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The Critical Periods After Stroke Study (CPASS, n = 72) showed that, compared to controls, an additional 20 hours of intensive upper limb therapy led to variable gains on the Action Research Arm Test depending on when therapy was started post-stroke: the subacute group (2-3 months) improved beyond the minimal clinically important difference and the acute group (0-1 month) showed smaller but statistically significant improvement, but the chronic group (6-9 months) did not demonstrate improvement that reached significance. Some have misinterpreted CPASS results to indicate that all inpatient motor therapy should be shifted to outpatient therapy delivered 2 to 3 months post-stroke. Instead, however, CPASS argues for a large dose of motor therapy delivered continuously and cumulatively during the acute and subacute phases. When interpreting trials like CPASS, one must consider the substantial dose of early usual customary care (UCC) motor therapy that all participants received. CPASS participants averaged 27.9 hours of UCC occupational therapy (OT) during the first 2 months and 9.8 hours of UCC OT during the third and fourth months post-stroke. Any recovery experienced would therefore result not just from CPASS intensive motor therapy but the combined effects of experimental therapy plus UCC. Statistical limitations also did not allow direct comparisons of the acute and subacute group outcomes in CPASS. Instead of shifting inpatient therapy hours to the subacute phase, CPASS argues for preserving inpatient UCC. We also recommend conducting multi-site dosing trials to determine whether additional intensive motor therapy delivered in the first 2 to 3 months following inpatient rehabilitation can further improve outcomes.

Bimanual coordination is an essential component of human movement. Cooperative bimanual reaching tasks are widely used to assess the optimal control of goal-directed reaching. However, little is known about the neuromuscular mechanisms governing these tasks. Twelve healthy, right-handed participants performed a bimanual reaching task in a three-dimensional virtual reality environment. They controlled a shared cursor, located at the midpoint between the hands, and reached targets located at 80% of full arm extension. Following a baseline of normal reaches, we placed a wrist weight on one arm and measured the change in coordination. Relative contribution (RC) was computed as the displacement of the right hand divided by the sum of displacements of both hands. We used surface electromyography placed over the anterior deltoid and biceps brachii to compute muscle contribution (MC) from root mean squared muscle activity data. We found RC was no different than 50% during baseline, indicating participants reached equal displacements when no weights were applied. Participants systematically altered limb coordination in response to altered limb dynamics. RC increased by 0.91% and MC decreased by 5.3% relative to baseline when the weight was applied to the left arm; RC decreased by 0.94% and MC increased by 6.3% when the weight was applied to the right arm. Participants adopted an optimal control strategy that attempted to minimize both kinematic and muscular asymmetries between limbs. What emerged was a trade-off between these two parameters, and we propose this trade-off as a potential neuromuscular mechanism of cooperative bimanual reaching. NEW & NOTEWORTHY This study is the first to propose a trade-off between kinematic and dynamic control parameters governing goal-directed reaching. We propose a straightforward tool to assess this trade-off without the need for computational modeling. The technologies and techniques developed in this study are discussed in the context of upper extremity rehabilitation.

Introduction: Stroke induces changes in plasma microRNA (miRNA) expression in the first 24hrs post-injury, but few have characterized miRNA expression during the early recovery phase. Hypothesis: We hypothesized that plasma miRNA expression would evolve over the first month post-stroke with fewer significantly altered miRNAs over time as inflammation and edema resolve. Methods: Longitudinal samples were collected 5, 15, and 30 days post-stroke from 2 studies (BIOREC and MORSE, n=55 combined at each time point) and compared to controls matched for age, sex, race and cardiovascular comorbidities. Stroke samples collected on average around day 15 from a second study (CPASS, n=48) were also compared to matched controls and used as a validation cohort. MiRNA expression was determined with OpenArray qRT-PCR quantifying 758 miRNAs. Significant miRNAs had a corrected p-value less than 0.05 and fold-change greater than |1.5|. Results: Eight miRNAs remained significantly altered across all 3 time points in the discovery cohort and in the day 15 validation cohort (decreased expression compared to controls: miR-101-3p, miR-107, miR-16-2-3p, miR-19a-3p, miR-19b-3p, and miR-26b-5p; increased expression: miRNA-199a-3p and miR-652-3p). The number of significant miRNAs more than doubled from post-stroke day 5 to days 15 and 30 (19, 53, and 45 miRNAs respectively in BIOREC/MORSE, 49 miRNAs at day 15 in CPASS). At day 5 most significant miRNAs (14/19) showed decreased expression compared to controls whereas by day 30 most demonstrated increased expression (36/45). Many of the significant miRNAs, including miR-107 and miR-652-3p, and many others at days 15 and 30 were enriched in brain or CSF in prior studies. Conclusions: While several miRNAs show significant change in expression consistently from 5 to 30 days post-stroke, there is also an expansion of significant miRNAs at days 15 and 30. This expansion includes many miRNAs enriched in brain or CSF and could represent a shift from inflammation to neural repair processes, but this requires further study.

The mature human brain is lateralized for language, with the left hemisphere (LH) primarily responsible for sentence processing and the right hemisphere (RH) primarily responsible for processing suprasegmental aspects of language such as vocal emotion. However, it has long been hypothesized that in early life there is plasticity for language, allowing young children to acquire language in other cortical regions when LH areas are damaged. If true, what are the constraints on functional reorganization? Which areas of the brain can acquire language, and what happens to the functions these regions ordinarily perform? We address these questions by examining long-term outcomes in adolescents and young adults who, as infants, had a perinatal arterial ischemic stroke to the LH areas ordinarily subserving sentence processing. We compared them with their healthy age-matched siblings. All participants were tested on a battery of behavioral and functional imaging tasks. While stroke participants were impaired in some nonlinguistic cognitive abilities, their processing of sentences and of vocal emotion was normal and equal to that of their healthy siblings. In almost all, these abilities have both developed in the healthy RH. Our results provide insights into the remarkable ability of the young brain to reorganize language. Reorganization is highly constrained, with sentence processing almost always in the RH frontotemporal regions homotopic to their location in the healthy brain. This activation is somewhat segregated from RH emotion processing, suggesting that the two functions perform best when each has its own neural territory.

Background and Purpose Brain stimulation is an adjuvant strategy to promote rehabilitation after stroke. Here, we evaluated the influence of inclusion/exclusion criteria on enrollment in a transcranial direct current stimulation (tDCS) trial in the context of a racially/ethnically diverse acute stroke service at University of Texas Southwestern (UTSW). Methods 3124 (59.7 ± 14.5 years) racially/ethnically diverse (38.4% non-Hispanic white, (W), Hispanic (H) 22%, African American (AA) 33.5%, Asian (A) 2.3%) patients were screened in the acute stroke service at UTSW. Demographics, stroke characteristics, and reasons for exclusion were recorded prospectively. Results 2327 (74.5%) patients had a verified stroke. Only 44 of them (1.9%) were eligible. Causes for exclusion included in order of importance: (1) magnitude of upper extremity (UE) motor impairment, (2) prior strokes (s), (3) hemorrhagic stroke, (4) psychiatric condition or inability to follow instructions, and (5) old age, of these (2) and (4) were more common in AA patients but not in other minorities. 31 of the 44 eligible individuals were enrolled (W 1.68%, H 1.37%, AA .77%, A 3.774%). 90.5% of verified stroke patients did not exhibit contraindications for stimulation. Conclusions 3 main conclusions emerged: (a) The main limitations for inclusion in brain stimulation trials of motor recovery were magnitude of UE motor impairments and stroke lesion characteristics, (b) most stroke patients could be stimulated with tDCS without safety concerns and (c) carefully tailored inclusion criteria could increase diversity in enrollment. Clinical Trial Registration-URL: http://clinicaltrials.gov . Unique identifier: NCT01007136.

Individuals with stroke show distinct differences in hand function impairment when the shoulder is in adduction, within the workspace compared to when the shoulder is abducted, away from the body. To better understand how shoulder position affects hand control, we tested the corticomotor excitability and intracortical control of intrinsic and extrinsic hand muscles important for grasp in twelve healthy individuals. Motor evoked potentials (MEP) using single and paired-pulse transcranial magnetic stimulation were elicited in extensor digitorum communis (EDC), flexor digitorum superficialis (FDS), first dorsal interosseous (FDI), and abductor pollicis brevis (APB). The shoulder was fully supported in horizontal adduction (ADD) or abduction (ABD). Separate mixed-effect models were fit to the MEP parameters using shoulder position (or upper-extremity [UE] side) as fixed and participants as random effects. In the non-dominant UE, EDC showed significantly greater MEPs in shoulder ABD than ADD. In contrast, the dominant side EDC showed significantly greater MEPs in ADD compared to ABD; %facilitation of EDC on dominant side showed significant stimulus intensity x position interaction, EDC excitability was significantly greater in ADD at 150% of the resting threshold. Intrinsic hand muscles of the dominant UE received significantly more intracortical inhibition (SICI) when the shoulder was in ADD compared to ABD; there was no position-dependent modulation of SICI on the non-dominant side. Our findings suggest that these resting-state changes in hand muscle excitabilities reflect the natural statistics of UE movements, which in turn may arise from as well as shape the nature of shoulder-hand coupling underlying UE behaviors.

Accurately recognizing and responding to the emotions of others is essential for proper social communication and helps bind strong relationships that are particularly important for stroke survivors. Emotion recognition typically engages cortical areas that are predominantly right-lateralized including superior temporal and inferior frontal gyri - regions frequently impacted by right-hemisphere stroke. Since prior work already links right-hemisphere stroke to deficits in emotion recognition, this research aims to extend these findings to determine whether impaired emotion recognition after right-hemisphere stroke is associated with worse social well-being outcomes. Eighteen right-hemisphere stroke patients (≥6 months post-stroke) and 21 neurologically healthy controls completed a multimodal emotion recognition test (Geneva Emotion Recognition Test - Short) and reported engagement in social/non-social activities and levels of social support. Right-hemisphere stroke was associated with worse emotion recognition accuracy, though not all patients exhibited impairment. In line with hypotheses, emotion recognition impairments were associated with greater loss of social activities after stroke, an effect that could not be attributed to stroke severity or loss of non-social activities. Impairments were also linked to reduced patient-reported social support. Results implicate emotion recognition difficulties as a potential antecedent of social withdrawal after stroke and warrant future research to test emotion recognition training post-stroke.

Background Wrist-worn accelerometry provides objective monitoring of upper-extremity functional use, such as reaching tasks, but also detects nonfunctional movements, leading to ambiguity in monitoring results. Objective Compare machine learning algorithms with standard methods (counts ratio) to improve accuracy in detecting functional activity. Methods Healthy controls and individuals with stroke performed unstructured tasks in a simulated community environment (Test duration = 26 ± 8 minutes) while accelerometry and video were synchronously recorded. Human annotators scored each frame of the video as being functional or nonfunctional activity, providing ground truth. Several machine learning algorithms were developed to separate functional from nonfunctional activity in the accelerometer data. We also calculated the counts ratio, which uses a thresholding scheme to calculate the duration of activity in the paretic limb normalized by the less-affected limb. Results The counts ratio was not significantly correlated with ground truth and had large errors ( r = 0.48; P = .16; average error = 52.7%) because of high levels of nonfunctional movement in the paretic limb. Counts did not increase with increased functional movement. The best-performing intrasubject machine learning algorithm had an accuracy of 92.6% in the paretic limb of stroke patients, and the correlation with ground truth was r = 0.99 ( P < .001; average error = 3.9%). The best intersubject model had an accuracy of 74.2% and a correlation of r =0.81 ( P = .005; average error = 5.2%) with ground truth. Conclusions In our sample, the counts ratio did not accurately reflect functional activity. Machine learning algorithms were more accurate, and future work should focus on the development of a clinical tool.

Significance Two types of evidence suggest different pictures of how language is represented in the brain during development. Studies of the anatomy, physiology, and fMRI activation of the two hemispheres show that language is lateralized to the left hemisphere from birth. In contrast, damage to the left versus right hemisphere in young children is equally likely to result in language impairment, suggesting that language is bilaterally represented in early development. The present study resolves this paradox by examining fMRI language activation in different ways. While group averages show LH lateralization throughout development, young children show RH language activation that declines systematically with age. Most important, this RH activation in children represents a possible mechanism for explaining language recovery following early stroke., We have long known that language is lateralized to the left hemisphere (LH) in most neurologically healthy adults. In contrast, findings on lateralization of function during development are more complex. As in adults, anatomical, electrophysiological, and neuroimaging studies in infants and children indicate LH lateralization for language. However, in very young children, lesions to either hemisphere are equally likely to result in language deficits, suggesting that language is distributed symmetrically early in life. We address this apparent contradiction by examining patterns of functional MRI (fMRI) language activation in children (ages 4 through 13) and adults (ages 18 through 29). In contrast to previous studies, we focus not on lateralization per se but rather on patterns of left-hemisphere (LH) and right-hemisphere (RH) activation across individual participants over age. Our analyses show significant activation not only in the LH language network but also in their RH homologs in all of the youngest children (ages 4 through 6). The proportion of participants showing significant RH activation decreases over age, with over 60% of adults lacking any significant RH activation. A whole-brain correlation analysis revealed an age-related decrease in language activation only in the RH homolog of Broca’s area. This correlation was independent of task difficulty. We conclude that, while language is left-lateralized throughout life, the RH contribution to language processing is also strong early in life and decreases through childhood. Importantly, this early RH language activation may represent a developmental mechanism for recovery following early LH injury.

Objective Patients show substantial differences in response to rehabilitation therapy after stroke. We hypothesized that specific genetic profiles might explain some of this variance and, secondarily, that genetic factors are related to cerebral atrophy post-stroke. Methods The phase 3 ICARE study examined response to motor rehabilitation therapies. In 216 ICARE enrollees, DNA was analyzed for presence of the BDNF val66met and the ApoE ε4 polymorphism. The relationship of polymorphism status to 12-month change in motor status (Wolf Motor Function Test, WMFT) was examined. Neuroimaging data were also evaluated (n=127). Results Subjects were 61±13 years old (mean±SD) and enrolled 43±22 days post-stroke; 19.7% were BDNF val66met carriers and 29.8% ApoE ε4 carriers. Carrier status for each polymorphism was not associated with WMFT, either at baseline or over 12 months of follow-up. Neuroimaging, acquired 5±11 days post-stroke, showed that BDNF val66met polymorphism carriers had a 1.34-greater degree of cerebral atrophy compared to non-carriers (P=.01). Post hoc analysis found that age of stroke onset was 4.6 years younger in subjects with the ApoE ε4 polymorphism (P=.02). Conclusion Neither the val66met BDNF nor ApoE ε4 polymorphism explained inter-subject differences in response to rehabilitation therapy. The BDNF val66met polymorphism was associated with cerebral atrophy at baseline, echoing findings in healthy subjects, and suggesting an endophenotype. The ApoE ε4 polymorphism was associated with younger age at stroke onset, echoing findings in Alzheimer’s disease and suggesting a common biology. Genetic associations provide insights useful to understanding the biology of outcomes after stroke.

Significance Restoration of postinjury brain function is a signal neuroscience challenge. Animal models of stroke recovery demonstrate time-limited windows of heightened motor recovery, similar to developmental neuroplasticity. However, no equivalent windows have been demonstrated in humans. We report a randomized controlled trial applying essential elements of animal motor training paradigms to humans, to determine the existence of an analogous sensitive period in adults. We found a similar sensitive or optimal period 60 to 90 d after stroke, with lesser effects ≤30 d and no effect 6 mo or later after stroke. These findings prospectively demonstrated the existence of a sensitive period in adult humans. We urge the provision of more intensive motor rehabilitation within 60 to 90 d after stroke onset., Restoration of human brain function after injury is a signal challenge for translational neuroscience. Rodent stroke recovery studies identify an optimal or sensitive period for intensive motor training after stroke: near-full recovery is attained if task-specific motor training occurs during this sensitive window. We extended these findings to adult humans with stroke in a randomized controlled trial applying the essential elements of rodent motor training paradigms to humans. Stroke patients were adaptively randomized to begin 20 extra hours of self-selected, task-specific motor therapy at ≤30 d (acute), 2 to 3 mo (subacute), or ≥6 mo (chronic) after stroke, compared with controls receiving standard motor rehabilitation. Upper extremity (UE) impairment assessed by the Action Research Arm Test (ARAT) was measured at up to five time points. The primary outcome measure was ARAT recovery over 1 y after stroke. By 1 y we found significantly increased UE motor function in the subacute group compared with controls (ARAT difference = +6.87 ± 2.63, P = 0.009). The acute group compared with controls showed smaller but significant improvement (ARAT difference = +5.25 ± 2.59 points, P = 0.043). The chronic group showed no significant improvement compared with controls (ARAT = +2.41 ± 2.25, P = 0.29). Thus task-specific motor intervention was most effective within the first 2 to 3 mo after stroke. The similarity to rodent model treatment outcomes suggests that other rodent findings may be translatable to human brain recovery. These results provide empirical evidence of a sensitive period for motor recovery in humans.

Background. As stroke survival improves, there is an increasing need for effective, low-cost programs to reduce deconditioning and improve mobility. Objective. To conduct a phase II trial examining whether the community-based Italian Adaptive Physical Activity exercise program for stroke survivors (APA-Stroke) is safe, effective, and feasible in the United States. Methods. In this single-blind, randomized controlled trial, 76 stroke survivors with mild to moderate hemiparesis >6 months were randomized to either APA-Stroke (N = 43) or Sittercise (N = 33). APA-Stroke is a progressive group exercise regimen tailored to hemiparesis that includes walking, strength, and balance training. Sittercise, a seated, nonprogressive aerobic upper body general exercise program, served as the control. Both interventions were 1 hour, 3 times weekly, in 5 community locations, supervised by exercise instructors. Results. A total of 76 participants aged 63.9 ± 1.2 years, mean months poststroke 61.8 ± 9.3, were included. There were no serious adverse events; completion rates were 58% for APA-Stroke, 70% for Sittercise. APA-Stroke participants improved significantly in walking speed. Sample size was inadequate to demonstrate significant between-group differences. Financial and logistical feasibility of the program has been demonstrated. Ongoing APA classes have been offered to >200 participants in county Senior Centers since study completion. Conclusion. APA-Stroke shows great promise as a low-cost, feasible intervention. It significantly increased walking speed. Safety and feasibility in the US context are demonstrated. A pivotal clinical trial is required to determine whether APA-Stroke should be considered standard of care.

Domain-specific endpoints are assessments that correspond to the output of individual neural systems and are useful for capturing treatment effects on specific behaviors. By contrast, global endpoints combine several attributes into a single score and are useful for capturing broad treatment effects in a summary way. While global endpoints have become the de facto mechanism required to define benefit in stroke trials, they also have important limitations, some of which might be addressed by simultaneously measuring domain-specific endpoints. Substantial opportunity remains to identify quantifiable patient benefit that would otherwise not be captured by global endpoints. Potential advantages of incorporating domain-specific endpoints in acute stroke trials are discussed, such as increased granularity of measurement, improved understanding of how therapies affect the brain between acute treatment and day 90, and optimized therapeutic translation. Potential disadvantages are also considered, including time and cost of administering domain-specific endpoints, as well as statistical implications. Domain-specific endpoints and global endpoints are not mutually exclusive, and both capture clinical benefits to patients. Incorporating a broader set of outcome assessments in stroke trials, including both global and domain-specific endpoints, is warranted.

Objective To determine the extent to which estimates of sample and effect size in stroke rehabilitation trials can be affected by simple summation of ordinal Upper Extremity Fugl-Meyer (UEFM) items compared with a Rasch-rescaled UEFM. Design Rasch analysis of Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) phase III trial data, comparing 3 upper extremity (UE) motor treatments in stroke survivors enrolled 45.8±22.4 days poststroke. Participants underwent a structured UE motor training known as the Accelerated Skill Acquisition Program, usual and customary care, or dose-equivalent care. UEFM data from baseline, postintervention, and 6 and 12 months later were included for analysis. Setting Outpatient stroke rehabilitation. Participants ICARE participants (N=361). Interventions Not applicable. Main Outcome Measures Item difficulties, person abilities, and sample size. Results Because of their ordinality, summed raw UEFM scores measured motor impairment inconsistently across different ranges of stroke severity relative to the rescaled UEFM. In the full ICARE sample, raw UEFM understated scores relative to the rescaled UEFM by 7.4 points for the most severely impaired, but overstated scores by up to 8.4 points toward the ceiling. As a result, 50.9% of all UEFM observations showed a residual error greater than 10% of the total UEFM score. Relative to the raw scores, the rescaled UEFM improved the effect size of change in motor impairment between baseline and 1 year (d=0.35). For a hypothetical 3-arm trial resembling ICARE, UEFM rescaling reduced the required sample size by 32% (n=108) compared with raw UEFM (n=159). Conclusions In UE rehabilitation trials, a rescaled UEFM potentially decreases sample size by one-third, decreasing costs, duration, and the number of subjects exposed to experimental risks. This benefit is obtained through increased measurement efficiency. Reductions in ceiling effects are also possible. These findings apply to ICARE-like trials. Confirmatory validation in another phase III trial is needed.

Author(s): Edwardson, Matthew A; Zhong, Xiaogang; Fiandaca, Massimo S; Federoff, Howard J; Cheema, Amrita K; Dromerick, Alexander W | Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BackgroundAnimal models of brain recovery identify the first days after lesioning as a time of great flux in sensorimotor function and physiology; these findings have implications for human stroke recovery. After rodent motor system lesioning, daily skill training in the less affected forelimb reduces skill acquisition in the more affected forelimb. We asked whether spontaneous human motor behaviors of the less affected upper extremity (UE) early after stroke resemble the animal training model, with the potential to suppress clinical recovery.MethodsThis prospective observational study used a convenience sample of patients ResultsAccelerometry indicated total paretic UE movement was reduced compared to controls, primarily due to a 44% reduction of bilateral UE use. Unilateral paretic movement was unchanged. Movement shifted to unilateral use of the nonparetic UE, which increased by 77%. Low correlations between movement time and motor performance prompted an exploratory factor analysis (EFA) revealing a 2-component solution; motor performance tests load on one component (motor performance) whereas accelerometry-derived variables load on a second non-orthogonal component (quantity of movement).ConclusionsEarly after stroke, spontaneous overall UE movement is reduced, and movement shifts to unilateral use of the nonparetic UE. Thus, spontaneously-arising UE motor behaviors early after stroke are potential substrates for two mechanisms associated with poorer motor outcomes in animal models: learned non-use and inhibition of motor recovery through training of the nonparetic side. Accurate UE motor assessment requires two independent constructs: motor performance and quantity of movement. These findings provide opportunities and measurement methods for studies to develop new behaviorally-based stroke recovery treatments that begin early after onset.

Background. Severe poststroke arm impairment is associated with greater activation of the nonlesioned hemisphere during movement of the affected arm. The circumstances under which this activation may be adaptive or maladaptive remain unclear. Objective. To identify the functional relevance of key lesioned and nonlesioned hemisphere motor areas to reaching performance in patients with mild versus severe arm impairment. Methods. A total of 20 participants with chronic stroke performed a reaching response time task with their affected arm. During the reaction time period, a transient magnetic stimulus was applied over the primary (M1) or dorsal premotor cortex (PMd) of either hemisphere, and the effect of the perturbation on movement time (MT) was calculated. Results. For perturbation of the nonlesioned hemisphere, there was a significant interaction effect of Site of perturbation (PMd vs M1) by Group (mild vs severe; P < .001). Perturbation of PMd had a greater effect on MT in the severe versus the mild group. This effect was not observed with perturbation of M1. For perturbation of the lesioned hemisphere, there was a main effect of site of perturbation ( P < .05), with perturbation of M1 having a greater effect on MT than PMd. Conclusions. These results demonstrate that, in the context of reaching movements, the role of the nonlesioned hemisphere depends on both impairment severity and the specific site that is targeted. A deeper understanding of these individual-, task-, and site-specific factors is essential for advancing the potential usefulness of neuromodulation to enhance poststroke motor recovery.

Background. Task-oriented therapies have been developed to address significant upper extremity disability that persists after stroke. Yet, the extent of and approach to rehabilitation and recovery remains unsatisfactory to many. Objective. To compare a skill-directed investigational intervention with usual care treatment for body functions and structures, activities, participation, and quality of life outcomes. Methods. On average, 46 days poststroke, 361 patients were randomized to 1 of 3 outpatient therapy groups: a patient-centered Accelerated Skill Acquisition Program (ASAP), dose-equivalent usual occupational therapy (DEUCC), or usual therapy (UCC). Outcomes were taken at baseline, posttreatment, 6 months, and 1 year after randomization. Longitudinal mixed effect models compared group differences in poststroke improvement during treatment and follow-up phases. Results. Across all groups, most improvement occurred during the treatment phase, followed by change more slowly during follow-up. Compared with DEUCC and UCC, ASAP group gains were greater during treatment for Stroke Impact Scale Hand, Strength, Mobility, Physical Function, and Participation scores, self-efficacy, perceived health, reintegration, patient-centeredness, and quality of life outcomes. ASAP participants reported higher Motor Activity Log–28 Quality of Movement than UCC posttreatment and perceived greater study-related improvements in quality of life. By end of study, all groups reached similar levels with only limited group differences. Conclusions. Customized task-oriented training can be implemented to accelerate gains across a full spectrum of patient-reported outcomes. While group differences for most outcomes disappeared at 1 year, ASAP participants achieved these outcomes on average 8 months earlier (ClinicalTrials.gov: Interdisciplinary Comprehensive Arm Rehabilitation Evaluation [ICARE] Stroke Initiative, at www.ClinicalTrials.gov/ClinicalTrials.gov . Identifier: NCT00871715).

Stroke is the second leading cause of death and the third leading cause of disability-adjusted life years worldwide. Although numerous therapies have been developed over the past 10 years to treat acute ischemic stroke, the stark reality remains that only 5% of these patients are so treated in the United States,1 in part, because of treatment window times 7 million stroke survivors …

Background. Stroke patients with mild-moderate upper extremity motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective. To determine whether stroke lesions in an upper extremity rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods. Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results. Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants

For veterans separated from the military as a result of acquired mild traumatic brain injury (mTBI), the transition from a military identity to a civilian one is complicated by health, cognitive, and psychosocial factors. We conducted in-depth interviews with 8 veterans with mTBI to understand how they perceived the experience of departure from the military, rehabilitation services provided at a Department of Veterans Affairs (VA) Polytrauma Network Site, and reentry into civilian life. Two distinct patterns of thinking about community reintegration emerged. The first pattern was characterized by the perception of a need to fade one's military identity. The second pattern, conversely, advanced the perception of a need to maintain the integrity of one's military identity though living in a civilian world. These perceptions may be linked to individuals' roles while in the military and whether violent acts were committed in carrying out the mission of service, acts not consonant with positive self-appraisal in the civilian world. The crisis of unplanned, involuntary separation from the military was universally perceived as a crisis equal to that of the precipitating injury itself. The perception that civilians lacked understanding of veterans' military past and their current transition set up expectations for interactions with health care providers, as well as greatly impacting relationships with friend and family. Our veterans' shared perceptions support existing mandates for greater dissemination of military culture training to health care providers serving veterans both at VA and military facilities as well as in the civilian community at large. (PsycINFO Database Record

Background. A common assumption is that changes in upper limb (UL) capacity, or what an individual is capable of doing, translates to improved UL performance in daily life, or what an individual actually does. This assumption should be explicitly tested for individuals with UL paresis poststroke. Objective. To examine changes in UL performance after an intensive, individualized, progressive, task-specific UL intervention for individuals at least 6 months poststroke. Methods. Secondary analysis on 78 individuals with UL paresis who participated in a phase II, single-blind, randomized parallel dose-response trial. Participants were enrolled in a task-specific intervention for 8 weeks. Participants were randomized into 1 of 4 treatment groups with each group completing different amounts of UL movement practice. UL performance was assessed with bilateral, wrist-worn accelerometers once a week for 24 hours throughout the duration of the study. The 6 accelerometer variables were tested for change and the influence of potential modifiers using hierarchical linear modeling. Results. No changes in UL performance were found on any of the 6 accelerometer variables used to quantify UL performance. Neither changes in UL capacity nor the overall amount of movement practice influenced changes in UL performance. Stroke chronicity, baseline UL capacity, concordance, and ADL status significantly increased the baseline starting points but did not influence the rate of change (slopes) for participants. Conclusions. Improved motor capacity resulting from an intensive outpatient UL intervention does not appear to translate to increased UL performance outside the clinic.

Robotic therapy enables mass practice of complex hand movements after stroke, but current devices generally enforce patients to reproduce prescribed kinematic patterns using rigid actuators, without considering individuals’ unique impairment characteristics, thereby reducing their efficacy. In this early-stage study, we tested the feasibility of a novel, theory-based “biomimetic” approach to restoring mechanics of complex hand tasks with subject-specific assistance patterns. Twelve chronic stroke survivors performed two simulated functional tasks, hand open and simulated pinch task (distal pad press). Assistance was provided by non-restraining actuators (exotendons) that counteracted ‘subject-specific’ impairments, identified during unassisted task performance. There was no constraint of movement to predefined patterns. Assistance patterns required to complete tasks were significantly different across subjects, reflecting high variability in impairment and required assistance patterns. For hand open, range of motion and interjoint coordination were significantly improved for severely impaired patients, while movement quality was enhanced (reduction in jerk) for those less impaired. For simulated pinch, subject-specific assistance restored task mechanics before injury, as patients were able to direct fingertip force towards the direction normal to surface; angular deviation reduced from 16.8°±10.4° to 3.7°±2.6°. Notably, electromyography data confirmed that subjects maintained an effort level under assistance comparable to unassisted conditions. The proposed method could lead to a novel paradigm for hand rehabilitation that restores complex task mechanics with a subject-specific assistance reflecting individual impairment characteristics while promoting subjects’ participation.

Background Student physicians are particularly prone to high rates of poor mental and physical quality of life, including depression, anxiety, and fatigue. We prospectively tested whether a structured, theory-based executive/life coaching program tailored to first year medical students in the United States was feasible, tolerable, and would be recommended by participants. Secondary goals included impact on coaching goals, resilience, and perceived stress. Methods This single-arm intervention study evaluated a program of two group and two private coaching sessions during the first year, second semester of the Georgetown University School of Medicine Class of 2019. Survey data (global and tailored questions, Connor-Davidson resilience scale, Friedricksson-Larsson stress question) were collected from participants at baseline and post-intervention. Results 37/40 students completed the intervention; 32 completed the pre-post surveys. Most (32/37) were willing to recommend the program (16/37 were very willing) and 29/37 recommended inclusion in the curriculum. Responses to tailored questions showed significant increases in self-efficacy regarding stress management (p

The majority of stroke survivors suffer from residual functional deficits in the Upper Extremity (UE) that limits the patients’ ability to incorporate the hemiparetic UE into daily function such as reaching and grasping objects. Correctly assessing the degree to which individuals with stroke use their UE would be important for rehabilitation. However, previous work shows that many stroke patients, when observed in the laboratory, can appear to use the paretic arm with adequate ability, yet do not use the arm at home with the expected regularity. The main purposes of this study are to use various machine learning techniques to examine associations between laboratory-based measures of limb functioning and actual home use. The UE kinematics during reaching and grasping tasks were measured in the laboratory, while the use of the paretic arm in the home environment was assessed with portable accelerometry and the Motor Activity Log (MAL). The study identified a subset of the biomechanical features that predicted well the paretic arm use at home. Arm use was also well predicted with clinical evaluations of impairment using Fugl-Meyer and Action Research Arm Test (ARAT) scores. However, combining the clinical and a subset of biomechanical features yielded the best model to predict UE use in individuals with stroke.

Upper Extremity (UE) rehabilitation is often needed post-stroke. The main goal of UE treatment in stroke survivors is to increase the use of the affected UE in the home and community. However, the effectiveness of UE treatments are difficult to quantify because no objective evaluation of UE use exists. In practice, a clinician rates the patient’s ability to perform specific motor tasks associated with functional use in a clinic or the patient self-reports the amount or quality of arm movement for a standard set of activities. Both methods do not objectively measure the performance of the affected UE in the home or community environment, and there is growing evidence that motor performance in the laboratory is a poor proxy for the actual amount of UE use. Using a single wrist-worn sensor (i.e., accelerometry data) and machine learning, we have reported that it is possible to separate UE functional use from nonfunctional movement after stroke. Specifically, we reported that we correctly classified sensor data with an average of 94.80% in controls and 88.38% in stroke subjects in intra-subject test trials, and 91.53% for controls and 70.18% in stroke subjects in inter-subject test trials. In this paper, we employed feature selection techniques and explored different machine learning methods to improve the classification accuracy. Our enhanced methods are robust and reliable, and work in both intra-subject and inter-subject training and testing. Our result showed better accuracy in stroke patients than previously reported with the same dataset. The enhanced models reached an average of 96% accuracy in control subjects and 94% in stroke subjects for intra-subject trials, and an average of 90% accuracy in control subjects and 83% in stroke subjects for the inter-subject trials. The proposed methods provide an inexpensive and feasible way to quantify the UE functional use in home and community. This information can provide guidance for clinical practice in the rehabilitative care of adults recovering from stroke.

IMPACT: This proof-of-concept study demonstrates that systematically altering limb dynamics with two exoskeleton devices alters ingrained, bilateral upper-limb coordination with the potential to rehabilitate functional reaching in chronic stroke survivors OBJECTIVES/GOALS: Advances in virtual reality and exoskeleton technologies have allowed researchers to alter upper limb coordination with more precision than ever before. The goal of this study was to systematically enhance the use of the nondominant limb during a bimanual reaching task, with an eye towards improving rehabilitative strategies post stroke. METHODS/STUDY POPULATION: Healthy, right-handed volunteers performed a bimanual reaching task in virtual reality (VR) space while simultaneously moving under the influence of two exoskeleton devices. The VR task had participants move a shared cursor, displayed at the midpoint between the hands, to targets arranged at shoulder and eye levels and located at 70% of full arm extension. Two exoskeleton devices applied either resistive torque to the dominant limb or assistive torque to the non-dominant limb. Three-dimensional hand position data were recorded at 50 Hz and analyzed offline. The primary outcome measure was relative contribution, calculated as the ratio of dominant/non-dominant displacement. RESULTS/ANTICIPATED RESULTS: Preliminary results from 3 participants showed that during baseline trials, when no torque was applied by the exoskeletons, relative contribution was 50.6% in favor of the dominant hand, with the dominant hand reaching on average 1.1cm farther than the left. When the exoskeletons resisted movement in the dominant limb while simultaneously assisting movement in the non-dominant limb, relative contribution was 49.7% indicating an increase in non-dominant limb usage. Further analysis showed that this effect was driven by one participant who reached 3.7cm farther with her non-dominant hand compared to baseline. DISCUSSION/SIGNIFICANCE OF FINDINGS: These pilot data suggest our testing platform is capable of altering normal coordination patterns and is likely the result of participants adopting an optimal control strategy imposed by the shared cursor. These findings will form the basis for a rehabilitation intervention to promote the use of the paretic limb in chronic stroke survivors.

OBJECTIVE The objectives of this work were to (1) determine whether higher doses of motor therapy in chronic poststroke hemiparesis result in better outcomes, compared to lower doses, and (2) evaluate potential modifiers of the dose-response relationship. METHODS Eighty-five adults with upper extremity paresis ≥6 months poststroke were randomized to one of four dose groups in this single-blind, parallel, randomized, control trial. The dosing parameter manipulated was amount of task-specific training, as indexed by the number of task repetitions. Groups received 3,200, 6,400, 9,600, or individualized maximum (IM) repetitions, during 1-hour sessions, 4 days/week for 8 weeks. The intervention was an individualized, progressive, task-specific upper-limb training program designed to improve upper-limb functional motor capacity. The primary outcome was the slope of the Action Research Arm Test (ARAT) during the intervention. Effects of dose and potential modifiers of the dose-response relationship were evaluated with hierarchical linear models. RESULTS ARAT scores for the 3,200, 9,600, and IM groups improved over time as indicated by slopes (ΔARAT/week, mean ± standard errors) of 0.40 ± 0.15, 0.31 ± 0.16, and 0.66 ± 0.14, respectively (p

Effective screening for mild traumatic brain injury (mTBI) is critical to accurate diagnosis, intervention, and improving outcomes. However, detecting mTBI using conventional clinical techniques is difficult, time intensive, and subject to observer bias. We examine the use of a simple visuomotor tracking task as a screening tool for mTBI. Thirty participants, 16 with clinically diagnosed mTBI (mean time since injury: 36.4 ± 20.9 days (95 % confidence interval); median = 20 days) were asked to squeeze a hand dynamometer and vary their grip force to match a visual, variable target force for 3 min. We found that controls outperformed individuals with mTBI; participants with mTBI moved with increased variability, as quantified by the standard deviation of the tracking error. We modeled participants' feedback response-how participants changed their grip force in response to errors in position and velocity-and used model parameters to classify mTBI with a sensitivity of 87 % and a specificity of 93 %, higher than several standard clinical scales. Our findings suggest that visuomotor tracking could be an effective supplement to conventional assessment tools to screen for mTBI and track mTBI symptoms during recovery.

Stroke is highly prevalent and a leading cause of serious, long-term disability among American adults. Impaired movement (i.e. paresis) of the stroke-affected arm is a major contributor to post-stroke disability, yet the mechanisms of upper extremity motor recovery are poorly understood, particularly in severely impaired patients who lack hand function. To address this problem, we examined the functional relevance of the contralesional hemisphere in paretic arm motor performance in individuals with severe arm paresis. Twelve individuals with severe stroke-induced arm paresis (Upper Extremity Fugl-Meyer Assessment=17.1 ± 8.5; maximum score=66) participated in the study. Participants performed a reaching response time task with their paretic arm. At varying time intervals following a 'Go' cue, a pair of transcranial magnetic stimulation (TMS) pulses were delivered to contralesional hemisphere primary motor (M1) or dorsal pre-motor cortex (PMd) to momentarily disrupt the pattern of neural firing. Response time components and hand-path characteristics were compared across the 2 sites for trials with and without TMS disruption. There was no significant effect of TMS disruption on overall Response time or Reaction time, but Movement time was significantly longer (i.e. slower) with disruption of the contralesional hemisphere (p=0.015), regardless of which area was stimulated. Peak hand-path velocity and hand-path smoothness were also significantly lower (p=0.005 and p

Objective To improve measurement of upper extremity (UE) use in the community by evaluating the feasibility of using body-worn sensor data and machine learning models to distinguish productive prehensile and bimanual UE activity use from extraneous movements associated with walking. Design Comparison of machine learning classification models with criterion standard of manually scored videos of performance in UE prosthesis users. Setting Rehabilitation hospital training apartment. Participants Convenience sample of UE prosthesis users (n=5) and controls (n=13) similar in age and hand dominance (N=18). Interventions Participants were filmed executing a series of functional activities; a trained observer annotated each frame to indicate either UE movement directed at functional activity or walking. Synchronized data from an inertial sensor attached to the dominant wrist were similarly classified as indicating either a functional use or walking. These data were used to train 3 classification models to predict the functional versus walking state given the associated sensor information. Models were trained over 4 trials: on UE amputees and controls and both within subject and across subject. Model performance was also examined with and without preprocessing (centering) in the across-subject trials. Main Outcome Measure Percent correct classification. Results With the exception of the amputee/across-subject trial, at least 1 model classified >95% of test data correctly for all trial types. The top performer in the amputee/across-subject trial classified 85% of test examples correctly. Conclusions We have demonstrated that computationally lightweight classification models can use inertial data collected from wrist-worn sensors to reliably distinguish prosthetic UE movements during functional use from walking-associated movement. This approach has promise in objectively measuring real-world UE use of prosthetic limbs and may be helpful in clinical trials and in measuring response to treatment of other UE pathologies.

Preclinical investigators have implicated several microRNAs as regulators of gene expression promoting neural plasticity following experimental stroke in rodent models. Our goal was to determine whether similar microRNAs might be identifiable in plasma of humans with variable recovery from stroke. Plasma was collected 19 days post-stroke from 27 participants with mild-moderate upper extremity impairment enrolled in the Critical Periods After Stroke Study (CPASS). MicroRNA expression was assessed using TaqMan microRNA assays. Good clinical recovery was defined as ≥6 point change in the Action Research Arm Test (ARAT) score from baseline to 6 months, with 22 subjects showing good and 5 showing poor recovery. When comparing the good versus poor recovery groups, six microRNAs showed significantly decreased expression – miR-371-3p, miR-524, miR-520g, miR-1255A, miR-453, and miR-583, while 3 showed significantly increased expression - miR-941, miR-449b, and miR-581. MiR-371-3p and miR-941 have previously been associated with neural repair mechanisms; none of the significant microRNAs have previously been associated with stroke. The 9 microRNAs converge on pathways associated with axonal guidance, developmental biology, and cancer. We conclude that plasma microRNAs may be informative regarding human neural repair mechanisms during stroke recovery and probably differ from those seen in experimental stroke models.

Neurological injuries often cause degraded motor control. While rehabilitation efforts typically focus on movement kinematics, abnormal muscle activation patterns are often the primary source of impairment. Muscle-based therapies are likely more effective than joint-based therapy. In this paper, we examined the feasibility of biomimetic input mimicking the action of human musculotendons in altering hand muscle coordination. Twelve healthy subjects produced a submaximal isometric dorsal fingertip force, while a custom actuator provided assistance mirroring the actions of either the extrinsic extensor or the intrinsic muscles of the index finger. The biomimetic inputs reduced the activation level of all task-related muscles, but the degree of change was different across the muscles, resulting in significant changes in their coordination (co-contraction ratios) and force-electromyography correlations. Each biomimetic assistance particularly increased the neural coupling between its targeted muscle and the antagonist muscle. Subjects appeared to fully take advantage of the assistance, as they provided minimal level of effort to achieve the task goal. The targeted biomimetic assistance may be used to retrain activation patterns post-stroke by effectively modulating connectivity between the muscles in the functional context and could be beneficial to restore hand function and reduce disability.

Background: Genetic factors may be useful to understand differences in outcomes post-stroke. We studied an imaging measure of brain atrophy in relation to two genotypes that may be associated with differences in stroke recovery, the val 66 met genotype for brain-derived neurotrophic factor (BDNF) and the ApoE e4 genotype. Each genotype has been associated with brain atrophy in non-stroke populations. The current study hypothesized that each genotype is associated with brain atrophy after stroke. Methods: The ICARE Study examined behavioral outcomes after stroke in relation to motor therapies. Of 361 ICARE enrollees, genetic and neuroimaging data were available in 127. The volume of the ventricles and the brain were measured, and brain atrophy expressed as the Ventricle-Brain Ratio (VBR). For MRI scans, VBR was first extracted from the scans using ALVIN then manually refined. For CT scans, VBR was extracted manually. All VBR measurements were verified by a neuroimaging expert. VBR was examined in relation to the two genotypes of interest, BDNF val 66 met and ApoE e4, controlling for the 3 covariates employed in ICARE: motor deficits, enrollment site, and time post-stroke at study entry. Results: There were 61 MRI and 66 CT scans. These were acquired 5±11 days post-stroke, which did not vary according to either genotype. Median ventricle volume=26.1 cc; brain volume=1,163 cc; and VBR=0.024. The BDNF val 66 met genotype was present in 23 subjects; ApoE e4, in 41; both were in HW equilibrium. Presence of the BDNF val 66 met genotype was associated with greater atrophy: median VBR increased 1.97-fold when this genotype was present vs. absent (p=0.01), controlling for above covariates; and remained significant (p=0.04) when also controlling for age. This BDNF gene-imaging correlate did not extend to gene-behavioral findings. The ApoE e4 genotype was not related to VBR (p=0.88). Conclusions: Median degree of brain atrophy is 97% greater in patients with stroke when the BDNF val 66 met genotype is present, at least for the mild-moderately impaired subjects enrolled in ICARE. Understanding the biology of inter-subject differences in brain anatomy after stroke can provide insights into patient heterogeneity and inform efforts to individualize stroke recovery therapies.

Introduction: MicroRNAs are small, non-coding RNAs that control gene expression by inhibiting protein translation. Preclinical studies in rodent stroke models suggest that changes in microRNA expression contribute to neural repair mechanisms. To our knowledge, no one has previously assessed microRNA changes during the recovery phase of human stroke. Hypothesis: Patients with significant upper limb recovery following stroke will have alteration of neural repair-related microRNA expression when compared to those with poor recovery. Methods: Plasma was collected at 19 days post-stroke from 27 participants with mild-moderate upper extremity impairment enrolled in the Critical Periods After Stroke Study (CPASS). MicroRNA expression was assessed using TaqMan microRNA assays (Thermo Fisher Scientific). Good recovery was defined as ≥ 6 point change in the Action Research Arm Test (ARAT) score from baseline to 6 months. Bioinformatics analysis compared the plasma microRNA expression profiles of participants with good vs. poor recovery. Candidate biomarkers were identified after correcting for multiple comparisons using a false discovery rate < 0.05. Results: Eleven microRNAs had significantly altered expression in the good (n=22) vs. poor (n=5) recovery groups, with two showing increased expression - miR-371-3p and miR-520g, and nine showing decreased expression - miR-449b, miR-519b, miR-581, miR-616, miR-892b, miR-941, miR-1179, miR-1292 and miR1296. Three of these could be implicated in neural repair mechanisms. Elevated miR-371-3p levels increase the likelihood that pluripotent stem cells will differentiate into neural progenitors. MiR-892b decreases levels of amyloid precursor protein, which has been implicated as a regulator of synapse formation. Finally miR-941, the only known human-specific microRNA, downregulates the CSPα protein which is involved in neurotransmitter release. Conclusions: This preliminary study suggests that circulating microRNAs in the plasma may help serve as biomarkers of neural repair and aid in understanding human neural repair mechanisms. If validated in larger studies with appropriate controls, these markers could aid in timing rehabilitation therapy or designing recovery-based therapeutics.

OBJECTIVES/SPECIFIC AIMS: There are currently no established blood-based biomarkers of recovery and neural repair following stroke in humans. Such biomarkers would be extremely valuable for aiding in stroke prognosis, timing rehabilitation therapies, and designing drugs to augment natural repair mechanisms. Metabolites, including lipids and amino acids, are engaged in many cellular processes and cross the blood-brain barrier more easily than proteins. Recent advances in liquid chromatography / mass spectrometry (LCMS) allow researchers to obtain a biochemical fingerprint of the metabolites in various biofluids. Thus, metabolite biomarkers of neural repair after brain injury are a promising avenue for future research. Objective: Design and conduct a study to identify metabolite changes in the blood associated with good and poor motor recovery following stroke. METHODS/STUDY POPULATION: We launched the Biomarkers of Stroke Recovery (BIOREC) study, which seeks to enroll 70 participants suffering arm motor impairment following stroke and 35 matched controls. BIOREC is a longitudinal observational study. Fasting blood samples are collected at 5, 15, and 30 days post-stroke, processed, and stored in the Georgetown Lombardi biorepository. Outcome measures, including measures of motor impairment, cognition and language, are assessed at 5, 15, 30, and 90 days post-stroke. The primary outcome measure is the upper extremity Fugl-Meyer score. Control participants are matched for age +/− 1 yr, race, gender, cardiovascular comorbities, and statin use through a computer algorithm that screens the entire MedStar electronic health record (EHR). Control participants provide 2 fasting blood samples one month apart. Once all samples are collected and sent for LCMS analysis, logistic regression analysis will identify potential metabolite biomarkers by comparing participants with good recovery to those with poor recovery as well as stroke participants to controls. RESULTS/ANTICIPATED RESULTS: To date, forty stroke participants have enrolled from 4 acute care hospitals in the Washington, DC metro region and completed all study procedures. Twenty stroke participants either dropped out or were withdrawn due to other medical concerns. Stroke patients ended up at a variety of venues following their acute hospitalization including the acute rehabilitation hospital, skilled nursing facilities, and home. We learned to overcome these logistical challenges by traveling to wherever the patients were sent and notifying medical providers of their study participation. In rare cases we have paid to transport patients from skilled nursing facilities to the clinic, which has reduced dropouts. In addition to the stroke participants, we have enrolled 7 healthy control participants using the EHR screening algorithm. DISCUSSION/SIGNIFICANCE OF IMPACT: Performing a longitudinal study in the early recovery phase following stroke is logistically challenging, but feasible. Difficulty in identifying participants with isolated motor impairment requires added effort to eliminate dropouts. Screening the EHR is an effective method to identify matched controls. Future metabolomics analysis of stored blood samples holds promise to identify biomarkers of stroke recovery and neural repair.

In well-recovered stroke patients with preserved hand movement, motor dysfunction relates to interhemispheric and intracortical inhibition in affected hand muscles. In less fully recovered patients unable to move their hand, the neural substrates of recovered arm movements, crucial for performance of daily living tasks, are not well understood. Here, we evaluated interhemispheric and intracortical inhibition in paretic arm muscles of patients with no recovery of hand movement (n = 16, upper extremity Fugl-Meyer Assessment = 27.0 ± 8.6). We recorded silent periods (contralateral and ipsilateral) induced by transcranial magnetic stimulation during voluntary isometric contraction of the paretic biceps and triceps brachii muscles (correlates of intracortical and interhemispheric inhibition, respectively) and investigated links between the silent periods and motor recovery, an issue that has not been previously explored. We report that interhemispheric inhibition, stronger in the paretic triceps than biceps brachii muscles, significantly correlated with the magnitude of residual impairment (lower Fugl-Meyer scores). In contrast, intracortical inhibition in the paretic biceps brachii, but not in the triceps, correlated positively with motor recovery (Fugl-Meyer scores) and negatively with spasticity (lower Modified Ashworth scores). Our results suggest that interhemispheric inhibition and intracortical inhibition of paretic upper arm muscles relate to motor recovery in different ways. While interhemispheric inhibition may contribute to poorer recovery, muscle-specific intracortical inhibition may relate to successful motor recovery and lesser spasticity.

Background and Purpose Trials of restorative therapies after stroke and clinical rehabilitation require relevant and objective efficacy end points; real-world upper extremity (UE) functional use is an attractive candidate. We present a novel, inexpensive, and feasible method for separating UE functional use from nonfunctional movement after stroke using a single wrist-worn accelerometer. Methods Ten controls and 10 individuals with stroke performed a series of minimally structured activities while simultaneously being videotaped and wearing a sensor on each wrist that captured the linear acceleration and angular velocity of their UEs. Video data provided ground truth to annotate sensor data as functional or nonfunctional limb use. Using the annotated sensor data, we trained a machine learning tool, a Random Forest model. We then assessed the accuracy of that classification. Results In intrasubject test trials, our method correctly classified sensor data with an average of 94.80% in controls and 88.38% in stroke subjects. In leave-one-out intersubject testing and training, correct classification averaged 91.53% for controls and 70.18% in stroke subjects. Conclusions Our method shows promise for inexpensive and objective quantification of functional UE use in hemiparesis, and for assessing the impact of UE treatments. Training a classifier on raw sensor data is feasible, and determination of whether patients functionally use their UE can thus be done remotely. For the restorative treatment trial setting, an intrasubject test/train approach would be especially accurate. This method presents a potentially precise, cost-effective, and objective measurement of UE use outside the clinical or laboratory environment.

Introduction: Lasagna’s Law, that the prevalence of a disease falls to 10% of your estimate the day you start recruitment , is relevant for stroke rehab trials. Data describing the problem are limited for very early trials (within 30 days) since most trials focus on more chronic survivors and moderate upper-extremity (UE) impairment (NIHSS motor arm > 0). Very early trials are important for rehab because animal data suggest very early intervention may improve recovery. We thus provide estimates on barriers to recruitment for very early rehabilitation trials in the US. Methods: We used screening data for the Phase II Critical Periods After Stroke Study RCT, designed to identify when after stroke patients are most responsive to motor training. Starting Aug 2014, 893 patients eventually admitted to inpatient rehab were screened (5 ±2 days post stroke). Results: We enrolled 4.3% of those screened, at 15.5 ±4.9 days post stroke. Participants had ischemic/hemorrhagic stroke within 28d, and moderate UE impairment (NIHSS motor arm > 0 and manual muscle test score >2- on shoulder flexion/abduction). The largest % were excluded for being “too mild” (35.7%, NIHSS motor arm = 0), or “too late” (18%, unable to receive first study-related treatment < 30 days of stroke). A smaller percentage were “too severe” (3.6%, UE motor assessment scale Conclusion: Frequent barriers to recruitment for inpatient rehab trials include persistent but too mild UE motor impairment and delayed admission to inpatient rehab. For early intervention studies, screening and treatment must begin in the acute hospital setting. Further, there is a patient subset whose motor impairment persists, but is too mild for most trials. These mildly affected individuals warrant more investigation.