Safety and effects of a therapeutic 15 Hz rTMS protocol administered at different suprathreshold intensities in able-bodied individuals.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) remains a promising strategy for neurorehabilitation. The stimulation intensity (SI) influences the aftereffects observed. Here, we examined whether single sessions of a 15 Hz rTMS protocol, administered at suprathreshold SI, can be safely administered to able-bodied (AB) individuals. Six right-handed men were included in this pilot study. HF-rTMS was delivered over the right M1, in 10 trains of 75 biphasic stimuli at 15 Hz, at 105-120% of the individual resting motor threshold (RMT). To assess safety, electromyography (EMG) was monitored to control for signs of spread of excitation and brief EMG burst (BEB) after stimulation. Additionally, TMS side effects questionnaires and the numeric rating scale (NRS) were administered during each session. We assessed corticospinal excitability (CSE) and motor performance changes with measures of resting (rMEP) and active (aMEP) motor evoked potential and grip strength and box and blocks test (BBT) scores, respectively. Overall, the sessions were tolerated and feasible without any pain development. However, EMG analysis during 15 Hz rTMS administration revealed increased BEB frequency with SI. Statistical models revealed an increase of CSE at rest (rMEP) but not during active muscle contraction (aMEP). No linear relationship was observed between 15 Hz rTMS SI and rMEP increase. No significant changes were highlighted for motor performance measures. Although feasible and tolerable by the AB individuals tested, the results demonstrate that when administered at suprathreshold intensities (≥ 105% RMT) the 15 Hz rTMS protocol reveals signs of persistent excitation, suggesting that safety precautions and close monitoring of participants should be performed when testing such combinations of high-intensity and high-frequency stimulation protocols. The results also give insight into the nonlinear existent relationship between the SI and HF-rTMS effects on CSE.NEW & NOTEWORTHY The results of this pilot study show the effects of a therapeutically promising 15 Hz repetitive transcranial magnetic stimulation (rTMS) protocol, administered at different suprathreshold intensities in able-bodied individuals. Although tolerable and feasible with a neuromodulatory potential, 15 Hz rTMS might result in persistent excitability that needs to be closely monitored if administered at suprathreshold stimulation intensity. These results reaffirm the importance of feasibility studies, especially in translational animal-to-human research.

Graph-theoretical analysis of EEG functional connectivity during balance perturbation in traumatic brain injury: A pilot study.

Traumatic brain injury (TBI) often results in balance impairment, increasing the risk of falls, and the chances of further injuries. However, the underlying neural mechanisms of postural control after TBI are not well understood. To this end, we conducted a pilot study to explore the neural mechanisms of unpredictable balance perturbations in 17 chronic TBI participants and 15 matched healthy controls (HC) using the EEG, MRI, and diffusion tensor imaging (DTI) data. As quantitative measures of the functional integration and segregation of the brain networks during the postural task, we computed the global graph-theoretic network measures (global efficiency and modularity) of brain functional connectivity derived from source-space EEG in different frequency bands. We observed that the TBI group showed a lower balance performance as measured by the center of pressure displacement during the task, and the Berg Balance Scale (BBS). They also showed reduced brain activation and connectivity during the balance task. Furthermore, the decrease in brain network segregation in alpha-band from baseline to task was smaller in TBI than HC. The DTI findings revealed widespread structural damage. In terms of the neural correlates, we observed a distinct role played by different frequency bands: theta-band modularity during the task was negatively correlated with the BBS in the TBI group; lower beta-band network connectivity was associated with the reduction in white matter structural integrity. Our future studies will focus on how postural training will modulate the functional brain networks in TBI.

Training with Agency-Inspired Feedback from an Instrumented Glove to Improve Functional Grasp Performance.

Sensory feedback from wearables can be effective to learn better movement through enhanced information and engagement. Facilitating greater user cognition during movement practice is critical to accelerate gains in motor function during rehabilitation following brain or spinal cord trauma. This preliminary study presents an approach using an instrumented glove to leverage sense of agency, or perception of control, to provide training feedback for functional grasp. Seventeen able-bodied subjects underwent training and testing with a custom-built sensor glove prototype from our laboratory. The glove utilizes onboard force and flex sensors to provide inputs to an artificial neural network that predicts achievement of "secure" grasp. Onboard visual and audio feedback was provided during training with progressively shorter time delay to induce greater agency by intentional binding, or perceived compression in time between an action (grasp) and sensory consequence (feedback). After training, subjects demonstrated a significant reduction (p < 0.05) in movement pathlength and completion time for a functional task involving grasp-move-place of a small object. Future work will include a model-based algorithm to compute secure grasp, virtual reality immersion, and testing with clinical populations.

Ventral attention and motor network connectivity is relevant to functional impairment in spatial neglect after right brain stroke.

Emerging research suggests spatial neglect after right stroke is linked to dysfunctional attention and motor networks. Advanced functional connectivity analysis clarified brain network recovery, however we need to know how networks participate in adaptive motor performance. We need to verify network changes associated with validated functional measures and spatial-motor performance in spatial neglect, especially in patients with large brain lesions and significant disability. This study tested whether disability-relevant spatial neglect associates with different patterns of resting state functional connectivity between motor, dorsal and ventral attention networks (MN, DAN and VAN). Right stroke patients had spatial neglect (n = 8) or not (n = 10) on the Behavioural Inattention Test-conventional. Spatial neglect patients had weaker intranetwork VAN connectivity, and reduced internetwork connectivity between VAN and left frontal eye field (DAN), and between VAN and the left primary motor area (MN). These network impairments might explain the co-occurrence of attention and motor deficits in spatial neglect, and open a path to assessing functional connectivity in clinical trials of combined spatial retraining and motor rehabilitation after stroke.

Corticospinal excitability is enhanced after visuomotor adaptation and depends on learning rather than performance or error.

We used adaptation to high and low gains in a virtual reality setup of the hand to test competing hypotheses about the excitability changes that accompany motor learning. Excitability was assayed through changes in amplitude of motor evoked potentials (MEPs) in relevant hand muscles elicited with single-pulse transcranial magnetic stimulation (TMS). One hypothesis is that MEPs will either increase or decrease, directly reflecting the effect of low or high gain on motor output. The alternative hypothesis is that MEP changes are not sign dependent but rather serve as a marker of visuomotor learning, independent of performance or visual-to-motor mismatch (i.e., error). Subjects were required to make flexion movements of a virtual forefinger to visual targets. A gain of 1 meant that the excursions of their real finger and virtual finger matched. A gain of 0.25 ("low gain") indicated a 75% reduction in visual versus real finger displacement, a gain of 1.75 ("high gain") the opposite. MEP increases (>40%) were noted in the tonically activated task-relevant agonist muscle for both high- and low-gain perturbations after adaptation reached asymptote with kinematics matched to veridical levels. Conversely, only small changes in excitability occurred in a control task of pseudorandom gains that required adjustments to large errors but in which learning could not accumulate. We conclude that changes in corticospinal excitability are related to learning rather than performance or error.

EEG Based Cortico-Muscular Connectivity During Standing Early Post Stroke.

In this exploratory study we studied brain activation and corticomuscular connectivity during standing in healthy individuals and persons with stroke within 40 days of cerebrovascular accident (CVA). EEG and EMG data were acquired during standing and analysis showed a trend of higher EEG power (hyper activation) in the stroke group. Direct corticomuscular connectivity between sensorimotor cortices and contralateral lower extremity muscles showed lower connectivity between affected motor, premotor, and sensory cortices, and contralateral lower extremity peripheral muscles with moderate effect size. The preliminary data in this paper suggest re-organization in left sensorimotor cortex role in controlling contralateral lower extremity muscles during standing. Correlational analysis in stroke group within 40 days of CVA showed a relationship between higher corticomuscular connectivity and better scores on balance assessments.Clinical Relevance- This study evaluates corticomuscular connectivity during standing in healthy controls and individuals with subacute stroke (within 40 days of injury). Better understanding of cortical control of standing post stroke is important to improve strategies used in mobility rehabilitation.

Lower extremity robotic exoskeleton devices for overground ambulation recovery in acquired brain injury-A review.

Acquired brain injury (ABI) is a leading cause of ambulation deficits in the United States every year. ABI (stroke, traumatic brain injury and cerebral palsy) results in ambulation deficits with residual gait and balance deviations persisting even after 1 year. Current research is focused on evaluating the effect of robotic exoskeleton devices (RD) for overground gait and balance training. In order to understand the device effectiveness on neuroplasticity, it is important to understand RD effectiveness in the context of both downstream (functional, biomechanical and physiological) and upstream (cortical) metrics. The review identifies gaps in research areas and suggests recommendations for future research. We carefully delineate between the preliminary studies and randomized clinical trials in the interpretation of existing evidence. We present a comprehensive review of the clinical and pre-clinical research that evaluated therapeutic effects of RDs using various domains, diagnosis and stage of recovery.

Augmented feedback modes during functional grasp training with an intelligent glove and virtual reality for persons with traumatic brain injury.

Introduction: Physical therapy is crucial to rehabilitating hand function needed for activities of daily living after neurological traumas such as traumatic brain injury (TBI). Virtual reality (VR) can motivate participation in motor rehabilitation therapies. This study examines how multimodal feedback in VR to train grasp-and-place function will impact the neurological and motor responses in TBI participants (n = 7) compared to neurotypicals (n = 13). Methods: We newly incorporated VR with our existing intelligent glove system to seamlessly enhance the augmented visual and audio feedback to inform participants about grasp security. We then assessed how multimodal feedback (audio plus visual cues) impacted electroencephalography (EEG) power, grasp-and-place task performance (motion pathlength, completion time), and electromyography (EMG) measures. Results: After training with multimodal feedback, electroencephalography (EEG) alpha power significantly increased for TBI and neurotypical groups. However, only the TBI group demonstrated significantly improved performance or significant shifts in EMG activity. Discussion: These results suggest that the effectiveness of motor training with augmented sensory feedback will depend on the nature of the feedback and the presence of neurological dysfunction. Specifically, adding sensory cues may better consolidate early motor learning when neurological dysfunction is present. Computerized interfaces such as virtual reality offer a powerful platform to personalize rehabilitative training and improve functional outcomes based on neuropathology.

Intensity Modulated Exoskeleton Gait Training Post Stroke.

Stroke is a leading cause of long-term disability. While major advances have been made in early intervention for the treatment of patients post stroke, the majority of survivors have residual mobility challenges. Recovery of motor function is dependent on the interrelationship between dosing, intensity, and task specific practice applied during rehabilitation. Robotic exoskeleton (RE) based gait training utilizes progressive repetitive task-oriented movements to promote functional recovery. The purpose of this investigation was to demonstrate the utilization of intensity modulated exoskeleton gait training on functional outcomes and walking speed post stoke. Preliminary data is presented for individuals diagnosed with stroke who received RE gait training. The intensity modulated RE gait training was delivered by a physical therapist and participants trained at 75-85% of calculated max heart rates at each session, over 10 weeks (30 sessions). After 10 weeks of training participants increased walking speed (10 meter walk test) and functional measures (timed up and go, berg balance assessment, dynamic gait index and functional ambulation category). These preliminary results demonstrate the utilization of intensity modulated gait training for improved functional ambulation and motor recovery using a robotic exoskeleton overground gait training post stroke.Clinical Relevance- Preliminary data provides initial evidence for intensity modulated exoskeleton gait training as a therapeutic intervention post stroke. More research is needed to demonstrate the potential relationships between intensity based gait training, exoskeletons and improved functional ambulation in post stroke rehabilitation.

Robots integrated with virtual reality simulations for customized motor training in a person with upper extremity hemiparesis: a case study.

BACKGROUND AND PURPOSE: A majority of studies examining repetitive task practice facilitated by robots for the treatment of upper extremity paresis utilize standardized protocols applied to large groups. Others utilize interventions tailored to patients but do not describe the clinical decision-making process utilized to develop and modify interventions. This case study describes a robot-based intervention customized to match the goals and clinical presentation of person with upper extremity hemiparesis secondary to stroke. METHODS: The patient, P.M., was an 85-year-old man with left hemiparesis secondary to an intracerebral hemorrhage 5 years prior to examination. Outcomes were measured before and after a 1-month period of home therapy and after a 1-month robotic intervention. The intervention was designed to address specific impairments identified during his physical therapy examination. When necessary, activities were modified on the basis of response to the first week of treatment. OUTCOMES: P.M. trained in 12 sessions, using six virtually simulated activities. Modifications to original configurations of these activities resulted in performance improvements in five of these activities. P.M. demonstrated a 35-second improvement in Jebsen Test of Hand Function time and a 44-second improvement in Wolf Motor Function Test time subsequent to the robotic training intervention. Reaching kinematics, 24-hour activity measurement, and scores on the Hand and Activities of Daily Living scales of the Stroke Impact Scale all improved as well. DISCUSSION: A customized program of robotically facilitated rehabilitation was associated with short-term improvements in several measurements of upper extremity function in a patient with chronic hemiparesis.

Visuomotor gain distortion alters online motor performance and enhances primary motor cortex excitability in patients with stroke.

OBJECTIVES: Determine if ipsilesional primary motor cortex (M1) in stroke patients processes online visuomotor discordance in gain between finger movement and observed feedback in virtual reality (VR). MATERIALS AND METHODS: Chronic stroke patients flexed (N= 7) or extended (N= 1) their finger with real-time feedback of a virtual hand presented in VR. Virtual finger excursion was scaled by applying a low-gain (G(0.25) ), high-gain (G(1.75) ), or veridical (G(1.00) ) scaling factor to real-time data streaming from a sensor glove. Effects of visuomotor discordance were assessed through analysis of movement kinematics (joint excursion, movement smoothness, and angular velocity) and amplitude of motor evoked potentials (MEPs) elicited with transcranial magnetic stimulation applied to ipsilesional M1. Data were analyzed with a repeated-measures analysis of variance (significance set at 0.05). RESULTS: G(0.25) discordance (relative to veridical) leads to significantly larger joint excursion, online visuomotor correction evidenced by decreased trajectory smoothness, and significantly facilitated agonist MEPs. This effect could not be explained by potential differences in motor drive (background electromyographic) or by possible differences related to joint angle or angular velocity, as these variables remained invariant across conditions at the time of MEP assessment. M1 was not significantly facilitated in the G(1.75) condition. MEPs recorded in an adjacent muscle that was not involved in the task were unaffected by visual feedback in either discordance condition. These data suggest that the neuromodulatory effects of visuomotor discordance on M1 were relatively selective. CONCLUSIONS: Visuomotor discordance may be used to alter movement performance and augment M1 excitability in patients following stroke. Our data illustrate that visual feedback may be a robust way to selectively modulate M1 activity. These data may have important clinical implications for the development of future VR training protocols.

Stimulation Parameters Used During Repetitive Transcranial Magnetic Stimulation for Motor Recovery and Corticospinal Excitability Modulation in SCI: A Scoping Review.

There is a growing interest in non-invasive stimulation interventions as treatment strategies to improve functional outcomes and recovery after spinal cord injury (SCI). Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulatory intervention which has the potential to reinforce the residual spinal and supraspinal pathways and induce plasticity. Recent reviews have highlighted the therapeutic potential and the beneficial effects of rTMS on motor function, spasticity, and corticospinal excitability modulation in SCI individuals. For this scoping review, we focus on the stimulation parameters used in 20 rTMS protocols. We extracted the rTMS parameters from 16 published rTMS studies involving SCI individuals and were able to infer preliminary associations between specific parameters and the effects observed. Future investigations will need to consider timing, intervention duration and dosage (in terms of number of sessions and number of pulses) that may depend on the stage, the level, and the severity of the injury. There is a need for more real vs. sham rTMS studies, reporting similar designs with sufficient information for replication, to achieve a significant level of evidence regarding the use of rTMS in SCI.

EEG-Based Spectral Analysis Showing Brainwave Changes Related to Modulating Progressive Fatigue During a Prolonged Intermittent Motor Task.

Repeatedly performing a submaximal motor task for a prolonged period of time leads to muscle fatigue comprising a central and peripheral component, which demands a gradually increasing effort. However, the brain contribution to the enhancement of effort to cope with progressing fatigue lacks a complete understanding. The intermittent motor tasks (IMTs) closely resemble many activities of daily living (ADL), thus remaining physiologically relevant to study fatigue. The scope of this study is therefore to investigate the EEG-based brain activation patterns in healthy subjects performing IMT until self-perceived exhaustion. Fourteen participants (median age 51.5 years; age range 26-72 years; 6 males) repeated elbow flexion contractions at 40% maximum voluntary contraction by following visual cues displayed on an oscilloscope screen until subjective exhaustion. Each contraction lasted ≈5 s with a 2-s rest between trials. The force, EEG, and surface EMG (from elbow joint muscles) data were simultaneously collected. After preprocessing, we selected a subset of trials at the beginning, middle, and end of the study session representing brain activities germane to mild, moderate, and severe fatigue conditions, respectively, to compare and contrast the changes in the EEG time-frequency (TF) characteristics across the conditions. The outcome of channel- and source-level TF analyses reveals that the theta, alpha, and beta power spectral densities vary in proportion to fatigue levels in cortical motor areas. We observed a statistically significant change in the band-specific spectral power in relation to the graded fatigue from both the steady- and post-contraction EEG data. The findings would enhance our understanding on the etiology and physiology of voluntary motor-action-related fatigue and provide pointers to counteract the perception of muscle weakness and lack of motor endurance associated with ADL. The study outcome would help rationalize why certain patients experience exacerbated fatigue while carrying out mundane tasks, evaluate how clinical conditions such as neurological disorders and cancer treatment alter neural mechanisms underlying fatigue in future studies, and develop therapeutic strategies for restoring the patients' ability to participate in ADL by mitigating the central and muscle fatigue.

Corrigendum: EEG-based spectral analysis showing brainwave changes related to modulating progressive fatigue during a prolonged intermittent motor task.

[This corrects the article DOI: 10.3389/fnhum.2022.770053.].

High-Frequency rTMS Combined with Task-Specific Hand Motor Training Modulates Corticospinal Plasticity in Motor Complete Spinal Cord Injury: A case report.

Since its first use in spinal cord injury (SCI) in the early 2000s [1], high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) demonstrated a capacity to modulate corticospinal excitability (CSE) and motor performance. Studies focused on individuals with incomplete SCI. Here, we examined the feasibility of a 15-day therapeutic stimulation protocol combining HF-rTMS with task-specific motor training targeting the weaker hand in an individual with early chronic complete SCI. In this case report, we present evidence of progressive increase of CSE at rest and during muscle activation, and decreased cortical inhibition, associated with a trend toward improvement in pinch function of the weaker hand. These promising findings need to be confirmed in a larger population. Clinical Relevance- These preliminary results are promising and demonstrate the importance of a large number of training session repetitions to induce consistent changes relevant to the recovery after a complete SCI.

Corticomuscular Connectivity during Walking in Able Bodied and Individuals with Incomplete Spinal Cord Injury.

This exploratory study used EEG as mobile imaging method to study cortico-muscular connectivity (CMC) during walking in able-bodied individuals (AB) and individuals with spinal cord injury (iSCI), while walking with and without exoskeleton walking robot (EWR) assistance. We also explored change in CMC after intensive training using EWR assistance in iSCI. Results showed no different in CMC within the AB group during walking with and without robot assistance. However, before training the iSCI subjects showed lower CMC during walking with robot assistance. The intensive 40 hours of walking training with EWR improved the walking function in iSCI participants allowing them to walk with robot assistance set to lower assistance level. This decrease in assistance level and improvement in walking function correlated with increase in CMC, reducing the difference in CMC during walking with and without EWR assistance. The findings suggest that high level of robot assistance and low walking function in iSCI correlates with weaker connectivity between primary motor cortices and lower extremity muscles. Further research is needed to better understand the importance of intention and cortical involvement in training of walking function using EWRs. Clinical Relevance - This study provides innovative data on CMC during walking and how it changes with EWR assistance and with training. This research is important to the clinical field to provide recommendations of how training of walking function can be delivered to maximize cortical engagement and improve rehabilitation outcomes.

EEG Based Resting State Connectivity Changes in the Motor Cortex Associated with Upper Limb Motor Recovery in the Subacute Period Post-Stroke.

Stroke is a heterogeneous condition that would benefit from valid biomarkers of recovery for research and in the clinic. We evaluated the change in resting state connectivity (RSC) via electroencephalography (EEG) in motor areas, as well as motor recovery of the affected upper limb, in the subacute phase post-stroke. Fifteen participants who had sustained a subcortical stroke were included in this study. The group made significant gains in upper limb impairment as measured by the Upper Extremity Fugl-Meyer Assessment (UEFMA) from baseline to four months post-stroke (24.78 (SD 5.4)). During this time, there was a significant increase in RSC in the beta band from contralesional M1 to ipsilesional M1. We propose that this change in RSC may have contributed to the motor recovery seen in this group. Clinical Relevance- This study evaluates resting state connectivity measured via EEG as a neural biomarker of recovery post-stroke. Biomarkers can help clinicians understand the potential for recovery after stroke and thus help them to establish therapy goals and determine treatment plans.

Robotically facilitated virtual rehabilitation of arm transport integrated with finger movement in persons with hemiparesis.

BACKGROUND: Recovery of upper extremity function is particularly recalcitrant to successful rehabilitation. Robotic-assisted arm training devices integrated with virtual targets or complex virtual reality gaming simulations are being developed to deal with this problem. Neural control mechanisms indicate that reaching and hand-object manipulation are interdependent, suggesting that training on tasks requiring coordinated effort of both the upper arm and hand may be a more effective method for improving recovery of real world function. However, most robotic therapies have focused on training the proximal, rather than distal effectors of the upper extremity. This paper describes the effects of robotically-assisted, integrated upper extremity training. METHODS: Twelve subjects post-stroke were trained for eight days on four upper extremity gaming simulations using adaptive robots during 2-3 hour sessions. RESULTS: The subjects demonstrated improved proximal stability, smoothness and efficiency of the movement path. This was in concert with improvement in the distal kinematic measures of finger individuation and improved speed. Importantly, these changes were accompanied by a robust 16-second decrease in overall time in the Wolf Motor Function Test and a 24-second decrease in the Jebsen Test of Hand Function. CONCLUSIONS: Complex gaming simulations interfaced with adaptive robots requiring integrated control of shoulder, elbow, forearm, wrist and finger movements appear to have a substantial effect on improving hemiparetic hand function. We believe that the magnitude of the changes and the stability of the patient's function prior to training, along with maintenance of several aspects of the gains demonstrated at retention make a compelling argument for this approach to training.

Relationship between DTI Brain Connectivity and Functional Performance in Individuals with Traumatic Brain Injury.

this study examines the relationship between brain structural connectivity, and physical and cognitive performances in individuals with Traumatic Brain Injury (TBI). Nine moderate to severe TBI participants were included in the study, and regression analysis was performed to explore if DTI connectivity of 16 regions of interest can predict individuals' : 1) Maximum Voluntary Contraction (MVC), 2) time component of Wolf Motor Function Test (WMFT), 3) Reaction Time (RT) during bimanual force matching task, 4) Performance Error Measurement (PEM) during bimanual force matching task, and 5) cognitive assessment of task switching using Trail Making (TM) test. Results showed that slower WMFT, PEM, and TM can be predicted by weaker cerebrospinal tract connectivity. Higher Caudate connectivity predicted higher WMFT and slower RT, and higher right Cingulum predicted faster TM. Current results suggest that measures of cognitive-motor interference may be better indicators of functional performance than single cognitive and motor performance tests.

Hand Focused Upper Extremity Rehabilitation in the Subacute Phase Post-stroke Using Interactive Virtual Environments.

Introduction: Innovative motor therapies have attempted to reduce upper extremity impairment after stroke but have not made substantial improvement as over 50% of people post-stroke continue to have sensorimotor deficits affecting their self-care and participation in daily activities. Intervention studies have focused on the role of increased dosing, however recent studies have indicated that timing of rehabilitation interventions may be as important as dosing and importantly, that dosing and timing interact in mediating effectiveness. This study is designed to empirically test dosing and timing. Methods and Analysis: In this single-blinded, interventional study, subjects will be stratified on two dimensions, impairment level (Fugl-Meyer Upper Extremity Assessment (FM) and presence or absence of Motor Evoked Potentials (MEPs) as follows; (1) Severe, FM score 10-19, MEP+, (2) Severe, FM score 10-19, MEP-, (3) Moderate, FM score 20-49, MEP+, (4) Moderate, FM score 20-49, MEP-. Subjects not eligible for TMS will be assigned to either group 2 (if severe) or group 3 (if moderate). Stratified block randomization will then be used to achieve a balanced assignment. Early Robotic/VR Therapy (EVR) experimental group will receive in-patient usual care therapy plus an extra 10 h of intensive upper extremity therapy focusing on the hand using robotically facilitated rehabilitation interventions presented in virtual environments and initiated 5-30 days post-stroke. Delayed Robotic/VR Therapy (DVR) experimental group will receive the same intervention but initiated 30-60 days post-stroke. Dose-matched usual care group (DMUC) will receive an extra 10 h of usual care initiated 5-30 days post-stroke. Usual Care Group (UC) will receive the usual amount of physical/occupational therapy. Outcomes: There are clinical, neurophysiological, and kinematic/kinetic measures, plus measures of daily arm use and quality of life. Primary outcome is the Action Research Arm Test (ARAT) measured at 4 months post-stroke. Discussion: Outcome measures will be assessed to determine whether there is an early time period in which rehabilitation will be most effective, and whether there is a difference in the recapture of premorbid patterns of movement vs. the development of an efficient, but compensatory movement strategy. Ethical Considerations: The IRBs of New Jersey Institute of Technology, Rutgers University, Northeastern University, and Kessler Foundation reviewed and approved all study protocols. Study was registered in https://ClinicalTrials.gov (NCT03569059) prior to recruitment. Dissemination will include submission to peer-reviewed journals and professional presentations.