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Background . After stroke, recovery of movement in proximal and distal upper extremity (UE) muscles appears to follow different time courses, suggesting differences in their neural substrates. Objective . We sought to determine if presence or absence of motor evoked potentials (MEPs) differentially influences recovery of volitional contraction and strength in an arm muscle versus an intrinsic hand muscle. We also related MEP status to recovery of proximal and distal interjoint coordination and movement fractionation, as measured by the Fugl-Meyer Assessment (FMA). Methods . In 45 subjects in the year following ischemic stroke, we tracked the relationship between corticospinal tract (CST) integrity and behavioral recovery in the biceps (BIC) and first dorsal interosseous (FDI) muscle. We used transcranial magnetic stimulation to probe CST integrity, indicated by MEPs, in BIC and FDI. We used electromyography, dynamometry, and UE FMA subscores to assess muscle-specific contraction, strength, and inter-joint coordination, respectively. Results . Presence of MEPs resulted in higher likelihood of muscle contraction, greater strength, and higher FMA scores. Without MEPs, BICs could more often volitionally contract, were less weak, and had steeper strength recovery curves than FDIs; in contrast, FMA recovery curves plateaued below normal levels for both the arm and hand. Conclusions . There are shared and separate substrates for paretic UE recovery. CST integrity is necessary for interjoint coordination in both segments and for overall recovery. In its absence, alternative pathways may assist recovery of volitional contraction and strength, particularly in BIC. These findings suggest that more targeted approaches might be needed to optimize UE recovery.

Background: New technologies, such as telerehabilitation and gaming devices offer the possibility for patients to train at home. This opens the challenge of safety for the patient as he/she is called to exercise neither with a therapist on the patients' side nor with a therapist linked remotely to supervise the sessions., Aim: To study the safety, usability and patient acceptance of an autonomous telerehabilitation system for balance and gait (the REWIRE platform) in the patients home., Design: Cohort study., Setting: Community, in the stroke patients' home., Population: Fifteen participants with first-ever stroke, with a mild to moderate residual deficit of the lower extremities., Methods: Autonomous rehabilitation based on virtual rehabilitation was provided at the participants' home for twelve weeks. The primary outcome was compliance (the ratio between days of actual and scheduled training), analyzed with the two-tailed Wilcoxon Mann-Whitney test. Furthermore safety is defined by adverse events. The secondary endpoint was the acceptance of the system measured with the Technology Acceptance Model (TAM). Additionally, the cumulative duration of weekly training was analyzed., Results: During the study there were no adverse events related to the therapy. Patients performed on average 71% (range 39 to 92%) of the scheduled sessions. The TAM Questionnaire showed excellent values for stroke patients after the training. The average training duration per week was 99±53min., Conclusions: Autonomous telerehabilitation for balance and gait training with the REWIRE-system is safe, feasible and can help to intensive rehabilitative therapy at home., Clinical Rehabilitation Impact: Telerehabilitation enables safe training in home environment and supports of the standard rehabilitation therapy.

Following a stroke, mirror movements are unintended movements that appear in the non-paretic hand when the paretic hand voluntarily moves. Mirror movements have previously been linked to overactivation of sensorimotor areas in the non-lesioned hemisphere. In this study, we hypothesized that mirror movements might instead have a subcortical origin, and are the by-product of subcortical motor pathways upregulating their contributions to the paretic hand. To test this idea, we first characterized the time course of mirroring in 53 first-time stroke patients, and compared it to the time course of activities in sensorimotor areas of the lesioned and non-lesioned hemispheres (measured using functional MRI). Mirroring in the non-paretic hand was exaggerated early after stroke (Week 2), but progressively diminished over the year with a time course that parallelled individuation deficits in the paretic hand. We found no evidence of cortical overactivation that could explain the time course changes in behaviour, contrary to the cortical model of mirroring. Consistent with a subcortical origin of mirroring, we predicted that subcortical contributions should broadly recruit fingers in the non-paretic hand, reflecting the limited capacity of subcortical pathways in providing individuated finger control. We therefore characterized finger recruitment patterns in the non-paretic hand during mirroring. During mirroring, non-paretic fingers were broadly recruited, with mirrored forces in homologous fingers being only slightly larger (1.76 times) than those in non-homologous fingers. Throughout recovery, the pattern of finger recruitment during mirroring for patients looked like a scaled version of the corresponding control mirroring pattern, suggesting that the system that is responsible for mirroring in controls is upregulated after stroke. Together, our results suggest that post-stroke mirror movements in the non-paretic hand, like enslaved movements in the paretic hand, are caused by the upregulation of a bilaterally organized subcortical system.

Among the genes that are up-regulated in response to a reaching training in rats, Tachykinin 1 (Tac1)-a gene that encodes the neuropeptide Substance P (Sub P)-shows an especially strong expression. Using Real-Time RT-PCR, a detailed time-course of Tac1 expression could be defined: a significant peak occurs 7 hours after training ended at the first and second training session, whereas no up-regulation could be detected at a later time-point (sixth training session). To assess the physiological role of Sub P during movement acquisition, microinjections into the primary motor cortex (M1) contralateral to the trained paw were performed. When Sub P was injected before the first three sessions of a reaching training, effectiveness of motor learning became significantly increased. Injections at a time-point when rats already knew the task (i.e. training session ten and eleven) had no effect on reaching performance. Sub P injections did not influence the improvement of performance within a single training session, but retention of performance between sessions became strengthened at a very early stage (i.e. between baseline-training and first training session). Thus, Sub P facilitates motor learning in the very early phase of skill acquisition by supporting memory consolidation. In line with these findings, learning related expression of the precursor Tac1 occurs at early but not at later time-points during reaching training.

Impaired hand function after stroke is a major cause of long-term disability. We developed a novel paradigm that quantifies two critical aspects of hand function, strength, and independent control of fingers (individuation), and also removes any obligatory dependence between them. Hand recovery was tracked in 54 patients with hemiparesis over the first year after stroke. Most recovery of strength and individuation occurred within the first 3 mo. A novel time-invariant recovery function was identified: recovery of strength and individuation were tightly correlated up to a strength level of ~60% of estimated premorbid strength; beyond this threshold, strength improvement was not accompanied by further improvement in individuation. Any additional improvement in individuation was attributable instead to a second process that superimposed on the recovery function. We conclude that two separate systems are responsible for poststroke hand recovery: one contributes almost all of strength and some individuation; the other contributes additional individuation. NEW & NOTEWORTHY We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity., (Copyright © 2017 the American Physiological Society.)

Objective: Stroke survivors with motor deficits often have pyramidal tract atrophy caused by degeneration of corticospinal fibers. The authors hypothesized that the degree of atrophy correlates with severity of motor impairment in patients with chronic stroke and predicts the response to rehabilitation training., Methods: They performed a post hoc analysis of 42 hemiparetic patients (>6 months) who had been randomized to either 6 weeks of bilateral arm training with rhythmic auditory cueing (BATRAC) or dose-matched therapeutic exercise (DMTE). Arm function was measured using the Fugl-Meyer (FM) and modified Wolf Motor Function Test (WMFT). Structural MRI and diffusion tensor imaging (DTI) on the pontine level measured corticospinal tract (CST) atrophy by planimetric measurement of the mesencephalon (mesencephalic atrophy ratio) and fractional anisotropy (FA), respectively. Voxel-based lesion symptom mapping (VLSM) was used to determine the lesions associated with highest degrees of atrophy. The predictive value of CST atrophy for impairment and training response was analyzed., Results: CST atrophy predicted baseline motor arm function measured by the FM and WMFT. The authors found only a trend for the correlation with FA. No measure of atrophy predicted response to either BATRAC or DMTE. CST atrophy was higher with larger lesions and those that affected the CST. VLSM identified internal capsule lesions as being associated with highest CST atrophy., Conclusion: Larger lesions, internal capsule lesions, and those overlapping the pyramidal tract are associated with greater CST atrophy. CST atrophy explains in part the variability of baseline deficits but does not seem to predict the response to BATRAC or unilateral arm training on upper-extremity function.

Dopaminergic projections to primary sensorimotor cortex (SMC) have been described anatomically, but their functional role is unknown. The objective here was to characterize how dopamine modulates the somatosensory evoked potential (SEP) and its receptive field in SMC. SEPs were evoked by median and tibial nerve stimulation and recorded using thin-film multielectrode arrays implanted epidurally over the caudal sensorimotor cortex of rats. SEP amplitudes and receptive fields were measured before and after intracortical injection of a D1- (SCH 23390) or a D2-receptor antagonist (raclopride). Both increased maximum SEP amplitudes by 107.5% and 82.1%, respectively (p<0.01), while vehicle application had no effect (5.9% change). SEP latencies and receptive fields remained unchanged. Dopamine antagonists increase the excitability of sensorimotor cortex to afferent signals. Dopamine, therefore, expectedly reduces SMC excitability thereby improving sensory signal-to-noise ratio. Dopaminergic modulation may render SMC circuitry more effective in processing sensory information from different sources., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Aerobic treadmill exercise (T-EX) therapy has been shown to benefit walking and cardiorespiratory fitness in stroke survivors with chronic gait impairment even long after their stroke. The response, however, varies between individuals., Objective: The purpose of this post hoc analysis of 2 randomized controlled T-EX trials was to identify predictors for therapy response., Methods: In all, 52 participants received T-EX for 3 (Germany) or 6 (United States) months. Improvements in overground walking velocity (10 m/6-min walk) and fitness (peak VO(2)) were indicators of therapy response. Lesion location and volume were measured on T1-weighted magnetic resonance scans., Results: T-EX significantly improved gait and fitness, with gains in 10-m walk tests ranging between +113% and -25% and peak VO(2) between -12% and 88%. Baseline walking impairments or fitness deficits were not predictive of therapy response; 10-m walk velocity improved more in those with subcortical rather than cortical lesions and in patients with smaller lesions. Improvements in 6-minute walk velocity were greater in those with more recent strokes and left-sided lesions. No variable other than training intensity, which was different between trials, predicted fitness gains., Conclusions: Despite proving overall effectiveness, the response to T-EX varies markedly between individuals. Whereas intensity of aerobic training seems to be an important predictor of gains in cardiovascular fitness, lesion size and location as well as interval between stroke onset and therapy delivery likely affect therapy response. These findings may be used to guide the timing of training and identify subgroups of patients for whom training modalities could be optimized.

Functional imaging studies in humans and electrophysiological data in animals suggest that corticostriatal circuits undergo plastic modifications during motor skill learning. In motor cortex and hippocampus circuit plasticity can be prevented by protein synthesis inhibition (PSI) which can interfere with certain forms learning. Here, the hypothesis was tested that inducing PSI in the dorsal striatum by bilateral intrastriatal injection of anisomycin (ANI) in rats interferes with learning a precision forelimb reaching task. Injecting ANI shortly after training on days 1 and 2 during 4 days of daily practice (n = 14) led to a significant impairment of motor skill learning as compared with vehicle-injected controls (n = 15, P = 0.033). ANI did not affect the animals' motivation as measured by intertrial latencies. Also, ANI did not affect reaching performance once learning was completed and performance reached a plateau. These findings demonstrate that PSI in the dorsal striatum after training impairs the acquisition of a novel motor skill. The results support the notion that plasticity in basal ganglia circuits, mediated by protein synthesis, contributes to motor skill learning.

Preliminary evidence indicates that dopamine given by mouth facilitates the learning of motor skills and improves the recovery of movement after stroke. The mechanism of these phenomena is unknown. Here, we describe a mechanism by demonstrating in rat that dopaminergic terminals and receptors in primary motor cortex (M1) enable motor skill learning and enhance M1 synaptic plasticity. Elimination of dopaminergic terminals in M1 specifically impaired motor skill acquisition, which was restored upon DA substitution. Execution of a previously acquired skill was unaffected. Reversible blockade of M1 D1 and D2 receptors temporarily impaired skill acquisition but not execution, and reduced long-term potentiation (LTP) within M1, a form of synaptic plasticity critically involved in skill learning. These findings identify a behavioral and functional role of dopaminergic signaling in M1. DA in M1 optimizes the learning of a novel motor skill.

Assessments of somatosensory and motor cortical somatotopy in vivo can provide important information on sensorimotor physiology. Here, novel polyimide-based thin-film microelectrode arrays (72 contacts) implanted epidurally, were used for recording of somatosensory evoked potentials (SEPs) and somatosensory cortex somatotopic maps of the rat. The objective was to evaluate this method with respect to precision and reliability. SEPs and somatosensory maps were measured twice within one session and again after 8 days of rest. Additionally, motor cortex maps were acquired once to assess the spatial relationship between somatosensory and motor representations of fore- and hindlimb within one individual. Somatosensory maps were well reproduced within and between sessions. SEP amplitudes and latencies were highly reliable within one recording session (combined intraclass correlation 90.5%), but less so between sessions (21.0%). Somatosensory map geometry was stable within and between sessions. For the forelimb the somatosensory representation had a 30% overlap with the corresponding motor area. No significant overlap was found for the hindlimb. No evidence for cortical injury was found on histology (Nissl). Thin-film epidural electrode array technology enables a detailed assessment of sensorimotor cortex physiology in vivo and can be used in longitudinal designs enabling studies of learning and plasticity processes.

Learning a complex motor skill is associated with changes in motor cortex representations of trained body parts. It has been suggested that representation changes reflect the storage of a skill, i.e., the motor memory trace. If a reflection of the trace, such modifications should persist after training is stopped for as long as the skill is retained. The objective here was to test the persistence of learning-related changes in the representation of the forelimb of the rat after learning a reaching task using repeated epidural stimulation mapping of primary motor cortex. It is shown that the forelimb representations enlarge after 8 days of training (n=8) but contract while performing arm movements without learning (n=7, p=0.006); hindlimb representations remain unchanged. Enlargement correlated with learning success (r=0.82; p=0.012). Subsequently, after 8 days without training, representation size reverted to baseline while the motor skill was retained. Somatotopy remained unaltered by a second training phase in which performance did not improve further (n=5). These findings suggest that successful acquisition but not storage of a motor skill depends on cortical map changes. The motor memory trace in rats may require changes in motor cortex organization other than those detected by stimulation mapping.

Many motor rehabilitation therapies are based on principles of motor learning. Motor learning depends on preliminary knowledge of the trained and other (similar) skills. This study sought to investigate the influence of prior skill knowledge on re-learning of a precision reaching skill after a cortical lesion in rat. One group of animals recovered a previously known skill (skill training, followed by stroke and re-learning training, TST, n = 8). A second group learned the skill for the first time after stroke (ST, n = 6). A control group received prolonged training without stroke (n = 6). Unilateral partial motor cortex lesions were induced photothrombotically after identifying the forelimb representation using epidural stimulation mapping. In TST animals, re-learning after stroke was slower than learning before stroke (post hoc repeated measures ANOVA P = 0.039) and learning in the control group (P = 0.033). De novo learning after stroke (ST group) was not different from healthy learning. These findings show that skill learning can be performed if the motor cortex is partially lesioned; re-learning of a skill after stroke is slowed by prior knowledge of the skill. It remains to be tested in humans whether task novelty positively influences rehabilitation therapy.

Stimulation mapping of motor cortex is an important tool for assessing motor cortex physiology. Existing techniques include intracortical microstimulation (ICMS) which has high spatial resolution but damages cortical integrity by needle penetrations, and transcranial stimulation which is non-invasive but lacks focality and spatial resolution. A minimally invasive epidural microstimulation (EMS) technique using chronically implanted polyimide-based thin-film microelectrode arrays (72 contacts) was tested in rat motor cortex and compared to ICMS within individual animals. Results demonstrate reliable mapping with high reproducibility and validity with respect to ICMS. No histological evidence of cortical damage and the absence of motor deficits as determined by performance of a motor skill reaching task, demonstrate the safety of the method. EMS is specifically suitable for experiments integrating electrophysiology with behavioral and molecular biology techniques.