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Stroke Rehabilitation
Marcela Pekna, MD, PhD; Milos Pekny, MD, PhD; Michael Nilsson, MD, PhD
DOI: 10.1161/STROKEAHA.112.654228
Stroke
October 2012
Cell Genesis
In the adult human brain, neural stem cells keep producing
new neurons, astrocytes, and oligodendrocytes in 2 defined
regions, the dentate gyrus of the hippocampus and the
subventricular zone, albeit at a much lower rate than during
Pekna et al
research to humans. Specific examples of multisensory
neurorehabilitation are mirror therapy and action observation, motor imagery and mental training, virtual reality
training, and music-related therapies.
In mirror therapy, the illusion of movement in the
affected limb is created by the reflection of the moving
unaffected limb while the affected arm is hidden behind
the mirror. The strongest evidence in support of the
effectiveness of this approach has come from a study of
subacute stroke patients who received 30 minutes of mirror
therapy program per day consisting of wrist and finger
flexion and extension movements in addition to a conventional program for 4 weeks. Compared with a control
group who received a sham instead of mirror therapy, the
mirror training patients showed a more improved distal
hand functioning at the end of therapy period and at
5-month follow-up.30 Similarly, severely hemiparetic patients who received mirror therapy regained more distal
function after 6 weeks of training 30 minutes per day, 5
days per week, for 6 weeks.31 However, little is known
about which patients are likely to benefit from mirror
therapy and how such a therapy should be preferentially
applied.32 Action observation for 4 weeks also led to
enhanced motor performance in stroke patients, and this
functional improvement was still present at 8 weeks of
follow-up.33 Action observation on motor training in combination with concurrent physical training of the observed
action enhanced the positive effects of task practice
alone.34
Mental training is based on conscious activation of brain
regions and networks involved in movement preparation and
execution. In a placebo-controlled trial of chronic stroke
patients, therapist-guided mental practice was associated
with increased dexterity and changes in patterns of cortical
activation.35 Because motor imagery is not dependent on
the actual ability to execute movements, mental training
can be used early in the rehabilitation process and even in
severely paretic patients, although it can be difficult in
patients with left parietal or left lateral prefrontal lesions.36
Virtual reality technologies provide multimodal, interactive, and realistic 3-dimensional environments with a high
level of control of the sensory input to suit each users needs.
The evidence of the effectiveness of virtual reality training
in stroke rehabilitation thus far is limited, with most
studies underpowered and lacking controls.37 However,
recent reports show that Nintendo Wii gaming technology
represents a potentially effective alternative to promote
motor recovery,38 and a rehabilitation gaming system
facilitates the functional recovery of the upper extremities
as compared with intense occupational therapy or nonspecific interactive games for stroke patients who received
this adjuvant therapy in combination with conventional
rehabilitation.39
A number of studies suggest that listening to music can
enhance a variety of cognitive functions, such as attention,
learning, communication, and memory, both in healthy subjects and in various patient groups.40 42 Music also can affect
the mood and motivation of the subject, and thus could be an
easy-to-conduct and inexpensive means to facilitate cognitive
and emotional recovery in numerous neurological and psychiatric disorders. A recent study of listening to music after
stroke demonstrated that patients who listened to self-selected
music had better cognitive recovery and mood compared with
those who listened to self-selected audio books or those with
no listening material.43 Further, listening to music or speech
in the acute phase after ischemic stroke induced long-term
plastic changes in early sensory processing that correlated
with improvement in verbal memory and focused attention.44
Patients with chronic poststroke visual neglect who performed tasks while listening to music of their choice showed
enhanced visual awareness of contralesional targets relative
to when tasks were performed either with unpreferred music
or in silence.45
Stroke
October 2012
Pharmacological Modulators of
Neural Plasticity
Recently, several promising approaches that promote the
recovery of function after stroke through the stimulation of
neural plasticity have been identified through experimental
animal research. Importantly, some of these compounds are
already in clinical use for other indications or are already
being tested in clinical trials.
D-Amphetamine
There is large body of laboratory work showing that administration of amphetamine, a potent psychomotor stimulant
that induces neuronal release of norepinephrine, dopamine,
and serotonin, coupled with motor practice can enhance
motor recovery in animal models of stroke or other brain
injury and these functional improvements are associated with
increased axonal plasticity and the formation of new anatomic pathways.49,50
Several double-blind placebo-controlled clinical studies
have evaluated the effects of amphetamine on poststroke
motor recovery in humans.49 A meta-analysis concluded that
there is no indication for the routine use of amphetamines to
improve recovery after stroke.51 Given the potentially critical
differences in trial designs, however, the interpretation of the
results of this meta-analysis is not clear.49 As pointed out by
Goldstein,49 several principles pertinent to the trial design
have been elucidated by the animal studies. First, the dose
effect relationship for amphetamine-promoted motor recovery has an inverted U shape. The drug is relatively
ineffective at lower and higher doses. Second, the effects of
certain drugs (eg, amphetamine) on recovery are dependent
on concomitant behavioral experience. Third, the timing of
the drug administration/experience intervention is critical and
also varies with the number and frequency of treatment
sessions. Fourth, some drugs (eg, haloperidol) impair recovery. Thus, the clinical value of D-amphetamine in combination with physiotherapy remains to be determined through
new clinical trials. The National Institute of Healthsponsored Amphetamine-Enhanced Stroke Recovery trial to evaluate the impact of the timing and duration of therapy was
started in 2003. Regrettably, this trial was put on hold in 2009
pending application for further funding and the data remain
unanalyzed. Recently, a pilot randomized clinical trial involving 16 patients showed that 10 mg amphetamine administered
2 days per week before physiotherapy augments the positive
effects of physiotherapy on recovery of activities of daily
living and arm function.52
Levodopa
Levodopa (L-3,4-dihydroxyphenylalanine) is the precursor of
dopamine that is further converted to norepinephrine. Delayed treatment with levodopa in combination with physiotherapy improves functional motor recovery in ischemic
stroke patients.53 Although the positive effects of levodopa
(and amphetamine) on recovery are mostly ascribed to the
increased levels of norepinephrine at the synapse,53,54 there is
also experimental evidence in support of the role of astrocytes
and dopamine signaling in recovery-enhancing actions of
levodopa.55
Fluoxetine
Acute increases in the amount of synaptic monoamines induced
by antidepressants produce secondary long-term neuroplastic
changes and involve transcriptional and translational changes
that mediate molecular and cellular plasticity.57 In the postischemic brain, selective serotonin reuptake inhibitors are neuroprotective through their anti-inflammatory effects and improve ischemia-induced spatial cognitive deficits by
promoting hippocampal neurogenesis in the rat.58 A clinical
study, fluoxetine for motor recovery after acute ischemic
stroke (FLAME), demonstrated in a larger cohort of patients
(n118) with moderate to severe hemiplegia after ischemic
stroke that physiotherapy in combination with early treatment
with fluoxetine enhances motor recovery and reduces the
number of dependent patients compared with physiotherapy
alone.59 These interesting results call for even larger and more
comprehensive trials with an extended focus on functional
outcome parameters. Because selective serotonin reuptake
inhibitors are not a homogeneous category of drugs, additional experimental and pharmacological studies are needed
to further deepen the understanding of their mechanism of
action.
Niacin
Niacin (nicotinic acid, vitamin B3) is the most effective drug
currently available for the treatment of dyslipidemia.60 Treatment with Niaspan, a prolonged-release formulation of niacin, starting 24 hours after focal brain ischemia improved
functional outcome in rats, conceivably through a combination of its effects on angiogenesis,61 arteriogenesis,62 and
increased synaptic plasticity and axon growth.63 The clinical
usefulness and efficacy of niacin in treatment of stroke
remain to be shown.
Inosine
Inosine is a naturally occurring purine nucleoside. Intracerebral infusion of inosine starting immediately after unilateral
stroke induction stimulated neurons on the undamaged side of
the brain to extend new projections to denervated areas of the
midbrain and spinal cord and improved behavioral outcome
in rats.64 Inosine altered gene expression in neurons contralateral to stroke and enhanced the ability of these neurons to
form connections on the denervated side of the spinal cord.65
Pekna et al
Inosine combined with a Nogo receptor blocker or with
environmental enrichment augmented the effects of these 2
treatment modalities on the restoration of skilled forelimb use
after stroke.66 These results demonstrate that the combination
of behavioral and pharmacological adjuvant therapies may
have additive or even synergistic effect in promoting the
recovery of function after stroke. A 2-year inosine treatment
was safe and well-tolerated in multiple sclerosis patients.67
Because inosine is currently in clinical trials for Parkinson
disease, it appears to be a particularly attractive candidate for
increasing brain plasticity and improving outcome in stroke
patients.
Nogo-A Inhibition
Nogo-A is a myelin-associated protein that limits plasticity
and recovery after CNS injury through neurite outgrowth
inhibition. Anti-Nogo-A antibody treatment enhanced functional recovery and promoted reorganization of the corticospinal tract and axonal plasticity originating in the uninjured
hemisphere to reinnervate deafferented areas after cortical
lesions,68 70 as well as increased dendritic arborization and
spine density of pyramidal neurons in the contralesional
sensorimotor cortex.71 Genetic manipulation of the Nogo
Nogo receptor system or the use of peptides that block the
signaling through the Nogo receptor have similar effects on
axonal plasticity and recovery of function after experimental
stroke.72 A recent study showed that Nogo-A immunotherapy
also leads to the improvement of chronic neurological deficits
and enhancement of neuronal plasticity and that this therapy
may be used to restore function even when administered
intracerebroventricularly for 2 weeks starting 9 weeks after
stroke.73 An obstacle in using the anti-Nogo-A antibodies or
peptide blockers could be their limited delivery into the brain
parenchyma after systemic administration because of the
inability to cross the blood brain barrier. This hindrance to
clinical testing of therapeutic strategies based on NogoNogo
receptor inhibition now may have been removed by a generation of a biologically active Nogo receptor blocker
NEP1 40 fusion proteins that cross the blood brain barrier
after systemic delivery.74 A phase I clinical trial applying
anti-Nogo-A antibody to subjects with acute spinal cord
injury has been successfully conducted, and a phase II trial is
in preparation.75
Phosphodiesterase 5 Inhibitors
Phosphodiesterase 5 is an isoenzyme that catalyzes the
hydrolysis of a second messenger molecule cyclic guanosine
monophosphate. Phosphodiesterase 5 is expressed in smooth
muscle cells of blood vessels as well as in neural cells.
Pharmacological inhibition of phosphodiesterase 5 leads to
vasodilation and is used for the treatment of erectile dysfunction.80 Phosphodiesterase 5 inhibitors (sildenafil, tadalafil)
administered orally for 6 to 7 days starting 24 hours after
stroke onset improved functional recovery in young and aged
experimental animals, conceivably through improved cerebral blood flow, enhanced angiogenesis, neurogenesis, and
synaptogenesis.81 83 In case studies, compassionate use of
sildenafil caused notable functional improvement in a patient
with locked-in syndrome84 and in a patient with spastic
quandruplegia.85 Two-week treatment with sildenafil (25 mg
daily) appeared to be safe in patients with mild to moderately
severe subacute ischemic stroke.86
Growth Factors
Several proteins or polypetides from the growth factor family
have shown beneficial effects on neural plasticity and recovery of function after stroke. For example, vascular endothelial
growth factor, a protein with angiogenic properties, is both
neuroprotective and exerts positive effects on neurogenesis
and angiogenesis function,87 although an early administration
of vascular endothelial growth factor can promote blood
brain barrier leakage and hemorrhagic transformation.88
Erythropoietin (EPO), a growth factor used for the treatment
of anemia, was shown to be neuroprotective when administered within the first 2 hours after stroke;89 however, in
combination with tissue plasminogen activator (tPA) treatment, EPO administered outside the therapeutic window
induces blood brain barrier permeability, exacerbates hemorrhagic transformation, and negates any neuroprotective
effect of EPO.90,91 The deleterious effects of combined tissue
plasminogen activator and EPO treatment are conceivably the
reason for the negative outcome of a phase III EPO Stroke
Trial on the efficacy and safety of EPO treatment in stroke.92
Neuroprotection aside, a recent study demonstrated that EPO
treatment started 3 days after stroke induction improves
functional recovery by promoting neuronal survival and
angiogenesis in the perilesional tissue as well as contralesional pyramidal tract plasticity.93
The hematopoietic growth factor granulocyte colonystimulating factor is used for the treatment of chemotherapyinduced neutropenia. In experimental stroke, granulocyte
colony-stimulating factor appears to have multiple effects
that lead to enhanced functional recovery, including neuroprotection, stimulation of neurogenesis and angiogenesis, and
modulation of immune response and bone marrow mobilization.94 Clinical studies showed that granulocyte colonystimulating factor treatment for 5 days starting within 12 hours
and 3 to 30 days after onset of ischemic stroke, respectively, is
safe and leads to mobilization of hematopoietic stem/precursor
Stroke
October 2012
Cell-Based Therapy
The therapeutic potential of cell transplantation for stroke
recovery has been shown in a number of animal studies. In
particular, bone marrow stromal cells, a mixed population of
stem and progenitor cells, have long-lasting positive effects
on recovery neurological function and a range of structural
and molecular plasticity parameters.19,105108 However, in
diabetic animals, such a cell therapy did not improve function
but increased mortality, blood brain barrier leakage, and
brain hemorrhage.109 This study pointed to the limitations and
potential risks of these and possibly other adjuvant neural
plasticity modulating therapies and the need to take into
consideration the associated diseases. Intravenous transplantation of autologous bone marrow derived mesenchymal
stem cells is safe and feasible in stroke patients followed-up
for 12 months, although the efficacy remains to be shown.110
Importantly, this study also showed that these cells can be
rapidly expanded in autologous serum, reducing cell preparation time and the risk of transmissible disorders.
A recent animal study demonstrated that intravenous administration of human umbilical tissue derived cells 24
hours after stroke induction improves functional outcome
along with increased angiogenesis, synaptogenesis, and re-
Pekna et al
pathological context. Immature astrocytes are a source of a
signal that triggers the expression of complement component
C1q in developing neurons.135 C1q localizes to synapses that
are thus tagged for elimination through the activation of the
complement cascade and deposition of C3b, an opsonin
derived from the proteolytic activation of the third complement component (C3).135 The complement-mediated elimination of synapses seems to be reactivated in neuropathologies
such as glaucoma.135 The possible implications of these
findings for modulation of synaptic plasticity after stroke
need to be experimentally addressed.
Conclusion
Given the complexity of the CNS response to brain ischemia,
and the role of neural plasticity in functional recovery, it is
likely that future treatment and rehabilitation protocols for
stroke survivors will target multiple molecular pathways, will
aim at adjusting multiple equilibria, and will be based on both
pharmacological and nonpharmacological neural plasticity
modulating approaches. Possible negative effects of comorbidities such as diabetes need to be carefully taken into
consideration when tailoring such combination treatments for
each patient.
Sources of Funding
The authors received research support from the Swedish Medical
Research Council (project 11548 and 20116), AFA Insurance,
Soderbergs Foundations, ALF Goteborg, Hjarnfonden, the Swedish
Stroke Foundation, the Swedish Society for Medical Research, the
Free Mason Foundation, U. and R. Amlovs Foundation, E. Jacobsons Donation Fund, Sten A. Olsson Foundation for Research and
Culture, the EU FP 7 Programs EduGlia (237956) and TargetBraIn
(279017), and NanoNet COST Action (BM1002).
Disclosures
None.
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