ANNALS SPECIAL EDITION: THERAPEUTIC PROSPECTS
Neurorehabilitation: Motor Recovery After Stroke as an Example Karunesh Ganguly, MD, PhD,1,2 Nancy N. Byl, PT, MPH, PhD,3 and Gary M. Abrams, MD1,2 The field of neurorehabilitation aims to translate neuroscience research toward the goal of maximizing functional recovery after neurological injury. A growing body of research indicates that the fundamental principles of neurological rehabilitation are applicable to a broad range of congenital, degenerative, and acquired neurological disorders. In this perspective, we will focus on motor recovery after acquired brain injuries such as stroke. Over the past few decades, a large body of basic and clinical research has created an experimental and theoretical foundation for approaches to neurorehabilitation. Recent randomized clinical trials all emphasize the requirement for intense progressive rehabilitation programs to optimally enhance recovery. Moreover, advances in multimodal assessment of patients with neuroimaging and neurophysiological tools suggest the possibility of individualized treatment plans based on recovery potential. There are also promising indications for medical as well as noninvasive brain stimulation paradigms to facilitate recovery. Ongoing or planned clinical studies should provide more definitive evidence. We also highlight unmet needs and potential areas of research. Continued research built upon a robust experimental and theoretical foundation should help to develop novel treatments to improve recovery after neurological injury. ANN NEUROL 2013;74:373–381
N
eurorehabilitation is the translation of basic and clinical neuroscience research to help patients with nervous system dysfunction to maximize mechanisms of neural recovery and compensation.1–5 The ultimate objectives are to restore and maintain functional independence, community participation, and quality of life despite impairments.1,3,4 Although this conceptual review will examine advances in the rehabilitation of patients poststroke, we emphasize that the fundamental principles are applicable to a broad range of congenital, degenerative, and traumatic neurological disorders.1 Stroke is among the leading causes of long-term disability in both developed and developing countries.6–8 It is also the leading cause of long-term disability in the United States.8 Of the >700,000 stroke survivors each year in the United States alone, approximately 30 to 45% become permanently disabled.8,9 The impact of stroke on individuals and families, as well as the financial burden on the health care system, are substantial and will only grow as the global population ages.6–8
The World Health Organization International Classification of Function differentiates between the primary disease process/body impairments, limitations in “activities,” and the restrictions that limit “participation” (http://www.who.int/classifications). One of the main causes of disability after stroke is upper extremity weakness that limits performance of activities of daily living (eg, feeding and self-care) as well as broader engagement in society.8,10 However, lower extremity weakness, spasticity, pain, dysphagia, dysarthria, aphasia, visual field deficits, depression, and cognitive deficits can also limit activities and access to the broader community.11–13 Although there has been substantial progress in stroke prevention, early stroke diagnosis (eg, using neuroimaging), and acute treatment, there has only been a modest improvement in functional outcomes.4,8,9 It is critical to develop novel medical treatments, refine rehabilitative techniques, and translate the principles of neural adaptation and interface technology to enhance recovery poststroke.
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.23994 Received May 27, 2013, and in revised form Jul 31, 2013. Accepted for publication Jul 31, 2013. Address correspondence to Dr Ganguly, 127 Neurology, 4150 Clement Street, San Francisco, CA 94121. E-mail: [email protected] From the 1Department of Neurology and Rehabilitation, San Francisco Veterans Administration Medical Center, and Departments of 2Neurology and 3 Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA.
C 2013 American Neurological Association V 373
ANNALS
of Neurology
Modern Understanding of Biology There is usually some spontaneous recovery over time in the vast majority of stroke patients.8,9 Unfortunately, it is typically incomplete, and patients are often left with disabilities. Spontaneous recovery is most pronounced over the first month and can continue over a period of several months.11 A combination of factors such as spontaneous recovery, compensation, and relearning are important for larger functional improvements.9,14–18 Recovery and Compensation Because of the complex relationship between neural processes, impairment, and disability, it can be challenging to assess for true neurological recovery. With recovery, the objective is to restore lost function.18–21 This may include multiple overlapping mechanisms such as recovering the function of injured neurons, activating new pathways, and neurogenesis.9,14–17,22 Compensation, in contrast, results in functional improvements via engaging the unaffected limb, using assistive devices, or modifying the movement sequence.18,23,24 From a purely clinical perspective and a patient’s viewpoint, the distinction between anatomical and physiological recovery versus substitution may not be important if disability is minimized and quality of life is restored. However, this distinction is of fundamental importance for understanding mechanisms of stroke recovery and the development of new therapies. There is strong evidence that task-oriented repetitive training can result in functional gains.23,25,26 Such gains are often seen in clinical studies using complex tasks to assess improvement (eg, ability to complete activities of daily living). There has been less documentation of changes in neurological impairments that might reflect true neurological recovery versus good compensation.18 Moreover, assessment of compensation versus recovery can be even more challenging in animals models and is not commonly performed.18,24 Animal Models of Stroke Neuroplasticity is essential for spontaneous recovery of function. Neuroplasticity can be defined as the ability of the nervous system to respond to and adapt to either extrinsic or intrinsic changes.27 During recovery after stroke, there appear to be distinct phases analogous to the molecular, cellular, and network phenomena evident during the development of the nervous system.28–30 A wealth of studies in rodents and nonhuman primates have found evidence for microscale (eg, molecular, synaptic, and single-neuron level), mesoscale (eg, at the level of sensorimotor maps within cortex), and macroscale (eg, at the level of anatomically distinct sensory and motor areas) modifications after a stroke.9,15–17,22,29,31–33 Thus, 374
in addition to the extensive peri-infarct modifications, an ischemic lesion affects cortical areas in both hemispheres as well as subcortical locations distant from the lesion.34–37 Both structural and functional changes in the periinfarct region correlate with motor recovery.22,32,38–42 This includes changes in inflammation, secretion of growth factors, changes in dendritic morphology, cell migration, neurogenesis, and modification of neural connectivity.22,32,38,39,43,44 Task-specific activity has been shown to be a critical factor for promoting such modifications.38,40,43 For example, after a “hand-area” stroke, intensive retraining in nonhuman primates was specifically associated with an expansion of the cortical representation for hand and digits into the previous proximal arm representation.38 Furthermore, a recent study found that increased extrasynaptic c-aminobutyric acidergic (GABAergic) activity in the perilesional area impeded spontaneous motor recovery.45 Blockade of GABAergic currents improved recovery in a rodent model. Moreover, innovative studies have shown that targeted modulation of peri-infarct circuits may enhance spontaneous recovery.30,42,46 Clinical Predictors of Recovery Both general characteristics and detailed clinical assessments can predict extent of recovery.9,11 In addition to predictors such as age, medical comorbidities, and initial stroke management, motivation and adherence can also impact recovery.9,47,48 Both detailed analysis of sensorimotor function (eg, using the Fugl–Myer scale) and selected measurements of voluntary movement (eg, ankle dorsiflexion or independent digit movements) can also predict subsequent motor outcomes.9,49 In general, those with prolonged distal impairments are the least likely to recover function. Recent studies also suggest that individualized prediction of recovery is possible.50–52 For example, multimodal assessment of corticospinal integrity offers a promising means to identify individual recovery potential.51,52 A recent study combined clinical measures with neuroimaging and neurophysiological tools to prospectively predict recovery of function.52 Forty participants were prospectively enrolled within 3 days of an ischemic stroke. They underwent a 3-step assessment: (1) shoulder abduction and finger extension strength at 72 hours using a standard neurological scale with a total possible score of 10, (2) transcranial magnetic stimulation (TMS) to assess descending motor pathways, and (3) diffusionweighted magnetic resonance imaging (MRI) to assess the posterior limb of the internal capsule. Thirty-two patients with a score of >8 and a positive TMS evoked Volume 74, No. 3
Ganguly et al: Neurorehabilitation
potential experienced good functional recovery. The remaining patients had no recovery or limited recovery. Interestingly, the diffusion-weighted imaging appeared to prospectively distinguish between the limited and no recovery groups. Thus, these 3 parameters could quite remarkably predict outcomes at 3 months. Neural Basis of Recovery in Stroke Patients Brain mapping studies using positron emission tomography, functional MRI, and magnetoencephalography have revealed important knowledge about the neural basis of motor recovery.33,53–57 Functional MRI (fMRI) studies indicate that there are changes in activation patterns over time after a stroke.54,56 Whereas movements of the affected hand are linked to increased bihemispheric activations in the acute phase, recovery is associated with more lateralized activation. Serial imaging studies have found that task-specific training can facilitate lateralization. Moreover, whereas patients with good recovery can have normal activation patterns, impaired patients continue to recruit larger portions of secondary motor areas.33,55 Recent multivariate analysis of fMRI data using functional and effective connectivity has also identified large-scale changes for several stroke subtypes.36 In contrast to the regional activations evident during task performance, this analysis compares the correlated fluctuations during functional imaging to estimate coupling between areas. These are conducted on resting-state data and not during a structured task. These studies suggest that recovery of motor function enhances intra- and interhemispheric connectivity36 and changes the alpha band connectivity in both perilesional and contralesional cortex.57 Noninvasive brain stimulation using TMS can transiently enhance or reduce excitability and thereby affect motor function and recovery after stroke.33,58–60 In addition to its potential therapeutic use, TMS can be used to test hypotheses about cortical function.61 Repetitive TMS (rTMS) has the potential to facilitate recovery by inducing longer-term excitability changes. Two commonly utilized rTMS paradigms include low-frequency inhibitory stimulation of the unaffected hemisphere and high-frequency excitatory stimulation of the affected hemisphere.33,37,60 Facilitation of the affected hemisphere and inhibition of the unaffected hemisphere may both transiently improve motor function.33,37 Together with the neuroimaging data showing greater contralesional activation in those with poor motor recovery, these findings suggest that interhemispheric interactions are an important therapeutic target. Maladaptive Neuroplasticity Importantly, some behavioral as well as involuntary adaptations represent maladaptive neuroplasticity.22,62 One September 2013
example is the phenomenon of learned disuse, a term that has been used to describe primate models of chronic hemiparesis after limb deafferentation.22 Animals ignored the affected limb and relied on the unaffected limb. Strategies for reversing this process form the basis of some rehabilitation techniques such as constraint-induced movement therapy (CIMT).22 Moreover, involuntary pathological synergies such as spasticity can also become learned when practiced on a daily basis during self-care and ambulation.13
Currently Available Therapies Targeted Rehabilitation Rehabilitation aims to maximize experience-dependent neural plasticity as well as integrate compensatory strategies to achieve improvements in function, independence, and quality of life.1–5 This process spans the time period from the acute inpatient ward to the outpatient setting. The current view is that rehabilitation should begin soon after stroke and patients should be transitioned out of the hospital as soon as possible.63,64 Each patient should have a customized program that is iteratively refined. Important steps include: (1) assessing needs, (2) establishing attainable goals, (3) developing progressive interventions matched to ability, and (4) evaluating progress over time.4 Developing a task- and context-specific training program can help optimize engagement and target functionally important outcomes. Although the optimal approach and intensity for an individual patient remains uncertain, there have now been several important randomized clinical trials (RCTs) on this topic. CIMT is based on the principles of (1) forced use of the affected arm by restraining the unaffected arm and (2) intensive practice.22,25,65 The EXCITE trial compared CIMT to usual care through an RCT. Participants (n 5 116) were 3 to 9 months poststroke and had the ability to extend the wrist, adduct/extend the thumb, and extend 2 other digits 10 three times in 1 minute.25 Two weeks of intense upper extremity rehabilitation led to both objective and subjective improvements in the Wolf Motor Test and the Motor Activity Log. Although one limitation of the trial was the lack of an active control group, there was a clear and sustained benefit of this intensive rehabilitation program. The benefits of intensity are further highlighted by several recent trials of robotic therapy for rehabilitation of either the upper or the lower limb.64,66,67 The ULRobot trial compared 2 groups (a robot-assisted and a dose-matched intervention group) to usual care.66 Although there were no significant differences between the 2 active groups, there were trends of sustained improvements of robotic training over usual care. The 375
ANNALS
of Neurology
LEAPS trial compared early (2 months poststroke) and late locomotor training (6 months poststroke) using body-weight support treadmill training (BWSTT) and a dose-matched home program in 408 participants with moderate (able to walk 0.4 to
Neurorehabilitation: Motor Recovery After Stroke as an Example Karunesh Ganguly, MD, PhD,1,2 Nancy N. Byl, PT, MPH, PhD,3 and Gary M. Abrams, MD1,2 The field of neurorehabilitation aims to translate neuroscience research toward the goal of maximizing functional recovery after neurological injury. A growing body of research indicates that the fundamental principles of neurological rehabilitation are applicable to a broad range of congenital, degenerative, and acquired neurological disorders. In this perspective, we will focus on motor recovery after acquired brain injuries such as stroke. Over the past few decades, a large body of basic and clinical research has created an experimental and theoretical foundation for approaches to neurorehabilitation. Recent randomized clinical trials all emphasize the requirement for intense progressive rehabilitation programs to optimally enhance recovery. Moreover, advances in multimodal assessment of patients with neuroimaging and neurophysiological tools suggest the possibility of individualized treatment plans based on recovery potential. There are also promising indications for medical as well as noninvasive brain stimulation paradigms to facilitate recovery. Ongoing or planned clinical studies should provide more definitive evidence. We also highlight unmet needs and potential areas of research. Continued research built upon a robust experimental and theoretical foundation should help to develop novel treatments to improve recovery after neurological injury. ANN NEUROL 2013;74:373–381
N
eurorehabilitation is the translation of basic and clinical neuroscience research to help patients with nervous system dysfunction to maximize mechanisms of neural recovery and compensation.1–5 The ultimate objectives are to restore and maintain functional independence, community participation, and quality of life despite impairments.1,3,4 Although this conceptual review will examine advances in the rehabilitation of patients poststroke, we emphasize that the fundamental principles are applicable to a broad range of congenital, degenerative, and traumatic neurological disorders.1 Stroke is among the leading causes of long-term disability in both developed and developing countries.6–8 It is also the leading cause of long-term disability in the United States.8 Of the >700,000 stroke survivors each year in the United States alone, approximately 30 to 45% become permanently disabled.8,9 The impact of stroke on individuals and families, as well as the financial burden on the health care system, are substantial and will only grow as the global population ages.6–8
The World Health Organization International Classification of Function differentiates between the primary disease process/body impairments, limitations in “activities,” and the restrictions that limit “participation” (http://www.who.int/classifications). One of the main causes of disability after stroke is upper extremity weakness that limits performance of activities of daily living (eg, feeding and self-care) as well as broader engagement in society.8,10 However, lower extremity weakness, spasticity, pain, dysphagia, dysarthria, aphasia, visual field deficits, depression, and cognitive deficits can also limit activities and access to the broader community.11–13 Although there has been substantial progress in stroke prevention, early stroke diagnosis (eg, using neuroimaging), and acute treatment, there has only been a modest improvement in functional outcomes.4,8,9 It is critical to develop novel medical treatments, refine rehabilitative techniques, and translate the principles of neural adaptation and interface technology to enhance recovery poststroke.
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.23994 Received May 27, 2013, and in revised form Jul 31, 2013. Accepted for publication Jul 31, 2013. Address correspondence to Dr Ganguly, 127 Neurology, 4150 Clement Street, San Francisco, CA 94121. E-mail: [email protected] From the 1Department of Neurology and Rehabilitation, San Francisco Veterans Administration Medical Center, and Departments of 2Neurology and 3 Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA.
C 2013 American Neurological Association V 373
ANNALS
of Neurology
Modern Understanding of Biology There is usually some spontaneous recovery over time in the vast majority of stroke patients.8,9 Unfortunately, it is typically incomplete, and patients are often left with disabilities. Spontaneous recovery is most pronounced over the first month and can continue over a period of several months.11 A combination of factors such as spontaneous recovery, compensation, and relearning are important for larger functional improvements.9,14–18 Recovery and Compensation Because of the complex relationship between neural processes, impairment, and disability, it can be challenging to assess for true neurological recovery. With recovery, the objective is to restore lost function.18–21 This may include multiple overlapping mechanisms such as recovering the function of injured neurons, activating new pathways, and neurogenesis.9,14–17,22 Compensation, in contrast, results in functional improvements via engaging the unaffected limb, using assistive devices, or modifying the movement sequence.18,23,24 From a purely clinical perspective and a patient’s viewpoint, the distinction between anatomical and physiological recovery versus substitution may not be important if disability is minimized and quality of life is restored. However, this distinction is of fundamental importance for understanding mechanisms of stroke recovery and the development of new therapies. There is strong evidence that task-oriented repetitive training can result in functional gains.23,25,26 Such gains are often seen in clinical studies using complex tasks to assess improvement (eg, ability to complete activities of daily living). There has been less documentation of changes in neurological impairments that might reflect true neurological recovery versus good compensation.18 Moreover, assessment of compensation versus recovery can be even more challenging in animals models and is not commonly performed.18,24 Animal Models of Stroke Neuroplasticity is essential for spontaneous recovery of function. Neuroplasticity can be defined as the ability of the nervous system to respond to and adapt to either extrinsic or intrinsic changes.27 During recovery after stroke, there appear to be distinct phases analogous to the molecular, cellular, and network phenomena evident during the development of the nervous system.28–30 A wealth of studies in rodents and nonhuman primates have found evidence for microscale (eg, molecular, synaptic, and single-neuron level), mesoscale (eg, at the level of sensorimotor maps within cortex), and macroscale (eg, at the level of anatomically distinct sensory and motor areas) modifications after a stroke.9,15–17,22,29,31–33 Thus, 374
in addition to the extensive peri-infarct modifications, an ischemic lesion affects cortical areas in both hemispheres as well as subcortical locations distant from the lesion.34–37 Both structural and functional changes in the periinfarct region correlate with motor recovery.22,32,38–42 This includes changes in inflammation, secretion of growth factors, changes in dendritic morphology, cell migration, neurogenesis, and modification of neural connectivity.22,32,38,39,43,44 Task-specific activity has been shown to be a critical factor for promoting such modifications.38,40,43 For example, after a “hand-area” stroke, intensive retraining in nonhuman primates was specifically associated with an expansion of the cortical representation for hand and digits into the previous proximal arm representation.38 Furthermore, a recent study found that increased extrasynaptic c-aminobutyric acidergic (GABAergic) activity in the perilesional area impeded spontaneous motor recovery.45 Blockade of GABAergic currents improved recovery in a rodent model. Moreover, innovative studies have shown that targeted modulation of peri-infarct circuits may enhance spontaneous recovery.30,42,46 Clinical Predictors of Recovery Both general characteristics and detailed clinical assessments can predict extent of recovery.9,11 In addition to predictors such as age, medical comorbidities, and initial stroke management, motivation and adherence can also impact recovery.9,47,48 Both detailed analysis of sensorimotor function (eg, using the Fugl–Myer scale) and selected measurements of voluntary movement (eg, ankle dorsiflexion or independent digit movements) can also predict subsequent motor outcomes.9,49 In general, those with prolonged distal impairments are the least likely to recover function. Recent studies also suggest that individualized prediction of recovery is possible.50–52 For example, multimodal assessment of corticospinal integrity offers a promising means to identify individual recovery potential.51,52 A recent study combined clinical measures with neuroimaging and neurophysiological tools to prospectively predict recovery of function.52 Forty participants were prospectively enrolled within 3 days of an ischemic stroke. They underwent a 3-step assessment: (1) shoulder abduction and finger extension strength at 72 hours using a standard neurological scale with a total possible score of 10, (2) transcranial magnetic stimulation (TMS) to assess descending motor pathways, and (3) diffusionweighted magnetic resonance imaging (MRI) to assess the posterior limb of the internal capsule. Thirty-two patients with a score of >8 and a positive TMS evoked Volume 74, No. 3
Ganguly et al: Neurorehabilitation
potential experienced good functional recovery. The remaining patients had no recovery or limited recovery. Interestingly, the diffusion-weighted imaging appeared to prospectively distinguish between the limited and no recovery groups. Thus, these 3 parameters could quite remarkably predict outcomes at 3 months. Neural Basis of Recovery in Stroke Patients Brain mapping studies using positron emission tomography, functional MRI, and magnetoencephalography have revealed important knowledge about the neural basis of motor recovery.33,53–57 Functional MRI (fMRI) studies indicate that there are changes in activation patterns over time after a stroke.54,56 Whereas movements of the affected hand are linked to increased bihemispheric activations in the acute phase, recovery is associated with more lateralized activation. Serial imaging studies have found that task-specific training can facilitate lateralization. Moreover, whereas patients with good recovery can have normal activation patterns, impaired patients continue to recruit larger portions of secondary motor areas.33,55 Recent multivariate analysis of fMRI data using functional and effective connectivity has also identified large-scale changes for several stroke subtypes.36 In contrast to the regional activations evident during task performance, this analysis compares the correlated fluctuations during functional imaging to estimate coupling between areas. These are conducted on resting-state data and not during a structured task. These studies suggest that recovery of motor function enhances intra- and interhemispheric connectivity36 and changes the alpha band connectivity in both perilesional and contralesional cortex.57 Noninvasive brain stimulation using TMS can transiently enhance or reduce excitability and thereby affect motor function and recovery after stroke.33,58–60 In addition to its potential therapeutic use, TMS can be used to test hypotheses about cortical function.61 Repetitive TMS (rTMS) has the potential to facilitate recovery by inducing longer-term excitability changes. Two commonly utilized rTMS paradigms include low-frequency inhibitory stimulation of the unaffected hemisphere and high-frequency excitatory stimulation of the affected hemisphere.33,37,60 Facilitation of the affected hemisphere and inhibition of the unaffected hemisphere may both transiently improve motor function.33,37 Together with the neuroimaging data showing greater contralesional activation in those with poor motor recovery, these findings suggest that interhemispheric interactions are an important therapeutic target. Maladaptive Neuroplasticity Importantly, some behavioral as well as involuntary adaptations represent maladaptive neuroplasticity.22,62 One September 2013
example is the phenomenon of learned disuse, a term that has been used to describe primate models of chronic hemiparesis after limb deafferentation.22 Animals ignored the affected limb and relied on the unaffected limb. Strategies for reversing this process form the basis of some rehabilitation techniques such as constraint-induced movement therapy (CIMT).22 Moreover, involuntary pathological synergies such as spasticity can also become learned when practiced on a daily basis during self-care and ambulation.13
Currently Available Therapies Targeted Rehabilitation Rehabilitation aims to maximize experience-dependent neural plasticity as well as integrate compensatory strategies to achieve improvements in function, independence, and quality of life.1–5 This process spans the time period from the acute inpatient ward to the outpatient setting. The current view is that rehabilitation should begin soon after stroke and patients should be transitioned out of the hospital as soon as possible.63,64 Each patient should have a customized program that is iteratively refined. Important steps include: (1) assessing needs, (2) establishing attainable goals, (3) developing progressive interventions matched to ability, and (4) evaluating progress over time.4 Developing a task- and context-specific training program can help optimize engagement and target functionally important outcomes. Although the optimal approach and intensity for an individual patient remains uncertain, there have now been several important randomized clinical trials (RCTs) on this topic. CIMT is based on the principles of (1) forced use of the affected arm by restraining the unaffected arm and (2) intensive practice.22,25,65 The EXCITE trial compared CIMT to usual care through an RCT. Participants (n 5 116) were 3 to 9 months poststroke and had the ability to extend the wrist, adduct/extend the thumb, and extend 2 other digits 10 three times in 1 minute.25 Two weeks of intense upper extremity rehabilitation led to both objective and subjective improvements in the Wolf Motor Test and the Motor Activity Log. Although one limitation of the trial was the lack of an active control group, there was a clear and sustained benefit of this intensive rehabilitation program. The benefits of intensity are further highlighted by several recent trials of robotic therapy for rehabilitation of either the upper or the lower limb.64,66,67 The ULRobot trial compared 2 groups (a robot-assisted and a dose-matched intervention group) to usual care.66 Although there were no significant differences between the 2 active groups, there were trends of sustained improvements of robotic training over usual care. The 375
ANNALS
of Neurology
LEAPS trial compared early (2 months poststroke) and late locomotor training (6 months poststroke) using body-weight support treadmill training (BWSTT) and a dose-matched home program in 408 participants with moderate (able to walk 0.4 to
