Journal of the Neurological Sciences 289 (2010) 128–134

Contents lists available at ScienceDirect

Journal of the Neurological Sciences

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Use of magnetoencephalography (MEG) to study functional brain networks in

neurodegenerative disorders
C.J. Stam
Department of Clinical Neurophysiology, VU University Medical Center, Amsterdam, The Netherlands

a r t i c l e i n f o a b s t r a c t

Available online 2 September 2009 The pathophysiological mechanisms underlying clinical symptoms in neurodegenerative disorders such as
Parkinson's disease (PD) and Alzheimer's disease (AD) are incompletely understood. Magnetoencephalography
Keywords: (MEG) is a relatively new functional neuroimaging technique, which allows the simultaneous recording of the
Magnetoencephalography brain's magnetic activity from large arrays of sensors covering the whole head. MEG studies in PD and AD have
Parkinson's disease identified characteristic patterns of abnormal oscillatory activity in different frequency bands. Furthermore, MEG
Alzheimer's disease studies aimed at the characterization of distributed functional networks have demonstrated distinct patterns of
Functional connectivity
abnormal connectivity in demented and non-demented PD, as well as in AD. In PD abnormal oscillatory activity
Synchronization
Oscillations
and disturbed connectivity may respond differently to dopaminergic treatment. Further studies in this field could
Resting state benefit from new technological developments such as ultra low field MRI and from the application of a well-
Graph analysis defined theoretical framework such as graph theory to the study of disturbed brain networks.
Small-world networks © 2009 Elsevier B.V. All rights reserved.

1. Introduction different brain regions may reflect functional interactions between

Neurodegenerative disorders such as Parkinson's disease (PD) and
Alzheimer's disease (AD) constitute a major health burden, especially in
the ageing Western population. Although there is a large and increasing
body of knowledge on the genetic, molecular and cellular mechanisms
involved in these disorders, the exact cause is unknown, except for
a few rare genetic variants. The pathophysiological mechanisms that
ultimately give rise to the cognitive and motor disturbances are
incompletely understood, even though treatment is likely to interact
exactly at this level. A better understanding of the neurophysiological
changes in neurodegenerative disease could bridge the gap between
molecular and cellular levels on the one hand, and clinical symptoms
on the other hand. Neurophysiological understanding could guide
early and differential diagnosis, and may suggest new ways to monitor
treatment response.
Tools from clinical neurophysiology have been used for many years
in the study of PD and AD. Since a few years the availability of whole-
head magnetoencephalography (MEG) systems has expanded the
scope of such studies. MEG can record brain activity directly, and has
several advantages compared to conventional EEG recordings. In
contrast to EEG, MEG is hardly affected by the skull, and does not
require a reference electrode. Therefore, MEG may provide a more
accurate image of ongoing brain activity. In addition, significant
advances have been made in neuroscience concerning the under-
standing of oscillatory and synchronized brain activities. In particular
it is now assumed that synchronization of neural activity between
E-mail address: CJ.Stam@VUmc.nl.
these regions [1]. Such synchronization processes can be measured at
the level of the scalp with EEG and even better with MEG. Interesting
patterns of abnormal oscillatory activity and interregional synchroni-
zation have now been described in various brain disorders, including
PD and AD [2].
In the present review we will give an overview of MEG studies in
PD and AD performed in the last decade. First we will briefly introduce
MEG as a technique. Next, a short summary of current understanding
of oscillations and synchronization will be given. We will then address
MEG studies in PD and AD, and consider distinct and overlapping
patterns of abnormalities in both disorders. Finally, we will address a
number of remaining problems and point out directions for future
research.
2. Magnetoencephalography
The continuously changing synaptic currents of cortical pyramidal
neurons give rise not only to an electric but also to a magnetic field
that can be recorded from outside the head. This is due to the fact that
a change in an electrical field induces a magnetic field and a change in
a magnetic field induces an electrical field. Recording of the brain's
electrical field, the electroencephalogram (EEG) is relatively simple,
and been used extensively in scientific studies and clinical practice
since its first description in humans in 1929 by Hans Berger. Recording
of the brain's magnetic field is much more difficult due to the low
field strength (The magnetic field of the brain has a strength of about
100 to 1000 fT; 1 fT = 10− 15 T) compared to magnetic fields in
the surroundings (The magnetic field of the earth has a strength of

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 C.J. Stam / Journal of the Neurological Sciences 289 (2010) 128–134
30–60 μT). Recording of the brain's magnetic fields became possible
by a combination of advanced techniques and was first described by
David Cohen of the Massachusetts Institute of Technology in 1968.
First, conductive coils are cooled to −269°C (3° above the absolute
lowest temperature) to make them superconductive. This cooling is
realized with liquid helium. As a result of superconductivity current
can flow in these coils without resistance. Magnetic fields can induce
currents in these coils, and thanks to the superconductivity very weak
magnetic fields can be measured. Converting the currents in the coils
to a signal that can be measured requires another delicate piece of
technology: the superconducting quantum interference device or
SQUID. These consist of small rings with a very small interruption,
which can be crossed by electrons thanks to quantum effects. SQUIDs
are the key elements in MEG systems. Further improvement of the
signal-to-noise ratio is achieved by measuring not the absolute field
strength but only local gradients (gradiometers). Finally, the whole
MEG recording system is shielded from magnetic fields of the
surroundings by placing it in a magnetically shielded room (MSR),
with thick walls made of layers of various metals. In such a setup any
stimulation apparatus that gives rise to electromagnetic fields has to
be placed outside the MSR, and the stimulus has to be transferred to
the subject inside the MSR in an appropriate way. For instance, visual
stimulation is often projected using a system of mirrors.
Initial systems consisted of either a single or only a small number of
sensors; since the mid nineties systems with large numbers of sensors
from 122 to over 300 covering the whole head have become available,
greatly facilitating fundamental and clinical MEG studies. Compared to
EEG, MEG has the following advantages: (i) in contrast to the electrical
field, the magnetic field is hardly affected by intervening tissues such
as the skull; (ii) measurements of the magnetic field do not require a
reference as is the case with EEG; this is an advantage, in particular in
studies of functional connectivity; (iii) measurements from a very
large numbers of sensors are relatively more easy with MEG than with
EEG, since the tedious application of electrodes on the scalp is not
necessary. MEG shares with EEG the advantages of directly measuring
brain activity and having a very high temporal resolution, which is only
limited by the sample frequency of the electronics. The advantages of
MEG come at a price however; very literally since MEG systems and
the MSR are quite expensive. Furthermore, in contrast to EEG, MEG
systems are immobile, and cannot be used in an operating room or
intensive care unit. This is more of a disadvantage for certain clinical
studies than for basic research.
3. Oscillations and synchronization
MEG, like EEG, can record ongoing and task-induced activity of the
brain. The signals are mainly generated in pyramidal neurons in the
cortex in layers 3, 5 and 6. The dendritic trees of these neurons are
covered with up to 10,000 excitatory and inhibitory synapses. Arrival of
action potentials at the presynaptic terminal induces release of
neurotransmitters, in particular aspartate and GABA, which bind to
postsynaptic receptors and induce excitatory or inhibitory postsynaptic
potentials (EPSPs and IPSPs). The electrical fields due to EPSPs and
IPSPs of the dendritic trees sum up thanks to the regular orientation
of the cortical pyramidal neurons, which are oriented perpendicular to
the surface of the cortex. This gives rise to an electrical and, oriented
perpendicular to this, a magnetic field that can be measured at a distance
and outside the skull thanks to volume conduction. Two features of the
brain's electromagnetic activity are of interest for understanding the
MEG studies to be described below: (i) oscillations or rhythmic activity;
(ii) synchronization of oscillatory activity over long distances.
Ongoing, spontaneous brain activity is characterized by the
presence of more or less regular oscillations in various frequency
bands, often referred to as EEG rhythms. The origin of these oscillations
is not completely understood, but at least three levels are known
to be involved: (i) some neurons can show intrinsic oscillatory or
129
bursting dynamics, depending on their membrane potential; (ii)
interconnected circuits of excitatory and inhibitory neurons can give
rise to oscillations by a process of delayed negative feedback; here
the delay in the feedback loop is an important determinant of the
frequency of the oscillation; (iii) finally, interactions between several,
spatially distributed oscillatory neural groups can also influence the
nature of oscillatory activity. A key example of such a system is the
cortico thalamic network.
The alpha rhythm, (8–13 Hz) which is the dominant oscillatory
activity in awake adults, probably originates from an interaction
between local negative feedback circuits in the thalamus and the
cortex. When the feedback circuits in the thalamus work in isolation
they can produce the faster sleep spindles of 14 Hz. Faster EEG
rhythms such as beta (13–30 Hz) and gamma (>30 Hz) are produced
by feedback circuits between cortical pyramidal neurons and local
inhibitory inter neurons. Some types of theta (4–8 Hz) may originate
in medial temporal circuits and are projected to other parts of the
cortex through projects from the hippocampus. Physiological EEG
rhythms thus arise in different neural circuits, and probably have
different functions. The alpha rhythm may play a role in attention and
semantic memory, but may also have an inhibitory effect on other
rhythms. Beta is often related to motor processes, and gamma to
perception and consciousness. Theta has been associated to working
memory. How these various rhythms sub serve these functions is still
an area of activity research. According to Buzsaki oscillations could be
a cost-effective way to keep large groups of neurons close to their
firing threshold [3]. Fries suggested that oscillations may reflect
rhythmic fluctuations of neuronal excitability and gain [4].
While oscillations may represent a mechanism to organize the
activity of local networks of neurons, many such local networks exist
in the brain, and an important question is how these distributed
systems interact. There is increasing evidence from fundamental
studies that distributed neural systems may communicate through
synchronization of their activity [1]. Synchronization here refers to
the existence of a consistent relationship between activity patterns of
two or more spatially separated neuronal groups. Synchronization can
be defined at the level of action potentials, but also at the level of
oscillatory activity. In the latter case it often implies that there is a
consistent relation between the phases of the oscillatory activity of
two brain regions. This is of considerable importance, since such
phase coupling between EEG or MEG rhythmic activity recorded
over different brain regions can be readily accessed experimentally.
Interregional synchronization has now been studied extensively, both
in animal studies as well as in humans. During a no-task resting-state
synchronization of activity recorded over distributed brain regions
constitutes a stable, reproducible pattern with a strong genetic
basis [5,6]). Synchronization in different frequency bands has been
associated with various cognitive functions and the integration of
information in the healthy brain. In neurological disorders this
process of functional integration can become disrupted and give rise
to various symptoms ranging from cognitive dysfunction to epileptic
seizures [7,8]. In the following discussion of MEG studies in PD and AD
we will encounter a number of examples of disrupted brain networks
and their functional consequences.
4. MEG in Parkinson's disease
4.1. Early studies
One of the first MEG studies in PD was aimed at auditory
evoked magnetic fields. Pekkonen et al. [9] studied 11 PD patients
and 11 healthy, age-matched controls, and showed an increased
interhemispheric latency difference of the auditory evoked field; they
suggest that this might reflect the combined effect of basal ganglia
disease and auditory cortex degeneration. In a series of investigations
a group of Greek investigators used MEG to demonstrate the effect of
130 C.J. Stam / Journal of the Neurological Sciences 289 (2010) 128–134
magnetic stimulation on brain function in PD patients. First, scanning
32 areas with a single channel MEG system, they reported abnormal
high amplitude/low frequency activity as well as a low complexity
of the recorded signals estimated by a correlation dimension [10].
These abnormalities were partly reversed after extracranial magnetic
stimulation. Next, using a 122 channel whole-head MEG system, they
reported the presence of abnormal slow frequencies in a group of
9 PD patients compared with age and gender matched controls [11].
Finally they demonstrated that treatment with transcranial magnetic
stimulation induced subjective improvement in PD patients, which
was accompanied by a normalization of the MEG signals [12].
Analogous to EEG/EMG studies of corticomuscular coherence, MEG
has also been used to investigate the interaction between central and
peripheral components of the motor system. In a small but very
elegant study in 6 patients with tremor dominant PD, Timmermann
et al. [13] investigated the cerebral network involved in the genesis
of the tremor. First they demonstrated a strong coherence between
muscle activity and contra lateral motor cortex at the tremor
frequency and double tremor frequency. Next, using a method called
dynamic imaging of coherent sources (DICS) they unraveled the
network of brain areas interacting with the primary motor cortex; this
network involved the cingulate gyrus, the supplementary motor area,
lateral premotor cortex, diencephalon, secondary somatosensory
cortex, posterior parietal cortex and the contra lateral cerebellum.
Using partial coherence the hierarchical organization within this
network and the chain of causal influences could be determined.
4.2. Slowing of background activity
In a study involving a large cohort of 70 non-demented Parkinson
patients and 21 healthy controls Stoffers et al. [14] explored changes
in the MEG powerspectrum and their relation with various disease
characteristics. Several important conclusions could be derived from
this study: (i) the MEG powerspectrum is abnormal even in the
earliest, untreated phase of the disease; changes involved a diffuse
increase in relative theta and lower alpha band power, and a decrease
of beta power; (ii) alpha band power correlated with cognitive
perseveration; (iii) MEG spectral changes were constant in later
stages of the disease, and did not correlate with disease severity; (iv)
comparing measurements ‘ON’ and ‘OFF’ levodopa, no effect on
spectral power was shown. Thus, slowing of MEG background activity
is an early and constant feature of PD, which probably reflects non-
dopaminergic, non-motor systems involved in the disease.
A qualitative different pattern emerges in demented Parkinson
patients. Whereas non-demented PD patients showed changes in theta,
beta and gamma bands and normal reactivity to eye opening, demented
patients showed an increase in relative power in the delta band, and a
decrease of power in the alpha and beta bands [15]. Furthermore,
reactivity to eye opening was impaired in the demented PD patients.
Thus, dementia in PD is characterized not by a simple increase of
spectral abnormalities found in non-demented PD, but by an extension
of the abnormalities to other frequency bands such as the delta and
alpha bands. This observation could imply the involvement of different
neurotransmitter systems in PD dementia. Of interest, spectral changes
are not responsive to dopamine treatment, but a small study in
demented PD patients showed that treatment with an acetylcholine
esterase inhibitor could reverse the slowing of the background activity
[16]. Possibly, spectral slowing in PD reflects cholinergic rather than
dopaminergic loss, which would be in line with the observations of
Osipova et al. [17] who showed that blockade of cholinergic receptors
could induce slowing of MEG activity in healthy elderly subjects.
4.3. Changes in functional connectivity
Functional interactions between brain regions have also been
investigated in demented and non-demented PD patients. These
studies were stimulated by the observation that PD may be associated
with an increase in EEG coherence in the beta band, possibly due to
the failure of a normal basal ganglia/thalamic drive to the cortex [18].
These changes were reversible after either dopaminergic treatment or
deep brain stimulation.
Functional connectivity was studied in the same large cohort of
non-demented PD patients mentioned above using the synchroniza-
tion likelihood [19]. In untreated, early phase PD patients a diffuse
increase in functional connectivity in the lower alpha band was found.
This abnormally high connectivity extended to other frequency bands,
in particular the theta, upper alpha and beta bands, with progression
of the disease. Disease severity was associated with abnormal connec-
tivity in theta and beta bands. Cognitive perseveration was correlated
with interhemispheric alpha band synchronization.
In contrast to spectral changes, functional connectivity in PD does
respond to treatment with levodopa. In 37 non-demented patients
compared during ‘ON’ and ‘OFF’ states connectivity in a broad frequency
range from theta to beta increased as a result of levodopa treatment
[20]. This increase was most outspoken over the central sensory and
motor areas. More detailed analysis showed that in a subgroup of
patients who showed the largest improvement during the ‘ON’ state,
beta band synchronization showed a decrease rather than an increase
with levodopa treatment; this subgroup may be comparable with the
patients described by Silberstein et al. [18] where treatment was also
associated with decreased beta band coherence.
Again, changes in demented PD patients are qualitatively different
from those in non-demented PD patients. Demented PD patients
showed a loss of functional connectivity, especially between the
frontal and temporal areas within each hemisphere, and between
the temporal areas of both hemispheres, in the alpha band [21].
Connectivity changes in dementia thus show a decrease rather than
an increase in connectivity, and a distribution that is more fronto
temporal compared to the central dominance of connectivity changes
in non-demented PD. The overall pattern of connectivity changes in
demented PD shows a similarity with similar studies in AD [22].
4.4. Conclusion
Although the number of MEG studies in PD is still very small, a
consistent pattern of changes in local band power and interregional
synchronization is becoming clear. Slowing of background activity
(increased theta; decreased beta) and increased alpha band connectiv-
ity occur early in non-demented, drug naïve PD patients; with disease
progression the spectral changes stay constant, whereas increased
connectivity extends to other bands. Dopamine affects connectivity, but
does not influence power. With the advent of dementia, slowing occurs
in different frequency bands (increased delta power; loss of alpha
power), and lower rather than higher connectivity is seen mainly in
the alpha band. Changes in demented PD may be reversible after
cholinergic rather than dopaminergic treatment. This characteristic
pattern of progressive neurophysiological changes in non-demented
and demented PD patients could reflect the progressive involvement
of different neurotransmitter systems, as well as subcortical and cortical
Lewy body pathology, during the course of the disease [23].
5. MEG in Alzheimer's disease
5.1. Mild cognitive impairment
Full blown AD, like PD, takes many years to develop. From a clinical
point of view early detection, if possible in a preclinical stage, is of
considerable importance. This requires knowledge of the pathophys-
iological processes involved, and the way in which they can affect
recordings of brain activity such as the MEG. In a very elegant study,
Osipova et al. [17] investigated how changes in central cholinergic
activity would affect spectral power and coherence of resting-state
 C.J. Stam / Journal of the Neurological Sciences 289 (2010) 128–134 131

MEG recordings in healthy elderly subjects. The cholinergic system is
of considerable interest, since cholinergic projection systems like the
n. basalis of Meynert are known to be involved in AD, and to some
extent also in PD. Osipova et al. [17] found that intravenous injection
of scopolamine, which is a muscarinic receptor antagonist, increased
theta band power, impaired MEG alpha band reactivity to eye
opening, and decreased inter and left intrahemispheric theta band
coherence, thereby replicating some of the MEG changes in AD.
In a subsequent study, the authors used source estimation of
ongoing MEG oscillations to detect changes in subjects with mild
cognitive impairment (MCI) a condition characterized by memory
impairment and an increased risk of developing AD [24]. In this study,
the distribution of alpha sources did not differ between subjects with
MCI and healthy elderly controls. Maestu et al. [25] showed that MEG
can provide useful information on the risk of developing MCI. They
recorded MEG during a memory task in 15 healthy subjects. After
two years, five of these subjects developed MCI. The subjects were
characterized by abnormal low frequency activity in the left temporal
lobe in the initial recording. The mean frequency of the MEG
powerspectrum in MCI subjects was decreased compared to healthy
controls, and increased compared to Alzheimer patients [26]. This
suggests that MCI is in some respects an intermediate state between
health and AD. Furthermore, an average decrease of 0.17 Hz/year of
the mean frequency in healthy subjects was shown. Slowing of MEG in
MCI could be related to risk of developing AD. Fernandez et al. [27]
showed that MCI subjects with increased parietal theta band dipole
density had a higher risk of AD.
Reactivity of the MEG in a 8–15 Hz band to eye opening, in-
vestigated with a beamformer analysis (a three-dimensional, topo-
graphic analysis of spectral power), was impaired in AD patients, but
did not distinguish between healthy controls and MCI subjects [28].
Thus, MEG studies do not show consistent differences between
healthy controls and MCI subjects, although the study of Maestu et al.
[25] does suggest a predictive value of left hemisphere changes in
healthy subjects, and the study of Fernandez et al. [27] an association
between parietal theta and risk of AD in MCI. Of interest, the study of
Osipova et al. [17] also suggests that the left hemisphere may be more
vulnerable to the effects of loss of cholinergic modulation.
power in fast (alpha, beta and gamma) and slow (delta theta) relative
power had a sensitivity of 75% and a specificity of 95%. A comparison
of spectral median frequency with various nonlinear measures
showed that median frequency was the single best discriminator
between AD patients and controls [35]. In conclusion, and in contrast
to the findings in MCI, AD shows a consistent pattern of slowing of
MEG background activity, and an accuracy of around 80% in
discriminating AD from healthy controls (Table 1).
5.3. Source analysis
Compared to routine EEG, whole-head MEG recordings in combi-
nation with structural MRI are especially suited for source analysis.
Historically this approach has been mainly used to localize the sources
of either evoked responses to various types of sensory stimuli, or to
localize the sources of abnormal activity such as epileptic spikes or
abnormal slow activity. The same approach can also be used to analyze
MEG background activity, by fitting dipoles to the instantaneous MEG
fields at each time point [36]. This results in ‘density maps’ of dipoles in
various brain areas.
Using a dipole analysis Fernandez et al. [37] showed increased
delta and theta band dipole densities in temporo parietal regions that
correlated with changes in cognitive performance. Combining
changes of delta and theta dipole density with volumetric measures
of left hippocampal atrophy yielded a diagnostic accuracy of 87.1%
[38]. Combining delta dipole density with measures from MRI
spectroscopy (myoinositol/N-acetyl aspartate) a sensitivity of 90%
and a specificity of 100% was reported in a small study involving 10 AD
patients and 10 controls [39]. The usefulness of combining dipole
density during a memory task with measures derived from MRI
spectroscopy has been studied by Maestu et al. [40]. Osipova et al. [41]
used minimum current estimates to study the sources of the alpha
rhythm in AD patients and healthy controls. In AD patients, alpha
sources were enhanced in posterior temporal areas and decreased in
parieto-occipital regions. In healthy controls an opposite pattern was

5.2. Spectral analysis Table 1

Diagnostic properties of MEG measures in Alzheimer's disease.
The first pilot study of MEG in AD was conducted by Berendse Reference Measure Sensitivity Specificity Accuracy
et al. in 2000 [29]. They demonstrated a general slowing of MEG
Gomez et al. Higuchi's fractal – – 87.8
background activity, consisting of an increase of absolute power in (2008) dimension
delta and theta bands, with a maximum over frontal and central areas, Hornero et al. Median frequency (MF) 80 71.4 75.6
and a decrease of absolute power in high frequency bands mainly over (2008) MF ApEn 80.0 81.0 80.5
posterior temporal and occipital areas. AD patients furthermore De Haan et al. Beta rel power 94 78 86⁎
(2008)
showed a diffuse decrease of coherence in all frequency bands, and Escudero et al. BSS + median freq 83.33
impaired reactivity to eye opening and mental tasks. These findings (2008) BSS + SpecEn 73.81
are in line with the general pattern of changes in many EEG studies Fernandez et al. Left hipp vol MRI + left 87.1
in AD [30]. A detailed analysis of spectral changes in a larger group (2003) temp theta
Fernandez et al. mI/NAA + delta dipole 90 100 95⁎
of 21 AD patients and matched healthy controls was undertaken
(2005) density
by Fernandez et al. [31]. They divided the whole spectrum in 2-Hz Fernandez et al. 2–4 Hz rel power 68 76 72⁎
subbands, and found the most significant changes in a 2–4 Hz (2006) 16–28 Hz rel power 81 80 81⁎
(sensitivity: 68%; specificity: 76%) and a 16–28 Hz band (sensitivity: Gomez et al. Auto mutual information 75 90.5 82.9
81%; specificity: 80%). This study stresses the importance of beta (2007)
Gomez et al. SampEn 75.6
band changes in distinguishing AD patients from healthy controls.
(2007) Multiscale entropy MSE 87.8
The importance of the beta band was confirmed in the recent study Hornero et al. Med Freq 80 71.4 75.6
of de Haan et al., where relative beta band power had a sensitivity (2008) MF + ApEn 80 81.0 80.5
of 94% and a specificity of 78% [32]. Poza et al. [33] evaluated the Poza et al. (2007) Mean freq 85 85.71 85.36⁎
SEF95 65 66.67 65.85⁎
discriminative power of five measures extracted from the MEG
Spectral entropy 90 76.19 82.93⁎
powerspectrum. The best measure was the spectral mean frequency, Poza et al. (2008) Tsallis SE Renyi SE 90 85.7 87.8
which had a sensitivity of 85% and a specificity of 85.71%, confirming Poza et al. (2008) (alfa + beta + gamma)/ 75 90.5 82.9
the presence of spectral slowing in AD. Spectral changes can also be (delta + gamma)
characterized in terms of ratios between power in different frequency Sensitivity, specificity and diagnostic accuracy are expressed as percentages. Accuracies
bands. In a later study Poza et al. [34] showed that a ratio of relative marked with ⁎ were computed from data in the papers.
132 C.J. Stam / Journal of the Neurological Sciences 289 (2010) 128–134
found. This study shows that background activity is characterized by
changes in topography in addition to the general slowing reported
earlier. Escudero et al. [42] showed that a blind source estimation
procedure could improve the diagnostic accuracy of MEG median
frequency and spectral entropy in AD.
5.4. Task data
Most of the studies discussed so far were performed during a no-
task, resting state. While there is increasing evidence that the brain is
highly active during such a condition, and that resting-state patterns
of brain activity may reveal consistent activation of functional brain
networks [43], it would seem logical to study MEG during tasks which
involved those functions which are especially disturbed in AD such as
memory. Only a few MEG studies in AD have attempted to do this.
In the previously mentioned pilot study of Berendse et al. [29]
reactivity of MEG oscillations to cognitive tasks was impaired in AD.
Maestu et al. [44] showed that healthy subjects had a higher number
of activity sources over temporal and parietal areas compared to AD
patients. In contrast AD patients showed increased activity over
frontal motor areas. Left temporal and parietal activations correlated
significantly with relative volume of the temporal lobe [45]. Using the
same experimental design Maestu et al. [46] showed that AD subjects
could be distinguished from both healthy controls as well as patients
with late onset depression. Osipova et al. [47] investigated the steady
state response to monaural 40-Hz stimulation in AD. The auditory
steady state response was significantly increased in AD compared to
controls, which was interpreted as a disinhibition phenomenon.
5.5. Nonlinear analysis
As an alternative to spectral or source analysis, several studies have
explored the usefulness of various nonlinear measures of MEG signals.
A motivation for this approach is the fact that ongoing oscillations in
the brain, and in particular the alpha rhythm, may be weakly nonlinear
[48]. Furthermore, there are indications that MEG may be more
sensitive in picking up this nonlinear information than EEG [49].
Poza et al. [50] compared relative power in various frequency bands
with several spectral entropy measures (Shannon entropy; Tsallis
spectral entropy; generalized escort-Tsallis spectral entropy and Renyi
spectral entropy). AD was characterized by increased relative power
in delta and theta, and decreased relative power in beta and gamma
bands. The entropy measures were lower in AD, suggesting a loss of
(spectral) complexity. The loss of spectral entropy was found in all
brain regions [51]. A lower sample entropy and a lower multiscale
entropy in AD were demonstrated by Gomez et al. [52] confirming the
notion of a loss of complexity. In another study Gomez et al. [53]
showed a slower decline rate of auto-mutal information of MEG in
AD, reflecting an abnormal type of brain dynamics in this disease.
Other sophisticated measures, such as the Lempel–Ziv complexity and
Higuchi's fractal dimension, were also shown to be declined in AD by
the same group [54,55]. In a very small study involving 9 AD patients
and 5 healthy controls a decrease of the correlation dimension was
reported in addition to apparent slowing of the MEG background
activity [56].
On a priori grounds one might expect that nonlinear measures
might be more effective in discriminating AD patients from healthy
controls, since nonlinear analysis picks up more information from the
signal than spectral analysis. However, there is little evidence that
nonlinear analysis is superior to simple spectral measures in this
respect (Table 1). Poza et al. [50] found that median frequency had a
slightly higher specificity than spectral entropy when comparing
healthy controls and AD patients. Hornero et al. [35] also demon-
strated that median frequency was superior to various nonlinear
measures in discriminating AD patients from controls.
5.6. Functional connectivity
Currently, a central question in neuroscience is how distributed
brain regions exchange information and coordinate their activity such
that large-scale functional processes underlying cognition can be
realized. There is increasing evidence that synchronization of
oscillatory activity in different brain regions plays a key role in this
process [1]. This raises the question whether these functional
interactions are disturbed in Alzheimer's disease, and to what extent
MEG can be used to detect and characterize the disrupted functional
networks. The usual approach is to record ongoing or task-induced
activity over different brain regions, and to determine statistical
interdependencies between these recordings using either the well
known linear measure of coherence, or one of the more recently
developed nonlinear measures of functional connectivity such as
neural complexity [57], the synchronization likelihood [58] or the
phase lag index [59].
Using the synchronization likelihood as a measure of functional
connectivity, a loss of functional interactions between brain regions in
alpha, beta and gamma bands was demonstrated in AD patients [60]. In
the same study coherence analysis did not show significant differences
between AD patients and controls, suggesting that nonlinear coupling
might play a role. In a further analysis of the same data, van Cappellen
van Walsum et al. [61] showed that a neural complexity measure was
increased in AD in delta and theta bands, whereas the multichannel
correlation dimension was increased in the beta band; these results
argue against a simple concept of ‘loss of complexity’ in AD, and suggest
a pattern of decreases as well as increases of functional connectivity in
different frequency bands. This pattern was subsequently elucidated in
another study showing a loss of mainly long distance left hemisphere
functional connectivity in low alpha and beta bands, and an increase in
parietal theta and occipito parietal beta/gamma connectivities in AD
patients compared to controls [22]. The preferential loss of left
hemisphere connectivity is interesting in view of the findings of Osipova
et al. [17] and Maestu et al. [27] that also suggest a special vulnerability
of the left hemisphere. The increased connectivity in occipital and
parietal areas is remarkable. Possibly, these changes could reflect a
kind of compensatory mechanism. Coherence analysis of the same
data showed a roughly comparable pattern of changes. Furthermore,
interhemispheric alpha band synchronization likelihood was signifi-
cantly correlated with the MMSE score, suggesting the functional
significance of these resting-state measurements.
A problem of functional connectivity studies based upon correla-
tions between raw EEG or MEG signals is that fact that a single source is
often picked up by many sensors, giving rise to spurious correlations.
This volume conduction problem can be solved by special measures
such as the phase lag index, which eliminate possible contributions
from common sources, and reflect more accurately true interactions
between distributed brain areas. Using the PLI the loss of alpha and
beta band functional connectivities in AD could be confirmed, again
with a strong left hemisphere preponderance [62]. In addition the
reconstructed functional brain networks were characterized with
tools derived from graph theory [63]. This approach allows the
classification of networks on a scale ranging from completely ordered
to completely random. It was shown that in the alpha band brain
networks in AD were more random than brain networks of healthy
controls. Finally, using a modeling approach it could be shown that the
process that gives rise to abnormal brain networks in AD probably
preferentially attacks critical connections between networks hubs.
5.7. Conclusion
Since the first pilot study in 2000 the number of MEG studies in AD
has increased rapidly. Undoubtedly this reflects the wider availability
of whole-head MEG systems and increasing collaboration with clinical
departments. MEG studies in AD have confirmed and extended the
 C.J. Stam / Journal of the Neurological Sciences 289 (2010) 128–134
findings of previous EEG work. There is strong evidence that AD is
characterized by a general slowing of background activity, reflected by
increased power in delta and theta bands, decreased power of alpha
and beta bands, decreased reactivity to eye opening, and a lower mean
or median frequency. Changes in nonlinear measures, especially
the various types of entropy, probably reflect this general slowing.
The diagnostic usefulness of MEG spectral and nonlinear analysis
is comparable with an accuracy that is around 80% (Table 1). This
number is comparable to the diagnostic accuracy that has been
reported previously for EEG [64].
The real value of MEG studies in AD at this stage may be the insight
it can give into the pathophysiological processes underlying cognitive
dysfunction. In this respect that studies aimed at functional
connectivity may be of special interest. AD, like Parkinson's disease,
is characterized by a complex but reproducible pattern of both
decreases and increased in coupling between different brain areas,
with a remarkable vulnerability of the left temporal areas. These
changes correlate with functional deficits, and point in the direction of
a loss of structure in the networks involved. Characterization of
patterns of connectivity loss could be helpful in differential diagnosis
of neurodegenerative disorders [65]. Finally, application of a theoret-
ical framework to the study of network changes could help derive
clues about the nature of the underlying disease process.
6. Conclusions
The advent of whole-head MEG systems, and the improvements in
the understanding of oscillatory and synchronized brain activity, have
opened up the way to study disturbances in large-scale brain
networks in neurodegenerative disorders such as PD and AD. Many
MEG studies, most of which were conducted in the last five years,
have confirmed and extended findings from previous EEG work. It is
becoming clear that PD and AD show characteristic patterns of
abnormal brain function, both locally as manifested by changes in
spectral power, as well as at the scale of functional networks,
manifested by changes in interregional synchronization. These
changes may reflect abnormalities in specific networks and neuro-
transmitter systems, and could become useful in differential diagnosis
and treatment monitoring.
While MEG may be superior to EEG especially for functional
connectivity studies, its high cost and the impossibility to combine it
directly with structural MRI remain important obstacles. In this
respect the development of ultra low field MRI (ULF MRI) could be a
very interesting new approach. In ULF MRI very weak magnetic fields
are used which has several important advantages. ULF MRI systems
can be more open than the tunnels of high field MRI, thus allowing
easy access to the patients during scanning. Furthermore, ULF field is
much less sensitive to magnetic artifacts. Also ULF systems could be
much cheaper than conventional MRI. In ULF MRI measurements of
the magnetic field are done with SQUIDS, similar to MEG. This opens
up the fascinating possibility of measuring structural MRI and MEG
with one and the same system. The first structural and functional
images of a human brain obtained with an experimental ULF MRI
system were recently published [66]. If this technology can be further
developed high quality integrated structural and functional studies of
brain networks may become feasible.
However, improvements on the acquisition side alone may not be
sufficient for a better understanding of normal and disturbed brain
networks. There is an urgent need for a proper theoretical framework
for the analysis and interpretation of the data obtained with advanced
functional imaging techniques. One attempt to deal with this problem
is the application of graph theory to functional neuroimaging data
[67]. This approach provides a theoretical framework for describing
the structure and function of complex networks. Early studies have
shown that the healthy human brain, both at structural as well as
functional levels, may be a so called small-world network, character-
133
ized by a combination of high clustering and short communication
pathways. This optimal small-world structure may be lost in
neuropsychiatric disorders such as AD [62]. Further studies along
these lines, backed up with appropriate modeling work, could help to
advance our knowledge of disrupted brain networks in neurodegen-
erative disease.
Acknowledgements
The author would like to thank mrs Els van Deventer for her
untiring help in retrieving and collecting the necessary literature and
mrs. Alexandra Linger for secretarial assistance. Many thanks also to
Henk Berendse, Bob van Dijk, Jeroen Verbunt, Jan de Munck, Arjan
Hillebrand, Andreas Daffertshofer, Guido Nolte, Diederick Stoffers,
Hans Bosboom, Willem de Haan, Bethany Jones, Teresa Montez, Klaus
Linkenkaer-Hansen, Ilonka Manshanden, PeterJan Ris, Erik Wolters
and Philip Scheltens for the fruitful collaboration enabling several of
the MEG studies in PD and AD described in this review.
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