Restorative Neurology and Neuroscience

As a result of an extensive search, we were able to obtain a limited number of macaque monkeys, New World squirrel monkeys, and prosimian galagos years after they had received a therapeutic amputation of a forelimb or hindlimb as a treatment for injury. Forelimb or hindlimb regions of primary motor cortex, M1, were stimulated in these primates with microelectrodes using amounts of current just sufficient to evoke a movement. Results were compared to those obtained from normal primates or from M1 contralateral to the intact limb in the same primates. In all cases, more sites in M1 contralateral to the amputated limb evoked movements of the limb stump and muscle in the adjoining shoulder or hip. In two of the macaque monkeys, injections in M1 reveal more widespread intrinsic connections than in normal M1, and in several monkeys and galagos, injections of tracers in muscles of the stump, shoulder, or hip labeled spinal cord motor neurons that normally project to the distal limb. These anatomical results suggest that the functional changes in M1 following amputation are mediated in part by the formation of new connections.

The effects of extreme disuse or overuse of the limbs in rat models of Parkinson's disease and stroke are discussed. In unilaterally lesioned rats, immobilizing one forelimb in a cast forces complete disuse of this limb and extreme overuse of the uncasted limb. This procedure has diverse effects on histological and behavioral outcomes in these models, depending upon how and when it is applied relative to the lesion. Effects on behavioral outcome, post-lesion plasticity events, and expression of trophic factors are discussed. The effects of forced disuse or overuse vary among lesion types and can include neuroprotection, changes in synaptogenesis, or even exaggeration of tissue loss. The diversity of behavior-driven structural changes in the brain underscores the potential importance of carefully tailoring physical restorative therapy to specific neurological problems in order to optimize outcomes. In addition, we stress the need to recognize the reciprocal influence that behavior and the brain can have upon each other.

Our genes interact with environmental stimuli throughout our lives. The attitude and reaction to an acute cerebral trauma or stroke, as well as the pre-lesion life event and activities, can influence functional outcome. Although difficult to separate in adult human beings, genetic and environmental factors can be selectively evaluated in animal studies. Post- ischemic housing in an enriched environment, i.e. larger cages which allow both social interaction and various activities improves functional outcome, modifies gene activation, and increases dendrite branching and number of dendritic spines in pyramidal neurons in layers II-III in the contra-lateral cortex. Furthermore, it alters lesion-induced progenitor cell differentiation and interacts with neocortical transplantation, drug treatment and training. It is proposed that the interaction between environment and specific treatment needs more clinical attention, and that a general stimulating and positive environment is the optimal base for specific interventions in neurological rehabilitation.

This review presents data from laboratory studies and clinical trials indicating the efficacy of the "Noradrenergic Strategy" for enhancing recovery after cortical injury. Short-term acute treatment combining Physical Therapy (PT) with drugs increasing noradrenaline (NA) levels enhances recovery of hemiplegia in both laboratory studies and clinical trials which also report improved aphasia recovery. Importantly these effects endure even when treatment is initiated months after stroke onset. The hypothesized mechanisms included modulation of neuronal processes underlying "spontaneous" recovery since drugs reducing NA levels slow spontaneous recovery. The effect of some drugs change with time after sensorimotor cortex (SMCx) injury. Drugs reducing NA levels, including clonidine and prazosin, and GABA receptor agonists at doses having little effect early after injury, when administered to animals or stroke patients after "complete recovery" transiently reinstate the original symptoms. Reinstatement by prazosin remains unchanged after repeated testing for over six months in rat, and the deficits can be as severe as the first days after injury. This suggests "completed" recovery is an inaccurate label for an enduring "fragile" state. This transient reinstatement of symptoms may be useful for distinguishing causal from corollary relationships between symptoms and physiological processes proposed as mechanisms for recovery of function.

Contrary to what previously believed, recent research advances have demonstrated that the adult brain has a certain capacity for plastic reorganization and self-repair after a lesion such as cerebrovascular accidents. The mechanisms subtending post-stroke recovery are probably complex and operating at different levels, from molecular to synaptic to anatomical reorganization. The integrated use of functional neuroimaging techniques, by overcoming the limitations of each specific methodology is likely to shed much light on plasticity mechanisms. In this review we discuss the neuroanatomy and neurophysiology possibly underlying reorganization of the central nervous system, as well as the experimental evidence of "in vivo" post-stroke plasticity. Better understanding of these mechanisms can provide neurorehabilitation with powerful tools in designing and implementing new therapeutic approaches to stroke patients both in the acute and the chronic stages after a brain tissue lesion has occurred and stabilized.

Animal experiments suggest that reorganisation of cerebral representations is the neurobiological basis of post-lesional recovery. In human ischemic brain disease recovery is a dynamic and sustained process beginning after stroke manifestation. The mechanisms underlying recovery can be investigated non-invasively in the human brain using functional neuroimaging and transcranial magnetic stimulation (TMS).

In the acute stage, the mismatch area of the perfusion deficit and the impaired water diffusion as assessed by magnetic resonance imaging (MRI) shows the brain tissue that potentially can be rescued by thrombolysis or emergency carotid endarteriectomy. Since spontaneous motor recovery is a function of the corticospinal tract integrity, early reperfusion of ischemic tissue is critical. In the subacute and chronic stage after stroke, recovery of motor function was shown to take place irrespective of a concomitant affection of the somatosensory system. Functional MRI with simultaneous recordings of the electromyogram provides evidence that the abnormal activation of motor and premotor cortical areas in both hemispheres related to finger movements has a large interindividual variability. As evident from TMS, recovery results from regression of perilesional inhibition and from remote intracortical disinhibition. Repetitive training, constraint induced training and motor imagery can augment recovery promoting a re-emerging activation in the affected hemisphere.

Evolution of altered local perilesional and large-scale bihemispheric circuits appears to allow for post-lesional deficit compensation.

Motor system impairments are common after stroke and are a major contributor to disability after stroke. Most patients show improvement in the weeks-months following a stroke. Understanding the neurobiological underpinnings of these behavioral gains may be useful for refining treatments that aim to improve outcome and reduce disability. A number of brain mapping studies have examined how stroke affects motor system function. Numerous changes have been identified in this setting and are reviewed herein, including reduced laterality, widespread changes across a distributed sensorimotor network, and a change in the site and size of key activation foci. Some of these changes have been found to correlate with features of injury, behavior, or treatment-induced behavioral gains. A current challenge is to extend these findings to improve clinical decision making.

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.

Modern cognitive neuroscience provides a powerful framework in which biological models of recovery and neurorehabilitation can be constructed and tested. The widespread availability, relatively low cost and informativeness of functional magnetic resonance imaging (fMRI) has made it the most popular of the techniques available to help with this task. Here, on the basis of functional imaging studies of stroke, diffuse microvascular disease and multiple sclerosis, we argue that processes of motor control and learning in the healthy brain share common mechanisms with those for adaptive functional reorganisation during spontaneous recovery after brain injury or with neurorehabilitation. Relatively stringent criteria can be met to confirm that adaptive functional reorganisation limits disability even in the adult brain: functional brain changes are related to disease burden, can be found in patients with demonstrable pathology but no clinical deficits and can be defined (in motor cortex) even in the absence of volitional recruitment. Initial studies of neurorehabilitation responses using fMRI and transcranial magnetic stimulation demonstrate that adaptive reorganisation can be manipulated directly with both pharmacological and behavioural interventions. The combination of strategies based on a strong biological rational with monitoring their effects using highly informative functional brain imaging methods heralds a new era of scientifically-founded neurorehabilitation.

Basic science studies demonstrated mechanisms of plasticity and metaplasticity. More recent human studies identified some of these mechanisms as operating in multiple areas of human cognition, such as learning and memory, and in functional recovery from lesions in the CNS, as in stroke. One of the goals of neurorehabilitation is the translation of these principles into rational strategies to promote recovery of function. Understanding the mechanisms and functional role of human plasticity could lead to the development of therapeutic options in situations in which there is virtually no treatment alternative, as in chronic stroke. We review some of the work performed to better understand the substrates and mechanisms underlying cortical plasticity and discuss some experimental approaches to enhance cortical plasticity and recovery of function, like cortical stimulation.

Introduction: A stroke may modulate motor cortex excitability. We examined if distinct ischemic brain lesions are associated with a specific pattern of excitability changes. We also investigated the effects of a rehabilitative therapy on motor excitability.

Methods: In stroke patients, the consequences of a) a lesion in the central somatosensory system, b) a cerebellar lesion and c) a two week period of Constraint-induced movement therapy (CIMT), on motor cortex excitability were studied. Transcranial magnetic stimulation techniques and functional magnetic resonance imaging (fMRI) were employed.

Results: Patients with a lesion in the primary somatosensory cortex or in the ventroposterolateral nucleus of the thalamus had a decreased intracortical inhibition on the affected side. Patients with lesions in the territory of the superior cerebellar artery had a loss of intracortical facilitation and an increase of intracortical inhibition. Patients with cortical lesions undergoing CIMT had a loss of intracortical inhibition prior to therapy. After CIMT, changes of ICI were stronger in the lesioned than in the non-lesioned hemisphere but could result either in an increase of ICI or a reduction of ICI. In three patients fMRI results showed that cortical activation was less post CIMT as compared to pre-treatment activation. In parallel, ICI was reduced after treatment.

Conclusions: Our results suggest that, physiologically, central somatosensory influence on the motor cortex is inhibitory. In contrast, the cerebellum normally exerts a facilitatory influence on the motor cortex. CIMT induces changes of intracortical excitability mainly in the affected hemisphere.

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.

Everyday activities can be affected by many different body dysfunctions (impairments). A multi-modal analysis of electric brain activity revealed that movement-related brain activity is differentially altered in patients with different impairments, i.e. paresis, somatosensory deficits, and apraxia. Each body dysfunction has its own characteristics in terms of the resulting sensorimotor control deficits. The Impairment-oriented Training concept intends to characterise the resulting sensorimotor control deficits for each impairment. Based on such analyses two specific training techniques have been developed for stroke patients with mild and severe arm paresis: (1.) The Arm Ability training for mild arm paresis trains different sensorimotor abilities such as dexterity, speed of isolated hand and finger movements, steadiness, aiming, or tracking under visual guidance. Improvement of these motor abilities leads to improved motor performance in every day life circumstances. (2.) The Arm BASI S training for severe arm paresis intends to restore more basic motor control, i.e. the full range of active non-segmented motion of all limb segments, both postural activities and dynamic motion control, interjoint-coordination, and adequate motor control when external forces are applied. Clinical trials with representative study populations supported both techniques' clinical efficacy.

Constraint-Induced Movement Therapy (CI therapy) refers to a family of treatments for motor disability that combines constraint of movement, massed practice, and shaping of behavior to improve the amount of use of the targeted limb. CI therapy has controlled evidence for efficacy that supports its benefit for patients with chronic disability following central nervous system injury, regardless of their age or the interval since illness onset. Furthermore, the benefits transfer to real-world measures of limb use. Significant functional improvement may occur even after the patient has been treated with conventional physical therapy. In this paper we review the evidence for the efficacy of CI therapy, particularly for chronic stroke hemiparesis, but also for diverse other chronic disabling illnesses, including non-motor disorders such as phantom limb pain and aphasia. The adaptation of the therapy to the stroke clinic is described, along with a review of the neurophysiologic mechanisms that are postulated to underlie the treatment benefit (overcoming learned nonuse, plastic brain reorganization). Critical to the success of CI therapy is its modification according to disease factors, economic considerations, limitations of the practice setting, and the cognitive and physical status of the patient. We conclude by recommending future areas for research on CI therapy.

Identifying effective rehabilitation interventions founded on sound theoretical and neurophysiological bases should decrease the prevalence of motor disabilities and chronic hemiparesis. This article addresses two theoretically sound behavioral interventions: (a) active neuromuscular stimulation on the impaired upper extremity and (b) coupled bilateral coordination training (i.e., mirrored movements on the less impaired limb combined with active stimulation on the impaired limb). The series of stroke motor recovery experiments currently reviewed clearly indicate that sensorimotor integration theory and bimanual coordination theory are viable candidates for directing behavioral rehabilitation approaches. Indeed, the reported evidence clearly supports activity dependent neural plasticity for progress toward stroke motor recovery.

This article reviews a decade of work aimed at developing effective interactive robotic tools to treat and understand motor impairment and disability. The success of an initial pilot study with acute-phase in-patients recovering from stroke prompted a larger study showing that these results could be replicated and a follow-up study showing that the benefits lasted. Studies of chronic-phase out-patients demonstrated that similar benefits could be obtained which also lasted and were accompanied by a concomitant reduction of pain. Exploration of the likely biology of recovery suggested an improvement of robotic treatment in the form of performance-based progressive therapy aimed at accelerating a process akin to motor learning postulated to underlie recovery. Initial studies of this method show a dramatic improvement over the previous successes. Kinematic studies of the recovery process show that, similar to the development of motor behavior in infants, it begins with stereotyped submovements and proceeds by progressively merging these to approach unimpaired motor performance.

The gait-lab at Klinik Berlin developed and evaluated novel physical and pharmacological strategies promoting the repetitive practise of hemiparetic gait in line with the slogan: who wants to relearn walking, has to walk. Areas of research are treadmill training with partial body weight support, enabling wheelchair-bound subjects to repetitively practice gait, the electromechanical gait trainer GT I reducing the effort on the therapists as compared to the manually assisted locomotor therapy, and the future HapticWalker which will allow the additional practise of stair climbing up and down and of perturbations. Further means to promote gait practice after stroke was the application of botulinum toxin A for the treatment of lower limb spasticity and the early use of walking aids. New areas of research are also the study of D-Amphetamine, which failed to promote motor recovery in acute stroke patients as compared to placebo, and the development of a computerized arm trainer, Bi-Manu-T rack, for the bilateral treatment of patients with a severe upper limb paresis.

Development and application of virtual reality (VR) systems for rehabilitation is an iterative process produced by collaboration of an inter-disciplinary team of engineers, neuroscientists and clinician-scientists. In this paper the use of virtual reality technology for the rehabilitation of individuals post-stroke is described. The development of the hardware is based on principles of motor control. Development of the software uses findings from the enrichment and motor plasticity and training literatures as well as principles of motor learning. Virtual environments are created to afford individuals post-stroke opportunities to practice tasks for which they require rehabilitation. These tasks, related to hand function and gait, are trained both at the impairment and functional level. The training engages users to allow for the repetitive intensive practice required for behavioral motor plasticity. Results from a series of upper and lower extremity studies indicate that use of VR technology to augment rehabilitation of individuals post-stroke merits further study.

Over the past two decades, experimental studies following brain injury have shown that the central nervous system is dynamic and malleable to internal and external inputs. Neuromodulation and/or direct manipulation of motor and sensory experience can modify brain plasticity and functional outcome after experimental lesions. Specifically, pharmacologic modulation has been found to facilitate recovery of various behavioral deficits following occlusive injury. Additionally, the behavioral experience that induces long-term plasticity in motor and sensory maps after injury appears to be limited to those that entail the development of new skills. These data have strong application to human rehabilitation. This review will: (1) overview critical experimental studies that show that pharmacologic manipulation and/or specific behavioral experience may modify the functional organization of the injured brain and (2) review beginning studies which are exploring the application of this knowledge clinically.

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.