Background:Stroke leads to complex chronic structural and functional brain changes that specifically affect motor outcomes. The brain-predicted age difference (brain-PAD) has emerged as a sensitive biomarker. Our previous study showed higher global brain-PAD associated with poorer motor function post-stroke. However, the relationship between local stroke lesion load, regional brain age, and motor impairment remains unclear. Methods:We studied 501 individuals with chronic unilateral stroke (>180 days post-stroke) from the ENIGMA Stroke Recovery Working Group dataset (34 cohorts). Structural T1-weighted MRI scans were used to estimate regional brain-PAD in 18 predefined functional subregions via a graph convolutional network algorithm. Lesion load for each region was calculated based on lesion overlap. Linear mixed-effects models assessed associations between lesion size, local lesion load, and regional brain-PAD. Machine learning classifiers predicted motor outcomes using lesion loads and regional brain-PADs. Structural equation modeling examined directional relationships among corticospinal tract lesion load (CST-LL), ipsilesional brain-PAD, motor outcomes, and contralesional brain-PAD. Findings:Larger total lesion size was positively associated with higher ipsilesional regional brain-PADs (older brain age) across most regions (p < 0.05), and with lower contralesional brain-PAD, notably in the ventral attention-language network (p < 0.05). Higher local lesion loads showed similar patterns. Specifically, lesion load in the salience network significantly influenced regional brain-PADs across both hemispheres. Machine learning models identified CST-LL, salience network lesion load, and regional brain-PAD in the contralesional frontoparietal network as the top three predictors of motor outcomes. Structural equation modeling revealed that larger stroke damage was associated with poorer motor outcomes (β = -0.355, p < 0.001), which were further linked to younger contralesional brain age (β = 0.204, p < 0.001), suggesting that severe motor impairment is linked to compensatory decreases in contralesional brain age. Interpretation:Our findings reveal that larger stroke lesions are associated with accelerated aging in the ipsilesional hemisphere and paradoxically decelerated brain aging in the contralesional hemisphere, suggesting compensatory neural mechanisms. Assessing regional brain age may serve as a biomarker for neuroplasticity and inform targeted interventions to enhance motor recovery after stroke. Fundings:Micheal J Fox Foundation, National Institutes of Health, Canadian Institutes of Health Research, National Health and Medical Research Council, Australian Brain Foundation, Wicking Trust, Collie Trust, and Sidney and Fiona Myer Family Foundation, National Heart Foundation, Hospital Israelita Albert Einstein, Australian Research Council Future Fellowship, Wellcome Trust, National Institute for Health Research Imperial Biomedical Research Centre, European Research Council, Deutsche Forschungsgemeinschaft, REACT Pilot, National Resource Center, Research Council of Norway, South-Eastern Norway Regional Health Authority, Norwegian Extra Foundation for Health and Rehabilitation, Sunnaas Rehabilitation Hospital HT, University of Oslo, and VA Rehabilitation Research and Development.

ObjectiveThe aim of the study is to evaluate the safety of onabotulinumtoxinA treatment for spasticity across dose ranges in real-world practice.DesignAdult Spasticity International Registry was a multicenter, prospective, observational study (NCT01930786) of onabotulinumtoxinA treatment for adult spasticity over 2 yrs. Adverse events, serious adverse events, treatment-related adverse events, and serious treatment-related adverse events were sorted into five categories (<= 200, 201-400, 401-600, 601-800, >= 801 U) based on cumulative dose per session.ResultsIn 3103 treatment sessions (T), 730 patients received >= 1 dose of onabotulinumtoxinA. Dose categories included the following: <= 200 U (n = 312, T = 811), 201-400 U (n = 446, T = 1366), 401-600 U (n = 244, T = 716), 601-800 U (n = 69, T = 149), and >= 801 U (n = 29, T = 61). Of these patients, 261 reported 827 adverse events, 94 reported 195 serious adverse events, 20 reported 23 treatment-related adverse events, and 2 patients treated with 201-400 U onabotulinumtoxinA reported 3 serious treatment-related adverse events. Treatment-related adverse events reported included <= 200 U (8/811, 0.9%), 201-400 U (7/1366, 0.5%), 401-600 U (6/716, 0.8%), 601-800 U (1/149, 0.7%), and >= 801 U (1/61, 1.6%).ConclusionsIn this post hoc analysis, most treatment sessions were performed with 201-400 U onabotulinumtoxinA. Patients treated with 201-400 U onabotulinumtoxinA had an adverse event profile consistent with onabotulinumtoxinA package inserts globally (e.g., United States, European Union, United Kingdom, Canada). No new safety signals were identified.

Background Repetitive task practice reduces mean upper extremity motor impairment in populations of patients with chronic stroke, but individual response is highly variable. A method to predict meaningful reduction in impairment in response to training based on biomarkers and other data collected prior to an intervention is needed to establish realistic rehabilitation goals and to effectively allocate resources. Objectives To identify prognostic factors and better understand the biological substrate for reductions in arm impairment in response to repetitive task practice among patients with chronic (≥6 months) post-stroke hemiparesis. Methods The intervention is a form of repetitive task practice using a combination of robot-assisted therapy and functional arm use in real-world tasks. Baseline measures include the Fugl-Meyer Assessment, Wolf Motor Function Test, Action Research Arm Test, Stroke Impact Scale, questionnaires on pain and expectancy, MRI, transcranial magnetic stimulation, kinematics, accelerometry, and genomic testing. Results Mean increase in FM-UE was 4.6 ± 1.0 SE, median 2.5. Approximately one-third of participants had a clinically meaningful response to the intervention, defined as an increase in FM ≥ 5. The selected logistic regression model had a receiver operating curve with AUC = .988 (Std Error = .011, 95% Wald confidence limits: .967–1) showed little evidence of overfitting. Six variables that predicted response represented impairment, functional, and genomic measures. Conclusion A simple weighted sum of 6 baseline factors can accurately predict clinically meaningful impairment reduction after outpatient intensive practice intervention in chronic stroke. Reduction of impairment may be a critical first step to functional improvement. Further validation and generalization of this model will increase its utility in clinical decision-making.

Research Objectives Examine onabotulinumtoxinA utilization in patients with upper limb (UL) and lower limb (LL) spasticity from the Adult Spasticity International Registry (ASPIRE) study to gain real-world insights into the treatment of spastic hemiparesis. Design Prospective, observational registry (NCT01930786). Setting International clinical sites. Participants Adults with spasticity across multiple etiologies. Interventions OnabotulinumtoxinA at the clinician's discretion. Main Outcome Measures OnabotulinumtoxinA utilization and safety data were collected at each treatment session. Patients with spastic hemiparesis were defined as receiving ≥ 1 UL treatment and ≥ 1 LL treatment during the study. Results ASPIRE patients (N=730) were on average 53.6 years old, 52%; female, 77% Caucasian, 37% naïve to botulinum toxin(s) for spasticity, and 56% post-stroke. Of N=730, n=284 patients were defined as hemiparetic. In hemiparetic patients treated for UL and LL at the same session (n=275), the mean total dose of onabotulinumtoxinA was 477 U for UL+LL, 257 U for UL, and 220 U for LL. Of n=275 hemiparetic patients, 56%; had a treatment interval of 10-15 weeks, 62% had 5-15 injections/session, and 82% had >5 muscles injected/session. Clenched fist was the most common UL presentation (n=219 patients), with 55% of sessions to the left side only. Equinovarus foot was the most common LL presentation (n=238 patients), with 52% of sessions to the left side only. Of the hemiparetic population (n=284), 115 patients (41%) reported 375 adverse events; 42 patients (15%) reported 80 serious adverse events. No new safety signals were identified. Conclusions This preliminary analysis from ASPIRE provides valuable, real-world evidence on the use of onabotulinumtoxinA to treat patients with combined upper limb and lower limb spasticity. OnabotulinumtoxinA was most frequently utilized to treat clenched fist (UL) and equinovarus foot (LL) in patients with spastic hemiparesis. Author(s) Disclosures Bavikatte: Consultant for Allergan(AbbVie); Francisco: Consulted/research grants from Allergan(AbbVie), Merz, and Ipsen; Esquenazi: Consulted for Allergan(AbbVie), Ipsen, and Merz. Received research grants from Allergan(AbbVie) and Ipsen; Dimyan: None reported; Ngo: None reported; Schwartz: Statistical consultant for Allergan(AbbVie); Zuzek: AbbVie employee; Jost: Speaker/consultant for Allergan(AbbVie), Ipsen, and Merz. Examine onabotulinumtoxinA utilization in patients with upper limb (UL) and lower limb (LL) spasticity from the Adult Spasticity International Registry (ASPIRE) study to gain real-world insights into the treatment of spastic hemiparesis. Prospective, observational registry (NCT01930786). International clinical sites. Adults with spasticity across multiple etiologies. OnabotulinumtoxinA at the clinician's discretion. OnabotulinumtoxinA utilization and safety data were collected at each treatment session. Patients with spastic hemiparesis were defined as receiving ≥ 1 UL treatment and ≥ 1 LL treatment during the study. ASPIRE patients (N=730) were on average 53.6 years old, 52%; female, 77% Caucasian, 37% naïve to botulinum toxin(s) for spasticity, and 56% post-stroke. Of N=730, n=284 patients were defined as hemiparetic. In hemiparetic patients treated for UL and LL at the same session (n=275), the mean total dose of onabotulinumtoxinA was 477 U for UL+LL, 257 U for UL, and 220 U for LL. Of n=275 hemiparetic patients, 56%; had a treatment interval of 10-15 weeks, 62% had 5-15 injections/session, and 82% had >5 muscles injected/session. Clenched fist was the most common UL presentation (n=219 patients), with 55% of sessions to the left side only. Equinovarus foot was the most common LL presentation (n=238 patients), with 52% of sessions to the left side only. Of the hemiparetic population (n=284), 115 patients (41%) reported 375 adverse events; 42 patients (15%) reported 80 serious adverse events. No new safety signals were identified. This preliminary analysis from ASPIRE provides valuable, real-world evidence on the use of onabotulinumtoxinA to treat patients with combined upper limb and lower limb spasticity. OnabotulinumtoxinA was most frequently utilized to treat clenched fist (UL) and equinovarus foot (LL) in patients with spastic hemiparesis.

Interhemispheric interactions are important for arm coordination and hemispheric specialization. Unilateral voluntary static contraction is known to increase bilateral corticospinal motor evoked potential (MEP) amplitude. It is unknown how increasing and decreasing contraction affect the opposite limb. Since dynamic muscle contraction is more ecologically relevant to daily activities, we studied MEP recruitment using a novel method and short interval interhemispheric inhibition (IHI) from active to resting hemisphere at 4 phases of contralateral ECR contraction: Rest, Ramp Up [increasing at 25% of maximum voluntary contraction (MVC)], Execution (tonic at 50% MVC), and Ramp Down (relaxation at 25% MVC) in 42 healthy adults. We analyzed the linear portion of resting extensor carpi radialis (ECR) MEP recruitment by stimulating at multiple intensities and comparing slopes, expressed as mV per TMS stimulation level, via linear mixed modeling. In younger participants (age ≤ 30), resting ECR MEP recruitment slopes were significantly and equally larger both at Ramp Up (slope increase = 0.047, p < 0.001) and Ramp Down (slope increase = 0.031, p < 0.001) compared to rest, despite opposite directions of force change. In contrast, Active ECR MEP recruitment slopes were larger in Ramp Down than all other phases (Rest:0.184, p < 0.001; Ramp Up:0.128, p = 0.001; Execution: p = 0.003). Older (age ≥ 60) participants’ resting MEP recruitment slope was higher than younger participants across all phases. IHI did not reduce MEP recruitment slope equally in old compared to young. In conclusion, our data indicate that MEP recruitment slope in the resting limb is affected by the homologous active limb contraction force, irrespective of the direction of force change. The active arm MEP recruitment slope, in contrast, remains relatively unaffected. Older participants had steeper MEP recruitment slopes and less interhemispheric inhibition compared to younger participants.

OBJECTIVE:To demonstrate the feasibility of algorithmic prediction using a model of baseline arm movement, genetic factors, demographic characteristics, and multimodal assessment of the structure and function of motor pathways. To identify prognostic factors and the biological substrate for reductions in arm impairment in response to repetitive task practice. DESIGN:This prospective single-group interventional study seeks to predict response to a repetitive task practice program using an intent-to-treat paradigm. Response is measured as a change of ≥5 points on the Upper Extremity Fugl-Meyer from baseline to final evaluation (at the end of training). SETTING:General community. PARTICIPANTS:Anticipated enrollment of community-dwelling adults with chronic stroke (N = 96; onset≥6mo) and moderate to severe residual hemiparesis of the upper limb as defined by a score of 10-45 points on the Upper Extremity Fugl-Meyer. INTERVENTION:The intervention is a form of repetitive task practice using a combination of robot-assisted therapy coupled with functional arm use in real-world tasks administered over 12 weeks. MAIN OUTCOME MEASURES:Upper Extremity Fugl-Meyer Assessment (primary outcome), Wolf Motor Function Test, Action Research Arm Test, Stroke Impact Scale, questionnaires on pain and expectancy, magnetic resonance imaging, transcranial magnetic stimulation, arm kinematics, accelerometry, and a saliva sample for genetic testing. RESULTS:Methods for this trial are outlined, and an illustration of interindividual variability is provided by example of 2 participants who present similarly at baseline but achieve markedly different outcomes. CONCLUSION:This article presents the design, methodology, and rationale of an ongoing study to develop a predictive model of response to a standardized therapy for stroke survivors with chronic hemiparesis. Applying concepts from precision medicine to neurorehabilitation is practicable and needed to establish realistic rehabilitation goals and to effectively allocate resources.

The laterality of the lesioned hemisphere is often overlooked in stroke recovery research due to small sample sizes. Here, we used a well-powered dataset from ENIGMA Stroke Recovery (a consortium that harmonizes post-stroke MRIs and behavioral data worldwide; http://enigma.usc.edu) to analyze the effects of left (LHL) versus right (RHL) hemisphere lesions on motor performance. Given the different functional roles of each hemisphere, we hypothesized that the LHL group should show better motor performance, and, consequently, different brain-behavior relationships, compared to the RHL group. Data from over 2000 stroke patients across 20 sites worldwide has been committed. To date, structural T1-weighted MRIs from n=343 (10 sites) have been analyzed (LHL n=174; RHL n=169). ENIGMA protocols extracted volumes of subcortical regions of interest and provided quality control. Regression analyses examined brain volumes as predictors of motor outcomes. Motor scores were combined across scales/sites, with each score expressed as a percentage of the maximum score. Covariates (e.g., age, sex, intracranial volume) and manually marked lesion effects were also modeled. Statistical significance was assessed nonparametrically by permutation. As anticipated, the LHL group had better motor performance compared to the RHL group (t(1,341)=3.07, p=0.0023). In addition, while the combined LHL+RHL analyses showed significant associations between motor scores and volumes of the basal ganglia/lateral ventricles, separate group analyses showed strong associations for the LHL group, but only one association for the RHL group (Table 1). This may suggest that motor recovery following RH lesions is more heterogeneous or relies more on cortical regions/networks that were not assessed here. While further research is needed, these results suggest that laterality of the lesioned hemisphere affects neural patterns related to motor recovery and should be carefully examined.

OBJECTIVE:To develop a clinically useful patient-reported screening tool for health care providers to identify patients with spasticity in need of treatment regardless of etiology.DESIGN:Eleven spasticity experts participated in a modified Delphi panel and reviewed and revised 2 iterations of a screening tool designed to identify spasticity symptoms and impact on daily function and sleep. Spasticity expert panelists evaluated items pooled from existing questionnaires to gain consensus on the screening tool content. The study also included cognitive interviews of 20 patients with varying spasticity etiologies to determine if the draft screening tool was understandable and relevant to patients with spasticity.RESULTS:The Delphi panel reached an initial consensus on 21 of 47 items for the screening tool and determined that the tool should have no more than 11 to 15 items and a 1-month recall period for symptom and impact items. After 2 rounds of review, 13 items were selected and modified by the expert panelists. Most patients (n = 16 [80%]) completed the cognitive interview and interpreted the items as intended.CONCLUSIONS:Through the use of a Delphi panel and patient interviews, a 13-item spasticity screening tool was developed that will be practical and easy to use in routine clinical practice.

Objective: To determine whether nonparetic arm force overinhibits the paretic arm in patients with chronic unilateral poststroke hemiparesis.Design: Case-control neurophysiological and behavioral study of patients with chronic stroke. Setting: Research institution.Participants: Eighty-six referred patients were screened to enroll 9 participants (N=9) with a > 6 month history of 1 unilateral ischemic infarct that resulted in arm hemiparesis with residual ability to produce 1Nm of wrist flexion torque and without contraindication to transcranial magnetic stimulation. Eight age- and handedness-matched healthy volunteers without neurologic diagnosis were studied for comparison.Interventions: Not applicable. Main Outcome Measure: Change in interhemispheric inhibition targeting the ipsilesional primary motor cortex (M1) during nonparetic arm force. We hypothesized that interhemispheric inhibition would increase more in healthy controls than in patients with hemiparesis.Results: Healthy age-matched controls had significantly greater increases in inhibition from their active to resting M1 than patients with stroke from their active contralesional to resting ipsilesional M1 in the same scenario (20% +/- 7% vs -1% +/- 4%, F (1,12)=6.61, P =.025). Patients with greater increases in contralesional to ipsilesional inhibition were better performers on the 9-hole peg test of paretic arm function.Conclusions: Our findings reveal that producing force with the nonparetic arm does not necessarily overinhibit the paretic arm. Though our study is limited in generalizability by the small sample size, we found that greater active contralesional to resting ipsilesional M1 inhibition was related with better recovery in this subset of patients with chronic poststroke. (C) 2014 by the American Congress of Rehabilitation Medicine

Approximately one-third of patients with stroke exhibit persistent disability after the initial cerebrovascular episode, with motor impairments accounting for most poststroke disability. Exercise and training have long been used to restore motor function after stroke. Better training strategies and therapies to enhance the effects of these rehabilitative protocols are currently being developed for poststroke disability. The advancement of our understanding of the neuroplastic changes associated with poststroke motor impairment and the innate mechanisms of repair is crucial to this endeavor. Pharmaceutical, biological and electrophysiological treatments that augment neuroplasticity are being explored to further extend the boundaries of poststroke rehabilitation. Potential motor rehabilitation therapies, such as stem cell therapy, exogenous tissue engineering and brain-computer interface technologies, could be integral in helping patients with stroke regain motor control. As the methods for providing motor rehabilitation change, the primary goals of poststroke rehabilitation will be driven by the activity and quality of life needs of individual patients. This Review aims to provide a focused overview of neuroplasticity associated with poststroke motor impairment, and the latest experimental interventions being developed to manipulate neuroplasticity to enhance motor rehabilitation.

One of the most challenging tasks of the brain is to constantly update the internal neural representations of existing memories. Animal studies have used invasive methods such as direct microfusion of protein inhibitors to designated brain areas, in order to study the neural mechanisms underlying modification of already existing memories after their reactivation during recall [1-4]. Because such interventions are not possible in humans, it is not known how these neural processes operate in the human brain. In a series of experiments we show here that when an existing human motor memory is reactivated during recall, modification of the memory is blocked by virtual lesion [5] of the related primary cortical human brain area. The virtual lesion was induced by noninvasive repetitive transcranial magnetic stimulation guided by a frameless stereotactic brain navigation system and each subject's brain image. The results demonstrate that primary cortical processing in the human brain interacting with pre-existing reactivated memory traces is critical for successful modification of the existing related memory. Modulation of reactivated memories by noninvasive cortical stimulation may have important implications for human memory research and have far-reaching clinical applications.

Background and Purpose— Recent work demonstrated that application of peripheral nerve and cortical stimulation independently can induce modest improvements in motor performance in patients with stroke. The purpose of this study was to test the hypothesis that combining peripheral nerve stimulation (PNS) to the paretic hand with anodal direct current stimulation (tDCS) to the ipsilesional primary motor cortex (M1) would facilitate beneficial effects of motor training more than each intervention alone or sham (tDCS Sham and PNS Sham ). Methods— Nine chronic stroke patients completed a blinded crossover designed study. In separate sessions, we investigated the effects of single applications of PNS+tDCS, PNS+tDCS Sham , tDCS+PNS Sham , and PNS Sham +tDCS Sham before motor training on the ability to perform finger motor sequences with the paretic hand. Results— PNS+tDCS resulted in a 41.3% improvement in the number of correct key presses relative to PNS Sham +tDCS Sham , 15.4% relative to PNS+tDCS Sham , and 22.7% relative to tDCS+PNS Sham . These performance differences were maintained 1 and 6 days after the end of the training. Conclusions— These results indicate that combining PNS with tDCS can facilitate the beneficial effects of training on motor performance beyond levels reached with each intervention alone, a finding of relevance for the neurorehabilitation of motor impairments after stroke.

1 Modulation of iTBS effects applied over primary motor cortex 2 (M1) by conditioning stimulation of the opposite M1 3 4 5 Patrick Ragert1,2, Mickael Camus1, Yves Vandermeeren1,3, Michael A. Dimyan1, 6 Leonardo G. Cohen 7 8 1 Human Cortical Physiology and Stroke Neurorehabilitation Section (HCPS), 9 National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of 10 Health (NIH), Bethesda, MD 20817, USA 11 2 Max Planck Institute for Human Cognitive and Brain Sciences, Department of 12 Cognitive Neurology, 04103 Leipzig, Germany 13 3 Neurology Department, Cliniques universitaires UCL de Mont-Godinne, Yvoir, 14 Belgium 15 16 * Correspondence: 17

The excitability of the human primary motor cortex (M1) as tested with transcranial magnetic stimulation (TMS) depends on its previous history of neural activity. Homeostatic plasticity might be one important physiological mechanism for the regulation of corticospinal excitability and synaptic plasticity. Although homeostatic plasticity has been demonstrated locally within M1, it is not known whether priming M1 could result in similar homeostatic effects in the homologous M1 of the opposite hemisphere. Here, we sought to determine whether down-regulating excitability (priming) in the right (R) M1 with 1-Hz repetitive transcranial magnetic stimulation (rTMS) changes the excitability-enhancing effect of intermittent theta burst stimulation (iTBS) applied over the homologous left (L) M1. Subjects were randomly allocated to one of four experimental groups in a sham-controlled parallel design with real or sham R M1 1-Hz TMS stimulation always preceding L M1 iTBS or sham by about 10 min. The primary outcome measure was corticospinal excitability in the L M1, as measured by recruitment curves (RCs). Secondary outcome measures included pinch force, simple reaction time, and tapping speed assessed in the right hand. The main finding of this study was that preconditioning R M1 with 1-Hz rTMS significantly decreased the excitability-enhancing effects of subsequent L M1 iTBS on RCs. Application of 1-Hz rTMS over R M1 alone and iTBS over L M1 alone resulted in increased RC in L M1 relative to sham interventions. The present findings are consistent with the hypothesis that homeostatic mechanisms operating across hemispheric boundaries contribute to regulate motor cortical function in the primary motor cortex.