or dress themselves (Critchley 1949).
Between 15% and 25% of patients are forced to retire prematurely, and 60% choose
not to apply for a job or promotion because of uncontrollable shaking (Rautakorpi
1978; Bain et al. 1994). Far from being benign, most patients with this disorder
must make adjustments in the way they perform their daily activities. Even among
community-dwelling patients, the majority (73%) report disability, with most
experiencing this in multiple functional domains (Louis et al. 2001a, b, c, d).
Moreover, studies have demonstrated that morale is lower in these community-
dwelling patients, further underscoring the effect of tremor on their quality on life
(Louis et al. 2008a, b, c, d, e, f).
As noted above, while the sine qua non of ET is the kinetic tremor of the arms,
tremor phenomenology is quite varied and complex. Kinetic tremor generally wors-
ens over time, and layered on top of that tremor patients may experience the pro-
gressive addition over time of tremors that occur under different conditions (e.g., at
rest, with intention) and in different bodily regions (e.g., jaw, head). In addition,
many other clinical features aside from tremor are now appreciated (Louis 2005a, b;
Benito-Leon and Louis 2006, 2007). These features may be subdivided into motor
features vs. nonmotor features.
A number of motor features aside from tremor have been described in ET patients.
Thus, in a growing number of studies (Louis et al. 2010a, b; Rao et al. 2011; Singer
et al. 1994; Deuschl et al. 2000; Stolze et al. 2001; Kronenbuerger et al. 2009) pos-
tural instability and mild to moderate ataxic gait, beyond that seen in normal aging,
have been demonstrated in patients with ET. In addition, subtle eye movement
abnormalities have also been observed in patients with ET (Helmchen et al. 2003).
These types of studies further support the notion that there is cerebellar dysfunction
in this disease.
The presence of a variety of nonmotor features, including specific personality
traits (Chatterjee et al. 2004; Lorenz et al. 2006), anxiety (Tan et al. 2005a, b),
depressive symptoms (Louis et al. 2001a, b, c, d, 2007a, b; Dogu et al. 2005; Miller
et al. 2007) and social phobia (Schneier et al. 2001), is gaining wider recognition
(Findley 2004; Louis 2005a, b). In one study (Louis et al. 2007a, b), depressive
symptoms were more common in ET cases than controls, and these symptoms pre-
ceded the onset of the motor manifestations, suggesting that they could be a primary
manifestation of the disease. Mild cognitive changes (esp. executive dysfunction)
have been documented in many studies (Gasparini et al. 2001; Lombardi et al. 2001;
Vermilion et al. 2001; Duane and Vermilion 2002; Lacritz et al. 2002; Benito-Leon
et al. 2006a, b), and increased odds or risk of dementia has been demonstrated in
two population-based studies (Benito-Leon et al. 2006a, b; Bermejo-Pareja et al.
2007). These data suggest that, as in several other progressive movement disorders
(Parkinson’s disease and Huntington’s disease), cognitive-neuropsychological features
are a part of this disease in addition to involuntary movements. The mechanistic
basis for these cognitive disturbances in ET is not clear, although the cerebellum has
been implicated in the milder deficits (Troster et al. 2002). The associated dementia
in ET is an Alzheimer’s type dementia. There is a sizable literature demonstrating
that neurodegenerative diseases may be associated with one another, with the notion
being that the development of one such disorder is a marker of a biological propen-
sity/vulnerability for the development of others (Louis and Okun 2011). For exam-
ple, the co-occurrence of amyotrophic lateral sclerosis with frontotemporal dementia
within individuals and within families is well-documented (Zago et al. 2011), and it
is well-established that a high proportion of Parkinson’s disease patients with
dementia have concurrent AD (Shi et al. 2010).
In summary, the traditional clinical view of ET as no more than an isolated
nonspecific action tremor is being challenged by a view of ET as a disease entity in
which the tremor phenomenology on the one hand is manifold (i.e., kinetic tremor,
postural tremor, intention tremor, rest tremor, arm tremor, leg tremor, cranial tremors,
etc.) but on the other hand follows certain distinctive, definable patterns (e.g., rest
tremor tends to occur as a late feature, women are more likely to develop head tremor,
later age of onset is associated with more rapidly progression). Along with the trem-
ors, gait abnormalities and other signs of cerebellar dysfunction as well cognitive-
psychiatric features seem to characterize this disease as well. The disease itself also
seems to increase the likelihood of developing other degenerative diseases of the
central nervous system, including Parkinson’s and Alzheimer’s disease, so that ET
itself may be viewed on some level as a risk factor for these other conditions.
10.2.5 Diagnosis
The diagnostic approach to patients with ET should begin with a medical history
and a physical examination. In select situations, laboratory tests may also be ordered
(Louis 2001a, b).
The diagnosis of ET is still made by history and physical examination. Thus,
there is no test to validate a clinical diagnosis of ET. To aid in the diagnosis, several
clinical criteria have been proposed, including those by the Consensus Statement on
Tremor by the Movement Disorder Society (Deuschl et al. 1998), which were
modified slightly by the Tremor Research Group (Elble 2000). The Washington
Heights-Inwood Genetic Study of ET criteria are similarly useful, particularly for
genetic and epidemiological studies, in which the distinction between ET and
enhanced physiological tremor is essential (Louis et al. 1997a, b). Each of these
diagnostic schemes focuses mainly on the severity and characteristics of the kinetic
tremor.
During the history, the clinician should collect information on localization of
tremor, the age of onset, and progression of tremor over time. Caffeinated beverages,
cigarettes, and numerous medications (e.g., bronchodilators, lithium, methylpheni-
date, prednisone, pseudoephedrine, theophylline, and valproic acid) can exacerbate
enhanced physiological tremor, which can resemble ET. Thus, taking a complete
184 E.D. Louis
inventory of current medications and use of caffeine and tobacco products is sug-
gested. Patients with tremor due to other disorders such as hyperthyroidism, Parkinson’s
disease, or Wilson’s disease frequently have concomitant symptoms that lead the cli-
nician to these diagnoses (Louis 2001a, b, 2005a, b; Benito-Leon and Louis 2007).
For example, patients with hyperthyroidism may complain of palpitations, hyperac-
tivity, increased sweating, heat hypersensitivity, fatigue, increased appetite, weight
loss, insomnia, weakness, frequent bowel movements, or hypomenorrhea (Nayak and
Hodak 2007; Nygaard 2007). Patients with Parkinson’s disease often complain of
limb stiffness and rest tremor. Psychiatric manifestations often accompany Wilson’s
disease; these may include psychosis or more subtle signs, such as difficulties with
school work or job performance, personality changes, emotionality, loss of sexual
inhibition, insomnia, and aggressiveness (Pfeiffer 2007; Mak and Lam 2008).
During the neurological examination, the clinician should carefully evaluate the
characteristics of the movements. To begin, the clinician should determine that the
movement is indeed a tremor and not some other type of involuntary movement.
Tremor, by definition, is a rhythmic and oscillatory movement. “Rhythmic” indi-
cates that it is regularly recurrent and “oscillatory” means that the movement
alternates around a central plane. Signs of systemic diseases should also be noted.
For example, patients with hyperthyroidism may have warm, moist skin, tachycar-
dia, widened pulse pressure, and atrial fibrillation (Louis 2001a, b, 2011).
It is important to distinguish ET patients from those with Parkinson’s disease.
While patients with Parkinson’s disease often manifest a mild to moderate postural
tremor or kinetic tremor (Koller et al. 1989; Jankovic et al. 1999), rest tremor is also
present in approximately 85% (Louis et al. 1997a, b) of patients with autopsy-
proven Parkinson’s disease. While rest tremor can accompany ET, it usually occurs
in the setting of severe kinetic tremor of long duration and generally involves the
arm and not the leg. While mild cogwheeling can occur in ET, it does not occur in
the setting of increased tone, as is seen in Parkinson’s disease. Other features of
Parkinson’s disease that generally do not occur in patients with ET are hemi-body
involvement (e.g., ipsilateral arm and leg tremor) and bradykinesia. The postural
tremor of ET also tends to involve wrist flexion and extension whereas in Parkinson’s
disease, wrist rotation often occurs. Furthermore, in Parkinson’s disease, the pos-
tural tremor may involve prominent thumb flexion and extension and it may be
greater in amplitude than the kinetic tremor (Louis 2011).
It is also important to distinguish ET from enhanced physiological tremor.
Enhanced physiological tremor is an 8–12 Hz postural and kinetic tremor that may
occur in the limbs and voice (but not the head) and may be further exacerbated by
emotion and by medications (Elble 2003). While the amplitude of kinetic tremor in
ET is generally higher and the frequency lower than that of enhanced physiological
tremor, mild ET and severe enhanced physiological tremor may have similar tremor
amplitudes (Elble 2003). In this setting, quantitative computerized tremor analysis,
with accelerometers attached to the arms, which is available at some tertiary care
centers, may guide the clinician; inertial loading of the limbs leads to a reduction
in tremor frequency in ET tremor but not in the predominant, peripherally gener-
ated component of enhanced physiological tremor (Louis 2011).
Patients with dystonic tremor are often misdiagnosed as having ET (Jain et al.
2006). Dystonic tremor may occur in the limbs or neck. Dystonic neck tremor is
often neither rhythmic nor oscillatory and it may be accompanied by dystonic pos-
turing of the neck and hypertrophy of neck muscles (esp. the sternocleidomastoid).
Also, it tends to continue when the patient is supine, in contrast to the head tremor
of ET, which generally resolves in the supine position. Dystonic hand tremor is
similarly often neither rhythmic nor oscillatory and it may be accompanied by dys-
tonic posturing of the hands. This is often best evidenced by asking the patient to
hold their arms extended in front of their body for 30–60 s. In this setting, dystonic
thumb flexion and other dystonic postures (flexion of the wrist with hyperextension
of the fingers [i.e., “spooning”]) may be evident (Louis 2011).
The final step in the evaluation of the patient who is suspected of having ET is
the laboratory evaluation. Thus, if symptoms or signs of hyperthyroidism are pres-
ent, then thyroid function tests should be performed. In younger patients (i.e., under
40 years old) with no family history of ET or dystonia, the possibility of Wilson
disease should be explored with a serum ceruloplasmin, which may be reduced; this
is usually not an issue in older patients. Striatal dopamine transporter imaging may
be useful in distinguishing patients with ET from Parkinson’s disease. Values in
Parkinson’s disease patients are lower than those of controls; while some ET patients
may have reduced values, in general, their values are similar to those of controls
(Antonini et al. 2001), but such testing is rarely necessary as the diagnosis of
Parkinson’s disease can generally be made with a careful history and physical
examination (Louis 2011).
10.3 Other Kinetic Tremors
As noted above, ET is the most common pathological form of kinetic tremor. Other
kinetic tremors include dystonic tremor and orthostatic tremor, both of which are
the topics of separate chapters in this book. Hence, the remainder of this discussion
will focus on those forms of kinetic tremor that are not covered in separate chap-
ters. These include drug-induced kinetic tremor, the kinetic tremors that may be
associated with various disease entities (Wilson’s disease, fragile X tremor ataxia
syndrome, peripheral neuropathy, Parkinson’s disease), primary writing tremor,
and rubral tremor.
10.3.1 Drug-Induced Kinetic Tremor
As noted above, a variety of medications may produce kinetic tremor, which can range
in severity from mild to marked (Deuschl et al. 1998; Morgan and Sethi 2005). These
medications include but are not limited to bronchodilators, lithium, methylphenidate,
prednisone, pseudoephedrine, theophylline, valproic acid, tricyclic antidepressants,
186 E.D. Louis
and calcineurin inhibitors (e.g., tacrolimus). Among the more commonly reported of
thee tremors is lithium-induced kinetic tremor (Gelenberg and Jefferson 1995; Morgan
and Sethi 2005).
The mechanism for drug-induced kinetic tremor is not fully established, although
it is believed to be a form of enhanced physiological tremor (Deuschl et al. 1998).
Thus, an increase in the gain of the muscle receptors and spinal reflex loops is
thought to lead to an enhancement of oscillations in peripheral physiological tremor
(Foley et al. 1967; Homberg et al. 1987; Raethjen et al. 2001). Yet there is also some
evidence that some forms of drug-induced kinetic tremor may also be mediated
through central mechanisms (Raethjen et al. 2001). Lithium salts may have a genu-
ine cerebellar toxicity (Grignon and Bruguereolle 1996).
The following features help to distinguish drug-induced kinetic tremor from
other forms of tremor (1) By history, there should be a link between the onset of
the tremor and the use of a medication that is presumed to be causing the tremor,
with the onset of tremor following the use of the medication. The onset may not
be immediate, but may occur gradually over several months. (2) There may be a
dose–response relation such that higher doses of medication are associated with
increased tremor amplitude. (3) Discontinuing the medication should result in the
complete resolution of tremor. (4) While limb tremor may be present, head tremor
should not be a feature of drug-induced action tremor. (5) The tremor should not
progressively worsen, in contrast to the tremor of ET or Parkinson’s disease
(Morgan and Sethi 2005).
10.3.2 Kinetic Tremor of Wilson’s Disease
Patients with Wilson’s disease may present with a wide range of movement disor-
ders, and tremor is among these (Lorincz 2010; Oder et al. 1991; Stremmel et al.
1991; Walshe and Yealland 1992; Frucht et al. 1998; Brewer 2005; Machado et al.
2006; Soltanzadeh et al. 2007), ranking among the eight major complaints reported
by neurological patients with this disease (Walshe and Yealland 1992). These trem-
ors are usually associated with other neurological signs, although there are rare
reports of isolated tremor and even rarer reports of isolated action tremor (Frucht
et al. 1998; Soltanzadeh et al. 2007). Most of the large case series focus on the broad
panoply of neurological signs, and a focused and detailed characterization of the
tremor phenomenology is generally lacking. Furthermore, the phenomenology does
seem to be considerably varied. Thus, across patients, a wide range of tremors may
accompany Wilson’s disease, and these may include kinetic tremor as well as resting
tremor, postural and intention tremors, tremors that are either symmetric or
asymmetric, those that are low amplitude and high amplitude, and those that are
intermittent and progressive (Lorincz 2010; Starosta-Rubinstein et al. 1987). Within
patients, a variety of different tremors may be present as well (Lorincz 2010;
Soltanzadeh et al. 2007). According to one series, 32% of patients exhibited tremor
at the time of their first neurological evaluation at a tertiary care center (Starosta-
Rubinstein et al. 1987); in another retrospective review of patients seen in a tertiary

referral center, 60% of patients exhibited tremor at some point (Machado et al.
2006). Tremor most commonly occurs in the hands, with 82% of patients having
hand tremor according to one report (Saito 1987). Although postural tremor has
been reported to be the most common type of tremor (Oder et al. 1991; Machado
et al. 2006), the classic wing-beat tremor, present on abduction of the shoulder and
flexion of the elbow, is well described, although it is not the most commonly
observed type of tremor (Lorincz 2010; Starosta-Rubinstein et al. 1987). Most
patients present well before the age of 40, and the laboratory work-up may reveal
low serum ceruloplasmin, abnormal brain MRI (lesions in the basal ganglia), high
24 h urine copper, abnormal slit lamp examination (Kayser Fleischer rings), ele-
vated liver function tests, or abnormal liver biopsy (Walshe and Yealland 1992).
10.3.3 Kinetic Tremor of Fragile X Tremor Ataxia Syndrome
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited degenera-

tive disorder that primarily affects older men and is associated with an array of
neurological symptoms and signs (Leehey 2009). The syndrome is caused by a
CGG repeat expansion in the premutation range (i.e., 55–200 repeats) in the 5¢
noncoding region of the fragile X mental retardation 1 (FMR1) gene. Classically,
FXTAS patients are men in their 60s who develop intention tremor, progressive
cerebellar ataxia, parkinsonism, and cognitive decline (Leehey 2009). Almost all
affected persons develop problematic cerebellar gait ataxia as the disorder pro-
gresses (Leehey 2009).
Tremor is one of the earliest signs (Leehey et al. 2007), and in one series, 70%
of FXTAS patients developed intention tremor and 10% had isolated rest tremor
(Leehey 2009). The tremor phenomenology in FXTAS has variably been
described as “action” or “intention” tremor (Berry-Kravis et al. 2007; Loesch
et al. 2007; Aguilar et al. 2008; Leehey 2009) and many patients likely have
mixed phenomenology (i.e., kinetic tremor with an intentional component)
(Berry-Kravis et al. 2007). Other authors have described the presence of postural
tremor in these patients (Berry-Kravis et al. 2007; Davous et al. 2007; Loesch
et al. 2007), again pointing to what is likely a mixed tremor that varies with posi-
tion. The tremor may vary in severity from mild and asymptomatic to severe and
disabling (Leehey 2009), although one retrospective cohort study reported that
tremor becomes considerably disabling within 13 years of onset of motor symp-
toms (Leehey et al. 2007). It has been noted that affected persons usually have
definite tremor reduction with use of medications that are commonly prescribed
in the treatment of ET (Leehey 2009), and an occasional patient will have iso-
lated action tremor that resembles that seen in patients with ET (Peters et al.
2006; Leehey 2009), although as noted above, most patients have a constellation
of neurological signs in addition to tremor.
188 E.D. Louis
10.3.4 Kinetic Tremor in Patients with Peripheral Neuropathy
Several types of acquired and familial neuropathies may be associated with postural
and kinetic tremors of the arms (Kamei et al. 1993; Pedersen et al. 1997; Saverino
et al. 2001; Budak et al. 2005; Alonso-Navarro et al. 2008) and in the case of some
neuropathies (e.g., IgM demyelinating paraproteinemic neuropathy), up to 90% of
patients are reported to have such tremor (Bain et al. 1996). Neuropathic tremor can
generally be diagnosed based on history and physical examination. By history,
patients with this type of tremor have a coexisting peripheral neuropathy of the
same limbs that are tremulous (i.e., the tremor occurs in limbs that are affected by
the neuropathy). Also, by history, the neuropathy and the tremor should be tempo-
rally linked, with tremor accompanying or following the neuropathy. On examina-
tion, a peripheral neuropathy characterized by sensory deficits, weakness, and/or
diminished/absent deep tendon reflexes is readily apparent in the tremulous limb(s)
(Said et al. 1982; Barbieri et al. 1984; Dalakas et al. 1984; Cardoso and Jankovic
1993; Bain et al. 1996; Budak et al. 2005); some data suggest that the severity of the
weakness does not correlate with the severity of the tremor (Dalakas et al. 1984).
The tremor is often asymmetric (Saverino et al. 2001; Budak et al. 2005). Tremor
may disappear if weakness becomes so severe that the muscle is no longer contract-
ing or conversely if muscle strength returns to normal. As the etiologies of neuro-
pathic tremor are diverse, the underlying mechanisms are likely to be equally
diverse. Even within the category of tremors associated with demyelinating periph-
eral neuropathy, data indicate that one groups of patients have tremor that is modified
by inertial weighting while other patients have tremor that is less affected by such
weighting (Pedersen et al. 1997). The latter suggests that there may be a central
component that underlies these demyelinating peripheral neuropathic tremors, and
some have suggested that this involves an abnormal afferent sensory input from the
periphery to the thalamus followed by changes in cerebellar output. Support for this
notion comes from the observation that some patients with such neuropathies
respond to deep brain stimulation surgery (Ruzicka et al. 2003; Bayreuther et al.
2009; Breit et al. 2009; McMaster et al. 2009).
10.3.5 Kinetic Tremor in Parkinson’s Disease
Although rest tremor is one of the hallmark features of Parkinson’s disease, a large
proportion of patients also have postural and/or kinetic tremors of the arms (Lance
et al. 1963; Hoehn and Yahr 1967; Koller et al. 1989; Rajput et al. 1991a, b; Brooks
et al. 1992; Louis et al. 1997a, b, 2001a, b, c, d; Jankovic et al. 1999; Forssberg et al.
2000). The kinetic tremor is often but not always more severe on the side with more
severe parkinsonism, and may range from mild to severe. Sometimes the postural
and kinetic tremor have a re-emergent quality; this so-called “re-emergent tremor”
surfaces after a latency of one or several seconds, has a frequency that is similar to
that of the rest tremor in Parkinson’s disease, and often attains amplitudes greater
than that seen in patients with ET (Jankovic et al. 1999). The tremor is often asym-
metric and tends to increase in severity (i.e., crescendo) with sustained posture or
during the course of repetitive movements during which much of the limb is immo-
bile (e.g., while pouring water between two cups, during which much of the move-
ment is proximal rather than distal). Re-emergent tremor may at times occur in
patients who do not have rest tremor (Louis et al. 2008a, b, c, d, e, f).
10.3.6 Primary Writing Tremor
This is a hand tremor that occurs primarily or only during writing but not during
other tasks that involve the active hand (Bain et al. 1995; Deuschl et al. 1998). The
present definition of primary writing tremor excludes patients who while writing
have dystonic postures with hand tremor (i.e., dystonic writing tremor) (Deuschl
et al. 1998). The tremor has a similar frequency to that seen in patients with ET (i.e.,
between 4 and 8 Hz) and in 30–50% of cases is relieved by ethanol consumption
(Bain et al. 1995). In one study, patients were subdivided into those having type A
and type B primary writing tremor, depending on whether tremor appeared during
writing (i.e., type A or “task induced tremor”) or while adopting the hand position
used in writing (i.e., type B or “positionally sensitive tremor”) (Bain et al. 1995). The
mechanisms that underlie primary writing tremor are unclear and it is debated
whether it represents a variant of ET or a variant of dystonia (Bain 2011; Kachi et al.
1985; Koller and Martyn 1986; Cohen et al. 1987; Elble et al. 1990; Deuschl et al.
1998), and in some families all three conditions may be present (Cohen et al. 1987).
10.3.7 Rubral Tremor
This type of tremor has also been referred to as “Holmes’ tremor” or “midbrain
tremor” (Kiriyama et al. 2011; Deuschl et al. 1998; Yang et al. 2005; Liou and Shih
2006). When occurring in the setting of a stroke, the tremor may arise after a latency
of months to years; the tremor may occur in a variety of other settings (e.g., in the set-
ting of a brain tumor or slowly expanding vascular lesion). The tremor is generally
unilateral and has three components: rest, postural, and kinetic/intentional with the
severity being such that kinetic > postural > rest. The tremor is usually severe and dis-
abling, often rendering the affected limb functionally useless. Patients may also have
other neurological signs (e.g., dystonia, ataxia). On brain imaging, a lesion is often but
not always present in the pontine-midbrain region, affecting cerebellar outflow tracts
and dopaminergic nigrostriatal fibers (Samie et al. 1990; Goto and Yamada 2004).
There are reports of lesions occurring elsewhere (e.g., thalamus) (Mossuto-Agatiello
et al. 1993; Tan et al. 2001), which is one of the motivations for referring to the tremor
as “Holmes’ tremor” rather than “rubral tremor” (Deuschl et al. 1998).
190 E.D. Louis
10.4 Kinetic Tremor. Conclusions
Kinetic tremors are extremely common. Indeed, physiological or enhanced physio-

logical tremor is the most common form of normal tremor (Elble 1998a, b, 2003;
Louis et al. 1998a, b, c), present in most normal individuals, and ET, the most com-
mon pathological form of kinetic tremor, occurs in 4% of individuals over the age
of 40 and as many as 20% of the oldest old (Louis and Ferreira 2010). A wide range
of other forms of kinetic tremor were discussed in this chapter. Hence, these tremors
are commonly seen in a variety of clinical practice settings. A basic understanding
of their underlying mechanisms and a detailed understanding of their clinical
features will aid in diagnosis and treatment of these disorders.
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Chapter 11
Dystonic Tremor
Stefania Lalli and Alberto Albanese
Abbreviations
CD Cervical dystonia
DAT-SPECT Dopamine transporter single photon emission computed tomography
DBS Deep brain stimulation
ET Essential tremor
PD Parkinson’s disease
PWT Primary writing tremor
SWEDD Scans without evidence of dopaminergic deficit.
Keywords Dystonia • Mirroring • Sensory tricks • Torticollis • Spasmodic dysphonia

• Primary writing tremor
Tremor is the most common movement disorder, known since the time of Galen,
and defined as a rhythmic involuntary movement of one or several regions of the
body (Albanese and Jankovic 2012). Many attempts have been made in the last
century to define and classify normal and pathological tremors, but a comprehen-
sive summary did not exist until the Movement Disorder Society developed a first
consensus statement (Deuschl et al. 1998). Among several types of tremor,
essential tremor (ET) is the most common, although its epidemiology is still
unclear (see also Chap. 10). The clinical signs and symptoms of ET are much
S. Lalli, M.D., Ph.D.

Fondazione Istituto Neurologico Carlo Besta, Via G. Celoria, 11 20133, Milano, Italy
e-mail: alberto.albanese@unicatt.it
A. Albanese, M.D. (*)
Fondazione Istituto Neurologico Carlo Besta, Via G. Celoria, 11 20133, Milano, Italy
Istituto di Neurologia, Università Cattolica del Sacro Cuore, Milano, Italy
e-mail: alberto.albanese@unicatt.it
204 S. Lalli and A. Albanese
broader than previously thought, ranging from a relatively benign postural tremor
to a disabling kinetic or intention tremor that affects the hands and also the head
(Leegwater-Kim et al. 2006). Even rest tremor has been observed in advanced ET.
A tremor similar to ET may occur in dystonia and can be mistaken for non-
dystonic tremor, particularly when it is isolated (Lalli and Albanese 2010). Various
types of focal task-specific tremors (e.g., vocal tremor, primary writing tremor)
have been described in the past 35 years and it is still a matter of debate whether
these tremors are focal tremulous dystonias, focal essential tremors, or an inde-
pendent condition.
The term “dystonic tremor” appeared in the 1980s in papers recognizing that
dystonic patients sometime have rhythmic movements, particularly in the arms and
neck, manifesting as tremor (Jankovic and Fahn 1980). This concept was not easy
to accommodate and the current consensus statement from the Movement Disorder
Society defines dystonic tremors by three features: an associated dystonic posture,
irregular amplitudes and frequency (usually 7 Hz), and postural/intentional tremor
rather than resting tremor (Deuschl et al. 1998). This consensus attempted to distin-
guish dystonic tremor from tremor associated with dystonia, a more generalized
tremor type observed in limbs that are not affected by the dystonia. This is a rela-
tively symmetrical type, often seen in the upper limbs in patients with spasmodic
torticollis (Munchau et al. 2001). Isolated action tremor can be the initial symptom
of dystonia, and dystonia may develop years after the onset of isolated tremor in the
neck, trunk, or limbs (Deuschl 2003). Consequently, isolated focal and task-specific
tremors should raise the suspicion of dystonia, and long-term follow-up may be
confirmatory.
11.1 Epidemiology
Primary dystonia, the most common form of dystonia, includes early-onset

dystonia with onset in a limb and a tendency to generalize, and late-onset dysto-
nia, which most commonly presents with a focal or a segmental form. Focal
dystonias are adult-onset forms that affect a specific area of the body: eyes,
mouth, vocal cords, neck, hands, and feet. Types of focal dystonia include
blepharospasm, cervical dystonia (spasmodic torticollis), oromandibular dysto-
nia (cranial dystonia), laryngeal dystonia (spasmodic dysphonia), and hand dys-
tonia (writer’s cramp) (Albanese 2003). Among focal dystonias, cervical dystonia
(CD) is the most common form seen by neurologists with a prevalence ranging
from 5.7 to 6.1 per 100,000 persons (Stacy 2008). Patients with CD may have
coexisting signs of limb tremor (Velickovic et al. 2001) or head tremor and trunk
(Rivest and Marsden 1990), which makes differential diagnosis between dys-
tonic and essential tremor difficult.
ET is the most common adult movement disorder, although its epidemiology
is still unclear. As a result of application of imprecise and variable diagnostic
11 Dystonic Tremor 205
criteria, prevalence estimates range from 0.4% to 3.9%, with an increase with
age (Louis et al. 1998). More recently, three large population-based surveys with
narrow diagnostic criteria found prevalence data of 4%, 4.8%, and 3.06% (Benito-
Leon et al. 2003; Dogu et al. 2005; Wenning et al. 2005). In a retrospective
45-year study, the age-adjusted incidence was estimated to be 17.5/100,000 per
year (Rajput et al. 1984); a large population-based study in Spain reported an
incidence rate of 616/100,000 per year in a population older than 65 years
(Benito-Leon et al. 2005).
The prevalence of dystonic tremor is not known. In one Brazilian cross-sectional
study, the evaluation of the frequency of postural hand tremor in idiopathic and
symptomatic dystonia patients showed that tremor might be seen in 22.5% of pri-
mary dystonia and in 21.5% of secondary dystonia (Ferraz et al. 1994). In a large
survey of patients from a large Indian movement disorder center, dystonic tremor
constituted about 20% of all patients presenting with non-parkinsonian and non-
cerebellar tremors (essential tremor, 60%) (Shukla and Behari 2004).
11.2 Phenomenology
ET is a slowly progressive tremor disorder that sometimes causes severe disability,

but is not life-threatening. Its phenomenology has been reviewed in Chap. 10
(Essential Tremor and Other Forms of Kinetic Tremor). The traditional view of ET
as a monosymptomatic disorder has been revised when its complexity and hetero-
geneity have been recognized (Lou and Jankovic 1991). ET may begin in childhood,
but its incidence increases after 40 years, with a mean onset of 35–45 years in dif-
ferent studies. The few data available on the progression of this condition have
shown a decrease of tremor frequency in the elderly with a linear relationship
between age and tremor frequency decrement and a tendency to develop larger
amplitudes (Elble 2000a).
ET usually starts with a postural tremor that can still be suppressed during goal-
directed movements. In advanced stages, an “intention” (kinetic) tremor can develop.
This is accompanied by signs of cerebellar dysfunction of hand movements like
movement overshoot and slowness of movements (Deuschl et al. 2000). In more
advanced stages, a resting tremor can develop. Also, a mild gait disorder observed
during tandem gait is frequently found (Stolze et al. 2001). Kinetic tremor develops
at various intervals between 3 and 30 years after the onset of postural tremor (Deuschl
et al. 2000). Disease-related disability varies greatly and is dependent on the severity
of intention tremor. ET affects the hands in 94% of cases, the head in 33%, the voice
in 16%, the legs in 12%, the jaw in 8%, the face in 3%, and the trunk in 3% (Elble
2006). In some body areas (e.g., head, voice, or chin), tremor may occur in isolation.
About 50–90% of the patients improve with alcohol ingestion.
11.2.2 Dystonia
Dystonia is a neurological syndrome characterized by involuntary muscle contrac-

tions causing twisting, repetitive movements, or abnormal postures. Etiologically
dystonia syndromes can be primary or secondary. In primary forms there is no
identifiable exogenous cause or evidence of neurodegeneration, and dystonia is the
only sign of the disease (with the only possible addition of tremor); the cause is
either genetic or unknown. Non-primary forms encompass heredodegenerative syn-
dromes, where dystonia is a prominent sign of a heredodegenerative condition and
symptomatic syndromes, where dystonia is due to exogenous factors (e.g., perinatal
injury, medications, brain tumor, infections, etc.). In 1984, an ad hoc committee of
the Dystonia Medical Research Foundation documented the occurrence in all forms
of dystonia “of sustained muscle contractions, frequently causing twisting and
repetitive movements, or abnormal postures” (Fahn et al. 1987); later, it was recog-
nized that the association of slow tonic posturing with faster (phasic) movements
and tremor is the clinical hallmark of this movement disorder (Albanese 2003). The
combination of tremor and dystonia is a feature of almost all dystonia syndromes
and may be easily recognized. Isolated dystonic tremor, instead, is often misdiag-
nosed for ET (Lalli and Albanese 2010).
Similarly to ET, the prevalence values for primary dystonia vary greatly. It is
reckoned that there are between 0.2 and 5 cases per 100,000 for early-onset cases,
and between 3 and 732 cases per 100,000 for late-onset cases (Defazio et al. 2004).
A possible explanation of such ample variability of incidence and prevalence values
is the difficulty or the delay of the clinical diagnosis and lack of diagnostic markers.
There is no dopaminergic denervation either in dystonia or in ET resulting in a nor-
mal dopamine transporter single photon emission computed tomography (DAT-
SPECT) (Kagi et al. 2010). The most obvious reason for diagnostic errors is lack of
appreciation of the specific clinical features of dystonia, which can be appreciated
by using a structured diagnostic flow chart (Albanese and Lalli 2009). Table 11.1
proposes a recently systematized description of the cardinal physical signs observed
in dystonia (Albanese 2007). Overflow is observed when dystonia extends to a con-
tiguous body region where it is not observed as an independent phenomenon. An
example is overflow to the upper limb in patients with cervical dystonia. Mirroring
occurs when, during a voluntary task involving a limb, similar albeit involuntary
movements (often with dystonic features) arise in the contralateral limb. Mirroring
is not a specific feature of dystonia, although it may reveal a latent dystonia, particu-
larly in subjects belonging to dystonia families. Mirroring can be considered as a
minimal expression of focal dystonia observed in otherwise unaffected body regions.
Dystonic movements and postures may be alleviated by some specific voluntary
movements, also called gestes antagonistes, or by “sensory tricks.” Their presence
strongly supports the diagnosis of dystonia. When the full-house phenomenology is
observed, the clinical diagnosis is plainly achieved by direct physical examination.
Otherwise, additional clinical signs are necessary. The observation of abnormalities
at the electromyography (EMG) that are typical of dystonia is helpful when the
clinical features are considered insufficient for the diagnosis (Pullman et al. 2000).
Table 11.1 Clinical criteria for the physical signs observed in patients with dystonia [from
Albanese and Lalli (2009)]
Physical sign Description
Dystonic postures • A body part is flexed or twisted along its longitudinal axis
(not available for blepharospasm or laryngeal dystonia)
• A sensation of rigidity and traction is present in the affected part
Dystonic movements These features have to be looked for in all movement disorders, either
fast or slow, also when the immediate impression is that of a
“tremor,” “tic,” “chorea,” or “myoclonus”
• A twisting nature or a pull in a preferred direction is detected
(also when the movement appears as tremor)
• Movements are repetitive and patterned (i.e., consistent and
predictable)
• Movements are often sustained at their peak to lessen when a given
posture (usually opposite to the preferred direction) is identified
(“null point”)
Gestes antagonistes • Alleviation of dystonia occurs during the geste movement, usually
(“sensory tricks”) soon after its start
• Alleviation may last for as long as the geste or slowly reverses
spontaneously before its end
• The geste movement is natural and “elegant,” never forceful
• The geste movement does not push or pull the affected body part,
but simply touches it (“sensory trick”) or accompanies it during
alleviation of dystonia
Mirror dystonia • At least three different types of repetitive tasks (e.g., finger sequence,
normal writing, or piano-like movements) are performed at low and
fast speed in the non-affected limb
Overflow dystonia • Dystonic movement or dystonic postures extend beyond the
commonly involved body region
• It is observed at least once, ipsilaterally or contralaterally, either
by inspection or EMG mapping, in coincidence with the peak of
dystonic movements
11.2.3 Dystonic Tremor
This is a debated entity and different descriptions have been made without achiev-
ing consensus on a unitary definition (Table 11.2). Dystonic tremor is frequently
observed in patients with dystonia who often show tremulous muscle activities.
Virtually any dystonic syndrome may manifest with dystonic tremor. The EMG-
pattern may be more variable than in other tremors such as essential tremor or par-
kinsonian tremors (Deuschl 2003). Burst-like activity may be synchronous or
asynchronous (Cohen and Hallett 1988), without a detectable agonist–antagonist
coupling. The Movement Disorder Society Consensus Statement on Tremor
(Deuschl et al. 1998) considered a continuous gradient between tremor and dystonia
with three possible transition spectra: dystonic tremor, tremor associated with dys-
tonia, and dystonia gene-associated tremor.
Dystonic tremor is considered a tremor in a body part affected by dystonia. This
involves: tremor in an extremity or body part that is affected by dystonia, focal
Table 11.2 Timeline for definitions of dystonic tremor

Year Descriptions of dystonic tremor
1976 Dystonia and tremor in spasmodic torticollis patients (Couch 1976)
1976 Benign essential tremor in combination with idiopathic torsion dystonia
(Marsden 1976)
1978 Clinical features of 12 patients with spasmodic dysphonia: the voice was
strained, harsh, tight, and tremulous (Aminoff et al. 1978)
1988 Focal tremor and focal dystonia related to generalized essential tremor and
generalized dystonia (Rosenbaum and Jankovic 1988)
1989 The “yips” is an involuntary motor disturbance affecting golfers described most
frequently as jerks, tremors, and spasms affecting the preferred arm distally
and primarily during putting (McDaniel et al. 1989)
1990 Patients presenting with isolated tremors of the trunk or neck are described.
Their clinical features were similar to seven other patients who presented
with head tremor, or arm and head tremor, but then eventually developed
obvious torticollis, sometimes with arm dystonia (Rivest and Marsden 1990)
1990 Patients with reflex sympathetic dystrophy (RSD) who manifested abnormalities
of movement. The patients had focal dystonia, weakness, spasms, tremor,
difficulty initiating movement, and increased tone and reflexes (Schwartzman
and Kerrigan 1990)
1991 Patients with early-onset ET were more likely to have hand involvement and
associated dystonia than patients with late-onset ET. Dystonia was more
frequently associated with mild ET than with severe ET (Lou and Jankovic
1991)
1991 Dystonic tremor in idiopathic dystonia described to be postural, localized, and
irregular in amplitude and periodicity, absent during muscle relaxation,
exacerbated by smooth muscle contraction. “Although it resembles essential
tremor, dystonic tremor seems to be a distinct entity: it is more irregular with
a broader range of frequencies; it is asymmetric and remains localized;
myoclonus is sometimes associated. This type of tremor is most often seen in
the presence of dystonia, but may be observed without evident dystonic
symptoms” (Jedynak et al. 1991)
1996 Cases of focal tremors induced by different specific tasks. There was no overt
dystonia in any of the cases, but these tremors may be forms of focal
dystonia, rather than a manifestation of essential tremor (Soland et al. 1996)
tremors, usually with irregular amplitudes and variable frequency (mainly less than
7 Hz), and mainly postural/kinetic tremors usually not seen during complete rest.
Tremor associated with dystonia is a tremor occurring in a body part not affected by
dystonia, although the patient has dystonia elsewhere. In dystonia gene-associated
tremor, tremor is an isolated finding in patients with a dystonic pedigree. These
definitions are quite clear, albeit artificial and unpractical. Furthermore, patients
who exhibit focal tremors without overt signs of dystonia have been retrospectively
considered to have a dystonic tremor (Rivest and Marsden 1990) because later
developed overt dystonia. There are neurophysiological evidences that such tremors
preceding the onset of dystonic tremor are common among patients presenting oth-
erwise with essential-like tremor (Munchau et al. 2001). It is not uncommon that
patients with dystonic tremor may be considered to have parkinsonian or essential
tremor and—at a closer look—are found to match diagnostic criteria for dystonia.
Gestes and mirroring are particularly helpful for orientation and should be looked
for in all cases of primary tremor disorder. Hand mirror movements have also been
described in ET (Louis et al. 2009), being more common in ET cases with rest
tremor (18.8%) than in cases without rest tremor (14.3%). Differently from ET,
dystonic tremor does not occur during rest and the incidence of a mirroring associ-
ated with postural or kinetic hand tremors should lead, at first, to a suspicion of
dystonic tremor.
There are no descriptions of mirroring in sites different from the hands in patients
with ET, whereas mirroring occurs in all districts of dystonic movements. Many
patients with dystonic tremor use their own tricks (geste antagoniste or sensory
tricks) to reduce the tremor amplitude. This is well known for dystonic head tremor
in the setting of cervical dystonia with tremor reduction if patients touch the head or
only lift the arm (Masuhr et al. 2000). The effect of these maneuvers can sometimes
be difficult to observe clinically, and may be revealed by suppression of surface
EMG from the affected muscles (Masuhr et al. 2000). Other important, albeit less
specific, diagnostic clues are the focal nature and low frequency of dystonic tremor.
In addition to these features, dystonic tremor may also be distinguished by some
other possible features, including a “null point” (i.e., specific posture which when
held by the patient alleviates the tremor), and features atypical for ET (e.g., lack of
tremor when the finger touches the nose, but severe tremor when attempting an arm
movement toward an extended target such as an examiner’s finger) (Jedynak
et al. 1991).
The diagnosis of dystonia can be missed or delayed in a number of patients with
task- and position-specific tremors, particularly primary writing tremor (PWT),
occupational tremors, or isolated voice tremor, as typical features of dystonia may
not develop until after many years from onset (Rivest and Marsden 1990). The dif-
ferential diagnosis between ET and dystonia may be difficult and their phenomeno-
logical overlap is well accounted. A tremor similar to ET may occur in dystonia and
can be mistaken for non-dystonic tremor, particularly when it is isolated (Lalli and
Albanese 2010). For example, head or voice tremors observed in tremulous forms
of cervical dystonia can be very hard to distinguish from ET (Elble 2000b). In some
cases, family history may orientate in favor of the correct diagnosis, particularly if
family members are ascertained to have dystonia. This differential diagnosis is not
always straightforward and the variability of epidemiological data for ET unveils
diagnostic uncertainties. There are also a number of ET cases where there is suspi-
cion that dystonia features may have been overlooked. Commonly, in epidemiologi-
cal studies on ET several aspects which might indeed have suggested a dystonia
phenotype (head tremor, voice tremor, very asymmetric limb tremor, and a positive
family history in absence of any known cause not considered in the inclusion crite-
ria) are not included (Benito-Leon et al. 2009).
Patients with dystonic tremor may have a resting tremor mimicking a Parkinson’s
disease (PD)-like tremor, especially in cases in which dystonic posturing is not well
evident (sometimes only a dystonic thumb extension) (Lalli and Albanese 2010).
Table 11.3 Clues suggesting a diagnosis of dystonia in patients presenting with tremor syndromes
[from Lalli and Albanese (2010)]
Clinical orientation Clues suggesting dystonic tremor
Parkinson’s disease Diagnostic inconsistencies
• There is no progression to develop features other than tremor and
dystonia
• There is no clear fatiguing or decrement while performing repetitive
movements
• DAT scan is normal (SWEDD)
• Features do not improve with dopaminergic treatment (consider acute
challenge)
Features suggesting the dystonic nature of movements or postures
• There is thumb extension tremor, and tremor does not have a
pill-rolling aspect
• Tremor is task- or position-specific
• There is head tremor
• Voice is dystonic
• Variation of tremor following positional changes of the arms
(positional dystonic tremor)
• EMG mapping supports a diagnosis of dystonia
Essential tremor Diagnostic inconsistencies
• Head tremor is isolated
• Patients with voice tremors cannot change pitch during vocalization
• Tremor does not improve with ET therapy (i.e., propanolol,
primidone)
Features suggesting the dystonic nature of movements or postures
• With head rotation there is clear asymmetry of tremor
• Tremor disappears with geste maneuver
• There is neck pain or hypertrophy or neck muscles (particularly if
asymmetric)
• EMG mapping or tremor analysis support a diagnosis of dystonia
• Mirroring produces torsional movements
• Family history is positive and dystonia has not been ruled out in other
family members
Dystonic patients sometimes have jaw tremor, facial hypomimia, loss of arm swing
on the affected side, increased limb tone, and clumsiness often misdiagnosed as
bradykinesia. In this contest, there is an intriguing condition in which patients who
received a diagnosis of PD present a scans without evidence of dopaminergic deficit
(SWEDD). The issue whether patients with PD-like phenomenology and normal
DAT-SPECT may in fact be affected by dystonia has recently emerged (Lalli and
Albanese 2010). Aside clinical features suggesting a diagnosis of dystonia, a nor-
mal DAT SPECT can rule out PD. This finding is not specific of primary dystonia
and also occurs in dopa-responsive dystonia, ET, psychogenic tremor, or cases of
vascular parkinsonism or of drug-induced parkinsonism (Albanese and Lalli 2010).
In order to familiarize with features that orientate to a diagnosis of dystonia, we
have listed a number of diagnostic clues for each condition in which misdiagnosis
has been reported (Table 11.3).
11.3 Pathophysiology
The pathophysiology of dystonic tremor is largely unknown. Inhibitory circuits

within the central nervous system may be abnormal in dystonic tremor. Especially
reciprocal inhibition was found to be reduced in those conditions associated with
dystonic tremors (Munchau et al. 2001; Berardelli et al. 1998). In addition, when
assessing the reciprocal inhibition between forearm muscles, two different pat-
terns have been described: patients with normal levels of presynaptic inhibition
are affected by an ET-like tremor starting simultaneously with torticollis; in
patients with reduced or absent presynaptic inhibition, arm tremor preceded onset
of torticollis by a longer interval (Munchau et al. 2001). Recent research studies
focus on reorganization of cortical motor maps for the hand (Byrnes et al. 1998)
as well as the abnormal finger representation in the primary sensorimotor cortex
in patients with focal hand dystonia (Bara-Jimenez et al. 1998, 2000). An abnor-
mal finger representation in sensorimotor cortex occurs in dystonia (Elbert et al.
1998), and this abnormality, in the absence of congenital brain abnormalities, is
thought to reflect the enlarged and overlapping receptive fields. Moreover, it has
been hypothesized that a possible clinical correlate of this cortical remodeling
is a dysfunction of spatial discrimination. This may cause difficulties to selec-
tively innervate individual muscle groups and may thereby contribute to dystonic
movements.
A specific secondary dystonia syndrome featuring tremor and associated with
thalamic lesions has been called “thalamic tremor” (Miwa et al. 1996). The phe-
nomenology here is part of a specific dystonia–athetosis–chorea–action tremor syn-
drome due to lateral–posterior thalamic strokes (Kim 2001). In the setting of a
well-recovered severe hemiparesis, the combination of tremor with a kinetic com-
ponent, dystonia, and a severe sensory loss are the important clues for the diagnosis.
Proximal segments are often involved. The syndrome also may develop with a cer-
tain delay after the initial insult.
11.4 Dystonic Tremor Phenotypes
11.4.1 Head and Upper Limb Tremor in Cervical Dystonia
Tremor is a common feature in patients with cervical dystonia. Dystonic head

tremor usually has a jerky attitude and side prevalence, being more pronounced
and forceful when the head is rotated on one side. All forms of genetically deter-
mined dystonia may present with dystonic tremors of the head or hands (Albanese
2003; Bressman et al. 2000). Most dystonic movements are accompanied by
tremulous movements. In some cases, tremor may occur in extremities which are
not or not yet affected by dystonia. Furthermore, tremor may precede the onset
of dystonia. Cervical dystonia patients presenting with head tremor often have
also hand tremor and a family history of tremor or other movement disorders (Pal
et al. 2000). Head tremor can be the presenting sign of cervical dystonia and
remain isolated for long periods and even for the whole disease course. In such
cases, the differential diagnosis with ET may become a difficult task. The pres-
ence of a sensory trick can help recognize the dystonic nature of head tremor
(Masuhr et al. 2000), for example when a light touch of the chin or of another
head region improves tremor.
Hand and arm tremors have been described in patients with primary cervical
dystonia (Couch 1976). This type of tremor usually has the same frequency and
recruitment characteristics as physiological tremor and is considered a variant of
physiological tremor (Deuschl et al. 1997). Some of these patients are considered to
have ET in addition to dystonia (Elble 2000b). The study of reciprocal inhibition
allowed to identify two groups of patients (Munchau et al. 2001): one with normal
levels of presynaptic inhibition and another with reduced or absent presynaptic inhi-
bition. In the first group, arm tremor started simultaneously with cervical dystonia
whereas in the other group it preceded the onset of dystonia. These physiological
data suggest that there may be two subgroups of cervical dystonia patients, one with
“dystonic arm tremor,” another with ET-like phenomenology, called “tremor associ-
ated with dystonia” (Berardelli et al. 1998). The description of these cases, however,
did not consider the occurrence of activation/deactivation features and other semeio-
logic maneuvers aimed at detecting the occurrence of mild limb dystonia. The
implementation of current diagnostic criteria (Albanese and Lalli 2009) may pro-
vide different views in future observations.
11.4.2 Voice Tremor in Spasmodic Dysphonia
Voice tremor has been described as a feature of a number of neurological condi-

tions, including PD (Midi et al. 2008), ET (Sulica and Louis 2010), ataxic dys-
arthria (Boutsen et al. 2011), and spasmodic dysphonia (SD) (Gillivan-Murphy
and Miller 2011; Kendall and Leonard 2011). SD affects the laryngeal muscles
causing involuntary and sustained muscle contraction. Patients with SD have an
approximate 7% risk that dystonia may spread to another body part (Svetel et al.
2007).
The clinical picture may be that of an adductor-type or an abduction-type speech
impairment (Barkmeier et al. 2001). The adduction-type dysphonia is a voice disor-
der characterized by a strained strangled voice quality and intermittent voice stop-
pages, or breaks associated with over-adduction of the vocal folds. These voice
breaks typically occur during speech associated with voiced speech sounds and dur-
ing sustained phonation in moderate to severe cases of the disorder. Stressful speak-
ing situations may exacerbate speech symptoms while they appear absent, or
reduced in severity, during activities such as laughing, throat clearing, coughing,
whisper, humming, and falsetto speech productions (Ludlow and Connor 1987).
Abductor spasmodic dysphonia is characterized by intermittent breathy breaks
associated with prolonged abduction of the vocal folds during voiceless consonants
in speech. These voice breaks typically occur during speech associated with
voiceless speech sounds (Ludlow et al. 1991). Vocal tremor often co-occurs in
dysphonia (Aminoff et al. 1978). A recent study (White et al. 2011) showed that
patients with spasmodic dysphonia were 2.8 times more likely to have co-prevalent
tremor than the control group (other voice disorders). This study suggests the need
to properly evaluate patients with voice tremor looking for body tremor and other
dystonias.
11.4.3 Primary Writing Upper Limb Tremor
PWT is a condition in which tremor, usually characterized by prominent pronation/

supination wrist movements, occurs predominantly or exclusively during writing
(Rothwell et al. 1979). No other neurological signs are evident except for slight
postural and terminal kinetic tremor. PWT can be task-induced or position-sensitive.
The epidemiology and the natural course of PWT have not been fully elucidated.
Age at onset varies and cases manifesting during childhood have been reported. The
disorder begins slowly, progresses for years, and becomes stabilized. Family history
is generally unremarkable (Klawans et al. 1982).
This focal task-specific tremor has been variably classified as an independent
entity, an ET variant, a focal dystonia, or a bridging entity (Soland et al. 1996). In
the first reported cases, the writing disorder and tremor were both temporarily abol-
ished by a partial motor point anesthesia of the pronator teres, suggesting that tremor
was caused by an abnormal central response to muscle spindle discharges originat-
ing in the pronator teres (Rothwell et al. 1979). Although it resembles ET (where
tremor is present on action, and on maintenance of a posture, and may affect hand-
writing), the task-specific nature, lack of response to propranolol, and the docu-
mented effect of central cholinergic drugs (Klawans et al. 1982) suggest that PWT
is more closely related to primary dystonia than ET (Elble 2000b; Elble et al. 1990).
The observation of an abnormal co-activation of antagonist muscles also supports
this view (Elble et al. 1990). However, PWT can be differentiated from focal task-
specific dystonia (such as writer’s cramp) by the lack of excessive overflow of EMG
activity into the proximal musculature, and the absence of reciprocal inhibition of
the median nerve H-reflex upon radial nerve stimulation (Bain et al. 1995; Modugno
et al. 2002).
11.5 Treatment
There is a paucity of information about the treatment of dystonic tremor. There are
no specific therapeutic trials evaluating treatment efficacy on dystonic tremor. The
efficacy of botulinum toxin for dystonic head tremor (Jankovic and Schwartz 1991)
and tremulous spasmodic dysphonia (Watts et al. 2006) is well documented.

A double-blind study has also documented the efficacy of botulinum toxin for hand
tremor (Brin et al. 2001), but its use for this indication is limited due to the risk of
secondary muscle weakness. Clonazepam was observed to be beneficial in cervical
dystonia with a predominant head tremor (Davis et al. 1995; Hughes et al. 1991).
The usual starting dose is 0.5 mg in the evening. Doses up to 8 mg can be used.
Propranolol (up to 320 mg per day) and primidone (up to 250 mg three times daily)
are the mainstay treatments for ET, but are also useful for patients with dystonic
tremor syndromes (Bain 2002).
Severe tremor cases in the setting of the context of a generalized dystonia
have been successfully treated with deep brain stimulation (DBS) of the internal
globus pallidus (Coubes et al. 2004). Bilateral subthalamic nucleus DBS has also
been reported to improve cervical dystonia, dystonic head tremor, and ET-like
hand tremor in one patient (Chou et al. 2005). DBS of the subthalamic region,
including the zona incerta, remarkably improved proximal dystonic tremor
refractory to Vim thalamotomy (Plaha et al. 2008). The subthalamic region con-
tains pallidal outflow pathways and may be considered a target equivalent to the
internal globus pallidus.
There are no controlled studies on PWT. Propranolol, primidone, levodopa,
and neuroleptics have proven ineffective. Anticholinergics, when tolerated, may
help (Klawans et al. 1982). Botulinum toxin has been reported to be helpful in
PWT (Papapetropoulos and Singer 2006). Notwithstanding this evidence, treat-
ment of PWT is often ineffective. The disability caused by this condition can
vary from mild to considerable, depending on the patient’s profession and needs.
The resulting functional impairment may be not considered sufficient to warrant
DBS treatment, particularly in the Western culture. In Eastern Asia, instead,
where calligraphy is an important occupation, thalamotomy has been considered
an indication for PWT when it threatens a patient’s professional career (Ohye
et al. 1982). Successful Vim DBS procedures have also been reported (Racette
et al. 2001).
Improvement of PWT with a simple hand orthotic device has also been
observed (Espay et al. 2005). Similar results have been reported using a thermo-
plastic hand orthosis for writer’s cramp patients, who showed improvement in
their writing ability (Tas et al. 2001). Other non-pharmacological approaches
considered in upper limb dystonia may apply to PWT. Immobilization by a plas-
tic splint has led to intriguing hypotheses (Priori et al. 2001) which have not
received confirmation. It has been affirmed that limb immobilization might be
useful particularly in patients with a short history of dystonia (<18 months)
(Pesenti et al. 2004), whereas patients with longer disease duration may fail to
obtain consistent benefit. Immobilization could be useful as a preparatory phase
for other rehabilitative approaches, such as sensory retraining (Zeuner et al.
2008). Studies on focal hand dystonia in musicians suggest that a combination of
constraint-induced therapy and specific motor control retraining may provide a
successful strategy for the treatment of focal dystonias (Altenmuller and Jabusch
2010; Berque et al. 2010).
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Chapter 12
Orthostatic Tremor
Julián Benito-León, Andrés Labiano-Fontcuberta, and Elan D. Louis
Keywords Electromyogram • Orthostatic tremor • Shaky legs syndrome
12.1 Introduction
The term “orthostatic tremor,” also known as “shaky legs syndrome” (Gates 1993;
Benito-León and Porta-Etessam 2000), was first used in 1984 by Heilman (1984),
although there may have been earlier descriptions of this entity (Pazzaglia et al.
1970). As there are no published population-based epidemiological data, the preva-
lence and incidence of orthostatic tremor are unknown; however, it is considered to
J. Benito-León, M.D., Ph.D. (*) • A. Labiano-Fontcuberta, M.D.

Department of Neurology, University Hospital “12 de Octubre”, Madrid, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
(CIBERNED), Madrid, Spain
Department of Medicine, Faculty of Medicine, Complutense University, Madrid, Spain
e-mail: jbenitol@meditex.es
E.D. Louis, M.D., M.Sc.
Unit 198 , Neurological Institute , 710 West 168th Street , New York , NY 10032 , USA,
New York, NY, USA
Department of Neurology, College of Physicians and Surgeons, Columbia University,
New York, NY, USA
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians
and Surgeons, Columbia University, New York, NY, USA
Department of Epidemiology, Mailman School of Public Health, Columbia University,
New York, NY, USA
e-mail: EDL2@columbia.edu
220 J. Benito-León et al.
Fig. 12.1 (a) Typical surface EMG recording in a patient presenting a primary orthostatic tremor
while standing. Recordings in left tibialis anterior (upper trace) and left gastrocnemius muscle
(bottom trace). Gain: ×1,000. The arrow shows an epoch of 2 s (rectified trace). High frequency
bursting is observed. (b) and (c) correspond to the respective fast Fourier transform (FFT) data.
A peak at about 19 Hz is identified in the agonist–antagonist muscle pair
be a rare entity. Orthostatic tremor may be primary (idiopathic) or secondary.

Secondary cases are associated with a variety of disorders, most commonly parkin-
sonism (Gerschlager et al. 2004).
Orthostatic tremor is characterized by high frequency (13–18 Hz) tremors of
the legs and an immediate sense of instability when the patient is standing; these
are relieved when sitting or walking. The tremor is thought to arise from a central
generator in the cerebellum or brainstem (Thompson et al. 1986; Gerschlager
et al. 2004). The diagnosis is clinical, although it is confirmed by surface electro-
myographic (EMG) recordings (for example, from the quadriceps muscle), where
there is typically a 13–18 Hz tremor (Fig. 12.1) (Deuschl et al. 1998). Nonetheless,
leg, trunk, and even arm muscles may exhibit this tremor, which is typically
absent during tonic activation while the patient is sitting and lying (Deuschl et al.
1998).
A small number of medications may provide partial relief from tremor; how-
ever, the pharmacological treatment of orthostatic tremor is not, in general,
optimal, and some patients with severe tremor may undergo bilateral deep brain
12 Orthostatic Tremor 221
stimulation, which seems to be effective (Espay et al. 2008; Guridi et al. 2008;
Magariños-Ascone et al. 2010).
12.2 Epidemiology
Orthostatic tremor is considered to be a rare condition. Although there are no avail-

able epidemiological data, in the Neurological Disorders of Central Spain (NEDICES)
study (Benito-León et al. 2004), our group detected one patient with orthostatic
tremor in a cohort of approximately 4,000 elderly subjects (data not published).
Orthostatic tremor can begin at any age. However, age at onset may differ depending
on whether orthostatic tremor is primary or secondary (Gerschlager et al. 2004). In
the study by Gerschlager et al. (2004), which recruited 41 cases of orthostatic tremor,
age at onset was significantly earlier in primary orthostatic tremor (50.4 years ± 15.1)
than in the orthostatic tremor with associated features group (61.8 ± 6.4, p = 0.006).
Review of published case series indicates that there is a 2:1 female:male predomi-
nance (Gerschlager et al. 2004; Piboolnurak et al. 2005).
Most cases of orthostatic tremor occur sporadically; however, a few examples of
familial cases in monozygotic twins (Contarino et al. 2006), brothers (Fischer et al.
2007), or in a mother and her son (Piboolnurak et al. 2005) have been reported.
Furthermore, there may be a family history of Parkinson’s disease (PD) or other
types of tremor (Piboolnurak et al. 2005).
Progression of orthostatic tremor has also been noted on occasion. While in most
of the orthostatic tremor patients followed by Gerschlager et al. (2004), the symp-
tom severity was relatively unchanged over time (Gerschlager et al. 2004), in 6 of
their 41 patients, there was a documented progression of symptom severity (i.e., the
amount of time they could stand still) with time (Gerschlager et al. 2004). In four of
these, a clear spread of tremor was confirmed, with tremor initially only involving
the leg muscles and then spreading proximally to involve the trunk and arm muscles
(Gerschlager et al. 2004).
Orthostatic tremor may be associated with other movement disorders. Thus, a
few orthostatic tremor patients may develop incident PD (Wills et al. 1999;
Gerschlager et al. 2004) or progressive supranuclear palsy months or years later
(de Bie et al. 2007). Similarly, orthostatic tremor may appear in long-standing PD
after 10 years (Apartis et al. 2001; Leu-Semenescu et al. 2007).
Although the disorder is known to most neurologists, it may not be familiar to
geriatricians or general physicians. In fact, it is often misdiagnosed as essential
tremor, PD, restless leg syndrome, lumbar stenosis, or psychogenic tremor
(Gerschlager et al. 2004; Piboolnurak et al. 2005). A lack of recognition may lead
to misdiagnosis; the fact that the key physical signs are subtle and easily missed can
further contribute to misdiagnosis (Gerschlager et al. 2004; Piboolnurak et al. 2005).
Indeed, in the study of Gerschlager et al. (2004), 5.7 years elapsed between symp-
tom onset and diagnosis.
12.3 Phenomenology and Clinical Features
12.3.1 General Characteristics
Patients with orthostatic tremor primarily report a sense of unsteadiness and a weak-
ness of the legs during stance. These feelings improve on sitting or walking (Deuschl
et al. 1998). Patients rarely report tremor or leg pain as a presenting symptom
(Gerschlager et al. 2004; Gerschlager and Brown 2011; Piboolnurak et al. 2005). To
reduce the feeling of unsteadiness, patients compensate by standing with a widened
stance and claw the floor with their toes (Jones and Bain 2011). The onset and ces-
sation of the leg tremor can be quite abrupt with position changes, from sitting to
standing and vice versa, and it may depend on the severity of the disease (Piboolnurak
et al. 2005). For example, some subjects with mild orthostatic tremor may have to
stand still for several minutes in order for the symptoms to appear (Gerschlager
et al. 2004; Gerschlager and Brown 2011; Piboolnurak et al. 2005). The symptoms
of orthostatic tremor characteristically decrease markedly on sitting, walking, or
when leaning against a wall. The need to sit down or to walk can be so disturbing
that patients tend to avoid situations in which they have to stand still, such as taking
a shower, waiting in line, or standing at a kitchen counter to prepare a meal
(Gerschlager et al. 2004; Gerschlager and Brown 2011; Piboolnurak et al. 2005).
When patients are forced to stand for long periods of time, they usually try to alter-
nate weight from one leg to the other, walk in place, or lean on an object such as a
chair or a countertop (Gerschlager and Brown 2011). In advanced stages, patients
may show tandem gait abnormalities which are indistinguishable from those seen in
patients with cerebellar diseases (Gerschlager and Brown 2011).
Patients with orthostatic tremor rarely fall. When falling is an issue, it mainly
occurs in elderly patients who have additional neurological problems (PD, senile
gait disturbances, etc.) (Deuschl et al. 1998). Falls are not a problem at the onset of
the condition, which usually occurs during middle age (Deuschl et al. 1998;
McManis and Sharbrough 1993; Piboolnurak et al. 2005). Frequent falls should
alert the clinician to reconsider the diagnosis and pursue other diagnoses such as
progressive supranuclear palsy (Gerschlager and Brown 2011).
The tremors are mainly seen in the legs, but tremor is often present in other areas
such as the hands, cranial muscles, and even the trunk (Köster et al. 1999; Piboolnurak
et al. 2005). Indeed, only a small proportion of patients have isolated leg tremors
(Piboolnurak et al. 2005). Patients with primary (idiopathic) orthostatic tremor may
be divided into those with vs. without a postural arm tremor. The postural tremor
resembles that seen in patients with essential tremor (Gerschlager et al. 2004). The
tremor becomes obvious when the patient maintains their arms outstretched against
gravity in front of their body (e.g., extending the upper limbs horizontally) and typi-
cally has a frequency of 5–10 Hz, which overlaps with the frequency seen in patients
with essential tremor (Piboolnurak et al. 2005). Most patients with orthostatic tremor
have such postural tremor, with the proportion ranging from 77.4% (24 of 31 cases)
in Gerschlager et al. (2004) to 92.3% (24 of 26 cases) in Piboolnurak et al. (2005).
12.3.2 Clinical Examination
The leg tremor is characteristically of high frequency (13–18 Hz), which means it
may not be visible on routine examination (Gerschlager et al. 2004; Gerschlager and
Brown 2011; Piboolnurak et al. 2005), and this may make the diagnosis challenging.
When patients complain that they feel unsteady on their feet, clinicians may overlook
the possibility of orthostatic tremor, and may focus on other causes of unsteadiness.
The examination reveals a rapid tremor of the legs on standing, which may some-
times be palpable as a fine-amplitude rippling of leg muscles (e.g., the gastrocnemius
or quadriceps muscles) with an associated knee tremor; the tremor may be more
easily felt than seen because of its high frequency (Ramtahal and Larner 2009). It
may also be useful to place the diaphragm of a stethoscope over the gastrocnemius
muscle while the patient is standing. In some instances, the tremor may be heard,
sounding rather like the distant rotor blades of a helicopter (Brown 1995).
12.3.3 Diagnostic Criteria
The diagnosis of orthostatic tremor is based on history and physical examination

and confirmed by surface EMG (Deuschl et al. 1998). The EMG is performed in the
lower limbs while the patient is standing, so that any rhythmic activity in the
13–18 Hz range may be detected and recorded (Deuschl et al. 1998; Jones and Bain
2011). This rhythmic activity disappears when the patient is seated or lifted off the
ground. The currently accepted criteria are those proposed in the Consensus
Statement on Tremor by the Movement Disorder Society (Deuschl et al. 1998)
(Table 12.1).
Arriving at the correct diagnosis is dependent on the medical history and detailed
clinical and electrophysiological (EMG) investigations. Although the definition of
orthostatic tremor states that the tremor frequency should be confirmed by EMG, in
practice, accelerometry is an acceptable alternative in cases with typical symptoms
(Jones and Bain 2011). Electrocardiogram recorded in the standing position could
also be a simple noninvasive tool to screen for or to support the clinical diagnosis of
orthostatic tremor. Littmann (2010) reported a patient with orthostatic tremor in
whom telemetry strips revealed continuous gross 13–18 Hz of oscillatory artifact,
present while standing, and identical to the frequency of EMG oscillations recorded
from the thigh muscles of patients with orthostatic tremor.
12.3.4 Laboratory Workup
Currently, there are no laboratory findings that are typical of orthostatic tremor.
Hence, the purpose of laboratory investigations is to help exclude other disorders or
Table 12.1 Consensus statement on tremor by the Movement Disorder Society. Criteria for
orthostatic tremor
Orthostatic tremor is a unique tremor syndrome characterized by:
1. A subjective feeling of unsteadiness during stance but only in severe cases during gait;
patients rarely fall. None of the patients have problems when sitting and lying
2. Sparse clinical findings that are mostly limited to a visible and occasionally, only
palpable fine amplitude rippling of the leg (quadriceps or gastrocnemius) muscles when
standing
3. The diagnosis that can be confirmed only by EMG recordings (for example, from the
quadriceps muscle) with a typical 13–18 Hz pattern. All of the leg, trunk, and even arm
muscles can show this tremor, which is typically absent during tonic activation while the
patient is sitting and lying
possible symptomatic cases. Among certain patients, screening investigations

should include thyroid function tests, serum protein electrophoresis to rule out gam-
mopathies, vitamin B12 levels, diagnostic studies to exclude Wilson’s disease (e.g.,
serum ceruloplasmin), and dopamine transporter imaging to rule out PD. Brain
magnetic resonance imaging is recommended to rule out structural causes of ortho-
static tremor such as pontine and midbrain lesions or cerebellar atrophy. However,
in general, these investigations are usually normal in orthostatic tremor cases.
12.3.5 Differential Diagnosis
The differential diagnosis includes a number of conditions that are characterized by

unsteadiness or tremor while standing.
Tremor of the legs may occur in essential tremor, but always with upper limb
tremor, and at frequencies less than 12 Hz, unlike orthostatic tremor (Benito-León
and Louis 2006). There is currently a debate as to whether orthostatic tremor is a
distinct condition or a variant of essential tremor. The main reason to consider the
link between orthostatic tremor and essential tremor is that a considerable number
of orthostatic tremor patients have a 5–10 Hz postural or kinetic arm tremor, although
few of them have a family history of essential tremor (Piboolnurak et al. 2005).
However, those lower-frequency arm oscillations in orthostatic tremor may repre-
sent a subharmonic of the higher-frequency tremors typical of orthostatic tremor,
spreading throughout the body (McAuley et al. 2000). The tremor of orthostatic
tremor has two unique features: first, its high frequency (13–18 Hz) and second,
high coherence values between homologous muscles of the two legs (e.g., the left
and right quadriceps) (Jones and Bain 2011). These findings are quite different from
those of essential tremor, in which tremor typically has a lower frequency (4–12 Hz)
and in which there are low coherence values between homologous muscles of the
right and left side (Benito-León and Louis 2006; Jones and Bain 2011). Also, the
tremor temporarily abates after ethanol intake in few orthostatic tremor patients
(Britton et al. 1992; Gerschlager et al. 2004; Piboolnurak et al. 2005), in contrast
with essential tremor, in which the tremor abates in a larger proportion of patients
(Benito-León and Louis 2006). Finally, in contrast to the tremor of essential tremor,
orthostatic tremor shows little response to propanolol (Gerschlager et al. 2004;
Piboolnurak et al. 2005).
Orthostatic myoclonus is a disorder that was first reported in 15 elderly subjects
by authors at the Mayo clinic (Glass et al. 2007). Similar to orthostatic tremor, this
condition is characterized by muscle contractions associated with upright stance,
and diagnosed using surface EMG recordings. As in orthostatic tremor, there are
bursts of muscle contraction; however, in orthostatic myoclonus, the bursts are
shorter in duration, nonrhythmic, and irregular compared to those of orthostatic
tremor. Seven of the patients described by Glass et al. (2007) had a neurodegenera-
tive disorder and two had a systemic illness known to be associated with myoclonus
(Glass et al. 2007). Leu-Semenescu et al. (2007) also described this syndrome in
three PD patients complaining of unsteadiness on standing.
In PD, low (4–6 Hz)-frequency leg tremor is rarely seen while patients are stand-
ing. In general, the response of this type of tremor to dopaminergic drugs is good
(Kim and Lee 1993; Leu-Semenescu et al. 2007). Thomas et al. (2007) reported
four patients with a disabling tremor during standing that appeared years before
parkinsonian symptoms were evidenced. The tremor, whose main frequency was
6.2–6.9 Hz, with sporadic subharmonics at 8–18 Hz, was refractory to gabapentin
and dramatically responded to levodopa administration (Thomas et al. 2007). The
authors suggested the term “Pseudo-Orthostatic Tremor” to define this levodopa
responsive, 6–7 Hz standing tremor, preceding a parkinsonian syndrome (Thomas
et al. 2007).
12.3.6 Health-Related Quality of Life in Orthostatic Tremor
There is increasing recognition that the global well-being of patients with chronic
neurological diseases is an important outcome in research and clinical practice alike
(Benito-León et al. 2003, 2011). Subjective (i.e., self-reported) measures of health-
related quality of life may serve to alert clinicians to areas that would otherwise be
overlooked (Benito-León et al. 2003, 2011). Orthostatic tremor is not always a
benign condition and it may negatively impact on patients’ health-related quality of
life, including occupational and daily living activities, as the patients tend to avoid
situations where they have to stand still (Jones and Bain 2011). There are only two
studies that have studied health-related quality of life in orthostatic tremor
(Gerschlager et al. 2003; Rodrigues et al. 2005). Gerschlager et al. (2003) applied
the SF-36 and the Beck Depression Inventory to measure health-related quality of
life and depression, respectively, in 20 orthostatic tremor patients (Gerschlager et al.
2003). All dimensions of the SF-36 were markedly reduced in orthostatic tremor
patients and depression was found in 11 out of 20 patients (Gerschlager et al. 2003).
Rodrigues et al. (2005), using a modified PD questionnaire (PDQ-39), observed that
mobility, activities of daily living, bodily discomfort, emotional well-being, and
cognition were domains that were affected in patients with orthostatic tremor, and
these problems improved slightly with treatment.
12.4 Secondary (Symptomatic) Orthostatic Tremor
The vast majority of cases of orthostatic tremor are primary (idiopathic), with nor-
mal brain magnetic resonance imaging, normal laboratory workup, and no evidence
of other associated conditions. However, there have been a few reports of patients
whose OT was associated with other features, mainly parkinsonism and specifically
PD (Gerschlager et al. 2004). Of the 41 patients included in Gerschlager et al.
(2004), other additional neurological features were evident in 10 (Gerschlager et al.
2004). Specifically, six had parkinsonism (four had typical PD, one vascular parkin-
sonism and restless leg syndrome, and one had drug-induced parkinsonism). Of the
remaining four patients, two also had restless leg syndrome, one had tardive dyski-
nesia of uncertain etiology, and one had orofacial dyskinesias of uncertain etiology
(Gerschlager et al. 2004).
There are also some rare examples of structural causes of orthostatic tremor or
after an extensive laboratory workup. Thus, other secondary (symptomatic) cases
have been described in patients with nontumoral aqueduct stenosis (Gabellini et al.
1990), relapsing polyradiculoneuropathy (Gabellini et al. 1990), head trauma
(Sanitate and Meerschaert 1993), pontine and midbrain lesions (Fig. 12.2) (Benito-
León et al. 1997; Setta and Manto 1998; Vetrugno et al. 2010), cerebellar degeneration
Fig. 12.2 Symptomatic

orthostatic tremor caused
by a lesion in the posterior
fossa. T1-weighted axial
MRI (500/20) showing a
lesion involving the right
pontine region,
compatible with a
cavernoma. Case 1 from
Benito-León J, Rodríguez
J, Ortí-Pareja M, et al.
(1997) Symptomatic
orthostatic tremor in
pontine lesions.
Neurology 49: 1439–
1441. Reprinted with
permission from Wolters
Kluwer Health
(Manto et al. 1999), essential tremor (Papa and Gershanik 1988; FitzGerald and
Jankovic 1991), paraneoplastic syndrome associated with small-lung cancer (Gilhuis
et al. 2005), Graves’ disease (Tan et al. 2008), biclonal IgG and IgA lambda gam-
mopathy of undetermined significance (Stich et al. 2009), thiamine deficiency
(Nasrallah and Mitsias 2007), and vitamin B12 deficiency (Benito-León and Porta-
Etessam 2000).
Although the pathophysiology of orthostatic tremor is unknown, there is an accu-

mulating body of evidence suggesting that orthostatic tremor might be caused by a
central generator located in the posterior fossa.
Firstly, a small number of symptomatic orthostatic tremor cases have cerebellar
atrophy or have lesions in the pons or midbrain (Benito-León et al. 1997; Setta and
Manto 1998; Manto et al. 1999; Vetrugno et al. 2010). In addition, one positron
emission tomography study of four patients with orthostatic tremor revealed bilat-
eral activation of the cerebellar hemispheres as well as activation of the cerebellar
vermis, thalamus, and lentiform nucleus (Wills et al. 1996).
Secondly, the tremors recorded in each leg have a high coherence. In other words,
they have an almost constant phase relationship, which is not typical for most other
pathological tremors (Jones and Bain 2011). These findings suggest that the ortho-
static tremors detected in each leg originate from the same central tremor generator
(Jones and Bain 2011). In addition, 16-Hz EMG bursts are time-locked in the arm,
leg, truncal, and even facial muscles, and are bilateral (McAuley et al. 2000). In
addition, the fact that orthostatic tremor can be reset by electrical stimulation, placed
over the posterior fossa, but not by peripheral nerve stimuli, supports this hypothesis
(Wu et al. 2001).
With respect to unsteadiness, Yarrow et al. (2001), using force platform record-
ings, showed that the unsteadiness reported by orthostatic tremor patients is at least
partly due to increased postural sway. However, in another study that assessed body
sway under several conditions, the researchers demonstrated that subjective
unsteadiness does not arise simply from an awareness of increased body sway (Fung
et al. 2001). The authors postulated that the sensation of unsteadiness arises from a
tremulous disruption of proprioceptive afferent activity from the legs. This distur-
bance gives rise to increased co-contracting drive to the leg muscles in order to
stiffen the joints and increase stability. Since muscle activity remains tremor-locked,
the tremulous proprioceptive feedback is increased, which then further increases the
sensation of unsteadiness, and so on, setting up and perpetuating a vicious cycle
(Fung et al. 2001). By contrast, Sharott et al. (2003) showed that a 16-Hz tremor
could be provoked in healthy individuals who were made unsteady through vesti-
bular galvanic stimulation or leaning backwards (Sharott et al. 2003).
Orthostatic tremor is not, however, always associated with orthostasis. In at
least some patients, it can be classified as an orthostasis-independent action tremor.
The tremors may occur during isometric contraction of the arm or leg muscles inde-
pendent of stance and are absent in the upright position without weight bearing
(Boroojerdi et al. 1999).
There is some evidence of a potential role of the nigrostriatal dopaminergic sys-
tem in the generation of orthostatic tremor. An association of orthostatic tremor
with parkinsonism and treatment effects of l-dopa and dopamine agonists have
been reported (Wills et al. 1999; Finkel 2000; Katzenschlager et al. 2003; Gerschlager
et al. 2004). Using 123I-FP-CIT single-photon emission computed tomography, the
dopaminergic system was affected in a group of 11 orthostatic tremor patients,
although to a lesser extent than in PD (Katzenschlager et al. 2003). When compared
to a group of 12 PD patients, tracer uptake in orthostatic tremor patients was
significantly higher and more symmetrical, and the caudates and putamens were
equally affected. A study using transcranial sonography to examine the morphology
of the substantia nigra in four orthostatic tremor patients (Spiegel et al. 2005)
showed echogenicity in all of them (unilateral in three and bilateral in one patient),
suggesting the presence of nigrostriatal dopaminergic deficits. However, these
findings are not universal, and other functional imaging studies have showed intact
serotonergic and dopaminergic systems (Vaamonde et al. 2006; Trocello et al. 2008;
Wegner et al. 2008).
12.6 Treatment
12.6.1 General Considerations
As with other chronic diseases, it is important to consider the psychological and

social impact of illness on patients. Patients with orthostatic tremor may be unable
to continue full-time work, and financial problems may rise. Physicians should
coordinate care with other healthcare professionals in order to address these social
and psychological issues. The impact of the disease on the patient’s family should
also be taken into account. It may be beneficial for orthostatic tremor patients to
bring their spouse or partner to a consultation, to help them better understand the
disease, and to discuss their difficulties and concerns.
Patient-centered associations may be of help in offering individual and group
support, education and advice. Through such interactions, patients may benefit by
learning ways to cope with the many practical day-to-day difficulties that arise for
those living with this disease.
There are physical aids as well as certain lifestyle changes that may be helpful in
patients with mild orthostatic tremor. Physical aids may offer some symptomatic
relief. For example, portable stools may permit patients to sit rather than have to
stand when they are waiting in line or are at social events. A tripod walking stick
could be also helpful for this purpose. Furthermore, weight reduction may be help-
ful in overweight patients (Jones and Bain 2011).
12.6.2 Pharmacological Agents
Overall, medical therapy often yields insufficient benefit. As a result of the rarity of
this condition, there are no randomized controlled trials. Several drugs have been
empirically used to treat orthostatic tremor, including clonazepam, gabapentin, pro-
pranolol, levetiracetam, valproic acid, primidone, phenobarbital, topiramate, zonis-
amide, carbidopa/levodopa, and pramipexole (Gerschlager et al. 2004; Piboolnurak
et al. 2005). Such treatments have side effects, and it is important to carefully con-
sider in each patient whether the benefits outweigh any side effects. Treatment
should be initiated when the tremor begins to interfere with the patient’s ability to
perform daily activities. Surgery may be the final option for a select group of patients
who have not responded adequately to medications.
Of all the medications, clonazepam is considered to be the first-line medication
in the treatment of primary and secondary orthostatic tremor (Benito-León et al.
1997; Pradalier et al. 2002). This drug reduces tremors in about one-third of people
who have the disorder. For some, it eliminates orthostatic tremor almost entirely
(Pradalier et al. 2002). However, is not clear whether this benefit is sustained (Papa
and Gershanik 1988; Uncini et al. 1989; FitzGerald and Jankovic 1991; Britton
et al. 1992; McManis and Sharbrough 1993; Benito-León et al. 1997; Gerschlager
et al. 2004; Piboolnurak et al. 2005). Clonazepam is typically started at 0.5 mg
daily, preferably at night, and, if tolerated, gradually titrated upwards to 2 mg three
times a day (Jones and Bain 2011). Second-line therapies, either as monotherapy or
in combination, include gabapentin in doses ranging from 300 to 2,400 mg per day
(Evidente et al. 1998; Onofrj et al. 1998; Rodrigues et al. 2005, 2006), and others
with variable benefit, such as primidone (van der Zwan et al. 1988; FitzGerald and
Jankovic 1991; McManis and Sharbrough 1993), sodium valproate (Piboolnurak
et al. 2005), carbamazepine (Gerschlager et al. 2004), phenobarbital (Cabrera-
Valdivia et al. 1991), and intravenous immunoglobulin (Hegde et al. 2011).
Dopaminergic drugs may be helpful in some patients over a short period of time,
especially those who subsequently develop PD (Gerschlager and Brown 2011).
Pramipexole, a dopaminergic agonist, was reported to be effective in a single patient
with orthostatic tremor (Finkel 2000). Wills et al. (1999) described a series of eight
orthostatic tremor patients treated with levodopa. Five of them experienced benefit
and elected to remain on long-term treatment (Wills et al. 1999). By contrast, a
2-month open-label trial of levodopa treatment (600 mg per day) led to a small
improvement in two of five patients but no significant overall change and no sus-
tained benefit (Katzenschlager et al. 2003).
12.6.3 Surgical Treatment
Advances in surgical interventions may offer patients an alternative treatment

modality when pharmacotherapy is inadequate. Sustained benefit with bilateral
deep brain stimulation of the ventral intermediate thalamic nucleus has been reported
in three orthostatic tremor patients (Espay et al. 2008; Guridi et al. 2008; Magariños-
Ascone et al. 2010). Clinical benefits were sustained for at least 1 year in the report
by Magariños-Ascone et al. (2010), for 18 months in the report by Espay et al.
(2008), and for 4 years in the report by Guridi et al. (2008). Nonetheless, in another
patient who was treated with unilateral deep brain stimulation of the ventral inter-
mediate thalamic nucleus, clinical benefits receded after 3 months (Espay et al.
2008). Alternatively, chronic spinal cord stimulation at the level of the lower tho-
racic spine demonstrated beneficial effect with long-term follow-up in two patients
with medically intractable primary orthostatic tremor (Krauss et al. 2006).
12.7 Summary
Orthostatic tremor is a rare and unique movement disorder that is characterized by

tremor of the legs and trunk, present on standing and improving on walking or sit-
ting. The origin and mechanism of this condition are not well understood; notwith-
standing neurophysiological and functional imaging studies suggest a spontaneous
oscillation in central structures, possibly the brainstem or cerebellum. Although
orthostatic tremor is generally considered to be a distinct and primarily “idiopathic”
disorder, with normal brain magnetic resonance imaging and laboratory workup,
symptomatic orthostatic tremor cases have been described as well. Little is known
about the natural history and progression of orthostatic tremor, the presence of other
associated features, or whether there are different subgroups of patients with ortho-
static tremor. Although a small number of medications (clonazepam, gabapentin,
and dopaminergic drugs) can provide partial relief from tremor in a few patients, the
pharmacological treatment of orthostatic tremor is not optimal, and some patients
with severe tremor may choose to undergo surgery.
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Chapter 13
Vocal Tremor
Katherine A. Kendall
Keywords Voice • Phonation • Essential Vocal Tremor • Spasmodic Dysphonia
Individuals with vocal tremor complain of rhythmic fluctuations in vocal loudness

and pitch that give the impression of a tremulous voice. Severe vocal tremor can
cause rhythmic vocal breaks during attempts at sustained phonation, usually associ-
ated with significant speech impairment.
The cause of tremor, in any location of the body, is a periodic contraction of ago-
nist/antagonistic muscles or muscle groups in an alternating or synchronous fashion.
Vocal tremor is the result of periodic contractions of the laryngeal muscles involved
in phonation and usually presents as a symptom of one of three pathophysiologic
entities: Essential Vocal Tremor (EVT), Spasmodic Dysphonia (SD), or generalized
neurologic disease. In Essential Tremor, a regional tremor that commonly involves
the upper extremities and head, vocal tremor is often a predominant symptom. Vocal
tremor may also exist in association with SD, a focal dystonia of the larynx. And
lastly, vocal tremor may be a symptom of a generalized neurologic disorder such as
Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), or multiple sclerosis. It is
critical to understand the cause of vocal tremor because treatment is determined by
the underlying pathophysiology. The workup and evaluation of patients presenting
with voice tremor complaints must, therefore, focus on identifying the tremor type.
13.1 Differential Diagnosis of Tremor
In general, it is not difficult to recognize mild to moderate vocal tremor that presents
in isolation or as part of a regional/generalized tremor disorder. However, when
tremor is severe enough to result in voice breaks, it must be differentiated from
K.A. Kendall, M.D. (*)

Division of Otolaryngology, University of Utah, Salt Lake City, UT, USA
e-mail: Katherine.kendall@va.gov
236 K.A. Kendall
other laryngeal conditions that cause voice breaks including SD (Sulica 2004; Sulica
and Louis 2010). Further complicating the clinical picture is that fact that vocal
tremor may coexist with SD in as many as one-third of SD patients (Blitzer et al.
1998; Schweinfurth et al. 2002; Kendall and Leonard 2011).
Muscle Tension Dysphonia is another common disorder of the larynx that
should be distinguished from vocal tremor. Muscle Tension Dysphonia is a func-
tional disorder of the larynx resulting from high resting muscle tone that can cause
a strained or gruff voice. Some clinicians report that voice breaks are commonly
found as a feature of Muscle Tension Dysphonia (Sulica 2004), placing the disor-
der within the differential diagnosis of vocal tremor. Others report that a lack of
voice breaks in Muscle Tension Dysphonia differentiates it from SD and Vocal
Tremor (Sapanza et al. 2000). Because Muscle Tension Dysphonia improves with
voice therapy, while SD and EVT do not, a trial of therapy can help make the
distinction.
When vocal tremor is identified, an enhanced physiologic tremor is also a pos-
sible cause. Physiologic tremor is usually not visible when the involved muscle
groups are relaxed, but becomes apparent with directed movement and posture
holding at a rate of 8–12 Hz. Physiologic tremor, including physiologic vocal tremor,
can be enhanced by certain drugs such as caffeine, lithium, prednisone, sodium
valproate, and asthma inhalers. Cigarettes may also enhance physiologic tremor, as
can some metabolic conditions such as hyperthyroidism. Physiologic vocal tremor
may also become more apparent with normal aging. Evaluation of changes in pho-
nation with aging has documented increases in the variability of the fundamental
frequency and vocal loudness during phonation. Vocal instability or tremor has been
considered to be indicative of an older speaker (Harnsberger et al. 2010).
13.2 Work Up of Tremor
A careful past medical history and review of systems is critical to the complete
evaluation of vocal tremor. It is important to consider drugs and metabolic condi-
tions as a possible etiology of enhanced physiologic tremor and other neurologic
causes of the tremor must also be excluded.
After completion of a head and neck physical examination, videostroboscopy of
the larynx is used to rule out other causes of abnormal voice. The use of flexible
endoscopy with stroboscopy is considered preferable over rigid endoscopy because it
allows the evaluation of the larynx during connected speech in a more natural posture.
In cases of vocal tremor, rhythmic movements of the laryngeal structures are often
apparent during endoscopic observation of the larynx (Kendall and Leonard 2011).
Like any tremor, Vocal Tremor can be categorized by the extent of the involved
muscle groups (focal, regional, or diffuse) and by its association with movement of
those muscles (resting, postural, or kinetic). Vocal tremor is considered to be a focal
tremor when it is associated with SD, and is limited to the muscles of the larynx.
When vocal tremor presents as part of an Essential Tremor, muscles beyond the
13 Vocal Tremor 237
larynx (pharynx, oral cavity, palate, neck) are typically also involved, making
Essential Voice Tremor a regional tremor disorder. Vocal tremor can also present as
part of a generalized tremor syndrome, such as Parkinson’s disease.
The association of tremor with movement is also helpful in differentiating the
diagnosis (Warrick et al. 2000a). For example, EVT is a postural and kinetic tremor
that is not task specific, so it occurs independently from specific phonatory activi-
ties. The lack of task specificity differentiates EVT from SD, also a kinetic disorder,
but one that is task specific.
13.3 Clinical Features of Essential Vocal Tremor
EVT is an action (kinetic) tremor that occurs during voluntary movement and pos-
ture holding without task-specific characteristics. It occurs in approximately 4% of
the population and the incidence of Essential Tremor increases with increasing age.
Essential Tremor occurs in a bimodal distribution but predominately affects patients
in their fifth to eighth decade. It is more common in individuals of Northern European
extraction and some patients will have a family history of essential tremor (Warrick
et al. 2000a, b; Lou and Jankovic 1991).
Approximately 25% of individuals with Essential Tremor have vocal involve-
ment (Bove et al. 2006; Louis 2005). The presentation of Essential Tremor in the
larynx is different than in other muscle groups because in the larynx, the muscles
are constantly active. Even during quiet respiration, the laryngeal muscles contract
as they act as a sphincter to control the outflow of air and to maintain distal pres-
sures in the lungs. Because a resting state is never truly achieved by the laryngeal
musculature, the historical distinction of EVT as an “action” tremor is not really
clinically applicable. Essential tremor, therefore, can be identified in the larynx dur-
ing all observed activities, voicing and quiet respiration.
The symptoms of EVT usually start insidiously and progress slowly. Patients
often complain of fluctuations in vocal volume associated with a sense of increased
effort during phonation (Sulica and Louis 2010). The tremulous voice that results
may cause significant social embarrassment and when symptoms are severe, patients
may give up employment or social hobbies secondary to speech impairment caused
by the vocal tremor. Emotional stress, physical fatigue, or caffeine ingestion can
worsen the severity of the vocal tremor. Conversely, relaxation is associated with
improvement of symptoms and many patients report improvement of vocal tremor
with ingestion of alcohol (Warrick et al. 2000a, b; Dromey et al. 2002).
In individuals with EVT, a voice assessment will reveal rhythmic fluctuations in
vocal pitch (frequency) and loudness (amplitude) that correspond to the perception
of an unsteady voice. In particular, fluctuation in the amplitude of the voice signal
(Fig. 13.1) is characteristic of individuals with EVT (Finnegan et al. 2003). Tremor
rates vary from 4 to 8 Hz and there is substantial inter-speaker variability in the
regularity and the intensity of the fluctuations (Dromey et al. 2002). It must be kept
in mind that the rate of the tremor does not distinguish among the different
238 K.A. Kendall
Fig. 13.1 Sustained vowel production from a patient with vocal tremor. Frequency plot is shown
in the display at the top and waveform at the bottom. Note the phonatory breaks experienced by the
patient as a result of severe vocal tremor
underlying pathologies (Ludlow et al. 1986). Patients with EVT demonstrate

increased levels of jitter (pitch or frequency perturbation) and shimmer (loudness
or amplitude perturbation) (Ramig and Shipp 1987; Lundy et al. 2004). Dromey
et al. found that EVT rates increase during high pitch phonation and decrease dur-
ing low pitch phonation. Essential Tremor rates also increase during loud phona-
tion and decrease during soft phonation. Their work further confirmed that EVT
represents an irregular and unsteady modulation of the voice that is not sinusoidal
in rhythm (Dromey et al. 2002).
Although fluctuations in vocal amplitude or loudness are characteristic of EVT,
there are usually associated fluctuations in frequency or pitch, even if they are not
the predominant feature of the tremor. It is these fluctuations in the frequency of the
voice that can help to distinguish EVT from SD, in which fluctuations in frequency
are uncommon. They are also helpful in distinguishing Essential Tremor from other
forms of generalized tremor. Lundy et al. determined that patients with EVT dem-
onstrate a larger range in their fundamental frequency during sustained phonation
compared to patients with ALS. They also found that the intensity of amplitude, or
loudness, variations were significantly greater in patients with Essential Tremor
compared to patients with ALS or SD (Lundy et al. 2004).
Physical examination of patients with EVT demonstrates involvement of three to
four sites within the upper aerodigestive tract. Involvement of the laryngeal muscles
alone does not occur, with EVT, putting it in the category of a regional tremor disorder
13 Vocal Tremor 239
(Sulica and Louis 2010; Warrick et al. 2000a, b). Muscle group involvement with
EVT varies from patient to patient, although the Thyroarytenoid muscles are involved
in the majority of cases that present with voice symptoms.
The Thyroarytenoid muscle normally controls tension of the vocal folds with
activity in the muscles correlating to changes in vocal loudness. Fluctuations in the
amplitude of the voice (loudness) in vocal tremor patients are correlated with
Thyroarytenoid muscle activity, rather than with activity in other intrinsic and
extrinsic laryngeal muscles, although the Cricothyroid, Sternothyroid, or Thyrohyoid
muscles may be involved in the tremor (Finnegan et al. 2003). Other muscles often
found to be involved with the tremor include muscles of the palate, mandible, and
pharyngeal walls. Koda and Ludlow reported different tremor rates for different
muscles of the pharynx and larynx ranging from 4 to 5.2 Hz (Koda and Ludlow
1992). Due to the variability of muscle involvement in different patients, flexible
laryngoscopy is critical to the evaluation of vocal tremor patients. Using acoustic
measures of voice without endoscopy is probably not sufficient to characterize the
predominant physiologic mechanism in any individual patient.
13.4 Etiology of Essential Vocal Tremor
In about half of the cases, essential tremor is an autosomal dominant inherited trait
with high penetrance. The rest of the cases are considered sporadic (Elble 2000).
Thus, a family history of essential tremor is considered to be a risk factor for the
development of the disease.
The etiology of essential tremor is unknown but is theorized to be the result of
abnormalities of neuron firing between the Inferior Olivary Nucleus and Cerebellar
Purkinje fibers. Presumably, increased synchronous activity in the Inferior Olivary
Nucleus affects the Cerebellothalamic output, and the result is vocal tremor. PET
abnormalities in the Cerebellum and Olivary Nucleus in patients with Essential
Tremor provide evidence to support this theory (Jenkins et al. 1993; Hallett and
Dubinsky 1993). Furthermore, rhythmic neuronal activation in the Thalamus has
also been identified in Essential Tremor (Deuschl et al. 2001; Hua and Lenz 2005).
With respect to EVT, it is believed that disordered Cerebellar control of vocal fold
tension causes poor control of fundamental frequency and vocal volume during
phonation (Elble 2000).
It has also been proposed that EVT is the result of abnormalities in the inter-
action of central control mechanisms with peripheral reflex loops that monitor
and control peripheral muscular tension. Phase delays and over-correction of
tension differences in the muscles may result in the rhythmic laryngeal move-
ments. The oscillations in the tension-correcting peripheral reflex loops are pro-
posed to be impacted by the mechanical properties of the end organ and thus
behave similar to a mass-spring model, which would naturally oscillate more
rapidly when made stiffer. This would explain the finding of faster rates of tremor
in high laryngeal muscle tension conditions such as elevated pitch and loudness
(Titze et al. 1994).
240 K.A. Kendall
13.5 Treatment: Essential Vocal Tremor
First-line therapy for the treatment of Essential Tremor typically involves the
empirical use of a number of different medications with various mechanisms of
action and widely variable results. Factors that predict a response to particular
drugs have not been identified. Variable medication response rates may be indica-
tive of heterogeneity in the etiology of the disease or variability in the degree of
peripheral versus central involvement. In patients that do respond to pharmaco-
logic treatment, the tremor is typically not eliminated, but reduced to a tolerable
level (Louis 2005).
The vocal symptoms of Essential Tremor have most commonly been treated with
Propranolol. Propranolol is a beta-adrenergic blocker whose effect on tremor is con-
sidered to occur through blockage of peripheral receptors, although interactions
with central receptors may play a role. Louis et al. report that 120 mg daily of
Propranolol are effective (Louis 2005). Symptomatic relief from tremor with
Propranolol therapy has been reported in up to 50% of patients (Koller et al. 2000).
Contraindications to the use of Propranolol include asthma, congestive heart failure,
diabetes mellitus, and arterio-ventricular block (Louis 2000).
Other first-line agents may have a central, rather than peripheral effect.
Primidone, an anticonvulsant belonging to the barbiturates, is effective in the con-
trol of tremor symptoms in about 50% of patients, but its exact mechanism of
action is unknown (Koller et al. 2000). Primidone can be difficult to tolerate, how-
ever (Louis 2000). Gabapentin is an anticonvulsant agent that is structurally simi-
lar to the neurotransmitter gamma amino butyric acid (GABA) and trials with
Gabapentin have shown it to be equally effective and well tolerated. Benzodiazepines
(clonazepam, diazepam) potentiate the effect of GABA by binding to the GABA
receptor, but in order to achieve a reduction of tremor with benzodiazepines, doses
that result in significant sedation are necessary (Louis 2000). Benzodiazepines
along with carbonic anhydrase inhibitors (Methazolamide) have response rates that
range from 25 to 40% (Busenbark et al. 1996; Koller et al. 1985; Hartman and
Vishwnanat 1984).
Currently, many patients with EVT are treated with Botulinum Toxin (Botox®)
injections into the Thyroarytenoid muscles. The injection of Botulinum Toxin into
the muscle blocks the release of acetylcholine from the nerve endings at the neuro-
muscular junction, preventing muscular contraction. The intended effect of the
injection is attenuation of muscle contraction and is of moderate duration, but tem-
porary, usually lasting 3–4 months. Response rates to this type of targeted therapy
are best if the tremor primarily involves the Thyroarytenoid muscles. However,
when tremor involves many anatomic sites, as is most often the case with EVT,
injection into only the Thyroarytenoid muscles is unlikely to result in a dramatic
improvement. As with systemic medical therapy, most studies evaluating the effect
of Thyroarytenoid muscle Botox injection demonstrate a diminution, but not elimi-
nation, of the tremor. Despite persistence of the vocal tremor, patients note a decrease
in perceived vocal effort that correlates with a decrease in the aerodynamic estimate
13 Vocal Tremor 241
of laryngeal resistance after injection of the Thyroarytenoid muscles with Botox®.

This reduction in vocal effort with phonation may be one of the primary benefits of
Botox® therapy for tremor (Warrick et al. 2000a, b; Hertegard et al. 2000; Adler
et al. 2004; Kendall and Leonard 2011).
Recognizing that results with Botox® injection are suboptimal because not all of
the involved muscles are treated by injection into the Thyroarytenoid muscle, Bove
et al. developed a Tremor scoring system in an attempt to predict which patients are
likely to respond to Botox injections. In this scoring system, the palate, base of
tongue, pharyngeal walls, larynx, supraglottis, and true vocal folds are evaluated for
tremor during phonation observed during flexible endoscopy. Tremor involvement
of the tongue base is evaluated during protrusion. Using the scoring system, the
authors were able to demonstrate that patients who responded to Botox therapy
were those whose tremor primarily involved the injected muscle groups (Bove et al.
2006).
Caution must be exercised when using Botox therapy in the muscles of the upper
aerodigestive tract. These muscles are essential to normal swallowing and airway
protection, in addition to voicing. Excessive injection of Botox can result in dys-
phagia, aspiration, and weak, breathy voicing. Patients, therefore, must be carefully
selected for this treatment. It is important to rule out preexisting or underlying neu-
romuscular abnormalities before starting a treatment that may cause further weak-
ness of the upper airway muscles. For this reason, patients with multiple upper
airway muscle groups involved in the tremor are unlikely to respond adequately to
Botox injections, because the side effects of injections into multiple muscle groups
outweigh the potential benefit of controlling of the vocal tremor.
Deep brain stimulation has also been used to treat EVT. Reduction of tremor
with chronic stimulation of the Thalamus has been reported and anecdotal cases
of improved EVT with this treatment have also been documented (Sataloff et al.
2002). Surgical intervention is typically recommended for medication refractory
patients.
13.6 Clinical Features of Spasmodic Dysphonia
Spasmodic dysphonia (SD) is a chronic action-induced and task-dependent focal

dystonia affecting the muscles of the larynx. The condition is characterized by
spasms of the vocal fold muscles, resulting in a strained-strangled vocal quality or
breathy vocal breaks, depending on which muscles are involved. The adductor-type
of SD is the most common and is an action-induced dystonia, provoked by phrases
containing many voiced onsets. Poor control of muscular tension in laryngeal adduc-
tors results in excessive tension, leading to vocal strain and voice breaks. Up to 30%
of these patients will also exhibit a vocal tremor. The abductor type of SD, involving
the posterior cricoarytenoid muscles, and a mixed type, involving both abductor and
adductor muscles, are less common. Approximately 50,000 individuals in North
America have SD (Blitzer et al. 1998; Tanner et al. 2011).
242 K.A. Kendall
SD is more common in women and usually begins during the fourth decade
(Blitzer et al. 1998; Schweinfurth et al. 2002; Sulica 2004). Breaks occur during
voicing and are not experienced during laughing, shouting, and singing. The diag-
nosis of adductor SD can be made by asking the patient to repeat sentences that
elicit voice breaks in a normal speaking voice and in a whisper. One or more voice
breaks per three sentences with a frequency that decreases during whisper are indic-
ative of SD (Ludow et al. 2008). Neither Essential Voice Tremor nor Muscle Tension
Dysphonia is associated with this type of task specificity (Sulica 2004).
Many authors consider the tremor associated with SD to be a form of Essential
Voice Tremor (Ludow et al. 2008), while others consider the combined presentation
of adductor spasms with tremor to be a unique diagnostic entity (Hillel 2001). In SD
with tremor, the tremor usually has many features consistent with EVT. It is typi-
cally a kinetic tremor that is not task specific. As such, the tremor associated with
SD will be present during quiet respiration and is exacerbated by high tension con-
ditions such as voicing loudly or in a high pitch. Unlike EVT, the tremor associated
with SD is usually limited to laryngeal muscles, although more than one laryngeal
muscle group is typically involved. In a study of 20 SD patients with tremor, Hillel
found that all laryngeal muscles exhibit tremor on laryngeal electromyography dur-
ing sustained phonation and connected speech (Hillel 2001). Inspection of wave-
forms and fundamental frequency plots for the vowel samples revealed substantial
variability in both the frequency and the amplitude of the tremor. For some patients,
marked phonation breaks also characterize both vowel and connected speech pro-
ductions (Kendall and Leonard 2011).
13.7 Etiology of Spasmodic Dysphonia

and Associated Tremor
The etiology of SD, with or without associated tremor, is not known, although it is
thought to be of central neurologic origin. Focal dystonias, such as SD, have been
found to be associated with a combination of genetic mechanisms and environmen-
tal factors. Ten percent of patients with SD have a family history of dystonia (Blitzer
et al. 1998). Tanner et al. studied 150 patients with SD and by comparing them to
matched controls from the general Otolaryngology clinic found that a personal his-
tory of hand tremor, vocal tremor, blepharospasm, and social anxiety was significantly
associated with the development of SD. Additionally, SD patients who also demon-
strated a Vocal Tremor were more likely to have a history of Essential Tremor, head
or neck tremor, immune disorder, thyroid problems, and panic disorder. An immedi-
ate family history of Essential Tremor, tic disorder, cancer, meningitis, and compul-
sive behaviors were significantly associated with the development of SD compared
to other individuals seeking treatment in a general Otolaryngology clinic.
Environmental factors found to be significant in this patient population included a
history of mumps, as well as intense occupational and vocational voice use. Patients
13 Vocal Tremor 243
with SD and Vocal Tremor are more likely to have a family history of neurological
conditions than patients with SD alone. The finding of a significant correlation with
mumps exposure led the authors to theorize that early viral exposures might result
in changes in the brain that set up the conditions necessary for development of the
movement disorder later in life. The SD patient group in this study reported fewer
immunizations than the control group (Tanner et al. 2011).
Research into the genetic causes of SD is ongoing. A specific amino acid
deletion in the 9q region, affecting a locus designated by the DYT1 gene, has been
found to be responsible for familial primary torsion dystonia, and is the most
studied dystonia disorder. DYT1 dystonia usually starts in the lower extremities
and typically does not involve the cranial region, so it is unlikely to be involved in
laryngeal dystonia. However, several other gene loci associated with dystonia
have been identified. DYT6 dystonia is an early onset dystonia that often involves
the cervical/cranial area including laryngeal dystonia. Evaluation of the specific
genetic aberrations leading to the dystonic symptoms in this group of individuals
may provide some clues into the etiology of the more focal laryngeal dystonia
(Djarmati et al. 2009).
13.8 Treatment of Tremor Associated

with Spasmodic Dysphonia
SD, with or without associated Vocal Tremor, is typically treated by the injection of
Botulinum Toxin into the involved muscles. As with the treatment of EVT, the
injection of Botox into the muscle blocks the release of acetylcholine from the nerve
endings at the neuromuscular junction, preventing muscular contraction. In cases of
adductor SD, with or without vocal tremor, the injection is usually done in one or
both Thyroarytenoid muscles. The intensity and the duration of the effect are dose
related and appropriate dosing allows the patient to achieve voicing that is relatively
spasm-free and not excessively breathy.
As previously discussed, laryngeal muscle involvement in SD-associated vocal
tremor has been studied using electromyography and it has been determined that all
intrinsic laryngeal muscles may be involved in the tremor. However, Koda and
Ludlow found that the Thyroarytenoid muscle is likely to be the most active in this
patient population (Koda and Ludlow 1992). Klotz et al. studied 77 patients with a
SD-associated vocal tremor and found that the Thyroarytenoid muscle was involved
in the tremor in 58% of patients, the Lateral Cricoarytenoid muscle was involved in
53%, and the Interarytenoid muscle was involved in 14%. There was no significant
difference between the Thyroarytenoid muscles and Lateral Cricoarytenoid muscles
with respect to predominant involvement with SD-associated tremor in contrast
with SD alone where the Thyroarytenoid muscle is more likely to be the predomi-
nant muscle involved in the adductor spasms. Several patients had predominant
tremor involvement of the Interarytenoid muscle (Klotz et al. 2004).
244 K.A. Kendall
One might conclude, therefore, that the majority of patients should experience
effective improvement after Thyroarytenoid muscle injection alone. And indeed,
whether categorized as a component of laryngeal dystonia or classified as a separate
entity, SD-associated Vocal Tremor has been reported to respond to isolated
Thyroarytenoid muscle Botox injection. Similar to the results with EVT,
Thyroarytenoid muscle injections for SD-associated Vocal Tremor have been found
to attenuate, but not to eliminate, the tremor (Warrick et al. 2000b).
Further improvements in vocal symptoms have been demonstrated when
Interarytenoid muscle Botox injection was added to Thyroarytenoid Muscle injec-
tion in those patients that did not respond to Thyroarytenoid muscle injection alone
(Kendall and Leonard 2011). The analysis of the voice recording data demonstrated
a significant improvement in the stability of both the amplitude and frequency pro-
duced by patients attempting to sustain a vowel, after the Interarytenoid muscle
injection was added to the Thyroarytenoid muscle injection. When compared to a
small group of normal control subjects, the patients in the study continued to dem-
onstrate significant vocal instability on objective acoustic analysis with respect to
frequency and amplitude. However, the addition of an Interarytenoid muscle Botox
injection resulted in an average improvement in the range of the fundamental fre-
quency by 44%. The percent of pitch perturbation improved by an average of 17%
overall (Kendall and Leonard 2011).
The technique used for laryngeal muscle injection combines laryngeal obser-
vation using flexible laryngoscopy and laryngeal electromyography. A team
made up of an Otolaryngologist and Speech Pathologist performs the injections.
The patient is placed in a sitting position in a procedure chair and a ground
electrode is placed over the patient’s clavicle or sternum and a referent electrode
is placed over the left sternocleidomastoid muscle. The nasal mucosa is prepped
for flexible laryngoscopy with a topical anesthetic spray. Next, 1–2 cc of 2%
Lidocaine without epinephrine is injected in the subcutaneous plane over the
Cricothyroid membrane. The needle is advanced and another 1–1.5 cc of local
anesthetic is injected directly into the trachea. The patient will cough, which
distributes the anesthetic over the laryngeal mucosa. The flexible laryngoscope
is then passed through the nares and positioned to allow visualization of the
larynx. The laryngoscope is attached to a camera so that the larynx can be
viewed on a television monitor placed behind the patient. A monopolar, hollow-
bore, Teflon-coated needle electrode is then passed through the Cricothyroid
membrane and visualized subglottically. It is advanced superiorly and posteri-
orly until it pierces the region of the selected target muscle. The tip of the nee-
dle-electrode advanced in the tissue until it is localized to an area demonstrating
electrical activity that corresponds to the observed tremor movements. Once an
area of contracting muscle is thus identified, a small dose (1.0–2.5 IU) of Botox®
is injected through the needle. Another muscle group can then be targeted for
injection by redirecting the needle-electrode into the anatomic location of that
muscle group. Botox® is injected when the electrical activity recorded during
voicing indicates that the tip of the needle is localized in the intended muscle
(Fig. 13.2).
13 Vocal Tremor 245
Fig. 13.2 Patient positioning for laryngeal muscle injection
13.9 Vocal Tremor Associated with Other Neurologic

Conditions
Vocal Tremor can be associated with many other generalized neurologic conditions
such as Parkinson’s disease, ALS, and Multiple Sclerosis. When vocal tremor occurs
in these conditions, the treatment relies on maximal medical treatment of the under-
lying condition, rather than targeted therapy in the larynx. Although Botox® therapy
can be used in selected cases, extreme caution must be used in order to prevent
difficulties with airway protection during swallowing.
Rather than review each of the generalized neurological conditions that may
have an associated vocal tremor, this section will briefly focus on the most common
condition with a high incidence of laryngeal involvement—Parkinson’s disease.
13.10 Clinical Features of Vocal Tremor in Parkinson’s Disease
Parkinson’s disease is a progressive central neurologic disease due to the degenera-

tion of the brainstem nuclei, particularly the Substantia Nigra, and results from a
dopamine deficiency in the Basal Ganglia. The disease is characterized by tremors
of the arms and legs and hands, rigidity, shuffling gate, and “masked” faces. Between
70 and 90% of patients with Parkinson’s suffer from associated vocal problems, and
these problems may be the first presenting symptoms of the disease.
246 K.A. Kendall
The predominant vocal problem is a soft and breathy voice, but up to 70% of patients
can also complain of vocal tremor (Perez et al. 1996; Logemann et al. 1978).
The soft, breathy voice exhibited in Parkinson’s disease is most commonly the
result of vocal fold bowing, or incomplete vocal fold closure during voicing. The
persistent glottic opening during phonation prevents the generation of the subglottic
pressure needed for louder voicing. Air flows through the vocal folds at higher rates,
as well, leading to a sense of breathlessness. Poor breath support and chest wall
rigidity further contribute to the condition. Difficulties with articulation must be
distinguished from the phonatory or laryngeal component of the speech difficulties
and include difficulty in initiating speech, stuttering, and poor articulation.
The vocal tremor in Parkinson’s disease occurs at a rate of 4–10 Hz, similar to
the rate of tremor in EVT. And like EVT, the vocal tremor of Parkinson’s disease
can be observed during all activity in the larynx, including quiet respiration. Zarzur
et al. found that vocal tremor was detected on voice spectrogram tracings in 70% of
patients with Parkinson’s disease while 61% were considered to demonstrate vocal
tremor on perceptive-auditory assessments. Interestingly, laryngeal EMG studies of
those patients with Parkinson’s disease and vocal tremor did not demonstrate tremor
on EMG tracings. The characteristic finding on laryngeal EMG was spontaneous
activity characterized by muscle recruitment during quiet respiration, possibly a
manifestation of muscle rigidity (Zarzur et al. 2007, 2010).
13.11 Treatment: Parkinson’s Disease-Associated Tremor
Treatment of Vocal Tremor associated with Parkinson’s disease relies on optimizing

the treatment of the underlying neurologic condition. Treatment of Parkinson’s disease
with Levodopa has been documented to result in a significantly higher acoustic inten-
sity level for phonation in patients when taking the medication compared to the un-
medicated state. In addition, post-medication voice signals had significantly less pitch
variation, indicative of less tremor, than pre-medication signals (Jiang et al. 1999).
Bilateral high-frequency stimulation of the subthalamic nucleus has become an
accepted treatment of patients with advanced Parkinson’s disease, but there has been
concern that this treatment may result in worsening of both the dysarthria and breathy
voice. However, a study conducted on 12 patients after implantation of a deep brain
stimulator using standardized assessment tools to evaluate motor and speech capa-
bilities and acoustic analysis found an improvement of speech and improvement of
vocal tremor with the deep brain stimulation (D’Alatri et al. 2008).
13.12 Summary
In conclusion, vocal tremor can have a significant impact on quality of life by

impairing an individual’s ability to communicate. Evaluation and treatment must
focus on determining the associated pathophysiologic entity so that appropriate
13 Vocal Tremor 247
treatment can be initiated. Patients must be counseled, however, that treatment will
result in a diminution, but not elimination, of the tremor.
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Chapter 14
Update in Familial Cortical Myoclonic Tremor
with Epilepsy
Eloi Magnin, Pierre Labauge, Lucien Rumbach, and Marie Vidailhet
Keywords Myoclonus • Epilepsy • Genetic • Cortical tremor
14.1 Introduction
Several names (“Cortical Tremor” = Crt Tr, Familial Adult Myoclonic

Epilepsy = FAME, Benign Adult Familial Myoclonic Epilepsy = BAFME, Autosomal
Dominant Cortical Myoclonus and Epilepsy = ADCME, Familial Cortical Myoclonic
Tremor = FCMT, Familial Cortical Tremor with Epilepsy = FCTE, Familial Essential
Myoclonus and Epilepsy = FEME, Familial Benign Myoclonus Epilepsy of Adult
onset = FMEA, Heredofamilial Tremor and Epilepsy = THE) have been used to
define a unique entity, Familial Myoclonic Cortical Tremor with Epilepsy (FCMTE),
as proposed by van Rootselaar et al. (2005). All patients with FCMTE criteria share
clinical and electrophysiological features. In contrast, Familial Infantile Myoclonic
Epilepsy (FIME) and Adult-onset Myoclonic Epilepsy (AME) cannot yet be
considered as FMCTE (Striano et al. 2009a).
E. Magnin, M.D. (*) • L. Rumbach, M.D., Ph.D.

Department of Neurology, CMRR de Franche-Comté, CHU Besançon, 25000 Besancon, France
Laboratoire de Neuroscience, Université de Franche-Comté (UFC), Besançon, France
e-mail: eloi.magnin@laposte.net
P. Labauge, M.D., Ph.D.
Department of Neurology, CHU de Montpellier, Montpellier 34295, France
M. Vidailhet, M.D, Ph.D.
AP-HP, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris 75013, France
Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière (CRICM),
CNRS UMR 7225 and Inserm UMR_S 975, AP-HP, Paris, France
250 E. Magnin et al.
14.2 History
FCMTE was first described by Ikeda et al. (1990) as “Cortical tremor.” It was
initially thought that this disease was only observed in Japan. Clinical diagnosis
of myoclonus was confirmed by electrophysiological examination (somatosen-
sory evoked potentials [SEP], C reflex examination, jerk-locked back-averaging
method) that demonstrated cortical hyperexcitability (Ikeda et al. 1990; Terada
et al. 1997). Some FCMTE families have been identified in Italy (Elia et al. 1998).
A locus (8q) was first mapped in the Japanese families (Plaster et al. 1999; Mikami
et al. 1999). The genetic heterogeneity of FCMTE was then demonstrated with a
second locus, 2p (Guerrini et al. 2001), and 8q/2p unlinked families (van Rootselaar
et al. 2002) in Dutch families. A third locus (5p) was recently identified in a
French family (Depienne et al. 2010). Approximately 60 families from all over
the world have been described in the literature, including in China (Deng et al.
2005), South Africa (Carr et al. 2007), Turkey (Saka and Saygi 2000), and Spain
(Labauge et al. 2002). Common clinical characteristics have been identified in all
these families, although a clinical heterogeneity could be observed in the same
pedigree.
14.3 Clinical Characteristics
Some clinical characteristics are common to all FCMTE families (i.e., “classi-
cal” FCMTE). In addition, uncommon clinical features may be observed in iso-
lated families or individual patients (van Rootselaar et al. 2005; Regragui et al.
2006).
14.3.1 Common Clinical Findings
14.3.1.1 Cortical Myoclonus or Cortical “Tremor”
Cortical myoclonus could be diagnosed as a “pseudotremor” with distal predomi-

nance of involuntary, oscillatory, irregular, tremor-like myoclonic jerks in upper and
sometimes lower limbs, usually without involvement of the trunk or head (except
orbicular muscles) at rest. Outstretched positions and action, tiredness/sleep depri-
vation, caffeine, vibration, glucose deprivation, intense visual contrast, and/or audi-
tory stimulation can enhance the myoclonus (Bourdain et al. 2006). Severe
myoclonus can alter quality of life and autonomy (precise hand movements, gait,
and balance), especially in young active patients. Sodium valproate, levetiracetam,
lamotrigine, clonazepam, and phenobarbital can improve cortical myoclonus. Beta
blockers are ineffective (Regragui et al. 2006).
14 Update in Familial Cortical Myoclonic Tremor with Epilepsy 251
14.3.1.2 Epilepsy
Generalized tonic–clonic seizures are the most frequent kind in epilepsy. Absence,
myoclonic seizure, complex partial seizures, and visual seizure have also been described.
Seizures can be triggered by lack of sleep, photic stimulation, sound, or painful sensa-
tion. Photosensitivity is frequently found. This type of epilepsy is usually benign with
infrequent seizures and a good response to antiepileptic drugs (especially sodium val-
proate). In European pedigrees, some patients have a more severe form, with more fre-
quent seizures requiring associations of other antiepileptic drugs (levetiracetam,
lamotrigine, clonazepam, and phenobarbital) and leading to a worse outcome (Guerrini
et al. 2001; Regragui et al. 2006). Status epilepticus has rarely been reported.
14.3.1.3 Onset
FCMTE is usually diagnosed during adulthood (second to fourth decade), but early
(10) and late (60) onset may be reported. Cortical myoclonus is usually the first symp-
tom of the disease, but some patients begin with seizures and develop cortical myoclo-
nus later or both at the same time (van Rootselaar et al. 2005; Regragui et al. 2006).
14.3.1.4 Autosomic Dominant Transmission
The transmission of FCMTE is autosomal dominant. Clinical penetrance is proba-

bly high as no unaffected generation transmitted FCMTE in the different pedigrees
described.
14.3.1.5 Pharmacosensitivity
Improvement of epilepsy and myoclonus can be obtained with various epileptic

drugs such as clonazepam, sodium valproate, phenobarbital, or levetiracetam. Beta
blockers are ineffective. The effect of carbamazepine remains unclear. The effec-
tiveness of alcohol (as in essential tremor or myoclonus-dystonia) has not been
specifically studied.
14.3.2 Uncommon Clinical Characteristics
14.3.2.1 Mental Retardation or Cognitive Impairment
Mental retardation has been described in Italian families (Elia et al. 1998; Guerrini
et al. 2001). Slight neuropsychological disorders have been reported in Dutch
families with short-term memory and attentional deficits (van Rootselaar et al.
2002). In a South African family, progressive cognitive disorders led to a quickly

evolving dementia: this may indicate a very severe FCMTE phenotype (Carr et al.
2007). Loss of cognitive function could be increased by severe epilepsy and antiepi-
leptic drugs.
14.3.2.2 Cerebellar Disorders
Cerebellar ataxia is not usually involved in the FCMTE phenotype, but slight ataxia
has been reported in a Dutch family associated with cerebellar atrophy on brain
imaging (van Rootselaar et al. 2004, 2007). Abnormal oculomotor findings (square
wave jerk, down beat nystagmus increasing with hyperventilation, reduced down-
ward smooth pursuit gain, reduced mean saccadic gain, etc.) are consistent with
cerebellar disorders in these pedigrees (Bour et al. 2008). The South African pedi-
grees described had a severe progressive cerebellar ataxia (Carr et al. 2007).
14.3.2.3 Parkinsonism and Gait Disorders
Isolated cases reported in a Japanese pedigree had progressive gait disorders and
possible extrapyramidal symptoms. Oculomotor abnormalities (increased amount of
expressed saccades in pro-saccade paradigm) are consistent with basal nuclei dysfunc-
tion (Bour et al. 2008). Extrapyramidal syndrome could not be diagnosed due to severe
cortical myoclonus (Okuma et al. 1997; Nagayama et al. 1998; Terada et al. 1997;
(Magnin et al. 2012). Moreover, severe myoclonus of the lower limbs may mimic a
pseudoparkinsonian transient akinesia with generalized stiffness and freezing but
without EEG abnormalities (Morita et al. 2003). In the French pedigree, five patients
aged over 60 had a progressive Parkinson-like gait impairment with significant loss of
autonomy (Magnin et al. 2009, Magnin et al. 2012). It may be difficult to understand
the clinical features of FCMTE because sodium valproate treatment may also induce
tremor or parkinsonism.
14.3.2.4 Visual Intolerance to Bright Light and Contrast
Cortical myoclonus and seizures could be made worse by visual intolerance to

bright light and to contrast (patterns) (Gardella et al. 2006; Magnin et al. 2009).
14.3.2.5 Night Blindness
Night blindness and abnormalities on electroretinography suggesting an alteration

in photoreceptor function (transduction or transmission) have been reported in a
Japanese family (Manabe et al. 2002).
14.3.2.6 Headache and Migraine
Some pedigrees had migraine-like headache (Saka and Saygi 2000; Gardella et al.
2006; Magnin et al. 2009). Myoclonus may worsen during headache crisis. Sodium
valproate may improve headache.
14.3.3 Outcome
Myoclonus, EEG abnormalities, and cortical hyperexcitability progressively

worsen between the second and sixth decades (Coppola et al. 2011; Hitomi et al.
2011). Poor outcome of gait disorders, cognitive impairment, and late appear-
ance of extrapyramidal syndrome have been observed in older members of the
FCMTE3 pedigree (Magnin et al. 2012).
14.4 Electrophysiological Characteristics
The cortical origin of myoclonus is supported by electrophysiological findings

(jerk-locked back averaging, SEP, C-reflex, etc.) showing widespread cortical
hyperexcitability (Ikeda et al. 1990; Terada et al. 1997).
14.4.1 Electroencephalogram
No specific characteristics of FCMTE may be found on EEG, but cortical hyperex-

citability can be observed. Spikes or poly-spike wave complexes have been reported
as well as photoparoxysmal or photomyoclonic responses. An EEG examination
may also be normal in FCMTE patients.
14.4.2 Polygraphic Examination and Tremor Frequency

Recording
These tests help to differentiate between cortical myoclonus and tremor. The main
characteristics are irregular 6–20 Hz bursts of short duration (50 ms), low amplitude
(mainly in the distal muscles of the upper limbs at rest), and triggering of the jerks
by action or posture (Fig. 14.1, reproduced from Bourdain et al. 2006 with permis-
sion from Movement Disorders).
Fig. 14.1 Polygraphic recording of the right upper limb muscles
14.4.3 Somatosensory Evoked Potential
After median nerve stimulation, giant cortical responses (P25–N33 amplitude larger
than 8.5–15 mV) are found, showing cortical hyperexcitability.
Fig. 14.2 Long loop C-reflex
14.4.4 C Reflex Examination
Median nerve stimulations in the abductor pollicis brevis muscle at rest induce a
long-latency (40 ms) C reflex response, showing the diffusion of the stimulus to the
cortex of contralateral hemisphere (Fig. 14.2, reproduced from Bourdain et al. 2006
with permission from Movement Disorders).
14.4.5 Jerk-Locked Back-Averaging EEG
Premovement cortical spikes or depolarizations are time-locked to the myoclonus

(with a short latency compatible with cortico-spinal descending pathways) and
recorded on the sensorimotor cortex contralateral to the myoclonus. Low (or con-
versely, high) frequencies of myoclonus may disturb the analysis of these data
(Fig. 14.3, reproduced from Bourdain et al. 2006 with permission from Movement
Disorders).
Fig. 14.3 Cortical premyoclonic potential
14.4.6 Other Electrophysiological Examinations
Coherence analysis of EMG and EEG, movement-related cortical potentials, visual

evoked potentials (Guerrini et al. 2001), transcranial magnetic stimulation and
reciprocal inhibition of the soleus H-reflex (van Rootselaar et al. 2007), and simul-
taneous EMG-functional MRI recording (van Rootselaar et al. 2008) correspond to
widespread cortical hyperexcitability.
14.5 Imaging of the Brain
MRI and CT show no specific abnormalities. Cerebellar atrophy has been reported (van
Rootselaar et al. 2004, 2007). Abnormal 1H-MR spectroscopy has been reported in
cerebellar cortex (Striano et al. 2009b). Frontal hypometabolism in cerebral SPECT
examination was reported in two elderly members of FCMTE3. DAT scan showed
dopaminergic depletion in these FCMTE3 patients (Magnin et al. 2012).
14.6 Neuropathological Findings
A neuropathological examination was performed in only one case. This patient

belonged to a 2p/8q unlinked family. Cerebellar degeneration, somal sprouting, and
loss of dendritic tree in Purkinje cells were reported in this case. These findings are
similar to those described in channelopathy as spinocerebellar ataxia subtype 6
(SCA-6) (van Rootselaar et al. 2004).
14.7 Differential Diagnosis
The most frequently reported differential diagnoses were essential tremor, progres-
sive myoclonic epilepsy, spinocerebellar ataxia (SCA), Creutzfeldt–Jakob disease
(CJD), dentatorubral–pallidoluysian atrophy (DRPLA), opsoclonus–myoclonus
syndrome, Lafora’s disease, neural ceroïd lipofuscinosis, sialidosis, Ramsay Hunt
syndrome, postanoxic encephalopathy, toxic poisoning (alcohol, sodium valproate,
etc.) depending on the clinical features associated with cortical myoclonus and epi-
lepsy (e.g., dementia, severe ataxia, other movement disorders, etc.).
14.8 Diagnostic Criteria (Table 14.1)
FCMTE pedigrees share common “core clinical and electrophysiological character-

istics” that represent the disease spectrum. Diagnostic criteria have been proposed
by different authors (Van Rootselaar et al. 2005; Magnin et al. 2009; Bourdain et al.
2006; Regragui et al. 2006). We propose composite diagnostic criteria from these
different studies (see Table 14.1).
14.9 Genetic Findings
FCMTE is characterized by an autosomal dominant transmission with high clinical

penetrance. Linkage analyses were done in order to identify the loci involved. We
aimed to find one or more specific mutations.
14.9.1 Genetic Heterogeneity
Three loci (FCMTE 1, FCMTE 2, and FCMTE 3) have already been mapped (Plaster
et al. 1999; Mikami et al. 1999; Guerrini et al. 2001; Saint-Martin et al. 2008;
Depienne et al. 2010). Some families do not seem to be linked to these three loci
(van Rootselaar et al. 2002; Deng et al. 2005). Mutated genes have not yet been
identified. Intra- and inter-family clinical heterogeneity is very high.
14.9.1.1 FCMTE 1/FAME 1: Chromosome 8q23.3-q24.11
Two studies have been carried out on FCMTE/FAME1 families with locus 8q
(Plaster et al. 1999; Mikami et al. 1999). Particular clinical characteristics were
observed: the main features were (a) myoclonus onset during the third decade
Table 14.1 Composite diagnostic criteria for FCMTE

Genetic criteria Major criteria:
Family history of “tremor” and epilepsy with autosomal dominant
inheritance.
Clinical criteria Major criteria:
Cortical myoclonus (pseudo-tremor)
Distal predominance of involuntary, oscillatory, irregular,
tremor-like myoclonic jerks in upper and sometimes lower limbs,
triggered by outstretched posture and action, tiredness/sleep
deprivation, caffeine, vibration, glucose deprivation, intense visual
and/or auditory stimulation or contrast
Seizures (generalized or partial)
Minor criteria:
Effectiveness of antiepileptic drugs (valproate) in myoclonus
and epilepsy
Electrophysiological Major criteria:
criteria Widespread cortical hyperexcitability
Long-latency (40 ms) C reflex
Giant somatosensory evoked potential
Premovement cortical spikes or depolarizations in Jerk-locked
back-averaging EEG method
Exclusion criteria Differential diagnosis for cortical myoclonus and epilepsy:
Essential tremor, progressive myoclonic epilepsy, spinocerebellar
ataxia, postanoxic encephalopathy, toxic poisoning (alcohol,
valproate, etc.)
Clinical examinations should look for symptoms (dementia, severe
ataxia, other movement disorders, etc.) that may lead to other
diagnoses
Additional criteria – Adult onset (second to fourth decade)
– Normal imaging or unspecific cortical atrophy or slight cerebellar
atrophy
– Mental retardation or cognitive impairment
– Headache and migraine
– Gait disorders (severe myoclonus inducing flexion, hypertonia or
negative myoclonus, akinesia, hypertonia)
– Night blindness
– Photosensitivity or Visual intolerance to bright light and contrast
– Slight ataxia
– Slight extrapyramidal syndrome
Definitely affected: Two major clinical criteria and the genetic criteria
Or Or One major clinical criteria and one major electrophysiological criteria
and the genetic criteria
Probably affected: One major clinical criteria and one minor clinical criteria and the genetic criteria
Possibly affected: One major clinical criteria and the genetic criteria
(average age: 30.5 years; range: 18–45 years; Mikami et al. 1999), (b) worsening of
myoclonus on long-term follow-up, (c) EEG is always abnormal and is sometimes
associated with photosensitivity [67% for Plaster et al. (1999)], (d) generalized
tonic–clonic seizures occur infrequently (1–4 during life span) and do not increase
with time.
14.9.1.2 FCMTE 2/FAME 2: Chromosome 2p11.1-q12.2
FCMTE/FAME2 families (2p) are the most frequently described in the literature
(Guerrini et al. 2001; Labauge et al. 2002; De Falco et al. 2003; Striano et al.
2004, 2005; Madia et al. 2008; Saint-Martin et al. 2008; Suppa et al. 2009).
Certain clinical characteristics in FCMTE/FAME2 families have been reported,
such as mental retardation in some patients (Elia et al. 1998; De falco et al. 2003;
Striano et al. 2004, 2005); earlier age of initial symptom onset (myoclonus), dur-
ing the second decade, except for the patients described by Labauge et al. who
developed the disease in the fourth decade, 2 of 10 patients first experiencing
seizures 3–22 years before the occurrence of myoclonus (Labauge et al. 2002);
complex partial seizures involving fronto-temporal cortex that were sometimes
resistant to antiepileptic treatment; cognitive impairment (Guerrini et al. 2001).
EEG examinations were normal in almost one-third of the cases (Labauge et al.
2002; De falco et al. 2003).
14.9.1.3 FCMTE 3/FAME 3: Chromosome 5p15.31-p15.1
An FCMTE3/FAME 3 family has recently been described (Magnin et al. 2009;

Depienne et al. 2010). This family shares some characteristics with the 8q and 2p
patients and those who were unlinked to currently known loci. Visual intolerance
and headache, with migraine without ophthalmic aura, were frequently observed
and were similar to those observed in patients from the “non-8q, non-2p group.”
Partial seizures (complex partial seizures and occipital seizures) were frequent.
These clinical features were similar to those in “2p families” (Guerrini et al. 2001).
Walking impairment (with progressive loss of autonomy) was related to progressive
worsening of myoclonus and was similar to observations in the “8q families”
(Plaster et al. 1999; Mikami et al. 1999) and in the Spanish “2p family” (Labauge
et al. 2002). Cognitive impairment associated with frontal hypometabolism (ECD-Tc
99 m perfusion SPECT scan) and dopaminergic depletion (I-123-FP-CIT DAT scan)
was reported in two subjects (Magnin et al. 2012). None of the patients had ataxia
despite some of them having nonspecific slight cerebellar atrophy such as those
reported in “non-8q, non-2p families” (van Rootselaar et al. 2002).
14.9.1.4 FCMTE Pedigree Unlinked to 8p and 2q Loci (5p Not Tested)
An absence of linkage to 2p and 8q was observed in some families (Van Rootselaar

et al. 2002; Deng et al. 2005; Gardella et al. 2006; Carr et al. 2007). The 5p locus of
FCMTE 3 has not yet been specifically tested in these families. It seems that they
share certain similar features. Ataxia with cerebellar atrophy has been reported (Van
Rootselaar et al. 2002; Gardella et al. 2006; Carr et al. 2007). Cognitive impairment
(Van Rootselaar et al. 2002), behavior disorders (Deng et al. 2005; Gardella et al.
2006), visual intolerance to bright light and to contrast without EEG abnormalities,
as well as headaches (Gardella et al. 2006) have been described. Two cases had
complex partial seizures (Van Rootselaar et al. 2002; Gardella et al. 2006). Overall,
there still appears to be some heterogeneity in these groups and different kinds of
phenotype seem to have been grouped together. The South African families have a
malignant form with presenile dementia, ataxia, and rapid deterioration leading to
death. This reflects a severe phenotype of FCMTE or, may be an as yet unidentified
disorder (Carr et al. 2007; Striano et al. 2008).
14.10 Physiopathological Findings
The physiopathology of FCMTE remains unclear. Clinical and electrophysiologi-

cal findings suggest a widespread cortical hyperexcitability. The most reported
hypothesis link this disorder to a channelopathy despite no mutation having been
found. The postmortem examination of one FCMTE patient showed features of
SCA-6, a channelopathy that also induces cortical hyperexcitability (van Rootselaar
et al. 2004). The night blindness and reduced b-wave responses found on elec-
troretinography may reflect dysfunction in calcium-mediated neurotransmitter
release from photoreceptors in response to light (Manabe et al. 2002). The associa-
tion with migraine may also suggest channelopathy, as in familial hemiplegic
migraine.
Cerebellar dysfunction is also frequently reported (mild ataxia, occulomotor
abnormalities, mild cerebellar atrophy, abnormal 1H-MR spectroscopy in cerebellar
cortex, and cerebellar degeneration with abnormal Purkinje cells) (van Rootselaar
et al. 2004, 2007; Striano et al. 2009b; Bour et al. 2008). No neuropathological
abnormality has been found in the sensorimotor cortex. Hyperexcitability may thus
result from a decrease in inhibition. The GABAergic system may play a role in corti-
cal excitability as clonazepam and sodium valproate are highly effective in FCMTE
(van Rootselaar et al. 2007). The cerebello-thalamo-cortical network may play a role
in this inhibiting system. Dopaminergic depletion has been found in two patients
with FCMTE3 (Magnin et al. 2012).
14.11 Conclusion
FCMTE is a rare and sometimes misdiagnosed entity with clinical and genetic het-
erogeneity. This pathology should be suspected in patients with atypical “tremor”
and/or epilepsy and with a family history of “tremor” and/or epilepsy. The physiopa-
thology of widespread cortical hyperexcitability remains unclear. A channelopathy is
suspected but has not yet been confirmed.
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Chapter 15
Posttraumatic Tremor and Other Posttraumatic
Movement Disorders
Jose Fidel Baizabal-Carvallo and Joseph Jankovic
Keywords Posttraumatic • Movement disorders • Injury
15.1 Introduction
Stress is defined as a state of threatened or disturbed homeostasis provoked by an

internal or external stimulus (Black 2002). Trauma can be considered as a cause of
mechanical stress. After trauma the organism responds with a series of reactions
aimed to repair the damage, promote healing, and recruit host defense mechanisms.
It is believed that the motor system may be involved in some of these mechanisms
giving rise to loss of motor control and a variety of abnormal movements. Movement
disorders (MDs) following trauma have been recognized in the medical literature
since 1888 when Gowers described two patients with involuntary movements after
neck and thumb trauma (Gowers 1888). Many types of MDs have been described
following trauma, including: dystonia, tremor, chorea, tics, myoclonus, hemifacial
spasm, hemimasticatory spasm, “jumping post-amputation stump,” painful legs
(arms) and moving toes (fingers), synkinesias secondary to aberrant regeneration,
and parkinsonism (Cardoso and Jankovic 1995; Jankovic 2009a).
15.2 Classification of Posttraumatic Movement Disorders
Posttraumatic MDs are classified according to their primary phenomenology and

the site of initial trauma. Direct trauma to the central nervous system (CNS), also
known as traumatic brain injury (TBI) (Krauss and Jankovic 2002) or spinal cord
J.F. Baizabal-Carvallo, M.D. • J. Jankovic, M.D. (*)

Department of Neurology, Parkinson’s Disease Center and Movement Disorders Clinic,
Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, USA
e-mail: josephj@bcm.edu
264 J.F. Baizabal-Carvallo and J. Jankovic
Table 15.1 Proposed criteria for movement disorders induced by peripheral trauma
1. The injury should be severe enough to cause local symptoms, persisting or requiring
medical attention, for at least two weeks after trauma
2. The onset of involuntary movements must have occurred within one year after the trauma
3. The abnormal movements should be anatomically related to the side of trauma
a. Absence of other etiologies explaining the origin of the involuntary movement
b. Presence of reflex sympathetic dystrophy
c. Poor response to conventional treatment
injury, as well as peripheral trauma (soft tissues, peripheral nerves, and cranial
nerves) have been documented to cause various involuntary movements and other
MDs (Jankovic 2009a, b). Despite the obvious temporary relationship between the
trauma and subsequent movement disorder, the cause-and-effect relationship and
the mechanisms of the disturbances in movement are not always well understood.
Along with local evidence of injury, the time between the trauma and the onset
of the movement disorder is a key feature in establishing a cause-and-effect rela-
tionship (Table 15.1). In some instances, however, a definite cause-and-effect
relationship cannot be established, partially due to various circumstances, including
lack of recall, delayed effects, and even medico-legal factors (Scarano and Jankovic
1998). This is particularly true in patients with peripherally induced MDs, as the
trauma may be relatively minor and seemingly inconsequential (Nobrega et al.
2002). In 1988, somewhat arbitrarily, we proposed a set of operational criteria, such
as regional evidence of injury and a maximum latency of 1 year after the trauma in
order to classify the motor disturbance as posttraumatic, peripherally induced move-
ment disorder (Jankovic and Van der Linden 1988) (Table 15.1). Although these
diagnostic criteria have been relatively well accepted, some authors have allowed
latencies of 2 (Marsden et al. 1984) and up to 8 years (Weiner 2001; Schott 1985).
In a review of cases with peripherally induced MDs, 95% of reported cases had a
latency shorter than 1 year after trauma, with a median of 21 days, and the clinical
characteristics did not differ between patients with latencies of less than a year and
more than a year (van Rooijen et al. 2011). Despite controversies about the exis-
tence of peripherally induced tremor, dystonia, and parkinsonism, other MDs have
a more generalized acceptance of a peripheral origin, including: hemifacial spasm
(Wang and Jankovic 1998), segmental myoclonus (Jankovic and Pardo 1986), eden-
tulous orodyskinesias (Koller 1983; Blanchet et al. 2008), and amputation stump
dyskinesias (Jankovic and Glass 1985; Kulisevsky et al. 1992).
15.3 Trauma to the Central Nervous System
In this part of the chapter, we will discuss the effects of head trauma in the patho-
genesis of different MDs as well as diagnostic procedures and treatment options.
15 Posttraumatic Tremor and Other Posttraumatic Movement Disorders 265
15.3.1 Movement Disorders Following Traumatic Brain Injury
MDs are well-recognized complications of head trauma. They have been reported
following different types of head trauma, and the prevalence seems to be related to
the severity of the TBI. In a study aimed to address the frequency and characteristics
of MDs after severe head trauma, defined as a Glasgow coma score (GCS) equal or
less of 8. The authors studied 221 patients, of whom 26.6% developed a MD,
described as transient in 23 patients (10.4%) and persistent in 27 (12.2%). Tremor
was the most common movement disorder, followed by dystonia. Generalized brain
edema was significantly associated with the appearance of MDs, including kinetic
tremor and dystonia (Krauss et al. 1996). In this study, subdural and epidural hema-
tomas were not associated with MDs. Only 5.4% of patients suffered disabling low-
frequency kinetic tremor (2.5–4 Hz), dystonia, or both. These MDs were associated
with significantly lower GCS on admission. Dystonia had a longer latency (up to 2
years) compared to kinetic tremor (6 months), but significant overlap was observed
between both MDs. Although the pathogenesis of these posttraumatic MDs is not
known, a variety of pathological changes have been documented after brain injury.
For example, diffuse axonal injury (DAI) and small deposits of hemosiderin in the
dentatothalamic pathway have been demonstrated on MRI in patients with posttrau-
matic head trauma, affecting the ipsilateral pre-decussional dentatothalamic path-
way in 56% and the contralateral post-decussational pathway in 28% of all cases
(Krauss et al. 1995).
MDs have been reported in 10.6% of patients with mild-to-moderate craniocere-
bral trauma (GCS ³9), the most common being low amplitude postural, kinetic tremor
resembling enhanced physiological or kinetic tremor. The MDs were more frequently
observed in patients with GCS between 9 and 14 than those with a score of 15 (Krauss
et al. 1997a). Most patients have a transient tremor, and do not require pharmacologi-
cal treatment. A 5- to -6 Hz tremor has been reported in patients with moderate head
trauma, without clear relationship with cerebellar damage (Biary et al. 1989). The
frequency of MDs following head trauma has also been studied in children. In a sur-
vey of 289 children with severe traumatic head injury; tremor was reported in 45% of
cases; it usually appears within the first 18 months after head injury and resolves
spontaneously in most cases (Johnson and Hall 1992). Other authors have reported a
“basal ganglia syndrome” in 4 of 31 (13%) children with severe closed head injury,
with hemiballism in half of those patients (Costeff et al. 1990).
15.3.2 Holmes and Other Tremors Following Traumatic

Brain Injury
Holmes tremor (HT), also known as “midbrain,” or “rubral” tremor, is considered

the most common posttraumatic tremor, and is caused by lesions affecting the mid-
brain. It has a low frequency (<4.5 Hz) with an irregular resting, postural and action
component (Holmes 1904; Deuschl et al. 1998). It has been proposed that the
occurrence of cerebellar (action tremor) and parkinsonian (rest tremor) features in
HT reflects a combined lesion in the cerebellothalamic (i.e., dentatothalamic and
dentatorubral tracts) rubro-olivary and nigrostriatal pathways. Patients with HT
may or not have contralateral parkinsonian symptoms. However, contralateral
striatal dopaminergic denervation has been demonstrated with functional imaging
using [123I]FP-CIT SPECT in some cases of HT (Remy et al. 1995; Reese et al.
2011; Zijlmans et al. 2002). Onset of HT varies from weeks to several months
after the insult; however, a delayed onset of 23 years after TBI has been reported
(Krack et al. 1994).
Pharmacological treatment of tremor secondary to TBI with propranolol, primidone,
benzodiazepines, cabamazepine, levodopa, and anticholinergics provides variable
results (Ellison 1978; Harmon et al. 1991; Jacob and Chand 1998). Botulinum toxin
injections can be also used to relief the tremor temporarily (Jankovic and Brin
1991). Marked improvement in contralateral HT and pain has been observed with
thalamotomy and stimulation of the ventral intermedius nucleus (Vim) (Broggi
et al. 1993). Deep brain stimulation (DBS) of the Vim, however, may not be enough
to suppress contralateral posttraumatic tremor. Therefore high-frequency stimula-
tion of the contralateral ventralis oralis anterior (Voa) and posterior (Vop) along
with the Vim DBS has been reported to successfully suppress the tremor and even
abolished contralateral hemiballism (Foote and Okun 2005; Foote et al. 2006;
Martínez-Mañas et al. 2002; Krauss et al. 1994).
15.3.3 Dystonia Following Traumatic Brain Injury
Dystonia is a neurological disorder dominated by involuntary, sustained or spas-

modic, repetitive, and patterned contractions of muscles, frequently causing twist-
ing and other abnormal movements or postures. There are many causes for dystonia,
including head trauma. Hemidystonia represents the most frequent type of dystonia
following head trauma (Krauss et al. 1992; Svetel et al. 2004; Wijemanne and
Jankovic 2009). Since the first report by Austregesilio in 1928 (Austregesilo and
Marques 1928), several series have correlated hemidystonia with structural lesions
of the contralateral caudate, putamen, and thalamus (Pettigrew and Jankovic 1985;
Wijemanne and Jankovic 2009); pallidal lesions resulting in dystonia are relatively
rare (Münchau et al. 2000). In patient series of symptomatic hemidystonia from dif-
ferent etiologies, head injury accounted for 7–9% of all cases (Marsden et al. 1985).
There is a predominance in men, which probably reflects the male preponderance of
craniocerebral trauma. Most patients suffer the syndrome in their infancy and ado-
lescence. The delay between the head trauma and the onset of dystonia is variable.
In a series of 18 cases with severe head trauma, the onset varied from 1 month to 9
years (median 18 months). This interval was longer than in patients with mild head
trauma (median: 14 days, range: 3 days to 5 years) (Lee et al. 1994). In that series,
up to 90% of patients presented with a focal form of dystonia, but spreading to other
limbs or body parts is common in the following months or years, leading to segmental,
hemi-, multifocal, or generalized dystonia (Lee et al. 1994). Latency to the onset of
dystonia may be related to the age at the time of the injury. In one study, a mean
latency between the injury and dystonia of 25.5 years was observed in infants
(2 years or younger), whereas a delay of 4.9 years was observed in children between
6 and 17 years, and much shorter latency was observed in adults (Scott and Jankovic
1996). Hemidystonia has also been attributed to traumatic vascular damage affecting
the lateral lenticulostriate branches of the middle cerebral artery (Maki et al. 1980).
Dystonia has also been reported following ischemic damage produced by blunt or
penetrating carotid artery injuries (Krauss and Jankovic 1997a).
Dystonia has been reported after traumatic pontomesencephalic lesions associ-
ated with brainstem hemorrhage and DAI (Loher and Krauss 2009). Patients have a
mean onset of dystonia 6 months after the initial brainstem insult and usually pres-
ent with a combination of hemidystonia, cervical dystonia, and cerebellar outflow
tremor. Anatomical structures typically involved include the pontomesencephalic
tegmentum and the postdecussational superior cerebellar peduncles, and the accom-
panying tremor suggests involvement of the dentatothalamic pathways (Deuschl
et al 1998; Loher and Krauss 2009). It has been observed that mesencephalic lesions
extending to the thalamus are associated with unilateral appendicular or hand dys-
tonia, while pontomesencephalic lesions are related to more severe hemidystonia or
cervical dystonia (Loher and Krauss 2009; Tränkle and Krauss 1997). A 4–5 Hz
postural and rest tremor with action-induced dystonia has been described 2 years
after penetrating trauma affecting the contralateral diencephalic–mesencephalic
regions involving the substantia nigra and subthalamic region (Krauss et al. 1997b).
Symptomatic cervical dystonia has been described with lesions in the posterior
fossa, particularly affecting the cerebellopontine angle (Krauss et al. 1997c).
The origin of acquired hemidystonia secondary to basal ganglia or thalamic lesions
has been assessed by regional cerebral blood flow studies, and has been attributed
to frontal overactivity secondary to disruption of inhibitory control by the basal
ganglia (Ceballos-Baumann et al. 1995).
A syndrome characterized by paroxysmal autonomic instability with focal
dystonia (PAID) has been well described in patients hospitalized in the intensive
care unit (Blackman et al. 2004). The syndrome, more commonly associated with a
traumatic cause particularly in adolescents or young adults, has been labeled in the
past with a variety of other terms, such as “brainstem attacks,” “neurostorm,” “acute
midbrain syndrome,” “hyperpyrexia associated with sustained muscle contractions,”
and others. Patients present with marked agitation, diaphoresis, hyperthermia,
hypertension, tachycardia, tachypnea, and muscular hypertonia (Srinivasan et al.
2007). Differential diagnoses include neuroleptic malignant syndrome, malignant
hyperthermia, autonomic dysreflexia, and central fever. Treatment can be attempted
with nonselective beta-blockers, morphine sulfate, bromocriptine, or clonidine.
Worsening might be observed with sedation with haloperidol (Rabinsten 2004).
There are controversies about the role of head trauma in the development of
organic dystonia. In a study of 202 patients with dystonia, and 202 age and age-
matched controls, head or facial trauma with loss of consciousness increased the
risk of developing dystonia (Defazio et al. 1998). A higher frequency of previous

cranial and facial trauma was found in a group of 159 patients with blepharospasm
(Defazio et al. 1999). However, in an Italian multicenter study conducted by the
same group of authors in 177 patients with primary adult-onset cranial dystonia and
217 controls with primary hemifacial spasm no association between trauma and
dystonia was found, and a previous history of trauma did not modify the age at onset
of cranial dystonia (Martino et al. 2007). The presence of the DYT1 mutation does
not seem to increase the risk of secondary dystonia (Bressman et al. 1997). However,
it has been recognized that trauma is a trigger factor in patients carrying DYT1
mutations (Edwards et al. 2003).
Dystonia secondary to head trauma can be treated similar to primary dystonia
with a trial of anticholinergics, levodopa, or botulinum toxin injections (Jankovic
2009a, b). However DBS of the globus pallidus internus (GPi) has provided
significant and sustained benefit in cases with posttratumatic hemi- and cervical
dystonia and should be considered in cases with lack of response to pharmacologi-
cal treatment (Loher et al. 2000; Chang et al. 2002).
15.3.4 Head Trauma and Parkinsonism
The relationship between trauma and Parkinson’s disease (PD) was first proposed
by James Parkinson in 1817 in his “Essay on the Shaking Palsy” when he theorized
that the location of the injury was in the superior cervical spine (Parkinson 1817).
The concept of head trauma and PD was revitalized during World War I, when cases
of concussion associated with mesencephalic injuries were reported. However this
association was highly criticized until 1928 when Paulian described a patient who
was shot in the head. The patient survived the initial insult and the autopsy 6 year
later revealed hemorrhagic lesions in the anterior aspects of the basal ganglia and
subthalamic nucleus (STN) (Cruzon and Justin-Besancon 1929). Other well-docu-
mented cases from early twentieth century were analyzed by Crouzon and Justin-
Besançon. This was followed by few other pathological reports revealing hemorrhagic
lesions in the midbrain involving the substantia nigra in patients with traumatic
head trauma and parkinsonism (Lindenberg 1964). Direct lesions to the substantia
nigra have been reported secondary to injuries by knives, screwdrivers, shell splin-
ters, or gunshots, presenting with hemiparkinsonism (Rondot et al. 1994; Krauss
et al. 1997b).
Despite its rarity, parkinsonism following severe head trauma is well documented
(Goetz and Stebbins 1991), although the pathogenesis is not always well under-
stood. Mechanical lesions to the mesencephalon can produce transient dysfunction
of the nigrostriatal system in humans (Slevin et al. 1987). MRI studies have shown
hematomas in the putamen and substantia nigra in the acute stage, and hemosiderin
deposits in the midbrain 3 months after the injury (Bhatt et al. 2000). Transcranial
ultrasound examinations have shown decreased echogenicity of the substantia nigra
in posttraumatic parkinsonism, in marked contrast with hyper-echogenicity observed
in patients with idiopathic PD (Kivi et al. 2005). Functional imaging with [18F]-
fluorodopa PET in six patients with contralateral parkinsonian tremor following a
traumatic peduncular lesion showed severe dopaminergic denervation of the basal
ganglia, more marked than in patients with idiopathic PD (Turjanski et al. 1997;
Remy et al. 1995). Proton magnetic resonance spectroscopy studies have shown a
marked reduction in the concentration of N-acetylaspartate in the lenticular nuclei
of patients with posttraumatic parkinsonism, compared to patients with PD and con-
trols (Davie et al. 1995). Patients with parkinsonism secondary to head trauma usu-
ally show a good response to levodopa (Bhatt et al. 2000). However, in cases with
refractory tremor, combined DBS of the Vim and dorsolateral STN resulted in
marked reduction of contralateral rest tremor, rigidity, and bradykinesia in a patient
with posttraumatic hemiparkinsonism (Romanelli et al. 2003; Reese et al. 2001).
Prognosis of parkinsonism following head trauma is variable. Reversible parkin-
sonism has been reported in the context of chronic subdural hematoma (Krul and
Wokke 1987; Bostantjopoulou et al. 2009) with compression of the midbrain from
central herniation (Trosch and Ransom 1990). Patients with PD who sustain head
trauma from motor vehicle accidents show increased disability right after trauma, but
they usually return to baseline in the following weeks (Goetz and Stebbins 1991).
Despite clear pathological evidence that severe TBI with selective damage to the
nigrostriatal structures causes parkinsonism, the question if mild-to-moderate head
trauma can cause PD has also been addressed in several studies with a case-control
design. In one study of 97 PD patients and 64 controls, the former had a higher
frequency of previous head trauma 32% vs. 17.8% P = 0.001; this difference was
also significant if altered or loss of consciousness was considered 20.6% vs. 7.8%
(Factor and Weiner 1991). Other retrospective studies have reported similar findings
(Tanner et al. 1987). In one retrospective study of 196 PD patients, with age- and
sex-matched subjects from the normal population, a history of head trauma was
significantly more frequent in PD patients (OR 4.4); loss of consciousness or severe
head trauma highly increased the odds ratio (OR) up to 11, but subjects who expe-
rienced mild head trauma with amnesia did not show a higher risk for developing
PD (Bower et al. 2003). The authors considered that the population attributable risk
was only 5% because head trauma is a relatively rare event. In another case-control
study of 140 PD patients and 147 controls assessing the environmental factors asso-
ciated with PD, head trauma had the highest odds ratio (OR) (OR = 6.23, CI: 2.58–
15.07), followed by family history of PD (OR = 6.08, CI: 2.35–15.58), family history
of tremor (OR = 3.97, CI: 1.17–13.50), and history of depression (OR = 3.01, CI:
1.32–6.88) (Taylor et al. 1999). A case-control study in 93 twin pairs discordant for
PD showed that prior head injury with amnesia or loss of consciousness resulted in
a significantly increased risk of PD (Goldman et al. 2006). These studies, however,
have been criticized due to lack of imaging documentation, possible recall bias, and
considerable time lag between the injury and the onset of symptoms (Bhatt et al.
2000). A nationwide population-based study from Denmark showed that a history
of severe head injury did not appear to increase the risk for PD more than a decade
after trauma (Spangenberg et al. 2009). An increased frequency of hospital contacts
for head injury was observed in another study, during the months of onset of PD
which was thought to be a consequence of the hypokinetic MDs rather than its cause
(Rugbjerg et al. 2008). A large prospective cohort study did not confirm the associa-
tion between PD and head trauma (Williams et al. 1991); therefore a history of head
trauma as a risk factor for PD is still controversial.
15.3.5 Pugilistic Parkinsonism, Dementia,

and Chronic Traumatic Encephalopathy
Pugilistic parkinsonism is a form of posttraumatic parkinsonism. It is secondary to

the cumulative effect of multiple subconcussive blows over many years and bouts.
A correlation between the severity of the neurological manifestations and the length
of career and number of bouts has been reported (Casson et al. 1984). Brain damage
using a multimodal approach, including clinical, neuroimaging, and EEG, has been
documented in up to 87% of former and active boxers (Casson et al. 1984). Three
clinical stages have been described: in the first stage affective and other psychiatric
symptoms are seen, in the second stage parkinsonism develops, followed by a final
stage of dementia and pyramidal tract manifestations (Guterman and Smith 1987).
Other manifestations including dysarthria and cerebellar dysfunction have been
identified as part of the syndrome (Factor et al. 1988). Postmortem examinations in
these patients have revealed petechial hemorrhages, degeneration of the substantia
nigra, with a notable lack of Lewy bodies (Koller et al. 1989). It has been proposed
that shearing forces secondary to rapid rotation of the cranium can cause degenera-
tion of the nigrostriatal pathways (Koller et al. 1989). The cognitive decline and
behavioral changes associated with boxing are frequently seen along with pugilistic
parkinsonism, and the syndrome has also been referred as “punch drunk,” “goofy,”
“slug-nutty,” and more formally as “dementia pugilistica.” The clinical and patho-
logical effects of repetitive trauma have been recognized to occur in other sports
besides boxing, including American football, professional wrestling, hockey, and
soccer, as well as other activities related to repetitive head trauma, such as epileptic
seizures, head banging, and physical abuse (Gavett et al. 2011).
In the last five decades evidence of a neurodegenerative disorder secondary to
repetitive trauma has led to coining the term “chronic traumatic encephalopathy”
(CTE). Recent advances in this field have shown prominent accumulation of
neurofibrillary tangles (NFT), neuropil threads (NYs) and glial tangles (GT) with a
more superficial (cortical laminea II and III), and scattered distribution compared to
Alzheimer disease (cortical laminae III and V) (McKee et al. 2009). Beta-amyloid
deposits are found in up to 45% individuals with CTE, whereas TDP-43 proteinopa-
thy has been reported in more than 80% of CTE cases by some authors (McKee
et al. 2010). It has been shown that high-exposure professional boxers with an
apolipoprotein epsilon4 allele have significantly greater scores on a scale measur-
ing chronic encephalopathy than those without the allele (Jordan et al. 1997). The
syndrome usually presents with behavioral (e.g., apathy, depression, irritability,
impulsiveness, suicidality) or cognitive changes; later in the course of the disease
parkinsonism, speech, and ocular abnormalities may emerge in the context of

declining cognition (Gavett et al. 2011).
15.3.6 Hemiballismus, Tics, and Other Hyperkinetic Movement

Disorders Following Traumatic Brain Injury
Hemiballismus and hemichorea are known to occur after traumatic head injury
(Dewey and Jankovic 1989; Richardson et al. 1987). Posttraumatic hemiballism is
associated with severe closed head injury. Hemorrhagic lesion of the STN may
result in hemiballismus as early as 1 day after brain injury (Kim et al. 2008).
However, a delay of 6 months has been reported in a patient who recovered from
coma (King et al. 2001). Paroxysmal dyskinesias have also been reported after brain
injury (Blakeley and Jankovic 2002; Drake et al. 1986). Putaminal lesions have
been observed in single cases of paroxysmal MDs (Biary et al. 1994). Positron
emission tomographic scans showed abnormal metabolism in the contralateral basal
ganglia during an attack of paroxysmal posttraumatic dystonia (Perlmutter and
Raichle 1984). Posttraumatic tic and tourettism have been identified in some patients
following head trauma (Singer et al. 1989; Siemers and Pascuzzi 1990; Majumdar
and Appleton 2002; Ranjan et al. 2011). In a series of six patients with tics after
craniocerebral trauma, all patients were male, and the mean age at the time of trauma
was 28 years. The injury was moderate or mild in five cases, and neuroimaging
studies did not reveal lesions in the basal ganglia (Krauss and Jankovic 1997b).
However, extensive periventricular and subcortical leukoencephalopathy was
observed in one case with tics and marked obsessive–compulsive behavior second-
ary to brain injury (Krauss and Jankovic 1997b). Myoclonus, opsoclonus, stereotyp-
ies, akathisia, and galloping tongue have also been described in patients with TBI
(Keane 1984; Stewart 1989; Desai et al. 2010).
15.4 Trauma to Peripheral Nervous System and Soft Tissues
Several different movement disorders have been described following peripheral

trauma. In this second part of this chapter we will discuss these MDs individually,
although overlap among them may exist. Table 15.2 summarizes the characteristics
of these MDs from a meta-analysis of 713 patients.
15.4.1 Peripherally Induced Tremor and Parkinsonism
Tremor following peripheral trauma is a well-recognized movement disorder. In a

recent systematic review and meta-analysis, tremor was the second most com-
mon peripherally induced MD after dystonia, and represented 25% of all cases.
(van Rooijen et al. 2011). In a study of 28 cases with peripherally induced tremor
Table 15.2 Clinical Demographics

characteristics of peripherally
Female: 64%
induced movement disorders
in 713 patients Age of onset (median): 38 years
Type of movement disorder
Dystonia 72%
Tremor 25%
Myoclonus 13%
Spasm 11%
Painful limbs and moving toes or
fingers 6%
Parkinsonism, chorea, tics: 4%
Type of trauma
Soft tissue injury 43%
Fracture 10%
Surgery 10%
Other 12%
Nerve entrapment 18%
Amputation 2%
Location of trauma
Limb: 66%
Neck and/or shoulder 25%
Oromandibular/vocal cords 6%
Truncal region; 25%
Spread to other body regions: 19%
Multifocal: 37%
Generalized: 25%
Contralateral: 12%
Ipsilateral: 11%
Segmental: 10%
Modified from van Rooijen et al. (2011)
and parkinsonism, trauma preceded the neurological manifestations by a mean of

47 days (Cardoso and Jankovic 1995). In 20 of these patients the movement disor-
der spread beyond the site of initial trauma. Several potential predisposing factors
have been identified in patients with peripherally induced tremor. In a study of 23
patients with tremor and dystonia induced by peripheral trauma, 15 patients (65%)
had conditions that may increase the risk of peripherally induced MDs, including
use of neuroleptics or stimulants, AIDS-related complex, family history of essential
tremor or dystonia, premature birth and developmental delay; in this study the
authors carefully excluded patients with possible psychogenic MDs (Jankovic and
Van der Linden 1988). Immobilization has also been reported as a cause of tremor
induction or exacerbation (Cole et al. 1989; Herbaut and Soeur 1989).
Neck whiplash injuries have been reported preceding limb tremor (Ellis 1997).
Some of these cases show root and/or spinal cord damage. Some studies have dem-
onstrated electromyography evidence of traumatic nerve injury preceding the tremor
(Costa et al. 2006; Jankovic and Van der Linden 1988). Tremor and other movement
disorders have been described in six patients following intervertebral cervical and
lumbar disc surgery, with a latency of 1 day to 12 months after the surgical proce-
dure. In these cases the MD is usually accompanied by persistence dermatomal
pain, with an anatomical distribution closely related to the root or spinal segment
involved in the surgery (Capelle et al. 2004).
Peripheral trauma as a cause of parkinsonism has been suggested since late nine-
teenth century (Factor et al. 1988). However the concept was barely studied until the
end of last century, when well-documented cases of peripheral trauma preceding
parkinsonism were reported in the literature. In those cases, the anatomical onset of
parkinsonism is related to the site of trauma. In a series of 11 patients reported by
Cardoso and Jankovic, seven of them showed clinical improvement with levodopa.
Three patients were investigated with (18F) fluorodopa uptake and raclopride bind-
ing. The authors reported findings similar to those encountered in patients with
idiopathic PD, excluding a functional (i.e., psychogenic) origin of the disorder. The
lack of response to levodopa in some cases suggests the possibility of postsynaptic
changes possibly induced by the trauma itself (Cardoso and Jankovic 1995). CNS
reorganization has been proposed as one of the underlying mechanisms of peripher-
ally induced tremor and parkinsonism. In an animal model with adult rats exposed
to 6-hydroxydopamine to produce dopamine depletion in their brain, the rats behave
normally in their cage; however they became akinetic after exposure to severe cold,
tail shock, and glucose deprivation (Snyder et al. 1985). The neurological impair-
ment was related to the intensity of stress and was reversible with dopaminergic
agents (Snyder et al. 1985). These findings suggest the possibility of a subclinical
dopaminergic loss may express when the organism is exposed to a severe enough
peripheral stimulus; however more clinical and experimental evidence (i.e., animal
models) is needed to clarify how this actually occur.
15.4.2 Peripherally Induced Limb Dystonia
Dystonia is defined as abnormal muscle contractions frequently holding a body part

in an abnormal posture, often associated with tremor (Fahn et al. 1998). Peripherally
induced dystonia may present with a pattern similar to other organic dystonias, with
sensory tricks, action-induced and even task-specific dystonic postures indistin-
guishable from primary dystonia (Fletcher et al. 1991; Frucht et al. 2000; Jankovic
and Van der Linden 1988). Another manifestation of peripherally induced dystonia
is fixed dystonia (Table 15.3) (Schrag et al. 2004). Trauma in peripherally induced
dystonia is usually to soft tissues, but fractures, operations, limb overuse, and immo-
bilization by casting may also precede or aggravate dystonia (Okun et al. 2002;
Singer and Papapetropoulos 2005; Schott 1985; Elbert and Rockstroh 2004). This form
of dystonia is often encountered in individuals who require repetitive performance
of a particular task, such as musicians (Jankovic and Ashoori 2008) and athletes,
including long-distance runners (Wu and Jankovic 2006). Monkeys trained to
perform repetitive hand grip opening and closing were found to have a reorganiza-
Table 15.3 Characteristics of primary and fixed dystonia

Primary or idiopathic dystonia Fixed dystonia
Gender predominance Variable, depends on the type Female
of dystonia
Induced by actions Typical, may be task specific. No
Improvement by sensory tricks Usually No
Association with complex Rare Yes, frequently
regional pain syndrome.
Overflow phenomenon Common No
Association with trauma Yes but less 5% of cases Yes, typically preceded
by minor trauma
Response to pharmacological Moderate to good Usually poor
treatment
tion and enlargement of the contralateral primary somatosensory cortical area 3b,
which has connections with putamen (Topp and Byl 1999; Meunier et al. 2001).
This observation may have implications for the mechanism of dystonia associated
with repetitive strain injuries (“the overuse syndromes”) (Jankovic 2009a, b).
Fixed dystonia is considered the most frequent form of peripherally induced,
posttraumatic dystonia and is characterized by limitation of passive range of motion,
contractures, and absence of sensory tricks. The association of fixed dystonia with
trauma is strong as up to 68% of patients who present with this syndrome have a
preceding traumatic event, which differs from the 5% in patients with classical dys-
tonia (Schrag et al. 2004). Fixed dystonia is not exclusively related to trauma and
may occur after acquired neurodegenerative disorders like corticobasal degenera-
tion (Vanek and Jankovic 2001). Other neurological or mechanical disorders may
resemble fixed dystonia, including stiff-limb syndrome and atlantoaxial disloca-
tions (Suchowersky and Calne 1988). It can also be observed without previous his-
tory of trauma; in those cases an underlying psychogenic etiology is frequently
suspected. Other MDs frequently coexist with posttraumatic fixed dystonia in the
same or different limb, including painful spasms, tremor, and involuntary jerks
(Schrag et al. 2004). Fixed dystonia share features with psychogenic dystonia
including the frequent coexistence of somatoform disorders, active resistance
against passive movement, pain, and lack to response of sensory tricks (Schrag et al.
2004; Hawley and Weiner 2011).
The prognosis of fixed dystonia is generally considered poor. In a study that
aimed to assess the clinical and neuropsychiatric evolution in 41 patients with fixed
dystonia, 83% were women and had a mean duration of illness of 11.8 years (Ibrahim
et al. 2009). After a mean follow-up of 7.6 years, 31% of patients worsened, 46% were
the same, 23% improved, and only 6% had a major remission. The presence of CRPS
at baseline predicted a worse outcome. Substantial proportion of these patients suf-
fered anxiety, depression, or meet the diagnostic criteria for somatoform disorders.
Pharmacological therapy is usually unsuccessful in patients with fi xed
posttraumatic dystonia. Contralateral pallidal and thalamic DBS did not improve
dystonia in a single report of a woman with posttraumatic painful leg dystonia (Capelle
et al. 2006). Treatment with occupational, physical therapy and psychotherapy has
resulted in at least modest benefit in some patients (Schrag et al. 2004).
15.4.3 Complex Regional Pain Syndrome and Dystonia
Peripherally induced, posttraumatic dystonia may coexist with pain or complex

regional pain syndrome (CRPS), characterized by the combination of pain, sensory,
autonomic, trophic, and motor manifestations usually preceded by trauma
(Schwartzman 1993). The condition is classified as type I when no evidence of
peripheral nerve lesion can be identified, and type II when a peripheral nerve dam-
age is documented (Marinus et al. 2011). Patients usually present after minor or
moderate tissue injury. Fractures is the most frequent type of associated trauma
(45%) followed by sprain (18%), and elective surgery (12%) (de Mos et al. 2007).
The severity of trauma is not necessarily linked to the development of CRPS, and
sporadic onset has been reported in up to 10% of patients. (Marinus et al. 2011). At
least three times more common in females than males, the incidence of CRPS
increases with age (de Mos et al. 2007). Diagnosis of CRPS is based on the Orlando
criteria, released by the International Association for the Study of Pain, or the
modified version called Budapest criteria, which has higher specificity and consid-
ers motor symptoms, including MDs (Table 15.4). Several motor symptoms and
MDs have been described along with CRPS, including focal dystonia, tremor, weak-
ness, difficulty initiating movement, increased muscle tone, and brisk osteotendi-
nous reflexes (Birklein et al. 2000; Schwartzman and Kerrigan 1990). Dystonia is
the most frequent MD observed in patients with CRPS, and the term “causalgia–
dystonia” has been used to refer to the coexistence of both conditions (Bhatia et al.
1993; Van Rijn et al. 2007). In a study that included 185 patients with CRPS, MDs
were identified in 121 patients, with dystonia being the most prevalent (91%) (Van
Rijn et al. 2007). Patients with dystonia were 11 years younger and more often had
CRPS in multiple limbs. The interval between the onset of CRPS and dystonia var-
ied from 1 week in 26% of patients to more than 1 year in 27% of cases.
The nature of dystonia in patients with CRPS has been a source of numerous
debates and some authors argue that the features are most likely “pseudoneuro-
logic” or psychogenic in origin (Verdugo and Ochoa 2000; Hawley and Weiner
2011). The term “posttraumatic syndrome” instead of posttraumatic dystonia has
been proposed by some authors (Kumar and Jog 2011). When dystonia is present in
patients with CRPS, more than 90% is of fixed type; however a combination of fixed
and mobile-type dystonia can be found in patients with CRPS (van Rooijen et al.
2011). CRPS has been proposed to be mediated via central sensitization involving
upregulation of glutamate receptors (Kuner 2010). Since CRPS-related dystonia
does not respond to intravenous ketamine (a glutamatergic antagonist) additional
CNS neuroplastic changes have been suggested to play a role in this syndrome
(Marinus et al. 2011). Furthermore, spinal GABAergic mechanism may also play a
Table 15.4 Budapest diagnostic criteria for complex regional pain syndrome (CRPS)
1. Continuing pain, which is disproportionate to any inciting event
2. Must report at least one symptom in three (clinical diagnostic criteria) or four
Sensory: hyperesthesia or allodynia
Vasomotor: temperature asymmetry, skin color changes, or skin color asymmetry
Sudomotor or edema: local edema, sweating changes or asymmetry
Motor or trophic: decreased range of motion, motor dysfunction (weakness, tremor, or
dystonia), or trophic changes (hair, nails, or skin)
3. Must display at least one sign at time of diagnosis in two or more of the following categories
Sensory: hyperalgesia (to pinprick) or allodynia (to light touch, deep somatic pressure, or
joint movement)
Vasomotor: temperature asymmetry, skin color changes or asymmetry
Sudomotor or edema: edema, sweating changes, or sweating asymmetry
Motor or trophic: decreased range of motion, or motor dysfunction (weakness, tremor, or
dystonia), or trophic changes (hair, nails, or skin)
4. No other diagnosis better explains the signs and symptoms
role in dystonia associated with CRPS as intrathecal baclofen (a GABA type B

receptor agonist), but not glycine (the main inhibitory neurotransmitter in the spinal
cord), improved dystonia in a dose–response fashion (van Rijn et al. 2009; Munts
et al. 2009). The observation that motor signs associated with CRPS improve after
sympathectomy or sympathetic blockade suggests a contribution of the autonomic
sympathetic system to the pathogenesis of CRPS-related dystonia (Marsden et al.
1984; Schwartzman and Kerrigan 1990). However, improvement of dystonia after
anesthetic blockade of sympathetic ganglia is not strongly supported by published
studies (Hord and Oaklander 2003). Other treatments include a short course of oral
corticosteroids, intranasal or intramuscular calcitonin, intravenous biphosphonates,
gabapentin, and spinal cord stimulation (Kemler et al. 2004; Eisenberg et al. 2007).
Physical and occupational therapy can also be useful in these cases.
15.4.4 Posttraumatic Cervical and Shoulder Dystonia
Cervical dystonia has also been described following neck trauma (Ellis 1997;
Troung et al. 1991; Goldman and Ahlskog 1993). “Acute-onset” cervical dystonia
appears within 3 months following trauma, usually in the first 4 weeks after the
injury. These patients usually exhibit marked limitation of the range of motion of
the neck, abnormal postures without much phasic movements, sustained laterocol-
lis, shoulder elevation, and trapezius hypertrophy, typically without sensory tricks
and with poor response to pharmacological therapy (O’Riordan and Hutchinson
2004). Pain is a common complain, often accompanied by nondermatomal sensory
loss (Sa et al. 2003; Frei et al. 2004). Intravenous sodium amytal often improves
the abnormal postures and pain in these patients (Sa et al. 2003). In these cases,
clinicians should rule out neck muscle contractures leading to abnormal head
postures, i.e., “pseudodystonia”; posttraumatic lesion of the eleventh cranial nerve

may also lead to shoulder elevation and head turning mimicking neck dystonia
(Suchowersky and Calne 1988; Cossu et al. 2004).
Another type of posttraumatic cervical dystonia occurs between 3 and 12 months
after the injury with clinical manifestations resembling nontraumatic idiopathic cervi-
cal dystonia, with gradual progression of motor symptoms, frequent sensory tricks,
and better neck mobility (Tarsy 1998). In these cases the cause-and-effect relationship
between the trauma and the cervical dystonia may be difficult to establish, especially
since 10–20% of patients with cervical dystonia report a preceding trauma. Congenital
muscular torticollis can be considered another type of posttraumatic cervical dystonia,
patients may present with contractures due to fibrosis of the sternocleidomastoid and
other neck muscles. Patients usually complain of neck pain and decreased range of
motion of the neck. While most cases start during infancy or early childhood, some
cases are not diagnosed until adulthood (Collins and Jankovic 2006). Cervical dysto-
nia has been reported following cervical and lumbar disc surgery, usually associated
with dermatomal or segmental pain (Capelle et al. 2004). Oral anticholinergics,
baclofen, botulinum toxin injections, or pallidal or STN DBS are treatment options in
patients with cervical dystonia (Jankovic 2009b; Ostrem et al. 2007, 2011).
Traumatic shoulder injuries have also been reported as a cause of dystonia or
dystonic tremor (Atadzhanov and Mwaba 2007; Höllinger and Burgunder 2000).
Fixed shoulder postures can also develop after shoulder trauma (Thyagarajan et al.
1998). In a series of 13 patients with isolated focal dystonic shoulder elevation, nine
patients developed the syndrome after shoulder trauma, two developed the symp-
toms after chronic heavy labor, and one had cervical radiculopathy. Most patients
had trapezius muscle hypertrophy, but good response to botulinum toxin injections
is the rule in these cases (Wright and Ahlskog 2000).
15.4.5 Other Forms of Peripherally Induced Dystonia
Other potential causes of posttraumatic dystonia include blepharospasm. Up to 12.1%

of patients reported a history of ocular lesions preceding the onset, in large series of 264
patients (Grandas et al. 1988). Oromandibular dystonia (OMD) may follow face,
mouth, or jaw trauma. In a large study, 27 patients with peripherally induced OMD had
a mean age at onset of 50 years, and there was a 2:1 female preponderance (Sankhla
et al. 1998). Age at onset, gender predominance, and clinical phenomenology in
patients with posttraumatic, peripherally induced OMD were similar to those features
in patients with idiopathic OMD. Both groups responded well to botulinum toxin ther-
apy. Edentulous patients may develop dyskinesias that can be considered a form of
peripherally induced dystonia; these patients usually display inadequate dental occlusal
relationship and unretentive dentures (Blanchet et al. 2008). Dental procedures have
been reported to trigger OMD and cranial dystonia, in some cases accompanied by
painful paraesthesias spreading to the tongue, lips, and neck (Schrag et al. 1999).
15.4.6 Psychogenic Movement Disorders Following

Peripheral Trauma
Psychogenic movement disorders (PMD) following trauma are well recognized.

In particular, the syndrome of fixed dystonia following trauma has been mainly
attributed to psychogenic mechanisms as discussed above (Schrag et al. 2004). In a
review of 713 patients with peripherally induced MDs reported in the literature by
van Rooijen and colleagues, a diagnosis of psychogenicity was noted in 14% (van
Rooijen et al. 2011). Patients with psychogenic MDs induced by peripheral trauma
had more frequently fixed dystonia (90% vs. 58%) and tremor (38% vs. 22%) com-
pared to patients with nonpsychogenic MDs induced by peripheral trauma, and less
often mobile dystonia (6% vs. 22%) and myoclonus (6% vs. 15%) (van Rooijen et al.
2011). Psychogenic MDs usually display an abrupt onset, inconsistency over time,
multiple somatisations, false neurological signs, and distractibility.
15.4.7 Pathophysiology of Peripherally Induced Tremor

and Other Movement Disorders
The cause-and-effect relationship of peripheral trauma and movement disorders is

still a controversial topic, as no biomarker has been recognized in these patients.
Furthermore, the pre-traumatic state of patients is largely unknown making it
difficult to establish a temporal relationship between the MDs and trauma. Pathologic
changes such as aberrant reinnervation, remyelination or late inflammatory changes,
sensitization of peripheral nociceptors, and ectopic or ephaptic transmission of
nerve impulses have been proposed as mechanisms for peripherally induced move-
ment disorders (Goetz and Pappert 1992; Jankovic 1994). The association of MDs
and pain suggest that the MDs originate in fashion that is analogous to phantom
pain and CRPS (Jankovic and Glass 1985; van Hilten et al. 2007). Experimental
studies have shown that sectioning the peripheral roots or nerves in animals can
change synaptic processing at spinal segmental and suprasegmental levels (Kaas
et al. 1983). Following peripheral nerve sectioning, reorganizational neuroplasticity
occurs in two phases: one immediate, and one more delayed leading to increased
excitatory or decreased inhibitory mechanism in the CNS. For example, reduction
in the GABA-A receptor binding in layer IV of primate somatosensory cortex has
been reported to occur 2–5 h after peripheral nerve transection (Wellman et al.
2002), whereas GABA-B receptor binding is decreased in layer IV one month after
nerve injury, with increased binding expression of glutamatergic AMPA receptors
in layer IV of the somatosensory cortex (Garraghty et al. 2006). These findings sug-
gest that the late cortical changes identified in primates after injuries of the periph-
eral nervous system resemble the N-methyl-d-aspartate (NMDA)-dependent
long-term potentiation observed in the hippocampus (Garraghty et al. 2006). In
humans, for example, it is well known that after limb amputation, there is a marked
reorganization of the somatosensory cortex (Karl et al. 2001) with possible preser-
vation of the movement representation (Mercier et al. 2006). Recently, it has been
suggested that amputation or deafferentation results in plasticity of connections
between the brain and the body with disappearance of the cortical motor representa-
tion but preservation of the sensory representation of the limb, which may explain
the phantom pain phenomenon (Sumitani et al. 2010). This may explain why inten-
sive motor training with reduction in cortical reorganization correlates with reduc-
tion of phantom limb pain (Maclver et al. 2008). Reorganization of the cerebral
cortex has also been demonstrated with extensive limb use (Elbert and Rockstroh
2004). Peripheral nerve injury is not only associated with physiological cortical
changes, as plastic changes in the spinal cord, brainstem nuclei, and thalamus have
been demonstrated, leading to atrophy and degeneration of some substrates as well
as reorganization and sprouting of other structures (Navarro et al. 2007). We postu-
late that some of these changes may occur in response to abnormal peripheral per-
turbation and may also be the origin of involuntary movements in susceptible
individuals. Changes in the cortical representation of affected limbs have been con-
sistently demonstrated in patients with nontraumatic organic dystonia (Hallet 2006).
Interestingly, patients with psychogenic dystonia show similar cortical and spinal
abnormalities to organic dystonia, with short and long cortical inhibition, cortical
silent period, and reciprocal inhibition of the forearm (Espay et al. 2006). Although
some have suggested that these changes could be the consequence rather than the
cause of the dystonia (Espay et al. 2006), many of these abnormalities are found in
asymptomatic body parts, suggesting that the abnormalities are the ones that predis-
pose to dystonia, and predisposed individuals can get organic or psychogenic dys-
tonia depending on the contributing factors (Hallet 2010).
15.4.8 Other Peripherally Induced Movement Disorders
Hemifacial spasm is perhaps the best example of peripherally induced movement

disorder (Jankovic 2009a, b). Vascular compression of the VII cranial nerve is the
suspected etiology in up to 80% of patients. The age of onset is 48.5 years, symp-
toms include involuntary, unilateral, intermittent, irregular, tonic or clonic contrac-
tions of muscles innervated by the ipsilateral facial nerve (Wang and Jankovic
1998). Other causes are found in 19% of patients and include Bell’s palsy (11%),
facial nerve injury (6%), demyelination, and brain vascular insults (Yaltho and
Jankovic 2011). Imitators of hemifacial spasm include tics, myoclonus, hemimasti-
catory spasm, dystonia, and psychogenic cases.
Segmental myoclonus has been reported in a series of 37 patients with a mean
age of onset of 48.5 years. Traumatic etiologies were identified for brachial (acute
cervicomedullary trauma) and spinal myoclonus (laminectomy, spinal cord injury,
post-operative pseudomeningocele, laparotomy, thoracic sympathectomy, lum-
bosacral radiculopathy, spinal extradural block, and electrical injury, and cervical
spondylosis (Jankovic and Pardo 1986). Treatment with clonazepam and tetra-
benazine has proved effective in most patients (Jankovic and Pardo 1986).
Spasm in amputation stumps are another, well-recognized form of peripherally

induced MDs or segmental myoclonus, often associated with phantom sensory phe-
nomena, severe pain, and lack of response to pharmacological therapy (Tyvaert
et al. 2009; Jankovic and Glass 1985). Pain, however, is not a universal feature of
amputation stumps (Kulisevsky et al. 1992). Treatment with botulinum toxin and
local xylocaine has been reported useful in these patients (Tyvaert et al. 2009) and
one case responded to oral pramipexole (Seidel et al. 2011).
“Painful legs and moving toes” syndrome is considered another form of peripher-
ally induced movement disorder. It is characterized by involuntary continuous or
intermittent writhing movements of one or more toes associated with pain, usually of
neuropathic quality (Reich 2011). Similar movements can be observed without pain
“painless legs-moving toes” (Walters et al. 1993), and in the upper extremities “pain-
ful arms-moving fingers” (Supiot et al. 2002). Mean age at onset is in the seventh
decade, and most patients present with bilateral involuntary movements (Alvarez et al.
2008). A lesion of the peripheral nerve and root is suspected as the primary cause
(Alvarez et al. 2008) although in most cases the specific cause cannot be found (Reich
2011). Treatment includes oral agents for neuropathic pain like gabapentin, botulinum
toxin injections, spinal blocks, and spinal cord stimulation (Reich 2011). Other periph-
erally induced movement disorders include hemimasticatory spasm (Cruccu et al.
1994) and tics (Erer and Jankovic 2008; Factor and Molho 1997).
15.5 Conclusions
In conclusion, posttraumatic movement disorders can originate from direct TBI or

peripheral trauma. Kinetic, cerebellar outflow tremor is the most common MD fol-
lowing TBI. The role of isolated head trauma as a risk factor for development of PD,
organic dystonia, and other MDs is controversial, although repeated head trauma may
lead to CTE, “dementia pugilistica,” or pugilistic parkinsonism. Peripherally induced
MD is still a controversial area as some such cases have been documented to be of
psychogenic origin. Nevertheless, we believe that there is an important subset of
patients in whom the MD after peripheral injury has organic basis. Evidence from
animal models supports the existence of reorganizational changes in the CNS follow-
ing peripheral tissue trauma that led to increased excitability or decreased inhibition,
which has been documented in other, organic, MDs. Treatment of posttraumatic
movement disorders may be challenging, but botulinum toxin injection and stereotac-
tic functional neurosurgery, including DBS, coupled with physical and occupational
therapy, have shown promising results in patients with disabling posttraumatic MDs.
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Chapter 16
Psychogenic Tremor
Luis Redondo-Vergé and Natividad Carrion-Mellado
Keywords Movement disorders • Tremor • Psychogenic • Somatoform • Depression
Psychogenic movement disorders are a daily challenge for neurologists. A mistake

in its recognition may have important consequences for the patients. Thus, this diag-
nosis must be considered very cautiously in clinical practice. Psychogenic movement
disorders are not unusual, mainly tremors, and a wrong diagnosis is common.
Psychogenic is an unspecific term that usually hides true mental disorders. The cor-
rect psychiatric syndrome somatoform disorders, factitious disorders, malingering,
depression, anxiety and histrionic personality disorder, although the absence of
psychiatric diagnosis does not preclude a psychogenic cause. Diagnosis may be
difficult and should be made by an expert neurologist. Organic movement disorders
must be excluded after a detailed neurological history, examination, and appropriate
diagnostic studies. Psychogenic tremor is a diagnosis of exclusion. It can be diag-
nosed positively by the following neurological signs the fact that it is inconsistent
(variation over time) and incongruous with the organic movement. Diagnosis is
mainly clinical but several tests can be used, especially accelerometry, electromyog-
raphy, and the analysis of the response to placebo or suggestion. New studies are
shedding light on our knowledge of the basic underlying mechanisms of such intrigu-
ing pathology. Treatment requires a strong alliance between the medical team and
patient. Psychogenic tremor should never be minimized. An early diagnosis should
be reached as soon as possible and treatment must always be tried.
L. Redondo-Vergé (*)
Servicio de Neurología, Hospital Virgen Macarena, Avda. Dr. Fedriani 3, 41071 Sevilla, Spain
e-mail: lredondov@meditex.es
N. Carrion-Mellado
Servicio de Psiquiatría, Hospital de Valme, Ctra. Cádiz-Bellavista, 41014 Sevilla, Spain
290 L. Redondo-Vergé and N. Carrion-Mellado
16.1 Introduction
Psychogenic disorders are becoming more frequent in medicine and sometimes are
called “medically unexplained symptoms.” Psychogenic Movement Disorders
(PMD) is a daily challenging issue for neurologists, both for diagnosis and treat-
ment. Labeling an organic movement disorder as psychogenic is often considered
an important mistake because it prevents a suitable treatment, implies a certain
stigma for the patient, and exposes the skill of the neurologist. Therefore, psycho-
genic diagnosis must be established with extreme caution. On the other hand, if a
PMD is mixed up with an organic cause it would imply multiple, expensive, and
pointless studies and treatments, and show the inability of the neurologist to per-
form an accurate diagnosis.
These conflicts are very common in daily clinical practice. It has been reported
that 6–30% of organic movement disorders were considered and treated as psycho-
genic (Putnam 1992). This mistake is more frequent in dystonia (Cooper et al.
1976). Conversely, 25–30% of PMD are diagnosed as organic. Moreover, it is
important to note that many patients with psychogenic disorders have a real organic
neurological disease, as it occurs in seizures and pseudoseizures, most of them
being unrelated (Ranawaya et al. 1990).
Movement disorders are among the most frequent symptoms in psychogenic
neurological disorders. The true incidence of PMD remains unclear, but its acknowl-
edgment is steadily increasing in last years. Since hardly ever diagnosed 30 years
ago, through retrospective surveys of specialists in movement disorders, with cer-
tain low bias, suggesting that 2–4% of patients have PMD (Fahn 1994; Portera-
Calliau et al. 2006), until lately reported that it stands about 15% (Hallet 2010). This
disorder can pretend to be any other organic movement disorder condition including
dystonia, parkinsonism, gait disorders, chorea, myoclonus, tics, hemiballismus, and
eventually tremor (Marjama et al. 1995). Tremor is the most common (50%), fol-
lowed by dystonia, postural and gait disturbances, and myoclonus (Fahn 1994;
Cubo et al. 2005; Jankovic and Thomas 2005).
In this chapter we review psychogenic tremor (PT) and we will try to:
1. Deal with underlying psychopathology
2. Summarize a diagnostic insight based on clinical features and tests
3. Gather the new advances in physiology
4. Introduce modern management
16.2 General View of Psychogenic Movement Disorders
The diagnosis of PMD may be difficult and should be left to neurologists with expe-
rience in movement disorders. The most important clinical features supporting a
diagnosis is that the movement is inconsistent (it varies over time and with selected
examination maneuvers), and incongruous with the organic movement disorder
16 Psychogenic Tremor 291
Table 16.1 Suggestive features 1. Abrupt onset

of psychogenic movement
2. Rapid progression
disorders
3. Static course
4. Spontaneous remissions and paroxysmal relapses
5. Variability in amplitude, frequency, and distribution
6. Task-selective inability
7. Lack of response to usual treatment
8. Improvement with psychotherapy and placebo
9. Attention dependence
10. Psychopathology
(Schrag and Lang 2005). Psychiatric evaluation is very important but there is no
obligatory correlation. The psychopathology in PMD may remain elusive, and the
coexistence does not prove the psychogenicity of any movement disorder. Therefore,
when an organic basis can be excluded reasonably after a comprehensive neurologi-
cal history and examination as well as appropriate diagnostic studies, certain clues
suggesting psychogenicity should be sought, such as sudden onset with rapid pro-
gression to maximum severity, static course with spontaneous remissions and par-
oxysmal relapses, marked variability of frequency, amplitude, distribution and
direction of tremor, selective disability for certain tasks, unresponsiveness to appro-
priate medications, striking response to placebo or psychotherapy, improvement
with distraction and worsening with attention, and a clearly diagnosed psychopa-
thology (Table 16.1) (Marjama et al. 1995; Lang and Voon 2011).
Other features suggesting psychogenicity but with lower importance include
multiple somatizations or complaints without an accurate diagnosis, false weak-
ness, pain or sensory complaints, exaggerated slowness, pending litigation or com-
pensation or presence of secondary gain, negative family history, and employment
in health professions (Koller et al. 1989).
Several features are considered unusual or even incompatible with PMD, such
as pill-rolling tremor, short duration jerks of myoclonus, or a very high-frequency
tremor (>12 Hz, as in orthostatic tremor). On the contrary, sometimes certain fea-
tures previously considered specific of organic movement disorders can be per-
formed voluntarily and they may be seen in PMD. These include the “geste
antagoniste” that characterizes idiopathic dystonias, dyskinesias following intra-
venous apomorphine abuse without any evidence Parkinson disease, and even
palatal tremor. Therefore, the diagnosis of PMD should not be discarded simply
because the movement disorder is difficult to imitate or the presentation has some
classical features of recognized organic movement disorder. Alternatively, it
should not be made only because the presentation is unknown or bizarre (Schrag
and Lang 2005).
Fahn and Williams have published their scale delineating the degree of certainty
of the diagnosis of psychogenic dystonia. These criteria could be applied to other
movement disorders (Table 16.2) (Fahn and Williams 1988).
Table 16.2 Criteria of certainty of psychogenic movement disorder (Adapted from Fahn et al. 1988)
1. Proved. Psychotherapy, suggestion or placebo significantly improves the symptoms sustained
in time or the patient remains asymptomatic when supposedly not observed
2. Clinically established. Movement is inconsistent or incongruent and simultaneous to other
psychogenic signs, somatizations, or psychopathology
3. Probable. Only inconsistent or incongruent movements
4. Possible. Only with emotional stress
However, the term “psychogenic,” derived from a Greek Word meaning “created
by the soul,” is sometimes quite unspecific. An extensive and excessive use of this
term is very usual and it commonly hides the psychiatric diagnosis. It is critical to
identify the underlying psychopathology in order to reach a rigorous diagnosis and
to establish an appropriate treatment.
16.3 Psychopathology of Psychogenic Movement Disorders
Psychogenic neurologic disorders may be classified as dissociative or somatization

(Arias 2004).
1. Dissociative disorders. Dissociation encompasses a variety of symptoms in
which there is a lack of integration or connection of normal conscious functions,
such as memory, personal identity, recent experiences, and movement control.
They could be shown as amnesia, stupor, identity disorders, trance, and posses-
sion. Unbearable issues, traumatic events, or personal relationship dysfunctions
are the cause of mental and organic symptoms.
2. Somatization disorders. Emotional conflicts lead to organic symptoms. They are
characterized by a hidden purpose to take some kind of advantage of this state,
psychological or financial. They could be classified by the degree of awareness
or voluntariness in:
2.1. Somatoform disorders: The disorder is involuntary, not apparently under
any conscious control. It is based on the idea that intolerable psychological
conflict leads to the conversion of distress into physical symptoms. They
are more frequent in subjects with low cultural level with alexithymia, who
consider mental disease as a stigma, with primitive religious beliefs, and a
history of cranioencephalic trauma or childhood abuse.
2.1.1. Somatization. Patients show a history of multiple symptoms unex-
plained by disease starting before the age of 30 years. They are the
cause of repeated medical attendance and disturbance in all facets
of their life. The definition in DSM-IV requires the presence of at
least four pain symptoms, two gastrointestinal symptoms (usually
irritable bowel syndrome), one sexual symptom, and one conversion
neurologic symptom. Drug abuse is very common in these patients

and they have undergone several pointless surgeries or invasive
procedures.
2.1.2. Conversion disorder or hysteria: It requires that psychological fac-
tors precede the onset or worsening of the symptoms. These are
involuntary and the patient is not feigning, although they could be
maintained because of its secondary gains. Patients suffer a great
emotional stress, but the symptoms cannot be a consequence of any
organic disease and are not restricted to sexual or painless sphere.
Several neurological signs suggestive of functional dysfunction have
been reported, such as Hoover sign (involuntary extension of a “par-
alyzed” leg following flexion against resistance of the contralateral
leg), hip abductor sign, dragging gait, give way weakness, absence
of hit on the face with upper limb palsy, simultaneous co-contraction
of agonist and antagonist muscles, unilateral weakness of sterno-
cleidomastoid, exact splitting of sensation at the midline or the
Pastor’s sign (RedondoVergé 2000).
2.1.3. Hypochondriasis. The patient demonstrates a lasting certainty, over
6 months, of undergoing a serious disease, with excessive anxiety
and against all medical criteria.
2.1.4. Persistent pain. It includes: atypical facial pain, chronic backache
pain, tension headache, chronic pelvic pain, and posttraumatic stress.
2.1.5. Body dysmorphia.
2.2. Factitious disorders. This behavior is done to fulfill a medical care, psycho-
logical need, or other nonfinancial gain. The disorder is voluntary and the
patients are lying when they say that it is involuntary.
2.2.1. Munchausen Syndrome: The patient wanders in hospitals typically
changing his name and story. It is associated with personality disorders.
2.2.2. Ganser Syndrome: In this case the patient wants to be considered
crazy or demented.
2.3. Malingering. The patients are conscious and the purposeful behavior is to achieve
a goal, such as avoiding work, obtaining certain drugs or financial gain.
Other psychiatric disorders are related with PMD. Depression is an important
cause in several series and antidepressant drugs solve the clinical features in many
cases (Marjama et al. 1995). Anxiety and personality disorders have also been
reported as a frequent cause of PMD. Ultimately, in some cases all these psychiatric
conditions are not identifiable. Therefore, an accurate psychiatric diagnosis is not
possible; however, this fact should not preclude the diagnosis.
As it has been previously mentioned, the coexistence of any movement disorder
with certain psychopathology is a bias which induces confusion when considering
an organic movement disorder as psychogenic. Therefore, it becomes essential to
know the clinical features of organic movement disorders, tremor in our case.
Table 16.3 General clinical 1. Progressive onset

signs of organic tremor
2. Unilateral onset
3. Related to rest, posture, or movement
4. Task independence
5. It increases with anxiety or distraction
6. Stable frequency
7. Spontaneous remission is not observed
16.4 Clinical Features of Organic Tremor
There are certain principles of organic tremors that may help to distinguish them
from psychogenic tremor, although they are not specific (Table 16.3). Organic
tremor usually begins gradually and has rarely an abrupt onset (except after vascular
injury or trauma). It starts unilaterally and then it becomes bilateral as it increases
in severity (except for cases induced by drugs or toxins). Its appearance is usually
more related with rest, posture, or movement. It is unusual to have an organic tremor
in all three states; however this is possible in midbrain rubral tremor or Holmes’s
tremor. Although it can be rarely task specific (mainly writing), its isolated presence
must raise suspicion of psychogenicity. Organic tremor increases with anxiety and
distraction. It can be observed with certain maneuvers that imply an important men-
tal concentration, such as walking or counting backwards. Its frequency is usually
steady; however its amplitude may decrease with therapy. Organic tremor never
remits spontaneously, although a mild reduction in severity has been reported with
placebo administration (Marjama et al. 1995).
The diagnosis of psychogenic tremor is usually based on negative criteria, i.e., in
the exclusion of any identifiable organic cause. Nevertheless, several distinctive fea-
tures found in psychogenic tremor allow its diagnosis on the basis of positive clini-
cal criteria rather than a purely exclusionary approach.
16.5 Clinical Features or Psychogenic Tremor
Psychogenic tremor may count for more than 10% of all tremors referred to a special-
ized unit of movement disorders (Fahn 1994). It is more common in women with a
female/male ratio of 2–4/1. Although it is more common in young and middle-aged
adult, it may be seen in all age groups, even in children (Kirsch and Mink 2004;
Schwingenschuh et al. 2008). Onset is abrupt and the diagnosis is usually delayed
from the beginning of the symptoms up to 2–3 years. Some patients also present pre-
viously unspecific functional dysfunction, often painful or psychiatric, although many
are healthy. Most of them exhibit a limb tremor. However, in some cases, tremor is
axial, appearing only during stance and gait. To accept the diagnosis of psychogenic
tremor, it is necessary to exclude the main causes of symptomatic tremor, such as
Table 16.4 Clinical signs of 1. Variability of direction, frequency, and amplitude

psychogenic tremor
2. Abrupt and bilateral onset, associated to stress
3. Static course
4. It does not affect fingers, tongue, or face.
5. Variable severity and frequent remissions
6. Selective functional inability, not task dependent
7. Coactivation
8. Previous somatization history
9. Response to placebo but not to usual anti-tremor treatment
10. Unrelated neurological signs
drugs, hyperthyroidism and other metabolic and hormonal dysfunction, essential and
parkinsonian tremor, and there must be a lack of evidence for any other neurologic
disorder. The patients must have had a period without tremor of at least 2 weeks during
the observation period (Deuschl et al. 1998a, b). Psychogenic tremor is not only a
diagnosis of exclusion, but on the contrary it presents several clinical features (none
of them being absolute) that can be helpful in the diagnosis by means of positive cri-
teria (Table 16.4). They include variability in direction, frequency and amplitude, sud-
den and bilateral onset mostly with a stressful life event, static course, and lack of
progression. It rarely affects fingers and never tongue or face; the severity fluctuates
with frequent and spontaneous remissions during several days.
Often selective disabilities exist that differ from task-specific impairment (the
patient could show incapacity to sign but not to draw). Functional disability is
disproportionate to examination findings. It is postural or kinetic and never appears
strictly related with rest. The amplitude often, but not always, decreases or even the
movement disappears during maneuvers of distraction, such as counting backwards
or complex motor tasks with the other side. Coactivation of agonist and antagonist
muscles is required for the genesis of psychogenic tremor. Once it disappears, so
does tremor. Organic tremor can occur without such coactivation. This sign could be
clinical and documented by an electromyogram (EMG). A history of previous som-
atizations is quite common, unresponsive to a drug treatment but responding to
placebo (also 30% of organic tremors reduce their amplitude with placebo) and
psychotherapy, and eventually appearance of additional and unrelated neurologic
signs (Deuschl et al. 1998a, b; Bhatia and Schneider 2007).
In generalized tremor the only relevant differential diagnoses are orthostatic
tremor, some essential stance tremor, and rare stance tremor in Parkinson’s disease.
Generalized body shaking is bizarre with variability in the frequency. Tremor usu-
ally ceases spontaneously because shaking periods are exhausting and psychogenic
features become more evident.
Entrainment test. The patient has to perform a rhythmic tapping movement with
the unaffected limb at 3 Hz. Also, the examiner may encourage the patient to imitate
his movements. If the tremor is psychogenic then several effects may be observed:
the patient might be unable to make such simple movement and cannot explain why,
the tremor stops, or the tremor acquires the frequency proposed, i.e., the tremor
entrains in the frequency proposed. There are rare false positive and negative results.
There is a change in the frequency in adapting to voluntary movements.

Performing sudden movements with the healthy hand (such as touching the examiner’s
finger), often makes the functional tremor stop during a short period of time.
Any mechanical attempt of reduction or immobilization, such as loading with
weights, brings as a result an increase in the amplitude of tremor, conversely to what
happens in organic tremors, to maintain the same frequency.
In a patient with these features, and no other unexplained clinical signs, there is
a definite evidence of psychogenic tremor. However, even in these cases many neu-
rologists still conduct standard neurological investigations to rule out any organic
causes, probably suggesting less clinical experience and less security in making the
diagnosis (Espay et al. 2009).
16.6 Diagnostic Techniques
Sometimes, certain tests permit the addition of a laboratory-supported definite

classification to the documented clinically categories initially stated. A suspected
diagnosis becomes firmly established by means of these techniques. In other cases,
the results of these techniques could be a surprise. The most important ones are
as follows:
1. Suggestion and placebo. Probably they are the most useful clinical methods to
“prove” the psychogenicity of any movement disorder. However, we should bear
in mind that 30% of organic tremors reduce their amplitude with placebo. The use
of placebo remains controversial, as it gives rise to ethical considerations and can
affect the physician–patient relationship. The use of placebo should be reserved
for cases in which the diagnosis of psychogenicity remains uncertain after a com-
prehensive investigation and follow-up. To evaluate the response to placebo and
psychotherapy, as well as allowing continuous observation, admission to hospital
should be necessary. This may convince the patient that the neurologist pays the
appropriate attention to his complaints (Bhatia and Schneider 2007).
2. Neurophysiologic tests.
2.1. Frequency and amplitude. Accelerometry and EMG are the classical meth-
ods used in the assessment of frequency and amplitude of tremor. Recently
it has been proposed to use the in-built accelerometer of the iPhone via the
iSeismo application for rapid measurement of tremor frequency (Joundi
et al. 2011). In psychogenic tremor there is variability in frequency and
amplitude recorded over minutes (Deuschl et al. 1998a, b). Amplitude may
vary moderately in organic tremor; thus frequency is a better parameter
(Gironell et al. 1997). Although there are no formal ranges reported and the
analysis remains subjective, it must be taken into account that any variabil-
ity higher than 2 Hz only appears in psychogenic tremor and small vari-
ability in frequency may be sometimes encountered in organic tremors
(Gironell 2008). If the frequency of a tremor is over 11 Hz, it is unlikely to
ESD
CON
TAG
ESE
17100
0.72s
Fig. 16.1 Accelerometry in psychogenic tremor. The trace from the right and left hands show a
brief pause during mental maneuver distraction (Figure kindly provided by Dr. A. Gironell,
Hospital Sant Pau, Barcelona, Spain)
be psychogenic (Brown and Thompson 2001). In fact, psychogenic tremor

has a frequency of less than 6 Hz, as hardly anyone can produce a voluntary
tremor over 7 Hz (Elble and Koller 1990).
2.2. Accelerometry with weight. Variability in the frequency is very suggestive
of psychogenic tremor. Typically, psychogenic tremor increases the ampli-
tude of shaking during loading with 500 g or 1,000 g to maintain the coacti-
vation mechanism in antagonist muscles. This is not observed in organic
tremors (Parkinson’s disease and essential tremor) when the extremity is
loaded with additional weights. The peak of frequency of shaking might
remain constant (Deuschl et al. 1998a) or more specifically decreases
(Gironell et al. 1997) during loading in psychogenic tremor, something that
does not happen in organic tremor as predicted (Deuschl et al. 1998a).
To summarize, several neurophysiological characteristics of psychogenic
tremor have been reported, such as variability in frequency giving rise to a
wide spectral peak, alternating pattern of muscle activity in EMG, increases
in amplitude or changes in frequency when limb is loaded with weight, and
improvement or disappearance of shaking with distraction (Fig. 16.1)
(Gironell 2008).
2.3. Co-activation sign. As it was mentioned previously, an electromyographic
equivalent of the clinical coactivation sign can be registered before the
onset of tremor. This tonic activation phase is usually shorter than 300 ms.
In comparison, bursts of reciprocal alternating pattern start at the onset of
tremor in Parkinson’s disease. It seems as if coactivation is the inductor of
movement (Deuschl et al. 1998b).
2.4. Coherence analysis. If psychogenic tremor is present in more than one body
segment, tremor bursts usually have the same rhythm across segments. This
includes the possible changes in frequency when they occur. On the con-
trary, organic tremors in different parts have only slightly different frequen-
cies, except in some cases of essential tremor that rarely has the same
frequency on both hands, and orthostatic tremor that always has the same
frequency on both sides of the body. Therefore, the demonstration of high
coherence is an argument against organic tremor.
2.5. Entrainment. The entrainment test could be electrophysiological measured
by an accelerometer or surface EMG signals. It is based on the inability
of healthy people to generate two voluntary rhythms of shaking in differ-
ent body parts with different frequencies of oscillations. This phenome-
non also happens in psychogenic tremor, suggesting that it uses the same
central oscillatory mechanism and therefore the same neural network as
that of voluntary movement. On the other hand, in organic tremor it is
possible to develop different frequencies of oscillation, one voluntary
and another from the organic tremor (McAuley and Rothwell 2004).
However, it has been reported that, in some cases of psychogenic tremor,
independent oscillation frequencies are maintained (Raethjen et al.
2004). Therefore, the specificity of this test could be reasonably
questioned.
2.6. Ballistic movement test. In a similar way, it has been demonstrated that bal-
listic movements of the contralateral hand stop or reduce tremor ampli-
tude in psychogenic tremor but not in tremor of Parkinson’s disease or
essential tremor (Kumru et al. 2004). It has also been reported that reac-
tion time increases in normal volunteers requested to perform voluntary
shaking with the contralateral hand and in psychogenic tremor. However,
in patients with Parkinson’s disease and essential tremor, reaction time is
normal. These data quantify and confirm those that clinic showed already,
i.e., psychogenic tremor is influenced by distractibility. These data are
consistent with the concept of dual task interference by which attention
cannot be divided in the performance of two “voluntary” tasks at a time.
Therefore, attention acts as a bottleneck in central processing. As a con-
sequence, the performance of one of the actions is impaired. Nevertheless,
whatever mechanism underlies tremor-related dual task interference, it
seems not to affect tremor of Parkinson’s disease or essential tremor
(Kumru et al. 2007).
2.7. Bereitschaftspotential. It is identified by back-averaging the EEG at the
beginning of EMG activity (Hallet 2010). It indicates the involvement of
premotor cortex, including supplementary motor area, in the preexecution
of movement. It can be observed in voluntary and in some cases of involun-
tary movements. By itself it does not indicate that the movement is volun-
tary; it is only indicative of certain brain mechanisms and areas for
generating movement (Fig. 16.2).
Potencial Premotor
CZ
C3
FZ
EMG
-1000 -880 -760 -640 -520 -400 -280 -160 -40 80 200
Essential tremor Potencial Premotor
CZ
C3
FZ
EMG
-1000 -880 -760 -640 -520 -400 -280 -160 -40 80 200
Psychogenic tremor
Fig. 16.2 Bereitschaftspotential in essential and psychogenic tremors. The record is a back-
averaging of 80 trials. In psychogenic tremor a movement-related cortical potential before the
onset of tremor is identified, pointing out its cortical generation (Figure kindly provided by
Dr. A. Gironell, Hospital Sant Pau, Barcelona, Spain)
All these neurophysiologic tests described above are not routinely used in clinical
practice. They should always be contextualized in the clinical environment.
16.7 Neurophysiological Basis
Such as Hallet has proposed, clinical neurophysiologic tests also provide some
insight into the nature of psychogenic tremor (Hallet 2010). Due to the same fre-
quency and phase of tremor in all limbs, then it must be only controlled by a single
generator. Moreover, since voluntary tapping (voluntary tremor) can drive this
generator, the generator must be the same as the voluntary movement generator.
Thus, the conclusion must be that psychogenic tremor shares a machinery with
voluntary tremor.
Those structures involved in planning and execution of movement, such as pre-

frontal cortex, supplementary motor area, and motor cortex, are obviously included
in this machinery. Different studies show that voluntary and psychogenic move-
ments interfere with each other like two voluntary plans. But these motor structures
are not isolated in movement generation; other parts of the brain are needed to moti-
vate the movement. Therefore the role of these other areas could be the difference
between voluntary and psychogenic tremor. These areas must be related with the
voluntariness in those cases of voluntary movement. In the feeling of voluntariness
probably is implicated a feed-forward mechanism arising from the frontal lobe
and processed in the parietal lobe. Hence, movement can be anticipated and
compared with the actual movement and also gives rise to the sense of property of
that movement. Property or agency is the sense that willed movements have been
executed (Hallet 2007).
Stimulating parietal lobe with low intensities can produce the desire of movement.
However, stimulating with high intensities produces the unreal sensation of move-
ment (Desmurguet et al. 2009). Stimulating prefrontal cortex can produce movement
without any feeling that movement has occurred. So, these findings are consistent
with the idea that movement is executed from the frontal lobe and volition and
agency arise in parietal lobe.
It has been proved that PMD patients have an enhanced startle response to stimuli
compared with healthy controls, suggesting a potential mechanism linking limbic
and motor responses (Seignourel et al. 2007).
A recent study shows a greater amygdala activity to arousing stimuli and greater
limbic-motor functional connectivity to affective stimuli (Voon et al. 2010a, b).
Greater amygdala activity could impair motor initiation and unconscious motor inhi-
bition. Major or repeated minor daily stressor could lead to failure in amygdala response,
and so to the onset or worsening of conversion disorder (Lang and Voon 2011).
Another study reports low temporoparietal activity in psychogenic tremor (Voon
et al. 2010a, b). This may be the result of the lack of the processing feed-forward
signal and therefore the predicted movement. So, the movement executed is not
under control.
Therefore, the difference between voluntary movement and psychogenic move-
ment is the sense of volition and property. Psychogenic patients have a failure only
for those movements that are psychogenic and this failure is likely in the source of
feed-forward mechanism proximal to premotor cortex.
16.8 Treatment
Prognosis of psychogenic tremor is far from benign. Tremor persists in most patients
and improves in roughly a third of them (Jankovic et al. 2006). Functional recovery is
relatively poor and more than half of the patients develop mild or severe disability for
work and social activities with worsening in quality of life (McKeon et al. 2009).
In terms of general functional neurologic symptoms, several facts are related to

a relatively good prognosis, such as acute onset, young patients, short-lasting dis-
ease, early diagnosis, healthy premorbid functioning, absence of coexisting organic
or psychogenic disease (anxiety, depression), presence and removal of an identifiable
stressor, mainly if this is a mechanical trauma, willingness to accept the potential
reversibility, an acceptance that psychological factors may play a role, and a good
interaction with the physician (Crimlisk et al. 1998). On the other hand, poor outcome
is related with beliefs in lack of reversibility, anger at the diagnosis, delayed diag-
nosis and treatment, other physical symptoms, somatization or personality disorder,
older age, sexual abuse, and pending of financial benefits or litigation.
In psychogenic tremor, most of complete recoveries and therapeutic success take
place in patients with short lasting evolution and mainly in young subjects more
than older patients. If there is no early diagnosis and if treatment is delayed, the
majority of patients have a fluctuating or constant course to impairment. Many
patients develop a certain degree of social isolation and those who were employed
before the onset of their tremor are subsequently retired, although it does not imply
disappearance or even improvement of tremor (Deuschl et al. 1998a, b). Iatrogenic
damage must be avoided as well as perpetuation of illness beliefs with an accurate
diagnosis and early treatment.
It has been reported that a good and sincere explanation to a patient with a func-
tional disorder is the key to successful further treatment. The components of the
explanation are what he does have, what the mechanism of the symptoms is, how it
is possible to establish the diagnosis, to explain what he has not, to show that we
believe him, to explain how common it is, to emphasize the reversibility, to empha-
size how important self-help is, metaphors may be useful (hardware versus soft-
ware, musical instrument out of tone), to explain the possible role of depression or
anxiety, to suggest antidepressant or psychiatric referral when appropriate, giving
written information, and eventually to involve the family and friends (Stone and
Carson 2011).
Often neurologists finish their involvement when psychogenic disorder is diag-
nosed, usually referring the patient to the family doctor or a psychiatrist. However
they are in a good position to have an important influence in the usual course of the
disease with a rational explanation and onward appropriate referral. If the patient
trusts the neurologist, it would be easy to tackle psychological problems or referral
to a psychologist.
Recently, it has been reported that patients with psychogenic seizures show
benefit from cognitive behavioral treatment as compared with standard therapy
(Goldstein et al. 2010). Therefore this could be a possible treatment in psychogenic
tremor although, to our knowledge, any trial back up. By cognitive behavioral treat-
ment the patient develops changes in the way he perceives the symptoms and his
resulting behavior. From an old thought such as “I have Parkinson’s disease or my
doctor does not know what is happening to me” to “I feel tremor but if I am dis-
tracted, it improves or my doctor seems to be right.”
Another psychiatrist approach is psychodynamic therapy. It is based on the fact
that the symptoms are a means to escape an interpersonal conflict. Therefore tremor
could be the result of an abnormal relationship during childhood, and knowledge of

these abnormal patterns is essential for resolution.
Physiotherapy and positive reinforcement to psychotherapy appear to reduce or
abolish symptoms in many cases. The use of placebo for diagnosis and treatment
is controversial. Anyway, it is recommended admitting the patient to the hospital
and explaining the results in an understanding manner, followed by immediate
treatment.
Other techniques also used in some cases are biofeedback via electromyography,
hypnosis, and sedation. Biofeedback and sedation allow the patient to learn self-
relaxation techniques. Under sedation the physician may demonstrate the improve-
ment of shaking awake condition. Repetitive transcranial magnetic stimulation
(rTMS) has shown benefits in some neurologic psychogenic disorders, but future
studies are needed to provide clear evidence.
There are few rigorous data concerning treatment with drugs in psychogenic tremor,
and in general all PMD. To our knowledge, no controlled trials are available and lim-
ited studies have been reported. The value of antidepressant and anxiolytic drugs has
been proposed, but there is no consensus for which antidepressant should be preferred.
However, some selective serotonin reuptake inhibitor (SSRI) has been useful in manag-
ing pseudoseizures and other functional symptoms in a variety of specialities, even in
the absence of depressed mood (LaFrance et al. 2010; O’Malley et al. 1999).
To summarize, therapeutic approach must be early and multidisciplinary. It
demands a strong alliance between patient and his family, neurologist, psychiatrist,
psychologist, and general practitioner. Many patients, and their families, are reluc-
tant to psychiatric assessment and treatment. How the clinician discusses the sus-
pected diagnosis of psychogenic tremor and approaches the treatment is critical. It
has been suggested that a possible neurobiological explanation should be presented
to the patient. It would be necessary to emphasize on explanations based on terms
such as “neurobiological disorder” or “mind–body relation imbalance” and also
helping to understand with other examples more acceptable such as angor pectoris
or peptic ulcer. From the beginning it is important to recommend the approaching
from different points of view and specialties simultaneously.
Due to inefficiency and counterproductive connotations, we should run away
from confrontation with the patient with terms that suggest “there is nothing I can
find wrong with you” because it is likely to be interpreted as “the physician does not
take me seriously” or even worse “he thinks I am crazy.”
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Chapter 17
Tremor in Childhood
Padraic J. Grattan-Smith and Russell C. Dale
Keywords Children • Newborn • Dopamine • Metabolism
Tremor particularly affects the upper limbs but can involve almost any part of the
body including the head, face, eyelids, tongue, vocal cords, and trunk. In a Consensus
Statement of the Movement Disorders Society, tremor is defined as “a rhythmic,
involuntary, oscillatory movement of a body part” (Deuschl et al. 1998). As with
most definitions of movement disorders there is an immediate problem with the
words used, in this case with “rhythmic.” In Webster’s dictionary there are 10
definitions of “rhythm” the first being “movement or procedure with uniform or pat-
terned recurrence of a beat, accent or the like.” In current clinical practice when
there are regular oscillations the term tremor is used with “rhythmic” and “regular”
essentially having the same meaning.
However rhythm is further defined in Webster’s Dictionary as being “regular or
irregular.” Gordon Holmes in his classic paper on tremor stated: “I would suggest that
the term tremor be used to denote a clinical phenomenon consisting in the involuntary
oscillation of any part of the body around any plane, such oscillations being either
regular or irregular in rate and in amplitude, and due to the alternate action of groups
of muscles and their antagonists” (Holmes 1904). The literature on tremor does not
always insist on regularity and in the following, we discuss conditions where the
word “tremor” is used rather than attempt to only deal with those where the move-
ment disorder has been demonstrated to be always regular. (There are in turn 26
entries under “regular” in Webster’s Dictionary but its meaning is usually clear.)
Tremor is the commonest movement disorder of adults (Louis and Ferreira 2010).
It has been suggested that as many as 23% of the elderly may have essential tremor
(Louis et al. 2001a). There is no data on the prevalence of tremor in childhood but
P.J. Grattan-Smith • R.C. Dale (*)

Children’s Hospital Westmead, The University of Sydney, Sydney, NSW 2145, Australia
e-mail: russelld@chw.edu.au
306 P.J. Grattan-Smith and R.C. Dale
in the personal series of Fernandez-Alvarez of children under 18 years, 129 (19%)

of 673 cases presented with tremor as the sole or predominant feature. It was seen
twice as commonly in boys and the apparent age of onset was typically around
6 years (Fernandez-Alvarez and Aicardi 2001).
In adult medicine discussions about tremor particularly concentrate on two com-
mon disorders—essential tremor and Parkinson’s Disease. The large number of
patients suffering from these conditions has meant that there is a vast literature on
their pathophysiology and treatment. In contrast, in childhood there are a large num-
ber of rare conditions that can produce tremor and in most, little is known about
their pathophysiology.
Although there are sophisticated techniques available for its measurement, the
assessment of tremor in children remains essentially clinical (Singer et al. 2010a).
Singer et al. note: “Electromyography, accelerometers, and other instruments are
sometimes used to quantitate tremors, but the clinical utility of this information,
that is, its ability to improve diagnostic and/or therapeutic medical decision mak-
ing, has not been demonstrated in children.” However, Canavese, in a retrospective
review of 61 children who had a tremor study, found that in 31% the polymyo-
graphic features allowed the identification of a clinically unclassified movement
disorder (Canavese et al. 2008). Further in 19.6% it disclosed an associated move-
ment disorder which was not clinically evident. It was also useful in supporting the
clinical diagnosis of psychogenic movement disorder. It is possible that in future,
tremor studies will have a greater role in children.
For the reasons outlined above, in this chapter we take a clinical approach to the
problem of the child with a tremor.
17.1 Classification
Tremor is traditionally divided into resting tremor and action tremor. Using tremor
of the upper limbs as an example, with resting tremor, the tremor is seen when the
arm is totally relaxed. Full relaxation is not always easy to achieve but asking the
child to rest the arm on the bed and let it become “loose” may be effective. Action
tremor is any tremor that is produced by voluntary contraction of muscle. It is fur-
ther subdivided into (1) postural tremor which occurs when a limb is voluntarily
maintained against gravity, e.g., when the arms are held out steadily straight out in
front of the patient and (2) kinetic tremor defined as any tremor that occurs during
voluntary movement.
Kinetic tremors can in turn be subdivided. Intention tremor worsens as a target is
approached, classically in the “finger–nose” test. Again there are problems with
terminology. The use of the word intention has been criticized as the problem is not
one of motive but the performance of a target directed, visually guided movement.
Terminal tremor has been advocated as an alternative but has not been widely
adopted, presumably in part because patients and their families may misinterpret
this as indicating a fatal tremor. Simple kinetic tremor occurs during voluntary
17 Tremor in Childhood 307
movements that are not goal directed, e.g., during pronation/supination movements
of the forearm. Task specific tremors occur during or are provoked by a particular
action, e.g., writing. Titubation is the slow head/trunk tremor typically seen with
cerebellar disease but also in adults with essential tremor.
Holmes tremor is present both at rest and with intention and often with posture.
It can be extremely disabling. With the finger–nose test as the hand returns to the
nose there may be extreme oscillations of the hand and the threat of injury to the eyes
or face. The term Holmes tremor is now preferred to such terms as rubral or midbrain
tremor which were used in the past. It is believed to be caused by involvement of
both the nigrostriatal and dentato-rubro-thalamic pathways (Deuschl et al. 1998).
Isometric and orthostatic tremors are conditions that occur mainly in adults and
will not be discussed further here.
There are difficulties with the term dystonic tremor as the movements are usually
not regular. However, the movements although usually jerky may be of large ampli-
tude and mimic a tremor. They present a very different sign to the twisting and sus-
tained postures of dystonia and to subsume them under dystonic movements deprives
us of a term that is clinically useful. The Consensus Statement restricts the term to
the situation where the movements occur in a body part affected by dystonia, e.g.,
torticollis combined with jerky head movements. A difficulty here is deciding
whether a posture such as a head tilt or wrist extension is a sign of dystonia or an
attempt to reduce the tremor (Elbe and Deuschl 2011). The label of dystonic tremor
is most confidently applied when it has the following features: irregularity, high
amplitude, posture-dependency, and complexity (i.e., it is multidirectional). Other
features which suggest that a tremor is dystonic are its appearance with specific
activities such playing a musical instrument and its relief by a geste antagoniste
(a physical gesture or a position which reduces or interrupts temporarily dystonia).
Another and more common disorder of childhood that comes into consideration in
the differential diagnosis of tremor is a stereotypy. Stereotypies have been defined as
involuntary patterned, repetitive often rhythmic (our emphasis) movements that are
goal directed and occur in the same fashion with each repetition (Singer et al. 2010b).
They can appear in multiple different settings such as when the child is bored or
excited. Stereotypies may take on many forms but common examples that are rhyth-
mic include hand flapping and body rocking. Some of the poorly understood complex
but rhythmic movement disorders of childhood such as shuddering attacks may be
stereotypies. When stereotypies occur in children who are otherwise normal, the child
often describes getting a feeling of pleasure or comfort from the movements.
17.2 Examination of the Child with a Tremor
A full and careful neurological and general physical examination should, of course,
be performed. Here we concentrate on the assessment of the tremor itself.
Tremor is a visual sign and the examination of tremor consists of initially viewing
the child at rest, then with posture and then in motion. With resting and postural
tremors, getting the older child to do mental arithmetic is effective in bringing out a
quiescent tremor and will often exaggerate a pathological tremor. If the tremor is
psychogenic it may disappear with mental arithmetic. Asking the child to hold both
index fingers as close to the nose as possible without touching it, with the arms
abducted and elbows flexed (the “wing posture”) can provoke both distal and proxi-
mal tremors. Getting the child to drink from a plastic cup, to write and to copy a
spiral are useful ways of assessing the disability caused by the tremor. Young chil-
dren are best observed during play with toys. Most enjoy taking the top on and off
a pen and the function of each arm can be assessed by holding the top of a marker
pen and asking the child to put the pen in it with one hand. Tremor amplitude is
usually inversely proportional to tremor frequency so that slow tremors (e.g., with a
frequency of 3 Hz) tend to be coarse and fast tremors (e.g., 12 Hz) tend to be fine.
As discussed above, there is a paucity of data specific to childhood on the pathophys-

iology of tremor and the authors suggest a review of other chapters in this publica-
tion. For completeness a brief review will be provided to give relevance to the
clinical descriptions.
All of us have a tremor which is usually only seen under conditions of stress such
as anger or extreme fatigue. This so-called physiological tremor is an action tremor
that takes the form of an oscillation of the outstretched hands at a frequency of
8–12 Hz. Marsden listed the multiple interacting systems that give rise to physiolog-
ical tremor (Marsden 1984). These include the ballistocardiogram (the expansion of
the intravascular space during systole), biomechanical and physical properties of
the muscle, motorneuronal firing, spindle feedback (which influences the synchro-
nization), supraspinal influences, and pharmacological influences (especially via
the beta receptors). Marsden further indicated that the human limbs possess a natu-
ral frequency of oscillation and the greater the mass, the lower the frequency. The
natural frequency of the finger is approximately 25 Hz whereas that of the wrist is
around 9 Hz and the elbow 2 Hz. Enhanced physiological tremor and essential
tremor can appear identical. However, the frequency of physiological tremor
decreases with mass loading whereas loading the limb has no effect on centrally
derived tremors such as essential tremor (Fahn and Jankovic 2007a).
Manto has discussed the various “loops” in the nervous system that when disor-
dered can give rise to tremor (Manto 2008). These include (1) the loop between
motor cortex and basal ganglia, (2) the loop between the cerebellum and the brain-
stem, especially the Guillain–Mollaret triangle, linking the dentate nucleus of the
cerebellum with the contralateral red nucleus and the inferior olive, (3) the loop
between the cerebellum, the thalamic nuclei, and the motor cortex (cerebello-thal-
amo-cortical pathway and cortico-ponto-cerebellar tracts), (4) the peripheral loops,
including the afferents from the muscle spindles to the alpha-motoneurons (spinal
loop), and (5) loops from the peripheral sensors to the motor cortex (transcortical
loop). Most pathological tremors arise from excessive oscillatory activity arising
from the so-called “central oscillators” in the brain. This may result from loss of
inhibition or changes within the networks that favor the development of excessive
synchronized activity.
17.4 An Approach to the Diagnosis of Tremor in Childhood
As discussed above, in adult medicine reviews of tremor disorders particularly con-

centrate on two common conditions—essential tremor and Parkinsonism. Recent
evidence has shown that even with these two disorders, long recognized and inten-
sively studied, everything is not as straightforward as it once seemed. The issues
around essential tremor will be discussed below. What was once regarded as a vari-
ant of Parkinson’s disease “benign tremulous Parkinsonism” is now thought to be
often a form of dystonic tremor without evidence of dopamine deficiency
(Schwingenschuh et al. 2010). In childhood the large number of rare conditions that
can produce tremor may result in long and rather confusing lists of potential causes.
Here we will approach the problem using the age of the child as the starting point.
Clearly there may be overlap between conditions that appear in infancy and early
childhood. Rather than listing all conditions where a tremor can be seen, we will
concentrate on conditions where tremor is the predominant feature or where it is an
important clue to the underlying diagnosis. We do not limit our review to conditions
that have been documented to show regularity of movements.
With the diversity of causes of childhood tremor, it is not possible to formulate
broad principles of treatment. Treatment is in general directed at the underlying
cause but in the following sections, there is insufficient space to deal with this in any
detail.
17.5 The Newborn
“Jitteriness” is seen in as many as half of all term infants and as such is the com-
monest form of tremor in childhood. In most it settles over a few days. Asphyxiated
babies may show this in an extreme form. In jitteriness the rhythmic oscillatory
movements can be provoked by startle and be stopped by gently holding the moving
limb or changing its position. The main differential is a clonic seizure where the
jerking will continue despite gentle restraint or repositioning. A fundamental differ-
ence is that the to and fro movements of jitteriness are of equal amplitude whereas
in clonic seizures, the phase of flexion is usually more sustained than that of exten-
sion (Scher 1997).
Asphyxiated babies may also develop rhythmic cycling movements involving
the arms or legs. These can be provoked by stimulation and the more repetitive the
stimulation and the greater the number of areas stimulated, the greater the response.
These are thought to be abnormal but non-epileptic behaviors “released” by injury

to the forebrain structures that normally inhibit them (Mizrahi and Kellaway 1987).
Benign neonatal sleep myoclonus is a non-epileptic form of myoclonus (Coulter
and Allen 1982). At times the myoclonic jerks come in flurries that can be rhythmic
and rapid and mimic a tremor. Although all four limbs are often involved, there can
also be asymmetry. The movements are only seen in sleep and the baby is otherwise
normal helping to differentiate this condition from seizures. A normal EEG is help-
ful in confirming the clinical diagnosis, especially when the jerks are recorded.
17.6 Infants
There are a relatively small number of causes of tremor in infancy. These are impor-
tant to identify as treatment has the potential to produce a marked improvement in
the neurological status of these children.
17.6.1 Inborn Errors of Dopamine Metabolism
These are rare and the infant is often misdiagnosed as having “cerebral palsy.”
Typically, the picture is of “dystonia-Parkinsonism” with dopamine deficiency caus-
ing akinesia, rigidity, tremor, dystonia, and oculogyric crises. As dopamine is con-
verted to noradrenaline, this is also deficient and results in the additional features of
ptosis, miosis, and excessive drooling. This may give the false impression that the
child has a neuromuscular disorder.
The tremor of dopamine deficiency is usually slow and coarse. It is not seen in
all cases but when present is a most important clue to the diagnosis. It has been
described with tyrosine hydroxylase deficiency (de Rijk-Van Andel et al. 2000),
6-pyruvoyl-tetrahydropterin synthetase deficiency (Factor et al. 1991), an undefined
disorder of biopterin synthesis (Snyderman et al. 1987) with aromatic acid decar-
boxylase deficiency (Korenke et al. 1997) and with sepiapterin reductase deficiency
(Neville et al. 2005). In the study of Neville of seven cases of sepiapterin reductase
deficiency, two of seven patients had an early onset of “parkinsonian tremor.” In a
personal case of tyrosine hydroxylase deficiency (Grattan-Smith et al. 2002), the
tremor was the first definite sign. It commenced at 2 months of age and over time
spread to involve the tongue, head, arms, and legs. It was coarse and presented a
dramatic clinical picture (videos accompany the article). It was present when the
infant appeared to be at rest and with attempts at movement. A tremor study from
the tibialis anterior muscle showed rhythmic muscle bursts at 4 Hz frequency. The
tremor responded rapidly to l-dopa therapy. It is of interest that the tremor in this
infant first appeared at around 2 months of age. This is the same time sleep spindles
first appear in the EEG of infants, representing a sign of thalamo-cortical synchro-
nization. Recent reviews describing 36 patients with tyrosine hydroxylase deficiency
(Willemsen et al. 2010) and 78 patients with aromatic acid decarboxylase deficiency
(Brun et al. 2010) have not emphasized the presence of tremor but when present it
is a very important sign.
17.6.2 Vitamin B12 Deficiency
In 1962 Jadhav reported the syndrome of vitamin B12 deficiency in Indian infants
characterized by apathy, developmental regression, involuntary movements, and
skin pigmentation (Jadhav et al. 1962). Subsequently there have been multiple simi-
lar reports from the “developed” world. The typical story is that the mother has
vitamin B12 deficiency due either to her diet or undiagnosed pernicious anemia.
The baby is exclusively breast fed. From around 4 to 8 months there is progressive
developmental regression. The infant may not be anemic but the blood film is often
macrocytic. The movement disorder can be present before diagnosis but is more
often seen after treatment with vitamin B12 has started. It is commonly described as
“choreoathetosis” (Graham et al. 1992) but in some children the movement disorder
is more rhythmic (Higginbottom et al. 1978). At times it takes the form of a violent
tremor that can cause the cot to shake (Emery et al. 1997). In a series of three
patients, two had pronounced limb shaking thought to be a mixture of tremor and
myoclonus with the first infant also having pronounced involvement of the tongue
and pharynx (Grattan-Smith et al. 1997). The third infant had persistent movements
of the right hand resembling epilepsia partialis continua (EPC) which appeared
before treatment was started. Both seizures and movement disorders can occur in
vitamin B12 deficiency and it is important to try to separate the two. The violent
tremor that appears after the initiation of treatment usually settles over 4–6 weeks.
Why it occurs is unknown. In the developing world, the “kwashiorkor shakes” has
been described in severely malnourished children on refeeding (Kahn and Falcke
1956). Again the cause is unknown.
17.6.3 Head Tremors of Infancy
Head tremors of all ages can be further subdivided into negative when the head
shakes from side to side and positive (or affirmative) when the shaking takes the
form of a vertical nodding. Some children with congenital nystagmus have head
shaking movements. It is not clear why these occur but there are usually no diagnos-
tic difficulties in the face of the coarse pendular nystagmus that is usually horizon-
tal. Totally blind children may also have repetitive head movements that may be a
form of self-stimulation (Fazzi et al. 1999). The term bobble-head doll syndrome
was introduced by Benton and subsequent reports have not improved upon the clini-
cal description (Benton et al. 1966). Two children were described with “to-and-fro
bobbing or nodding of the head and trunk. The movement is reminiscent of that seen
in dolls with weighted heads resting on a coiled spring.” Both children had cysts in
relation to the third ventricle with associated hydrocephalus. With the first child it
was noted that: “The head and trunk were involved in a slow, 2- to 3-per-second
nodding, forward-and-backward tremor which was evident whenever she sat or
stood without support. Each excursion of the trunk from the back to forward posi-
tion or in the reverse was associated with a full cycle of head movement-extension,
flexion, and extension.” The head movements could be inhibited voluntarily for
brief periods and disappeared on intended movement and at complete rest. (This
breaks the rule that the ability to stop a movement with distraction generally means
there is no serious underlying pathology.) Subsequent reports have confirmed that is
typically caused by mass lesions around the third ventricle causing CSF
obstruction.
Nellhaus (1983) lists hypomagnesemia, uremia, thyrotoxicosis, citrullinaemia,
antihistamine drugs, antipsychotic agents, and amphetamine as other causes of head
tremor in childhood. He also recalled a child with post-encephalitic Parkinsonism
who had a transient head tremor. (In older children head nodding can also be seen
during absence seizures, but the seizure is usually the dominant clinical feature.)
In spasmus nutans there is rapid head nodding, nystagmus (often monocular)
and head tilt or torticollis. The nystagmus and head shaking typically occur in bursts
lasting 5–30 s in association with fixation (Aicardi 1998). Classically described as
a benign phenomenon, at times it is caused by an anterior visual pathway glioma
(Anthony et al. 1980).
Head Stereotypies. Some infants and young children have rhythmic side to side
head movements that can persist for years with no other signs present. Sometimes
these will be more obvious when the child is otherwise unoccupied and the move-
ments may disappear with intense concentration or if the child is asked to stop the
movement. However, this is not always the case. This appears to be an unusual form
of stereotypy. Hottinger-Blanc et al. described eight children with onset in the first
year of life of an isolated head stereotypy (Hottinger-Blanc et al. 2002). All were of
normal intelligence but were clumsy and two had abnormalities of cerebellar devel-
opment. DiMario (2000) described four children with persistent head tremor with
no cause identified. Three of these four children had shuddering attacks prior to the
development of the head movements, giving further credence to the possibility that
the movements represent a stereotypy (see shuddering attacks below).
Because of the number of potentially serious underlying causes, neuroimaging
should be considered in children with head tremors.
17.6.4 Shuddering Attacks
In shuddering attacks, the infant often stiffens and the body trembles. The typical
description is that it is as though water has been poured down the child’s back.
A large number of episodes can occur per day. In the initial description (Vanasse et al.
1976), it was thought these attacks might represent an early presentation of essential
tremor, but subsequent studies have not supported this. (As they grew older most of
the children described in this paper also developed tics.) Shuddering attacks may be
another form of stereotypy.
17.7 Childhood and Beyond
A common situation is the child thought to have a tremor at home or school but
when examined, there is either nothing to see or there are intermittent, subtle, and
not uncommonly irregular finger movements. Investigations such as thyroid func-
tion tests, copper and caeruloplasmin, a urine metabolic screen, and neuroimaging
are normal. Whether this represents enhanced physiological tremor, the earliest pre-
sentation of essential tremor or a mild form of dystonic tremor without other signs
of dystonia is unclear. However, it is prudent to follow these children over time.
17.7.1 Enhanced Physiological Tremor
The amplitude of physiological tremor is determined by the degree of synchroniza-

tion of motor unit discharges modulated by muscle spindle 1a afferents (Fahn and
Jankovic 2007a, b). This process is exaggerated during anxiety and exercise and
other conditions that enhance peripheral b adrenergic activity. Probably the com-
monest example of enhanced physiological tremor in childhood is the child with
severe asthma receiving intensive bronchodilator therapy. Other causes include thy-
rotoxicosis, hypoglycaemia, withdrawal syndromes, and a phaeochromocytoma. In
a recent review, 110 cases of acquired thyrotoxicosis were identified over a 1-year
period in the United Kingdom and Ireland (Williamson and Greene 2010). Tremor,
identified in 58% of children, was the second most common sign with only goiter
(78%) more common. As the data was derived from a surveillance program no
further details of the tremor were provided. Fernandez-Alvarez and Aicardi (2001,
p. 44) report that they have seen children with intellectual handicap whose exagger-
ated physiological tremor was so intense in stressful situations that the tremor was
more disabling than the intellectual problems.
Essential tremor (ET) is typically a bilateral, largely symmetric postural or kinetic

tremor involving mainly the arms (Deuschl et al. 1998). The head and voice may
also be involved. An epidemiological study from Rochester found that the annual
incidence of ET in the 0–19 year age group was 2.3 per 100,000 (Rajput et al. 1984).
In contrast in the over 80 age group, the annual incidence was 84.3 per 100,000.
There is a paucity of literature on ET in the first decade. Reflecting this, we have

seen only a small number of children who have the typical features of ET. Further,
despite the frequency of ET in adults and its apparently dominant inheritance,
genetic studies have failed to identify a single causative gene. It seems likely that it
is a heterogeneous condition. This is supported by the clinical variability. Some
patients have additional cerebellar signs such as difficulty with tandem gait and the
finger–nose test (Elbe and Deuschl 2011). Some adult patients with advanced dis-
ease develop a resting tremor without other evidence of Parkinsonism (Deuschl and
Elbe 2009). However, this is not seen in the absence of an action tremor.
In the study of Louis of 19 children with ET, the mean age at the time of publica-
tion was 12.7 years, and the median age of onset was 7 years (Louis et al. 2001b).
All had arm tremor. In most cases tremor was both with posture and with move-
ment, and the latter was usually more pronounced. Problems occurred with hand
shaking during tasks requiring precise motor control, drinking from a cup and writ-
ing. Only one patient had head tremor. Four patients had received treatment at some
time and this was usually propanolol. Jankovic described 39 patients, with a mean
age at evaluation of 20 ± 14 years (Jankovic et al. 2004). The mean age of onset was
determined to be around 8 years and there was also a male predominance. Forty six
percent had neurological co-morbidity with 11 patients (28%) having dystonia.
Jankovic discussed the problem of referral bias in such studies emanating from units
devoted to the study of movement disorders.
In a child suspected of having ET, as well as taking a careful family history, the
parents should be examined. ET is typically improved by alcohol intake but this is
not specific to ET. Other movement disorders may be alcohol responsive including
myoclonus dystonia, focal dystonias, task specific dystonias, post-anoxic myoclonus,
and tics (Mostile and Jankovic 2010).
It has been suggested that in the adolescent with ET where there is significant
impairment (and no history of asthma), propanolol can be started in a dose of 30 mg
per day (Keller and Dure 2009). The dose may subsequently need to be increased to
60–80 mg per day. Long acting preparations may have a role.
A number of conditions can produce a tremor that may be mistaken for ET
including hydrocephalus, hereditary and motor sensory neuropathies, Wilson’s disease,
and Klinefelter syndrome (Fernandez-Alvarez and Aicardi 2001). Hyperthyroidism
should also be considered.
17.7.3 Drugs and Toxins
Drugs commonly give rise to tremor in adults. The causes include alcohol with-
drawal, neuroleptics, lithium, and tricyclic antidepressants (Tolosa et al. 1998).
Drugs that cause tremor in both children and adults include salbutamol and other
bronchodilators, and valproic acid. The tremor produced by valproic acid appears to
be dose related and is similar to essential tremor (Hyman et al. 1979). Abuse of
cocaine and other stimulants may produce tremor as well as tics, chorea, and dystonia
(Brust 2010 ). Chronic inhalation of petrol and organic solvents can also cause
a tremor as well as other neurological disturbance (Kaelan et al. 1986; Lazar
et al. 1983). Lewis reported the case of an elderly couple who suddenly developed
a “severe muscle tremors” after consuming a soup contaminated by the fungus
Penicillium crustosum which produces the mycotoxin penitrem A (Lewis et al.
2005). This is a widely distributed fungus that causes spoilage of a wide range
of foods and is therefore a risk for children as well as adults. Serotonin syn-
drome comes into the differential diagnosis of acute poisonings associated with
jerkiness but the movement disorder is generally described as myoclonus (Kipps
et al. 2005).
17.7.4 Hydrocephalus
Older children with “arrested” hydrocephalus may present with a tremor similar to
essential tremor. The presence of macrocephaly is an important diagnostic clue.
17.7.5 Palatal Tremor
Palatal tremor was previously called palatal myoclonus and is classified into symp-
tomatic and essential forms (Deuschl et al. 1994). Symptomatic palatal tremor is
usually seen in adults and results from a stroke or other lesion involving the dentato-
olivary pathway. There may be hypertrophy of the inferior olivary nucleus which
can be demonstrated on MRI scans. The palatal movement is produced by contrac-
tion of levator veli palatine. There may be widespread jerks involving muscles of
many areas including the face and diaphragm which are synchronous with the pala-
tal movements. There are no ear clicks. In essential palatal tremor, the movements
result from contraction of tensor veli palatine. Ear clicks are commonly present and
the movements are restricted to the palate. There are no abnormalities of the inferior
olivary nucleus. Campistol-Plana reported four children with a mean age of 6 years
with essential palatal tremor and found there was a good response to piracetam
(Campistol-Plana et al. 2006). Some cases of essential palatal tremor appear to be
psychogenic.
17.7.6 Holmes Tremor Following Head Injury
Probably first described by Kremer et al. in 1947, the delayed onset of tremor fol-
lowing severe head injury can be a particularly disabling condition. Andrew
reviewed eight cases where the mean age at the time of the head injury was 14 years
(Andrew et al. 1982). The patients were comatose after the head injury, usually for
several weeks. A third nerve palsy suggesting brainstem injury was common.
Tremor developed between 1 and 18 months after the initial injury. It was unilateral
and often the emergence of tremor coincided with an improvement in the initial
weakness of the limb. In five patients the tremor was so severe that the limb was
useless. It was present at rest in three patients and in all was made worse by attempts
at movement. In six patients it was felt there were also myoclonic jerks. In one
patient the movements were so wild they suggested hemiballismus and another
would sit on her hand to control the limb. As well as cranial nerve palsies there were
often other signs such as dysarthria. In this series the tremor of each patient improved
after stereotaxic thalamotomy. The ventral intermediate nucleus was the primary
target but often multiple lesions were required. There have been a number of subse-
quent case reports suggesting deep brain stimulation can also be effective (Peker
et al. 2008). Levetiracetam has also been reported to improve Holmes tremor
(Ferlazzo et al. 2008).
17.7.7 Wilson’s Disease
Wilson’s disease in childhood usually presents with liver failure or a hemolytic

anemia and a neurological presentation is rare. Nevertheless as a treatable condition
it must be always considered in the differential diagnosis of tremor. It has been said
that every patient with Wilson’s Disease has his or her own unique movement dis-
order. The classic tremor is the high amplitude proximal tremor seen when the
fingers are held close to the nose with the shoulders abducted and elbows flexed—
the so-called “wing-beating” tremor. Patients with Wilson’s disease may also exhibit
a rest tremor, intention tremor, and an action tremor when trying to write or drink
from a cup (Hoogenraad 1996).
17.7.8 Hereditary Geniospasm
Hereditary geniospasm (literally chin spasm) or chin quivering is a highly distinctive

disorder involving the mentalis muscle of the chin. Typically there is “up and down”
movement of the chin with quivering of the lip. The movements do not have the
rhythmicity of tremor but tend to come in irregular bursts. They tend to be worse with
anxiety. The movements can be quite strong and may give the impression that they
emanate from the jaw. If there is significant social disability from the movements,
botulinum toxin injections can quell them. In some families as well as the cosmetic
problems severe tongue lacerations from nocturnal tongue biting can be a significant
cause of disability (Jarman et al. 1997). The inheritance is autosomal dominant.
17.7.9 Spinal Muscular Atrophy and Neuropathies
Moosa and Dubowitz (1973) citing the works of others who had gone before them
emphasized the diagnostic value of the presence of a tremor in children with what
we now call Types II and III spinal muscular atrophy (SMA). They described 13
children with SMA and tremor. In only two was the tremor obvious. In the others
it represented a subtle but important sign. They found limb tremor to be more com-
mon than fasciculations of the tongue, a better known sign of SMA. The tremor
was an action tremor present with outstretched hands or noted during the manipu-
lation of toys. Similar movements can also be seen in children with congenital
neuropathies (Yiu et al. 2011) and in chronic inflammatory demyelinating neu-
ropathy (Ouvrier et al. 1999). The movements are due to the firing of large motor
units in a muscle with decreased numbers of motor units (Riggs et al. 1983) and are
a sign of chronic denervation and reinnervation. They are not entirely rhythmic and
terms such as contraction fasciculations (Denny-Brown and Pennybaker 1938)
have been used. Spiro (1970) describing children with SMA, called these move-
ments minipolymyoclonus, a term coined by his colleague Dennis Giblin and now
confusing as it was subsequently used in the setting of epileptic myoclonus (Wilkins
et al. 1985). Riggs suggested contraction pseudotremor of chronic denervation
might be the best term.
17.7.10 Glut-1 Deficiency
Glucose transporter 1 deficiency is due to a heterozygous mutation in the glucose

transporter 1 gene. Early reports defined a syndrome characterized by the onset of
seizures early in infancy, often with associated intellectual handicap and micro-
cephaly (De Vivo et al. 1991). Over time it has become clear that this condition can
present with movement disorders including exercise-induced dykinesia, action dys-
tonia, ataxia, tremor, chorea, and myoclonus (Pons et al. 2010). Roubergue and
colleagues have described a woman who presented at 11 years of age with a dys-
tonic tremor (Roubergue et al. 2011). Her mother was also found to have a dystonic
tremor with onset in her teenage years. Both were heterozygous for a thr137ala mis-
sense mutation in the Glut-1 gene. The index case had a generalized action tremor
which interfered with writing and the ability to carry a glass of water. Her voice was
jerky and “slight postural and action tremor” were observed in the upper limbs. A
tremor study supported the diagnosis of dystonic tremor. On careful questioning,
both also had action dystonia. Neither agreed to be treated with either carbam-
azepine or the ketogenic diet. A literature review by Roubergue revealed 12 other
cases where tremor was associated with Glut-1 deficiency and in 2, tremor was the
only constant symptom.
17.7.11 Segawa Disease
Although typically presenting as leg dystonia with diurnal variation, children of

10 years and older with GTP cyclohydrolase deficiency may have a postural tremor.
Segawa observed that a postural hand tremor was present in 14 of 28 gene-proven
patients (Segawa et al. 2003). He believes that a parkinsonian resting tremor does
not occur in this condition.
17.7.12 Epilepsia Partialis Continua
In EPC there is continuous focal jerking of a body part, usually localized to a distal
limb, occurring over hours, days, or even years (Cockerell et al. 1996). Sometimes
it ceases in sleep. Usually there is sufficient variability in timing and amplitude for
the movements to be recognized as not a tremor but there is a report in the adult
literature of a man with EPC initially felt to have a parkinsonian tremor (Al-Hayk
and LeDoux 2003). There are many causes of EPC but if it is due to a focal cortical
dysplasia, there may be mainly localized jerking and no alteration of consciousness
causing potential diagnostic difficulty. Other causes include Rasmussen syndrome,
viral encephalitis including measles and POLG mutations (Cardenas and Amato
2010). In these conditions, there is usually alteration of consciousness and intense
seizure activity taking the diagnosis away from the possibility of a tremor.
17.7.13 Familial Cortical Myoclonic Tremor with Epilepsy
Is a rare disorder which can be mistaken for essential tremor (van Rootselaar et al.
2005). Although more common in adults, the onset can be as early as 10 years of
age. Typically there is no tremor at rest but the tremor appears with posture and
movement. In the video of a case shown by van Rootselaar et al. the tremor was
mainly present in the fingers and hands. It was high frequency, semirhythmic, and
of varying amplitude. It was stimulus sensitive and neurophysiology was consistent
with a cortical reflex myoclonus. The condition shows autosomal dominant inheri-
tance. Tremor is usually the first symptom with epilepsy developing over time in
around 80% of affected individuals.
17.7.14 Task Specific Tremors
In 1979 Rothwell et al. described a male who presented at age 12 years with jerking
of the right forearm on writing (Rothwell et al. 1979). Although both myoclonus
and dystonic jerking was considered as possible causes, electrophysiological studies
suggested that the jerks were due to short bursts of tremor. It was felt he suffered
from a primary writing tremor (PWT). PWT is the commonest task specific tremor
in adults. It has been subdivided into two types depending on whether tremor
appeared during writing alone or whilst writing and adopting the hand position used
in writing (Bain et al. 1995). It is rare in childhood and in our experience a more
common situation is the older child with DYT1 dystonia presenting with writing
difficulties due to dystonic tremor. Subsequently the dystonia spreads to involve
other parts of the body.
17.7.15 Gene Microdeletions and Microduplications
There is emerging evidence that microdeletions or microduplications of whole

genes or parts of genes are important causes of neurological and neurodevelopmen-
tal syndromes such as autism. Methods such as Comparative Genomic Hybridization
microarray are replacing the karyotype as an investigation of the child with autism
(Miller 2010). It is becoming increasingly clear that there will also be a role for such
techniques in the investigation of children with movement disorders, especially if
they are complex and there are associated learning difficulties or intellectual handi-
cap (Bodzioch et al. 2011; Dale et al. 2011).
17.7.16 Psychogenic Tremor
Psychogenic tremors are here discussed last, the traditional position for psycho-
genic problems in publications by neurologists. However, they are much more com-
mon in childhood than many of the conditions discussed above. The features of
psychogenic tremor described in adults are also seen in children. It is often present
at rest, with posture and with movement (Fahn and Jankovic 2007b). It tends to vary
in frequency, amplitude, and location especially if the patient is engaged in conver-
sation. A gross psychogenic tremor may disappear if the child attempts to do mental
arithmetic at a level that challenges her or him. Entrainment may also be present,
i.e., if the examiner moves his or her hand at a certain frequency, the tremor of the
patient may change to this same frequency. The subject of psychogenic disorders is
huge and beyond the scope of this chapter. A taste of the complexity of the situation
is given by the following observation from the Consensus Statement: “In psycho-
genic tremor, the tremor may be produced voluntarily, although awareness that the
tremor is voluntary may be subconscious” (Deuschl et al. 1998).
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Part III
Assessment of Tremor:
Clinical, Neurophysiological
and Neuroimaging Aspects
Chapter 18
Assessment of Tremor: Clinical
and Functional Scales
Keywords Clinical scales • Functional assessment • Ratings • Transducer
Although tremor can be estimated clinically, its nonstationary feature and the difficulties
related to the pure clinical evaluation (with inherent subjectivity) make the use of sensi-
tive, reliable, and accurate sensors mandatory to quantify tremor (see also Chaps. 19
and 20). Motion transducers allow to corroborate changes in clinical rating given the
logarithmic relationship with tremor ratings, as predicted by the Weber–Fechner
law of psychophysics (Elble et al. 2006; Elble and Deuschl 2011). The logarithm of
tremor amplitude (T), measured with a motion transducer, is proportional to the clinical
rating score (CRS) according to the equation (Deuschl et al. 2011):
log T = a × CRS + b ,
where a is the slope and b is the y-intercept.

From this equation, changes of the tremor magnitude can be estimated from
changes in clinical ratings during successive assessments. The parameter a lies
typically in the range of 0.3–0.6 (mean about 0.5; log base 10) for measurements of
upper limb tremor with accelerometry or a digitizing tablet and a five-point (0 to 4)
tremor rating (Elble et al. 2006; Elble and Deuschl 2011). The logarithmic relation-
ship explains some of the inconsistencies that have been published between accel-
erometry and clinical ratings, and why a drop from a CRS of 4 to 3 is not equivalent
in terms of magnitude reduction to a drop from 3 to 2, for instance.
The clinical evaluation and the follow-up of patients are improved with the use
of validated clinical scales. Taking into account the impact of tremor on activities of
daily living (ADL) and on functional tests are two important aspects that will be
discussed in this chapter.

18.1 Clinical Evaluation
The first step in evaluating any patient with tremor is to characterize the tremor on
inspection and to look for possible associated movement disorders. Activation tests
are performed and topographical distribution is noted.
The selection of the maneuvers on the basis of which clinicians focus their inter-
est to characterize tremor varies according to the type of tremor. Some of these
maneuvers are mentioned along the book (see for instance the Chap. 7). We provide
here a systematic list.
Rest tremor is detectable while the patient is seated with the upper limbs resting on
the thighs (showing the dorsal side of the hands to the examiner remaining in front
of the patient), or while the patient is lying down. For lower limbs, rest conditions
can be achieved crossing one leg on the other or in supine position. Cognitive tasks,
for instance counting down, and tapping of the contralateral foot, can trigger or
enhance tremor (Raethjen et al. 2008).
Postural tremor is assessed by the following maneuvers (Grimaldi and Manto
2008):
– Holding the upper limbs outstretched with the hands in supination, parallel to the
floor.
– Index-to-index test: the patients has to maintain the two index fingers medially,
pointing at each other at a distance of about 1 cm. Forearms are maintained
horizontally.
Kinetic tremor is evaluated during the followings tests (Manto 2002):
– Finger-to-nose test: patient is asked to make successive movements of one upper
limb with the hand first resting on the thigh and then touching the nose with the
index.
– Finger-to-finger test: the examiner can move abruptly the index finger (target) in
front of the patient and asks the patient to touch (with his/her finger) the target
with accuracy.
– Knee–tibia test: this maneuver is executed in supine position. The patient is
asked to raise one leg and place the heel on the contralateral knee (with
accuracy) which is kept motionless. The patient slides down the tibial surface
in a regular way towards the ankle. The heel is then raised again up to the rest-
ing knee.
The key-points in the description of tremor are:
– Body segments involved (head, trunk, upper limbs, lower limbs)
– Enhancing/reducing effect (effect of mental calculation/contralateral voluntary
contractions)
– Distribution (symmetry/asymmetry)
– Grade/amplitude (see Table 18.1)
– Estimation of the frequency
18 Assessment of Tremor: Clinical and Functional Scales 327
Table 18.1 Modified Fahn–Tolosa–Marin rating scale (see below, TRS)

Description of tremor amplitude Score
None 0
Slight (amplitude <0.5 cm), may be intermittent 1
Moderate amplitude (0.5–1 cm), may be intermittent 2
Marked amplitude (1–2 cm) 3
Severe amplitude (>2 cm) 4
Neurological examination of a patient complaining and/or presenting tremor

includes (Grimaldi and Manto 2008):
– The assessment of cranial nerves, including the testing for oculomotor distur-
bances (ocular fixation, saccades, pursuit).
– The observation of the presence of vertical or side-to-side head movement.
– Speech evaluation: search for a concomitant dysarthria which is evaluated by
repetition of standard sentences, for instance: “A mischievous spectacle in
Czechoslovakia” (Trouillas et al. 1997).
– The evaluation of voluntary force in each limb segment.
– Tendon/plantar reflexes.
– Detailed sensory testing.
– The observation of abnormal movements occurring at rest.
– Checking for the occurrence of tremor triggered by postural tasks or voluntary
muscle contraction.
– Looking for the presence of other abnormal movements (dystonia, tics, etc.).
– Assessing amyotrophy or muscle hypertrophy.
– Evaluating abnormalities of stance and gait.
Assessment of writing includes drawing the Archimedes’ spiral. The subject is
comfortably seated in front of a table. A sheet of the paper with a predrawn spiral is
fixed on the table with tape to avoid motion artifacts. The subject is asked to per-
form the task without timing requirements. Dominant hand is examined. The patient
is also asked to write standard sentences (Grimaldi and Manto 2008).
18.2 Clinical Scales
Scales are used to quantify the degree of severity of a clinical deficit. They system-
atize the information by assigning certain numbers to certain conditions. A diagnos-
tic measure aiming to produce quantifiable results and bound to psychometric
accuracy standards should meet the following main criteria for quality:
– Objectivity: independence of results from examiner
– Reliability: repeating a test application on the same person after a certain amount
of time should give in the same results
– Validity: a diagnostic method is valid if it actually measures the appropriate

variable
– Standardization
– Comparability, economy and usefulness
Sensitivity (higher sensitivity means fewer false-negative cases), specificity
(higher specificity means less false-positive cases), and predictive values should be
taken into account (Masur 2004).
According to Weber’s law of psychophysics, the smallest discernible change in
tremor DT is
ΔT = K × T 1,
where T1 is the initial amplitude of tremor and K is Weber’s constant (Gescheider
1997). Thus, Weber’s law states that the smallest discernible change in tremor will
be proportional to the initial tremor amplitude. This relationship predicts that any
tremor rating procedure will be a nonlinear measure of tremor amplitude. The
knowledge of the relationship between tremor rating and precise measures of tremor
is useful in interpreting the clinical significance of changes in ratings produced by
disease or therapy. Analysis of data from 928 patients revealed a logarithmic rela-
tionship between a 5-point (0–4) tremor rating procedure and tremor amplitude
(Elble et al. 2006). A 1-point change in TRS represents a substantial change in
tremor amplitude.
The Clinical Tremor Rating scale (TRS) developed by Fahn–Tolosa–Marin
(1988) is dedicated to the evaluation of tremor and is a gold standard. Tremor is
evaluated trough 22 items (see Table 18.2): the first 10 items evaluate the clinical
manifestation of the tremor and its distribution in various regions of the body. The
other items characterize patient’s disability in daily life. Performance tests, such as
handwriting and drawing, are included. The test is performed during 30–90 min.
The range of results is 0–88 with a higher score meaning a more debilitating disease
(Masur 2004).
A study on the inter-rater and intra-rater reliability of the TRS in essential tremor
has been conducted by comparing tremor scores assigned by 59 raters on videotape
recordings (Stacy et al. 2007). This evaluation revealed fair (Part A: magnitude of
tremor in different body parts) to poor (Part B: tremor in writing and drawings)
concordance between raters and very good intra-rater reliability in repeated assess-
ments, although still not as good for Part B. These findings emphasize the impor-
tance of using a consistent rater in follow-up assessments of a patient, while
suggesting that better assessment criteria for tremor in writing and drawings are
needed in the future (for instance, digitizing tablets see Chap. 19).
Many other scales include a section for the evaluation of tremor, among them
The Unified Parkinson Disease Rating Scale (UPDRS). UPDRS has been published
in 1987 by Fahn, Elton, and the Members of the UPDRS development Committee.
It is composed of four sections:
Table 18.2 Clinical tremor rating scale (from Fahn et al. 1988)
1–10 Tremor
Rate tremor at rest in items 1and 2. Rate tremor with posture holding in items 3–10
Abbreviations: UE: upper extremities, LE: lower extremities
Score: 0 = none; 1 = slight (amplitude < 0.5 cm), may be intermittent; 2 = moderate amplitude
(0.5–1 cm), may be intermittent; 3 = marked amplitude (1–2 cm); 4 = severe amplitude
(>2 cm)
1. Head
2. Trunk
3. UE: arms outstretched, wrist midly extended, fingers spread apart
4. LE: legs flexed at hips and knees
5. Foot dorsiflexed
6. Tongue: when protruded
7. Head and Trunk: when sitting or standing
8. Rate tremor with action and intention
9. UE: finger to nose and other actions
10. LE: toe to finger in flexed posture
11. Handwriting
Have patient write the standard sentence: “This is a sample of my best handwriting,” sign his
or her name and write the date
Score: 0 = normal; 1 = mildly abnormal, slight untidy, tremulous; 2 = moderate abnormal,
legible but with considerable tremor; 3 = marked abnormal, illegible; 4 = severely
abnormal, unable to keep pencil or pen on paper without holding hand down with the
other hand
12.–14. Drawings
Ask the patient to join both points of the various drawings without crossing the lines. Test each
hand, beginning with the lesser involved, without leaning the hand or arm on the table
Score: 0 = normal; 1 = slightly tremulous, may cross lines occasionally; 2 = moderately
tremulous or crosses lines frequently; 3 = accomplishes the task with great difficulty,
many errors; 4 = unable to complete drawing
15. Pouring
Use firm plastic cups (8 cm tall), filled with water to 1 cm from top. Ask the patient to pour
water from one cup to another. Test each hand separately
16. Speaking
This includes spastic dysphonia if present
Score: 0 = normal; 1 = mild voice tremulousness when “nervous” only; 2 = mild voice
tremulousness, constant; 3 = moderate voice tremor; 4 = severe voice tremor, some word
difficult to understand
17. Feeding Other than liquids
Score: 0 = normal; 1 = mildly abnormal, can bring all solid to mouth, spilling only rarely;
2 = moderately abnormal, frequent spills of peas and similar foods, may bring head at
least half way to meet food; 3 = markedly abnormal, unable to cut or uses two hands to
feed; 4 = severely abnormal, needs help to feed
18. Bringing liquids to mouth
Score: 0 = normal; 1 = mildly abnormal, can still use a spoon, is completely full; 2 = moderately
abnormal, unable to use a spoon, uses cups or glasses; 3 = markedly abnormal, can drink
from cup or glass, but needs help two hands; 4 = severely abnormal, must use a straw
(continued)
Table 18.2 (continued)

19. Hygiene
Score: 0 = normal; 1 = mildly abnormal, able to do everything but is more careful than the
average person; 2 = moderately abnormal, able to do everything but with errors, uses
electric razor because of tremor; 3 = markedly abnormal, unable to do most fine tasks,
such as putting on lipstick or shaving (even with electric shaver), unless using two
hands; 4 = severely abnormal, unable to do any fine movement tasks
20. Dressing
Score: 0 = normal; 1 = mildly abnormal, able to do everything but is more careful than the
average person; 2 = moderately abnormal, able to do everything but with errors;
3 = markedly abnormal, needs some assistance with buttoning or other activities, such as
tying shoelaces; 4 = severely abnormal, requires assistance even for gross motor
activities
21. Writing
Score: 0 = normal; 1 = mildly abnormal, legible, continue to write letters; 2 = moderately
abnormal, legible but no longer writes letters; 3 = markedly abnormal, illegible;
4 = severely abnormal, unable to sign checks or other documents requiring signature
22. Working
Score: 0 = tremor does not interfere with job; 1 = able to work, but needs to be more careful
than the average person; 2 = able to do everything but with errors, poorer than usual
performance because of tremor; 3 = unable to do regular job, may have changed to a
different job because of tremor, tremor limits housework, such as ironing; 4 = unable to
do any outside job, housework very limited
Total score
– The first one assesses the psychological effects of the disease and the drugs used
– The second section features 13 subitems covering ADL
– In the third section (Motor examination), the clinical symptoms of parkinsonism
are assessed
– The fourth section describes the complications and side effects of drug therapies
The test has a duration of 40–60 min. The range of results is 0–154 with impair-
ments classified from minimum to maximal points (0–5 = no impairment; 154 = max-
imum clinical impairment) (Masur 2004).
Other specifically-designed and detailed composite scales combining clinical and
functional evaluation do exist. A composite CNF-TES (Clinical, Neurophysiological,
Functional Tremor Evaluation Scale; Table 18.3) has been developed in order to
provide an in-depth evaluation of tremor. The CNF-TES takes into account the clini-
cal, neurophysiological, and functional results (Grimaldi and Manto 2010).
In a study aiming to determine prospectively the efficacy and safety of unilateral
ventralis intermedius (Vim) deep brain stimulation (DBS) to control disabling
kinetic arm tremor related to multiple sclerosis (MS), Hosseini et al. have quantified
the severity of tremor using to the Fahn–Tolosa–Martin scale. The impact of tremor
on quality of life was evaluated by the Short Form-36 scale (SF-36, a short-form
health survey with 36 questions). Manual capacity was estimated with a 0–12 score
scale (that included writing, drawing, and pouring water). Functional disability was
Table 18.3 The composite clinical/neurophysiological/functional tremor evaluation scale (CNF-TES)

C-TES (Clinical-TES)
Anamnesis
Assessment of disability (Activities of Daily Living scales/ADL-T24)
General physical and neurological examination
Tremor evaluation by visual inspection
Brain imaging (CT-scan—MRI—SPECT—PET studies)
Blood studies
N-TES (Neurophysiological-TES)
EMG (surface/needle) and EEG recordings
Evaluation of pinch force
Analysis of writing (spirals, standard sentences)
F-TES (Functional-TES)
Mechanical counters test (MCT)
Box and block Test
9-Hole-Peg Test
Adapted from Grimaldi and Manto (2010)
evaluated with a 0–24 score testing scale (that included oral expression, feeding,
drinking, grooming, dressing, and manual activities) (Hosseini et al. 2012).
18.3 Functional Evaluation
Functional evaluation of a patient presenting tremor may be conducted using func-

tional tests and tasks requiring both coordinated proximal/distal movements and
fine execution. These tests present the great advantage to provide time-based mea-
sures, with published norms. They focus on different aspects of upper extremity
function and are not symptom- or condition-specific (Héroux et al. 2006). Some of
these tests are described here (Fig. 18.1).
The Box and Block test (BBT) is a test of manual dexterity (see Fig. 18.1a). The
box is divided in two by a partition in the center. The patient sits near a table facing
the box and is asked to grasp one block at a time, transport it over the partition and
release it into the opposite compartment. The score corresponds to the number of
blocks carried from one compartment to the other in 1 min (Masur 2004).
Nine Hole Peg Test (9HPT) is an upper limb motor function test requiring a set of
wooden or plastic equipment (see Fig. 18.1b) consisting of 9 pegs and a support with
9 holes. Patient sits near a table and is asked to place pegs in holes. The examiner
records the number of pegs placed in 50 s. The procedure has a duration of about 30 s
in healthy persons (Mathiowetz et al. 1985). Alusi and colleagues found out that
right arm postural tremor scores correlate with right arm Finger Tapping Test and
9HPT scores (p < 0.005). A good correlation between postural tremor scores and
patient’s perceived disability—as quantified by the ADL questionnaire—was also
found. Tremor scores from spiral drawings of both dominant and nondominant hands
and dominant handwriting had a high correlation with the 9HPT. Tremor scores from
the nondominant hand spirals correlated less with the tremor ADL, because most of
the items on the scale are usually performed by the dominant hand (Alusi et al. 2000).
9HPT showed a good correlation with BBT (personal observation; Fig. 18.2).
Fig. 18.1 Example of a patient performing the Box and Block test (BBT) (a), the 9 Hole Peg Test
(9HPT) (b), and the Mechanical Counter Test (MCT) (c)
Fig. 18.2 Correlation between 9HPT and BBT. Data from a group of nine patients presenting with
upper limb tremor (M/F = 6/3; mean age ± SD = 59 ± 17 years). Best fit: y = −16.3 ln(x) + 108.3
Mechanical Counter
80
60
score
40
20
1 2 3
Sessions
Fig. 18.3 Inter-session reliability of the Mechanical counter test (MCT). Mean ± SEM from a group
of six neurological patients presenting with tremor (M/F = 4/2; mean age ± SD = 63 ± 11 years). Patients
executed three trials with the dominant hand. The score is the sum of the number of taps for the two
counters; the best score amongst the three trials is considered. Inter-sessions delay: 2–6 months
The Mechanical Counter Test (MCT) is a multijoint coordination test of the upper
limb. During the task the patient hits with the index finger on two mechanical coun-
ters fixed on a table with an inter-counter distance of 39 cm (see Fig. 18.1c). The
score is the number of taps executed in 30 s, summing the number of hits of each
counter (Du Montcel et al. 2008). We have found that the Mechanical counter scores
correlate very well (R = 0.9) with the Crest Factor (PSD) (CF: a spectral parameter
of tremor corresponding to the ratio peak amplitude of dominant frequency/integral
of the 1–40 Hz band) during maintenance of a postural task in a group of six patients
presenting a neurological tremor (Grimaldi and Manto 2010). The MCT has a good
inter-sessions reliability (personal observation, Fig. 18.3).
Purdue Pegboard Test consists of placing the maximum amount of pegs into slots
on a board—done unilaterally and bilaterally—and a bilateral assembly task with
pegs, washers, and collars. This test provides four outcome measures: number of
pegs placed with each of the dominant and nondominant hands in separate 30-s trials;
number of pairs of pegs placed using both hands in 30 s; and number of component
parts placed during the assembly task in 60 s (Tiffin 1998; Desrosiers et al. 1995).
Functional tests are often combined in batteries with tasks exploring manual
ability and mimicking daily life activities; as well as with clinical scales and clinical
evaluation protocols (Payan et al. 2011). However, the correlation between tremor
severity and functional disability is not universally accepted. An exponential rela-
tion between tremor severity and functional deficits has been reported for the non-
dominant upper limb (Héroux et al. 2006). Tremor severity range plays a role in the
identification of this relation severity/disability. As reported by Louis et al. (1999),
a less significant correlation for mild tremor cases has been revealed by using a
15-item test to assess functional performance in ET subjects. In this scale, tasks
such as pouring liquid, copying sentences, and placing keys in locks were rated 0
(no difficulty) to 4 (unable to perform) by an observer.
18.4 Activities of Daily Living Scales
ADL scale is a questionnaire for assessing disability related to everyday functions.

It is addressed to the patients themselves. Dressing, mobility, personal hygiene, and
eating are investigated. The measure of dependence is indicated on a defined scale.
Two general examples (Tables 18.4 and 18.5) are the Extended ADL Scale accord-
ing to Nouri and Lincoln (1987) and the Schwab and England ADL (Gillingham
and Donaldson 1969).
Recently, an ADL scale called ADL-T24 scale dedicated to tremor has been
developed (Grimaldi and Manto 2010). This scale (Table 18.6) includes a core of
eight key-activities that have been extracted on the basis of interviews (so called
Table 18.4 Extended ADL scale according to Nourie and Lincoln (Nottingham Stroke Score)
Scoring: 0 = no/with help On my own
1 = on my own with difficulty/on my own No With help with difficulty On my own
Mobility
– Do you walk around outside?
– Do you climb stairs?
– Do you get in and out of the car?
– Do you walk over uneven ground?
– Do you cross roads?
– Do you travel on public transport?
In the kitchen
– Do you manage to feed yourself?
– Do you manage to make yourself a hot
drink?
– Do you take hot drinks from one room
to another?
– Do you do the washing up?
– Do you make yourself a hot snack?
Domestics tasks
– Do you manage your own money when
you are out?
– Do you wash small items of clothing?
– Do you do your own housework?
– Do you do your own shopping?
– Do you do a full clothes wash?
Leisure activities
– Do you read newspapers or books?
– Do you use the telephone?
– Do you write letters?
– Do you go out socially?
– Do you manage your own garden?
– Do you drive a car?
Total score: ............/22
Table 18.5 Schwab and England activities of daily living scale

100% = Completely independent. Able to do all chores without slowness, difficulty or impairment.
Essentially normal. Unaware of any difficulty
90% = Completely independent. Able to do all chores with some degree of slowness, difficulty
and impairment. Might take twice as long. Beginning to be aware of difficulty
80% = Completely independent in most chores. Takes twice as long. Conscious of difficulty and
slowness
70% = Not completely independent. More difficulty with some chores. Three to four times as
long in some. Must spend a large part of the day with chores
60% = Some dependency. Can do most chores, but exceedingly slowly and with much effort.
Errors; some impossible
50% = More dependent. Help with half, slower, etc. Difficulty with everything
40% = Very dependent. Can assist with all chores, but few alone
30% = With effort, now and then does a few chores alone or begins alone. Much help needed
20% = Nothing alone. Can be a slight help with some chores. Severe invalid
10% = Totally dependent, helpless. Complete invalid
0% = Vegetative functions such as swallowing, bladder and bowel functions are not functioning.
Bedridden
Table 18.6 ADL-T24 score

To move a glass full of water on a table To write words on a sheet of paper or to sign
No problem 0 No problem 0
Slight difficulties 1 Slight difficulties 1
Important difficulties 2 Important difficulties 2
Impossible 3 Impossible 3
To drink To read a book
To eat (use of forks and knives) To drive a car
To shave To dress one-self
Total score: ……………./24
ADL-T24 clinic vs telephone

24
23
22 R2 = 0.87
21
20
19
18
17
16
15
ADL-T24 tel
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
ADL-T24 clinic
Fig. 18.4 ADL-T24 scores obtained from “in clinic” and telephone interviews. There is no “phys-
ical presence of the examiner” effect. Data from a group of nine patients presenting with rest,
postural and/or kinetic upper limb tremor (M/F = 6/3; mean age ± SD = 59 ± 17 years)
focus groups) in a group of patients suffering with tremor (n = 10; mean

age = 55 ± 19 years). The patients provided a core of activities which mainly cause
difficulties in daily life due to either functional problems, social problems, or a
combination of functional and social difficulties. The ADL-T24 allows tremor
patients to subjectively report on the impact of tremor upon daily activities and aims
to complement existing clinical/functional measures in tremor. Time required to
complete the ADL-T24 score is about 3 min and most patients find this scale accept-
able. The comparison between telephone and “in clinic” interviews (mean of
delay = 3.5 ± 1.3 months) revealed a strong correlation, indicating that ADL-T24
scale could be used also in the tele-management of neurological patients (personal
observation, Fig. 18.4). ADL-T24 shows a good inter-session reliability (Fig. 18.5).
Moreover, ADL-T24 is characterized by a good correlation with the existing ADL
scales (Fig. 18.6). When looking for the correlation between ADL-T24 and the
functional task such as 9HPT and BBT, a good correlation is also found, more evi-
dent for the 9HPT (Fig. 18.7).
ADL-T24
24
23
22 session 1
21 session 2
20
19 session 3
18 session 4
17
16
15
14
13
score
12
11
10
9
8
7
6
5
4
3
2
1
0
1 2 3 4 5 6 7 8 9 10
Patients
Fig. 18.5 Inter-session reliability of ADL-T24 scores from a group of 10 patients presenting with
rest, postural, and/or kinetic upper limb tremor (M/F = 7/3; mean age ± SD = 55 ± 19.5 years). The
patients were evaluated four times, except patient 4 (evaluated twice) and patient 9 (three times).
Delay between interviews: 2–7 months
Fig. 18.6 Top panel. Correlation between ADL-T24 and Schwab and England ADL (SE) scores.
Data from ten patients, five of which have been evaluated twice with a delay of 4 months (n = 4;
pairs of colored pointers) and 9 months (n = 1; green pointers). Middle panel: Correlation between
ADL-T24 and Nourie and Lincoln Extended ADL (NL) scores; data from nine patients, five of
which have been evaluated twice with a delay of 4 months (n = 4; pairs of colored pointers)
Fig. 18.7 Correlation between ADL-T24 scores and functional tests. Data from a group of nine
neurological patients with tremor in upper limbs (two of which have been evaluated twice with a
delay of 4 months) and executing the functional tests with the dominant hand. Patients exhibited
combinations of rest, postural, and/or kinetic tremor. Top: correlation between ADL-T24 and
9HPT. Bottom: correlation between ADL-T24 and BBT
Fig. 18.6 (continued) and 9 months (n = 1; green pointers). Bottom panel: Correlation between SE
and NL scores. Notice that R2 values are not influenced by the inclusion of the repeated measures
when comparing ADL-T24 and SE scales, and SE and NL scales; while R2 is reduced from 0.68 to
0.61 when comparing ADL-T24 and NL scales and repeated measures are excluded
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Alusi SH, Worthington J, Glickman S, Findley LJ, Bain PG. Evaluation of three different ways of
assessing tremor in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2000;68(6):756–60.
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aged 60 and over. Disabil Rehabil. 1995;17:217–24.
Deuschl G, Raethjen J, Hellriegel H, Elble R. Treatment of patients with essential tremor. Lancet
Neurol. 2011;10(2):148–61.
du Montcel ST, Charles P, Ribai P, Goizet C, Le Bayon A, Labauge P, Guyant-Maréchal L, Forlani
S, Jauffret C, Vandenberghe N, N’guyen K, Le Ber I, Devos D, Vincitorio CM, Manto MU, Tison
F, Hannequin D, Ruberg M, Brice A, Durr A. Composite cerebellar functional severity score:
Validation of a quantitative score of cerebellar impairment. Brain. 2008;131(Pt 5):1352–61.
Elble R, Deuschl G. Milestones in tremor research. Mov Disord. 2011;26:1096–105.
Elble RJ, Pullman SL, Matsumoto JY, Raethjen J, Deuschl G, Tintner R, Tremor Research Group.
Tremor amplitude is logarithmically related to 4- and 5-point tremor rating scales. Brain.
2006;129(Pt 10):2660–6.
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Grimaldi G, Manto M. Tremor: From pathogenesis to treatment. San Rafael, CA: Morgan &
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tremor. Arch Phys Med Rehabil. 2006;87:661–70.
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Cesaro P, Palfi S, Nguyen JP. Unilateral thalamic deep brain stimulation for disabling kinetic
tremor in multiple sclerosis. Neurosurgery. 2012;70:66–9.
Louis ED, Wendt KJ, Albert SM, Pullman SL, Yu Q, Andrews H. Validity of a performance-based
test of function in essential tremor. Arch Neurol. 1999;56(7):841–6.
Manto M. Clinical signs of cerebellar disorders. In: Manto MU, Pandolfo M, editors. The cerebel-
lum and its disorders. Cambridge: Cambridge University Press; 2002.
Masur H. Scale and scores in neurology. New York: Thieme; 2004.
Mathiowetz V, Weber K, Kashman N, Volland G. Adult norms for the Nine Hole Peg Test of finger
dexterity. Occup Ther J Res. 1985;5(1):24–37.
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Rehabil. 1987;1:301–5.
Payan CA, Viallet F, Landwehrmeyer BG, Bonnet AM, Borg M, Durif F, Lacomblez L, Bloch F,
Verny M, Fermanian J, Agid Y, Ludolph AC, Leigh PN, Bensimon G, NNIPPS Study Group.
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Chapter 19
Instrumentation: Classical and Emerging
Techniques
Peter H. Kraus
Abbreviations
2D Two-dimensional
3D Three-dimensional
6DoF Six degrees of freedom
BCI Brain–computer interface
EEG Electroencephalography
EMG Electromyography
ET Essential tremor
FES Functional electrical stimulation
IMU Inertial measuring units
MEMS Micro-electro-mechanical systems
PD Parkinson’s disease
UWB Ultra wideband
Keywords Tremor assessment • Kinematic and Kinetic measures • Sensors
19.1 Introduction
19.1.1 Tremor: Definition
Tremor is defined as a “rhythmical, involuntary oscillatory movement of a body part,”

according to the consensus statement of the Movement Disorder Society (Deuschl
et al. 1998). Clinically, tremors are typically classified by the conditions under which
P.H. Kraus, M.D. (*)

Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56,
44791 Bochum, Germany
e-mail: peter.h.kraus@ruhr-uni-bochum.de
342 P.H. Kraus
they appear (e.g., action, rest, task) or by their underlying cause (Deuschl et al.
1998).
Only a few tremors, such as “physiological tremor” and thermo-regulatory
shivering, are normal in humans. Pathological tremors can be a common symptom
of a variety of neurological disorders. essential tremor (ET) is the most prevalent
tremor, but it is no longer considered a mono-symptomatic disorder or a benign
condition (see also Chap. 10). Some ET patients may show signs of cerebellar dys-
function (Deuschl and Elble 2000) with gait disturbance (Stolze et al. 2001), and
some develop subtle cognitive deficits or dementia (Benito-Leon 2006), and other
non-motor symptoms (Elble and Deuschl 2009). Thus, ET is no longer considered
a single entity, but more likely represents a family of tremor diseases. This family
of diseases has multiple pathophysiologies (Ondo 2006) that are unified by the
common presence of action tremor (Benito-Leon and Louis 2006).
Modern classification of tremors and their underlying pathophysiology has improved
with new technical methods. To avoid pitfalls and appropriately interpret the results of
a tremor assessment, it is essential to understand the relevant clinical information.
19.1.2 Historical Review
In the nineteenth century, Ernst Heinrich Weber (1795–1878) (Weber and Hering
1850) and Gustav Theodor Fechner (1801–1887) (Fechner 1860) were the first sci-
entists to measure physiological (especially sensory) data, establishing the field of
psychophysics. In the 1880s, these abnormal movements could be documented, for
the first time, using “chronophotography” (Étienne-Jules Marey, 1830–1904). Lanska
et al. have written a thorough historical overview of the evaluation of tremor (Lanska
2000; Lanska et al. 2001). Most techniques for assessing tremor have used graphical
recording devices, such as tambours and sphygmographs, which were modified from
instruments developed for other purposes (Lanska et al. 2001). Also worthy of men-
tion is the work of Jean Martin Charcot (1825–1893), who used mechanical devices
to analyze differences between parkinsonian tremor and intention tremor in multiple
sclerosis, and Charles Loomis Dana, who was one of the first to attempt to classify
tremors based on frequency (Lanska et al. 2001). Eshner (1897) used a tambour
recording apparatus for simultaneous recording from different body parts. Eshner
showed that tremor amplitude and frequency are inversely related, that tremor of
Parkinson’s disease is generally synchronous in corresponding body parts, and that
tremor of Parkinson’s disease is suppressed with action (Fig. 19.1).
The introduction of electricity enabled new methods of studying tremors. Techniques
for studying tremors ranged from early myographs and Leyden jars to electrophysio-
logical examinations that lacked any data storage capacity. Potentiometer-like sensors,
simple buttons, and electrodes in combination with oscilloscopes were standard for
many years. These simple methods produced results that remain valid today. In 1977,
Ackmann et al., the pioneers of long-term tremor measurement, used a low-torque
potentiometer as a transducer, along with a telemetry receiver, to measure angular
19 Instrumentation: Classical and Emerging Techniques 343
Fig. 19.1 Eshner’s tambour recording apparatus from 1896 for simultaneous recording from
different body parts (Eshner 1897)
displacement of flexion–extension tremors of the wrist and metacarpal phalangeal

joints (Ackmann et al. 1977). Over time, sensors have become more sophisticated, and
digital signal processing has significantly improved data processing and storage. As
documented in PubMed, accelerometers were first used for assessment of tremor in
1968 (Bard 1964; Randall and Stiles 1964). In the pre-digital-era, 3D vector measures
were processed electronically (Jankovic and Frost 1981). Today, it is possible to visual-
ize many physiological processes in real time and in slow motion, and we can use
complex instruments with sensors and effectors to provide real-time feedback about
neuromuscular processes. Even today, most of the techniques that researchers use to
evaluate movement disorders are based on devices that were modified from instru-
ments developed for other purposes; the main sources of innovative hardware are the
automotive industry, aerospace engineering, and robotics. Interestingly, home enter-
tainment products, including video game consoles and mobile phones with integrated
sensors, are beginning to be used to study movement disorders.
19.2 From Clinical Features of Tremor

to Quantifiable Parameters
The current clinical classification of tremors leaves room for the identification of
further subgroups, allows for changes in features due to aging or progression
of disease, and allows for more differentiated classification based on the application
of more sophisticated instrumental analysis. These modifications took place in
344 P.H. Kraus
recent decades (Deuschl and Elble 2000; Elble 2000; Köster et al. 2002). Therefore,
it is particularly advantageous to note specific observable features of the tremor
before taking measurements. This will help in standardizing definitions and differ-
entiating between different tremors, such as “action tremor” and “kinetic tremor”
(Deuschl et al. 1998; Kraus et al. 2006). This approach may even improve discrimi-
nation between tremors that have not been adequately defined, such as “intention
tremor” and “terminal kinetic tremor.” Although tremors have many common
features, it is a challenge to identify subtle differences between the subgroups to
better understand their pathophysiology and possible therapeutic options.
19.2.1 Clinical Standards and Updates on Tremor
Deuschl et al. in 1998 published the “Consensus Statement of the Movement Disorder
Society on Tremor” that is standard to this day containing many helpful details
(Deuschl et al. 1998). Independent postural tremor in Parkinson’s disease (PD) was
defined as the combination of tremor at rest plus postural tremor with a frequency of
more than 1.5 Hz higher than the tremor at rest. This tremor needs instrumental
support to discriminate it from re-emergent tremor (Jankovic et al. 1999). Hallett and
Deuschl (2010) presented a worth reading review with the critical title “Are We
Making Progress in the Understanding of Tremor in Parkinson’s Disease?” including
aspects of recent resetting experiments and findings of neuroimaging. Quinn et al.
(2011) have also frankly discussed “some controversial aspects” of tremor. This arti-
cle will hopefully improve the quality of tremor classification.
Recently, Elble and Deuschl published a very useful review entitled “Milestones
in tremor research” (Elble and Deuschl 2011). Like Quinn (Quinn et al. 2011), they
discuss the diagnostic challenge presented by patients who have a head tremor either
with or without hand tremor. This presentation might represent ET or tremulous
cervical dystonia (Elble and Deuschl 2011). Masuhr et al. (2000) have found that
the geste antagoniste (“sensory trick”) can significantly decrease tremor in patients
with tremulous cervical dystonia and dystonic head tremor, but not in patients with
essential head tremor. Thus, a reduction in head tremor with the use of a sensory
trick supports the diagnosis of tremulous dystonia (Masuhr et al. 2000). In addition,
an irregular, jerky, and often complex tremor pattern with abnormal posturing and
an amplitude that varies depending on head position also support a diagnosis of
dystonic head tremor (O’Sullivan and Lees 2000). Similar tricks with sensory feedback
even may work in (rare) cases of PD tremor (Lewitt and Gostkowski 2010).
The question of position-specific changes in tremor seems especially problematical
in patients with ET who experience intention tremors of the head in a certain position
(e.g., neck flexed forward) (Leegwater-Kim et al. 2006), considering the results
from Deuschl et al. (Deuschl and Elble 2000).
Further possible pitfalls: Extreme asymmetry of tremor and one-sided tremor
as well as tremor at rest, especially, may indicate PD. In contrast to the scientific
consensus, Louis et al. found that ET is often asymmetric at onset and that, ultimately,
the tremor usually becomes more severe on the nondominant side. This was true
even for two left-handed subjects with tremors that were more severe on the right
side (Louis et al. 1998b). In patients with PD, Louis et al. found action (posture and/
or kinetic) tremors in 93.4% of 197 patients, including 63 patients with re-emergent
tremor (Louis et al. 2001). Most of the 870 patients with PD had combined postural-
kinetic-resting tremor (“tremor triad”) in a study by Kraus et al. (2006). Cohen et al.
(2003) found that one in five patients with ET had resting tremor and Deuschl and
Elble (2000) found cerebellar signs in alternating movements in ET could be misin-
terpreted as bradykinesia (Duval et al. 2006).
19.2.2 Observable Features of Tremor
Observational information is important in determining where to place sensors on the

body, choosing interventions and interpreting results. It is helpful to document, at a
minimum, information about the tremor’s location (e.g., wrist, head, leg), axis, man-
ner of oscillation (flexion–extension or rotatory), and the conditions provoking the
oscillation (rest, posture, other action or specific tasks). Accompanying abnormalities
of muscle tone (dystonia, rigidity, spasticity, hypotonia) may not only change the
physical conditions but also suggest the correct diagnosis (Quinn et al. 2011).
Direct observation can usually capture the amplitude of the tremor; frequency
can be rated using raw categories. The tremor frequency is a useful feature when
looking at the extremes of all tremor frequencies. This makes it easier to correctly
diagnose very slow tremors (with frequencies usually less than 4.5 Hz) like Holmes’
tremor [defined as a unique tremor syndrome by consensus (Deuschl et al. 1998),
bringing together different earlier naming like “rubral tremor,” “midbrain tremor,”
“thalamic tremor,” “myorhythmia,” and “Benedikt’s syndrome” under a general
label (Deuschl et al. 1998)]. Titubation is another very low-frequency tremor (pos-
sibly as low as 3 Hz) that can produce large amplitudes depending on postural inner-
vation. Titubation probably results from pathology of the cerebellum or its afferent/
efferent pathways and affects usually proximal extremities, head and trunk. In con-
trast primary orthostatic tremor typically shows a very high frequency (13–18 Hz)
(Deuschl et al. 1998). The high-frequency orthostatic tremor is not visualized in
most patients, but in many instances, this tremor can be easily palpated as a muscular
vibration over the flexor and extensor muscles of the thighs (Bain 1993). Patients with
this tremor often complain of postural instability or dizziness (Karlberg et al. 2005).
All other tremors have overlapping frequency distributions, so frequency is not
helpful in diagnosing most kinds of tremors.
Trained personnel can also recognize fluctuations and irregularity of amplitude
as well as raw fluctuations in frequency. Nonobservable parameters include com-
plex properties of the time series that represent deviation from the sinus wave in
addition to linear forces and torques.
Pitfalls: what is tremor frequency? Spectral frequency of tremor is always a kind
of mean value during the analyzed interval (see Signal processing). In reality there
346 P.H. Kraus
Fig. 19.2 Short-time variability of tremor amplitude and frequency: uncommon action tremor in
a PD patient with a change of tremor about every 2 s. This type of rapid changes can only be
observed by analysis of short (moving) windows (e.g., length 1 s). Amplitude and frequency are
approximately related inversely
might be huge variation not only of amplitude but also of frequency, what itself could
be an interesting parameter to establish the variability of tremor intensity (Fig. 19.2).
19.2.3 Therapy Control and Diagnostic
The particular features of tremors that contribute to impairment are controversial (e.g.,
amplitude, frequency, energy). Bain et al. previously defined tremor impairment based
on the relative extent to which tremor is suppressed during functional tasks when
compared to the absolute amplitudes during posture or rest (coefficient of tremor sup-
pression) (Aziz and Bain 1996; Bain et al. 1993). An often forgotten component of
impairment caused by tremor is psychosocial burden (Lorenz et al. 2011), which is
different from functional degree of disability (Chen and Swope 2007).
Raethjen et al. (2004) pointed out the supplemental clinical diagnostic value of
accelerometry and/or electromyography (EMG) for all tremors, which has been sup-
ported by several other articles (Bain 1993; Deuschl 1999; Louis and Pullman 2001;
Louis et al. 1998b). For clinical diagnostic purposes, there are two main goals: (1)
early detection of pathological tremor (“pathological tremor” vs. “no pathological
tremor”) and (2) differential diagnosis (i.e., identifying a certain pathological tremor).
Therefore, it is necessary to have a standard for what is normal. Louis et al. [How
normal is “normal”? (Louis et al. 1998a)], Elble [changes of tremor frequency with
age (Elble 2000)], and Elble et al. [Electrophysiological transition from physiological
tremor to ET (Elble et al. 2005)] provide some insight into this topic.
In the context of Sects. 19.2.1–19.2.3, it is important that the subcommittee of
the American Academy of Neurology (Zesiewicz 2005) included accelerometric
results in their standards for judging the magnitude of the therapeutic effect of drugs
for ET in 2005. They recommended that the outcome measures used to assess
tremor should be standardized and correlated with clinical rating scales to better
determine the magnitude of the effect of pharmacological or surgical treatments
(Zesiewicz 2005). The following quote from Beuter et al. (1994) exemplifies the
criticism of this approach:
One of the difficulties in doing tremor analysis is that there has been little or no agreement
regarding a standard and appropriate way to measure tremor. For example, the variables exam-
ined have included position, velocity, acceleration, jerk, force, or electromyography, recorded
in different joints (finger, wrist, elbow, ankle, etc.), in different postures, at different frequen-
cies, for different durations, and with different instructions to the subjects (Beuter et al. 1994).
19.3 Standards of Quantitative Research
19.3.1 Technical
Most instrumental measurements produce ratio-scaled data. Measuring any physi-

cal property requires the use of calibrated transducers and, usually, additional
electronic devices, including preamplifiers and amplifiers. In the next step, data
sampling, the continuous streaming signal is digitized with the help of an analog–
digital converter (ADC) into a series of discrete values (the digital amplitude) at
repeated (usually constant) intervals of time. The number of samples per unit of
time is called the sampling rate. The level of amplification, the resolution of the
amplitude (e.g., 12 bit = 4,096 ADC increments), and the sampling rate must be
chosen according to particular demands. Because all measures are contaminated
with unavoidable errors and noise, it is helpful to use appropriate filtering.
Following the Nyquist–Shannon sampling theorem, the minimum sampling rate
to assess a tremor oscillation, the Nyquist frequency, is twice the frequency to be
measured. Because this procedure provides poor information about the main fre-
quency, with only two samples per full oscillation, oversampling with a sampling
rate that is many times greater than the Nyquist frequency is recommended. Even
more oversampling may be needed to answer special questions, as in the examina-
tion of harmonic frequencies, or for the correct identification of extreme values:
100 Hz (Mellone et al. 2011), for tremor analyses based on time domain character-
istics: 200 Hz (Edwards and Beuter 2000), or in combination with low-pass filtering
for noise reduction.
If the sampling rate is too low, so-called “aliasing” may produce (false) frequen-
cies lower than the Nyquist frequency from spectral parts actually lying above the
Nyquist frequency (Fig. 19.3).
348 P.H. Kraus
Fig. 19.3 Time series for

measured acceleration plus
calculated velocity and
position (top-down) from a
PD-tremor sequence of 1 s
and a frequency of 5.2 Hz:
deviations from sinusoidal
function are most evident in
the acceleration signal while
being hidden in the
displacement signal. Blue
dots represent sampling time
in case of 128 Hz sampling
rate and red dot in case of
12.8 Hz sampling rate.
Connecting the red dots only
demonstrates that this time
series, since sampled very
low, represent only few
information of the oscillation
19.3.2 Methodological
The main criteria of a test’s quality are objectivity, reliability, and validity. The
objectivity of measures is important in ensuring that measured results are indepen-
dent of the subjective assessment of an individual scientist. Accuracy [similar to
“validity”; nomenclatorial critics see (Streiner and Norman 2006)] is the degree of
conformity with the true value (constant). Responsiveness is the accuracy of the
measured change in a variable’s value. Low accuracy produces systematic errors.
Precision [similar to “reliability”; nomenclatorial critics see (Streiner and Norman
2006)] is the degree to which a series of repeated, individual measures of the same
state are similar. Lack of precision causes random errors.
19.4 Technical Solutions and Approaches
The following section is a review of the scientific literature and technical sources
(manuals) on techniques and applications, and we cannot claim that this section is
complete. Examples of the most important and interesting techniques for measure-
ment of tremors are presented. There might be unpublished results, existing follow-
up models or new developments that are not included. Moreover, some companies
may have different products of interest for future use in tremor assessment. We
recommend that readers contact the producers or specialist retailers directly if
interested.
Long-term surface EMG recordings are mentioned so that they can be compared
with newer kinematic sensor techniques. Applications of EMG for assessment of
tremor include the established techniques using flexor–extensor electrodes (Breit
et al. 2008; Spieker et al. 1997, 1998) and a new 44-channel wearable acquisition
system with electrode arrays (Pozzo et al. 2004). Breit et al. (2008) demonstrated
that, with linear discriminant analysis, the parameters “mean tremor frequency”,
“tremor occurrence”, and “standard deviation of the phase” are sufficient for an
almost complete separation between PD tremor and ET. All of those parameters can
also be assessed with modern kinematic sensor techniques alone.
19.4.1 Kinematics and Kinetics for Tremor Assessment
Definitions: Kinesiology (human kinetics) is the study of movement, performance,

and function using methods from biomechanics, anatomy, physiology, psychology,
and neuroscience. Kinematics and kinetics are both subdivisions of dynamics which
is a subdivision of mechanics (physical science).
350 P.H. Kraus
Table 19.1 Kinematics of tremor oscillation

Displacement = A sin (wt) Position/displacement (meters)
Velocity = A w cos(wt) Velocity (change of displacement per time interval,
meter per second)
Acceleration = −A w2 sin(wt) Acceleration (change of displacement per squared time
interval, meter per second2)
19.4.1.1 Kinematics of Tremor Oscillation
Kinematics describes the motion of objects and groups of objects without consider-
ing the forces that cause the motion. Therefore, for linear motion, the parameters of
kinematics include displacement (vector), distance (absolute value), velocity (vec-
tor), speed (absolute value), and acceleration (vector). For rotational movements,
the parameters are angular position, angular velocity, and angular acceleration. The
amplitude of an oscillation is the difference between two successive extreme values
(maximum and minimum); the number of oscillations per unit of time is the
frequency (Table 19.1).
To describe the position and orientation of physical bodies and their translational
and rotational movements in three-dimensional (3D) space, we need 6 degrees of
freedom (6DoF) with 3D translation movement (in three orthogonal planes, best
calculated in Cartesian coordinates) and 3D rotation (about three orthogonal axes of
rotation: roll-pitch-yaw, best calculated in polar coordinates).
19.4.1.2 Kinetics of Tremor Oscillation
In contrast to kinematics, kinetics is concerned with the effect of forces and torques
on the motion of bodies that have mass. A driven, or forced, oscillation is described
by a mathematical function of an inertial mass (the hand or arm, for example), a
restoring force, a damping drag force (friction), and elastic contributions (or stiff-
ness). If the driving is basically sinusoidal, deviations from sinus shape are usually
not easily visible as displacement, but are more clearly observed in acceleration (see
Fig. 19.3). Such deviation is represented by nonlinear terms in the equation and by
harmonic frequencies in the spectra.
Amplitudes of driven oscillations depend on forces and on difference between
frequency of driving oscillation and Eigen frequency (resonance) of the driven
oscillator, as well as damping.
Example of a kinetic measure: Forssberg et al. measured action tremor in PD
during object manipulation as function of the change in force per second (N/s) with
time (Forssberg et al. 2000). They used strain-gauge transducers to assess both
horizontal grip force and the vertical load force.
19.4.2 Instrumentation: Sensors and Techniques

for Tremor Assessment
19.4.2.1 Transducers and Techniques for Kinematic Measures
Accelerometers measure linear acceleration in m/s2. In the case of piezoelectric

accelerometers, the sensing system consists of a mass (also called the “seismic mass”
or “proof mass”) that is fixed to one side of a piezo-crystal. The crystal’s opposite side
is mounted to the base of the accelerometer, which is connected to the tremulous part
of the body. During tremor oscillation, the inertial force alternately pushes and pulls
the piezo-crystal, producing acceleration-dependent changes in the electrical charges
due to the piezo-effect. Piezo-resistive accelerometers use substances with an acceler-
ation-dependent change of electrical resistance. Complete fixed mounted 3D acceler-
ometers are available that measure acceleration along three orthogonal axes. MEMS
accelerometers are manufactured by lithography, so they are very small.
Most other accelerometers, such as capacitive accelerometers, have different trans-
duction methods, but their mechanics follow similar principles. Many other types of
accelerometers, such as Force-Balance-Servo-Accelerometers, are constructed for
quite different purposes and are generally used for seismic imaging or industrial con-
trol. Many are unsuitable for tremor assessment due to their large size.
Disadvantages: Accelerometers cannot be used for truly static accelerations or
accelerations occurring at low frequencies. The accelerometers have a transverse
sensitivity, which is the sensitivity of the accelerometer at 90° to the sensitive axis
of the sensor, producing an error of approximately 5%. Additionally, the amplitude
varies with the distance between the axis of rotation and the position of the
accelerometer.
Gravitational artifact (Elble 2003, 2005): Tremor is often simplified as a linear back-
and-forth oscillation. The most common tremor, the flexion–extension tremor of the
hand around the wrist axis, has a circular trajectory by approximation (see Fig. 19.4).
An accelerometer that is mounted vertically onto the back of the hand follows this
trajectory. Therefore, the absolute value of the acceleration that is caused by the tremor
is zero at the midpoint of the oscillation (where velocity is maximal) and it is maximal
at the upper and the lower turning points (where velocity is zero). For this tangential
accelerometer, the acceleration of gravity is measured to be 9.81 m/s2 when passing in
the horizontal direction. In other positions it is less than 9.81 m/s−2 in dependency
from the deflection independent in up and down position. This produces an artifact
due to gravity that oscillates with twice of the tremor’s frequency.
The centrifugal inertial oscillation measured by a radially oriented accelerometer
has twice the frequency of the sinusoidal tangential tremor oscillation. Therefore, in
both t-axis and r-axis, there is a purely mechanical component of double tremor
frequency that can be misinterpreted as neurogenic.
352 P.H. Kraus
Fig. 19.4 The accelerometer

sketch shows the topologic
and dynamic situation of
movements and forces
Example of use as long-term measure: Thielgen et al. used a set of four channels,
calibrated accelerometers to combine standardized tremor recording under defined
conditions, including posture and rest, with a 24 h recording of tremor with param-
eters for position and movement (Thielgen et al. 2004).
The CATSYS Tremor Pen® is an optional component of the CATSYS system
(see Catsys 2000 Manual, Danish Product Development Ltd., Snekkersten,
Denmark). The tremor [described as “subtle tremor at the fingertips” (Danish
Product and Development 2011)] is recorded using a two-axis micro-accelerometer
with a sampling rate of 31 samples per second with usual time interval for single
measures of 8.2 s. The system provides Fourier analysis for frequencies between
2 Hz and 15 Hz, as well as “tremor intensity” (root mean square of accelerations).
Analysis of the resting tremor, with the tremor pen inserted between the index and
middle fingers bordered by the thumb, as described by Papapetropoulos et al. (2010)
does not meet the typical resting conditions. Orsnes and Sorensen (1998) found a
good correlation between the clinical objective score, the peg board test and tremor
activity as measured with the accelerometer for kinetic tremor—but not for resting
tremor. The accelerometer measurements varied considerably in patients with the
same clinical grading of tremor (Orsnes and Sorensen 1998). The description how
the resting tremor was measured (Orsnes and Sorensen 1998) [following instruc-
tions from the manual (Danish Product Development 2011)]: “…the patient held the
tremor-pen like a pencil a couple of centimeter’s in front of the navel, with the arm
supported and bent 90° at the elbow joint…. ” is not that of a resting position of the
hand [for the basic CATSYS system see Després (Després et al. 2000)].
Gyroscopes measure rotation in angular degrees. Triaxial gyroscopes are avail-
able. Initially rotation was measured with the help of spinning wheels using the
principles of conservation of angular momentum. Since the 1980s, laser gyroscopes
began to replace their mechanical or electronic forebears. A few years ago, gyro-
scopes were much larger than accelerometers. However, modern gyroscopes are
only a few millimeters thick. MEMS gyroscopes are manufactured by lithography
and are comprised of micromechanically vibrating or resonant solid mini-components,
so they are very small. Three-axis (roll-pitch-yaw) MEMS-based gyroscopes are
also used in consumer electronic devices.
Advantages: Gyroscopic sensors are not sensitive to gravity.

Disadvantages: Gyroscopes are blind to linear translational movements.
The electromagnetic tracking device from FASTRAK™ (Polhemus, Vermont)
used by Spyers-Ashby et al. (Spyers-Ashby and Stokes 2000; Spyers-Ashby et al.
1999) measures position and displacement of three coils that are monitored within
an artificial magnetic field with a sampling rate of 120 Hz. This device is able to
detect movement over 6DoF. It was possible to distinguish between postural tremor
in normal subjects and in neurological patients (Spyers-Ashby et al. 1999).
Standard video (Television) in America and Japan is NTSC, with 30 frames per
second, most other countries use the PAL or SECAM standard with 25 frames per
second. HDTV as new standard uses 50 or 60 frames per second. Conventional cinema
technique is based on 24 frames per second. The number of frames per second is
equivalent to the sampling rate in conventional data acquisition. In terms of kinematics,
a 100-m sprint in 10 s is represented by only 250 video frames (in PAL) with a mean
distance of 0.4 m covered per frame. In the case of a tremor with a frequency of 10 Hz
and 25 frames per second, the resulting number of measurements per full oscillation is
only 2.5 pictures. This is not enough to visualize the details of the oscillation.
A video quality of 25 or 30 fps has only limited resolution for video-rating or
objective analysis. The situation is different for very slow tremors or for high-speed
video techniques (see also “sampling-theorem” under Sect. 19.3.1). Nevertheless, it
is not only possible to determine the amplitude and frequency of a tremor from
video sequences, but Uhrikova et al. (2009, 2010, 2011) demonstrated an automatic
tremor frequency analysis (TremAn-tool) from video sequences with a duration of
at least 5 s that yields results comparable to accelerometry or electromyography
after validation (Uhrikova et al. 2011).
Comment: With higher speed and shorter exposure, this type of assessment seems
promising.
With infrared videometry with reflecting or active markers (e.g., Qualisys,
Gothenburg, Sweden), position is measured in 3D. According to the model and set-
ting, different maximum samples per second are obtained between 120 and 1,000 Hz.
The maximum number of cameras is 32, and the maximum number of markers is
150 at 60 Hz (or 250 LEDs). Markers reflect the infrared flash that is received by the
cameras. Markers are located using the information from the cameras, and the 3D
position is calculated using all of the information. Deuschl and Elble (2000)
confirmed the manufacturer’s specification of 4.0 mm for spatial accuracy, which
may vary with different settings, such as marker size and distance. The technique
(MacReflex®, Qualisys) was used by Deuschl et al. (Deuschl and Elble 2000) with
a four-camera system and a sampling frequency of 50 Hz in combination with an
accelerometer to differentiate ET with cerebellar dysfunction from ET without
cerebellar dysfunction. The authors reported that, during their kinematic analysis,
approximately 10% of the trials had to be excluded because the markers were
354 P.H. Kraus
obscured (Deuschl and Elble 2000). Furthermore, Fasano et al. (2010) analyzed gait
and postural sway in ET patients using a treadmill and six cameras at 240 Hz.
Kraus and Hoffmann (2010) used infrared videometry (MacReflex®, Qualisys,
three-camera system, 240 Hz sampling) as a reference technique for development of
spiralometry.
Alternatives include Vicon motion systems, USA and UK
Comment: Videometry is ideal for assessment of complex motor tasks with many
marked spots, though its resolution is too low for analysis of physiological tremor.
Ultrasound (e.g., Zebris, Germany): Budzianowska and Honczarenko
(Budzianowska and Honczarenko 2008) examined resting tremor in 95 PD patients
with the CMS 10 from Zebris before and 1–2 h after taking levodopa. This ultra-
sound-based motion analyzer system allows for the parallel use of up to six active
markers with ultrasound signals at 40 kHz. Ultrasound pulses are recorded by spa-
tially arranged ultrasound microphones. For tremor assessment, a wired setting is
used with the digital exposure in real time. Tremor parameters (Budzianowska and
Honczarenko 2008) are frequency (Hz), angular amplitude (degrees), angular
velocity (degrees/ms), and angular acceleration (degrees/ms2).
Spiral drawing has a long tradition as examination of kinetic tremor and is
recommended by the Movement Disorder Society (Deuschl et al. 1998). Many
reports evaluate drawn spirals with visual rating, with some including additional
manual measures (Bajaj et al. 2011).
There are also a number of instrumental approaches for analysis of spiral drawing
such as digitizing tablets (Eichhorn et al. 1996; Elble et al. 1990, 1996; Pullman
1998) or electromyography (Elble et al. 1996; Milanov 2001). Both procedures pro-
vide amplitudes (usually x- and y-position as a time series, which allows for the evalu-
ation of frequencies). They also provide the chronological order of the measures,
which is important for the correction of possible errors. Some of the digitizing tablets
also provide the pressure of the pen on the tablet as additional virtual axis (Saunders-
Pullman et al. 2008). The use of digitizing tablets is common in early PD (Saunders-
Pullman et al. 2008), and for clinical trials of ET (Haubenberger et al. 2011). Details
about technical specifications and test settings are rare. Almeida et al. investigated
age-related changes in physiological kinetic tremor (Almeida et al. 2010). The patients
were instructed to draw at a “natural speed” spirals that were digitized to 64 Hz
through a digitizing tablet with a resolution of 120 lines/mm (Almeida et al. 2010).
Only a few methods focus on the evaluation of tremor from spiral drawings as a
pure paper-and-pencil test by digitizing the complete drawing with a scanner. In this
approach, any information about time and frequency is lost. Kraus and Hoffman
developed a fully automated, computerized evaluation of pixel coordinate-based
data (spiralometry) (Kraus and Hoffmann 2010) and used the original 32 spirals
from the handbook from Bain and Findley (1993) for cross-validation. This spiral-
ometry technique with an interpolation process, the moving window technique, is
based on the drawn spiral line and therefore does not require a preprinted line or
center detection (Wang et al. 2008). A simplifying intermediate step for evaluation
is the transposition from Cartesian to polar coordinates. The whole process, from
scanning a drawing to receiving the tremor-amplitude results, takes less than 30 s

per spiral. Using unique barcodes on the forms, this technique is suitable for large
numbers of patients and telemedical studies using fax transmission (see Fig. 19.5).
Miralles et al. (2006) also developed a technique to analyze paper-and-pencil
drawings, which requires preprinted spirals and manual intervention in the case of
drawing errors.
In both the tablet and the paper tests, the tremor is visible only while it is orthog-
onal to the direction in which the patient is drawing. The tremor cannot be observed
when the oscillation is parallel with the direction of drawing. For example, a
flexion–extension tremor of the right hand appears only in the right upper and left
lower quadrants of the drawing.
Possible pitfalls: Spontaneous spiral drawings from patients with PD with hypokinesia
will typically be very small. If the amplitude of the tremor approximates the diameter
of the spiral, the drawing will be difficult to distinguish from the tremor. If a patient
chooses to draw spirals very rapidly, the turns per second and the tremor frequency
become too similar and produce a poor resolution. At the same time, rapid drawing
and/or drawing only a few spirals reduces the length of the line and the time taken to
complete the drawing, which then decreases the number of tremor oscillations.
Therefore, the best instructions restrict speed and maximize the length of the line.
Laser-based systems for tremor recording work as distance transducer or velocity
transducer, as used by Beuter et al. (1994). They tested two lasers with different
specifications for resting tremor and action tremor (postural/kinetic) and compared
the results with those from an accelerometer (Beuter et al. 1994). The technique
works with an optical triangulation range measurement based on the reflection of a
white paper fixed to the fingernail. Norman et al. (1999) used two different lasers for
transducing velocity and displacement in addition to an accelerometer and surface
EMG. A high-resolution laser-displacement sensor technique was used by Duval
et al. (2004) for analysis of physiological tremor during slow alternating movements
in elderly adults (Duval et al. 2004) and for measuring the physiological index finger
tremor with the laser-displacement sensor simultaneously with a miniature acceler-
ometer under the loading condition (Duval and Jones 2005).
Comment: This is an interesting technique, but it seems to be restricted to a small
number of parallel measures (channels) that are dependent on configuration and
require restriction of the patient’s mobility. There is no information concerning its
use for higher amplitude tremors or for larger movements.
Human interface devices (HID), such as keyboards, mouses, trackballs, touch-
pads, pointing sticks, joysticks, gamepads, digitizing tablets, and touchscreens, are
interesting devices for tremor assessment. Liu et al. (1997) analyzed wrist action
and (comment: kinetic) tremor with a low-resistance handheld joystick during a
visually guided wrist-tracking task in patients with MS. The amplitude of the kinetic
tremor in these patients was significantly reduced with elimination of visual cues
(“target off” and “cursor off”) (Liu et al. 1997). Liu et al. (1999) found with the
same technique that neither tremor frequency nor amplitude was significantly
affected by eliminating visual feedback in patients with PD.
Fig. 19.5 (a) Spiral drawing by a PD patient with moderate action tremor of the right hand (Cartesian
coordinates). The gray line shows the best-fit spiral curve following the deviations from an ideal
mathematical spiral leaving the shorter tremor oscillations. (b) The identical information as above in
polar coordinates. Long ranging movements represent the deviation from Archimedean spiral; tremor
signal is stretched between the two arrows for didactical reasons (Comment: tremor amplitude of this
drawing = 5.8 mm in original scaling). Arrowheads mark the identical position on (a) and (b)
Locating systems measure distances using UWB radar (Ultra-wide-band-

Radar = “through wall radar”) or special techniques with RFID (Radio-frequency
identification) or positional coordinates (GPS = Global Positioning System). All of
these techniques were initially developed for slower, larger signals and for lower
sampling rates and lower amplitudes.
In contrast to Radar systems as used earlier for quantification of involuntary
movements in Huntington’s disease [as “Doppler effect” (Buruma et al. 1982; Kemp
et al. 1982; Roos et al. 1982), with “distinct wavelength”: “microwave” (Pratley
et al. 2000)], UWB radar employs electromagnetic pulses and short wave-packets
(Staderini 2001, 2002). Blumrosen et al. (2010) used this technique to measure the
mimicked tremor of a mechanical arm model. Although their noncontact method
looks promising, the effort required for measuring tremor seems too great.
Potentiometers were among the first tools that were used to assess motion and
tremor (Ackmann et al. 1977). In 1999, Matsumoto et al. used a “mechanical link-
age system” with three precision potentiometers placed orthogonally to sense the
rotation of lightweight aluminum lever arms for 3D measurement of ET (amplitude:
displacement) (Matsumoto et al. 1999). Comment: Single-item production.
19.4.2.2 Sensors or Transducers for Kinetic Measures
Strain gauges are dependent on construction specifications, force transducers, or

goniometers. Electro-goniometers are flexible angular sensors that lack elements
for measuring force. They only measure changes in angles (in degrees) (Legnani
et al. 2000). Tuttle et al. (1951) used a strain gauge with four stretched wires as
resistance elements to record neuromuscular tremor in an early tremor assessment.
McAuley et al. (1997) analyzed physiological tremor with an accelerometer and
surface EMG under voluntary abduction of the index finger against an elastic band
(stiffness approximately 30 N/m) that was connected to a strain gauge to register the
force of contraction. Force transducers such as dynamometers or load cells for lin-
ear or even torsional force measurement (also called torsiometers) may embody
more than one specially configured strain gauge (Legnani et al. 2000). The strain
gauges are not easy to use due to the difficulty of calibrating them. It is possible to
measure tremor amplitude as a change in force (Rozman et al. 2007), which may be
helpful in answering certain kinetic questions.
Posturography is infrequently used as a tool to extract orthostatic tremor’s
frequency from posturographic recordings (Karlberg et al. 2005).
19.4.2.3 Combined Sensors and Actigraphs
Combined sensors and actigraphs mainly measure nonspecific activity. They may
contain different and multiple sensors or transducers.
The Activity classifier (AC) (Xsens, Enschede, The Netherlands) was used by
Zwartjes et al. (2010) to measure motor activity in patients with PD using four
358 P.H. Kraus
“MT9 inertial sensors” that were placed on the trunk, wrist, thigh, and foot of the
more affected side (50-Hz sample frequency). Each of these four MEMS provides
3D acceleration, 3D rate of turn (gyroscope), and 3D earth-magnetic field data. This
promising technique combines several algorithms to differentiate between lying,
sitting, and standing and standing up and uses these results to classify tremors of the
arms and legs as resting, postural or kinetic tremors.
The ASUR (Autonomous Sensing Unit Recorder), as used by Salarian et al.
(2007), is a 2D gyroscope system that is combined with an integrated data-logger to
measure PD-associated tremor and bradykinesia simultaneously, along with long-
term measures using a sampling rate of 200 Hz and recording for up to 14 h.
Van Someren et al. (2006) used the wireless Actiwatch (Cambridge
Neurotechnology, Cambridge, UK) for a multivariate discrimination method to dis-
criminate tremor from voluntary movements in long-term tremor recordings (van
Someren et al. 2006) using a sampling rate of 64 Hz and 8-bit resolution covering
−5 g to +5 g. Binder et al. (2009) used the same equipment and algorithm with iden-
tical parameters (van Someren et al. 2006) in a study of tremor with cabergoline.
The Actiwatch is one element of the At-Home Testing Device that may yield an
objective measure of motor impairment in early PD (Goetz et al. 2009).
The basic Kinesia™ motor assessment System (Great Lakes NeuroTechnologies,
former CleveMed, Cleveland) is a portable, wireless device integrating triaxial
accelerometers and gyroscopes to assess tremor. The system is worn on the wrist
and measures 3D motion with 6DoF using three orthogonal accelerometers and
three orthogonal gyroscopes located in the sensor module, which wirelessly
transmits data to a computer (radio link) (Giuffrida et al. 2009; Mostile et al.
2010). Furthermore, the system provides two channels of electromyography
(EMG). One practical setting uses an additional 6DoF sensor unit worn on the
finger. Data from the sensors are analyzed within the software to automatically
calculate a tremor score. Mostile et al. (2010) cross-validated TETRAS ratings
(Elble et al. 2008) and Kinesia™ measures. Access on raw data seems to be
possible.
Hoff et al. (2001) examined tremor in PD under ambulatory conditions using
CAMCA (continuous ambulatory multichannel accelerometry) for 24-h recordings
of tremor. In this system, three piezo-resistive uniaxial accelerometers (range ± 5 g;
frequency response 0–500 Hz) were oriented perpendicularly. The sampling fre-
quency was 128 Hz, and the data were stored on a portable multichannel recorder.
The accelerometer data were processed offline, and the unit was attached to the
dorsal surface of the wrist most affected by the tremor.
The SHIMMER device (Real-time Technologies, Dublin, Ireland) contains
tri-axial accelerometers and tri-axial gyroscopes to measure the rotational velocity.
It was used for continuous at-home monitoring of tremor over a 9-h period in PD
patients (El-Gohary et al. 2010). Real-time Technologies offers development kits
with different sets of sensors that can be used for different purposes.
Mobile phones: Two research teams have used the accelerometers within the
iPhone (Apple, Cupertino, USA) to measure tremor (Joundi et al. 2011) and were
even able to accomplish wireless data transfer (Lemoyne et al. 2010).
19.4.2.4 Indirect Unspecific Measures of Tremor
There are batteries of tests that allow indirect estimation of tremor by assessing
performance or deficits in patients with PD.
A number of tests can help to assess motor impairment caused by tremor without
directly measuring the tremor. For example, the TEMPA (test évaluant la perfor-
mance des membres supérieurs des personnes âgées) is designed to assess the dis-
ability caused by tremor (Heroux et al. 2006; Norman et al. 2011). The performance
of most motor tasks, including aiming, tapping, tracking, and using a pegboard, is
usually impaired by action tremors in a nonspecific way. The MLS (Motor perfor-
mance test after Schoppe) was developed by Schoppe (1974), based on the results
published by Fleishman (1954). The test battery consists of several subtests: tap-
ping, using a pegboard, aiming, line tracing, and steadiness. The steadiness subtest
utilizes eight holes of different sizes. The patient must hold a stylus in a hole for a
certain amount of time, avoiding contact with the wall of the hole. Normative data
have been published by Kraus et al. (2000), including age variations. Ringendahl
has also published results, including the factor structure, normative data, and test–
retest reliability in patients with PD. Auff et al. (1991) used the MLS to compare
functional disability and subjective impairment in patients with ET. The Kløve-
Matthews Static Steadiness Test is composed of a stylus-and-hole apparatus, includ-
ing the Nine Hole Steadiness Tester and the Groove Type Steadiness Tester. The
task is similar to that of the MLS steadiness test: the patient attempts to hold the
stylus for 15 s in nine successively smaller holes without touching the sides. Bast-
Pettersen et al. compared the Kløve-Matthews static steadiness test with the DPD-
TREMOR test (accelerometric tremor test, Danish Product Development)
(Bast-Pettersen and Ellingsen 2005). Louis et al. used a modified version for
measuring tremor and found this test battery to be a reliable and valid measure of
tremor severity. Their finding that this test quantifies motor steadiness rather than
tremor frequency and tremor amplitude is important (Louis et al. 2002).
19.4.2.5 Fundamental Differences Between Different Techniques
In contrast to most classical electrophysiological techniques, such as EMG, evoked

potentials and nerve conduction, passive kinematic sensors do not transfer energy to
the patient or have direct contact with electricity.
The main advantage of measuring acceleration rather than displacement is its
simplicity as kinematic assessment (Morgan et al. 1975). Furthermore, the inte-
gration of acceleration to velocity is mathematically less problematic than the
differentiation of displacement or velocity due to noise amplification during dif-
ferentiation—while integration always provides advantageous noise attenuation
(Ovaska 1999). Nevertheless, an appropriate filtering of slow signal shifts or
constant onset will be necessary.
For marker-based techniques, like some of the infrared videometries and the
ultrasound systems all markers share the maximum sampling frequency of the system.
360 P.H. Kraus
For example, the CMS 10 system, with a maximum sampling frequency of 200 Hz
with five markers, results in a sampling frequency of 40 Hz per channel.
Gyroscopes have the advantage to directly providing joint rotational speed without
the limitations of traditional tremor recording with accelerometers. Accelerometers’
signals are sensitive to rotation in gravity (gravitational artifact, see Sect. 19.4.2.1),
whereas gyroscopes are not sensitive to acceleration (including gravity). Signal drift
(e.g., due to temperature) may be a problem for both accelerometers and gyroscopes,
but some sensors are constructed with electronic drift compensation.
While kinematic and kinetic sensors provide results in units of time and displace-
ment, long-term EMG tremor assessment results are usually reported as “tremor-
occurrence rates.”
Comment: A combination of gyroscopes and accelerometers up to 6DoF provides a
more accurate measurement of overall movement and spatial location and will be
the most promising procedure for scientific research and clinical applications. A
fundamental advantage of the 6DoF combination is the control of gravitational
artifacts.
19.4.3 The Use of Quantification in Combined and Complex Settings
19.4.3.1 Accelerometry and EMG
Lakie and Combes (2000) were unable to find a temporal relationship between the
initiation of rapid reactive hand movements and the phase of enhanced physiologi-
cal tremor using a temporal comparison of averaged accelerometric measures and
rectified surface EMG data. They used a signal averager with 25 sweeps and a
recording epoch of 2.0 s, with a time lag of 1.0 s before the trigger. The sampling
rate was 1,000 Hz, EMG signals were bandpass filtered (2–300 Hz), and the tremor
signal was low-pass filtered with a 40 Hz cutoff frequency.
19.4.3.2 Physiological Approaches: Peripheral Influences on Tremor
Usually measures of the effect of stimuli on tremors (such as mass loading or phase
resetting) are obtained by EMG. However, if pure mechanical components are of
interest, a combined EMG and kinematic measure is essential. In a pure mechanical
tremor there is a tremor peak in the acceleration trace, but the EMG does not show
this peak (Hallett 1998). Because mechanical reflex tremors reduce their frequency
under loading with increasing inertia, it is possible to separate such tremors from
those that are produced by a central oscillator (Hallett 1998). Since Findley (1996),
peripheral inputs such as mechanical wrist perturbations or median nerve shocks
have been shown to have a number of methodological problems that have led to
conflicting results and interpretations. These techniques appear to have little
discriminatory power and are not useful for classification purposes (Findley 1996).
19.4.4 Examples of Use for Kinematic Studies
19.4.4.1 Interference of Tremor and Voluntary Action
Measuring Bradykinesia
Tremor may be an important disturbance in the instrumental analyses of other symptoms

of PD, such as bradykinesia. In this case, the tremor must be eliminated by lowpass filters
(fc = 5 Hz) with automated tremor discrimination (Jun et al. 2011; Kim et al. 2011).
Possible pitfalls: There may be individual interference between a tremor and rapid alter-
nating movements, sometimes leading to dys- or even brady-diadochokinesia. PD patients
sometimes show a disturbance of voluntary rhythm generation. This “hastening phenom-
enon” (Nagasaki et al. 1978; Nakamura et al. 1978) is characterized by a tendency to
increase the speed of voluntary oscillatory movements towards the faster frequency of the
tremor [like a kind of “attractor” (Logigian et al. 1991)], which, e.g., makes tapping an
unusable parameter for speed. In addition, multiple contacts from the tremor can distort
tapping results as measured with the tapping subtest of the MLS (Schoppe 1974).
Ballistic Wrist Movements in Patients with ET
Britton et al. (1994) examined ballistic wrist movements in patients with ET and
healthy controls with the help of a potentiometer and evaluated muscular activity
with rectified EMG. In contrast to the triphasic agonist–antagonist pattern observed
in healthy controls, patients with ET showed a strong association between the tim-
ing of the second agonist and the tremor period (Britton et al. 1994).
Inter- and Intra-Limb Coordination in Physiological Arm Tremor
Morrison and Newell (1996) used eight uniaxial accelerometers positioned on both
upper limbs of healthy subjects to analyze inter- and intra-limb coordination in
physiological arm tremor during a pointing task with normal and obscured vision.
They found no linkage between the arms in either the time or frequency domain
(Morrison and Newell 1996).
Comment: Under the assumption of a simplified wrist tremor model as a spherical
movement around the wrist joint, a two-axial accelerometer may be sufficient in
cases of low-amplitude tremors, where rotation of the accelerometers in gravita-
tional field can be neglected.
Parkinsonian Action Tremor’s Contribution to Muscle Weakness in PD
Brown et al. (1997), using the same technique as Corcos et al. (1996), found
incompletely fused muscle contractions due to tremor synchronization, which they
interpreted as an important factor contributing to the weakness present in PD patients
362 P.H. Kraus
while being off medication. Force was measured with a strain gauge and then
converted to torque (action torque of extension). The force of contraction was mea-
sured by a strain gauge and could be preset by altering the tension on the elastic
band (McAuley et al. 2001). Tremor was also measured using rectified EMG (Brown
et al. 1997). McAuley et al. (2001) also analyzed strength in small hand muscle
using a strain gauge for measuring force in combination and a miniature piezo-
resistive accelerometer to record the tremor of the index finger. Using surface EMG
of the adducting palmar interosseous muscles, they were clearly able to demonstrate
marked small hand muscle weakness that improved with levodopa. In addition, they
found that normal Piper frequency (about 40 Hz) components of tremor and EMG
oscillations were lost in PD patients without medication (McAuley et al. 2001).
Treating Intention Tremor by Weighting the Affected Limb
Hewer et al. (1972) showed a beneficial effect of applying weight to a limb with an
intention tremor using ratings and spiral drawing, including the “Gibson Spiral
Maze test” (Gibson 1964, 1969). A subgroup of 18 patients was examined using a
photographic method; a small light source was strapped to the index finger that was
used to trace the path of the movement during a 10-s exposure.
Kinetic Tremor Prolongs Reaction Times in PD
In a parallel measure of force and EMG, Staude et al. (1995) analyzed the entrain-
ment of voluntary movement by tremor. Tremor seems to affect reaction time in
proportion to the tremor period. Initiation of voluntary movement may be delayed
by up to half the length of the tremor period. Elble et al. (1994) also suggested this
amount of time as an average period of prolongation.
Tremor Assessments to Improve Everyday Live Conditions
In occupational medicine, techniques are under development to improve the user-

friendliness of modern multi-touch interfaces for patients with tremors (e.g., to
improve recognition of a tremor-patient’s swabbing movements) (Wacharamanotham
et al. 2011). There has been a similar approach to modifying manual control devices
for patients with tremors by selecting suitable interface characteristics that improve
control and accuracy (Riley and Rosen 1987). Riley et al. used a force-sensing
joystick with two axes and reported that the parameters of this tool needed very
individual adaption for different patients (Riley and Rosen 1987).
Comment: These studies and similar tremor analyses could contribute valuable
information to understanding individual strategies for reducing tremors.
19.4.5 Modern Class of Instrumentation with Complex

Multi-sensor Measures and functional Outputs
Devices are available to analyze EMG, EEG, kinematic and kinetic measures partly
in real-time, and in some cases, using these myoelectric signals in combination
with a haptic interface, to produce mechanical and/or electrical feedback (Grimaldi
et al. 2008a, b). Some of those methods are based on exoskeletons or wearable
technologies.
“Sensor fusion approach” allows the combination of information from various
sensors [electroencephalography (EEG), electromyography (EMG), and inertial
sensors (IMUs)].
19.5 Planning an Appropriate Technical Test Setting
The test must provide reliable measures of tremor amplitudes. Neither the results
nor patient well-being should be affected by the procedure.
The protocol should use established nomenclature and international units and
include detailed information on instrument settings. Technical equipment
specifications and adequate test settings will usually be dependent on the scientific
questions being addressed. Different questions concerning storage and transfer of
data may arise depending on whether the measure is a short- or long-term assess-
ment (e.g., over 24 h). In addition, decisions may be influenced by multiple condi-
tions, including the examination site (laboratory, hospital, or patient’s home),
personnel resources and staff competence (e.g., medical experts, ancillary staff,
patient self-assessment).
For support of selecting equipment for tremor assessment and technical informa-
tion, see details under Sect. 19.4. It is always helpful to have access on raw data and
to know all changes of data material when working with predefined modes (e.g.,
automated filtering, etc.).
19.5.1 Special Cases and Aspects
Very small tremor amplitudes may require more sensitive recording devices (Findley
1996). Alternatively, approximation with a simplified spherical rotatory model that
neglects longitudinal direction (no tremor in the direction of the arm axes) is
sufficient. With small amplitudes this model allows reliable measures with use of
one or two axis sensors [e.g., those used by Salarian et al. with two-dimensional
configuration of gyroscopes in case of physiological tremor (Salarian et al. 2007)].
Measuring fast processes (e.g., harmonics and frequencies) necessitates
oversampling (see Nyquist-Shannon, Sect. 19.3.1).
364 P.H. Kraus
Sensor placement seems obvious, but precisely defining a reproducible position

is important because alterations in lever arm length or sensor orientation can produce
inter-test errors of 10% or more. Furthermore, accelerometer mounting affects the
frequency response; the mounted natural frequency is directly dependent on the
stiffness of the mounting, including the skin motion artifact (elasticity of skin and
subcutaneous fatty tissue). Additional noise may come from stiff or loosely hanging
cables. Velcro®, double-sided adhesive tapes or special patches, should be used to
fix the sensor to the body.
Tip: To have standardized conditions for tremor assessment, it is helpful to ask
the subject to complete stressful tasks, such as mental arithmetic.
19.6 Concluding Considerations and Emerging Techniques
The history of tremor assessment clearly shows that “reality mining” (Pentland
et al. 2009) helps to expedite the application of these new techniques to obtain
practical medical results.
The progression of MEMS technology has greatly advanced sensor accessibility,
and sensors are now becoming commonplace in everyday life. In parallel, the power
of kinesiology (human kinetics) is rapidly progressing. A broad range of promising
techniques now exist for kinetic and kinematic assessment of motor impairment and
motor performance (see Fig. 19.6).
One of the numerous advantages of miniaturization of sensors is the improve-
ment of spatial sensor integration; another benefit is the reduced inconvenience
during utilization.
For future field of application, simple, cost-effective methods and highly sophis-
ticated techniques are both required. The former are useful during screening and
tele-medical home tests, while the latter are necessary to answer precise scientific
questions. To this point, practical considerations, such as telemedical examinations
of tremor (Barroso et al. 2011) and PD (Goetz et al. 2009), in the literature have
only been discussed sparsely. Considering increasing life expectancy, the use of
sensors under special conditions, such as assisted living (therapy control) and vir-
tual environments using, e.g., data gloves (therapy or diagnostics), seems to be very
promising for questions of improved monitoring. An increasing number of wearable
solutions for controlling tremor and other PD symptoms have been developed for
use in assisted living environments. Some of these devices even include internet
connectivity (Chen et al. 2011; Cole et al. 2010; Patel et al. 2009; Pozzo et al. 2004;
Yang and Hsu 2009, 2010), but not all devices can be used for tremor assessment.
Innovative devices will require sophisticated sensor solutions with multiple
detection system types (e.g., “hybrid sensors”). Existing or projected approaches
demonstrate that electrophysiological signal assessments (central nervous system
activity and neuromuscular activity) will remain essential, especially for techniques
using real-time feedback. Kinetic and even kinematic measures will also be advan-
tageous components of a multi-sensor orchestra.
Fig. 19.6 Latest sensors

based on MEMS are very
small. The picture shows
three-axis gyroscopes as
positioned on quarter Dollars
(4 × 4 × 0.9 mm, MPU-3000,
InvenSense, Sunnyvale,
USA)
From the realization of the idea of artificial peripheral real-time closed loops, as
implemented in the wristalyzer (Grimaldi and Manto 2010; Manto et al. 2010) and
the results of Popovic Maneski et al. (2011) with asynchronous activation, interest-
ing and important results on tremors’ pathomechanism can be expected, exceeding
the establishment of an innovative therapy.
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Chapter 20
Signal Processing
James McNames
Keywords Signal processing • Power spectral density • Fast Fourier Transform

• Autocorrelation • Windowing • Coherence
20.1 Introduction
As summarized in the previous chapter, many instruments have been developed to

measure tremor using a variety of technologies. These instruments include accelerom-
eters, gyroscopes, magnetometers, audio, video, tablets, lasers, motion capture systems,
electromyograms, electromagnetic systems, microelectrode recordings, local field
potentials, and many others. Each of these instruments produces one or more continu-
ous signals that are obtained from one or more points in or on the body. No instrument
has become accepted as a gold standard for quantifying tremor. All instruments have
some disadvantages, and new instruments are continuing to be developed.
Signal processing algorithms for tremor are usually applied in sequential stages
of processing. The initial stages of processing are usually specific to the instrument.
For example, signal processing of accelerometer signals sometimes includes a pro-
cessing stage to reduce the effects of gravity, which can otherwise cause rotational
oscillations to appear as large accelerations (Elble 2005; Mamorita et al. 2009;
Veltink et al. 1303). Electromyograms are typically rectified and demodulated
(Journée et al. 1983). Action potentials are extracted from microelectrode record-
ings and converted into spike trains (Kim and McNames 2007; Wilson and Emerson
2002). Motion capture systems based on markers often contain periods of occlusion
that require some form of interpolation (Das et al. 2011).
In advanced applications, further processing may be applied after extraction of the
relevant signal metrics to perform a diagnosis or to combine multiple measurements,
J. McNames (*)
Portland State University, 1900 SW Fourth Avenue, Portland, OR 97201, USA
e-mail: mcnames@pdx.edu
372 J. McNames
possibly from multiple tasks and instruments, into overall scores similar to those
provided by clinical rating scales (Heldman et al. 2011). These integration methods
are typically well-known statistical methods for classification or regression.
The chapter focuses on spectral analysis of tremor signals. These methods can be
used to process one or more signals obtained from one or multiple instruments.
However, these methods cannot be applied to instruments that only provide
intermittent information such as electronic pegboards and tests that use buttons,
since these instruments do not provide continuous signals (Synnott et al. 2011).
We assume the signals have been sampled at a known sample rate (fs) with an
appropriate anti-alias filter applied prior to sampling. Anti-alias filters are analog
low-pass filters that prevent high-frequency signals from appearing as lower-frequency
signals after sampling. An overview of recent and emerging signal processing
methods for tremor can be found in Grimaldi and Manto (2010).
20.2 Power Spectral Density Estimation
Most signal processing algorithms are either for the purpose of signal analysis,
which usually provide insights through a visual display, or for the purpose of extract-
ing metrics from the signal for a specific application, such as the estimation of
tremor amplitude. Power spectral density (PSD) estimation is the most common
type of analysis employed for tremor signals.
20.2.1 Statistical Preliminaries
Most signal processing algorithms are developed within a statistical framework.

This enables us to define and estimate important properties, such as confidence inter-
vals that enable us to interpret our results. However, a statistical framework requires
some assumptions and an understanding of the fundamentals of random signals. This
section briefly summarizes some of the important fundamentals and ideas about prop-
erties of random signals and statistical estimators. This framework and these ideas are
discussed in much greater detail elsewhere (Manolakis et al. 2005; Priestley 1981).
Within this framework, each signal is treated as a sequence of random numbers
with some type of statistical relationship. Because the signal values are random, our
interest and characterization of the signals focuses on statistical properties of the
signal that are assumed to be static.
The statistical framework usually rests on two key assumptions. First, we assume
that the signal is stationary, which means the statistical properties of the signal do
not change over time. In most cases, we only need to assume that the signal is wide
sense stationary, which means that the mean,
E [x(n)] = E éë x (n + m )ùû , (20.1)

20 Signal Processing 373
and autocorrelation,
éë x (n + )x(n)ùû = éë x (n + + m )x (n + m )ùû = r ( ), (20.2)
do not change with time. Here E[⋅] is used to denote the expectation,
¥
E[ x ] = ò xp( x ) dx, (20.3)
-¥
where p(x) is the probability density function of the random variable x. The expecta-
tion can be thought of as a statistical average over the ensemble of possible values.
If a signal is wide sense stationarity, then the variance,
E[ x(n)] = s 2x (20.4)
is also constant.
Our second assumption is called erogodicty. This means that if the signal
were recorded many times under similar circumstances that the statistical prop-
erties would not change from recording to recording, and that the properties
obtained from averages over time would converge to the statistical averages, or
expected values. For example, if a signal is ergodic, the time average converges
to the statistical mean,
N
1
lim
N ®¥ 2 N + 1
å x(n) = E [ x(n)].
n= - N
(20.5)
Signal processing uses a finite recording of N samples, {x(n)}nN=-01 and estimates

some of the statistical properties. Because our estimate is calculated from a random
signal, the estimate itself will be a random variable. For example, let us define the
true tremor amplitude as a. Our estimate of the amplitude, â, will be some function
of the recording
â = f éë{x(n)}nN=-01 ùû . (20.6)
The bias of this estimate is defined as

ˆ = a - E[a]
b(a) ˆ (20.7)
and the variance is defined as

2
ˆ = E é(aˆ - E[a]
s 2 (a) ˆ ) ù. (20.8)
ë û
Ideally, we would like our estimate to be unbiased, b(a) ˆ = 0 , and have as little
variance as possible. In practice, it is difficult to find an estimator with these
properties, and the algorithm designer usually must make decisions that involve
a trade-off between bias and variance.
374 J. McNames
20.2.2 Definition
A stationary random signal is usually characterized by the autocorrelation (20.2)

or the PSD. They are related by the discrete-time Fourier transform (DTFT),
¥
- j w
Rx ( w ) = å r ()e
= -¥
x , (20.9)
where j = -1 , w is the discrete time frequency in units of radians per sample, and
Rx (w ) is the PSD of interest. It can be shown that for real-valued signals the PSD is
an even function of frequency
Rx (w ) = Rx ( -w ) (20.10)
and that the PSD is a periodic function of frequency

Rx (w ) = Rx (w + 2 p). (20.11)
As a consequence of these two properties, the PSD is completely represented

over the frequency range of 0 £ w £ p, and so in most applications only this
frequency range is displayed or analyzed.
20.2.3 Relating Continuous- and Discrete-Time Representations
In most applications, discrete-time signals are sampled from continuous-time

signals with appropriate anti-aliasing. Usually, the continuous time PSD is of inter-
est, so it is important to know how the dicrete-time and continuous-time PSDs are
related. The continuous-time PSD is defined as
¥
Px ( f ) = ò rx (t)e - j2 pft dt, (20.12)
-¥
where f is the frequency in units of Hz and rx (t) is the continuous-time autocorrela-

tion. Over the frequency range of 0 £ f £ fs / 2 , the continuous-time PSD is related
to the discrete-time PSD as follows:
1 æ 2p f ö fs
Px ( f ) = Rx ç for 0 £ f £ . (20.13)
fs è fs ÷ø 2
The units of Px ( f ) are the square of the units of the signal per Hz. For example,
if the tremor signal is obtained from an accelerometer with units of m/s2, then the
units of Px ( f ) would be (m/s2)2/Hz. Note that although the PSD is only plotted for
positive frequencies, the signal power is related to the PSD by integrating over both
positive and negative frequencies by Parseval’s theorem,
fs
E[ x 2 (t )] = ò 2fs Px ( f )df . (20.14)
-
2
20.2.4 Autocorrelation Versus Power Spectral Density
The autocorrelation and PSD are equivalent representations of the second-order sta-
tistical properties of signals. One can be obtained from the other and they form a
Fourier transform pair. For tremor analysis, the PSD is a more common and useful
characterization because tremor is approximately periodic, x(t) » x(t + T), and peri-
odic signals have their power concentrated at frequencies that are integer multiples
of the fundamental signal frequency, which are called harmonics. Thus, the PSD
will generally contain a few peaks at frequencies that can be readily interpreted as
integer multiples of the tremor frequency whereas the autocorrelation will contain
oscillations that spread out across a broad range of lags . Thus, it is more difficult
to accurately estimate the relevant properties of tremor signals from the autocorrela-
tion than the PSD.
20.2.5 Types of PSD Estimation
There are three broad types of PSD estimators that are best understood by statistical
model of the random process that each is based on. Parametric estimators are usu-
ally based on a statistical model in which white noise is filtered by a unknown linear
system. The estimation problem is then reduced to estimating the parameters of the
linear system and the power of the white noise process. These methods are accurate
when the model is appropriate, but this is not a suitable model for quasi-periodic
signals and this type of PSD estimation is seldom applied to tremor signals.
Harmonic PSD estimators are based on a statistical model in which the signal is
represented as a sum of sinusoids and white noise. The methods estimate the ampli-
tude, phase, and frequency of each sinusoidal component. These methods are rarely
used for tremor signals because the amplitude, phase, and frequency of tremor
fluctuate over time.
Nonparametric methods do not employ an explicit statistical model, but assume
that the PSD is a smooth, continuous function of frequency. They are used widely
for estimating the PSD of tremor signals. Application of these methods requires a
number of algorithm design decisions that affect properties of the PSD estimate and
how it is interpreted. This remainder of this section describes nonparametric methods
in detail.
376 J. McNames
20.2.6 Periodogram
The simplest nonparametric estimator is the periodogram

N -1 2
1
Rˆ x (w ) = å x(n)e - jwn . (20.15)
N n=0
It can be shown that mathematically this is equivalent to estimating the autocor-

relation with
N -1 - | |
1 (20.16)
rˆx () = å x ( n + ) x ( n)
N n=0
and then calculating the DTFT of rˆx () with (20.9).
20.2.7 Hazards of the Fast Fourier Transform
It is important to note that although the signal is sampled at discrete times for
only N samples, the PSD is estimated over a continuum of frequencies 0 £ w £ p .
The fast Fourier transform (FFT) is often used to calculate nonparametric estimates
of the PSD, and only evaluates the DTFT at N discrete frequencies. Specifically, the
FFT is a fast algorithm to calculate the discrete Fourier transform
N -1 2p
- jkn
X ( k ) = å x ( n) e N
, (20.17)
n=0
2p
which is equivalent to evaluating the DTFT at frequencies w = k for
k = 0,1,…,N. N
The algorithm attains the greatest computational efficiency when the recording
length is an integer power of 2. If the recording contains N samples, then the FFT
produces estimates at N / 2 + 1 frequencies over the range 0 £ w £ p . For recordings
of short duration, this can result in a sparse representation of the PSD with wide
frequency spacing. The limitation of the FFT to recordings with the number of sam-
ples equal to an integer multiple of 2 and the sparse representation of the PSD can
both be overcome by simply appending zeros to the end of the signal before applying
the FFT. This enables one to create a padded signal that is an integer power of 2 and
enables the fast evaluation of the PSD with a dense representation at many frequencies.
Zero padding is a well known and simple method, but it often overlooked and not
applied in the analysis of tremor signals. This results in PSD estimates that appear to
be sharp and jagged due to the combination of sparse representation of the PSD and
piecewise linear interpolation that is often used in plots.
Figure 20.1 shows an example of the hazard of insufficient zero padding. The top
plot shows a spike train (bottom, gray) obtained from a 10 s microelectrode
recording sampled at 22.05 kHz from a patient with Parkinson’s disease during
stereotactic neurosurgery. The blue signal shows the spike density after deci-
mating the signal by 484 to a decimated sample rate of 45.6 Hz. The bottom plot
shows the periodogram without zero padding and piecewise linear interpolation
(red) and the periodogram with zero padding such that the padded signal con-
tained 213 + 1 samples. The periodograms agree exactly at the estimated frequen-
cies, but the estimate without zero padding is badly distorted by coarse sampling
and piecewise linear interpolation.
20.2.8 Signal Windowing
The primary limitation that prevents us from estimating the true PSD perfectly from
(20.9) is that our recordings are finite and only comprised of N samples.
Mathematically, the effect of observing the signal for only N samples can be mod-
eled as multiplying the signal of interest s(n) with a window w(n)
x(n) = w(n)s(n), (20.18)
where the window has a finite duration
w(n) = 0 for n < 0 and n ³ N . (20.19)
It can be shown that the PSD of x(n) is related to the PSD of s(n) as follows:
E éR(w )ù = 1 p R (u) 1 R ( w- u)du,

û 2 p ò- p x
(20.20)
ë N
w
where
N -1
Rw (w ) = å rw () e - jw (20.21)
= - ( N -1)
and
N -1 - | |
rw () = å w(n + ) w(n). (20.22)
n=0
378 J. McNames
Spike Density (spikes/s)

300
200
100
0
0 1 2 3 4 5 6 7 8 9 10
Time (s)
Density PSD (spikes/s)2/Hz
15000
10000
5000
0
0 2 4 6 8 10 12
Frequency (Hz)
Fig. 20.1 The top figure shows a spike train (gray) and the estimated spike density (blue) of a
spike train. The bottom figure shows the periodogram with (thick gray) and without (thin red) zero
padding. This example demonstrates the distortions caused by insufficient zero padding and piece-
wise linear interpolation
Conceptually, one can understand windowing as a weighted averaging of adja-

cent frequencies, as represented mathematically by (20.20). One can interpret the
effect of windowing as smoothing or blurring the PSD estimate. This causes some
bias in the estimate, and particularly near sharp features in the spectrum such as
peaks. The shorter the recording is, the more difficult it is to distinguish adjacent
frequencies. As a rule of thumb, one should aim to ensure the signal duration is
sufficiently long to capture ten or more cycles at the lowest frequency of interest.
Tremor rarely approaches frequencies below 2 Hz (Deuschl et al. 2001). Thus,
recording durations should be at least 5 s in duration, and preferably much longer.
Figure 20.2 shows an example of the periodogram applied to the signal in
Fig. 20.1. White noise was added to the signal such that the signal-to-noise ratio is
approximately 1. The example illustrates the estimate is smoother and more biased
for shorter recording durations, but the variance of the estimate is unaffected by the
signal duration. This is the primary limitation of the periodogram.
It is important to keep the effect of windowing in mind when interpreting PSD
estimates, particularly when comparing recordings of different durations. Even if
the statistical properties of the signals are identical, the recording with a shorter
duration will produce an estimate that is smoother. This means any peaks at
frequencies corresponding to tremor will be shorter and broader in the shorter dura-
tion recording. The effect of windowing is also important to keep in mind when
calculating the tremor frequency or amplitude from PSD estimates.
1
PSD Est. (scaled) PSD Est. (scaled) PSD Est. (scaled)
10 s Recording
0.5
0
1
5 s Recording
0.5
0
1
2 s Recording
0.5
0
0 2 4 6 8 10 12
Frequency (Hz)
Fig. 20.2 Example of the periodogram applied to the signal from the previous example for record-
ing durations of 10 s (top), 5 s (middle), and 2 s (bottom). White noise was added to better show
the variance of the PSD estimates. Longer signal durations produce PSD estimates that have greater
resolution (less bias), but the same variance
Intuitively one would expect that a rectangular window
ì1 0 £ n £ N - 1
wr (n) = í (20.23)
î0 Otherwise
would be the best choice. However, windows that are tapered can generate better
performance, though this depends on the application. Virtually all time-domain
windows of interest are symmetric and smooth functions of time. As long as the
window is scaled such that
N -1
2
å w( n )
n=0
=N
(20.24)
the periodogram is asymptotically unbiased.

The Fourier transform of the windows contains oscillations as shown in Fig. 20.3.
The windows give the most weight to adjacent frequencies and give some weight to the
entire range of frequencies. The primary trade-off in selection of a window is between
the width of the main lobe and the height of the side lobes. A wider mainlobe creates a
smoother estimate with more averaging of adjacent frequencies and generally results in
smaller sidelobes, as shown in the bottom of Fig. 20.3. A narrower mainlobe results
in higher sidelobes with can give significant weighting to distant frequencies.
Rectangular windows have the narrowest main lobe, but the highest sidelobes.
380 J. McNames
1.5
Window w(n)
0.5
0
0 5 10 15 20 25 30 35 40 45
Sample (n)
Window Magnitude |W(ω)|
100
Rectangular
Hamming
10−2 Blackman
Blackman−Harris
10−4
10−6
0 0.5 1 1.5 2 2.5 3
Frequency (radians/sample)
Fig. 20.3 The top plot shows examples of four types of common data windows as a function of
time. The windows were scaled to satisfy (20.24). The bottom plot shows the magnitude of the
same four windows as a function of frequency. To illustrate the trade-off between main lobe width
and side lobe height, the windows were scaled to have the unity gain at w = 0
Most software packages used for signal processing of tremor signals provide a variety
of windows to choose from. More guidance on the selection of windows can be found
in Manolakis et al. (2005) and Oppenheim and Schafer (1999). The window selected
should always be reported as part of the methodology. As discussed in Sect. 20.2.11,
this decision is generally less critical than selecting the extent of smoothing.
20.2.9 PSD Smoothing
Although the periodogram is a simple estimator, it is not statistically consistent and

should not be used to estimate the PSD of tremor signals. A consistent estimator is
one that converges to the true PSD as the recording duration increases, N → ∞. The
variance of the periodogram at any given frequency remains constant as the record-
ing duration increases, though longer recordings decrease bias and smoothing due
to the windowing effect. In most applications, the high variance of the periodogram
is unacceptable for applications involving the estimation of tremor.
20.2.9.1 Welch–Bartlett Method
There are two popular nonparametric methods to estimate the PSD. One approach
divides the entire recording into segments, possibly with some overlap, calculates a
periodogram for each segment, and creates a final estimate as the average of the
segment periodograms. This approach is sometimes called the Welch–Bartlett
method (Manolakis et al. 2005). It is both easy to implement and understand, and it
is the most common method used to estimate the PSD of tremor signals.
The primary trade-off between bias and variance is determined by the segment
length, L. Shorter segment lengths result in larger averages that reduce variance, but
at the expense of smoothing the PSD estimates, which causes bias.
The user must also specify the extent to which the segments overlap. Increasing
the overlap results in more PSD segments to average, which decreases variance
without increasing bias, although at the expense of additional computation. A large
degree of overlap can substantially increase the computation without significantly
decreasing the bias because the estimated PSDs from segments with a lot of over-
lap are correlated and contain a lot of the same information. In practice, 50% over-
lap is often used. This is viewed as the point of diminishing returns where more
overlap does not decrease the variance sufficiently to make up for the additional
computation.
20.2.9.2 Blackman–Tukey Method
The second nonparametric method calculates the estimated signal autocorrelation,

applies a correlation window, and calculates the DTFT of the windowed autocorre-
lation estimate to produce the PSD estimate. Specifically, the autocorrelation is esti-
mated with
N -1 - | |
1
rˆx () = v() å x(n + ) x(n), (20.25)
N n=0
where v(l) is the correlation window. The estimated PSD is calculated from
(20.9). To prevent bias, v(l) is scaled such that v(0) = 1. We assume that v(l) has a
duration of L samples, v(l) = 0 for |l| ³ L and L < N. Note that the effect of this
windowing is to bias the autocorrelation estimate toward zero. This multiplica-
tion of the autocorrelation and window in the time domain results in a convolu-
tion, or filtering, of the periodogram PSD with the Fourier transform of the
window. This has the effect of smoothing the PSD estimate, which reduces the
variance at the expense of bias.
This method is sometimes called the Blackman–Tukey method (Manolakis
et al. 2005). It can be shown that when the Welch–Bartlett method is applied
with maximum overlap, which minimizes the variance of the estimate, it
becomes equivalent to the Blackman–Tukey method (Priestley 1981), though
the Blackman–Tukey method is more efficient computationally. The Blackman–
Tukey method generally produces estimates with less variance for an equiva-
lent degree of smoothing and is computationally efficient, particularly if the
FFT is used to both compute the autocorrelation estimate and the DTFT of the
windowed autocorrelation.
382 J. McNames
The variance of the PSD estimated from the Blackman–Tukey method is

approximately
L -1
å v 2 ( )
= - ( L -1)
{ }
var Rˆ x (w ) » R (w ) 2
x
N
. (20.26)
Thus, the estimated PSD variance at a given frequency is proportional to the

square of the true PSD, proportional to the energy of the correlation window, and
inversely proportional to the recording duration.
Approximate confidence intervals for the Blackman–Tukey method can be
obtained from the following:
Rˆ x (w ) Rˆ x (w )
< Rx ( w ) < , (20.27)
1 -2 1 -2
c (1 - a / 2) c (a / 2)
v v v v
where c -2 (1 - a / 2) is the inverse cummulative distribution function of a c2 distri-

bution with n degrees of freedom and a specifies the level of confidence. A typical
value of a = 0.05 generates a 95% confidence interval. The degrees of freedom n is
approximated as
2N
v= L -1
. (20.28)
å v 2 ( )
= - (L -1)
Both estimates of the variance and confidence intervals are based on approxima-
tions that assume that the bias is small due to a large recording duration and that
L < N. In practice, this assumption is often not satisfied and the variance estimate
and confidence intervals should be treated with due caution, particularly near peaks
in the estimated PSD.
20.2.9.3 Smoothing Spectral Peaks
Fundamentally both nonparametric PSD estimators, and other less common non-
parametric PSD estimators, effectively smooth the PSD estimates as compared to the
periodogram. If the true PSD is a smooth function of frequency and the recording is
of sufficient duration, this smoothing can significantly reduce variance without creat-
ing significant bias. However, if the PSD contains sharp features such as peaks caused
by nearly sinusoidal signal components, the bias can be significant and detrimental.
Figure 20.4 shows some examples of this trade-off with a tremor signal.
Tremor signals share some of the properties of periodic signals, but the ampli-
tude, phase, and frequency of the harmonic components are not constant over time.
When estimating the PSD from a given recording, these have the effect of broaden-
ing the peaks in the estimated PSD as compared to a sinusoidal peak. Thus, the
spectral peaks are not as sharp and some degree of smoothing is justified to reduce
the variance of the estimated PSD.
20.2.10 Interpreting the Power Spectal Density
It is well known that any periodic signal with fundamental period T can be repre-
sented as a sum of sinusoids with frequencies at integer multiples of 1/T. Periodic
signals that are smooth have their power concentrated in low frequencies and
periodic signals with sharp features, such as impulse trains, have more power at
high frequencies.
Tremor signals are called quasi-periodic because they do not meet the strict
definition of a periodic signal due to slow changes in amplitude, phase, and
frequency. Tremor signals tend to be smooth and most of the signal power is
contained in 2–3 harmonics.
20.2.11 Recommendations and Trade-offs
There are four decisions that the user must make to apply a nonparametric method
of spectral estimation. First, the amount of zero padding should be adequate to per-
mit a dense evaluation of the spectral estimate over the frequency range of interest.
The PSD of tremor is rarely plotted for frequencies higher than 20 Hz. Generally
sufficient zero padding should be used to evaluate the PSD at 200–2,000 different
frequencies. Mathematically, the length of the padded signal should be at least
fs
N ³ np , (20.29)
fmax
where np is the minimum number of frequencies used in the plot, fs is the sample
rate, and fmax is the maximum frequency displayed.
Second, the user must select a signal window. If the recording duration is
sufficiently long, say >30 s, then little bias is incurred by the smoothing of the PSD
estimate caused by the signal window, then one should prioritize minimizing side-
lobe leakage with a sidelobes of no more than 0.1% of the peak amplitude (60 dB).
The Blackman window is a simple window that achieves this. If the recording dura-
tion is short, say £30 s, a rectangular window is recommended to reduce bias due to
smoothing.
384 J. McNames
Third, the user must select a PSD estimator. The Blackman–Tukey method
generally has better statistical properties than the Welch–Bartlett method and is
recommended. With modern computers and the computational efficiency gained
from use of the FFT, the differences in computational demands of these two meth-
ods is not significant, and the Blackman–Tukey method is often more efficient.
Because of excessive variance, the periodogram is not recommended.
Fourth, the user must decide how much smothing to apply. For the Welch–Bartlett
method, this is determined primarily by the segment duration. For the Blackman–
Tukey method, this is determined primarily by the correlation window duration.
This is the most critical decision because it is the primary means to control the
trade-off between bias and variance of the estimate. Generally, the duration should
be sufficient to include at least 5–20 cycles of the slowest expected frequency com-
ponent. For most tremor signals, a duration of 5–10 s is recommended.
20.2.12 Power Spectral Density Statistics
Although the statistical properties of PSD estimates are well understood, the statisti-
cal properties of metrics calculated from the estimated PSD are not. For example, in
many applications the tremor frequency is calculated as the frequency at which the
PSD is maximized, though the statistical properites of this estimator are not known.
The amplitude of the tremor is difficult to estimate from the PSD because the
amplitude of the tremor is spread across a range of frequencies due to windowing and
smoothing effects, and is usually spread across 2–3 harmonics. Although it is com-
mon practice to estimate the tremor amplitude as the height of the peak of the PSD,
this practice is not recommended. The recording duration, window selection, amount
of zero padding, and degree of PSD smoothing can all have a significant impact on
the height of peaks in the estimated PSD, as illustrated in Fig. 20.4. The peak ampli-
tude can also be affected by degree of fluctuation in the frequency of the tremor.
A better estimate of tremor amplitude can be obtained by calculating the total
power over the range of frequencies covered by each of the harmonic peaks.
However, this approach is also imperfect because it does not distinguish between
the tremor signal and noise over these frequencies and because it can be difficult to
accurately estimate the beginning and end of each peak in the PSD. Some efforts
have been made to overcome these limitations (Bartolić et al. 2009).
20.3 Coherence Analysis
Coherence is analogous to measuring correlation as a function of frequency. It was not

used until relatively recently for tremor signals (Deuschl et al. 2001), even though it has
been known in the time series analysis and signal processing literature since the 1930s.
30
20
Omega (rad/s)
10
0
−10
−20
−30
0 5 10 15 20 25 30
Time (s)
80
PSD (rad/s)2/Hz
60
40
20
0
0 5 10 0 5 10 0 5 10
Frequency (Hz) Frequency (Hz) Frequency (Hz)
Fig. 20.4 The top plot shows a 30 s recording from a gyroscope placed on the wrist of a person
with Parkinson’s disease in an unmedicated, practically-defined off state. The bottom plots show
the PSD estimated with the Blackman–Tukey method. The PSD estimated was calculated with a
rectangular signal window and a Blackman correlation window. 95% confidence intervals are
shown in gray. The correlation window durations were 2 s (bottom left), 5 s (bottom middle), and
20 s (bottom right)
Consider two ergodic, jointly stationary random signals x(n) and y(n). Coherency
is defined as
Ryx (w )
Gyx (w ) = , (20.30)
Rx ( w ) Ry ( w )
where Rx (w ) and Ry (w ) are the PSDs as defined in (20.9). Ryx (w ) is the joint PSD
of x(n) and y(n), which is defined as
¥
- j w
Ryx (w ) = å r ()e
= -¥
yx , (20.31)
where ryx ( ) is the cross-correlation
ryx ( ) = E éë y (n + )x(n)ùû . (20.32)

386 J. McNames
The coherency is analogous to a Pearson correlation coefficient as a function of

frequency. The magnitude squared coherence (MSC), or simply coherence, is
defined as Gxy2 (w ). The coherence is analogous to a coefficient of determination.
Coherence has many interesting and useful properties. Like the coefficient of deter-
mination, coherence is bounded such that 0 £ Gxy2 (w ) £ 1, and it is invariant to the
scale of the signals. If y(n) is the output of an arbitrary linear system with x(n) as an
input signal, then Gxy2 (w ) = 1 for all w. If the signals are uncorrelated such that
rxy ( ) = 0 or if the signals are zero mean and statistically independent, then Gxy2 (w ) = 0
for all w. The coherence is a symmetric function of frequency, so like PSDs, it is only
calculated for positive frequencies over the range 0 £ w £ p.
Like the coefficient of determination, the coherence can be interpreted as the
fraction of signal variation that could be explained by an optimal linear dynamic
model applied to the other signal. For example, a coherence of 0.5 at a frequency
w 0 indicates that half of the variation of Ry (w 0 ) can be explained by estimating
y(n) with an optimal linear model that processes x(n).
20.3.1 Coherence Estimation
Coherence may be estimated using either of the nonparametric methods discussed

earlier. However, the statistical properties of the estimate is only well established for
the Welch–Bartlett method under the assumption that the random signals are
Gaussian, the segments are statistically independent, and there is no spectral leak-
age or bias from windowing effects (Amjad et al. 1997; Carter 1987; Wang and
Tang 2004). It is common practice to assume these conditions are approximately
met when the Welch–Bartlett method is used with nonoverlapping signal segments.
However, the assumption of indepenence is especially questionable for signals with
strong spectral peaks, such as tremor, with autocorrelations and cross-correlations
that decay slowly with time. Thus, in practice, the assumptions are not satisfied and
the statistical properties of coherence estimates should be viewed and interpreted
with due caution.
As a practical example, suppose we have a stationary 30 s tremor recording.
A typical tremor recording duration may range from 10 to 60 s. Kinetic and postural
tremor are difficult to maintain consistently for longer periods due to subject fatigue.
If we assume a minimum expected tremor frequency of 2 Hz, and we wish to select
a segment duration of at least 10 cycles of the lowest frequency, then our segment
duration is 5 s. If we use the Welch–Bartlett method with nonoverlapping segments
to strengthen compliance with our assumption of independent segments, then we
have merely six independent segments to work with. The exact 95% confidence
intervals, given the aforementioned assumptions, are shown in Fig. 20.5 (Wang and
Tang 2004). The confidence intervals are narrow for large values and values very
close to zero, but at intermediate values the confidence intervals are very large.
As expected, the intervals become narrower as the number of intervals becomes
1
6 Segments
0.9 12 Segments
24 Segments
0.8 60 Segments
95% Confidence Intervals
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Estimated Coherence
Fig. 20.5 Exact confidence intervals as a function of estimated coherence
larger, but still cover a substantial range even when 24 intervals are used, which
corresponds to a recording duration of 120 s.
There are additional, less well-known hazards and trade-offs when working with
coherence. Random signals with strong spectral peaks and low noise, as often occurs
with tremor, can suffer from strong bias due to spectral leakage. The fluctuations in
power densities at the tremor harmonics cause induced fluctuations at adjacent fre-
quences due to the spectral leakage, which can artificially elevate the estimates of
coherence at these frequencies, and particularly in signals with low noise levels.
This problem can be reduced, but not completely eliminated, by selecting a window
with small sidelobe leakage.
Figure 20.6 shows three pairwise coherence estimates from three signals col-
lected from gyros mounted on the wrists of a subject with Parkinson’s disease in an
unmedicated, practically-defined off state. At the time of the recording, the subject
was performing a categorical naming task designed to activate the disease symp-
toms. The first two signals were obtained from gyros mounted in orthogonal direc-
tions from the right wrist. The third signal was obtained from the right wrist. As
expected, the coherence between the two signals obtained from the right wrist was
coherent at the tremor frequency. The two coherence estimates between the gyro
signals on the right wrist and the signal on the left wrist were not coherent. Note the
large fluctuations in coherence at frequencies other than the tremor frequency. These
illustrate the high variance of the coherence estimate.
388 J. McNames
1
100
Coherence 12
Gyro 1 (rad/s)
50
0 0.5
−50
−100
0
1
100
Coherence 13
Gyro 2 (rad/s)
50
0 0.5
−50
−100
0
1
100
Coherence 23
Gyro 3 (rad/s)
50
0 0.5
−50
−100
0
0 10 20 30 0 2 4 6 8 10 12
Time (s) Frequency (Hz)
Fig. 20.6 The plots on the left show the signals from three gyroscopes. Two of the gyroscopes
were mounted on the right wrist with sensor axes at 90° angles (Gyro 1 and Gyro 2). Gyro 3 was
mounted on the left wrist. The three plots on the right show the coherence estimated with the
Blackman–Tukey method with a rectangular signal window and a Blackman correlation window
with a duration of 5 s. The estimated PSD from Gyro 1 is shown in Fig. 20.4. This example illus-
trates that the signals from the gyroscopes on the right wrist were coherent at the tremor frequency
(»5.2 Hz), but the signals from the left and right wrists were not
20.4 Discussion and Summary
Many types of signal processing algorithms have been developed for the analysis
and characterization of tremor signals for a variety of applications (Grimaldi and
Manto 2010). The methods described in this chapter are not comprehensive, but
provide a foundation for the two most common types of analysis that are applied to
tremor signals. Both methods are powerful and widely used, but require informed
decisions to ensure the analysis is accurate and interpreted appropriately.
References
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comparing and combining several independent coherence estimates: Theory and application to
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Bartolić A, Šantić M, Ribarič S. Automated tremor amplitude and frequency determination from
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Carter GC. Coherence and time delay estimation. Proc IEEE. 1987;75(2):236–55.
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Boston, MA, USA. p. 6789–6792.
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lular neural recordings. J Neurosci Methods. 2007;165(2):165–74.
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ment and analysis of tremor using a three-axis accelerometer. Methods Inf Med. 2009;48(6):589–
94. doi:10.3414/ME9243.
Manolakis DG, Ingle VK, Ingle V, Kogon SM. Statistical and adaptive signal processing: Spectral
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Prentice Hall; 1999.
Priestley MB. Spectral analysis and time series. London: Academic; 1981.
Synnott J, Chen L, Nugent CD, Moore G. WiiPD – an approach for the objective home assessment
of Parkinson’s disease. Proceedings of the 33rd Annual International Conference of the IEEE
EMBS; 2011; Boston, MA, USA. p. 2388–2399.
Veltink PH, Engberink EGO, Van Hilten BJ, Dunnewold R, Jacobi C. Towards a new method for
kinematic quantification of bradykinesia in patients with Parkinson’s disease using triaxial
accelerometry. Proceedings of IEEE 17th Annual Conference Engineering in Medicine and
Biology Society, vol. 2, pp. 1303–1304 (1995). 10.1109/IEMBS.1995.579693.
Wang S, Tang M. Exact confidence interval for magnitude-squared coherence estimates. IEEE
Signal Process Lett. 2004;11(3):326–9. doi:10.1109/LSP.2003.822897.
Wilson S, Emerson R. Spike detection: A review and comparison of algorithms. Clin Neurophysiol.
2002;113:1873–81.
Chapter 21
Diffusion Imaging in Tremor
Johannes C. Klein
Keywords Diffusion • Fractional anisotropy • Tractography • Parkinson’s disease

• Essential tremor
21.1 Introduction
In recent years, diffusion-weighted magnetic resonance imaging (DWI) has

complemented established imaging techniques for studying the human brain in
health and disease. DWI is an MR technique that probes the motion of free water
undergoing spontaneous diffusion in the living tissue. Unlike conventional, structural
MRI, this method provides insights into the microscopic composition, integrity, and
orientation of structures in the human brain (Le Bihan 2003).
Water diffusion in the brain is hindered by the presence of microscopic barriers,
such as cell membranes, intracellular materials, or myelin sheaths. Water diffuses
more readily along those barriers than across them, resulting in anisotropic, i.e.
directed diffusion (Fig. 21.1a). DWI is sensitive to this diffusion process, allowing
for measurements of diffusion restriction within the brain in any desired direction of
diffusion with the use of special gradients.
From these measurements, quantitative indices of the microstructural composi-
tion of the tissue can be derived. Most commonly, the tensor model is applied to
infer on local microstructure, giving information on the directionality, the shape,
and the overall restriction of the diffusion process. For tensor estimation, DWI
must sample a minimum of six directions of diffusion in the brain. However, the
information obtained with such a low number of diffusion directions is inadequate
for reliable estimation of the tensor’s parameters. DWI must obtain higher angular
J.C. Klein, M.D. (*)

Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16,
60528 Frankfurt am Main, Germany
e-mail: klein@med.uni-frankfurt.de
392 J.C. Klein
c
a 2 µm b
Fig. 21.1 Water diffuses more readily along cellular barriers in the brain than across them, result-
ing in anisotropic diffusion (a). (b) Example of tensors with isotropic diffusion in CSF, and highly
anisotropic diffusion in the callosal fibres. (c) The principal diffusion direction obtained from the
tensor field. (a) Reprinted with kind permission by Nature Publishing Group (Le Bihan 2003)
resolution of diffusion directions to generate stable estimates of the diffusion

tensor (Jones et al. 1999), resulting in longer scanning times and higher load on
the gradient hardware.
From the diffusion tensor, we can derive quantitative, scalar measurements
informing us about the structure and integrity of the tissue under scrutiny. The
most commonly used measurements are fractional anisotropy (FA), a measure of
the directionality of diffusion, and MD, a quantitative measurement of the overall
amount of diffusion with typical values around 0.5–2 × 10−3 mm2/s in brain tissue.
FA is dimensionless and can take values between 0 and 1, where 0 denotes per-
fectly isotropic, or undirected, diffusion, while a value of 1 refers to a theoretical,
perfectly anisotropic (line-shaped) diffusion process.
Figure 21.1b illustrates example tensors: In CSF, there are no structures hinder-
ing the diffusion process, and the tensor takes a spherical shape with an FA value of
0. In the callosal body, densely packed and highly collinear fibres traverse, connect-
ing the two hemispheres of the brain. These axons form a coherent barrier to the
diffusion process, and it is easy to imagine that the principal direction of free water
diffusion must follow the path of these axons. Consequently, the tensor observed
inside and close to the callosal body takes the shape of a cigar, with an FA value
around 0.7. The detail on the right (Fig. 21.1c) shows the principal diffusion direc-
tion obtained from the tensor field and overlaid as red lines onto the FA image.
Intuitively, the arrangement of the principal diffusion directions corresponds well
with the known architecture of callosal fibres, and tractography methods aim to
replicate the underlying fibre anatomy.
Crucially, diffusion imaging probes microstructural properties of the tissue
under study, complementing the macroscopic information available through con-
ventional MRI techniques. It is particularly useful in white matter, which contains
parallel bundles of axons that lend strong anisotropy to the diffusion signal
observed. In grey matter, the presence of cell bodies and the lower volume propor-
tion of directed nerve fibres entail that the diffusion process will encounter a more
21 Diffusion Imaging in Tremor 393
heterogeneous set of diffusion barriers. Thus, FA in white matter is generally

higher than in grey matter. In the context of tremor disorders, these measurements
allow for the assessment of dysintegrity of both central motor pathways and their
grey matter terminations.
In addition to the quantitative measurements just outlined, we can exploit the
directionality of the diffusion process to infer underlying neural connections.
Diffusion tractography generally follows the pathway of least hindrance of free
water diffusion through the brain, exploiting the fact that water diffuses more read-
ily along cellular barriers, such as axons, than across them. Algorithms based on the
tensor model generally follow the principal direction of diffusion, resulting in a
simple, deterministic pathway. However, there are many different fibre systems
interdigitating throughout the brain. Pathways can fan out or contract, they can
touch or cross, and it is easy to imagine that a single tensor cannot provide a com-
plete model for the complicated fibre geometry encountered in an imaging voxel in
the brain. Probabilistic tractography approaches were developed to overcome some
of these limitations, using both the tensor model and more data-driven approaches
[e.g. (Behrens et al. 2003; Parker and Alexander 2003)].
The information given by tractography is not complete, and the evidence
provided by tractography studies does not reach the same level of confidence asso-
ciated with classical tract-tracing studies (Johansen-Berg and Rushworth 2009).
However, invasive tract-tracing studies are unavailable in humans for obvious rea-
sons. Diffusion tractography estimates the pathway of axons in the brain from non-
invasive MR imaging, enabling reconstruction of white matter pathways in the
living human brain. It is the only modality to do such reconstruction, and thus our
most valuable tool in the assessment of white matter pathology in living subjects.
21.2 Methodological Considerations
Standard voxel-wise analysis techniques for brain imaging are readily adaptable for
use with diffusion imaging. These involve spatial registration of individual brains,
deforming individual images to match a pre-specified template, smoothing the
results, and then performing voxel-wise statistical tests to assess group differences.
Diffusion images pose certain inherent problems with this approach. Spatial regis-
tration is driven largely by interfaces between white and grey matter structures, or
interfaces between the brain and the cerebrospinal fluid compartment, where image
contrast is high. White matter has very low intrinsic contrast on both conventional
and parametric diffusion images, and thus, it is “dragged along” when registration
takes place. Unfortunately, this also means that standard spatial registration algo-
rithms cannot align white matter pathways satisfactorily, and we cannot guarantee
that a voxel in standard space coordinates centres on the same white matter tract in
all study subjects.
Tract-based spatial statistics, or TBSS, aims to address this issue (Smith et al.
2006): TBSS derives a skeletonised representation of white matter, and projects the
nearest maximum FA values onto this skeleton in each individual study subject.
394 J.C. Klein
This way, TBSS isolates dominant fibre pathways from the brain and residual
variability after spatial registration is reduced. Note that this type of analysis is
confined to white matter structures only.
21.3 Diffusion Tensor Imaging in Tremor
Currently, there are no routine applications for DWI in the clinical evaluation of
tremor. However, changes in tensor-derived parameters such as MD and FA have
been investigated in comparison to healthy control groups in a research context.
These are summative measures of diffusion, and as such, white matter features such
as myelination, packing density of axons, or axonal diameter have been shown to
influence both FA and MD (Beaulieu 2009).
21.4 Parkinsonian Syndromes
In Parkinson’s disease (PD), Yoshikawa et al. (2004) evaluated FA in structures of

the extrapyramidal system in 12 patients with PD and 8 patients with progressive
supranuclear palsy. They report significant reduction of FA in both PSP and PD in
the substantia nigra, and in ROIs placed along the nigrostriatal pathway. PSP patients
generally exhibited changes of greater magnitude than those with PD. Still, changes
in PD were detectable early in the course of disease, suggesting that diffusion imag-
ing is sensitive to the underlying neurodegenerative process.
Vaillancourt et al. (2009) analysed FA within the substantia nigra in a group of
14 patients with a diagnosis of early-stage Parkinson’s disease. The authors report
decreased FA in the substantia nigra in PD patients, establishing complete separa-
tion of PD patients from control subjects in their study group. A subsequent study
in 10 PD patients confirmed a trend for lower FA of substantia nigra in PD patients,
but failed to achieve the same separation from controls based on FA measurements
(Menke et al. 2009). The authors reported alterations in connectivity of the substan-
tia nigra, such that the integrity of its connections to the putamen and the thalamus
is reduced in PD. The authors argue that this alteration of the diffusion signal is
caused by degeneration of the substantia nigra pars compacta, leading to degenera-
tion of its projections.
Notably, there is only one study so far that reports DTI findings on a specific
subgroup of tremor-dominant PD patients (Tessa et al. 2008). Here, histograms of
whole brain FA and MD measurements were compared to normal controls, and a
subgroup of akinetic-rigid PD patients. The authors did not detect significant change
of diffusion parameters in tremor-dominant PD, but they report a trend for higher
FA in the highest quartile of brain voxels. The interpretation of this finding is not
straightforward, and the authors argue for a possible partial volume effect due to
grey matter loss.
21.5 Essential Tremor
The neuropathology of essential tremor, the most common movement disorder, is

currently under intense discussion, with some evidence pointing at an underlying
neurodegenerative process (for details, please refer to Chap. 10). If, indeed, degen-
eration takes place, it should be possible to locate changes in the microstructure of
the brain consecutive to axonal loss or damage.
Shin et al. (2008) report on a diffusion tensor imaging study in a group of 10
patients with ET. The authors use voxel-wise analysis to test for significant differ-
ences of FA with respect to an age-matched group of healthy controls. In this study,
FA decreases were found in the cerebellum, the midbrain, and in the white matter of
the cerebral hemispheres, suggesting a widespread alteration of white matter integ-
rity. The authors speculate that fibres of the cerebello-thalamo-corticocerebellar
loop may be affected, suggesting involvement of a tremor oscillator within this
motor loop. Central oscillations are a mechanism putatively involved in the
generation of ET (Deuschl et al. 2001), and these results argue for a role of
axonal dysfunction in the evolution of a central oscillator.
Another study (Martinelli et al. 2007) in 10 ET patients used a region-of-interest
approach, testing for differences in the apparent diffusion coefficient (a measure
related to MD) in a set of brain regions between ET patients and healthy controls.
These regions comprised cortical, subcortical, and cerebellar structures. Here, the
authors did not report any significant differences between the two groups.
However, a later study (Nicoletti et al. 2010) in a larger group with familial
essential tremor (25 patients) reported significant changes of FA and MD in the
superior cerebellar peduncles, and change of FA in the dentate nucleus, differentiat-
ing these patients from both normal controls and patients suffering from PD. Perhaps
the larger number of patients studied and different methodology of ROI analysis
explain this apparent discrepancy.
Klein et al. (2011a) employed both a traditional ROI analysis and TBSS (Smith
et al. 2006) to study a group of 14 ET patients. ROI analysis was performed in the
cerebellar peduncles, carrying all inputs and outputs of the cerebellum in a highly
collinear fibre system. This study reported increased MD bilaterally in the inferior
cerebellar peduncles, and reduced FA in the right-sided ICP of ET patients, suggest-
ing alteration of the white matter pathways feeding spinal input into the cerebellum.
On TBSS, the authors detected widespread increase of MD in bihemispheric cere-
bral white matter of ET patients, with special emphasis on the left hemisphere of the
brain (Fig. 21.2). Moreover, a regression analysis demonstrated that MD in the
affected brain regions was strongly correlated with Fahn tremor scores (p = 0.02,
R2 = 0.81), indicating a functional relationship between white matter abnormalities
and tremor severity. Recently, a variant of the LINGO1 gene was identified as a risk
factor in ET (Stefansson et al. 2009). LINGO1 is involved with myelination of the
central nervous system, suggesting a link between myelination and tremor genera-
tion in the brain. With these findings, the authors suggest that distributed myelin
dysintegrity plays a role in tremor generation, supporting the idea of a tremor-
generating network in the human brain (Deuschl et al. 2001).
396 J.C. Klein
Fig. 21.2 Diffusion tractography in a patient with Holmes’ tremor. The authors found disruption
of the dopaminergic nigrostriatal pathway ipsilateral to the hemorrhage (left), and the cerebello-
rubro-thalamic pathway (right). Reprinted with kind permission by BMJ Publishing Group Ltd
(Seidel et al. 2009)
In conclusion, there is mounting evidence that the underlying pathology of ET

can be detected with diffusion imaging. However, the exact location of changes
reported across research groups varies considerably.
21.6 Diffusion Tractography in Tremor
21.6.1 Lesion Evaluation
Diffusion tractography can inform us about the distribution of neuronal connections

in the brain. Disruption of these neural pathways can play a role in the generation of
tremor, such as deafferentiation caused by ischemic stroke or cerebral haemorrhage.
Tractography can depict pathways affected by a lesion, allowing the observer to draw
conclusions on the possible remote effects of the disconnection caused. In this context,
it is important to keep in mind that tractography can be hampered by many factors
such as perilesional oedema, shifts of brain tissue caused by a macroscopic lesion, or
infiltrating disease. Thus, failure to track a particular tract is not firm evidence that the
track in question is indeed completely transected. However, with supporting clinical
evidence, reduced traceability can be indicative of tract disruption.
Seidel et al. (2009) report on a case of dopamine-responsive Holmes tremor
caused by localised haemorrhage into the pons and brainstem. Dopamine transporter
imaging showed extensive damage to the presynaptic dopaminergic terminals in the
striatum ipsilateral to the haemorrhage. On diffusion tractography, the authors found
that connectivity was reduced between the tegmentum, where these dopaminergic
projections arise, and the striatum ipsilateral to the haemorrhage (Fig. 21.3, left).
Fig. 21.3 In a group of patients with essential tremor, TBSS analysis demonstrated reduced MD
bihemispherically [transaxial (a, b) and coronal view (c)]. The corpus callosum was spared (d).
Reprinted with kind permission by Wiley (Klein et al. 2011a)
Moreover, they report diminished connectivity entering and exiting the middle and
superior cerebellar peduncle (Fig. 21.3, right). In conclusion, the haemorrhage
affected the red nucleus directly, and affected nigrostriatal projections and the cor-
tico-rubro-cerebellar loop via disruption of fibre pathways traversing the region of
the haemorrhage. These findings point to remote deafferentiation as a plausible
mechanism for the clinical syndrome found in this patient.
21.6.2 Deep Brain Stimulation
Deep brain stimulation (DBS) is employed in the management of medically intrac-

table tremor (Benabid et al. 1996). While the success rates of surgery are high,
there is ongoing debate on the ideal target point for tremor-suppressive DBS
(Speelman et al. 2002). Most commonly, VIM DBS is employed in the manage-
ment of ET and tremor-dominant PD patients. The subthalamic nucleus (STN) is a
frequent target in PD that is not tremor dominant, since it has effects on both tremor
398 J.C. Klein
Fig. 21.4 3D rendering of the implanted electrodes in a patient with DBS for head tremor, dem-
onstrating the relationship between deep brain nuclei, the dentatorubrothalamic tract, and the
implanted, tremor-suppressive DBS electrodes. (a) frontal, (b) lateral view. DN dentate nucleus,
PG precentral gyrus, scp superior cerebellar peduncle, stp superior thalamic radiation, THA thala-
mus. Reprinted with kind permission by Springer (Coenen et al. 2011)
and akinetic symptoms (Limousin et al. 1995). As such, it is the most common
target for DBS altogether. Details of surgical therapy options are available in Chap.
10 of this book.
Coenen et al. (2011) employed diffusion tractography to target the dentato-
rubro-thalamic tract (DRT) in a patient with head tremor. They were able to identify
the DRT on pre-operative DWI, and used the tract’s location relative to a standard
stereotactic coordinate in the thalamus to plan the location for subsequent electrode
implantation. Clinically, this approach achieved successful reduction of tremor.
Figure 21.4 shows the location of the implanted electrode relative to deep brain
nuclei and the DRT traced bilaterally. While this is a single-patient study, it is
encouraging to see that the clinically effective electrode is collocated with the DRT,
indicating a functional relationship.
A study in a group of 12 tremor patients undergoing DBS of the ventral interme-
diate nucleus of thalamus (VIM) mapped out the brain network of successful,
tremor-suppressive DBS after stereotactic surgery planning and intra-operative
electrode testing (Fig. 21.5) (Klein et al. 2011b). This study described a network of
remote targets comprising primary sensorimotor, premotor, pallidal, and cerebellar
sites that is reproducible across patients, and in line with previous functional imag-
ing studies into the effects of VIM DBS. In this study, the spatial location of the
tremor-suppressive target was considerable, and spanned several millimetres across
subjects. This is because the individual, planned target site is always mapped elec-
trophysiologically, and the electrode position is adjusted, during surgery. In contrast
a b
11
Number of subjects
Number of subjects
R L R L
Fig. 21.5 Population probability map of connectivity estimated from individually effective VIM
(ventral intermediate nucleus) stimulation sites in a group of tremor patients. Note the strong
evidence of connectivity to primary sensorimotor, premotor, pallidal, and cerebellar sites
to spatial variability, the signature of the remote connections traced from these
individually effective target sites is remarkably similar across the group of patients
studied here. These findings point to a possible application of presurgical tractogra-
phy to map out thalamus and its vicinity with respect to the remote sites whose
modulation was effective in the patient collective reported here.
The connections of the STN were recently investigated with diffusion tractog-
raphy (Aravamuthan et al. 2007). The authors assessed its connections to a
predefined set of remote targets, informed by previous knowledge from tract
tracing studies in animals. The STN has connections with motor, limbic, and
associative circuits. Ideally, DBS should avoid the latter two portions, whose
stimulation is thought to contribute to potential neuropsychological side effects of
the procedure. In this study, motor representations were found in the superior
portion of the STN, as expected from both animal studies and clinical evaluation
of DBS efficacy. Furthermore, the authors confirmed a somatotopic layout of the
connections between primary motor cortex and motor STN, similar to what was
found in non-human primates previously. The topography confirmed in human
STN could be exploited for DBS in the future, enabling neurosurgeons to
specifically target motor regions in an individual patient to suppress both tremor
and akinetic symptoms in PD patients.
In conclusion, diffusion tractography expands our knowledge about the tracts
and remote connectional partner structures affected by DBS in tremor disorders.
This information may serve to guide stereotactic planning, and may enable presur-
gical evaluation of novel stimulation targets for DBS.
Diffusion imaging plays a unique role in the evaluation of tremor disorders: it
is the only non-invasive modality that can reconstruct white matter pathways in
the brain, and assess the microstructural integrity of the tissue at the same time.
The integrity of these pathways, or of grey matter structures involved in motor
400 J.C. Klein
functions, provides information on the specific pathophysiology of tremor

disorders. Moreover, recent research suggests that diffusion tractography can aid
in surgical targeting for DBS in invasive tremor therapy.
As a young modality, there is only limited evidence on the utility of diffusion
imaging in the differential diagnosis of tremor disorders thus far. Further research
is needed to assess the validity of diffusion-derived parameters for diagnosis or
treatment planning in a clinical context.
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Chapter 22
Metabolic Networks in Parkinson’s Disease
Michael Pourfar, Martin Niethammer, and David Eidelberg
Keywords Parkinson’s disease • Metabolic networks • Motor • Cortico–striato–

pallidal–thalamocortical circuits • Patterns • Atypical parkinsonian syndromes
22.1 Introduction
The idea that Parkinson’s disease (PD) is a “network” disorder has emerged along-
side our evolving understanding of the basal ganglia’s complex interconnections.
The notion of a direct and indirect pathway has remained an important concept even
as we have increasingly come to acknowledge the oversimplifications of the con-
struct. Fortunately, metabolic brain imaging with [18F]-fluorodeoxyglucose (FDG)
positron emission tomography (PET) has allowed us to explore and expand upon
these network ideas in novel ways. The application of network-oriented image anal-
ysis to FDG PET provides valuable information concerning functional connectivity
and is thus particularly well suited to the study of complex brain disorders like PD
and related parkinsonian syndromes. In this chapter, we will review these PD-related
metabolic networks along with their research and clinical applications.
M. Pourfar
Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA
M. Niethammer • D. Eidelberg (*)
Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA
Center for Neurosciences, The Feinstein Institute for Medical Research, 350 Community Drive,
Manhasset, NY 11030, USA
e-mail: david1@nshs.edu
404 M. Pourfar et al.
22.2 Metabolic Networks in Parkinson’s Disease
22.2.1 The Derivation of Metabolic Networks
Glucose metabolism provides a measure of regional synaptic activity (Eidelberg

et al. 1997). In humans, [18F]-FDG (and its tritiated or [14C]-labeled 2-deoxyglu-
cose homologue in animals) PET has been used to map focal areas of abnormal
metabolic activity in the brain. Parallel efforts employing [15O]-labeled water
(H215O) have been used to identify disease-related abnormalities in regional cere-
bral blood flow (Ma and Eidelberg 2007). Early studies employing these approaches
yielded inconsistent results. Apart from methodological challenges, some of the
inconsistencies were likely to have been attributable to the substantial variability
in brain activity that exists between subjects and brain regions. Indeed, assess-
ments confined to local metabolism often did not take into account the metabolic
impact on connected brain regions. As is now better appreciated, localized pathol-
ogy can alter functional connectivity across the entire brain in a disease-specific
manner (Eidelberg 2009). For example, the degeneration of nigral dopaminergic
neurons can result in changes in the activity of the thalamus, pallidum, and cortex.
These metabolic changes can be evaluated at the regional (voxel) level using stan-
dard mass-univariate approaches. Disease-related abnormalities in brain func-
tional organization can also be assessed at the network level using multivariate
analytical procedures. That is, techniques like spatial covariance analysis are
implemented to isolate specific disease-related metabolic patterns that reflect
functional–pathological changes taking place at multiple interconnected sites.
A strength of the network approach is that it takes into account large-scale func-
tional changes within a defined neural system as opposed to examining the regional
changes in isolation.
Specific disease-related brain networks can be identified in resting-state
metabolic imaging data using the Scaled Subprofile Model (SSM) (Moeller and
Strother 1991; Alexander and Moeller 1994). This approach, a form of double-
centered principal component analysis (PCA), has been described in detail
elsewhere (Eidelberg 2009; Habeck and Stern 2010; Spetsieris and Eidelberg
2011). Individuals affected by a particular disorder may have different magni-
tudes of pattern expression depending on a number of factors such as the severity
or duration of disease. The degree of pattern expression can be quantified based
upon reference data from healthy populations. Individuals with higher (i.e., more
abnormal) subject scores typically exhibit more severe clinical manifestations
than those with lower network expression values. Changes in pattern expression
can be assessed in a given individual over time. Pattern expression usually
increases as the disease progresses, making this approach particularly useful for
the objective evaluation of neurodegenerative disorders with variable rates of
progression (Feigin et al. 2007a; Tang et al. 2010a).
22 Metabolic Networks in Parkinson’s Disease 405
22.2.2 The PD-Related Motor Pattern
PD is particularly amenable to network analysis. The relatively localized loss of

nigral dopaminergic neurons leads to specific functional changes involving anatomi-
cally interconnected elements of cortico–striato–pallidal–thalamocortical (CSPTC)
circuits and related pathways. For example, functional overactivity of the subtha-
lamic nucleus (STN) and the internal segment of the globus pallidus results in reduced
output from the ventrolateral thalamus to the motor cortices (Alexander et al. 1990;
Parent and Hazrati 1995). In patients with hallmark motor features of PD, network
analysis of FDG PET data has consistently demonstrated the expression of an abnor-
mal spatial covariance pattern characterized by increased pallidal, thalamic, and pon-
tine metabolism associated with relative reductions in premotor, supplementary
motor, and parietal association cortices (Fig. 22.1a). This Parkinson’s disease-related
motor pattern (PDRP) has been identified in seven independent cohorts of PD and
control subjects and is highly reproducible between and within populations (Eidelberg
2009; Moeller et al. 1999; Ma et al. 2007). In all tested populations, higher PDRP
subject scores were associated with more advanced motor signs and symptoms
(Eidelberg 2009). Moreover, longitudinal increases in pattern expression were found
to correlate with progression in motor disability ratings and concurrent PET mea-
surements of presynaptic nigrostriatal dopamine function (Tang et al. 2010a; Huang
et al. 2007a). Interestingly, PDRP expression has also been found to correlate with
spontaneous discharge firing rates recorded from the STN during deep brain stimula-
tion (DBS) surgery (Lin et al. 2008). In this vein, both dopamine replacement therapy
and surgical interventions targeting the STN (such as subthalamotomy, STN DBS, and
subthalamic AAV-GAD gene therapy) are associated with reductions in PDRP expres-
sion that correlated with clinical improvement in motor ratings (Feigin et al. 2007a;
Trost et al. 2006; Asanuma et al. 2006; Mure et al. 2011).
Regional cerebral metabolic activity has been found to correlate with corresponding
regional blood flow measurements, particularly in the untreated baseline state (Ma and
Eidelberg 2007; Ma et al. 2007; Hirano et al. 2008). Thus PDRP activity can be mea-
sured with methods that measure cerebral perfusion, including radionuclide imaging
with H215O PET (Ma and Eidelberg 2007; Ma et al. 2007) or 99mTc-ethylcysteine
dimer (ECD) single photon emission computed tomography (SPECT) (Feigin et al.
2002; Eckert et al. 2007). Similarly, PDRP expression can be quantified noninvasively
with perfusion-weighted magnetic resonance imaging (MRI) methods such as arterial
spin labeling (ASL) (Ma et al. 2010; Melzer et al. 2011). Unlike PET or SPECT, ASL
uses an endogenous material, namely magnetically labeled arterial blood water, to
measure cerebral blood flow. This approach potentially allows for repeated network
measurements in a single subject without concerns over radiation exposure. In a pilot
study of 9 PD patients and 9 healthy controls, Ma et al. (2010) showed that PDRP
expression can be measured with continuous ASL imaging. PDRP expression in indi-
vidual subjects has been found to be tightly coupled regardless of whether measured
using FDG PET, H215O PET, or MRI ASL (Ma et al. 2007, 2010).
Fig. 22.1 Abnormal metabolic networks in Parkinson’s disease. (a) Parkinson’s disease
motor-related pattern (PDRP) identified by network analysis of [18F]-fluorodeoxyglucose
(FDG) PET scans from 33 PD patients and 33 age-matched normal volunteer subjects
(Ma et al. 2007). This spatial covariance pattern is characterized by increases (red) in the
metabolic activity of the putamen/globus pallidus (GP), thalamus, pons, cerebellum, and
sensorimotor cortex, associated with relative decreases (blue) in the lateral premotor cortex
(PMC) and in parieto-occipital association regions (Adapted from Trends Neurosci, D.
Eidelberg, Metabolic brain networks in neurodegenerative disorders: A functional imaging
approach, 548–557, Copyright 2009, with permission from Elsevier). (b) PD tremor-related
metabolic pattern (PDTP) identified using a within-subject network analysis of FDG PET scans
from nine tremor-dominant PD patients scanned at baseline and during ventrointermediate
(Vim) thalamic deep brain stimulation (DBS) (Mure et al. 2011). This pattern is characterized
by covarying increases in the metabolic activity of the sensorimotor cortex (SMC), cerebellum,
pons, and putamen (Reprinted from NeuroImage, Mure et al., Parkinson’s disease tremor-
related metabolic network: characterization, progression, and treatment effects, pp. 1244–1253
Copyright 2010, with permission from Elsevier). (c) PD cognition-related metabolic pattern
(PDCP) identified in a separate network analysis of FDG PET scans from 15 non-demented PD
patients (Huang et al. 2007b). This spatial covariance pattern is characterized by decreases in
the metabolic activity (blue) of the rostral supplementary motor area (pre-SMA), precuneus,
and the posterior parietal and prefrontal regions, associated with relative increases (red) in the
dentate nucleus (DN) and cerebellar cortex (Reprinted from Trends Neurosci, D. Eidelberg,
Metabolic brain networks in neurodegenerative disorders: A functional imaging approach,
548–557, Copyright 2009, with permission from Elsevier)
Fig. 22.2 Validation of PD tremor-related metabolic pattern (PDTP) expression as a network cor-
relate of parkinsonian tremor. (a) PDTP expression values (Mure et al. 2011) computed in a testing
group of 41 PD patients correlated (r = 0.54, p < 0.001) with UPDRS subscale ratings for tremor.
(b) However, multiple regression analysis (Mure et al. 2011) revealed that the correlation between
PDTP values and tremor ratings was of significantly greater magnitude (p < 0.01) than the corre-
sponding correlation with akinesia-rigidity ratings. (a, b: Reprinted from NeuroImage, H. Mure
et al., Parkinson’s disease tremor-related metabolic network: characterization, progression, and
treatment effects, pp. 1244–1253 Copyright 2010, with permission from Elsevier)
22.2.3 The PD-Related Tremor Pattern
The pathophysiology of tremor in Parkinson’s remains uncertain but to be appears

distinct from that of the other cardinal motor features (Hughes et al. 1993). Tremor
does not appear to correlate strongly with the degree of dopaminergic loss and does
not uniformly respond to dopaminergic replacement (Benamer et al. 2003; Eidelberg
et al. 1995). Similarly, as opposed to rigidity and bradykinesia, this manifestation of
PD is not captured by the PDRP metabolic network. Indeed, PDRP expression has
been observed to be similar in patients with the same degree of akinetic rigidity, irre-
spective of the presence or intensity of tremor (Antonini et al. 1998; Isaias et al. 2010).
To identify a discrete PD tremor-related metabolic covariance pattern (PDTP), we
used FDG PET to scan a cohort of tremor-predominant PD patients who had under-
gone ventrointermediate (Vim) thalamic DBS for these symptoms (Mure et al. 2011).
Metabolic images obtained on- and off-stimulation were analyzed using a within-
subject guided PCA method termed Ordinal Trends Canonical Variates Analysis
(OrT/CVA) (Habeck et al. 2005). This approach revealed a stable PDTP topography
(Fig. 22.1b) that was characterized by covarying increases in the activity of the cere-
bellum and primary cortex as well as, to a lesser degree, the caudate and putamen.
Indeed, in contrast to the PDRP, prospectively computed PDTP scores (Fig. 22.2)
were found to correlate well with tremor but not with bradykinesia and rigidity ratings.
Further highlighting the difference between the two patterns was the observation
(Fig. 22.3) that Vim thalamic stimulation (which is generally not effective for rigidity
Fig. 22.3 Changes in metabolic network activity with deep brain stimulation for PD tremor. (a) Bar
graphs (Mure et al. 2011) showing mean baseline PDTP expression (±SE) in the Vim DBS patients
(black), the STN DBS patients (gray), and the healthy control subjects (white). There was a significant
difference in PDTP expression across the three groups (p < 0.001; one-way ANOVA), with compa-
rable elevations in baseline pattern expression in both the Vim DBS (p < 0.005) and STN DBS groups
(p < 0.001) relative to controls. (b) Baseline PDRP expression also differed across the three groups
(p < 0.001), with higher expression in both treatment groups relative to controls (p < 0.001).
Nonetheless, PDRP expression was higher in the STN than in the Vim DBS group (p < 0.01).
(c) Treatment-mediated changes (Mure et al. 2011) in mean PDTP expression (±SE) in the Vim DBS
patients (black), the STN DBS patients (gray), and the test–retest PD control subjects (white).
Changes in PDTP expression were different across the three groups (p < 0.001; one-way ANOVA),
with stimulation-mediated declines in network activity in both DBS groups (Vim: p < 0.001; STN:
p = 0.01, relative to the test–retest control group). PDTP modulation was greater with Vim than STN
stimulation (p < 0.05). (d) There was also a significant group difference in treatment-mediated PDRP
modulation (p = 0.02). Treatment-mediated reductions in PDRP expression reached significance
(p < 0.05) with STN stimulation, but not with Vim stimulation (p = 0.16). (a–d: Reprinted from
NeuroImage, H. Mure et al., Parkinson’s disease tremor-related metabolic network: characterization,
progression, and treatment effects, pp. 1244–1253 Copyright 2010, with permission from Elsevier)
or akinesia) reduced baseline elevations in PDTP—but not PDRP—expression,

whereas STN stimulation (effective for all cardinal features) reduced both PDTP and
PDRP network expression (Mure et al. 2011). Moreover, both the PDRP and PDTP
were found to progress over time (Fig. 22.4), although the tremor pattern did so at a
Fig. 22.4 Changes in the whole-brain expression of metabolic networks with disease progression.
Time courses of the whole-brain expression of the PD-related motor (PDRP), cognitive (PDCP), and
tremor (PDTP) patterns. All three networks exhibited significantly increased activity over time
(PDRP: p < 0.0001; PDCP: p < 0.0001; PDTP: p = 0.01), but at different rates of progression (p < 0.01).
PDRP expression increased at the fastest rate while PDTP the slowest. Subject scores for each net-
work were z-transformed so that the normal mean is 0 and standard deviation is 1 (Reprinted from
NeuroImage, H. Mure et al., Parkinson’s disease tremor-related metabolic network: characterization,
progression, and treatment effects, pp. 1244–1253 Copyright 2010, with permission from Elsevier;
also reprinted from Progress in Brain Research, C.C. Tang and D. Eidelberg, Abnormal metabolic
brain networks in Parkinson’s disease: From blackboard to bedside, pp. 160-176 Copyright 2010)
much slower rate than the PDRP. In aggregate, these findings point to major
differences between tremor-and akinesia/rigidity-related brain networks, in terms
of clinical correlates, treatment effects, and natural history.
Tremor-related circuitry has also been studied by quantifying the effects of
differing intensities of stimulation on brain metabolism. Several studies have
demonstrated differences in metabolic activity when comparing effective versus
subtherapeutic levels of stimulation (Deiber et al. 1993; Parker et al. 1992), help-
ing to differentiate between the physiological effect of tremor suppression and the
nonspecific effect of electrical stimulation. Deiber et al. demonstrated with H215O
PET that effective stimulation was associated with metabolic decreases in the
contralateral cerebellum whereas ineffective stimulation was associated with
decreases in ipsilateral supplementary motor cortices (SMC) (Deiber et al. 1993).
Using correlation statistical parametric mapping (SPM) analysis, we investigated
how differing degrees of Vim stimulation modulated cerebello–thalamo–cortical
activity, using H215O PET to study eight tremor-predominant PD patients with
Vim DBS with stimulation turned off, partially effective stimulation, and optimal
stimulation (Fukuda et al. 2004). Tremor reduction was associated with decreases
in the SMC ipsilateral to stimulation and in the contralateral cerebellum with
concurrent increases in the ventral thalamus localized to the DBS target.
Furthermore, changes in SMC activity were preferentially modeled by tremor

amplitude whereas changes in cerebellar activity were better modeled by tremor
frequency. Thus, both changes in regional glucose metabolism and cerebral blood
flow point to enhanced cerebello–thalamo–cortical activity with tremor and the
suppression of this pathway by thalamic stimulation.
22.2.4 The PD-Related Cognitive Pattern
In addition to motor symptoms, FDG PET has been used to study the cognitive
changes associated with PD. The prevalence of frank dementia in PD can range
from 17% to 43% (Riedel et al. 2008), but the presence of mild cognitive deficits is
higher still and can be present from a relatively early stage (Caviness et al. 2007).
Early identification of such cognitive changes, particularly as they segue from mild
to moderate, is clinically important as cognitive dysfunction can exact a toll as high
as, if not higher than, the motor aspects of the disease. A distinct and highly repro-
ducible metabolic pattern associated with cognitive dysfunction in non-demented
PD patients has been identified. This PD-related cognitive pattern (PDCP)
(Fig. 22.1c) is statistically unrelated to the PDRP and is characterized by hypome-
tabolism in medial frontal and parietal association cortices with relative increases in
the cerebellar vermis and dentate nuclei (Eidelberg 2009; Huang et al. 2007b; Mattis
et al. 2011). It can differentiate PD subjects with mild cognitive impairment from
those without (Huang et al. 2008) and has been found to correlate with neuropsy-
chological test performance, particularly with tests of executive function. The slow
rate of PDCP progression is particularly evident when assessed in individual sub-
jects undergoing serial longitudinal PET imaging (Tang et al. 2010a; Huang et al.
2007a) (Fig. 22.4). The PDCP is typically expressed later, reflecting the usual
latency between onset of motor and cognitive symptoms. The trajectory of PDCP
progression over time is nonlinear and independent of the PDRP. It also differs from
the PDRP in that PDCP activity is not significantly altered by treatment of motor
symptoms with levodopa, stereotaxic interventions, or gene therapy (Asanuma et al.
2006; Hirano et al. 2008; Feigin et al. 2007b). That said, recent evidence points to
PDCP modulation by levodopa treatment at the individual subject level, in propor-
tion to the degree that the pattern is expressed in the baseline (unmedicated) condi-
tion (Mattis et al. 2011). These observations are particularly meaningful in assessing
interventions targeting the cognitive aspects of PD (captured by changes in PDCP
expression), as compared with the more treatment-responsive motor symptoms
(captured by changes in PDRP expression).
22.3 Atypical Parkinsonian Syndromes
Differentiating typical from atypical parkinsonian syndromes (APS) on clinical

grounds can often be challenging, particularly early in the course of disease. Many
parkinsonian syndromes first present with common features of rigidity and bradykinesia,
with hallmark characteristics of each disorder (e.g., dysautonomia in multiple system

atrophy (MSA)) developing only years later. The occasional initial response to dop-
aminergic therapy in atypical syndromes further clouds the early clinical impression.
This is evidenced by postmortem pathological confirmation of atypical syndromes in
up to 10% of the patients who were diagnosed with PD in life (Hughes et al. 2002;
Schrag et al. 1999). In up to one-third of patients, the correct diagnosis is not made until
the fifth year of symptoms. Standard dopaminergic neuroimaging approaches (such as
fluorodopa PET and DAT SPECT imaging) can help rule out essential tremor and drug-
induced parkinsonism in a patient with clinical parkinsonism but cannot reliably dif-
ferentiate between PD and APS. As the prognosis and treatment implications differ
considerably between parkinsonian syndromes, having the ability to identify the cor-
rect diagnosis early on is of help to the clinician, the researcher, and the patient.
Two of the most common atypical syndromes include MSA and progressive
supranuclear palsy (PSP). Specific and highly stable metabolic networks have simi-
larly been characterized for both MSA and PSP in two independent patient groups
compared with control subjects (Eckert et al. 2008). This was accomplished by per-
forming FDG PET imaging on subjects who carried diagnoses of either MSA or
PSP and were evaluated by a movement disorders specialist on at least two occa-
sions with further corroboration by a blinded movement disorders specialist who
reviewed the chart and applied published clinical criteria to each case (Tang et al.
2010b). The MSA-related pattern (MSARP) demonstrates bilateral metabolic
reductions in the putamen and cerebellum (Fig. 22.5a). The PSP-related pattern
(PSPRP) demonstrates more diffuse abnormalities compared with both PD and
MSA and is characterized by metabolic reductions in the upper brainstem, medial
prefrontal cortex, medial thalamus, caudate, anterior cingulate, ventrolateral pre-
frontal cortex, and frontal eye fields (Fig. 22.5b). One clear differentiator between
the PDRP and the metabolic patterns for both atypical syndromes is the presence of
basal ganglia hypometabolism in atypical syndromes (as opposed to hypermetabo-
lism in idiopathic PD (IPD)), resulting from pre- and postsynaptic degeneration that
occurs in both MSA and PSP (Tang et al. 2010b; Poston et al. 2012).
These differentiating features allow for increased diagnostic certainty early in
the disease course when the clinical diagnosis remains unclear—as has been dem-
onstrated with approximately 90% accuracy in one prospective study (Eckert and
Edwards 2007). In a recent study of 167 subjects with parkinsonian features and no
firm clinical diagnosis (Tang et al. 2010b), pattern analysis (Fig. 22.5c, d) was able
to identify PD with high specificity and positive predictive value (PPV), as is suit-
able for a diagnostic biomarker. Similarly, high specificity and PPV were found for
MSA (96%, 97%) and for PSP (94%, 91%). Diagnostic accuracy remained excel-
lent in a subset of 55 patients with under 2 years of symptoms (IPD: 92%, 92%;
APS: 97%, 95%). Importantly, clinical follow-up of these subjects at an average of
2.6 years following imaging confirmed the accuracy of the pattern-based diagnosis
of the individual subjects; the accuracy of the computer-based classifications was
not influenced by the duration of symptoms at the time of imaging. Similar
approaches aimed at identifying other atypical syndromes such as corticobasalgan-
glionic degeneration (CBGD) are underway (Niethammer et al. 2011), which will
further disambiguate these clinically overlapping syndromes.
Fig. 22.5 Spatial covariance patterns associated with multiple system atrophy and progressive
supranuclear palsy. (a) Metabolic pattern (Eckert et al. 2008) associated with multiple system
atrophy (MSARP) characterized by covarying metabolic decreases in the putamen and cerebel-
lum. (b) Metabolic pattern (Eckert et al. 2008) associated with progressive supranuclear palsy
(PSPRP) characterized by covarying metabolic decreases in the medial prefrontal cortex (PFC),
frontal eye fields, ventrolateral prefrontal cortex (VLPFC), caudate nuclei, medial thalamus, and
in the upper brainstem. (a, b: Reprinted from Mov Disord, T. Eckert et al., Abnormal metabolic
networks in atypical parkinsonism, pp. 727–733, Copyright© 2008 with permission of John
Wiley & Sons, Inc.) (c, d) Receiver operating characteristic (ROC) curves for categorization
based on the MSARP and the PSPRP are displayed (Tang et al. 2010b). The areas under each
curve are, respectively, 0.95 (95% CI 0.89–1.00) and 0.93 (95% CI 0.86–0.99). (The covariance
patterns were overlaid on T1-weighted MR-template images. The displays represent regions that
contributed significantly to the network and that were demonstrated to be reliable by bootstrap
resampling. Voxels with negative region weights (metabolic decreases) are color-coded blue.)
(Reprinted from The Lancet Neurology, vol. 9, C.C. Tang et al., Differential diagnosis of parkin-
sonism: a metabolic imaging study using pattern analysis, pp. 149–158, Copyright 2010, with
permission from Elsevier)
22.4 Future Research Applications
In recent years, substantial interest has developed in the discovery of predictive

biomarkers for use in individuals at high risk for PD, such as those with rapid eye
movement sleep behavior disorder (RBD). These patients have been found to
exhibit cell loss in the same brain regions as in PD (Uchiyama et al. 1995; Braak
et al. 2003; Boeve et al. 2004, 2007). Prior imaging studies have reported deficits
in presynaptic nigrostriatal dopaminergic function in RBD patients at intermediate
levels between healthy controls and PD patients (Albin et al. 2000; Eisensehr et al.
2000; Stiasny-Kolster et al. 2005). It has, therefore, been proposed that RBD rep-
resents a prodromal form of PD. The investigation of this population with meta-
bolic imaging and spatial covariance analysis may reveal new network biomarkers
for the evaluation of preclinical disease progression and the objective assessment
of potential neuroprotective therapies in at-risk individuals.
Investigations are currently designed to study disease progression in patients
with atypical parkinsonism. Abnormal metabolic networks have been characterized
for atypical forms of parkinsonism including MSA and PSP, and in preliminary
form in CBGD. Indeed, these patterns have been used in concert with the PDRP for
accurate differential diagnosis of individual cases, even at early clinical stages of
disease (Tang et al. 2010b; Spetsieris et al. 2009). Nonetheless, rates of network
progression in MSA and PSP are not currently available. Longitudinal studies
conducted in atypical populations will provide critical data concerning network
progression in these patient groups.
Lastly, studies are underway to determine whether the network substrates of
essential tremor (ET) are topographically similar to the analogous patterns reported
in tremulous PD patients. By employing analytical strategies similar to those used
to extract the PDTP topography (see above), it will be possible to identify specific
tremor-related spatial covariance patterns in ET patients treated with Vim thalamic
stimulation. How such metabolic networks compare with PDTP expression in
predicting biodynamic features of tremor (cf. Mure et al. 2011; Fukuda et al. 2004)
will be critical in clinical trials designed to assess novel interventions targeting this
disabling symptom.
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Part IV
Therapies of Tremor
Chapter 23
Pharmacological Treatments of Tremor
Keywords • Levodopa • Anticholinergic • Dopamine agonist • Beta-blocker • Primidone

• Topiramate • Benzodiazepines • Botulinum toxin
23.1 Introduction
This chapter discusses the drugs used in the treatment of tremor and provides a
pharmacological therapeutical approach for the management of the main neurologi-
cal disorders characterized by tremor. Tremor severity and related handicap may
vary substantially between patients, and some patients may consider that tremor
does not interfere with their quality of life.
Drugs remain the first-line therapy for most forms of tremor. However, the
response is variable and a combination of agents is often required. Levodopa,
anticholinergic medications, dopamine agonists, and b-blockers such as propranolol
are effective drugs for rest tremor. Both primidone and propranolol reduce the
magnitude of hand postural tremor and remain the medications of choice for essen-
tial tremor (ET). However, patients may stop therapy because of side effects or lack
of response. Given the high prevalence of tremor, there is a clear need for novel
drugs, which are both more effective and with less side effects.
The following drugs may trigger or enhance tremor and should not be overlooked
(iatrogenic tremor): antipsychotic agents (rest tremor), flunarizine and cinnarizine
(calcium channels blockers; rest tremor), tricyclic agents (postural tremor), valproic
acid (postural tremor), lithium salts (postural/kinetic tremor), beta-2 adrenergic
agonists and methylxanthines (postural tremor), calcineurin inhibitors (cyclosporin,

tacrolimus—postural/kinetic tremor), administration of thyroid hormones (postural

tremor), amiodarone (postural/kinetic tremor), steroids (postural tremor). Rapid
discontinuation of these drugs is the obvious first step, before considering adding a
novel agent. Tremor due to environmental toxics such as methylmercury occurs
mainly in areas at risk (Iwata et al. 2006). Also, tremor may have a metabolic cause
such as in case of hypoglycemia. Caffeine intake and high carbohydrate meals
enhance tremor (food ingestion causes tremor probably through a sympathetic
nervous system activation). Withdrawal syndromes (ethanol, tobacco, benzodiaz-
epines) are typically associated with a postural tremor, resulting from an overactivity
of the autonomous nervous system.
23.2 Drugs Used in the Therapy of Tremor
Although not considered as a classical drug, ethanol decreases postural ET, but not
parkinsonian rest tremor or the genuine cerebellar kinetic tremor (which is often
worsened by small doses of ethanol). Ethanol improves gait ataxia in patients with
ET (Klebe et al. 2005). However, the improvement is temporary and followed by a
rebound phenomenon when the alcohol effect wears off. A case of ethanol respon-
sive tremor in a patient with MS has been also reported (Hammond and Kerr 2008).
Tolerance develops with time (Habib-ur-Rehman 2000). For obvious reasons,
regular alcohol intake cannot be recommended. Therefore, ethanol is not used in
the treatment of tremor, but as a clue for the diagnosis of ET. The improvement of
tremor after ethanol ingestion is likely due to a direct effect on a central oscillator
(Zeuner et al. 2003). Experimental studies in rodent suggest that ethanol antago-
nizes a dysregulation of glutamatergic pathways in the cerebellum (Manto and
Laute 2008). Ethanol decreases the extracellular concentrations of glutamate
during NMDA (N-methyl-d-aspartate) stimulation. In addition, it enhances gabaer-
gic transmission (Grimaldi and Manto 2008).
Primidone is significantly superior to placebo in reducing the magnitude of hand
postural tremor. Its efficacy is similar to propranolol (Findley et al. 1985). Long-
term efficacy of primidone (range of doses 375–750 mg per day) in ET has been
evaluated. Tremorolytic effects last for up to 1 year or more (Sasso et al. 1990). In
some studies, low doses of primidone (250 mg per day) were demonstrated to
provide an equal or more effective effect than high doses (750 mg per day) in the
control of ET with the subsequent advantage of fewer undesirable effects (Serrano-
Dueñas 2003). Low doses should be considered at the very beginning of the treat-
ment (12.5–60 mg for 1–3 weeks). Total daily doses of 150 mg or less are often
sufficient (Deuschl et al. 2011), however, a progressive increase of the dose up to
750 mg per day is often required in daily practice (see below the treatment of ET).
Primidone is confirmed as a “Level A” drug (established as effective) in the treat-
ment of ET (Zesiewicz et al. 2011). Primidone reduces tremor by about 50–60%.
Side effects include sedation, dizziness, fatigue, nausea, and depression, as well as
ataxia and confusion in severe cases (Abboud et al. 2011). Side effects are fre-
quently dose limiting (especially drowsiness, dizziness, or disequilibrium), occurring
23 Pharmacological Treatments of Tremor 421
in most patients when the total daily dose is titrated to 500 mg or higher. It should
be kept in mind that various combinations of nausea, sedation, malaise, ataxia,
dizziness, and confusion may occur as an acute toxic reaction to the first dose of
primidone. This may be quite troublesome, being so severe that some patients refuse
to take additional doses. Clearly, starting with very low doses (25 or even 12.5 mg
per dose), caution and education for patients about these side effects are advisable
when starting primidone. Tolerance to the side effects and reduction of efficacy with
time has been reported with primidone therapy, even in those patients who initially
benefit dramatically (Deuschl et al. 2011).
Propranolol (a nonselective b-Adrenergic blocking drug) and b2-selective
blocker drugs have been the mainstay for the treatment of ET with upper limb
tremor. b-adrenergic blockers might reduce the stretch-reflex sensitivity (Deuschl
et al. 2011). Propranolol improves tremor in 50–70% of patients with ET and
achieves an average tremor reduction of 50–60% (Abboud et al. 2011). Propranolol
has been confirmed as a “Level A” drug (established as effective) in the treatment
of ET (Zesiewicz et al. 2011). Other b-blockers, such as nadolol and timolol, are
also effective against tremor but are less potent than propranolol. The selective
b1-blocker metoprolol may be effective and has fewer noncardiac side effects as
compared to propranolol, so it can be considered in patients who discontinue pro-
pranolol because of adverse events (Abboud et al. 2011). b-Adrenergic blockers
are probably less effective in the treatment of voice and head tremor (Habib-ur-
Rehman 2000). The efficacy of sustained propranolol on isolated or prominent
essential head tremor is less predictable and satisfactory than expected on the
basis of the single-dose response, as compared with hand tremor (Calzetti et al.
1992). A double-blind crossover study comparing the effects of long-acting pro-
pranolol hydrochloride (160 mg per day), primidone (250 mg at night), and clon-
azepam (4 mg per day) in parkinsonian patients, showed that long-acting
propranolol is a useful adjuvant therapy for the parkinsonian tremor. In fact, long-
acting propranolol reduced the mean amplitude of resting tremor by 70% and the
mean amplitude of postural tremor by 50%, without the occurrence of noticeable
side effects (Koller and Herbster 1987). Long-acting propranolol is usually not
effective to reduce drug-induced parkinsonian tremor (Metzer et al. 1993).
Interestingly, propranolol is a useful adjunct in the early treatment of both the
tremor and tachycardia of hyperthyroidism (Henderson et al. 1997). b-Blockers
should be used very cautiously in case of respiratory disease (asthma) or conduc-
tion block (heart disease), especially in the elderly. Side effects of propranolol
include bronchoconstriction, bradycardia, hypotension, depression, impotence,
fatigue, and gastrointestinal disturbances (Abboud et al. 2011), the majority of
which are dose limiting (Deuschl et al. 2011).
Benzodiazepines are also used in the treatment of tremor. Benzodiazepines pos-
sibly target the low-threshold calcium currents in membrane oscillations (Deuschl
et al. 2011). Among the benzodiazepines medications, alprazolam can be used in
elderly patients with ET who do not tolerate primidone or propranolol (Gunal et al.
2000). Clonazepam alone or in combination with gabapentine or primidone
improve orthostatic tremor (Gates 1993) and may provide benefit in tremor associ-
ated with myoclonus. Common side effects of benzodiazepines include sedation,
cognitive dysfunction, hypotension, respiratory inhibition, and addiction after

prolonged use. In the elderly, they can cause a confusional state and disinhibition,
and may increase the risk of falls. Stopping benzodiazepines should be done gradu-
ally to avoid withdrawal symptoms, including the aggravation of tremor which
occurs during withdrawal states (Abboud et al. 2011).
Some of the medications belonging to the family of antiepileptic drugs are
successfully used in the treatment of tremor, although others show no benefit. In
view of the widespread neuronal oscillations associated in the genesis of tremor,
anticonvulsants are thought to act through ion channel and gamma-aminobutyric-
acid (GABA) receptor modulation (Deuschl et al. 2011). Gabapentin is the most
effective treatment for OT. It is the first-line therapy, reducing both tremor and pos-
tural instability and improving quality of life (Rodrigues et al. 2006). Pregabalin,
which binds to the a2d (alpha2-delta) subunit of the voltage-dependent calcium
channel, showed significant improvements in ET patients in a double-blind, pla-
cebo-controlled, randomized trial (Zesiewicz et al. 2011), both in terms of acceler-
ometry recordings and action tremor limb scores on the Fahn–Tolosa–Marin rating
scale (see Sect. 8.1). Experimental data in the harmaline model of tremor in rodents
(see Chap. 3) also show a benefit (personal data). Nevertheless, according to the
most recent recommendations, there is no sufficient evidence to confirm or exclude
efficacy of pregabalin in ET (which therefore is a level U drug) (Deuschl et al.
2011). A case of ET responding to oxcarbazepine has been reported recently (Raj
et al. 2006). Topiramate (up to a maximum of 400 mg per day) is effective in the
treatment of moderate to severe ET. Tremor reduction is accompanied by functional
improvements, such as writing or speaking (Ondo et al. 2006; Connor et al. 2008).
Improvement of ET has been also reported with low doses (50 mg per day) (Gatto
et al. 2003). The main cause of dropout in controlled trials with topiramate was the
occurrence of side effects (weight loss, anorexia, extremity paresthesias, troubles
concentrating, memory disturbances, increased risk of kidney stones) (Deuschl
et al. 2011). Studies on levetiracetam have shown contradictory results regarding its
antitremor effect. It is not beneficial in the treatment of ET, as demonstrated by
double-blind placebo-controlled crossover trials (Elble et al. 2007; Handforth and
Martin 2004) and a 4-week, open label trial (Ondo et al. 2004). Nevertheless one
double-blind, placebo-controlled study demonstrated a significant reduction of hand
tremor for at least 2 h in ET patients treated with a single dose (1 g) of levetiracetam
(Bushara et al. 2005). Levetiracetam has also been proposed for the management of
cerebellar tremor in Multiple Sclerosis (Striano et al. 2006).
Levodopa, dopamine agonists, and anticholinergic agents are widely used in the
treatment of Parkinson’s disease and parkinsonian tremor. The main side effects of
long-term treatment with levodopa are motor fluctuations and dyskinesia. Resting
tremor as an initial manifestation of PD is associated with reduced risk of develop-
ing levodopa-induced dyskinesias (Kipfer et al. 2011). Dopamine agonists, such as
pramipexole and ropinirole, are probably the most effective tremorolytic drugs
among all dopaminergic agonists treatments and should be considered in newly
diagnosed PD patients exhibiting tremor in absence of cognitive impairment.
Improvement of tremor has also been reported with other dopamine agonists,
including pergolide and bromocriptine. Dopamine agonists are also useful in

advanced PD patients exhibiting a tremor refractory to levodopa and anticholin-
ergics (Bhidayasiri 2005). Apomorphine (subcutaneous, puffs) is used in advanced
forms of PD. Dopaminergic and anticholinergic agents are equally effective in
patients with parkinsonian tremor, but dopaminergic agonists improve other parkin-
sonian signs also (Habib-ur-Rehman 2000). Monoamine oxidase B (MAO-B) inhib-
itors are used in the symptomatic treatment of Parkinson’s disease as they increase
synaptic dopamine by blocking its degradation. Selegiline and rasagiline are cur-
rently used for the symptomatic improvement of early PD and to reduce off-time in
patients with more advanced PD and motor fluctuations related to levodopa.
Safinamide (MAO-B inhibitor) is currently under development in phase III clinical
trials (Schapira 2011). Midbrain tremor in patients with symptomatic dystonia and
mesencephalic lesions may significantly improve with levodopa (Vidailhet et al.
1999). Levodopa can also provide symptomatic relief in primary OT (Wills et al.
1999). Anticholinergics are not recommended in patients with cognitive decline,
heart disease, or in elderly patients over 65 years of age (Bhidayasiri 2005). In a
study comparing the effects of trihexiphenidyl, carbidopa–levodopa, and amanta-
dine hydrochloride in PD, tremor amplitude was reduced by 59% with trihexi-
phenidyl, 55% by carbidopa–levodopa, and 23% by amantadine (Koller 1986).
A case of successful monotherapy of midbrain tremor with high-dose trihexyphenidyl
has been reported (Liou and Shih 2006).
Other drugs have also shown efficacy in the treatment of tremor. Clozapine
could be considered for resistant parkinsonian tremor (see also Chap. 7) and in
selected cases of resistant ET but requires a close hematologic follow-up (Ceravolo
et al. 1999). Olanzapine might be effective in ETs (Yetimalar et al. 2005). The
calcium-channel blocker nicardipine might provide minor benefits (Jiménez-
Jiménez et al. 1994). Zonisamide might also be beneficial in ET. Few dramatic ET
responders to the barbiturate T2000 have been reported (Melmed et al. 2007).
Several new agents including 1-octanol and sodium oxybate are currently under
investigation (Sadeghi and Ondo 2010). Methazolamide previously reported as
possibly effective—particularly in ET patients with head and voice tremor (Muenter
et al. 1991)—has been considered ineffective subsequently (Deuschl et al. 2011).
Mirtazapine (a novel antidepressant widely used in Parkinson disease as both an
antidepressant and a sleeping aid) showed efficacy in both ET and parkinsonian
tremor case studies. These findings are not confirmed by controlled studies and
mirtazapine received a recommendation against its use (Deuschl et al. 2011).
However, this agent can be reasonably proposed in patients presenting tremor and
coexisting depression or insomnia (Abboud et al. 2011). Ondansetron (a 5HT3-
antagonist) provides no benefit or minor reduction on cerebellar tremor (Rice et al.
1997; Gbadamosi et al. 2001; Bier et al. 2003). Jaw tremor can be successfully
treated with botulinum toxin injections to the masseters (Gonzalez-Alegre et al.
2006). Tremor associated with peripheral neuropathy in the context of chronic
inflammatory demyelinating polyneuropathy (CIDP) may respond to steroid ther-
apy, cytotoxic drugs, intravenous immunoglobulin therapy, and plasma exchanges
(Cook et al. 1990; Dyck 1990).
23.3 Pharmacological Treatment of the Most Common

Neurological Disorders Associated with Tremor
23.3.1 Rest Tremor
Details on the pharmacological approach of rest and parkinsonian tremor are

discussed in Chap. 7. Briefly, the therapy of rest tremor is often based on anticho-
linergics (biperiden 2–6 mg per day, trihexyphenidyl 5–10 mg per day). Levodopa-
based medications (Levodopa + carbidopa; Levodopa + COMT inhibitors) and
dopamine agonists (pramipexole, ropinirole) are beneficial to reduce tremor inten-
sity, as mentioned earlier. Inhibitors of monoamine oxidase B (selegiline 10 mg per
day, rasagiline 0.5–1 mg per day) as adjunctive therapies of levodopa reduce tremor
intensity (Table 23.1).
The diagnosis of ET still relies on clinical examination, since there is no reliable

biomarker available. The disorder is probably underdiagnosed since patients may not
look for a medical care and misdiagnosis is not rare. For instance, drug-induced tremor
or enhanced physiological tremor can be misdiagnosed as ET. In addition, it should be
underlined that the neurotransmitter deficits remained unclear in ET (Manto and Laute
2008) and that drugs currently administered have been developed originally for other
disorders, with a “trial-and-error methodology” (Deuschl et al. 2011).
Table 23.1 Posology of the main Drugs Dose (mg)

drugs in the treatment of PD (adapted
from Grimaldi and Manto 2010) l-Dopa 375–1,000
Dopamine agonists
Bromocriptinea 5–20
Pergolideb 1–3
Ropinirolec 5–15
Pramipexolec 0.7–2.8
Apomorphine 1–4
Anticholinergics
Biperiden 2–6
Trihexyphenidyl 5–10
Inhibitors of MAO-B
Selegiline 10
Rasagiline 0.5–1
a
Risk of pulmonary fibrosis at high doses
b
Risk of valvular dysfunction due to cardiac fibrosis
c
Extended release (ER) forms are available
A recent update of the 2005 American Academy of Neurology practice

parameter on the treatment of ET provided the following recommendations and
conclusions (Zesiewicz et al. 2011; Deuschl et al. 2011):
– Propranolol, primidone (Level A, established as effective)
– Alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate (Level B,
probably effective)
– Nadolol, nimodipine, clonazepam, clozapine, botulinum toxin A (Level C, pos-
sibly effective). Ratings of postural and kinetic tremor improve slightly with
injections of botulinum toxin for essential hand tremor, but the benefit is modest
at best and side effects limit their use (Deuschl et al. 2011)
– Clonidine, gabapentin (adjunct therapy), glutethimide, l-tryptophan/pyridoxine,
metoprolol, nicardipine, octanol, olanzapine, phenobarbital, pregabalin, quetiapine,
T2000, theophylline, tiagabine, sodium oxybate, zonizamide (Level U, inadequate
evidence to confirm or exclude efficacy)
The agents with recommendations against use (ineffective) are the following—
into brackets the previous recommendations—(Deuschl et al. 2011):
– Trazodone (level A)
– Acetazolamide (level B), amantadine (level B), carisbamate (level B), isoniazid
(level B), levetiracetam (level B), pindolol (level B), 3,4-diaminopyridine (level B)
– Methazolamide (level C), mirtazapine (level C), nifedipine (level C), verapamil
(level C)
Changes to conclusions and recommendations, by comparing the 2005 guidelines
and the update from the group of Zesiewicz et al. (2011), include the following:
– Levetiracetam and 3,4-diaminopyridine probably do not reduce limb tremor in
ET and should not be considered (Level B)
– Flunarizine possibly has no effect in treating limb tremor in ET and may not be
considered (Level C)
– There is insufficient evidence to support or refute the use of pregabalin, zoniz-
amide, or clozapine as treatment for ET (Level U, insufficient evidence)
Medications for ET can be classified according to recommendation level (see
Table 23.2):
– As first-line agents (propranolol and primidone)
– As second-line agents (topiramate, gabapentin, levetiracetam, benzodiazepines)
– As third-line agents (clozapine, mirtazapine) (Abboud et al. 2011)
Patients with constant bothersome tremor should be started on a first-line agent,
either propranolol or primidone. The dosage should be optimized gradually according
to the patient’s response and the tolerability. A combination of the two first-line agents
can be used if ET is not sufficiently controlled with one single agent at the higher
tolerable dose. A second-line agent can be added to either of the first-line agents or to
the combination of both if tremor control is not yet sufficient. Combining two or more
second- and third-line agents is another option. A second-line or third-line agent can
Table 23.2 Posology of the main drugs in the treatment of ET (Grimaldi and Manto 2010;
Abboud et al. 2011; Zesiewicz et al. 2011)
Agent Starting dose Dose range per day Level of recommendation
Primidone 25 mg or even 12.5 mg 150–250 mg up to A
750 mg
Propranolol 10 mg (3 per day) 60–240 mg up to 320 A
Gabapentine 300 mg 1.200–1.800 mg B
(monotherapy)
Topiramate 25 mg Up to 400 mg B
Alprazolam 0.25 mg 0.75–2 mg B
Pregabaline 75 mg 75–300 mg U
A: effective; B: probably effective; U: inadequate evidence of efficacy
Table 23.3 Pharmacological treatment of the other disorders presenting with tremor
(see corresponding chapters in the book)
Disorder Pharmacological treatment
Dystonic tremor Botulinum toxin injections
Clonazepam (up to 8 mg per day)
Propranolol (up to 320 mg per day)
Primidone (up to 250 mg three times daily)
Orthostatic tremor Clonazepam (start with 0.5 mg up to 6 mg per day)
Gabapentin (300–2,400 mg per day)
Primidone, sodium valproatea, carbamazepine
Vocal tremor Propranolol (120 mg)
Primidone, gabapentin, benzodiazepine
Botulinum Toxin injections into the thyroarytenoid muscles
a
May induce a postural tremor mimicking essential tremor (Mehndiratta et al. 2005). See
also introduction of the chapter
also be used as the primary treatment if both first-line agents are contraindicated or not
tolerated. The choice of a given specific agent instead of another should be guided by
the patient’s characteristics and comorbidities in relation to the agent’s side effects and
contraindications (Abboud et al. 2011).
23.3.3 Other Disorders Presenting with Tremor
Therapies of the other disorders presenting with tremor (dystonic tremor, orthostatic
tremor, Familial Myoclonic Cortical Tremor with Epilepsy, etc.) as well as the
therapeutic strategies of the isometric tremor occurring in the frame of a given
disorder (PD, ET, etc.), are discussed in the dedicated chapters. Table 23.3 provides
a summary.
23.4 Conclusions and Perspectives
The importance of reaching the accurate diagnosis facing a patient exhibiting tremor
should be stressed once again. This is particularly the case for ET. Widely accepted
criteria are still missing, although an important effort has been made in that direc-
tion. A non negligible number of patients develop side effects with current medica-
tions, hence the need to promote research for novel therapies with a good safety and
efficacy profile. The lack of homogeneous methodology in the various clinical trials
has hampered research on effective drugs for tremor. However, validated rating
scales and performant motion transducers are now available. There is a lack of long-
term randomized controlled crossover trials with appropriate washout periods and
efforts should be made to gather a critical mass of patients in future pharmacologi-
cal studies, since many trials have included small number of patients and can be
considered as pilot studies. Validated scales of quality of life and standardized func-
tional tests included in composite scales (see Sect. 8.1) should be considered.
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Chapter 24
Thalamotomy
Julie J. Berk and Olga S. Klepitskaya
Keywords Thalamotomy • Stereotactic surgery • Thalamus • Vim nucleus

• Ablation • Lesion
24.1 Definition
Thalamotomy is a stereotactic ablation of specific thalamic nuclei for treatment of

movement disorders, in particular tremor.
24.2 History
The first surgical treatments of movement disorders date back to more than a cen-
tury ago when, in the late 1800s, British neurosurgeon Sir Victor Horsley (Fig. 24.1)
attempted cortical ablation for dyskinesia. Although surgical intervention within the
pyramidal nervous system did improve abnormal involuntary movements, they
resulted in severe adverse events such as paresis and paralysis. Discovery of the role
of the extrapyramidal nervous system in movement control became crucial for
switching surgical attention to subcortical structures. Several neurosurgeons per-
formed ablation of various subcortical structures. They reported improvement of
J.J. Berk
Department of Neurology, School of Medicine, University of Colorado, Aurora, CO, USA
O.S. Klepitskaya (*)
University of Colorado Denver, Mail Stop B185, 12631 East 17th Avenue, Aurora,
CO 80045, USA
e-mail: Olga.Klepitskaya@ucdenver.edu
432 J.J. Berk and O.S. Klepitskaya
Fig. 24.1 Sculpture

of Victor Horsley,
MD, created by
Dr. Emil Seletz
rigidity and bradykinesia in parkinsonian patients without inducing weakness and

spasticity. However, it was not until an accidental discovery by American neurosur-
geon Dr. Cooper that these findings were confirmed and reproduced in several
patients. During a pedunculotomy, an ablative surgery for severe tremor and rigidity
in a parkinsonian patient, Dr. Cooper accidentally tore the anterior choroidal artery.
This error resulted in complete abolishment of the tremor and improvement in rigid-
ity without weakness, thus confirming previous observations by others. This
approach, however, did not prove to be safe in subsequent surgeries due to the fact
that anterior choroidal artery provides blood supply to several other important struc-
tures in the subcortical area and has a high variability of vascular distribution.
Overall, open surgeries for tremor carried high risks of morbidity and mortality.
The evolution of the thalamotomy was made possible by the development of the
stereotactic neurosurgical technique. The first apparatus for cerebral localization
actually dates back to the 1860s and was developed by Paul Broca, famous for his
“brain mapping” work. Later, Russian neurosurgeons Zernov and Rossolimo inde-
pendently developed an “encephalometer” for neurosurgical procedures (Kandel
and Schavinsky 1972). Finally, in 1908, physiologist Robert H. Clarke, who worked
with Victor Horsley, MD, developed an apparatus designed to hold and guide an
electrode in the three-dimensional coordinate system. Although they were not the
first who designed such an apparatus, they were the first to call it stereotactic and
use it in animal research. The Horsley–Clarke stereotactic apparatus (Fig. 24.2) was
further developed into a stereotactic frame to use on humans (Fodstad et al. 1991).
24 Thalamotomy 433
Fig. 24.2 Clarke–Horsley’s

stereotactic device, first
presented in “The structure
and functions of the
Cerebellum Examined
by a New Method.” Brain
(31:45–124, 1908)
The advent of radiological techniques such as ventriculography and pneumoen-

cephalography allowed the use of intracranial instead of extracranial landmarks for
localization, thus improving the precision of targeting. The first human surgeries
using the stereotactic frame were performed by Wycis and Spiegel, also well known
for a modern stereotactic brain atlas (Spiegel 1952). This atlas is still being used for
the verification of localization during various stereotactic brain surgeries. During
that time period, several investigators independently developed stereotactic devices.
Finally, the most striking results of stereotactic pallidotomy were achieved by
Swedish neurosurgeon Lars Leksel in the 1940s (Leksell 1951) (Fig.24.3).
In the 1950s, in addition to the advent of stereotaxis during this period, the
medical community was faced with a spike in the population of patients with
postencephalitic parkinsonism. Few medicinal therapies at that time, in conjunction
with a more permissive environment for surgical research, led to the development of
several neurosurgical approaches to tremor and related movement disorders. The
first ablative procedure of the thalamus came about in the early 1950s. The thala-
mus, as a target for treatment of intractable tremor, was first introduced by Hassler,
who postulated that improvement of parkinsonian tremor might also be achieved by
a lesion of thalamic nucleus ventrolateral (VL) and nucleus ventro-oralis (Vo),
receiving pallidal input (Hassler et al. 1979). Later, with the development of
neurophysiological recording, it was found out that the cerebellar receiving zone of
thalamic nucleus ventro-intermediate (Vim) exhibits rhythmic bursting activity
similar to tremor. Vim has since become the most common target for thalamotomy.
Several others, such as the posterior subthalamic area, are being studied as alterna-
tive targets for tremor control.
Fig. 24.3 Leksell stereotactic

frame
With the introduction of levodopa in the late 1960s, surgical treatments were no
longer that popular with the exception of cases where tremor was non-levodopa
responsive. Over the period of a decade, however, the failure of long-term effective-
ness and unexpected adverse effects of levodopa led to the rebirth of surgical treat-
ment for tremor. The post-levodopa era of thalomotomy was advanced by improvements
in stereotactic frames and the use of computed tomography (CT) and magnetic reso-
nance imaging (MRI), introducing image-guided techniques. In addition, advances in
the understanding of basal ganglia neurophysiology and circuitry provided confirmation
of targets and the introduction of alternative targets for ablation.
The physiologic rationale for thalamotomy is based on the fact that the thalamus is a
key structure in the neuronal circuits thought to be responsible for the development
of tremor of different etiologies. The two neural circuits that have been proposed to
be responsible for tremor activity include (1) a basal ganglia-thalamocortical motor
loop and (2) a loop involving the cerebellum. The basal ganglia-thalamocortical
motor loop involves the globus pallidus, anterior ventrolateral thalamic nucleus (VL),
and supplementary motor area. This circuit is thought to be affected in Essential
Tremor (ET) and Parkinson Disease (PD). The cerebellar loop involves the cerebel-
lum, the posterior ventrolateral thalamic nucleus, and the motor cortex, and may
represent the etiology of the cerebellar tremor observed in patients with cerebellar
disorders, various lesions in cerebellar thalamic pathway, and sometimes in Multiple
Sclerosis (MS).
24 Thalamotomy 435
Tremor activity is consistently detected in the VL thalamic nucleus of patients

with ET and PD. The thalamic Vim nucleus is accepted to be the most common target
for treatment of ET. In the case of PD, however, this approach is usually not effective
for treatment of rigidity and bradykinesia. Other targets in the subthalamic-pallidal
pathway, such as the subthalamic nucleus (STN) and the Globus pallidus part interna
(Gpi), are more commonly used for PD. It was noticed, however, that all targets in
this pathway, such as thalamic Vim, STN, Gpi, as well as the posterior subthalamic
area, can result in the reduction of parkinsonian tremor. Therefore, further studies are
needed to determine the best surgical target in cases of tremor-predominant PD. For
cerebellar tremor, the Vim is currently the most common target, although emergent
data show that the posterior subthalamic area might be effective as well.
24.4 Stereotactic Surgical Technique
The surgical procedure consists of three major steps (1) anatomical targeting based
on radiologic landmarks, (2) neurophysiologic confirmation of intended target, and
(3) ablation or creation of lesion.
24.4.1 Image-Guided Anatomical Targeting
CT and/or MRI images are currently used for accurate localization of the target for
thalamotomy. The most commonly used landmarks are the anterior–posterior com-
missural (AC–PC) line and the border between the internal capsule and the thala-
mus. The intended ideal target is located 3 mm above AC–PC line and 2 mm anterior
to the principal sensory nucleus defined neurophysiologically (Lenz et al. 1995).
24.4.2 Neurophysiologic Confirmation of Intended Target
Intraoperative microelectrode recording (MER) is used for neurophysiologic

conformation of the ideal target location. The goal of MER is to localize the ventral
caudate nucleus (Vc) posterior to Vim and tremor-related neuronal discharges
within Vim (Lenz et al. 1988). MER within Vc reveals the response of sensory
cells to sensory stimulation applied by the examiner as touch and deep pressure.
The representation of these cells has clear oral to caudal medio-lateral somatotopic
distribution. Stimulation of Vc, sometimes applied via microelectrode (microstim-
ulation) for further confirmation, provokes the sensory response of paresthesias
(Lenz et al. 1994). MER within Vim reveals neuronal firing related to passive and
active movements and rhythmic tremor-related bursts. Stimulation of Vim pro-
vokes motor response and suppression of tremor. Suppression of tremor under
1.5 V indicates optimal location (Bittar et al. 2005).
Fig. 24.4 MRI brain depicts

a postoperative unilateral
lesion created by
thalamotomy
24.4.3 Neuroablation
The most common technique for neuroablation is thermocoagulation with a

radiofrequency generator used to heat the tip of the electrode. The temperature
initially is held constant at 60°C (140•F) for 1 min and then slowly increases in
5°C increments with 1-min intervals to 80°C. The procedure is done on an awake
patient and a neurological exam is performed carefully to assess the function of
adjacent structures such as speech, cerebellar function (dysmetria), pyramidal
tract function (strength), sensory pathways (paresthesias), etc. Lesions are made
within these tremor-related cells with the radius of 2.0–5.0 mm and volume 40 to
200 mm3 9 cubic mm or microliters (Fig. 24.4). The studies had shown that the
lesions as small as 40 mm3 can be effective for tremor suppression and that larger
lesions are naturally associated with higher incidence of adverse events. Therefore,
smaller lesions are preferable and currently the recommended average volume is
about 60 mm3. It was postulated, however, that this size of lesions is adequate to
control low amplitude tremor, such as tremor in ET and PD, but larger lesions are
still required to control cerebellar, posttraumatic, and other types of high ampli-
tude tremor (Nagaseki et al. 1986).
24 Thalamotomy 437
24.5 Clinical Outcomes
24.5.1 Conventional Thalamotomy
Surgical treatment of tremor is reserved for cases of severe disabling tremor resis-
tant to pharmacological treatment. Thalamotomy provides long-lasting tremor
suppression in patients with ET, PD, and other types of intention tremor, such as
tremor secondary to MS, posttraumatic tremor, etc. The majority of patients who
underwent thalamotomy for their tremor enjoy compete abolishing or reduction of
their tremor (Fig. 24.5). Most patients are able to discontinue pharmacological
treatment of their tremor and many are able to return to work. The prospective of
such improvement should be carefully weighed against possible side effects and
surgical complications, some of which can be severe and permanent.
The review of literature on this subject reveals several large-scale clinical trials
and many case presentations and case series. Overall, the results of these studies
demonstrate improvement in tremor severity 70–90% in PD; even higher 80–100%
in ET; less, but still quite significant, in other tremor etiologies ranging from 44 to
82% (Nagaseki et al. 1986; Jankovic et al. 1995; Krauss et al. 1992; Schuurman
et al. 2000; Yap et al. 2007; Zirh et al. 1999). Importantly, these positive results are
long lasting. Long-term follow up conducted up to 10 years postthalamotomy
reported sustained tremor control in about 80% of patients, and diminished, but still
significant, in the rest. The decreased tremor suppression is most frequently seen in
patients with ET and other types of intention tremor and is usually stable in parkin-
sonian tremor (Schuurman et al. 2008).
The reports of incidence of complications after thalamotomy have significant
variation in literature and range between 14 and 58% (Jankovic et al. 1995; Zesiewicz
et al. 2005). The adverse events from surgical procedure include intracerebral and
extracerebral hemorrhage, seizures, infection, tension pneumocephalus, pulmonary
embolism. Clinically significant hemorrhages occur in 1–6% of surgeries, while
radiologically defined hemorrhage is detected in up to 22%, which is slightly higher
than in nonablative stereotactic brain surgeries. The incidence of infection, in con-
trast, is lower and reported to be around 1%. Postoperative neurological complica-
tions include dysarthria (29%), dysphagia, postural instability, ataxia (8%),
paresthesias (3%), hemiparesis (34%), blepharospasm, and cognitive impairment.
Transient postoperative functional deficits are reported in up to 58% of cases
(Jankovic et al. 1995). Persistent neurological deficits are reported in 9–28% of
patients with unilateral thalamotomy and much more frequently 28–88% with bilat-
eral. Most disabling permanent neurological deficits include hemiparesis, dysarthria
and dysphagia, and cognitive impairment (Krauss et al. 1992; Schuurman et al. 2000;
Yap et al. 2007; Zirh et al. 1999; Goldman and Kelly 1992; Niranjan et al. 1999).
Therefore, unilateral thalamotomy is considered to be much safer, and bilateral is no
longer recommended due to unacceptably high incidence of permanent irreversible
neurological deficits.
Fig. 24.5 Example of spiral drawings and handwriting demonstrates dramatic improvement after
thalamotomy
24.5.2 Radiosurgical Thalamotomy
Radiosurgery using the Gamma Knife (GK) or linear accelerator to create a lesion
in the thalamus has been considered to replace conventional thalamotomy. It has the
theoretical advantage of being less invasive, and it does not require anesthesia.
Therefore, it was thought to carry minimal risk. Several studies showed positive
results with excellent tremor control in 88–93% of patients (Young et al. 1998;
Friedman et al. 1996). Unfortunately, due to technical difficulties and unpredictable
tissue response to radiation, the lesions following GK thalamotomy are often larger
24 Thalamotomy 439
than expected (Lindquist 1992). In addition, both benefits and side effects resulting
from GK thalamotomy are delayed 1–12 months following the treatment (Okun
et al. 2001). This is due to the fact that following radiation, lesions tend to expand
over time. Some examples of delayed side effects post-GK treatment include swal-
lowing difficulty, visual field deficits, weakness, numbness, pseudobulbar affect,
hypophonia, and thalamic aphasia (Okun et al. 2001). Problems with variability in
lesion size, delayed growth of lesion, and consequent delay of adverse effects
indicate a complication rate that is larger than in conventional thalamotomy
(Niranjan et al. 1999; Jankovic 2001; Schuurman et al. 2002).
24.5.3 Deep Brain Stimulation Versus Thalamotomy
In 1987, Benabid (Benabid et al. 1996) first reported successful treatment of medi-
cation-resistant tremor in PD by chronic high frequency stimulation of the Vim
nucleus of the thalamus via implanted electrode. This started a new era in the surgi-
cal treatment of movement disorders: the era of Deep Brain Stimulation (DBS). The
major advantage of DBS over ablative surgery is the adjustable and reversible nature
of this treatment compared to the permanent and irreversible lesion placed during
thalamotomy. In the case of side effects related to certain stimulation settings, DBS
can be reprogrammed to maximize benefits and minimize side effects. In the case of
suboptimal electrode location, which can happen even in the hands of the best surgi-
cal team, the electrode can be repositioned to achieve better results. Finally, in the
case of emergence of a new, superior type of treatment for tremor, stimulation can
be discontinued and the DBS electrode can potentially be explanted. Therefore, in
late 1990s, thalamic DBS largely replaced thalamotomies in most of the centers
throughout the world.
Schuurman et al. (2000) provided scientific conformation of the validity of this
approach. To test the hypothesis that thalamic DBS provides greater functional
improvement than thalamotomy, they conducted a randomized comparison of these
two types of surgical treatments in patients with PD-, ET-, and MS-related tremor.
The results of this study demonstrated that both surgeries were equally effective: 27
out of 34 patients in the DBS group and 30 out of 33 patients in the thalamotomy
group had complete or almost complete suppression of tremor. Thalamic DBS,
however, had fewer adverse events and resulted in greater improvement of function
than thalamotomy: functional status was reported as improved in 18 out of 34
patients with thalamic DBS and only 8 out of 33 with thalamotomy. The major rea-
son for this was higher morbidity from thalamotomy compare to DBS. In addition,
patients with bilateral tremor had the advantage of receiving bilateral thalamic DBS
compared to only unilateral thalamotomy, because at that time bilateral thalamo-
tomy was no longer used in clinical practice due to an unacceptable side effect
profile (Jankovic et al. 1995; Goldman and Kelly 1992; Matsumoto et al. 1976).
Furthermore, these scientists later reported the long-term outcomes of this study.
After 5 years of follow up, the tremor suppression effect was stable in PD, but
diminished in half of patients with ET and MS in both groups, slightly more in DBS
group. There were six DBS equipment complications reported, but overall neuro-
logical side effects were higher in thalamotomy group. Overall, the functional out-
comes were still in favor of DBS (Schuurman et al. 2008).
In another publication, researchers compared thalamic DBS and thalamotomy
in 20 patients with MS-related tremor (Bittar et al. 2005). In their experience,
DBS was less efficacious for tremor suppression compared to thalamotomy. They
demonstrated only 64% vs. 78% improvement in postural tremor and 36% vs.
72% improvement of intention tremor in DBS vs. thalamotomy group respect-
fully. Despite less efficacy, they also concluded that DBS is a preferred surgical
strategy due to the significantly higher incidence of persistent neurological deficits
in the thalamotomy group (10% vs. 30%). The recent review of literature (Yap
et al. 2007) also supported this conclusion, but emphasized that adverse events,
including severe and permanent, can happen in both surgical groups.
The current consensus is that DBS is superior to thalamotomy for treatment of
tremor. DBS is safer and has many advantages comparative to ablative surgeries, but
has some disadvantages as well. The major disadvantages of DBS include high cost
and, the need for long-term maintenance and hardware-related complications. In
order to achieve maximum benefits from DBS, the surgery and the programming
should be performed by experienced physicians working as a part of a comprehen-
sive multidisciplinary team of experts (Bronstein et al. 2011). It requires lengthy
initial programming and multiple further stimulation adjustments over the total span
of DBS treatment. Replacement of implantable pulse generator (IPG) is usually
needed every 3–5 years, although new rechargeable IPG recently became available.
The latest, however, require patients’ compliance with frequent and sometimes daily
recharging that might be a burden to some patients. Hardware-related complica-
tions, such as fractures of extension wires and infections are common. As a matter
of fact, the recent large-scale multicenter study of DBS for treatment of PD reported
the rate of infection complications to be as high as 9.9% (Weaver et al. 2009).
Although DBS is considered to be superior to thalamotomy, in certain cases
where the difficulties associated with DBS might present serious limitations, thala-
motomy still can be a valuable surgical treatment option for disabling tremor. These
cases include, but not limited to poorly compliant, elderly, or cognitively impaired
patients; situations when the access to regular specialized medical care is limited,
for example the patient lives in remote or economically deprived regions, etc.
(Schuurman et al. 2000, 2002; Niranjan et al. 1999).
24.6 Current Expert Consensus Regarding Thalamotomy
The expert consensus regarding management of tremor is reflected in the practice

parameters periodically issued by American Academy of Neurology (AAN) and
several recent consensus statement publications based on evidenced-based review
of all up-to-date world literature.
24 Thalamotomy 441
For ET, the last AAN guidelines were issued in 2005 (Zesiewicz et al. 2005) and
are currently in revision. These guidelines concluded that “unilateral thalamotomy
may be used to treat limb tremor that is refractory to medical management (Level C,
positive recommendation),1 but bilateral thalamotomy was not recommended due to
increased risk of adverse side effects” (Level C, positive recommendation), including
permanent neurological deficits. DBS had been shown to have fewer adverse events
than thalamotomy. However, it was emphasized that “the decision to use either
procedure depends on each patient’s circumstances and risks for intraoperative
complications compared to feasibility of stimulator monitoring and adjustments.”
The evidence-based review of surgical treatment options for PD was issued by
AAN in 2000 (Hallett and Litvan 1999), then in 2006 (Pahwa et al. 2006), and was
recently updated in the expert consensus statement in 2011 (Bronstein et al. 2011).
In the first publication, unilateral thalamotomy was recommended as an effective
and safe treatment for severe, medically intractable, asymmetric parkinsonian
tremor, especially in cases of tremor predominant PD (Level C, positive recommen-
dation). However, thalamotomy was associated with high adverse events, specifically
speech and swallowing problems, therefore the recommendations were against
bilateral thalamotomy (Level D, negative recommendation),2 and thalamic Vim
DBS was recommended as a treatment of choice for the other side if necessary. It
was emphasized that thalamotomy has “immediate and complete effect at the time
of surgery, but it is irreversible,” and DBS produced fewer adverse effects and
greater improvement of function. It is interesting that 2006 publication did not
address thalamotomy, probably reflecting the fact that this procedure was largely
replaced by DBS; but expert consensus statement regarding surgical treatment of
PD in 2011 admitted that “ablative therapy is still an effective alternative to DBS
and should be considered in a select group of patients” (Bronstein et al. 2011). This
change in views probably reflects the fact that long-term complications and side
effects of DBS, specifically the high incidence of infections at the hardware implan-
tation site, became more evident over the years. It is important to recognize that
thalamotomy improves only tremor and cannot help bradykinesia and other
symptoms of PD, and, therefore, other targets should be considered to address full
spectrum of parkinsonian motor impairments.
Guidelines concluded that the data regarding the use of radiofrequency GK
thalamotomy for the treatment of tremor in ET and PD were insufficient to make
any recommendations in this regards.
Contraindications for surgery in all tremor etiologies include significant cogni-
tive impairment, medical comorbidities, especially bleeding disorders, untreated or
unstable psychiatric disease, abnormalities on brain imaging, and predisposition to
infections. However, in patients with these problems and very severe disabling
tremor, the ratio of risks to benefits could favor thalamotomy over DBS.
1
Level C: positive recommendations based on strong consensus of Class III evidence.
2
Level D: negative recommendations, based on inconclusive or conflicting Class II evidence or
consensus of Class III evidence.
All experts agree with the fact that surgical treatments of tremor require a
neurosurgeon with a high level of expertise in stereotactic techniques working as
a part of a multidisciplinary team that includes a neurologist, a neurophysiologist, a
psychiatrist, a psychologist, a neuroradiologist, and physical and speech therapists
with expertise in the diagnosis, assessment, and treatment of movement disorders.
This is especially important in the case of ablative surgeries, such as thalamotomy,
because of the irreversible nature of these procedures. Inexperienced centers will
likely have fewer good results and more adverse events (Bronstein et al. 2011;
Hallett and Litvan 1999).
24.7 Conclusion
Stereotactic ablation of Vim nucleus of thalamus, known as thalamotomy, is a very

effective and long-lasting treatment for contralateral resting, postural, and intention
tremor associated with various neurological diseases, most commonly ET, PD, and
MS. Unfortunately, the use of this procedure is limited by high incidence of
unacceptable and irreversible adverse events, especially if done bilaterally.
Therefore, bilateral thalamotomy is no longer recommended. Nevertheless, unilateral
thalamotomy is still a valuable alternative for treatment of disabling, medication
intractable tremor when other surgical modalities are not feasible.
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Chapter 25
Deep Brain Stimulation
Ioannis U. Isaias and Jens Volkmann
Keywords Deep Brain Stimulation • Surgery • Thalamus
Tremor is one of the most elusive clinical signs being part of several different diag-
nosis and presenting variably (e.g., at rest, postural or action tremor) within the
clinical spectrum of a single disease. Many neurological disorders are associated
with tremor; the most common are Essential tremor (ET) and Parkinson disease
(PD) (Deuschl et al. Mov Disord 13(Suppl 3):2–23, 1998). Although pharmaco-
logic treatments for tremor are available, the result may be inconsistent or there may
be no benefit (Lyons et al. Drug Saf 26:461–481, 2003; Olanow et al. 56(Suppl
5):S1–S88, 2001; Pahwa and Lyons Am J Med 115:134–142, 2003; Deuschl et al.
Mov Disord 17(Suppl 3):S102–S111, 2002). DBS is currently the treatment of
choice for medication-resistant tremor (Benabid et al. J Neurosurg 84:203–214,
1996; Tasker Surg Neurol 49:145–154, 1998; Schuurman et al. N Engl J Med
342:461–468, 2000; Pahwa et al. Mov Disord 16:140–143, 2001) and proved com-
parable benefit with fewer side effects than thalamotomy, especially with bilateral
procedures (Hassler et al. Brain 83:337–350, 1960). The Food and Drug
Administration (FDA)-approved indications for thalamic DBS are ET and PD, but
only unilateral DBS has FDA approval. There is increasing evidence though that
thalamic DBS is effective for tremor secondary to other causes, such as multiple
sclerosis, or for complex tremor syndromes. In such cases, bilateral thalamic DBS
or DBS for non-ET and non-PD would be considered “off-label” and eventually
experimental or investigational.
I.U. Isaias (*) • J. Volkmann

Neurologische Klinik und Poliklinik, Universitätsklinik Würzburg, Würzburg, Germany
e-mail: iuisaias@yahoo.it
446 I.U. Isaias and J. Volkmann
25.1 Introduction
25.1.1 Anatomical Target for Deep Brain Stimulation

in Tremor Disorders
Several nomenclatures have been used for nuclei of the motor thalamus (Hassler
1959; Walker 1982; Hirai and Jones 1989; Jones 1990). According to Hassler
(1959), the motor thalamus lies ventral lateral nucleus of the thalamus. This area
consists of the lateral polaris (Lpo), which receives input from the globus pallidus
interna (GPi) and substantia nigra pars reticulata; the ventralis oralis anterior (Voa)
and ventral oralis posterior (Vop), which receive input from the GPi; and the ventral
intermediate nucleus (VIM), which receives input from the cerebellum and
lemniscal system (Krack et al. 2002). Microelectrode recordings during stereotactic
surgery identified the presence of tremor cells within the VIM (Jones and Tasker
1990; Lenz et al. 1988, 1994). Subsequently, this area was found to be the most
effective target for ablative surgical treatment (Hassler et al. 1960). Accordingly, the
standard stereotactic coordinates for thalamic DBS are located at the border between
the VIM and the subthalamic white matter (Benabid et al. 1996; Krack et al. 2002).
Of relevance, rhythmic, tremor-locked neural activity can be identified in these
thalamic nuclei, but also in the GPi, putamen, caudate nucleus, and subthalamic
nucleus (STN) (Bergman et al. 1994; Hutchison et al. 1997; Magnin et al. 2000) and
its pathophysiologic role in causing tremor is uncertain. The optimal anatomical
target structure for neurostimulation is still debated. Besides VIM, the posterior
subthalamic area (PSA), including the zona incerta, and the prelemniscal radiation
was introduced as a possible target for subthalamotomies in patients with tremor
(Wertheimer et al. 1960; Mundinger 1969), but the interest for applying DBS to this
area has been limited (Velasco et al. 2001). Recent case series have challenged the
concept of tremor abolition by neurostimulation of the thalamus proper and located
the most effective stimulation site within the subthalamic fiber area (Kitagawa et al.
2000; Murata et al. 2003; Plaha et al. 2004; Herzog et al. 2007; Blomstedt et al. 2010;
Sandvik et al. 2011). Last, in one patient with long-standing pure head tremor from
myoclonus dystonia, bilateral DBS of the dentate–rubro–thalamic tracts greatly
improved tremor (Coenen et al. 2011).
25.1.2 Mechanism of Action
The brain can basically be compared with an electronic device. Information is

processed by integrating excitatory and inhibitory postsynaptic electrical potentials
and is encoded in the subsequent train of electrical action potentials. Although the
basic physiological mechanism of DBS is unknown, most evidence suggests that
DBS effects rely on the electrical excitation of fiber tracts (Holsheimer et al. 2000;
Kiss et al. 2003; Anderson et al. 2004, 2006; Montgomery and Gale 2008) and
25 Deep Brain Stimulation 447
presynaptic terminals in the vicinity of the DBS electrode, including those that project
to and from neurons in the stimulated target (Beurrier et al. 2001; Kiss et al. 2002;
Magariños-Ascone et al. 2002; Montgomery 2010). Accordingly, the stimulation
within the thalamus proper might influence neuronal activity of thalamo–cortical pro-
jection neurons (McIntyre et al. 2004); whereas, stimulation of the subthalamic area
would eventually impact afferent cerebello–thalamic fibers (Anderson et al. 2006).
Still, this may be just an oversimplistic description, as electrical stimulation has
ortho- and antidromic effects. Therefore, when stimulating the VIM, one may still act
upon the dentate–thalamic fibers antidromically. DBS systems use pulses of electrical
energy. The main goal of DBS is to excite the intended brain target while minimizing
stimulation or spread of this current to other elements (see later, adverse events).
Stimulation parameters that can be modulated in order to achieve this result include
electrode location and polarity, voltage or current amplitude (which are interrelated
by Ohm’s law), pulse width, and frequency of stimulation. Besides proficient elec-
trode programming, successful DBS therapy also relies on a series of interrelated
issues, including accurate candidate selection, precise lead placement, expert medica-
tion adjustment, management of side effects, patient education, and support (Moro
et al. 2006; Isaias and Tagliati 2008). Currently available DBS pulse generators
(IPGs) differ on whether voltage or electrical current is controlled. Constant-current
IPGs provide a specified amperage (electrical current), whereas constant-voltage
IPGs provide a specified voltage, in this second case electrical current would vary
according to impedance (Montgomery 2010). Accordingly, in some patients with
constant-voltage stimulation, likely because of increases in tissue impedance during
the postoperative formation of the electrode–tissue interface, voltage needs to be
increased over the first weeks following surgery to preserve tremor control (Benabid
et al. 1987a, b; Hariz et al. 1999; Tarsy et al. 2005). The surgical method for VIM
DBS (Baker et al. 2004) and programming (Isaias and Tagliati 2008) has been
reviewed elsewhere. Last but not least, it is important that patients are aware that DBS
does not cure the underlying neurological disorder and disease-related symptoms
may progress despite DBS surgery.
25.2 Thalamic DBS as a Symptomatic Treatment for Tremor
25.2.1 Parkinson Tremor
Before the introduction of l-Dopa, thalamotomy was the most common surgical
procedure for the treatment of parkinson tremor. This was because of its lower mor-
bidity compared with pallidotomy and striking benefit for tremor. Thalamic DBS
was originally introduced as an adjunct to thalamotomy for patients requiring a
bilateral procedure, which carries a high risk of permanent dysarthria if lesioning is
applied to both hemispheres (Benabid et al. 1987a, b). Subsequently, it rapidly
replaced thalamotomy due to the nonablative nature of surgery, the reversibility of
the procedure, and the ability to adjust stimulation parameters to improve efficacy
and reduce adverse effects. There are relatively few studies comparing thalamotomy
and VIM DBS. The major difference between the two is the rate of permanent
surgery-related neurological deficits. Patients undergoing thalamotomy may report
cognitive deterioration, dysarthria, gait or balance disturbance, and arm ataxia. Of
relevance, in several thalamotomy cases, surgery may need to be repeated to achieve
a satisfactory response. Increasing thalamotomy size increases morbidity (Stellar
and Cooper 1968; Hirai et al. 1983; Benabid et al. 1996; Pollak et al. 2002; Tasker
1998; Lund-Johansen et al. 1996; Schuurman et al. 2000). Numerous studies
confirmed the great therapeutic effect of VIM DBS on parkinson tremor (Lyons
et al. 2001; Pahwa et al. 2006; Rehncrona et al. 2001; Albanese et al. 1999; Hariz
et al. 2008). VIM DBS also proved some efficacy in patients with previous contral-
ateral thalamotomies (Benabid et al. 1987a, b) or pallidotomies (Nishio et al. 2009).
Still, VIM DBS has little or no effect on other parkinsonian signs, especially
bradykinesia or gait disorder, and it does not prevent levodopa-associated motor
complications. Therefore, GPi or STN DBS is preferred if these problems are
prominent (Tarsy et al. 2003; Krack et al. 1998) or may appear along with disease
progression (Tarsy et al. 2005). It is important to note, however, that this recom-
mendation is purely based on clinical experience and that there is no randomized
controlled clinical trial available comparing the targets in the short- or long-term for
tremor control. Advantage of VIM DBS, in comparison to GPi or STN DBS, is that
advanced age is not an absolute contraindication because it is a simpler and shorter
procedure. Moreover, clinical efficacy on tremor can be reliably assessed intraop-
eratively, while the beneficial effects of STN- or GPi-DBS may require prolonged
stimulation, sometimes for months. Therefore, in elderly non-fluctuating patients
with a stable mostly unilaterally dominant tremor or in patients suffering from
benign tremulous parkinsonism, VIM DBS may be suggested (Hariz et al. 2008;
Savica et al. 2011). Bilateral thalamic stimulation is also possible in the case of
severe bilateral tremor, although a higher incidence of speech and balance problems
could be expected (Ondo et al. 2001). Finally, when VIM DBS is used to control PD
resting tremor, drugs for PD are either unchanged (Krack et al. 1998) or slightly
reduced (Hubble et al. 1997; Tasker 1998). Therefore, it is not advisable to perform
VIM DBS in PD patients with drug-induced adverse events (e.g., dyskinesia), for
whom a drugs reduction is desirable.
Essential tremor is the most common tremor disorder (Zesiewicz et al. 2011). At
present, the VIM of the thalamus is the most commonly targeted site for DBS in
medication-resistant, disabling patients with ET. There have been several retro-
spective, unblinded, and uncontrolled studies reporting the benefits of DBS of the
VIM of the thalamus for the treatment of ET (Pahwa et al. 2001, 2006; Koller et al.
1997, 2001; Limousin et al. 1999; Sydow et al. 2003; Putzke et al. 2003, 2004).
Multiple long-term studies, with follow-up ranging from 1 to 7 years, demonstrated

a significant improvement up to 91% in hand tremor after thalamic DBS (Koller
et al. 2001; Sydow et al. 2003; Rehncrona et al. 2003; Putzke et al. 2004; Pahwa
et al. 2006). These studies have also shown significant benefit in head and voice
tremor, ranging from 15% to 100%; although greater benefit was achieved by bilat-
eral procedures. DBS efficacy in patients with ET was in most of the cases main-
tained over time. Still, some decrement in efficacy was reported. It is unclear if this
is related to disease progression, tolerance, or some other phenomenon. Only one
randomized and double blind study is available on VIM DBS efficacy for ET. In
this study 18 patients were investigated in the stimulation on and off condition and
followed up for 2 years; other 13 patients reached a 6 or 7 years follow-up after
thalamic DBS. Total tremor scores improved 49% at 2 years and 47% at last
follow-up postoperatively. Similarly, tremor presence when writing, drawing, and
pouring improved 75% at 2 years and 55% at 6–7 years. The stimulation off
condition at follow-up did not differ from baseline (Rehncrona et al. 2003).
25.2.3 Isolated Head Tremor
One single study specifically investigated thalamic DBS for isolated head tremor
(Berk and Honey 2002). Berk and Honey reported complete resolution of head
tremor 9 months after bilateral thalamic DBS in two patients. Besides this case
report, several studies (Limousin et al. 1999; Koller et al. 1999; Obwegeser
et al. 2000; Ondo et al. 2001; Sydow et al. 2003; Putzke et al. 2004, 2005)
reported improvements in head tremor in patients who received thalamic DBS
because of disabling hand tremor. In these studies, a consistent and sustained
improvement of head tremor ranged from 15% to 51% for unilateral procedures
and 39% to 100% for bilateral procedures.
25.2.4 Essential Voice Tremor
Carpenter et al. specifically studied the effect of VIM DBS on voice tremor in five ET
patients with bilateral DBS and two with unilateral implants. Four patients showed a
remarkable improvement, especially with bilateral DBS. DBS efficacy on voice tremor
was not paralleled by improvement on upper limbs tremor. Patients with more severe
symptoms showed greater results (Carpenter et al. 1998). No other study specifically
addressed voice tremor. Still, thalamic DBS proved some efficacy in ameliorating voice
tremor in patients with ET. In particular, voice tremor improved about 30% on average
with unilateral implants and 60% on average with bilateral DBS (Limousin et al. 1999;
Obwegeser et al. 2000; Sydow et al. 2003). In some cases, unilateral DBS was not
effective on voice tremor (Sydow et al. 2003; Obwegeser et al. 2000).
25.2.5 Orthostatic Tremor
Orthostatic tremor (OT) is a rare syndrome mainly characterized by high-frequency

tremor of weight-bearing limbs, typically when standing and with isometric muscle
activation. Many patients also suffer from tremor, at lower frequencies, of the face,
hands, or trunk (Gerschlager and Brown 2011). There are only a limited number of
case reports concerning DBS in OT. Espay and colleagues reported outcomes in two
patients who underwent, respectively, unilateral and bilateral VIM DBS for medi-
cally refractory OT. Both subjects significantly improved after surgery. Still, the
patient implanted unilaterally returned to pre-surgical severity of symptoms shortly
after surgery, although a reduction of drugs dose was possible. The other subject,
with bilateral DBS, showed an improvement in tolerance and latency to symptom
onset when standing to 18 months after surgery (Espay et al. 2008). Guridi and col-
leagues (2008) described a patient with severe OT unresponsive to pharmacological
treatments that was successfully controlled with VIM DBS over a 4-year period. Of
relevance, DBS re-programming (with progressive voltage increments) was required
about 4 weeks after implants for reoccurrence of tremor. Last, Magariños-Ascone
et al. confirmed in one patient the efficacy of VIM DBS for drug refractory OT
providing electrophysiological evidence of tremor cessation both during standing
and during the stance period of gait cycle (Magariños-Ascone et al. 2010).
25.2.6 Tremor After Focal Brain Lesions (Posttraumatic

Tremor, Post-stroke Tremor)
It is generally accepted that Holmes tremor (a combination of a lower frequency

resting tremor and a 6–7 Hz action and intention tremor) occurs after different
lesions centered to the brainstem/cerebellum and thalamus. The dopaminergic
nigrostriatal system, the cerebellothalamic, and possibly pallidothalamic fibers
must be affected. Remarkable and sustained benefit has been obtained by VIM DBS
on Holmes tremor secondary to hemorrhage (Samadani et al. 2003; Goto and
Yamada 2004; Lim et al. 2007), infarct (Nikkhah et al. 2004; Hertel et al. 2006),
tumor, or abscess (Pahwa et al. 2002; Piette et al. 2004) also in young patients.
Peker et al. reported a case of a 14-year-old girl who developed Holmes tremor due
to a thalamic abscess and was successfully treated by thalamic DBS reaching 90%
improvement at 2.5 years follow-up (Peker et al. 2008). Acar et al. (2010) described
tremor suppression after VIM DBS in a young patient with drug resistant resting,
action, and postural tremor in both arms and orolingual region due to a subarach-
noid hemorrhage. Sanborn and colleagues (2009) described symptomatic and func-
tional improvement after VIM DBS of Holmes-like left-upper-extremity tremor
refractory to medical treatment due to a cystic degeneration of the brainstem. Beside
the thalamus, other anatomical targets have been proposed in alternative, or
associated, to VIM. Goto and Yamada managed to suppress tremor by means of a
pallidotomy in a patient with tremor reoccurrence 1 year after VIM implants (Goto
and Yamada 2004). Lim et al. reported moderate tremor suppression by DBS of the
GPi in one subject that poorly responded to VIM DBS (Lim et al. 2007). Foote and
colleagues performed two parallel lead insertions in the thalamus (VIM and Voa/
Vop border) of three patients with Holmes tremor with proximal and distal tremor.
Greatest benefit was described when both the VIM and Voa/Vop electrodes were
active (Foote et al. 2006). DBS of the STN might also be an effective treatment for
residual rest tremor after VIM DBS (Romanelli et al. 2003). Last, DBS of the con-
tralateral lenticular fasciculus proved some efficacy on debilitating post-midbrain
infarction tremor in one patient with Benedikt syndrome (Bandt et al. 2008).
Tremor has been described also as a possible consequence in about 5% of the
patients after severe head injury (Krauss and Jankovic 2002). In this case tremor
may appear weeks or months after injury and it is coarse and irregular, with a fre-
quency of about 2–3.5 Hz. The most frequent clinical presentation is a Holmes
tremor or a cerebellar tremor resulting from either hemorrhage or diffuse axonal
injury at the level of midbrain. Most posttraumatic tremors resolve spontaneously,
but some are persistent, refractory to medical therapy and result in severe disability.
Only few case reports are available and the efficacy of DBS in posttraumatic tremor
is still debated (Krauss and Jankovic 2002; Broggi et al. 1993; Nguyen and Degos
1993; Umemura et al. 2004). Surgical treatment in these cases aims to improve
activities of daily living, rather than completely suppress tremor. Nguyen and Degos
reported that stimulation of the lower part of the VIM was most effective in the
distal component of the tremor, whereas its proximal component was specifically
reduced by stimulation of its upper part (Nguyen and Degos 1993). Umemura and
colleagues (2004) described better results when effective contacts were located in
the middle part of VIM. Krauss et al. prefers zona incerta or its combination with
VL thalamus (Krauss et al. 1994). A combined neurostimulation of the VIM and
STN is also possible and can be a successful treatment for posttraumatic tremor and
hemiparkinsonism, even in the long term (Reese et al. 2011).
25.2.7 Tremor Secondary to Multiple Sclerosis
Tremor is a common and often very disabling complication of Multiple sclerosis

(MS). About half of patients with MS may suffer from disabling tremor (part of
Charcot’s triad 1) due to cerebellar or brainstem lesions. Tremor is generally a
large-amplitude, 2.5- to 7-Hz postural, kinetic, or intention tremor that most com-
monly affects the upper extremities, although the lower extremities, head, neck, or
trunk can be affected (Koch et al. 2007). Several studies examined the effects of
thalamic DBS on MS tremor. The majority of these are single-center studies with
small sample sizes (Geny et al. 1996; Schulder et al. 1999, 2003; Berk et al. 2002;
Wishart et al. 2003). Few reports have follow-up longer than 1 year (Nguyen and
Degos 1993; Montgomery et al. 1999; Krauss et al. 2001; Torres et al. 2010).
Results are consistent in showing that VIM DBS significantly reduces tremor in
subjects with MS and that the benefit is sustained over time, at least up to 3 years
after surgery (Wishart et al. 2003; Yap et al. 2007). Unfortunately, it is rare for a
patient with MS to have tremor as their sole disability and DBS is not effective on
other MS-related symptoms (e.g., ataxia). Therefore, candidates for VIM DBS
must be carefully selected and the tremor affected body region should not present
additional weakness, ataxia, or sensory loss that could cause persistent disability
after successful alleviation of tremor. Tremor involving proximal limb is poorly
responsive to VIM DBS. Preliminary evidence suggests that both Vop and the
zona incerta might be better targets to improve proximal and axial motor control
(Nandi and Aziz 2004). A frequent problem in patients with action tremor,
especially when secondary to MS, is the rapid development of tolerance to the
DBS settings, which can occur within days. The mechanisms for tolerance are
uncertain. To avoid tolerance, most patients may turn the stimulator off at times,
eventually during the night. Another option is to implant impulse generators that
allow the patient and/or caregiver some minimal changes, such as a small reduc-
tion in stimulation voltage. Another issue of VIM DBS in MS patient is the risk
for triggering a relapse of MS coincident with the DBS procedure. Such a risk
may range between 10% and 20% of all procedures (Montgomery et al. 1999;
Wishart et al. 2003). Surgical candidate should therefore present stable symptoms
for at least 6 months previous to implants. Patients should be advised that DBS
does not cure the underlying neurological disorder and that MS may progress
despite VIM DBS surgery. The decision to proceed with VIM DBS surgery should
therefore carefully consider whether a major reduction in tremor is sufficient to
justify the surgical risk of DBS, estimated as a 2–3% risk of a significant and/or
persistent neurological complication (see later).
25.2.8 Primary Writing Tremor and Dystonic Tremor
Primary writing tremor (PWT) is the most frequent task-specific tremor and
typically presents with a 5–7 Hz frequency only during the act of writing (Bain
et al. 1995). The pathophysiology of PWT is not clear. In particular, it is still not
clear if it is a variant of ET, dystonia, a combination of both, or a separate entity
(Bain 2011). Preliminary data suggest that VIM DBS is a valid therapeutic
option for PWT providing nearly complete relief of tremor (Minguez-Castellanos
et al. 1999; Racette et al. 2001).
Dystonic tremor may present with many different clinical presentations
(rhythmic oscillations, abnormal posture, and/or pain) and DBS of the GPi is
greatly effective (Vidailhet et al. 2007; Azoulay-Zyss et al. 2011). Anecdotal
reports suggest early (minutes to days), target-dependent, improvement of myo-
clonus and tremor. To this regard, thalamic DBS seems to be associated with
more rapid improvement compared with pallidal DBS (Gruber et al. 2010). The
optimal target for dystonia and particularly for dystonic tremor is still debated
(Blomstedt et al. 2009; Morishita et al. 2010).
25.2.9 Tremor Secondary to Spinocerebellar Degeneration
Spinocerebellar ataxia are a heterogeneous group of neurological disorders charac-

terized by progressive ataxia and variable combinations of cerebral, basal ganglia,
brainstem, spinal, and peripheral nervous system involvement. Only few case reports
are available on DBS in these syndromes. Pirker and colleagues (2003) reported suc-
cessful VIM DBS in one patient with SCA 2 and parkinsonism and severe, disabling
resting and action tremor. Remarkable clinical improvement of severe postural tremor
was also described in a second patient with SCA 2 treated with a combined subtha-
lamic–thalamic DBS: two upper electrode leads within the ventral portions of the
Vop-VIM nuclei and two lower leads in the underlying white matter including the
zona incerta and the cerebello-thalamic projection (Freund et al. 2007). It should be
noted that, while VIM DBS might be effective on action tremor, in these patients
disability from ataxia, or other cerebellar signs, remains (Shimojima et al. 2005).
25.2.10 Neuropathic Tremor
Neuropathic tremor is defined as tremor that develops in association with peripheral

neuropathy when no other neurological condition associated with tremor is encoun-
tered. Postural and action tremor in peripheral neuropathy is characteristic of Roussy–
Levy syndrome (hereditary sensorimotor neuropathy; CMT1A). Breit and colleagues
(2009) reported a 30% reduction in tremor in a 72-year-old patient with severe demy-
elinating neuropathy and disabling neuropathic tremor after bilateral VIM DBS.
Unilateral DBS of the PSA greatly diminished action tremor in one subject with
tremor related to severe peripheral neuropathy. The stimulation did also abolish the
head tremor. The benefit on proximal component of tremor was limited to the first
year after surgery (Blomstedt et al. 2009). Unilateral VIM DBS proved some effect
also in one subject suffering from neuropathy associated with monoclonal gammo-
pathy (Ruzicka et al. 2003).
25.2.11 Other Diseases with Tremor
Schramm and colleagues (2005) reported a case of a 51-year-old man with a rare
dominant inherited cerebellar ataxia with accompanying visual loss and tremor
(CICALVT) resembling a Behr Syndrome variant. In this patient, tremor greatly
improved after unilateral VIM DBS.
Thalamic DBS also showed some efficacy in controlling phenylketonuria-
induced cerebellar tremor in one patient. The patient experienced nearly complete
resolution of intention tremor and great benefit of resting tremor immediately after
surgery and at over 2-year follow-up (Payne et al. 2005).
Thalamic tremor is a mixture of intentional tremor and dystonia, following

lateral posterior thalamic stroke. Diederich and colleagues described mild but
significant improvement after surgery in one patient with calcifications at the
posterior edge of the right thalamus, abnormal collateralization of the posterior
cerebral artery at the thalamic level, and mild hemiatrophy of the right mesen-
cephalon. Still, a second patient with post-stroke thalamic tremor did not improve
after VIM DBS (Diederich et al. 2008).
25.3 Thalamic Stimulation-Related Adverse Events
25.3.1 Surgical Adverse Events
The most potentially serious neurologic adverse effect is intracranial hemorrhage.

The incidence of intracranial hemorrhage ranges between 2% and 5%. Hemorrhages
include subdural and intracerebral hematomas. Many intracerebral hematomas are
asymptomatic, may be limited to a region along the electrode tract and are discov-
ered only by postoperative brain imaging (Benabid et al. 1996; Koller et al. 1997;
Limousin et al. 1999; Medtronic, Inc. 2002). Risk of severe complications (death or
severe permanent neurological deficits) accounts for less than 0.5% in larger series
of experienced centers (Voges et al. 2006).
25.3.2 Device Complication Including Lead Replacements
Most frequent hardware-related adverse events are open circuits and IPG malfunc-
tion, lead fractures, misplacements or migrations, lead erosion, lead infections, for-
eign body reactions, and cerebrospinal fluid leaks. Overall, 10–25% of the patients
experience hardware-related complications (Oh et al. 2002; Joint et al. 2002; Kumar
2003; Voges et al. 2006). Useful references providing detailed methodology for
troubleshooting hardware complications are available (Volkmann et al. 2002; Kumar
2003; Isaias and Tagliati 2008). Explantation of the intracerebral electrode is only
occasionally necessary and is indicated in the presence of active infection or skin
erosion unresponsive to medical management or skin grafting. In the case when
explantation is required and reimplantation is not feasible, it may be possible to
generate a permanent thalamotomy using the DBS electrode to create a radiofre-
quency lesion prior to its removal (Oh et al. 2001; Kumar and McVicker 2000).
25.3.3 Stimulation Related Adverse Events
The most frequent side effect of VIM stimulation is paresthesia involving the
contralateral limbs or the face (Dowsey-Limousin 2002; Schuurman et al. 2000).
This is usually caused by diffusion of the electrical field into the ventral caudal
nucleus or to the lemniscal fibers entering the thalamus (Kiss et al. 2003).
Paresthesia usually appear when the stimulation is switched on or the amplitude
of stimulation is rapidly increased. When paresthesia rapidly habituate they are of
little concern, but if they persist (Alesch et al. 1995) alternative contacts or
configurations should be explored (Isaias and Tagliati 2008).
Dysarthria (Pahwa et al. 2006) and gait ataxia with postural instability may also
be induced by thalamic stimulation (Albanese et al. 1999; Schuurman et al. 2000;
Alesch et al. 1995; Lyons et al. 2001; Obwegeser et al. 2001), especially with bilat-
eral stimulation (Pahwa et al. 2006; Limousin et al. 1999; Benabid et al. 1996) or in
patients that had undergone previous contralateral thalamotomy. The nature of
dysarthria and balance abnormalities during thalamic DBS has not been well eluci-
dated. Possibly, they are related to the involvement of cerebellar output to the cortex
and/or unwanted spread of the electrical field to corticobulbar fibers. The presence
of dysarthria (or dysphagia) in patients with MS should therefore be considered a
relative contraindication to VIM DBS in these patients.
Last, VIM DBS appears to have no significant effect on the cognitive abilities of
PD patients (Voon et al. 2006; Troster et al. 1999; Troster and Fields 2003; Caparros-
Lefebre et al. 1992), although mild deficits in verbal fluency have been documented
(Benabid et al. 1996).
25.4 Final Remarks
Thalamic surgery is one of the best options for treating medically intractable tremor
and it is approved by the U.S. FDA for unilateral placement for the treatment of ET
and tremor due to PD. In many countries, health insurance services contribute to
reimbursement of the devices. Preliminary evidence suggests that thalamic DBS
might be a possible treatment also for tremor secondary to other causes such as MS
and traumatic brain injury. The precise mechanism by which DBS affects its
therapeutic response is unknown. Consequently, best DBS settings, the search for
optimal targets, and multiple lead placements are open questions that need to be
systematically addressed. Such studies will also contribute to a better understanding
of oscillatory networks and in particular the role of the cerebellum that seems to
contribute to the pathophysiology of various tremors of different etiology.
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Chapter 26
Dopaminergic Influences on Rest and Action
Parkinsonian Tremors and Emerging Therapies
for Tremor
Quincy J. Almeida, Fariborz Rahimi, David Wang,

and Farrokh Janabi-Sharifi
Keywords Action tremor • Rest tremor • Neural stimulation • Tremor suppression
26.1 Introduction
While pharmacological and surgical treatments remain the primary treatment

options for tremor, recent research and technological advances have the potential
to lead to improved understanding of the underlying mechanisms of tremor, as well
as the potential for new noninvasive treatments. Since Parkinsonian resting tremor
has been well documented (see Chap. 7), this chapter examines the relationship
between resting and coexisting physiological tremor in a Parkinson disease (PD)
patient. This is accomplished with the demonstration of a patient with an unusually
severe but dopa-responsive tremor. With improved understanding of the mecha-
nisms of tremor, the chapter then also reviews new emerging therapies including
tremor orthoses, different models of electrical and magnetic stimulation, and other
alternative therapies.
Q.J. Almeida (*)

Sun Life Financial Movement Disorders Research and Rehabilitation Center,
Faculty of Science, Wilfrid Laurier University, 75 University Avenue West,
Waterloo, ON, Canada N2L 3C5
e-mail: qalmeida@wlu.ca
F. Rahimi • D. Wang
Department of Electrical Engineering, University of Waterloo, Waterloo, ON, Canada
F. Janabi-Sharifi
Department of Industrial and Mechanical Engineering, Ryerson University,
Toronto, ON, Canada
464 Q.J. Almeida et al.
26.2 A Parkinson’s Model of Tremor: Influences of Dopamine

and Force Production
Utilizing the original “shaking palsy” common to PD to understand other types

of tremor may be a particularly interesting model, since the majority of motor
symptoms (including bradykinesia, rigidity, posture, and gait instability) are
generally known to improve with dopaminergic replacement therapy. However,
the responsiveness of PD tremor to dopamine is considerably more variable
(Elble 2002), and in some cases PD tremor may be entirely dopa resistant. Thus,
it may be important to consider whether multiple forms of tremor may coexist
and be superimposed within the same patient. In fact, action (AT) and postural
tremor (PT) have been reported to occur as commonly as 40–93.4% in PD patients
experiencing rest tremor (Lance et al. 1963; Deuschl et al. 2007; Koller et al.
1989; Louis et al. 2001), which intimates that they may be the result of a com-
mon underlying mechanism.
The most common difference between the classical PD “pill rolling” rest
tremor and other Parkinsinian tremors is the presenting frequency. It is well known
that typical rest tremor is observed with a frequency between 4 and 6 Hz, whereas
coexisting tremors present with a higher frequency ranging between 5 and 12 Hz
(Lang and Zadikoff 2005; Deuschl et al. 2000; Beuter et al. 2003). Additionally,
action tremor can occur during any force-producing voluntary muscle contraction
and is considered a more comprehensive term for postural, kinetic, isometric, and
task specific tremors (Bain 1993). One important reason for this distinction in PD
is that the action tremor can interfere with activities of daily living, and hence can
be more disabling than rest tremor (since rest tremor normally dissipates with
voluntary action). Thus, when considering the factors (and possible mechanisms)
that influence tremor, the quantity of force being produced should be carefully
considered.
Postural tremor as a subcategory of action tremor is a particularly interesting
example of how force production might influence Parkinsonian tremor, given that
it could be considered a midpoint between rest (where no cortically driven voluntary
force contributes) to voluntary movement (where cortically driven force dominates
limb position). During a set isometric posture, rest tremor appears to re-emerge,
not while the limbs are voluntarily moved to the isometric posture, but specifically
when a force must be applied to hold the limbs in an isometric position for several
seconds (Jankovic et al. 1999). As such, when considering underlying mechanisms
of tremor, it might be reasonable to expect a relative decrease in tremor amplitude
when comparing rest to postural/isometric situations (mild force applied to main-
tain posture), and a more dramatic decrease in amplitude during voluntary action,
where an increase in cortical drive to initiate movement is necessary (see solid line
in Fig. 26.1).
While the influence of cortical drive (through force production) on Parkinsonian
tremor appears to be clear, the pathophysiology of action tremor continues to be
debated (Louis et al. 2001). It has been proposed that action tremor might represent
26 Dopaminergic Influences on Rest and Action Parkinsonian Tremors… 465
Fig. 26.1 Possible amplitudes for classic rest tremor (RT-solid) which is in 4–6 Hz frequency
range at rest and during action and enhanced physiological tremor (EPT-dotted ) which is in
8–12 Hz frequency range and does not respond to medication
an amplification of physiologic tremor in PD patients (Wenzelburger et al. 2000).

Common to both physiological and enhanced physiological tremor (EPT) is that
they both present with a frequency that is approximately double to the frequency
of classical rest tremor (RT). Even in healthy populations, physiological tremor is
barely noticeable with the naked eye unless carefully scrutinized (subclinical), but
it is important to recognize the EPT can produce clinical symptoms that are
significantly bothersome to patients (Huang and Tetrud 2005). Due to these simi-
larities between action tremor and EPT, it has been assumed that Parkinson’s action
tremor is in fact enhanced (or exaggerated) physiological tremor (Lance et al.
1963; Forssberg et al. 2000; McLeod 1971; Findley et al. 1981; Milanov 2001).
However, this may not be true in some patients, as will be demonstrated with the
case study presented in this chapter. It should also be pointed out that action tremor
has been reported in some PD patients without visibly identifiable rest tremor
(Beuter et al. 2005), yet in other cases, action tremor and EPT have been described
as an indistinguishable variant of essential tremor (Deuschl et al. 2000). The case
study presented in this chapter allows a careful evaluation of dopa-responsive and
dopa-resistant tremors, as well as the influence of cortical drive from voluntary
force production in a severe case of tremor dominant Parkinson’s disease.
26.2.1 Distinguishing Features of Rest and Exaggerated

Physiological Tremor
In contrast to the 4–6 Hz resting tremor of PD, exaggerated physiological tremor

(EPT) is a weak and rapid (with single peak frequency in 8–12 Hz) tremor which is
typically absent at rest. EPT appears or intensifies in posture and remains present
during movement with no increase in amplitude (Huang and Tetrud 2005). However,
as described earlier RT may still be visible during movement (Duval 2006; Forssberg
et al. 2000; Wenzelburger et al. 2000) or re-emerge in a static posture after a delay
(Jankovic et al. 1999).
In this chapter, we evaluate whether rest tremor (RT) and EPT may coexist, with
dopaminergic treatment and at different levels of force production (rest, isometric
posture, voluntary movement). Depending on severity of RT at rest, one might
expect three different cases as predicted in Fig. 26.1; (case-1): If RT has a strong
and noticeable amplitude at rest, then the dominant tremor during posture and
movement would resemble RT; (case-2): In cases where RT is weaker at rest, the
cortical drive necessary to hold a mild isometric force (static posture maintenance)
would be expected to dissipate RT amplitude, while EPT might be more likely to
pose a more dominating influence in both static posture and during voluntary
movement; (case-3): If RT is barely visible at rest, then EPT would be significantly
apparent during static and voluntary movement tasks. Furthermore, with the
assumption that only RT is dopa responsive, it might be expected that all three
cases might reveal a shift toward decreased rest tremor amplitude, thus providing
an opportunity for a predominantly EPT form of tremor to be more visible. The
case study presented here evaluates this coexistence hypothesis on a PD patient
with remarkably strong but dopa-responsive tremor.
26.2.2 Evaluating the Coexistence of RT and EPT: A Case Study

of Force and Dopa-Responsiveness
Patient DK was a 53-year-old, right-handed female with Parkinson’s disease

demonstrating strong rest and action tremors on the dominant (right) side. The
tremors were surprisingly noticeable at elbow, and the patient self-reported that
tremor was extremely responsive to her levodopa/carbidopa medication.
Tremor was measured at the elbow utilizing a reaction torque sensor (OMEGA®
TQ301, 45 ± 0.09 N m), while DK was seated upright in a chair facing the apparatus
(Fig. 26.2). Shoulders were fully adducted, lower arms fully supinated, and palms
facing up. All samples were performed at an elbow angle of q = 135°. Subject’s
applied torque was collected along four channels of bipolar EMG with a 16-bit data
acquisition card (National Instruments, PCI-6221) at a sampling frequency of
1 kHz. Ag–AgCl surface EMG electrodes (Meditrace, center-to-center distance
2.5 cm) were used to collect the signals. Before being sampled, EMG signals were
Fig. 26.2 Subject at experimental apparatus. (a) Software interface. (b) Torque amplifier. (c) EMG
amplifier. (d) Surface EMG electrodes. (e) Torque sensor. Trials were applying isometric elbow
torque which was either constant at rest and MVT, or changing stepwise according to random
patterns. All trials were performed at elbow angle of 135°
amplified 2,000 times and band-pass filtered (20–500 Hz). The EMG signals were
collected from two of the primary elbow flexor (biceps brachii (both heads [BIC])
and brachioradialis [BRD] but not the deeper brachilis) and extensor muscles
(medial and lateral heads of triceps) (T-med and T-lat) (Kendall et al. 2005). The
torque signal was also amplified using a full bridge amplifier (Entran®PS-A, calibra-
tion was performed once with amplifier included ). Software user interface was
written in LabVIEW®8.0 (Laboratory Virtual Instrumentation Engineering
Workbench). The software interface provided on-line information about the acquired
signal facilitating different stages of the experiment and provided the subject with
real-time visual feedback of the applied force (torque) along with a target torque
line which DK was asked to follow.
In order to assess the dopa responsiveness of the tremor, DK repeated the identi-
cal task in two separate sessions (Off and On dopaminergic placement therapy). In
the first session, dopaminergic replacement medications were withheld for 18 h (Off
state), while the second session was completed two hours post-administration of
dopaminergic medications (On state). Prior to both testing sessions, the Unified
Parkinson’s Disease Rating Scale (UPDRS) was administered to confirm that DK
was experiencing a true On and Off dopaminergic state. Prior to beginning of session
Righth and Before meds

a6
4
N.m
2
0
2
Applied Torque
Right hand After meds Pattern
b 4
2
N.m
2
0 5 10 15 20 25 30 35 40
Time (sec)
Fig. 26.3 Subject’s actual applied torque in following one of the patterns. (a) Before medication.
(b) After medication the same tremor dominant (TD) hand
one, patient’s skin was prepared for surface EMG electrodes that were attached on
the related four muscles and remained there for the rest of experiment. In each ses-
sion patient sat at the experimental apparatus and performed the experimental with
each hands, one at a time, with a short break in between. Before each data collection
session, noise signal was recorded (for 2-s) for an Off/On session-to-session com-
parison. Two Maximum Voluntary Torques (MVTs) were collected from each limb
in both the extension and flexion directions for a 2-s duration (and with a 2-min rest
in between to avoid fatigue). Also a 2-s rest segment was recorded to analyze rest
tremor. All the mentioned data was also used for calibration purposes. Then main
data collection was carried out in five separate 40-s trials. In each trial, the subject
attempted to exert torques according to a randomly chosen pattern displayed on the
computer monitor. Each pattern included ±50%, ±20% and 0% MVT (or rest) inter-
vals of 8 s each. Samples of such trials can be seen in Fig. 26.3. Overall, data from
four such data collection sessions was recorded for analysis and comparison.
Frequency analysis was applied on torque signal as well as on EMG signals
acquired from the related flexor and extensor muscles. All the analysis were done
off-line using MATLAB®2007b (MathWorks) and STATISTICA™ 7.0 (StatSoft).
EMG signals were passed through notch filters at 60 Hz and 180 Hz (6th order
Butterworth) to remove power line interference components. Power spectrum of
EMG signals was checked for possible fatigue during the trials. Before working
with torque signal, rest torque averages were subtracted to account for gravitational
components. To find the tremor signal, the trend was removed from torque signal
(using smooth command in MATLAB ® with local regression using weighted least
squares and a span of 350 points) and was low-pass filtered with a 6th order
Butterworth filter at 20 Hz.
For each trial (whether rest, target tracking, or MVT), power spectral densities
(PSDs) for EMG and tremor signals were estimated and tremor amplitudes were
calculated, as follows:
1. EMG PSD (and its peak-frequency): After EMG signals were digitally rectified
and their averages were removed, their PSDs were estimated using periodogram
in MATLAB® with nfft = 214. The shape of each muscle’s surface EMG-PSD or
its dominant frequency (which can be mean, or median frequency (Sornmo and
Laguna 2005), or just peak frequency) provided information about tremor
components.
2. Tremor PSD (and its peak frequency): Trends were removed from the torque signal
and then low-pass filtered with a 6th order Butterworth filter at 20 Hz. The result-
ing signal was digitally differentiated to provide the torque-rate signal and its PSD
was estimated with periodogram. The main advantage of such a differentiation
(using torque-rate dT/dt instead of T) was to suppress non-tremor low-frequency
oscillations in torque (or force) signals and is discussed more in (Norman et al.
1999; Forssberg et al. 2000). There are different measures of predominant fre-
quency in the tremor, each of which can help identify the tremor’s nature. The most
trivial ones are spectrum’s peak frequency and median frequency.
3. Tremor Amplitude: Assuming that drift and all other non-tremor movements
have frequencies below 1–2 Hz (Beuter et al. 2003), it is customary to consider
any component in the range 3–17 Hz as related to tremor. After detrending torque
signal from each trial and band-pass filtering with a 10th order Butterworth filter
3–17 Hz , its root mean square (RMS) was calculated as the most obvious mea-
sure of tremor amplitude (Beuter et al. 2003; Forssberg et al. 2000).
The total score on the UPDRS (motor section III) was 32 during the first testing
session (Off state) and 21 during the second session (On state), confirming a strong
response of patient’s motor symptoms to dopaminergic medication. Dopaminergic
medication effect was also evident in the tremor-dominant (TD) hand. Before medi-
cation, patient was almost incapable of following the required force patterns dictated
by the visual feedback monitor, because of a high amplitude tremor with an oscilla-
tion of 4.5 Hz. In contrast, during the second session (On medication state) tracking
the visual feedback was very much improved, with a smaller amplitude of oscillation
tremor which was at a higher (»9 Hz) frequency. The above-mentioned tremor char-
acteristics were evaluated for rest and MVT trials and for each of the five target-
tracking trials as well. In the tremor dominant limb (TD), during the Off medication
state, EMG from antagonist muscles exhibited alternating pattern of bursts and had
peak frequencies that often closely followed the peak frequency in tremor. Tremor
peak frequency at rest was 3.9 Hz and during action (±20%, ±50%, and ±100% iso-
metric MVT) was between 4 and 5 Hz, although RMS amplitude was not significantly
different between rest, tracking, and MVT (p > 0.05). RMS amplitude ranged between
0.4 and 0.7 Nm (newton-metre). Interestingly, during the “On medication state”
DK’s tremor dominant hand displayed a rest tremor frequency which had nearly
doubled to 8.2 Hz (compared to off medication) and action tremor frequency ranged
between 7.2 and 10.5 Hz (almost physiological tremor band).
a Off - Meds x 10-5 On - Meds

4
0.02
0.01
0
x 10-4
Power Spectral Density
b 0.04
0.02 2
0
x 10-5 x 10-5
c 4
10
2
0
x 10-3 x 10-3
d 1 5
0.5
0
0 5 10 15 20 00 5 10 15 20
Frequency (Hz) Frequency (Hz)
Fig. 26.4 Comparison of tremor signals’ PSDs [from TD hand’s torque rate signals, rows (a–b)
and NTD hand (rows c–d)]. Left column shows the results off medication and right column is the
results of similar trials after medication. Rows (a) and (c) correspond to rest trials and rows (b) and
(d) correspond to one of the MVT trials (flexion #2)
Tremor amplitude was drastically reduced both at rest and in action to 0.02–0.06
Nm and was significantly lower at rest (p < 0.01). Figure 26.4 shows representative
PSDs for both the tremor dominant (TD a–b) and non-tremor-dominant (NTD c–d)
limbs, which illustrates the coexistence of two different tremors (peaks in two
different bands) for both hands in rest as well as with action.
For the non-tremor dominant hand, specifically in the off dopaminergic state, rest
tremor PSDs exhibited two almost equal peak frequencies (Fig. 26.4c, one between 4
and 6 Hz and the other in the 8 and 12 Hz band) with an RMS amplitude of 0.03 Nm.
During voluntary action, tremor frequencies were between 7.7 and 11.7 Hz (resembling
the physiological tremor band) and their amplitudes were between 0.05 and 0.11 Nm
which was significantly higher than rest tremor (p < 0.01). After medication the rest
tremor’s peak frequency was 10 Hz, while those of the action tremor were between 8.7
and 12.7 Hz. Tremor amplitude in the On medication state for rest was 0.02 Nm and
those during action were between 0.04 and 0.11 Nm (significantly higher p < 0.01).
Figure 26.5 utilizes box-plots to graphically highlight the peak frequency and
RMS amplitude for tremors in the On and Off dopaminergic medication state for
both the tremor dominant and nondominant limbs. For each state, the three columns
represent rest, MVT, and target tracking trials, respectively, from left to right.
26.2.3 Summary of Case Study Findings
Patient DK had very strong coexisting action and rest tremors in her tremor dominant
hand, and this was most apparent in the Off dopaminergic state (TD-OFF). Interestingly,
Tracking
MVT
Rest
12
10
Frequency (Hz)
8
b 0.7
0.6
0.5
Amplitude (N.m) 0.4

0.1
0.05
0
NTD-OFF NTD-ON TD-OFF TD-ON
Fig. 26.5 Boxplots, representing the sample minimum and maximum, median, and lower and
upper quartiles (Mason et al. 2003) for frequency and amplitude of tremor in all 4-conditions
(i.e. on and off meds for both the tremor dominant and non-dominant hands). (a) Represents peak
(or dominant) frequencies for each trial’s PSD. (b) Represents RMS amplitude of all tremors in
3–17 Hz range
when treated with dopaminergic medication, or when we look at the non-tremor dom-
inant limb, tremors reached only a subclinical level (TD-ON, NTD-OFF, and
NTD-ON). However, at this subclinical level, coexisting tremors could be confirmed
in both hands in rest and also in action. Amplitude comparison revealed that tremor in
Off state were nearly 10-fold stronger for the tremor dominant limb, compared to all
other states (whether at rest or in different levels of isometric contraction).
It should be noted that the low-frequency tremor (of 3.9–5.1 Hz) was not
apparent after dopaminergic medication was administered but was replaced with
a high-frequency (of 7.2–10.5 Hz) and barely visible tremor. Therefore, this
hand’s tremors would fit into case-3 with a considerable downward shift in RT
amplitude dopaminergic therapy, thereby permitting EPT amplitude to be larger
than RT even at rest. From the dominant frequencies, this resembles a Type I
Parkinsonian tremor [according to (Deuschl et al. 1998, 2007)] with rest and
postural/action tremors of the same frequency.
While it might have been expected that rest tremor should have the highest amplitude,
no significant difference was identified between the amplitudes at rest, compared to
movement and MVT trials. Rest tremor did however show a slight decrease in ampli-
tude during MVT and a slight increase on average during tracking tasks. One explana-
tion for this increase may be related to mental overload or contralateral movements
(when DK was not able to track the target force in the Off state) (Deuschl et al. 2007).
In the non-tremor dominant hand, frequency and amplitude comparisons only

revealed a noticeable effect of dopaminergic medication, in that one low-frequency
rest tremor component dissipated with dopaminergic therapy. The remaining tremors
were all high frequency (7.7–12.7 Hz) regardless of medication state or whether at
rest or during isometric contraction. Thus the rest tremor in the non-tremor dominant
limb was comparable to EPT in amplitude at rest, but disappeared with isometric
contractions, which fits into the case-1 scenario. In both hands, EPT had significantly
lower amplitudes at rest which was expected.
To conclude, the coexistence of RT and EPT for this patient could be verified not
only in the non-tremor dominant limb (as subclinical tremor), but also in tremor
dominant limb. In the case of the unusually strong rest tremor, the amplitude was
sufficiently large enough to act as the predominant tremor during both rest and
isometric contractions. This notion of coexisting tremors appears to better predict the
characteristics of tremor in different PD patients during rest and action. While further
study with a larger sample of tremor dominant PD patients is needed to evaluate the
proposed hypothesis, this case study suggests the importance of carefully evaluating
tremor characteristics for the design of orthoses that can suppress tremor in coexist-
ing bands. Indeed, tremor suppression through the use of a custom-made orthosis is
one of the potential emerging therapies discussed in the next section.
26.3 Emerging Therapies for Tremor
26.3.1 Mechanical Tremor Suppression
Given some of the limitations and risks associated with drug and surgical therapies for
tremor, the search for noninvasive interventions for tremor continues to be an impor-
tant issue. As discussed earlier, since action tremor may be considered more disabling
with its greater impact on activities of daily living, it is not surprising that tremor sup-
pression has been an area of great interest. Patients who have had the need to hide their
tremors have resorted to many suppression strategies including sitting on one’s hand
or hiding the hand within a pocket. Others who deal with lower limb tremors will
attempt to cross their legs, or wrap the afflicted limb around the leg of a chair, but of
course all of these strategies have their obvious limitations. The notion of a mechani-
cal orthotic has been explored for action tremor as early as the early to mid-1990s by
Rosen and colleagues (Rosen et al. 1995; Aisen et al. 1993). While reasonably effec-
tive for cerebellar and intention tremors, these early devices needed to be fastened or
mounted on a chair or table top. As such, these sorts of devices limit the potential for
tremor to be controlled during ambulation. Since then, smaller and more portable
devices have been proposed to dampen tremor through the use of viscous fluids
(Kotovsky and Rosen 1998), although limited clinical trials have been completed.
More recently, tremor suppression exoskeletons have shown promising evidence
that orthotic devices reduce the power associated with tremor as much as 60% (Manto
et al. 2007). Tremor suppression devices equipped with robotics offer the benefit of
being able to monitor and dynamically respond to tremor (Rocon et al. 2007),
in addition to the value of still being able to use the limb. As suggested by the previ-
ous case study, for such devices critical considerations are to be able to accommodate
different frequencies and amplitudes of tremors, as well as to adapt to various joints
where tremor may occur (Rahimi et al. 2009). It is also necessary to evaluate tremor
suppression devices in a wider spectrum of tremor populations. Comfort issues, esthet-
ics, and easiness to wear orthoses might be limitating factors. First exoskeletons were
bulky and even somewhat stressful for naïve patients, requiring refinements before
reaching the clinical use. Given the problem of sizes and shapes and the need for
customization, production at middle/large scales might face obstacles.
26.3.2 Neural Stimulation
In contrast to deep brain stimulator implantations, recent research has investigated

repetitive transcranial magnetic stimulation (rTMS) as a potential noninvasive alter-
native to surgical implantations. Repetitive magnetic stimulation over specific and
localized targets on the surface of the cortex has the potential to decrease hyper-
excitability of neural substrates that may be linked to tremor. For example, a recent
study demonstrated the effectiveness of rTMS at the premotor cortex (but not pri-
mary motor cortex) in decreasing action tremor (Houdayer et al. 2007). In this
specific case, the sensorimotor cortex was overactive, suggesting a potential limita-
tion for those patients with tremor resulting from deeper subcortical damage (for
example, the PD patient described earlier in the case study). Nevertheless, tremor
improvements have been reported to last up to a full day following stimulation. In a
more recent study, TMS treatment was attempted in a group of patients with psy-
chogenic tremor (Dafotakis et al. 2011). While lasting symptomatic improvement
occurred in seven of the eleven participants, TMS was reported to help diagnosis of
patients and also improve the patient’s insight into the cause of the psychogenic
tremor. Long-term effects (and side effects) of chronic TMS use need to be more
fully studied before this becomes a viable treatment for tremor.
Vibration may be another (albeit indirect) method of neural stimulation. Physioacoustic
vibration has been shown to significantly reduce tremor in a single-blind crossover study
of Parkinson’s patients (King et al. 2009). It has been proposed that vibratory hyper-
stimulation of cutaneous receptors throughout the body may operate by deactivating
cortical networks associated with tremor through sensory feedback loops to the motor
cortex. It should be recognized, however, that the effects of vibration have only been
studied in the short term, and long-term benefits still need to be explored.
26.3.3 Other Emerging Strategies
While commonly used as a treatment for other hyperactive or tonically active move-
ment disorders such as dystonia, to our knowledge only a single study with only 5
patients has examined botulinum toxin as a treatment for tremor. This study reported
a success rate of 60% (3 of 5 patients) improvement in tremor, but with an unfortu-
nate and disabling loss of hand function (Domzal 1998). Thus, botulinum toxin
treatment might only be warranted when tremor is severely disabling.
Surprisingly, we were only able to find a single study on exercise rehabilitation
for the treatment of tremor. Strength training is believed to improve neuromuscular
integration and hence has the potential to provide general improvements to limb
motor control. With this perspective in mind, strength training was attempted in three
groups of patients diagnosed with essential tremor. Interestingly, only the group
trained with heavy loads (compared to light load and no load) revealed a significant
improvement in hand steadiness, although no functional improvements were reported
in any of the groups (Bilodeau et al. 2000). As such, strength training requires further
investigation with long-term follow up in tremor patient populations.
26.4 Summary
Noninvasive treatments or adjuncts to drug and surgical intervention for tremor will
continue to be an important area for research and technological development.
Several strategies exist that have shown potential to at least decrease disabling trem-
ors, although more clinical trials with much larger sample sizes are needed. Daily
comfort and esthetics should be taken into account if orthoses are considered. At the
present time, methods of tremor suppression and neural stimulation appear to have
the most promising evidence for tremor treatment.
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Index
A rest tremor, 129

Acar, G., 450 APN. See Acquired pendular nystagmus
Accelerometers (APN)
description, 351 Apomorphine, 423
disadvantages, 351 Aprataxin (APTX) gene, 66
gravitational artifact, 351, 352 APS. See Atypical parkinsonian syndromes
long-term measure, 352 (APS)
Ackmann, J.J., 342 AR-JP. See Autosomal recessive juvenile
Acquired pendular nystagmus (APN) parkinsonism (AR-JP)
multiple sclerosis (MS), 26–27 ASUR. See Autonomous Sensing Unit
oculopalatal tremor (OPT), 27–28 Recorder (ASUR)
Action tremor a-Synuclein gene (SNCA), 55–56
classification, 306 Ataxias
definition, 4 AT, 66
description, 306 APTX, 66
isometric tremor (see Isometric tremor) CA, 66
Activities of Daily Living (ADL) scale description, 63–64
ADL-T24 scale FXTAS, 65–66
functional tests correlation, 336, loci and genes, 64
338, 339 SCA2, 64
inter-session reliability, 336, 337 SCA3, 64
score, 334, 335 SCA12, 65
tele-management, 336 SCA15, 65
description, 334 SCA16, 65
extended, 334–335 SCA20, 65
Activity classifier (AC), 357–358 SETX, 66
ADL scale. See Activities of Daily Living Ataxia-telangiectasia (AT), 66
(ADL) scale ATP13A2 gene, 58
Adrenergic agonists, 26 Atypical parkinsonian syndromes (APS)
Aicardi, J., 313 description, 410–411
Albanese, A., 207, 210 MSA, 411
Almeida, M.F.S., 354 PSP, 411
Alprazolam, 421 spatial covariance patterns, 411, 412
Alusi, S.H., 331 Auff, E., 359
Andrew, J., 315 Autonomous Sensing Unit Recorder (ASUR),
Anticholinergics 358
Parkinson’s disease, 422, 423 Autosomal dominant dystonias, 68–69
Disorders, Contemporary Clinical Neuroscience, DOI 10.1007/978-1-4614-4027-7,
478 Index
Autosomal dominant PD C
LRRK2, 56–57 Caffeine-induced tremor, 25
PARK1, 55–56 CAMCA. See Continuous ambulatory
PARK4, 55–56 multichannel accelerometry
PARK 8, 56–57 (CAMCA)
SNCA, 55–56 Campistol-Plana, J., 315
Autosomal recessive juvenile parkinsonism Canavese, C., 306
(AR-JP), 57 Cardoso, F., 273
Autosomal recessive PD Carignan, B., 135, 142
ATP13A2 gene, 58 CATSYS system, 352
DJ-1, 58 Cayman ataxia (CA), 66
PARK2, 57 Central nervous system (CNS)
PARK6, 57–58 head trauma (see Traumatic brain
PARK7, 58 injury)motoneurons, 86
PARK9, 58 neural oscillators, 91
parkin, 57 reorganization, 273
PINK-1, 57–58 Central neural oscillator
Matsuoka’s neural oscillator model
structure of, 92
B tremors with different frequencies, 93
Bain, P.G., 346, 354 types, 91
Ballistic movement test, 298 Central neurogenic tremor
Ballistic wrist movements, 361 description, 113–114
Barbeau, A., 144 enhancement, 116
Behr syndrome variant, 453–454 finger tremors, 115
Benabid, A.L., 439 frequencies, 114–115
Benign neonatal sleep myoclonus, 310 Cerebellar disorders
Benign tremulous parkinsonism, 448 FCMTE, 252
Benito-León, J., 226 isometric tremor
Bennett, D.J., 89 diagnosis criteria, 160
Benton, J.W., 311 pathophysiology, 160–162
Benzodiazepines therapeutic strategies, 162
EVT, 240 Cerebellar tremor, 6
pharmacological treatments, 421–422 Cervical dystonia (CD)
Bereitschaftspotential, 298, 299 clonazepam, 214
Berk, C., 449 epidemiology, 204
Beta-carboline derivatives, 38 head and upper limb tremor, 211–212
Beuter, A., 347, 355 posttraumatic, 276–277
Binder, M.D., 86, 87 Charcot, J.M., 342
Binder, S., 358 Charcot–Marie–Tooth (CMT)
Blackman–Tukey method, 381–382 disease, 69–70
Blumrosen, G., 357 Cholinomimetic-induced generalized tremor,
Bobble-head doll syndrome, 311–312 41–42
Botulinum toxin Chromosome 5p15.31-p15.1, 259
EVT, 240–241 Chromosome 2p11.1-q12.2, 259
hereditary geniospasm, 316 Chromosome 8q23.3-q24.11, 257–258
jaw tremor, 423 Chronic traumatic encephalopathy (CTE),
PWT, 214 270–271
SD, 243 Clarke, R.H., 432
Box and Block test (BBT), 331, 332 Clinical, neurophysiological, functional tremor
Bradykinesia, 361 evaluation scale (CNF-TES),
Breit, S., 349, 453 330–331
Britton, T.C., 361 Clinical tremor rating scale (TRS), 328–330
Broca, P., 432 Clonazepam
Brown, P., 361 cortical myoclonus, 251
Index 479
orthostatic tremor, 229 Behr syndrome variant, 453–454

pharmacological treatments, 421 CICALVT, 453–454
Clozapine, 129, 423, 425 essential voice tremor, 449
CMT disease. See Charcot–Marie–Tooth ET, 448–449
(CMT) disease isolated head tremor, 449
Coenen, V.A., 398 MS, 451–452
Cohen, O., 345 neuropathic tremor, 453
Coherence analysis OT, 450
description, 384–386 Parkinson tremor, 447–448
estimation post-stroke tremor, 450–451
exact confidence intervals, 386, 387 posttraumatic tremor, 450–451
three pairwise coherence, 387, 388 PWT, 452
Welch-Bartlett method, 386 spinocerebellar ataxia, 453
properties, 386 thalamic stimulation-related
Combes, N., 360 adverse events
Complex regional pain syndrome (CRPS), device complication, 454
275–276 stimulation related, 454–455
Budapest diagnostic criteria, 275–276 surgical, 454
description, 275 vs. thalamotomy, 439–440
Congenital nystagmus, 311 tremor suppression applications, 103–104
Continuous ambulatory multichannel VIM, 398–399
accelerometry (CAMCA), 358 Degos, J.D., 451
Conventional thalamotomy, 437, 438 Deiber, M.P., 409
Cooper, I.S., 432 Dementia pugilistica, 270
Corcos, D.M., 361 Després, C., 352
Cortical myoclonus Deuschl, G., 344, 345, 353
FCMTE, 250 Diffuse axonal injury (DAI), 265, 267
rhythmic, 6 Diffusion tractography
Cortical tremor. See Familial cortical DBS
myoclonic tremor with epilepsy description, 397–398
(FCMTE) diffusion imaging, 399–400
Crago, P.E., 85, 89 implanted electrodes, 3D rendering,
C reflex, 253, 255 398
CTE. See Chronic traumatic encephalopathy population probability map, 398, 399
(CTE) STN, 399
VIM, 398–399
lesion evaluation, 396–397
D Diffusion-weighted magnetic resonance
DAI See Diffuse axonal injury (DAI) imaging (DWI)
Dana, C.L., 342 description, 391
Daneault, J.F., 135, 142 ET, 395–396
DBS. See Deep brain stimulation (DBS) FA, 392–393
Deep brain stimulation (DBS) methodological considerations, 393–394
action mechanism, 446–447 PD, 394
anatomical target, 446 water diffusion
description, 397–398 anisotropic diffusion, 391, 392
diffusion imaging, 399–400 tensors, 392
dysarthria, 455 DiMario, F.J., 312
dystonic tremor, 214 Dissociative disorders, 292
EVT, 241 DJ-1 gene, 58
gait ataxia, 455 Dopamine agonists
implanted electrodes, 3D rendering, 398 Parkinson’s disease (PD), 125, 422–423
population probability map, 398, 399 rest tremor, 129
STN, 399 Dopaminergic replacement therapy, 464–465
symptomatic treatment Dromey, C., 238
480 Index
Drug-induced tremor Electromyography (EMG)

kinetic tremor, 185–186 rectified-filtered spectrum, 112, 114, 116
membrane physiology reflex-induced modulation, 115
adrenergic agonists, 26 Elton, R., 328
caffeine, 25 Enhanced physiological tremor (EPT),
lithium, 24 136–138
neuroleptics, 25 in children, 313
valproate, 24 definition, 4
Dubowitz, V., 317 EMG, 115–116
Duval, C., 141, 355 Epilepsia partialis continua (EPC), 311, 318
DWI. See Diffusion-weighted magnetic Eshner, A.A., 342, 343
resonance imaging (DWI) Espay, A.J., 230, 450
Dystonia Essential tremor (ET)
cardinal physical signs, 206, 207 Alzheimer’s type dementia, 183
cervical, 276–277 ballistic wrist movements, 361
and CRPS, 275–276 Bielschowsky-stained cerebellar cortical
description, 206 section, 174, 176
diagnostic clues, 210 in children, 313–314
epidemiology, 204 clinical disease-defining feature, 179
vs. ET, 209 clinical presentation, 179–183
head trauma, 266–268 DBS, 448–449
mirroring, 206 description, 60
OMD, 277 diagnosis, 183–185
pathophysiology, 211 DWI, 395–396
peripheral trauma, 273–275 vs. dystonia, 209
prevalence, 206 environmental factors, 170–171
primary and fixed dystonia characteristics, etiology, 168–171
273, 274 ETM1, 61–62
shoulder, 277 ETM2, 62
transition spectra, 207–208 ETM3, 62
Dystonic tremor genetic factors, 170
aetiological classification, 67 hand mirror movements, 209
autosomal dominant dystonias, 68–69 head tremor, 180–181
definition, 6 isometric tremor
definitions, 207, 208 frequency, 155
epidemiology, 204–205 pathophysiology, 155
features, 204, 307 therapeutic strategies, 155–156
isometric tremor jaw tremor, 181
pathophysiology, 162 Lewy bodies, 177
therapeutic strategies, 163 LINGO1, 62–63
loci and genes, 67, 68 loci and genes, 61
pathophysiology, 211 membrane mechanisms
phenotypes alcohol, 22–23
head and upper limb tremor, 211–212 beta-blockers, 22
primary writing upper limb tremor, 213 conductance-based model, 21
voice tremor, 212–213 gabapentin, 22
recessive dystonias, 69 harmaline model, 17
terminology, 204 inferior olive neurons, 15
treatment, 213–214 isolated inferior olive neurons,
synchronization mechanisms, 20–21
isolated thalamic neurons,
E synchronization mechanism, 18–19
Elble, R.J., 344–347, 353, 362 olivocerebellar pathway, 12
Electroencephalogram (EEG), 253 primate motor system, 12, 13
Index 481
primidone, 22 tremor amplitude, 469

thalamic neurons, 13–15 tremor signals comparison, 470
thalamocortical pathway, 12 UPDRS, 467, 469
zonisamide, 22 Extended activities of daily living scale,
methodological issues, 169 334–335
misdiagnosis, 168
motor features, 182
natural history, 179–183 F
New York series, 177 FA. See Fractional anisotropy (FA)
nomenclatural issue, 168 Factitious disorders, 293
nonmotor features, 182 Fahn, S., 291, 328
olivary hypothesis, 172 Familial cortical myoclonic tremor with
onset, 179 epilepsy (FCMTE)
pathophysiology, 175–178 brain imaging, 256
pharmacological treatments, 424–426 in children, 318
postmortem examination, 178 clinical characteristics
postural tremors autosomic dominant transmission, 251
load-dependant component, 139 cerebellar disorders, 252
occurence, 138 cognitive impairment, 251–252
vs. PD, 144–145 cortical myoclonus, 250
spectral characteristics, 140 epilepsy, 251
thalamus, 140 gait disorders, 252
prevalence, 180, 205 headache, 253
progression, 205 mental retardation, 251–252
Purkinje cells, 174, 175 migraine, 253
risk factors, 169 night blindness, 252
rodent models, 45–47 onset, 251
severity, 182 parkinsonism, 252
torpedoes, 173, 174 pharmacosensitivity, 251
Essential vocal tremor (EVT) visual intolerance, 252
clinical features description, 66–67
patient physical examination, 238–239 diagnostic criteria, 257, 258
symptoms, 237 differential diagnosis, 257
thyroarytenoid muscle, 239 electrophysiological characteristics
voice assessment, 237, 238 cortical premyoclonic potential, 255,
DBS, 449 256
description, 237 C reflex response, 255
etiology, 239 EEG, 253
treatment, 240–241 jerk-locked back-averaging EEG, 255,
ET. See Essential tremor (ET) 256
Ethanol polygraphic examination, 253, 254
membrane physiology, 22–23 SEP, 254
pharmacological treatments, 420 tremor frequency recording, 253, 254
ETM1, 61–62 genetic heterogeneity
ETM2, 62 FAME1 families, 257–258
ETM3, 62 FAME2 families, 259
EVT. See Essential vocal tremor (EVT) FAME3 families, 259
Exaggerated physiological tremor vs. RT, force pedigree unlinked, 8p and 2q loci,
and dopa-responsiveness 259–260
experimental apparatus, 466, 467 history, 250
features, 466 loci and genes, 67
power spectral densities, 469 neuropathological findings, 256
summary of, 470–472 physiopathological findings, 260
torques, 468 Fasano, A., 354
482 Index
Fast Fourier transform (FFT), 376–378 Gyroscopes

FBXO7 gene, 59 advantages, 353
Fechner, G.T., 342 description, 352
Fernandez-Alvarez, E., 306, 313 disadvantages, 353
FES. See Functional electrical stimulation
(FES)
FFT. See Fast Fourier transform (FFT) H
Findley, L.G., 354, 360 Hallett, M., 299, 344
Fleishman, E.A., 359 Halliday, D.M., 115
Foote, K.D., 451 Happee, R., 84
Forssberg, H., 350 Harmaline
Fourier power spectra, wrist (hand) tremor chemical structure, 38
central-neurogenic tremor, 113, 114 induced tremor, 38
enhanced physiologic tremor, 115, 116 inferior olivary nucleus (ION), 38–39
mechanical-reflex oscillation, 112 Purkinje cell damages, 40–41
Fractional anisotropy (FA), 392–393 tolerance, 39–40
Fragile X-associated tremor/ataxia syndrome Hassler, R., 446
(FXTAS), 65–66, 187 Hassler, R.G.M., 433
Fuhr, T., 83, 84 He, J., 83, 84, 86
Functional electrical stimulation (FES) Head trauma. See Traumatic brain injury
block diagram, 102, 103 Head tremor
control system, 103, 104 essential tremor, 180–181
description, 102 infants
drawbacks, 104–105 bobble-head doll syndrome, 311–312
FXTAS. See Fragile X-associated tremor/ congenital nystagmus, 311
ataxia syndrome (FXTAS) spasmus nutans, 312
stereotypies, 312
Heckman, C.J., 86
G Heilman, K.M., 219
Gabapentin Hemiballismus, 271
essential tremor, 22 Hemifacial spasm, 279–280
EVT, 240 Hereditary geniospasm, 316
pharmacological treatments, 422 Hereditary motor and sensory neuropathies
Gait ataxia, 420, 455 (HSMN), 69–70
Gait disorders, 252 Hermsdörfer, J., 157, 158
Gamma Knife (GK) thalamotomy, 438–439 Heroux, M.E., 140
García-Martín, E., 18 Hewer, R.L., 362
Gerschlager, W., 221, 222, 225, 226 HID. See Human interface
Giblin, D., 317 devices (HID)
Gillard, D., 89 Hillel, A.D., 242
Glasgow coma score (GCS), 265 Hill-type muscle model, 83, 85
Glass, G.A., 225 Hoff, J.I., 358
Glucocerebrosidase (GBA), 59–60 Hoffmann, A., 354
Glucose transporter 1 (Glut-1) deficiency, 317 Holmes tremor (HT)
Golgi tendon organ (GTO) in children, 315–316
feedback, 90 description, 307
physiological structure, 90 head trauma, 265–266
proprioceptive sensory receptor, 89 isometric tremor, 163
Goto, S., 450 Honey, C.R., 449
Gowers, W.R., 263 Horsley–Clarke stereotactic
Grimaldi, G., 4, 7, 331, 372 apparatus, 432–433
Guridi, J., 230, 450 Hottinger-Blanc, P.M., 312
GYGYF2 gene, 58 Houk, J.C., 89
Index 483
HSMN. See Hereditary motor and sensory therapeutic strategies, 163

neuropathies (HSMN) essential tremor
Human interface devices (HID), 355, 357 frequency, 155
Hydrocephalus, 315 pathophysiology, 155
6-hydroxydopamine(6-OHDA), 43–44 therapeutic strategies, 155–156
Hyperthyroidism, 25 frequent movement disorder synopsis, 153
Holmes tremor
definition, 163
I pathophysiology, 163
Ikeda, A., 250 therapeutic strategies, 163
Image-guided anatomical targeting, 435 occurence, 151
Infants, tremor orthostatic tremor
dopamine metabolism, 310–311 diagnostic clue, 164
head tremors pathophysiology, 164
bobble-head doll syndrome, 311–312 therapeutic strategies, 164
congenital nystagmus, 311 Parkinson’s disease
spasmus nutans, 312 frequency, 156
stereotypies, 312 L
-Dopa medication, 159
shuddering attacks, 312–313 pathophysiology, 156–158
vitamin B12 deficiency, 311 therapeutic strategies, 159, 160
Instrumentation, tremor assessment phenomenology, 152
historical review, 342–343 physiological tremor
kinematics pathophysiology, 154
ballistic wrist movements, 361 therapeutic strategies, 154–155
bradykinesia measurement, 361
everyday live conditions improvement,
J
362
Jadhav, M., 311
intention tremor treatment, 362
Jankovic, J., 273, 314
inter-and intra-limb coordination, 361
Jaw tremor
kinetic tremor prolongs reaction times,
botulinum toxin injections, 423
362
essential tremor (ET), 181
muscle weakness, 361–362
Jerk-locked back-averaging EEG, 255, 256
MEMS technology, 364–365
sensors and techniques
combined sensors and actigraphs, K
357–358 Kinematics, tremor assessment
gyroscopes, 360 interference and voluntary action
indirect estimation, 359 ballistic wrist movements, 361
kinematic measures, 351–357 bradykinesia measurement, 361
kinetic measures, 357 everyday live conditions improvement,
marker-based techniques, 359–360 362
technical test setting plan, 363–364 intention tremor treatment, 362
Intraoperative microelectrode recording inter-and intra-limb coordination, 361
(MER), 435 kinetic tremor prolongs reaction times,
Isometric tremor 362
cerebellar disorders muscle weakness, 361–362
diagnosis criteria, 160 transducers and techniques
pathophysiology, 160–162 accelerometers, 351–352
therapeutic strategies, 162 gyroscopes, 352–353
classification, 152 HID, 355, 357
definition, 6, 152 spiral drawing, 354–356
diagnose, 153 ultrasound, 354
dystonic tremor videometry, 353–354
pathophysiology, 162 of tremor oscillation, 350
484 Index
Kinetics, tremor assessment Lincoln, N.B., 334

sensors or transducers, 357 LINGO1 gene, 62–63
of tremor oscillation, 350 Lithium-induced tremor, 24
Kinetic tremor. See also Dystonic tremor; Littmann, L., 223
Orthostatic tremor Liu, X., 355
classification, 306–307 Louis, E.D., 144, 333, 344–346, 359
clinical evaluation, 326 LRRK2. See Leucine-rich repeat kinase 2
definition, 6, 167 (LRRK2)
description, 306 Ludlow, C.L., 239
drug-induced, 185–186 Lumped model, peripheral nervous system,
essential tremor (ET) 80, 81
clinical presentation, 179–183 Lundy, D.S., 238
diagnosis, 183–185
etiology, 168–171
misdiagnosis, 168 M
natural history, 179–183 Ma, Y., 405
nomenclatural issue, 168 Macroscopic musculoskeletal model, 81, 82
pathophysiology, 175–178 Magariños-Ascone, C., 230, 450
FXTAS, 187 Magnitude squared coherence (MSC). See
Parkinson’s disease, 188–189 Coherence analysis
peripheral neuropathy, 188 Manolakis, D.G., 380
primary writing tremor, 189 Manto, M., 4, 7, 308, 331, 372
rubral tremor, 189 MAPT. See Microtubule-associated protein tau
simulation, 96–97 (MAPT)
Wilson’s disease, 186–187 Marin, C., 328
Klein, J.C., 395 Marsden, C.D., 308
Klotz, D.A., 243 Masuhr, F., 344
Koda, J., 239, 243 Matsumoto, J.Y., 357
Kraus, P.H., 345, 354, 359 Matsuoka’s neural oscillator model
Kremer, M., 315 structure of, 92
tremors with different frequencies, 93
McAuley, J.H., 357, 362
L MDs. See Movement disorders (MDs)
Labauge, P., 259 Mechanical counter test (MCT), 331–333
Lakie, M., 360 Mechanical-reflex tremor
Lalli, S., 207, 210 enhancement, 115–116
Lanska, D.J., 342 frequency, 112
Lauk, M., 137 muscle contractions, 113
Leksell, L., 433 normal mechanical-reflex oscillation,
Leksell stereotactic frame, 433, 434 111–112
Lemay, M.A., 85 occurence, 113
Leucine-rich repeat kinase 2 (LRRK2), 56–57 Mechanical tremor suppression, 472–473
Leu-Semenescu, S., 225 Membrane electrophysiology, 21
Levetiracetam Membrane mechanisms, ET
cortical myoclonus, 250 conductance-based model, 21
Holmes tremor, 316 harmaline model, 17
pharmacological treatments, 422 inferior olive neurons, 15
Levodopa isolated inferior olive neurons,
Parkinson’s disease (PD), 125 synchronization mechanisms, 20–21
pharmacological treatments, 422–423 isolated thalamic neurons, synchronization
rest tremor, 129 mechanism, 18–19
Lévy, G., 70 olivocerebellar pathway, 12
Lewis, P.R., 315 primate motor system, 12, 13
Lim, D.A., 451 thalamic neurons, 13–15
Index 485
thalamocortical pathway, 12 GTO, 89–90

MER. See Intraoperative microelectrode muscle spindles, 87–89
recording (MER) neuronal pool dynamics, 86–87
Methazolamide, 423 Renshaw cell, 90–91
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine reflex loops, 80, 81
(MPTP), 43 simulation
Microtubule-associated protein tau (MAPT), central vs. peripheral oscillation,
59 98–102
Midbrain tremor, 6 kinetic tremor, 96–97
Miralles, F., 355 postural tremor, 97–98
Modified Fahn–Tolosa–Marin rating scale, primary simulation, 94–96
326, 327 wrist joints, 93, 94
Moosa, A., 317 skeletal dynamics, 85–86
Morrison, S., 361 tremor suppression applications
Mostile, G., 358 DBS, 103–104
Movement disorders (MDs) FES, 102–105
peripheral trauma
clinical characteristics, 271, 272
criteria, 264 N
posttraumatic (see Posttraumatic Neck whiplash injuries, 272–273
movement disorders) Nellhaus, G., 312
MS. See Multiple sclerosis (MS) Neural stimulation, 473
MSARP. See Multiple system atrophy--related Neuroablation, 436
pattern (MSARP) Neuroleptic-induced tremor, 25
Multiple sclerosis (MS) Neurological disorders
APN, 26–27 dystonia, 266–268
DBS, 451–452 pharmacological treatment, 424–426
Multiple system atrophy–related pattern spinocerebellar ataxia, 453
(MSARP), 411 Neuronal pool dynamics, 86–87
Muscle spindles Neuropathic tremor, 188, 453
anatomical structure, 88 Neville, B.G.R., 310
contraction dynamics, 89 Newell, K.M., 361
intrafusal tension, 88–89 New York series, 176, 177
physiological structure, 87 Nguyen, J.P., 451
sensory and motor component, 88 Nicardipine, 423
Muscle tension dysphonia, 236 Nicotine-induced tail tremor, 42
Muscle weakness, 361–362 Night blindness, 252
Musculoskeletal models Nine Hole Peg Test (9HPT), 331, 332
activation dynamics, 82, 83 Nisticò, R., 126
central neural oscillator Norman, K.E., 355
Matsuoka’s neural oscillator model, Nourie and Lincoln Extended ADL (NL)
92–93 scores, 338
types, 91 Nouri, F.M., 334
central oscillation, 81 Nowak, D.A., 157, 158
contraction dynamics
active force generation, 84–85
description, 83 O
force-velocity relationship, 84 Ocular flutter, 26
Hill-type muscle model, 83, 85 Ogihara, N., 83
muscle active force, 83 Olanzapine, 423
description, 79–80 Olivary hypothesis, 172
lumped model, 80, 81 OMD. See Oromandibular dystonia (OMD)
macroscopic model, 81, 82 OMI/HTRA2, 58
peripheral nervous system modeling Ondansetron, 423
486 Index
Oppenheim, A.V., 380 SNCA, 55–56

Opsoclonus, 26 autosomal recessive
Organic tremor ATP13A2, 58
clinical features of, 294 DJ-1, 58
coherence analysis, 298 parkin, 57
entrainment test, 298 PINK-1, 57–58
frequency and amplitude, 296 bradykinesia measurement, 361
Oromandibular dystonia (OMD), 277 description, 54, 403
Orsnes, G.B., 352 dopamine and force production influences,
Orthostatic tremor (OT) 464–465
characteristics, 220 DWI, 394
clinical examination, 223 genetic screening, 54, 55
consensus statement, 223, 224 and head trauma, 268–270
DBS, 450 isometric tremor
definition, 6 frequency, 156
diagnosis, 223 L
-Dopa medication, 159
differential diagnosis, 224–225 pathophysiology, 156–158
epidemiology, 221 therapeutic strategies, 159, 160
features, 224 kinetic tremor, 188–189, 362
health-related quality of life, levodopa, 422–423
225–226 loci and genes, 54, 55
isometric tremor membrane mechanisms, 23–24
diagnostic clue, 164 metabolic networks
pathophysiology, 164 derivation, 404
therapeutic strategies, 164 PDCP, 410
laboratory workup, 223–224 PDRP, 405, 406
nigrostriatal dopaminergic system, 228 PDTP, 407–410
orthostatic myoclonus, 225 muscle weakness, 361–362
pathophysiology, 227–228 peripheral trauma, 271–273
secondary, 226–227 postural tremors
symptoms, 222 vs. essential tremor (ET), 144–145
treatment imaging studies, 143
pharmacological agents, 229 spectral characteristics, 141, 142
physical aids, 228 putative PARK genes
surgical, 229–230 FBXO7, 59
Ortí-Pareja, M., 226 GYGYF2, 58
OMI/HTRA2, 58
PLA2G6, 59
P UCH-L1, 58
PAID. See Paroxysmal autonomic instability RBD, 412–413
with focal dystonia (PAID) rest tremor
Painful legs and moving toes syndrome, 280 autopsy studies, 128
Palatal tremor cardinal features, 123
in children, 315 clinical progression, 123
definition, 7 clinical signs, 125
Papapetropoulos, S., 352 dopamine levels, 128
Parkin, 57 heterogeneous presentation, 123
Parkinson’s disease (PD) motor unit synchrony, 127
APS non-motor signs and symptoms, 125
description, 410–411 oscillatory activity, subthalamic
MSA, 411 nucleus, 127
PSP, 411 vascular parkinsonism, 125
spatial covariance patterns, 411, 412 rodent models, 47–48
autosomal dominant RT vs. EPT
LRRK2, 56–57 coexistence evaluation, 466–472
Index 487
features, 466 on central tremor, 101–102

susceptibility genes on peripheral tremor, 101
additional loci, 60 limit cycle behavior, 99–101
GBA, 59–60 phase shift, muscle spindle, 99
MAPT, 59 Pharmacotherapy, 22–23
vocal tremor Physiological tremor
characterization, 245 arm tremor, 361
description, 245 definition, 4
treatment, 246 isometric tremor
vocal fold bowing, 246 pathophysiology, 154
Parkinson’s disease-related cognitive pattern therapeutic strategies, 154–155
(PDCP), 410 postural tremors
Parkinson’s disease-related motor pattern description, 134
(PDRP), 405, 406 oscillation categories, 135
Parkinson’s disease-related tremor pattern vs. rest PT, 134–135
(PDTP) thalamotomy, 136
description, 407 sensitive motion transducers, 111
network activity change, 407, 408 Piboolnurak, P., 222
supplementary motor cortices, PINK-1. See PTEN-induced putative kinase 1
409–410 gene (PINK-1)
validation, 407 Pirker, W., 453
whole-brain expression, 408, 409 PLA2G6, 59
Parkinson tremor, DBS, 447–448 Plante-Bordeneuve, V., 70
Paroxysmal autonomic instability with focal PMD. See Psychogenic movement disorders
dystonia (PAID), 267 (PMD)
PD. See Parkinson’s disease (PD) Popovic Maneski, L., 365
Peker, S., 450 Post-stroke tremor, 450–451
Penitrem A, 44 Posttraumatic movement disorders
Peripheral nervous system cassification, 263–264
modeling description, 263
GTO, 89–90 head trauma
muscle spindles, 87–89 CTE, 270–271
neuronal pool dynamics, 86–87 DAI, 265
Renshaw cell, 90–91 dementia pugilistica, 270
movement disorders dystonia, 266–268
cervical and shoulder dystonia, GCS, 265
276–277 hemiballismus, 271
clinical characteristics, 271, 272 HT, 265–266
CRPS, 275–276 PD, 268–270
dystonia, 273–275 pugilistic parkinsonism, 270
hemifacial spasm, 279 tics, 271
OMD, 277 peripheral trauma
painful legs and moving toes syndrome, cervical and shoulder dystonia,
280 276–277
and parkinsonism, 271–273 clinical characteristics, 271, 272
pathophysiology, 278–279 CRPS, 275–276
PMD, 278 dystonia, 273–275
segmental myoclonus, 279–280 hemifacial spasm, 279
Peripheral neuropathy OMD, 277
kinetic tremor, 188 painful legs and moving toes syndrome,
neuropathic tremor, 453 280
spinocerebellar ataxia 12, 65 and parkinsonism, 271–273
Perturbation test pathophysiology, 278–279
criterion, 98 PMD, 278
inertial load test segmental myoclonus, 279–280
488 Index
Postural tremors DBS, 452

clinical evaluation, 326 definition, 6
definition, 6 kinetic tremor, 189
description, 306 upper limb, 213
enhanced physiological tremor (EPT), Primidone
136–138 essential tremor, 22
essential tremor (ET) essential tremor (ET), 214
load-dependant component, 139 EVT, 240
occurence, 138 pharmacological treatments, 420–421
vs. PD, 144–145 Prochazka, A., 89
spectral characteristics, 140 Progressive supranuclear palsy (PSP), 411
thalamus, 140 Progressive supranuclear palsy-related pattern
Parkinson’s disease (PD) (PSPRP), 411
vs. essential tremor (ET), 144–145 Propranolol
imaging studies, 143 essential tremor (ET), 214
spectral characteristics, 141, 142 EVT, 240
physiological tremor pharmacological treatments, 421
description, 134 PSD estimation. See Power spectral density
oscillation categories, 135 (PSD) estimation
vs. rest PT, 134–135 Pseudotremor. See Familial cortical myoclonic
thalamotomy, 136 tremor with epilepsy (FCMTE)
relationships between, 140–141 PSP. See Progressive supranuclear palsy (PSP)
simulation, 97–98 PSPRP. See Progressive supranuclear
Posturography, 357 palsy-related pattern (PSPRP)
Pourcher, E., 144 Psychogenic movement disorders (PMD)
Powers, R.K., 87 degree of certainty, 291–292
Power spectral density (PSD) estimation diagnosis, 290–291
vs. autocorrelation, 375 features, 291
continuous-and discrete-time peripheral trauma, 278
representations, 374–375 psychopathology of
definition, 374 dissociative disorders, 292
FFT, 376–378 somatization disorders, 292–293
harmonic estimators, 375 Psychogenic tremors (PT)
interpretion, 383 in children, 319
nonparametric estimators, 375 clinical features, 294–296
parametric estimators, 375 definition, 7, 290
periodogram, 376 diagnostic techniques
recommendations and trade-offs, 383–384 accelerometry, 297
signal windowing ballistic movement test, 298
common data windows, 379, 380 bereitschaftspotential, 298, 299
insufficient zero padding, 378 co-activation sign, 297
periodogram, 378, 379 coherence analysis, 298
piecewise linear interpolation, 378 entrainment, 298
smoothing frequency and amplitude, 296–297
Blackman–Tukey method, 381–382 suggestion and placebo, 296
smoothing spectral peaks, 382–383 neurophysiologic tests, 299–300
Welch–Bartlett method, 380–381 treatment
statistical preliminaries, 372–373 biofeedback, 302
statistical properties, 384, 385 cognitive behavioral treatment, 301
types, 375 functional disorder, 301
Pramipexole, 129, 229, 280, 422, 424 physiotherapy and positive
Pregabalin, 422, 425 reinforcement, 301
Primary writing tremor (PWT) prognosis, 300–301
in children, 319 psychodynamic therapy, 301
Index 489
PTEN-induced putative kinase 1 gene pharmacological treatments, 424

(PINK-1), 57–58 therapy, 129
Pugilistic parkinsonism, 270 time-frequency analysis, 122, 124
PWT. See Primary writing tremor (PWT) VLa neurons, 126
Rhythmic cortical myoclonus, 6
Riener, R., 83, 84
Q Riggs, J.E., 317
Quinn, N.P., 344 Riley, P.O., 362
Ringendahl, H., 359
Rocca, W.A., 144
R Rodent models
Radiosurgical thalamotomy, 438–439 beta-carboline derivatives, 38
Raethjen, J., 134, 159, 346 cholinergic agents
Rapid eye movement sleep behavior disorder cholinomimetic-induced generalized
(RBD), 412–413 tremor, 41–42
Rasagiline, 423 nicotine-induced tail tremor, 42
Recessive dystonias, 69 tacrine-induced tremulous jaw
Re-emergent tremor. See Kinetic tremor movements, 42
Renshaw cell, 90–91 tremor-generating mechanisms, 42
Repetitive transcranial magnetic stimulation dopaminergic neurotoxins
(rTMS), 473 genetic mutants, 44–45
Rest tremor (RT) 6-hydroxydopamine(6-OHDA), 43–44
clinical description, 121–122 MPTP, 43
clinical evaluation, 326 penitrem A, 44
definition, 4–6, 121 GABA receptors, 44–45
description, 306 Purkinje cell damages, 40–41
disorders associated with, 122–126 representative human tremor disorders
electromyographic pattern, 126 essential tremor, 45–47
electromyographic pattern, 126 Parkinson’s disease, 47–48
vs. EPT, force and dopa-responsiveness tolerance, 39–40
experimental apparatus, 466, 467 tremor-generating mechanisms, 38–39
features, 466 Rodrigues, J.P., 225
power spectral densities, 469 Rodríguez, J., 226
summary of, 470–472 Ropinirole, 422
torques, 468 Rosen, M.J., 472
tremor amplitude, 469 Rossolimo, G., 432
tremor signals comparison, 470 Rothwell, J.C., 318
UPDRS, 467, 469 Roubergue, A., 317
frequency range, 121, 122 Roussy, G., 70
local field potential activity, 127 Roussy–Lévy syndrome, 69–70
neuronal mechanisms, 126 rTMS. See Repetitive transcranial magnetic
Parkinson’s disease stimulation (rTMS)
autopsy studies, 128 Rubral tremor. See Holmes tremor; Midbrain
cardinal features, 123 tremor
clinical progression, 123 Rymer, W.Z., 89
clinical signs, 125
dopamine levels, 128
heterogeneous presentation, 123 S
motor unit synchrony, 127 Saccadic oscillation, membrane mechanisms,
non-motor signs and symptoms, 125 28–29
oscillatory activity, subthalamic Safinamide, 423
nucleus, 127 Salarian, A., 358
vascular parkinsonism, 125 Sanborn, M.R., 450
pathophysiology, 126–128 SCAs. See Spinocerebellar ataxias (SCAs)
490 Index
Schafer, R.W., 380 Sorensen, P.S., 352

Schoppe, K.J., 359 Spasmodic dysphonia (SD)
Schramm, P., 453 abductor type, 241
Schuurman, P.R., 439 adductor-type, 241, 242
SD. See Spasmodic dysphonia (SD) description, 241
Segawa, M., 318 etiology, 242–243
Segawa’s disease, 318 treatment, 243–245
Segmental myoclonus, 279–280 voice tremor, 212–213
Seidel, S., 396 Spasmus nutans, 312
Selegiline, 423 Spiegel, E.W.H., 433
Seletz, E., 432 Spinal muscular atrophy (SMA), 317
Senataxin (SETX), 66 Spinocerebellar ataxias (SCAs), 453
Shaikh, A.G., 17, 19 type 2, 64
Shaky legs syndrome. See Orthostatic tremor type 3, 64
Sharott, A., 227 type 12, 65
SHIMMER device, 358 type 15, 65
Shin, D.H., 395 type 16, 65
Shuddering attacks, 312–313 type 20, 65
Signal processing Spiral drawing, 354–356
coherence analysis Spiro, A.J., 317
description, 384–386 Spyers-Ashby, J.M., 353
estimation, 386–388 Staude, G., 362
properties, 386 Stereotactic surgical technique
description, 371–372 image-guided anatomical targeting, 435
PSD estimation neuroablation, 436
vs. autocorrelation, 375 neurophysiologic confirmation, of intended
continuous-and discrete-time target, 435
representations, 374–375 STN. See Subthalamic nucleus (STN)
definition, 374 Strain gauges, 357
FFT, 376–378 Subthalamic nucleus (STN), 399
interpretion, 383 Symptomatic orthostatic tremor, 226–227
periodogram, 376
recommendations and trade-offs,
383–384 T
signal windowing, 377–380 Tacrine-induced tremulous jaw movements, 42
smoothing, 380–383 Tanner, K., 242
statistical preliminaries, 372–373 Task-specific tremors
statistical properties, 384, 385 in children, 318–319
types, 375 definition, 4
Signal windowing TBSS. See Tract-based spatial statistics
common data windows, 379, 380 (TBSS)
insufficient zero padding, 378 Terminal tremor, 306
periodogram, 378, 379 Thalamic tremor, 6
piecewise linear interpolation, 378 Thalamotomy
Singer, H.S., 306 clinical outcomes
SMA. See Spinal muscular atrophy (SMA) conventional thalamotomy, 437, 438
SNCA. See a-Synuclein gene (SNCA) vs. DBS, 439–440
Somatization disorders radiosurgical thalamotomy, 438–439
description, 292 definition, 431
factitious disorders, 293 expert consensus, 440–442
malingering, 293 history
somatoform disorders, 292–293 Horsley–Clarke stereotactic apparatus,
Somatoform disorders, 292–293 432–433
Somatosensory evoked potential (SEP), 254 Leksell stereotactic frame, 433, 434
Index 491
radiological techniques, 433 Segawa’s disease, 318

Sir Victor Horsley’s sculpture, 431, 432 SMA, 317
stereotactic neurosurgical technique, stereotypies, 307
432 task specific tremors, 318–319
pathophysiology, 434–435 toxins, 314–315
stereotactic surgical technique Wilson’s disease, 316
image-guided anatomical targeting, 435 classification, 306–307
neuroablation, 436 clinical scales
neurophysiologic confirmation, of CNF-TES, 330–331
intended target, 435 criteria, 327–328
Thomas, A., 225 TRS, 328–330
Titubation, 307 clinical standards and updates, 344–345
Tolosa, E., 328 definition, 3, 305–306, 341–342
Topiramate, 156, 422 differential diagnosis, 7
Torpedoes, 173, 174, 176 diffusion tensor imaging, 394
Tract-based spatial statistics (TBSS), 393 diffusion tractography (See Diffusion
Trans-synaptic excitotoxicity model, 40–41 tractography)
Traumatic brain injury disorders associated, 4
CTE, 270–271 Eshner’s tambour recording apparatus, 342,
DAI, 265 343
dementia pugilistica, 270 functional evaluation
dystonia, 266–268 BBT, 331, 332
GCS, 265 description, 331
hemiballismus, 271 9HPT, 331, 332
HT, 265–266 MCT, 331–333
PD, 268–270 hyperthyroidism, 25
pugilistic parkinsonism, 270 infants
tics, 271 dopamine metabolism, 310–311
Tremor head tremors, 311–312
ADL scale shuddering attacks, 312–313
ADL-T24 scale, 334–339 vitamin B12 deficiency, 311
description, 334 instrumentation (See Instrumentation,
extended, 334–335 tremor assessment)
in children vs. involuntary movement disorders, 7
benign neonatal sleep myoclonus, 310 membrane mechanisms
cycling movements, 309–310 acquired pendular nystagmus (APN),
diagnosis, 309 26–28
drugs, 314–315 drug-induced tremor, 24–26
enhanced physiological tremor, 313 essential tremor, 12–23
EPC, 318 Parkinson’s disease, 23–24
ET, 313–314 saccadic oscillation, 28–29
examination, 307–308 modified Fahn–Tolosa–Marin rating scale,
familial cortical myoclonic tremor, 318 326, 327
Glut-1 deficiency, 317 newborn, 309–310
hereditary geniospasm, 316 observable features, 345–346
HT, 315–316 perturbation test
hydrocephalus, 315 (see Perturbation test)
jitteriness, 309 pharmacological treatments
microdeletions and microduplications, antiepileptic drugs, 422
319 benzodiazepines, 421–422
palatal tremor, 315 clozapine, 423
pathophysiology, 308–309 essential tremor, 424–426
PT, 319 ethanol, 420
PWT, 319 gabapentin, 422
492 Index
Tremor (cont.) Visual intolerance, 252

levetiracetam, 422 Vitamin B12 deficiency, 311
levodopa, 422–423 Vocal tremor
pregabalin, 422 categories, 236–237
primidone, 420–421 description, 235
propranolol, 421 differential diagnosis, 235–236
rest tremor, 424 EVT (see Essential vocal tremor (EVT))
topiramate, 422 neurologic conditions, 245
properties, healthy adults and adolescents, Parkinson’s disease
117 characterization, 245
quantitative research standards description, 245
methodological, 349 treatment, 246
technical, 347, 348 vocal fold bowing, 246
rodent models (see Rodent models) Voxel-based morphometry (VBM), 128
sources, 9 Voxel-wise analysis techniques, 393
suppression applications
DBS, 103–104
FES, 102–105 W
therapies Water diffusion
botulinum toxin treatment, 474 anisotropic diffusion, 391, 392
control and diagnostic, 346–347 tensors, 392
mechanical tremor suppression, 472–473 Weber, E.H., 342
neural stimulation, 473 Welch–Bartlett method, 380–381, 386
tremorogenesis, motor pathways and main Williams, D.T, 291
loops, 8, 9 Wills, A.J., 229
types, 4–7 Wilson’s disease
Weber–Fechner law, 325 in children, 316
Tuttle, W.W., 357 description, 70, 316
kinetic tremor, 186–187
rest tremor, 122, 123
U Wrist joint simulation, 93, 94
UCH-L1, 58 Wycis, H.T., 433
Uhrikova, Z., 353
Umemura, A., 451
Unified Parkinson’s disease rating scale Y
(UPDRS), 467, 469 Yamada, K., 450
Yamazaki, N., 83
Yarrow, K., 227
V Yoshikawa, K., 394
Vaillancourt, D.E., 394
Valproate-induced tremor, 24
van Rooijen, D.E., 272, 278 Z
van Rootselaar, A.F., 249, 318 Zajac, F.E., 82
van Someren, E.J.W., 358 Zarzur, A.P., 246
Vascular parkinsonism (VP), 125 Zernov, D., 432
Ventral intermediate nucleus of thalamus Zesiewicz, T.A., 425
(VIM), 398–399 Zonisamide, 22, 423
Videometry, 353–354 Zwartjes, D.G.M., 357

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Contemporary Clinical Neuroscience

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Mechanisms and Emerging

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Springer is part of Springer Science+Business Media (www.springer.com)

Institut du Cerveau et de la Moëlle épinière

can by itself contribute to a correct diagnosis of the underlying neurological disorder.

Unité d’Etude du Mouvement (UEM) Giuliana Grimaldi

Findley LJ, Capildeo R. Movement disorders: Tremor. Macmillan, London; 1984.

Part I Fundamental Aspects

1 Definition of Tremor ............................................................................... 3

Part II The Various Forms of Tremor in Clinical Practice:

6 Physiologic Tremor ................................................................................. 111

10 Essential Tremor and Other Forms of Kinetic Tremor ....................... 167

Part III Assessment of Tremor: Clinical, Neurophysiological

18 Assessment of Tremor: Clinical and Functional Scales ....................... 325

Part IV Therapies of Tremor

23 Pharmacological Treatments of Tremor ............................................... 419

25 Deep Brain Stimulation .......................................................................... 445

Index ................................................................................................................. 477

Alberto Albanese, M.D. Fondazione Istituto Neurologico Carlo Besta,

Russell C. Dale Children’s Hospital Westmead, The University of Sydney,

Andrés Labiano-Fontcuberta, M.D. Department of Neurology,

Fariborz Rahimi, Ph.D. Department of Electrical Engineering, University of

Giuliana Grimaldi and Mario Manto

Keywords Rhythmic • Rest • Postural • Kinetic • Action • Movement disorders

Tremor is generally deﬁned as a rhythmic shaking of a body part (Deuschl et al.

G. Grimaldi (*) • M. Manto

G. Grimaldi and M. Manto (eds.), Mechanisms and Emerging Therapies in Tremor 3

1.2 Types of Tremor

Table 1.2 Principal types of tremor

with the naked eye

Table 1.3 Differential diagnosis of involuntary movements

Palatal tremor (also called palatal myoclonus) may be symptomatic or essential.

1.2.1 Differential Diagnosis Between Tremor and the Other

1.2.2 Sources of Tremor

Bhidayasiri R. Differential diagnosis of common tremor syndromes. Postgrad Med J. 2005;81:

Aasef G. Shaikh, Lance M. Optican, and David S. Zee

Keywords Membrane • Neurons • Oscillations • Loops • Spikes • Coupling

A number of neurological and psychogenic disorders present with tremor. In some,

A.G. Shaikh, M.D., Ph.D. (*)

G. Grimaldi and M. Manto (eds.), Mechanisms and Emerging Therapies in Tremor 11

In this chapter we will focus on membrane electrophysiology and its relationship to

2.3 Membrane Mechanisms of Essential Tremor

2.3.1 Membrane Oscillations in Thalamic Neurons

Thalamic neurons express voltage activated ion conductances such as 4-amin-

met isolated thalamic neurons generate spontaneous action potentials. Thalamic

2.3.2 Membrane Oscillations in the Inferior Olive Neurons

2.3.3 Thalamic and Inferior Olive Oscillation and Relation

The mechanisms underlying spontaneous oscillations in the thalamus and inferior

2.3.4 Synchronization of Isolated Neuronal Oscillations

Now that we have described underlying mechanisms for oscillations in isolated

2.3.4.1 Coupling of Neurons in Thalamus

Reciprocal inhibition of agonist and antagonist neurons is necessary to generate

2.3.4.2 Experimental and Computational Evidence of Thalamic

It was hypothesized that sufficient external inhibition is nature’s solution to inher-

frequencies of allelic variants in the genotypes of GABA receptors from the

2.3.4.3 Other Causes of Thalamic Neuronal Excitability in Essential Tremor

2.3.4.4 Coupling of Neurons in Inferior Olive

Isolated inferior olive neurons generate small amplitude, episodic, subthreshold

2.3.4.5 Influence of Cerebellum and Conditional Learning on Synchronized