Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation

HomeStrokeVol. 43, No. 10Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBModulation of Neural Plasticity as a Basis for Stroke Rehabilitation Marcela Pekna, MD, PhD, Milos Pekny, MD, PhD and Michael Nilsson, MD, PhD Marcela PeknaMarcela Pekna 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. , Milos PeknyMilos Pekny 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. and Michael NilssonMichael Nilsson 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. Originally published23 Aug 2012https://doi.org/10.1161/STROKEAHA.112.654228Stroke. 2012;43:2819–2828Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 IntroductionCurrent 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 InjuryExperience-Dependent Plasticity of the Cerebral CortexCerebral 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 StrokeLoss 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 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.2Cortical Map RearrangementsAs 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.3–5 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 ipsilesional 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.2Contralateral Hemisphere InvolvementThe 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.13–15 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.18Contralesional Axonal Remodeling of the Corticospinal SystemWhereas 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 GenesisIn 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.24Increasing Neural Plasticity Through Behavioral Manipulations and Adjuvant TherapiesEvidence 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 StimulationA 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.27–29 However, we are only beginning to understand how to translate the positive effects of enriched environment in experimental animal 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.34Mental 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.36Virtual reality technologies provide multimodal, interactive, and realistic 3-dimensional environments with a high level of control of the sensory input to suit each user's 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.39A 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.45Noninvasive Brain StimulationNoninvasive 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 γ-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.46,47In 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.48Pharmacological Modulators of Neural PlasticityRecently, 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-AmphetamineThere 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.49,50Several 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 Health–sponsored 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.52LevodopaLevodopa (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 of of receptor is in brain tissue from that were in enriched environment after cerebral A more of the of receptor in recovery after stroke showed that the of receptor is in the cells, particularly astrocytes, in the region of animals with recovery of neurological The receptor is in membrane of astrocytes and neurons and plays an essential role in membrane and Importantly, a potent and receptor enhanced functional recovery in rat models of stroke when administered within 2 days after stroke promising is in a stroke clinical phase increases in the of induced by long-term changes and and changes that and cellular In the brain, serotonin are neuroprotective through their effects and improve cognitive by neurogenesis in the A clinical for motor recovery after acute ischemic stroke demonstrated in a larger of patients with to after ischemic stroke that physiotherapy in combination with early treatment with motor recovery and the number of dependent patients compared with physiotherapy These results for even larger and more with an on functional outcome Because serotonin are not a of experimental and studies are to further the understanding of their of acid, is the most effective drug for the treatment of with a of after brain improved functional outcome in through a combination of its effects on and increased plasticity and The clinical and of in treatment of stroke remain to be is a of after unilateral stroke neurons on the side of the brain to new to areas of the and spinal cord and improved behavioral outcome in altered in neurons contralateral to stroke and enhanced the ability of these neurons to connections on the side of the spinal with a receptor or with environmental enrichment the effects of these 2 treatment on the of use after These results that the combination of behavioral and adjuvant therapies may have or even effect in the recovery of function after stroke. A treatment was and in Because is in clinical for it appears to be a particularly for brain plasticity and outcome in stroke is a that plasticity and recovery after CNS injury through treatment enhanced functional recovery and reorganization of the corticospinal tract and axonal plasticity in the uninjured hemisphere to areas after cortical as well as increased dendritic and spine of pyramidal neurons in the contralesional sensorimotor of the receptor system or the use of that the signaling through the receptor have effects on axonal plasticity and recovery of function after experimental A recent study showed that also leads to the improvement of chronic neurological and of neuronal plasticity and that this therapy may be used to function even when administered for 2 weeks weeks after in using the or could be their into the brain after administration because of the to the to clinical of based on receptor may have been by a of a active receptor that the after A phase clinical trial to subjects with acute spinal cord injury has been and a phase trial is in stroke, the zone shows increased neuroplasticity which sensorimotor to from However, this important for rehabilitation, is by neuronal mediated by γ-aminobutyric and is caused by an in the ability of astrocytes to γ-aminobutyric is a drug that acts as for the of γ-aminobutyric treatment with 3 days after stroke the γ-aminobutyric and in an early and sustained recovery of function in In stroke was increased in with from stroke showing that in the acute phase is neuroprotective and the timing of drug is critical for the treatment These results provide a basis for the of to promote recovery after 5 5 is an that the of a 5 is expressed in cells of blood as well as in neural of 5 leads to and is used for the treatment of 5 administered for 6 to days after stroke improved functional recovery in and experimental through improved cerebral blood enhanced and In studies, use of caused functional improvement in a patient with and in a patient with treatment with mg to be in patients with to subacute ischemic or from the growth factor have shown effects on neural plasticity and recovery of function after stroke. 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