Modulation of Neural Plasticity as a Basis for

Stroke Rehabilitation
Marcela Pekna, MD, PhD; Milos Pekny, MD, PhD; Michael Nilsson, MD, PhD

of hypometabolism, neurovascular uncoupling, and aberrant

neurotransmission, jointly called diaschisis.1 Some recovery
of function occurs spontaneously after stroke in humans as
well as in animal models. It is believed that this functional
recovery involves 3, to some extent overlapping, phases: (1)
reversal of diaschisis, activation of cell genesis, and repair;
(2) changing the properties of existing neuronal pathways;
and (3) neuroanatomical plasticity leading to the formation of
new neuronal connections.1 The basic processes underlying
phases 2 and 3 also are involved in normal learning and it has
been recognized that functional improvement after CNS
injury is a relearning process.2

urrent understanding of the mechanisms underlying

neural plasticity changes after stroke stems from experimental models as well as clinical studies and provides the
foundation for evidence-based neurorehabilitation. In this
review, we first describe the main structural and functional
constituents of neural plasticity that are believed to contribute
to recovery of function after stroke. Next, we discuss selected
behavioral manipulations and adjuvant therapies that can
stimulate neural plasticity and improve recovery of function,
particularly when applied in combination with task-specific
physiotherapy and in a stimulating environment.

Neural Plasticity After Brain and Spinal

Cord Injury

Cortical Map Rearrangements

As stated, the brain, and especially the cerebral cortex, has a
capacity to alter the structure and function of neurons and to
reorganize its neural networks in response to the changes in
input and output demands. Thus, when the normal input to a
particular area of the primary somatosensory cortex is lost
because of injury, rapid structural and functional reorganization results in this area being activated by sensory stimulation
of the surrounding intact body regions. Thus, spinal cord
injuries lead to both unmasking of existing latent connections
as well as changes in somatosensory cortex anatomy attributable to the growth of new lateral connections.35 Similarly,
the motor maps in the primary motor cortex change in
response to task-specific training or after injury. Training
human subjects or animals to perform a specific task leads to
an increase in the area of motor cortex that controls the
muscles used during the task.2 Injury to the motor cortex
leads to the recruitment of motor areas that were not making
significant contribution to the lost function before the injury.
For example, in macaque monkeys, recovery of dexterity
after unilateral motor cortex lesion is mediated by the
ipsilesional premotor cortex. Inactivation of this region abolishes recovered movement, whereas it does not affect the
performance in uninjured monkeys.6 The notion that the
activity of cortical areas recruited after injury plays a role in
functional recovery in humans is supported by a study
showing that in well-recovered stroke patients, the ipsile-

Experience-Dependent Plasticity of the

Cerebral Cortex
Cerebral cortex is an assembly of neuronal cells that are
highly interconnected. The morphology as well as function of
these complex and spatially distributed networks are modulated or even controlled by the glial component of the central
nervous system (CNS). The ability to adapt in response to the
changing environment is the most fundamental property of
the nervous tissue and constitutes the basis for learning.
Neural plasticity is the neurobiological basis for the ability to
adapt and learn in an experience-dependent manner.1 At the
structural level, neural plasticity could be defined in terms of
dendritic and axonal arborization, spine density, synapse
number and size, receptor density, and in some brain regions
also the number of neurons. These structural constituents of
neural plasticity jointly determine the complexity of neuronal
networks and their activity and contribute to recovery of
function after stroke and other CNS injury.

Spontaneous Recovery of Function After Stroke

Loss of function attributable to stroke is caused by cell death
in the infarcted region as well as cell dysfunction in the areas
surrounding the infarct. In addition, the function of remote
brain regions, including the contralateral areas that are connected to the area of tissue damage, is compromised because

Received February 16, 2012; accepted April 20, 2012.

From the Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and
Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Elements of this review constitute part of chapter 3 in Stroke Rehabilitation: Insights from Neuroscience and Imaging, Oxford University Press, New
York, 2012, ISBN 0199797889 (with the permission from the publisher).
Correspondence to Marcela Pekna, MD, PhD, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology,
Sahlgrenska Academy at the University of Gothenburg, Box 440, SE-405 30 Gothenburg, Sweden. E-mail Marcela.Pekna@neuro.gu.se
(Stroke. 2012;43:00-00.)
2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.112.654228

Stroke

October 2012

sional dorsal motor cortex shows increase in activity.7 Even

stronger evidence stems from clinical studies showing that,
when the function within such a newly recruited area is
disrupted using transcranial magnetic stimulation, the recovered movement of the limb affected by stroke is impaired.8 11
Functional redundancy attributable to substantial degree of
overlap within and across brain regions can also contribute to
the ability of the brain to adapt to injury.2

Contralateral Hemisphere Involvement

The contralesional hemisphere has the capacity to contribute
to movement on the ipsilateral side but does not make any
significant contribution in healthy subjects.12 However, significant increases in contralesional motor cortex activity can
be observed in stroke patients during movement of the
affected foot or arm.1315 These and other studies have
demonstrated that in the early phase of stroke recovery
process, there is an increased activation of the motor areas in
both hemispheres but is substantially more pronounced on the
contralesional side. The contralesional activation is often
reduced in the later stage of recovery. Although there is no
general consensus concerning the role of contralesional somatosensory and motor area activation in recovery of function, it appears that the best recovery is associated with an
early recruitment of the supplementary motor areas on the
ipsilesional side, whereas persistent activation of the
contralesional prefrontal and parietal cortex predicts a
slower and less complete recovery and also is often
associated with larger infarct.16,17 Notably, a recent functional magnetic resonance imaging study has shown that
the pattern of brain activation present in the early phase
after stroke could be predictive of subsequent recovery of
motor functions.18

Contralesional Axonal Remodeling of the

Corticospinal System
Whereas the capacity for functional and structural rearrangements has been studied for decades and is well-documented
for the neural networks within the cerebral cortex, the
plasticity responses induced by stroke at the level of the
spinal cord have been demonstrated only recently. Using a rat
stroke model, Liu et al19 showed that the spontaneous
behavioral motor recovery highly correlates with the remodeling of corticospinal tract axons in the cervical spinal cord as
well as the reorganization of pyramidal neurons in the
cerebral cortex of both hemispheres. Consistent with conclusions from human imaging studies, they further showed that
functional recovery is highly correlated with contralesional
cortical wiring only in the acute phase, with a negative
correlation later.19 Although the capacity for remodeling of
the corticospinal tract axons at the spinal cord level remains
to be demonstrated in stroke patients, these findings add a
new dimension to the rehabilitative efforts for improved
functional recovery after stroke.

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

earlier ontogenetic stages.20 A structure analogous to the

rostral migratory stream in rodents connecting the subventricular zone with the olfactory bulb exists also in the human
brain.21 Having originated from dividing neural stem cells,
differentiating cells migrate through the rostral migratory
stream to the olfactory bulb. In the rodent stroke models,
some of these cells divert from the rostral migratory stream
and reach the ischemic penumbra, where some of them
transiently persist and others turn into neurons and astrocytes.22 We do not know yet the functional significance of the
adult mammalian neurogenesis because no animal models
exist in which neurogenesis could be specifically inhibited
without simultaneous inhibitory or modulatory effects on
other plasticity responses. However, an enriched environment
applied to adults of various vertebrate species stimulates both
baseline and ischemia-triggered neurogenesis. Thus, it is
possible that newly formed neurons, astrocytes, or oligodendrocytes positively affect brain plasticity and functional
recovery after stroke. In a mouse CNS, gap junctional
coupling occurs between introduced neural stem cells and
residential neuronal cells, and is essential for the neuroprotective effect of neural stem cells on the endogenous neuronal
cells.23 Thus, apart from the plasticity-promoting trophic
effects of newly born and partially differentiated neuroectodermal cells, these cells also might protect the ischemic
penumbra by a direct cell cell transfer of signaling and other
molecules.
Angiogenesis, the formation of new vessels, plays an
important role in remodeling of ischemic brain tissue after
stroke through enhanced perfusion as well as blood flow
independent mechanisms.24

Increasing Neural Plasticity Through Behavioral

Manipulations and Adjuvant Therapies
Evidence accumulated during the past 2 decades together
with recent advances in the field of stroke recovery clearly
show that the effects of neurorehabilitation can be enhanced by behavioral manipulations and combination with
adjuvant therapies that stimulate the endogenous neural
plasticity. However, the dose, timing after stroke, and
coupling with appropriate physical therapy may be critical
for the outcome.

Enriched Environment and

Multimodal Stimulation
A large number of animal studies have demonstrated that
experience in an enriched environment (housing conditions
that facilitate enhanced sensory, cognitive and motor
stimulation) stimulates all the structural and functional
components of neural plasticity and cognitive performance
in healthy animals as well as promotes recovery of
sensorimotor function after experimental stroke.25,26 Human equivalents of the environmental enrichment are
multimodal stimulation and multisensory training protocols. These have been shown to be more effective for
learning in healthy subjects.2729 However, we are only
beginning to understand how to translate the positive
effects of enriched environment in experimental animal

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

Neural Plasticity and Stroke Rehabilitation

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

Noninvasive Brain Stimulation

Noninvasive brain stimulation can be performed using repetitive transcranical magnetic stimulation and transcranial direct current stimulation (tDCS). These therapies have the
potential to enhance neuroplasticity during stroke rehabilitation, thereby supporting recovery of motor and cognitive
impairments.46,47 The differences between tDCS and transcranial magnetic stimulation are based on presumed mechanisms of action in which transcranial magnetic stimulation
acts both as a neurostimulator and a neuromodulator, whereas
tDCS acts as a neuromodulator. Depending on the frequency,
duration of the stimulation, the strength of the magnetic field,
and the shape of the coil, transcranial magnetic stimulation
can activate or suppress the activity in different cortical
regions. The tDCS delivers weak polarizing currents to the
cerebral cortex, which induce sustained changes in neural cell
membrane potential, leading to either hyperpolarization or
depolarization. The basic cellular mechanisms underpinning
the effects of noninvasive brain stimulation are only partially
known. Animal studies indicate that the effects of transcranial
magnetic stimulation could be analogous to other interventions
inducing long-term potentiation or long-term depression in the
hippocampus. Different neurotransmitters and neuromodulators
such as -aminobutyric acid, glutamate, dopamine, and serotonin are altered in defined regions of the brain after stimulation
with both repetitive transcranial magnetic stimulation and tDCS.
Further, immediate early genes like c-fos and genes coding for
neurotrophic factors like brain-derived neurotrophic factor are
expressed in the rat brain after repetitive transcranial magnetic
stimulation.46,47
In humans, both repetitive transcranial magnetic stimulation and tDCS are shown to induce long-term effects on
cortical excitability that last for months after the intervention,47 which may, in turn, lead to long-lasting behavioral
modifications. These effects are believed to engage mechanisms of neural plasticity, rendering noninvasive brain stimulation well-suited to promote recovery of cognition and
motor functions, especially in combination with other types
of rehabilitative interventions. Results from several studies
show, for example, that active stimulation of either the
affected or the unaffected motor cortex in combination with
physical and occupational therapy improves motor outcome
after stroke.48

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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

Sigma-1 Receptor Agonists

The expression of -1 receptor is upregulated in brain tissue

from rats that were housed in enriched environment after
focal cerebral ischemia.56 A more detailed analysis of the
involvement of -1 receptor in recovery after stroke showed
that the expression of -1 receptor is upregulated in the
surviving cells, particularly astrocytes, in the peri-infarct
region of animals with good recovery of neurological function.56 The -1 receptor is located in membrane rafts of
astrocytes and neurons and plays an essential role in membrane raft trafficking and neurite outgrowth. Importantly, a
potent and selective -1 receptor agonist SA45031 enhanced
functional recovery in rat models of stroke when administered within 2 days after stroke induction.56 This promising
compound is presently investigated in a stroke clinical phase
II trial.56

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

Reducing Tonic Inhibition

After stroke, the peri-infarct zone shows increased neuroplasticity which allows sensorimotor functions to remap from damage
areas.76,77 However, this peri-infarct neuroplasticity, critically
important for rehabilitation, is counteracted by tonic neuronal
inhibition mediated by extrasynaptic -aminobutyric acidA
receptors and is caused by an impairment in the ability of
astrocytes to take- up -aminobutyric acid.78 L-655 708 is a
cognition-enhancing drug that acts as benzodiazepine inverse
agonistspecific for the 5 subunit of -aminobutyric acid
receptors.79 Chronic treatment with L-655 708 starting 3 days
after stroke counteracted the excessive -aminobutyric acid
mediated tonic inhibition and resulted in an early and sustained recovery of function in mice. In contrast, stroke
volume was increased in mice treated with L-655 708 from
stroke onset, showing that tonic inhibition in the acute phase

Neural Plasticity and Stroke Rehabilitation

is neuroprotective and the timing of drug delivery therefore is

critical for the treatment outcome.78 These results provide a
rational basis for the development of novel pharmacological
strategies to promote recovery after stroke.

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

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October 2012

cells.95,96 Also, in chronic stroke patients with concomitant

vascular disease, a 10-day treatment with granulocyte colonystimulating factor was safe and well-tolerated.97 Clinical efficacy
of granulocyte colony-stimulating factor with regard to functional recovery poststroke remains, however, unproven.
Daily intravenous treatment with brain-derived neurotrophic factor improved behavioral outcome after experimental stroke by increased neurogenesis and migration of
SVZ progenitor cells98 and transient upregulation of binding
densities of excitatory glutamate receptors.99 High serum levels
of insulin-like growth factor 1 after stroke are associated with
neurological recovery and better functional outcome.100,101 In
experimental stroke, insulin-like growth factor 1 treatment improved motor recovery, paralleled by enhanced neovascularization and neurogenesis.102,103 However, because of its inability to
pass through blood brain barrier, insulin-like growth factor 1
was administered intranasally starting 10 minutes after stroke
induction102 or by adeno-associated virus-mediated gene transfer
3 weeks before stroke.103 The clinical applicability of these
results remains to be determined.
Basic fibroblast growth factor (fibroblast growth factor-2,
trafermin) is a mitogenic factor for a variety of cell types,
including neural progenitor cells, glia, and endothelial cells.
In addition to its role in cell proliferation, basic fibroblast
growth factor supports neuronal cell survival and axonal
growth. Despite strong neuroprotective effects of basic fibroblast growth factor demonstrated by a number of experimental studies, phase III clinical trials were terminated because
they did not demonstrate benefit of basic fibroblast growth
factor over placebo when administered within 6 hours from
stroke onset and showed higher incidence of adverse effects
and mortality.104 However, because of its positive effects on
neural plasticity, the possible enhancement of recovery by
delayed administration of basic fibroblast growth factor could
be worth testing.104

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-

duction of apoptotic cell death.111 Similar positive effects on

motor function recovery and brain plasticity were observed
when these cells were transplanted directly into the ischemic
cortex.112 Thus, the umbilical tissue derived cells could
represent an interesting cell-based therapy alternative, especially for patients from whom autologous bone marrow
derived cells could not be obtained. Also, peri-lesion injection of genetically engineered neural stem cell line
(CTX0E03) 14 to 28 days after stroke induction improved
behavioral dysfunctions in a dose-related manner.113,114 A
first clinical safety trial, in which the CTX0E03 cells are
delivered intracranially in chronic stroke patients (Pilot Investigation of Stem Cells in Stroke [PISCES]), has recently
started (ClinicalTrials.gov/NCT01151124).

Astrocytes and the Innate Immune System

The emergence of astrocytes as an interesting target in stroke
intervention is intriguing. Astrocytes control blood flow,115 a
function highly relevant for both physiological and pathological situations such as stroke.116 In the ischemic brain lesions,
astrocytes stimulate the formation of new blood vessels
through the secretion of vascular endothelial growth factor
and thus are strong contributors to neurorestorative processes,
including synaptogenesis.117 Astrocytes are of major importance in the detoxification process of different reactive
oxygen species after cellular stress, which is a major component of ischemic stroke.118,119 Beta-lactam antibiotics had a
neuroprotective effect in in vitro models of ischemia, conceivably through the stimulation of the glutamate transporter
GLT1 (EAAT2) in astrocytes.120 Stroke leads to massive
activation of astrocytes and prominent reactive gliosis in the
ischemic penumbra.121124 Attenuation of reactive gliosis in
ischemic stroke by genetic ablation of GFAP and vimentin
(proteins that constitute the highly dynamic astrocyte intermediate filament system) leads to increased infarction, suggesting that reactive astrocytes play an important role in the
protection of the ischemic penumbra.125 Thus, modulation of
astrocyte activity may provide novel therapeutic paradigms
for ischemic stroke.125 Astrocytes directly control the number
and function of neuronal synapses.126 Mice deficient in GFAP
and vimentin exhibit a more pronounced loss of synapses in
the hippocampus in the acute phase after partial deafferentation of the dentate gyrus of the hippocampus by entorhinal
cortex lesion, but show remarkable synaptic recovery later.127
They also exhibit improved integration of neural grafts or
neural stem cells transplanted in the CNS, improved axonal
regeneration and increased baseline and injury-induced hippocampal neurogenesis.128 132 An interesting link exists between astrocytes, trombospondins, and synaptic response and
axonal sprouting in ischemic stroke. Thrombospondins 1 and
2 are extracellular glycoproteins with synaptogenic properties
secreted by astrocytes.133 Their deficiency leads to reduced
synaptic density during development.133 Astrocyte expression
of thromobospondin 1 and 2 is increased after experimental
stroke,134 and mice deficient in thromobospondin 1 and 2
exhibit synaptic density and axonal sprouting deficit associated with impaired motor function recovery after stroke.134
Astrocytes also play a role in the elimination of supernumerary synapses during development and also possibly in a

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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KEY WORDS: adjuvant therapies multisensory stimulation
neural plasticity neurorehabilitation stroke