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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.

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: Recruitment of patients in early subacute rehabilitation trials (6 months post-stroke. Preclinical studies suggest treatments be initiated sooner after stroke, thus requiring stroke rehabilitation trials be conducted within days post-stroke. How do specific inclusion and exclusion criteria affect trial recruitment rates for early stroke rehabilitation trials?Objectives: Provide estimates of trial recruitment based on screening and enrollment data from a phase II early stroke rehabilitation trial.Methods: CPASS, a phase II intervention trial screened ischemic stroke patients in acute care (18-months, N = 395) and inpatient rehabilitation (22-months, N = 673). Patients were stratified by upper extremity (UE) impairment into mild (NIHSS motor arm = 0, 1); moderate (NIHSS = 2, 3); severe (NIHSS = 4) and numbers of patients disqualified due to CPASS exclusion criteria determined. We also examined if a motor-specific evaluation (Action Research Arm Test, ARAT) increases the pool of eligible patients disqualified by the NIHSS motor arm item.Results: CPASS recruitment in acute care (5.3%) and inpatient rehabilitation (5%) was comparable to prior trials. In acute care, a short stay (7–17-days), prior stroke (13.5% in moderately; 13.2% in severely impaired) disqualified the majority. In inpatient rehabilitation, the majority (40.8%) were excluded for “too mild” impairment. The next majority were disqualified for reaching inpatient rehabilitation “too late” to participate in an early stroke trial (15% in moderately; 24% in severely impaired). Mean ARAT in the “too mild” showed significant impairment and potential to benefit from participation in select UE rehabilitation trials.Conclusions: Screening of ischemic stroke patients while they are still in acute care is crucial to successful recruitment for early stroke rehabilitation trials. A significant proportion of eligible patients are lost to “short length of stay” in acute care, and arrive to inpatient rehabilitation “too late” for an early rehabilitation trial. Additional screening of mildly impaired patients using a motor function specific scale will benefit the trial recruitment and generalizability.Trial Registration Number:http://www.clinicaltrials.gov Identifier: NCT02235974.

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 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.

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.

The purpose of this review is to provide an update on the latest neurorehabilitation literature for motor recovery in stroke and traumatic brain injury to assist clinical decision making and assessing future research directions.The emerging approach to motor restoration is now multimodal. It engages the traditional multidisciplinary rehabilitation team, but incorporates highly structured activity-based therapies, pharmacology, brain stimulation and robotics. Clinical trial data support selective serotonin reuptake inhibitors and amantadine to assist motor recovery poststroke and traumatic brain injury, respectively. Similarly, there is continued support for intensity as a key factor in activity-based therapies, across skilled and nonskilled interventions. Aerobic training appears to have multiple benefits; increasing the capacity to meet the demands of hemiparetic gait improves endurance for activities of daily living while promoting cognition and mood. At this time, the primary benefit of robotic therapy lies in the delivery of highly intense and repetitive motor practice. Both transcranial direct current and magnetic stimulation therapies are in early stages, but have promise in motor and language restoration.Advancements in neurorehabilitation have shifted treatment away from nonspecific activity regimens and amphetamines. As the body of knowledge grows, evidence-based practice using interventions targeted at specific subgroups becomes progressively more feasible.

Importance Data from animal models show that the administration of dextroamphetamine combined with task-relevant training facilitates recovery after focal brain injury. Results of clinical trials in patients with stroke have been inconsistent. Objectives To collect data important for future studies evaluating the effect of dextroamphetamine combined with physiotherapy for improving poststroke motor recovery and to test the efficacy of the approach. Design, Setting, Participants This pilot, double-blind, block-randomized clinical trial included patients with cortical or subcortical ischemic stroke and moderate or severe motor deficits from 5 rehabilitation hospitals or units. Participants were screened and enrolled from March 2001 through March 2003. The primary outcome was assessed 3 months after stroke. Study analysis was completed December 31, 2015. A total of 1665 potential participants were screened and 64 were randomized. Participants had to begin treatment 10 to 30 days after ischemic stroke. Data analysis was based on intention to treat. Interventions Participants were allocated to a regimen of 10 mg of dextroamphetamine (n = 32) or placebo (n = 32) combined with a 1-hour physical therapy session beginning 1 hour after drug or placebo administration every 4 days for 6 sessions in addition to standard rehabilitation. Main Outcomes and Measures The primary outcome was the difference between groups in change in Fugl-Meyer motor scores from baseline to 3 months after stroke (intention to treat with dextroamphetamine). Secondary exploratory measures included the National Institutes of Health Stroke Scale, Canadian Neurological Scale, Action Research Arm Test, modified Rankin Scale score, Functional Independence Measure, Ambulation Speed and Distance, Mini-Mental State Examination, Beck Depression Inventory, and Stroke Impact Scale. Results Among the 64 patients randomized to dextroamphetamine vs placebo (55% men; median age, 66 years; age range, 27-91 years), no overall treatment-associated difference in the mean (SEM) change in Fugl-Meyer motor scores from baseline to 3 months after stroke was noted (−18.65 [2.27] points with dextroamphetamine vs −20.83 [2.94] points with placebo;P = .58). No overall treatment-associated differences in any of the study’s secondary measures and no differences in subgroups based on stroke location or baseline severity were found. No adverse events were attributed to study treatments. Conclusions and Relevance Treatment with dextroamphetamine combined with physical therapy did not improve recovery of motor function compared with placebo combined with physical therapy as assessed 3 months after hemispheric ischemic stroke. The studied treatment regimen was safe. Trial Registration ClinicalTrials.gov identifier:NCT01905371

OBJECTIVES/SPECIFIC AIMS: 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. Our goal was to determine whether patients with significant upper limb recovery following stroke have alteration of neural repair-related microRNA expression when compared to those with poor recovery. METHODS/STUDY POPULATION: 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. 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 Versus poor recovery. Candidate biomarkers were identified after correcting for multiple comparisons using a false discovery rate

Background. Studies have demonstrated the efficacy of functional electrical stimulation in the management of foot drop after stroke. Objective. To compare changes in walking performance with the WalkAide (WA) foot-drop stimulator and a conventional ankle–foot orthosis (AFO). Methods. Individuals with stroke within the previous 12 months and residual foot drop were enrolled in a multicenter, randomized controlled, crossover trial. Subjects were assigned to 1 of 3 parallel arms for 12 weeks (6 weeks/device): arm 1 (WA–AFO), n = 38; arm 2 (AFO–WA), n = 31; arm 3 (AFO–AFO), n = 24. Primary outcomes were walking speed and Physiological Cost Index for the Figure-of-8 walking test. Secondary measures included 10-m walking speed and perceived safety during this test, general mobility, and device preference for arms 1 and 2 for continued use. Walking tests were performed with (On) and without a device (Off) at 0, 3, 6, 9, and 12 weeks. Results. Both WA and AFO had significant orthotic (On–Off difference), therapeutic (change over time when Off), and combined (change over time On vs baseline Off) effects on walking speed. An AFO also had a significant orthotic effect on Physiological Cost Index. The WA had a higher, but not significantly different therapeutic effect on speed than an AFO, whereas an AFO had a greater orthotic effect than the WA (significant at 12 weeks). Combined effects on speed after 6 weeks did not differ between devices. Users felt as safe with the WA as with an AFO, but significantly more users preferred the WA. Conclusions. Both devices produce equivalent functional gains.

Background and Purpose— The National Institute of Neurological Disorders and Stroke initiated development of stroke-specific Common Data Elements (CDEs) as part of a project to develop data standards for funded clinical research in all fields of neuroscience. Standardizing data elements in translational, clinical, and population research in cerebrovascular disease could decrease study start-up time, facilitate data sharing, and promote well-informed clinical practice guidelines. Methods— A working group of diverse experts in cerebrovascular clinical trials, epidemiology, and biostatistics met regularly to develop a set of stroke CDEs, selecting among, refining, and adding to existing, field-tested data elements from national registries and funded trials and studies. Candidate elements were revised on the basis of comments from leading national and international neurovascular research organizations and the public. Results— The first iteration of the National Institute of Neurological Disorders and Stroke (NINDS) stroke-specific CDEs comprises 980 data elements spanning 9 content areas: (1) biospecimens and biomarkers; (2) hospital course and acute therapies; (3) imaging; (4) laboratory tests and vital signs; (5) long-term therapies; (6) medical history and prior health status; (7) outcomes and end points; (8) stroke presentation; and (9) stroke types and subtypes. A CDE website provides uniform names and structures for each element, a data dictionary, and template case report forms, using the CDEs. Conclusions— Stroke-specific CDEs are now available as standardized, scientifically vetted, variable structures to facilitate data collection and data sharing in cerebrovascular patient-oriented research. The CDEs are an evolving resource that will be iteratively improved based on investigator use, new technologies, and emerging concepts and research findings.

Rationale PROTECT DC examines whether stroke navigators can improve cardiovascular risk factors in urban underserved individuals newly hospitalized for stroke or ischemic attack. Within one-year of hospital discharge, up to one-third of patients no longer adhere to secondary prevention behaviors. Adherence rates are lower in minority-underserved groups, contributing to health disparities. In-hospital programs increase use of stroke prevention therapies but may not be as successful in underserved individuals. In these groups, low literacy, limited healthcare access, and sparse community resources may reduce adherence. Lay community health workers (navigators) improve adherence in other illnesses through education and assisting in overcoming barriers to achieving desired health behaviors and obtaining needed healthcare services. Aims and design PROTECT DC is a Phase II, single-blind, randomized, controlled trial comparing in-hospital education plus stroke navigators to usual care. Atherogenic ischemic stroke and transient ischemic attack survivors are recruited from Washington, DC hospitals. Navigators meet with participants during the index hospitalization, perform home visits, and meet by phone. They focus on stroke education, medication compliance, and overcoming practical barriers to adherence. The interventions are driven by the theories of reasoned action and planned behavior. Study outcomes The primary dependent measure is a summary score of four objective measures of stroke risk factor control: systolic blood pressure, low-density lipoprotein, hemoglobin Hb A1C, and antiplatelet agent pill counts. Secondary outcomes include stroke knowledge, exercise, dietary modification, and smoking cessation. Conclusion PROTECT DC will determine whether a Phase III trial of stroke navigation for urban underserved individuals to improve adherence to secondary stroke prevention behaviors is warranted.

Stroke rehabilitation is evolving into a clinical field based on the neuroscience of recovery and restoration. There has been substantial growth in the number and quality of clinical trials performed. Much effort now is directed toward motor restoration and is being led by trials of constraint-induced movement therapy. Although the results do not necessarily support that constraint-induced movement therapy is superior to other training methods, this treatment has become an important vehicle for developing clinical trial methods and studying the physiology underlying activity-based rehabilitation strategies. Other promising interventions include robotic therapy delivery, magnetic and electrical cortical stimulation, visualization, and constraint-driven aphasia therapies. Amphetamine has not been demonstrated to be effective, and studies of other pharmacologic agents are still preliminary. Future studies will incorporate refinements in clinical trial methods and improved activity- and technology-based interventions.

Constraint-induced movement therapy (CIMT) is among the most developed training approaches for motor restoration of the upper extremity (UE).Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS) was a single-blind phase II trial of CIMT during acute inpatient rehabilitation comparing traditional UE therapy with dose-matched and high-intensity CIMT protocols. Participants were adaptively randomized on rehabilitation admission, and received 2 weeks of study-related treatments. The primary endpoint was the total Action Research Arm Test (ARAT) score on the more affected side at 90 days after stroke onset. A mixed model analysis was performed.A total of 52 participants (mean age 63.9 +/- 14 years) were randomized 9.65 +/- 4.5 days after onset. Mean NIHSS was 5.3 +/- 1.8; mean total ARAT score was 22.5 +/- 15.6; 77% had ischemic stroke. Groups were equivalent at baseline on all randomization variables. As expected, all groups improved with time on the total ARAT score. There was a significant time x group interaction (F = 3.1, p0.01), such that the high intensity CIT group had significantly less improvement at day 90. No significant differences were found between the dose-matched CIMT and control groups at day 90. MRI of a subsample showed no evidence of activity-dependent lesion enlargement.Constraint-induced movement therapy (CIMT) was equally as effective but not superior to an equal dose of traditional therapy during inpatient stroke rehabilitation. Higher intensity CIMT resulted in less motor improvement at 90 days, indicating an inverse dose-response relationship. Motor intervention trials should control for dose, and higher doses of motor training cannot be assumed to be more beneficial, particularly early after stroke.

Lang CE, Edwards DF, Birkenmeier RL, Dromerick AW. Estimating minimal clinically important differences of upper-extremity measures early after stroke. Objective To estimate minimal clinically important difference (MCID) values of several upper-extremity measures early after stroke. Design Data in this report were collected during the Very Early Constraint-induced Therapy for Recovery of Stroke trial, an acute, single-blind randomized controlled trial of constraint-induced movement therapy. Subjects were tested at the prerandomization baseline assessment (average days poststroke, 9.5d) and the first posttreatment assessment (average days poststroke, 25.9d). At each time point, the affected upper extremity was evaluated with a battery of 6 tests. At the second assessment, subjects were also asked to provide a global rating of perceived changes in their affected upper extremity. Anchor-based MCID values were calculated separately for the affected dominant upper extremities and the affected nondominant upper extremities for each of the 6 tests. Setting Inpatient rehabilitation hospital. Participants Fifty-two people with hemiparesis poststroke. Interventions Not applicable. Main Outcome Measures Estimated MCID values for grip strength, composite upper-extremity strength, Action Research Arm Test (ARAT), Wolf Motor Function Test (WMFT), Motor Activity Log (MAL), and duration of upper-extremity use as measured with accelerometry. Results MCID values for grip strength were 5.0 and 6.2kg for the affected dominant and nondominant sides, respectively. MCID values for the ARAT were 12 and 17 points, for the WMFT function score were 1.0 and 1.2 points, and for the MAL quality of movement score were 1.0 and 1.1 points for the 2 sides, respectively. MCID values were indeterminate for the dominant (composite strength), the nondominant (WMFT time score), and both affected sides (duration of use) for the other measures. Conclusions Our data provide some of the first estimates of MCID values for upper-extremity standardized measures early after stroke. Future studies with larger sample sizes are needed to refine these estimates and to determine whether MCID values are modified by time poststroke.

Dromerick AW, Edwards DF, Kumar A. Hemiplegic shoulder pain syndrome: frequency and characteristics during inpatient stroke rehabilitation. Objective To clarify the pathophysiology of hemiplegic shoulder pain by determining the frequency of abnormal shoulder physical diagnosis signs and the accuracy of self-report. Design Prospective inception cohort. Setting Academic inpatient stroke rehabilitation service. Participants Consecutive admissions (N=46) to stroke rehabilitation service. Interventions Not applicable. Main Outcome Measures The Neer test, Speed test, acromioclavicular shear test, Rowe test, and palpation for point tenderness. Results Participants were enrolled at a mean time to evaluation of 18.9±14.1 days after stroke. Weakness of shoulder flexion, extension, or abduction was present in 94% of subjects, and neglect was found in 29%. Pain was present by self-report in 37%. The most common finding, which was found in nearly all persons with abnormalities in the study physical examination maneuvers, was bicipital tendon tenderness (54%), followed by supraspinatus tenderness (48%). The Neer sign was positive in 30%; 28% had the triad of bicipital tenderness, supraspinatus tenderness, and the Neer sign. Self-reported pain was a poor predictor of abnormalities elicited on the examination maneuvers, even in those without neglect. Conclusions Our data implicate 2 vertical stabilizers of the humerus in early onset hemiplegic shoulder pain, the long head of the biceps and the supraspinatus. Our results also suggest that simple questioning of stroke rehabilitation inpatients about shoulder pain may not be adequate for clinical care or research purposes, even in the absence of neglect.

Dromerick AW, Schabowsky CN, Holley RJ, Monroe B, Markotic A, Lum P. Effect of training on upper-extremity prosthetic performance and motor learning: a single-case study. Objectives To examine the impact of a new prosthesis on an experienced and highly motivated prosthetic limb user, to evaluate the effects of training and the ability of clinical measures to detect change, and to gain insight into the mechanisms by which improvement occurs. Design A single-case study. Setting An outpatient clinic. Participant A bilateral high-arm amputee (right shoulder disarticulation, left above elbow). Interventions Provision of new prosthesis and occupational therapy. Main Outcome Measures Action Research Arm Test, box and block test of manual dexterity, Jebsen-Taylor Hand Function Test, and speed and accuracy of reaching movements with and without visual guidance. Results In this experienced prosthesis user, provision of a new prosthesis led to an immediate worsening in functional limitation. With training, the subject recovered his baseline status and then exceeded it in both proximal and distal function. All study clinical measures detected change, but the change detected varied as much as 300-fold depending on the measure chosen. The clinical improvements were associated with modest improvements in the speed of reaching but not the accuracy of reaching under visual guidance. Improvements in reaching accuracy without visual guidance were seen after 10 trials, suggesting that some motor learning had occurred. Conclusions Provision of a new prosthesis can cause functional decline even in an experienced user; this decline can be reversed with training. There is wide variability in sensitivity to change among functional limitation measures. Although some training-related improvements may have been due to increased speed and accuracy of reaching without visual guidance, skill in prosthesis use also plays a role.

This study investigated differences in adaptation to a novel dynamic environment between eight trans-radial upper extremity (UE) prosthetic users and eight naive, neurologically intact subjects. Participants held onto the handle of a robotic manipulandum and executed reaching movements within a horizontal plane following a pseudo-random sequence of targets. Curl field perturbations were imposed by the robot motors, and we compared the rate and quality of adaptation between the prosthetic and control subjects. Adaptation was quantitatively assessed by peak error, defined as the maximum orthogonal distance between an observed trajectory and an ideal straight trajectory. Initial exposure to the curl field resulted in large errors, and as the subjects adapted to the novel environment, the errors decreased. During the early phase of adaptation, group differences in the rate of motor adaptation were not significant. However, during late learning, both error magnitude and variability were larger in the prosthetic group. The quality of adaptation, as indicated by the magnitude of the aftereffects, was similar between groups. We conclude that in persons with trans-radial arm amputation, motor adaptation to curl fields during reaching is similar to unimpaired individuals. These findings are discussed in relation to mechanisms of motor adaptation, neural plasticity following an upper extremity amputation (UEA), and potential motor recovery therapies for prosthetic users.

The purposes of this report were to: 1) determine the amount of upper extremity use in people with hemiparesis post stroke during their inpatient rehabilitation stay, and 2) to examine the relationships between upper extremity use and impairments and activity limitations at this early time point after stroke. We studied 34 subjects with mild-to-moderate acute hemiparesis (mean time since stroke = 9.3 days) and 10 healthy control subjects. Upper extremity use was measured over 24 hours using bilateral wrist accelerometers. Upper extremity impairments and activity limitations were measured using standard clinical techniques and tests. We found that healthy control subjects use their dominant and nondominant upper extremities 8-9 hours per day. Hemiparetic subjects used their affected and unaffected upper extremities substantially less than control subjects, 3.3 and 6.0 hours per day, respectively. Seven of ten impairment level measures and each of the activity level measures were related to affected upper extremity use. The impairment measures that were related to upper extremity use were those measures that assessed the ability to activate muscles (ie active range of motion and force production) and the measurement of shoulder pain. Our data show that affected upper extremity use is minimal during the inpatient rehabilitation stay, especially given that patients in this setting are required to have 3 hours of therapy per day. We speculate that accelerometer measurements of upper extremity use could be used in a variety of settings and that the objective information they provide would be of great value to clinicians as they select treatments and evaluate progress.

To investigate upper extremity muscle activation and recovery during the first few months after stroke.Subjects with hemiparesis following stroke were studied performing a reaching task at an acute time point (mean=9 days post-stroke) and then again at a subacute time point (mean=109 days post-stroke). We recorded kinematics and electromyographic activity of six upper extremity muscles.At the acute time point, the hemiparetic group had delayed muscle onsets, lower modulation ratios, and higher relative levels of muscle activation (%MVIC) during reaching than controls. From the acute to the subacute time points, improvements were noted in all three variables. By the subacute phase, muscle onsets were similar to controls, while modulation ratios remained lower than controls and %MVIC showed a trend toward being greater in the hemiparetic group. Changes in muscle activation were differentially related to changes in reaching performance.Our data show that improvements in muscle timing and decreases in the relative level of volitional activation may underlie improved reaching performance in the early months after stroke.Given that stroke is one of the leading causes of persistent physical disability, it is important to understand how the ability to activate muscles changes during the early phases of recovery after injury.

© 2015 Dromerick, Edwardson, Edwards, Giannetti, Barth, Brady, Chan, Tan, Tamboli, Chia, Orquiza, Padilla, Cheema, Mapstone, Fiandaca, Federoff and Newport. Introduction: Seven hundred ninety-five thousand Americans will have a stroke this year, and half will have a chronic hemiparesis. Substantial animal literature suggests that the mammalian brain has much potential to recover from acute injury using mechanisms of neuroplasticity, and that these mechanisms can be accessed using training paradigms and neurotransmitter manipulation. However, most of these findings have not been tested or confirmed in the rehabilitation setting, in large part because of the challenges in translating a conceptually straightforward laboratory experiment into a meaningful and rigorous clinical trial in humans. Through presentation of methods for a Phase II trial, we discuss these issues and describe our approach. Methods: In rodents there is compelling evidence for timing effects in rehabilitation; motor training delivered at certain times after stroke may be more effective than the same training delivered earlier or later, suggesting that there is a critical or sensitive period for strongest rehabilitation training effects. If analogous critical/sensitive periods can be identified after human stroke, then existing clinical resources can be better utilized to promote recovery. The Critical Periods after Stroke Study (CPASS) is a phase II randomized, controlled trial designed to explore whether such a sensitive period exists. We will randomize 64 persons to receive an additional 20 h of upper extremity therapy either immediately upon rehab admission, 2–3 months after stroke onset, 6 months after onset, or to an observation-only control group. The primary outcome measure will be the Action Research Arm Test (ARAT) at 1 year. Blood will be drawn at up to 3 time points for later biomarker studies. Conclusion: CPASS is an example of the translation of rodent motor recovery experiments into the clinical setting; data obtained from this single site randomized controlled trial will be used to finalize the design of a Phase III trial.

Background: Cognitive dysfunction has been considered a primary deficit to be addressed after mild stroke. Higher order cognitive deficits immediately after mild stroke may lead to poor longitudinal outcomes. However, existing stroke outcome studies tend to focus on physical capacity and mood rather than cognitive function. Aim: To examine contribution of acute impairment of executive function(EF) and verbal memory (VM) after mild stroke to one year outcomes on Stroke Impact Scale (SIS, health-related quality of life), Activity Card Sort (ACS, activity participation), and Reintegration to Normal Living (RNL, life satisfaction), independent of demographics, ADL and depression. Methods: Patients with ischemic stroke and initial NIHSS ≤ 5 enrolled in PROTECT-DC trial were included. Multiple linear regression analyses identified baseline variables significantly associated with each outcome of interest for all patients completing both baseline and one-year assessments. For each outcome, Model 1 included covariates: age, sex, race, education, lesion side, NIHSS, Barthel Index, Lawton IADL, and depression. In Model 2, all Model 1 variables and dichotomized cognitive variables (impaired versus not impaired) were entered into the equation. Examination of R2 change between Models 1 & 2 identified unique contributions of impaired EF or VM to each one-year outcome beyond Model 1 variables. Results: A total of 86 participants completed baseline assessment and one-year SIS were included for analyses. Our results show that EF was significantly and independently associated with the SIS total score beyond other baseline variables. Participants with acute EF deficits at baseline had poorer SIS outcome at one year: mean 7.47 lower SIS score compared to patients without EF deficits (p = .021). Similar results were found for ACS and RNL. Conclusion: Analyses suggest impact of EF deficits on activity participation, health-related quality of life, and life satisfaction one year after mild stroke. The findings highlight importance of assessment of EF deficits after mild stroke. We suggest that rehabilitation interventions aimed at improving long-term outcomes require careful consideration of assessing and treating EF deficits during the acute phase of mild stroke.

Therapeutic activity is a mainstay of clinical neurorehabilitation, but is typically unstructured and directed at compensation rather than restoration of central nervous system function. Newer activity-based therapies (ABTs) are in early stages of development and testing. The ABTs attempt to restore function via standardized therapeutic activity based on principles of experimental psychology, exercise physiology, and neuroscience. Three of the best developed ABTs are constraint-induced therapy, robotic therapy directed at the hemiplegic arm, and treadmill training techniques aimed at improving gait in persons with stroke and spinal cord injury. These treatments appear effective in improving arm function and gait, but they have not yet been clearly demonstrated to be more effective than equal amounts of traditional techniques. Resistance training is clearly demonstrated to improve strength in persons with stroke and brain injury, and most studies show that it does not increase hypertonia. Clinical trials of ABTs face several methodological challenges. These challenges include defining dosage, standardizing treatment parameters across subjects and within treatment sessions, and determining what constitutes clinically significant treatment effects. The long-term goal is to develop prescriptive ABT, where specific activities are proven to treat specific motor system disorders. Activity-based therapies are not a cure, but are likely to play an important role in future treatment cocktails for stroke and spinal cord injury.

Patients with mild stroke are assumed to achieve full recovery with little or no intervention. However, recent studies suggest that such patients may experience persistent disability and difficulty with complex activities. We prospectively assessed the impact of mild stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 5) with standard assessments of function, health-related well-being, activity participation, and stroke-specific quality of life. Of 771 patients admitted over 12 months, 377 had an NIHSS score of ≤ 5; of these, 244 met additional inclusion criteria, and 219 were assessed 6 months after stroke onset. Despite full independence in basic activities of daily living, many patients (87%) reported residual stroke-related changes. On average, 7 (standard deviation [SD] = 6.21) stroke-related problems (SD = 6.21) were reported on the Stroke-Adapted Sickness Impact Profile (SA-SIP). Changes in work, driving, and recreational activities were reported. Motor impairment as measured by the NIHSS or the Functional Independence Measure (FIM) motor subscale did not influence scores on outcome measures. Regression analysis predicting life satisfaction ( R 2 = .62) was computed. Our results indicated that SA-SIP score, emotional well-being, and activity participation were significant, but age, race, sex, NIHSS score, and FIM motor and cognitive scores were not significant. In our sample, the determinants of life satisfaction after mild stroke differed from those reported after more severe stroke. Given the mild motor impairments in our sample, other, more subtle consequences of stroke, such as depression, impaired executive function or attention, or other neurologic impairments, may play more important roles in life satisfaction.

Background. The authors assessed patients with acute stroke to determine whether the systematic use of brief screening measures would more efficiently detect cognitive and sensory impairment than standard clinical practice. Methods. Fifty-three patients admitted to an acute stroke unit were assessed within 10 days of stroke onset. Performance on the screening measures was compared to information obtained from review of the patient’s chart at discharge. Cognition, language, visual acuity, visual-spatial neglect, hearing, and depression were evaluated. Results. Formal screening detected significantly more impairments than were noted in patient charts in every domain. Only 3 patients had no impairments identified on screening; all remaining patients had at least 1 impairment detected by screening that was not documented in the chart. Thirty-five percent had 3 or more undetected impairments. Memory impairment was most likely to be noted in the chart; for all other domains tested, undocumented impairment ranged from 61% (neglect) to 97% (anomia). Conclusion. Many acute stroke patients had cognitive and perceptual deficits that were not documented in their charts. These data support the Post-Stroke Rehabilitation Guidelines for systematic assessment even when deficits are not immediately apparent. Systematic screening may improve discharge planning, rehabilitation treatment, and long-term outcome of persons with stroke.

Dromerick AW, Edwards DF. Relation of postvoid residual to urinary tract infection during stroke rehabilitation. Arch Phys Med Rehabil 2003;84:1369–72. Objectives To examine (1) risk factors for urinary tract infection (UTI) during stroke rehabilitation and (2) the relation of postvoid residual (PVR) to the frequency of UTI. Design Prospective case series. Setting Academic specialty stroke rehabilitation service. Participants One hundred one consecutive admissions for stroke rehabilitation. Interventions Not applicable. Main outcome measure Presence or absence of UTI. Results Previously undiagnosed UTI was found in 28 of 101 subjects. Two or more PVR determinations of 150mL or more were an independent risk factor for UTI. In multivariate analysis, factors associated with increased risk of UTI included only use of β-blockers and 2 peak PVR determinations of 150mL or more. Single determinations were not significant. Conclusion The optimal PVR for initiating bladder catheterization during stroke rehabilitation remains unknown, but the risk of UTI increases only when 2 or more ultrasound PVR readings are more than 150mL.

OBJECTIVES/SPECIFIC AIMS: Upper-extremity (UE) impairment affects 88% of stroke survivors due to dysfunctional shoulder-hand coordination. Patients may be able to grasp with the arm at rest, but unable to grasp in a functional context (eg, from a high shelf) because shoulder use elicits involuntary hand muscle activity. Further, much rehabilitation research is directed at unsuccessful stroke recovery (patients with persistent UE impairment) but very little towards patients who show successful clinical recovery (such as those with mild UE impairment) even though these patients have attained the desired rehabilitation outcome. We examined the neurophysiological trajectory of successful compared to unsuccessful post-stroke recovery in the context of functional UE movements to clearly identify what factors are necessary for successful recovery of functional UE movements after stroke. METHODS/STUDY POPULATION: We studied 3 populations: (1) mildly-impaired patients, early (at 6-months post stroke) with persistent hand function impairment, as a model of incomplete post-stroke recovery (unsuccessful recovery), and (3) Healthy age-range matched controls. We used transcranial magnetic stimulation (TMS) in all 3 groups at the given time points to measure corticomotor excitability (motor evoked potentials, recruitment curve), corticomotor inhibition (short-interval intracortical inhibition, long-interval intracortical inhibition), and intracortical facilitation of hand muscles with the shoulder positioned in different degrees of flexion or abduction (these shoulder positions are known to elicit involuntary, undesired hand muscle activation, which leads to UE dysfunction and impairment in individuals with stroke). RESULTS/ANTICIPATED RESULTS: Data collection are in process and will be presented. Preliminary data from controls shows that corticomotor excitability of selected hand muscles is affected by changes in shoulder position. Preliminary findings in controls are consistent with clinical findings in stroke that certain shoulder positions elicit involuntary and undesired hand muscle activation, leading to UE dysfunction and disability. Findings from the stroke groups will be presented. DISCUSSION/SIGNIFICANCE OF IMPACT: We hypothesize that this centrally-facilitated coupling between shoulder and hand muscles is disrupted after stroke, which may play a central role in the inability of patients to perform functional UE movements. By comparing the TMS metrics in mildly-impaired Versus moderately-impaired chronic patients, we will be able to identify the longitudinal change in neurophysiology underlying shoulder-hand coordination that is associated with successful or unsuccessful clinical recovery of UE function after stroke. Thus, these findings will help us distinguish between the neurophysiology underlying successful from unsuccessful UE recovery leading to more mechanism-based interventions for UE dysfunction post stroke in the future.

Background: A NIHSS total score ≤ 5 is a common criteria for mild stroke. Persons with scores in this range are often considered too mild for tPa treatment and not in need of rehabilitation. There may be distinct patterns of stroke symptoms, possibly not all deficits or combination of deficits produce similar levels of disability. Aim: To investigate if patient profiles created by analysis of initial NIHSS item scores predict 90 day and 1 year outcome on the Modified Rankin Scale (mRS) and Stroke Impact Scale (SIS). Methods: Patients with ischemic stroke and initial NIHSS score ≤ 5 enrolled in the PROTECT DC trial were included. Latent class analysis of NIHSS items was used to create discrete symptom profiles: patients with similar item responses were grouped within the same profile group. Logistic regression using profile groups as independent variables predicted 90 day and 1 year mRS scores. Kruskal-Wallace tests examined differences on Stroke Impact Scale (SIS) Participation scores across the groups. Results: 153 participants were included in the latent class analysis, yielding a 3-profile model. Profile A (82 patients, 54%) represented mild strokes with low probability of abnormality on all NIHSS items. Profile B (16 patients, 11%) patients had right-side motor impairment and sensory deficits. Profile C (55 patients, 36%) patients were more likely to have facial palsy and dysarthria. The median NIHSS score decreased from the most severe Profile B (mdn=3.00) to the most mild Profile A (mdn=1.00), with Profile C (mdn=2.00) between the two extremes. Profile B had significantly higher rates (p Conclusion: Patients with initial NIHSS scores ≤ 5 with right-side motor weakness and sensory deficits had more unfavorable outcomes. We suggest that mild strokes are not a homogenous group and should not be treated equally in clinical settings.

Background and Purpose —We sought to determine predictors of acute hospital costs in patients presenting with acute ischemic stroke to an academic center using a stroke management team to coordinate care. Methods —Demographic and clinical data were prospectively collected on 191 patients consecutively admitted with acute ischemic stroke. Patients were classified by insurance status, premorbid modified Rankin scale, stroke location, stroke severity (National Institutes of Health Stroke Scale score), and presence of comorbidities. Detailed hospital charge data were converted to cost by application of department-specific cost-to-charge ratios. Physician’s fees were not included. A stepwise multiple regression analysis was computed to determine the predictors of total hospital cost. Results —Median length of stay was 6 days (range, 1 to 63 days), and mortality was 3%. Median hospital cost per discharge was $4408 (range, $1199 to $59 799). Fifty percent of costs were for room charges, 19% for stroke evaluation, 21% for medical management, and 7% for acute rehabilitation therapies. Sixteen percent were admitted to an intensive care unit. Length of stay accounted for 43% of the variance in total cost. Other independent predictors of cost included stroke severity, heparin treatment, atrial fibrillation, male sex, ischemic cardiac disease, and premorbid functional status. Conclusions —We conclude that the major predictors of acute hospital costs of stroke in this environment are length of stay, stroke severity, cardiac disease, male sex, and use of heparin. Room charges accounted for the majority of costs, and attempts to reduce the cost of stroke evaluation would be of marginal value. Efforts to reduce acute costs should be monitored for potential cost shifting or a negative impact on quality of care.