One right can make a left: sentence processing in the right hemisphere after perinatal stroke.

When brain regions that are critical for a cognitive function in adulthood are irreversibly damaged at birth, what patterns of plasticity support the successful development of that function in an alternative location? Here we investigate the consistency of language organization in the right hemisphere (RH) after a left hemisphere (LH) perinatal stroke. We analyzed fMRI data collected during an auditory sentence comprehension task on 14 people with large cortical LH perinatal arterial ischemic strokes (left hemisphere perinatal stroke (LHPS) participants) and 11 healthy sibling controls using a "top voxel" approach that allowed us to compare the same number of active voxels across each participant and in each hemisphere for controls. We found (1) LHPS participants consistently recruited the same RH areas that were a mirror-image of typical LH areas, and (2) the RH areas recruited in LHPS participants aligned better with the strongly activated LH areas of the typically developed brains of control participants (when flipped images were compared) than the weakly activated RH areas. Our findings suggest that the successful development of language processing in the RH after a LH perinatal stroke may in part depend on recruiting an arrangement of frontotemporal areas reflective of the typical dominant LH.

Expansion of plasma MicroRNAs over the first month following human stroke.

Few have characterized miRNA expression during the transition from injury to neural repair and secondary neurodegeneration following stroke in humans. We compared expression of 754 miRNAs from plasma samples collected 5, 15, and 30 days post-ischemic stroke from a discovery cohort (n = 55) and 15-days post-ischemic stroke from a validation cohort (n = 48) to healthy control samples (n = 55 and 48 respectively) matched for age, sex, race and cardiovascular comorbidities using qRT-PCR. Eight miRNAs remained significantly altered across all time points in both cohorts including many described in acute stroke. The number of significantly dysregulated miRNAs more than doubled from post-stroke day 5 (19 miRNAs) to days 15 (50 miRNAs) and 30 (57 miRNAs). Twelve brain-enriched miRNAs were significantly altered at one or more time points (decreased expression, stroke versus controls: miR-107; increased expression: miR-99-5p, miR-127-3p, miR-128-3p, miR-181a-3p, miR-181a-5p, miR-382-5p, miR-433-3p, miR-491-5p, miR-495-3p, miR-874-3p, and miR-941). Many brain-enriched miRNAs were associated with apoptosis over the first month post-stroke whereas other miRNAs suggested a transition to synapse regulation and neuronal protection by day 30. These findings suggest that a program of decreased cellular proliferation may last at least 30 days post-stroke, and points to specific miRNAs that could contribute to neural repair in humans.

The Critical Period After Stroke Study (CPASS) Upper Extremity Treatment Protocol.

Objective: To present the development of a novel upper extremity (UE) treatment and assess how it was delivered in the Critical Periods After Stroke Study (CPASS), a phase II randomized controlled trial (RCT). Design: Secondary analysis of data from the RCT. Setting: Inpatient and outpatient settings the first year after stroke. Participants: Of the 72 participants enrolled in CPASS (N=72), 53 were in the study groups eligible to receive the treatment initiated at ≤30 days (acute), 2-3 months (subacute), or ≥6 months (chronic) poststroke. Individuals were 65.1±10.5 years of age, 55% were women, and had mild to moderate UE motor capacity (Action Research Arm Test=17.2±14.3) at baseline. Intervention: The additional 20 hours of treatment began using the Activity Card Sort (ACS), a standardized assessment of activities and participation after stroke, to identify UE treatment goals selected by the participants that were meaningful to them. Treatment activities were broken down into smaller components from a standardized protocol and process that operationalized the treatments essential elements. Main Outcome Measures: Feasibility of performing the treatment in a variety of clinical settings in an RCT and contextual factors that influenced adherence. Results: A total of 49/53 participants fully adhered to the CPASS treatment. The duration and location of the treatment sessions and the UE activities practiced during therapy are presented for the total sample (n=49) and per study group as an assessment of feasibility and the contextual factors that influenced adherence. Conclusions: The CPASS treatment and therapy goals were explicitly based on the meaningful activities identified by the participants using the ACS as a treatment planning tool. This approach provided flexibility to customize UE motor therapy without sacrificing standardization or quantification of the data regardless of the location and UE impairments of participants within the first year poststroke.

Concurrent validity of machine learning-classified functional upper extremity use from accelerometry in chronic stroke.

Objective: This study aims to investigate the validity of machine learning-derived amount of real-world functional upper extremity (UE) use in individuals with stroke. We hypothesized that machine learning classification of wrist-worn accelerometry will be as accurate as frame-by-frame video labeling (ground truth). A second objective was to validate the machine learning classification against measures of impairment, function, dexterity, and self-reported UE use. Design: Cross-sectional and convenience sampling. Setting: Outpatient rehabilitation. Participants: Individuals (>18 years) with neuroimaging-confirmed ischemic or hemorrhagic stroke >6-months prior (n = 31) with persistent impairment of the hemiparetic arm and upper extremity Fugl-Meyer (UEFM) score = 12-57. Methods: Participants wore an accelerometer on each arm and were video recorded while completing an "activity script" comprising activities and instrumental activities of daily living in a simulated apartment in outpatient rehabilitation. The video was annotated to determine the ground-truth amount of functional UE use. Main outcome measures: The amount of real-world UE use was estimated using a random forest classifier trained on the accelerometry data. UE motor function was measured with the Action Research Arm Test (ARAT), UEFM, and nine-hole peg test (9HPT). The amount of real-world UE use was measured using the Motor Activity Log (MAL). Results: The machine learning estimated use ratio was significantly correlated with the use ratio derived from video annotation, ARAT, UEFM, 9HPT, and to a lesser extent, MAL. Bland-Altman plots showed excellent agreement between use ratios calculated from video-annotated and machine-learning classification. Factor analysis showed that machine learning use ratios capture the same construct as ARAT, UEFM, 9HPT, and MAL and explain 83% of the variance in UE motor performance. Conclusion: Our machine learning approach provides a valid measure of functional UE use. The accuracy, validity, and small footprint of this machine learning approach makes it feasible for measurement of UE recovery in stroke rehabilitation trials.

Measurement of Functional Use in Upper Extremity Prosthetic Devices Using Wearable Sensors and Machine Learning.

Trials for therapies after an upper limb amputation (ULA) require a focus on the real-world use of the upper limb prosthesis. In this paper, we extend a novel method for identifying upper extremity functional and nonfunctional use to a new patient population: upper limb amputees. We videotaped five amputees and 10 controls performing a series of minimally structured activities while wearing sensors on both wrists that measured linear acceleration and angular velocity. The video data was annotated to provide ground truth for annotating the sensor data. Two different analysis methods were used: one that used fixed-size data chunks to create features to train a Random Forest classifier and one that used variable-size data chunks. For the amputees, the fixed-size data chunk method yielded good results, with 82.7% median accuracy (range of 79.3-85.8) on the 10-fold cross-validation intra-subject test and 69.8% in the leave-one-out inter-subject test (range of 61.4-72.8). The variable-size data method did not improve classifier accuracy compared to the fixed-size method. Our method shows promise for inexpensive and objective quantification of functional upper extremity (UE) use in amputees and furthers the case for use of this method in assessing the impact of UE rehabilitative treatments.

Interpreting the CPASS Trial: Do Not Shift Motor Therapy to the Subacute Phase.

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.

Language and developmental plasticity after perinatal stroke.

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.

Barriers to Enrollment in Post-Stroke Brain Stimulation in a Racially and Ethnically Diverse Population.

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.

A trade-off between kinematic and dynamic control of bimanual reaching in virtual reality.

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.

Genetic Factors, Brain Atrophy, and Response to Rehabilitation Therapy After Stroke.

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.

Emotion recognition impairments and social well-being following right-hemisphere stroke.

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.

Critical Period After Stroke Study (CPASS): A phase II clinical trial testing an optimal time for motor recovery after stroke in humans.

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.

Why Are Stroke Rehabilitation Trial Recruitment Rates in Single Digits?

Background: Recruitment of patients in early subacute rehabilitation trials (<30 days post-stroke) presents unique challenges compared to conventional stroke trials recruiting individuals >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.

Shoulder position and handedness differentially affect excitability and intracortical inhibition of hand muscles.

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.

Inaccurate Use of the Upper Extremity Fugl-Meyer Negatively Affects Upper Extremity Rehabilitation Trial Design: Findings From the ICARE Randomized Controlled Trial.

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.

Improving Accelerometry-Based Measurement of Functional Use of the Upper Extremity After Stroke: Machine Learning Versus Counts Threshold Method.

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.

The neural basis of language development: Changes in lateralization over age.

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.

Characterizing upper extremity motor behavior in the first week after stroke.

BACKGROUND: Animal models of brain recovery identify the first days after lesioning as a time of great flux in sensorimotor function and physiology. 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. METHODS: This prospective observational study used a convenience sample of patients (n = 25, mean 4.5 ±1.8) days after stroke with a wide severity range; Controls were hospitalized for non-neurological conditions (n = 12). Outcome measures were Accelerometry, Upper-Extremity Fugl-Meyer (UEFM), Action Research Arm Test (ARAT), Shoulder Abduction/ Finger Extension Test (SAFE), NIH Stroke Scale (NIHSS). RESULTS: Accelerometry 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. Thus, movement shifted early after stroke; bilateral use was reduced and unilateral use of the non-paretic UE was 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 orthogonal component (quantity of movement). CONCLUSIONS: Early after stroke, spontaneous overall UE movement is reduced, and movement shifts to unilateral use of the non-paretic UE. Two mechanisms that could influence motor recovery may already be in place 4.5 ± 1.8 days post stroke: (1) the overuse of the less affected UE, which could set the stage for learned non-use and (2) skill acquisition in the non-paretic limb that could impede recovery. 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.

Author Correction: Plasma microRNA markers of upper limb recovery following human stroke.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Roles of Lesioned and Nonlesioned Hemispheres in Reaching Performance Poststroke.

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.