The role of timing and intensity of rehabilitation therapies

In both animal and clinical studies, motor rehabilitation and training increase cortical representation and improve recovery, whereas lack of training decreases cortical representation for particular motor functions. In animals, delays in providing rehabilitation reduce the impact of therapy with a worsening in motor outcomes and a corresponding reduction in cortical reorganization. In clinical studies, there is an association between earlier admission to rehabilitation and better outcomes that correlates with animal work both in terms of functional gains from chronic stroke deficits and cortical reorganization. There is a likely relationship between therapy intensity and improvements in functional outcomes. Clinically, greater intensity of stroke rehabilitation has been associated with improved outcomes.     

Progress in clinical neurosciences: stroke recovery and rehabilitation

BACKGROUND: Recent literature has provided new insights into the role of rehabilitation in neurological recovery post-stroke. The present review combines results of animal and clinical research to provide a summary of published information regarding the mechanisms of neural recovery and impact of rehabilitation. METHODS: Plasticity of the uninjured and post-stroke brain is examined to provide a background for the examination of brain reorganization and recovery following stroke. SUMMARY AND CONCLUSIONS: Recent research has confirmed many of the basic underpinnings of rehabilitation and provided new insight into the role of rehabilitation in neurological recovery. Recovery post stroke is dependent upon cortical reorganization, and therefore, upon the presence of intact cortex, especially in areas adjacent to the infarct. Exposure to stimulating and complex environments and involvement in tasks or activities that are meaningful to the individual with stroke serves to increase cortical reorganization and enhance functional recovery. Additional factors associated with neurological recovery include size of stroke lesion, and the timing and intensity of therapy.     

Cortical reorganization--effects of intensive therapy

Recovery from hemiparesis after stroke largely depends on widespread functional and structural neuronal plasticity. Based on animal studies of rehabilitative and pharmacological interventions on recovery, recent neuroscientific findings suggest that new rehabilitative interventions may also have benefits by modulating neuroplastic mechanisms in stroke patients. Neurofunctional imaging methods such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) as well as transcranial magnetic stimulation (TMS) now permit direct studies of training-induced plasticity in stroke patients. Prospectively conducted studies using these techniques have investigated how plasticity relates to recovery of motor function and how intensive training modulates cortical reorganization. Despite technical and methodological differences, consistent neuroanatomic findings on training-induced reorganization of the motor system have been reported. These discoveries have important implications for the future development of neurorehabilitative training methods. With continuously improving methods to study cortical reorganization and over 100 randomized clinical trials on stroke rehabilitation published during the past five years, this promises to be an exciting time in stroke rehabilitation research.     

Rehabilitation approaches to stroke

This article describes the state of the science in stroke rehabilitation dealing with three main topics: (1) General approach to stroke rehabilitation (stroke services and stroke units), (2) Neurophysiological and pharmacological interventions (facilitation of brain repair mechanisms) and (3) Experimental approaches (neuronal transplantation). Stroke rehabilitation is an active process beginning during acute hospitalisation, progressing to a systematic program of rehabilitation services and continuing after the individual returns to the community. There is world-wide consensus that stroke patients should be treated at specialised stroke unit with specially trained medical and nursing staff, co-ordinated multidisciplinary rehabilitation and education programs for patients and their families. Stroke Unit has been shown to be associated with a long-term reduction of death and of the combined poor outcomes of death and dependency, independent of patients age, sex, or variations in stroke unit organisations. No study has clearly shown to what extent the beneficial effect is due to specific rehabilitation strategies. New imaging studies in stroke patients indicate altered post stroke activation patterns, which suggest some functional reorganisation. Reorganisation may be the principle process responsible for recovery after stroke. It is assumed that different post ischaemic interventions like physiotherapy, occupational therapy, speech therapy, electrical stimulation, etc. facilitates such changes. Scientific evidence demonstrating the values of specific rehabilitation interventions after stroke is limited. Comparisons between different methods in current use have so far mostly failed to show that any particular physiotherapy, occupational therapy, speech therapy or stroke rehabilitation strategy is superior to another. Clinical data are strongly in favour of early mobilisation and training. Pharmacological interventions in animals revealed that norepinephrine, amphetamine and other alpha-adrenergic stimulating drugs can enhance motor performance after unilateral ablation of the sensory motor cortex. The clinical data in humans are rather contradictory. Neural grafting and neurogenesis are new potential modes of stroke therapy. Neural grafting enhanced functional outcome and reduced thalamic atrophy in rats only when combined with housing in enriched environments. Recent studies have shown that stem cells can differentiate to neurons in the adult human dentate gyrus in vivo.     

Early poststroke experience differentially alters periinfarct layer II and III cortex

Early poststroke rehabilitation effectively improves recovery of function, likely by engaging multiple plasticity processes through use-dependent activation of neural circuits. The loci of such neuroplastic reorganization have not been examined during the initial phase of behavioral recovery. In the current study, we sought to evaluate sub-components of rehabilitation and to identify brain sites first engaged by early rehabilitation. Rats were subjected to endothelin-1 ischemia and placed in either enriched environment (EE), daily reach training (RT), combination of enriched environment and reach training (ER), or standard housing (ST) starting 7 days post ischemia. Functional and histopathological assessments were made after 2, 5, and 10 days of treatment. Animals exposed to 10 days of ER treatment exhibited significantly more use-dependent neuronal activity (FosB/ΔFosB expression) in perilesional cortex than those exposed to EE, RT, or ST treatments. Similar trends were observed in both perilesional striatum and contralesional forelimb motor cortex. This use-dependent plasticity was not explained by differences in neuronal death, inflammation, or lesion volume. The increased activity likely contributes to the neuroplastic changes and functional recovery observed after extended periods of rehabilitation. Importantly, EE or RT alone did not lead to enhanced activity suggesting that combination therapy is necessary to promote maximum recovery.     

Developmental and Interventional Plasticity of Motor Maps after Perinatal Stroke

Within the perinatal stroke field, there is a need to establish preclinical models where putative biomarkers for motor function can be examined. In a mouse model of perinatal stroke, we evaluated motor map size and movement latency following optogenetic cortical stimulation against three factors of post-stroke biomarker utility: (1) correlation to chronic impairment on a behavioral test battery; (2) amenability to change using a skilled motor training paradigm; and (3) ability to distinguish individuals with potential to respond well to training. Thy1-ChR2-YFP mice received a photothrombotic stroke at postnatal day 7 and were evaluated on a battery of motor tests between days 59 and 70. Following a cranial window implant, mice underwent longitudinal optogenetic motor mapping both before and after 3 weeks of skilled forelimb training. Map size and movement latency of both hemispheres were positively correlated with impaired spontaneous forelimb use, whereas only ipsilesional hemisphere map size was correlated with performance in skilled reaching. Map size and movement latency did not show groupwise changes with training; however, mice with the smallest pretraining map sizes and worst impairments demonstrated the greatest expansion of map size in response to skilled forelimb training. Overall, motor map size showed utility as a potential biomarker for impairment and training-induced modulation in specific individuals. Future assessment of the predictive capacity of post-stroke motor representations for behavioral outcome in animal models opens the possibility of dissecting how plasticity mechanisms contribute to recovery following perinatal stroke.SIGNIFICANCE STATEMENT We investigated the utility of two cortical motor representation measures (motor map size and movement onset latency) as potential biomarkers for post-stroke motor recovery in a mouse model of perinatal stroke. Both motor map size and movement latency were associated with functional recovery after perinatal stroke, with map size showing an additional association between training responsiveness and severity of impairment. Overall, both motor map size and movement onset latency show potential as neurophysiological correlates of recovery. As such, future studies of perinatal stroke rehabilitation and neuromodulation should include these measures to help explain neurophysiological changes that might be occurring in response to treatment.     

Getting neurorehabilitation right: what can be learned from animal models?

Animal models suggest that a month of heightened plasticity occurs in the brain after stroke, accompanied by most of the recovery from impairment. This period of peri-infarct and remote plasticity is associated with changes in excitatory/inhibitory balance and the spatial extent and activation of cortical maps and structural remodeling. The best time for experience and training to improve outcome is unclear. In animal models, very early (<5 days from onset) and intense training may lead to increased histological damage. Conversely, late rehabilitation (>30 days) is much less effective both in terms of outcome and morphological changes associated with plasticity. In clinical practice, rehabilitation after disabling stroke involves a relatively brief period of inpatient therapy that does not come close to matching intensity levels investigated in animal models and includes the training of compensatory strategies that have minimal impact on impairment. Current rehabilitation treatments have a disappointingly modest effect on impairment early or late after stroke. Translation from animal models will require the following: (1) substantial increases in the intensity and dosage of treatments offered in the first month after stroke with an emphasis on impairment; (2) combinational approaches such as noninvasive brain stimulation with robotics, based on current understanding of motor learning and brain plasticity; and (3) research that emphasizes mechanistic phase II studies over premature phase III clinical trials.     

Effects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellular reorganization following stroke

Post-ischemic inflammation plays a critical role in cellular reorganization and functional recovery after stroke. We therefore address the hypothesis whether anti-inflammatory treatment with either indometacin or minocycline combined with rehabilitative training improve functional recovery and influence perilesional cellular response following focal cortical infarcts. Using the photothrombosis model in adult rats, focal cortical infarcts were induced in the fore- and hindlimb sensorimotor cortex. Inflammatory processes were blocked by intraperitoneal application of indometacin or minocycline twice daily during the first 2 weeks of the experiment. Immediately after the infarct, the animals received a daily session of skilled reaching training of the impaired forelimb. In addition, Bromodeoxyuridine (BrdU) was administrated for 5 sequential days post infarct. Proliferation and differentiation of astrocytes, microglia, immature and mature neurons in the perilesional zone were immunocytochemically quantified at days 14 and 42. Functional recovery was assessed in a sensorimotor walking task preoperatively and 4, 14 and 28 days post surgery. Combined rehabilitative training and indometacin or minocycline strongly improved sensorimotor performance and significantly reduced the number of proliferating microglia compared to reaching training alone. Furthermore, the combination increased the survival of proliferating astrocytes and, moreover, minocycline increased the doublecortin-positive cells in the perilesional zone. Anti-inflammatory drug application combined with rehabilitative training demonstrates improved functional recovery and significantly modifies proliferation and survival of distinct glial and neuronal subpopulations in the direct vicinity of cortical infarcts compared to reaching training alone.     

Bilateral and unilateral movement training on upper limb function in chronic stroke patients: A TMS study

The use of activity-dependent interventions has shown some success in promoting recovery of upper limb function in chronic stroke patients. This study compared the neurophysiological and behavioural changes associated with two such rehabilitation protocols: unilateral and bilateral movement training. Twelve chronic stroke patients were randomly assigned to the two training protocols involving six daily practice sessions. Each session consisted of 50 trials of a dowel placement task performed either with both impaired and unimpaired arm moving synchronously (bilateral training group) or with only the impaired arm moving (unilateral training). Kinematic measurements of upper limb movements were made in four unilateral test trials performed prior to and following each practice session. Functional assessments of the impaired upper limb and neurophysiological assessments, using transcranial magnetic stimulation (TMS), of the affected and non-affected cortical hemispheres were made prior to and following the intervention sessions. Individuals receiving bilateral training showed a reduction in movement time of the impaired limb and increased upper limb functional ability compared to individuals receiving unilateral training. In some patients changes to upper limb function were associated with changes to the cortical representation of a target muscle in the non-affected hemisphere. Overall, these findings suggest that a short-term bilateral training intervention may be effective in facilitating upper limb motor function in chronic stroke patients.     

Brain plasticity and stroke rehabilitation. The Willis lecture

Neuronal connections and cortical maps are continuously remodeled by our experience. Knowledge of the potential capabilityof the brain to compensate for lesions is a prerequisite for optimal stroke rehabilitation strategies. Experimental focal cortical lesions induce changes in adjacent cortex and in the contralateral hemisphere. Neuroimaging studies in stroke patients indicate altered poststroke activation patterns, which suggest some functional reorganization. To what extent functional imaging data correspond to outcome data needs to be evaluated. Reorganization may be the principle process responsible for recovery of function after stroke, but what are the limits, and to what extent can postischemic intervention facilitate such changes? Postoperative housing of animals in an enriched environment can significantly enhance functional outcome and can also interact with other interventions, including neocortical grafting. What role will neuronal progenitor cells play in future rehabilitation-stimulated in situ or as neural replacement? And what is the future for blocking neural growth inhibitory factors? Better knowledge of postischemic molecular and neurophysiological events, and close interaction between basic and applied research, will hopefully enable us to design rehabilitation strategies based on neurobiological principles in a not-too-distant future.     

Leap Motion-based virtual reality training for improving motor functional recovery of upper limbs and neural reorganization in subacute stroke patients

Virtual reality is nowadays used to facilitate motor recovery in stroke patients. Most virtual reality studies have involved chronic stroke patients; however, brain plasticity remains good in acute and subacute patients. Most virtual reality systems are only applicable to the proximal upper limbs(arms) because of the limitations of their capture systems. Nevertheless, the functional recovery of an affected hand is most difficult in the case of hemiparesis rehabilitation after a stroke. The recently developed Leap Motion controller can track the fine movements of both hands and fingers. Therefore, the present study explored the effects of a Leap Motion-based virtual reality system on subacute stroke. Twenty-six subacute stroke patients were assigned to an experimental group that received virtual reality training along with conventional occupational rehabilitation, and a control group that only received conventional rehabilitation. The Wolf motor function test(WMFT) was used to assess the motor function of the affected upper limb; functional magnetic resonance imaging was used to measure the cortical activation. After four weeks of treatment, the motor functions of the affected upper limbs were significantly improved in all the patients, with the improvement in the experimental group being significantly better than in the control group. The action performance time in the WMFT significantly decreased in the experimental group. Furthermore, the activation intensity and the laterality index of the contralateral primary sensorimotor cortex increased in both the experimental and control groups. These results confirmed that Leap Motion-based virtual reality training was a promising and feasible supplementary rehabilitation intervention, could facilitate the recovery of motor functions in subacute stroke patients. The study has been registered in the Chinese Clinical Trial Registry(registration number: Chi CTR-OCH-12002238).     

New directions in occupational therapy: implementation of the task-oriented approach in conjunction with cortical stimulation after stroke

Chronic upper extremity hemiparesis following stroke is a significant impairment that can limit a person's independence in all aspects of ADL, IADL, and functional mobility. Although recovery of functional independence may be more efficient using traditional compensatory techniques, these therapeutic methods often do not encourage integration of the hemiparetic arm and hand. In contrast, the task-oriented approach to motor recovery of poststroke hemiparesis emphasizes integration of the impaired limb into all functional tasks via skill-based training. Cortical changes have been documented following skill-based training of the upper limb in the healthy animal model. Additionally, the combination of subthreshold cortical stimulation combined with skill-based forelimb training in the induced-stroke rat model has demonstrated better outcomes than training alone. Preliminary research with human stroke survivors using task-oriented training and subthreshold cortical stimulation has shown promising results. The purpose of this article is to introduce an upper limb training protocol that was used in a national multisite trial that compares cortical stimulation in conjunction with taskoriented training to training alone.     

Movement-dependent stroke recovery: a systematic review and meta-analysis of TMS and fMRI evidence

Evidence indicates that experience-dependent cortical plasticity underlies post-stroke motor recovery of the impaired upper extremity. Motor skill learning in neurologically intact individuals is thought to involve the primary motor cortex, and the majority of studies in the animal literature have studied changes in the primary sensorimotor cortex with motor rehabilitation. Whether changes in engagement in the sensorimotor cortex occur in humans after stroke currently is an area of much interest. The present study conducted a meta-analysis on stroke studies examining changes in neural representations following therapy specifically targeting the upper extremity to determine if rehabilitation-related motor recovery is associated with neural plasticity in the sensorimotor cortex of the lesioned hemisphere. Twenty-eight studies investigating upper extremity neural representations (e.g., TMS, fMRI, PET, or SPECT) were identified, and 13 met inclusion criteria as upper extremity intervention training studies. Common outcome variables representing changes in the primary motor and sensorimotor cortices were used in calculating standardized effect sizes for each study. The primary fixed effects model meta-analysis revealed a large overall effect size (ES=0.84, S.D.=0.15, 95% CI=0.76-0.93). Moreover, a fail-safe analysis indicated that 42 null effect studies would be necessary to lower the overall effect size to an insignificant level. These results indicate that neural changes in the sensorimotor cortex of the lesioned hemisphere accompany functional paretic upper extremity motor gains achieved with targeted rehabilitation interventions.     

Bimanual training after stroke: are two hands better than one?

Functional recovery of the paretic upper extremity eludes the majority of patients post stroke. Although many tasks require the coordinated participation of both hands, rehabilitation strategies for the most part have focused on the paretic limb. This article reviews the behavioral basis of bimanual coordination both in health and after stroke hemiparesis and reviews clinical research studies that have used a bimanual training protocol for rehabilitation. Our intent is to examine and evaluate the evidence for the application of such an approach to enhance recovery of upper extremity function. Based on our review, we suggest a set of prerequisite task features and patient characteristics for consideration in the application of bimanual training protocols for poststroke rehabilitation.     

Understanding the pattern of functional recovery after stroke: facts and theories

Longitudinal studies show that almost all stroke patients experience at least some predictable degree of functional recovery in the first six months post stroke. However, the non-linear pattern as a function of time is not well understood. Several mechanisms are presumed to be involved, such as recovery of penumbral tissues, neural plasticity, resolution of diaschisis and behavioural compensation strategies. Rehabilitation is believed to modulate this logistic pattern of recovery, probably by interacting with these underlying processes. However, prediction models that are adjusted for the effects of time after stroke onset suggest that outcome is largely defined within the first weeks post stroke, although functional improvement has been found to extend beyond six months post stroke. In addition, kinematic studies show that functional improvement is more than recovery from impairments alone, suggesting that patients are able to improve in terms of gait or dexterity deficits using behavioural compensation strategies. Therefore, understanding the impact of task-dependent cortical activation patterns in non-invasive methods requires not only information derived from longitudinal studies pertaining to functional outcomes, but also a better understanding of what is kinematically learned during the acquisition of new skills.     

Rehabilitation following spinal cord injury:how animal models can help our understanding of exercise-induced neuroplasticity

Spinal cord injury is a devastating condition that is followed by long and often unsuccessful recovery after trauma. The state of the art approach to manage paralysis and concomitant impairments is rehabilitation, which is the only strategy that has proven to be effective and beneficial for the patients over the last decades. How rehabilitation influences the remodeling of spinal axonal connections in patients is important to understand, in order to better target these changes and define the optimal timing and onset of training. While clinically the answers to these questions remain difficult to obtain, rodent models of rehabilitation like bicycling, treadmill training, swimming, enriched environments or wheel running that mimic clinical rehabilitation can be helpful to reveal the axonal changes underlying motor recovery. This review will focus on the different animal models of spinal cord injury rehabilitation and the underlying changes in neuronal networks that are improved by exercise and rehabilitation.     

Facilitatory effect of neglect rehabilitation on the recovery of left hemiplegic stroke patients: A cross-over study

A study of the effect of specific training for visual neglect on the recovery of motor and functional impairment in stroke patients is reported. Two groups of right hemisphere stroke patients with hemispatial neglect and one group without neglect were assessed by means of three functional and neurological scales (Rivermead Mobility Index, Barthel Index, Canadian Neurological Scale). Three evaluations were made at 0, 2 and 4 months from the beginning of physical rehabilitation. During the first 2 months of physical rehabilitation one of the two groups of neglect patients was randomly assigned to specific training for neglect, and the second group to a general cognitive intervention; during the final 2 months of rehabilitation the types of training were switched in the two groups. The non-neglect patients improved steadily during physical rehabilitation. In contrast, the functional recovery of the two neglect groups was time-locked to the period of the specific training for neglect. At the time of admission, the two neglect groups performed at the same level; after 2 months of rehabilitation, the group with neglect training showed higher functional recovery than the group with only general cognitive intervention. When the latter group received neglect training, there was no longer any difference between the two neglect groups. This pattern was present for both of the functional scales used but not for the neurological scale. Motor and functional recovery of stroke patients with neglect seems to be significantly improved by the simultaneous presence of a treatment specifically focused on neglect.     

Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult

Recovery of motor function following stroke is believed to be supported, at least in part, by functional compensation involving residual neural tissue. The present study used a rodent model of focal ischemia and intracortical microstimulation (ICMS) to examine the behavioral and physiological effects of cortical stimulation in combination with motor rehabilitation. Adult rats were trained to criterion on a single pellet reaching task before ICMS was used to derive maps of movement representations within forelimb motor cortex contralateral to the trained paw. All animals then received a focal ischemic infarct within the motor map. A cortical surface electrode was implanted over the motor cortex. Low levels of electrical stimulation were applied during rehabilitative training on the same reaching task for 10 days and ICMS used to derive a second motor map. Results showed that both monopolar and bipolar cortical stimulation significantly enhanced motor recovery and increased the area of cortex from which microstimulation movements could be evoked. The results demonstrate the behavioral and neurophysiological benefits of cortical stimulation in combination with rehabilitation for recovery from stroke.     

Advances in adjuvant pharmacotherapy for motor rehabilitation: effects of levodopa

Hemiparesis is common after stroke and often severely disabling. Until very recently, the only therapeutic option for motor recovery was physiotherapeutic training. Experimental animal studies have shown that when applied in addition to exercises pharmacological interventions that affect the norepinephrine system can enhance the rate of functional motor recovery. These effects were observed when an increase in norepinephrine concentration in the CNS was pharmacologically induced. We recently showed that 3 weeks of single daily doses of 100 mg L-dopa, which is metabolized into norepinephrine in the brain, increase the efficacy of physiotherapy in hemiparetic stroke patients. Two additional randomized controlled trials with stroke patients also demonstrated the clinical relevance of this approach for motor recovery and independence in activities of daily living. Modifying effects of other frequently occurring clinical symptoms such as spasticity, neglect, and attention were also investigated. Thus, in view of its minimal side effects, L-dopa can be recommended in conjunction with exercise therapy to improve the functional outcome in stroke rehabilitation.     

Changes in brain activation in stroke patients after mental practice and physical exercise： a functional MRI study

Mental practice is a new rehabilitation method that reters to the mental rehearsal ot motor imagery content with the goal of improving motor performance. However, the relationship between activated regions and motor recovery after mental practice training is not well understood. In this study, 15 patients who suffered a firstever subcortical stroke with neurological deficits affecting the right hand, but no significant cognitive impairment were recruited. 10 patients underwent mental practice combined with physical practice training, and 5 patients only underwent physical practice training. We observed brain activation regions after 4 weeks of training, and explored the correlation of activation changes with functional recovery of the affected hands. The results showed that, after 4 weeks of mental practice combined with physical training, the Fugl-Meyer assessment score for the affected right hand was significantly increased than that after 4 weeks of practice training alone. Functional MRI showed enhanced activation in the left primary somatosensory cortex, attenuated activation intensity in the right primary motor cortex, and enhanced right cerebellar activation observed during the motor imagery task using the affected right hand after mental practice training. The changes in brain cortical activity were related to functional recovery of the hand. Experimental findings indicate that cortical and cerebellar functional reorganization following mental practice contributed to the improvement of hand function.