OBJECTIVE:The aim of the study was to compare the effects of repetitive transcranial magnetic stimulation targeting the contralesional dorsal premotor versus the ipsilesional primary motor cortex in chronic stroke survivors with severe hand paresis. DESIGN:This assessor-blinded pilot randomized trial enrolled 16 participants ≥6 mos after stroke with severe hand paresis, defined by the absence of either 10° distal extension in wrist/fingers/thumb or motor evoked potentials in paretic muscles. Participants received 5-Hz repetitive transcranial magnetic stimulation to the contralesional dorsal premotor or the ipsilesional primary motor cortex target, combined with upper extremity rehabilitation for 6 wks. Outcomes included Upper Extremity Fugl-Meyer, Wolf Motor Function Test, Stroke Impact Scale-16, and interhemispheric inhibition. RESULTS:Baseline characteristics were similar across groups, although the ipsilesional stimulation group had more participants with motor evoked potentials and ≥10° thumb extension (P = 0.04). Both groups achieved similar gains on Fugl-Meyer, but wrist subscore changes favored the ipsilesional stimulation group (P = 0.011). No differences were observed for other outcomes. CONCLUSIONS:Stimulation of the contralesional dorsal premotor cortex was not superior to stimulation of the ipsilesional primary motor cortex for upper extremity rehabilitation outcomes in chronic stroke survivors with severe hand paresis, though both approaches yielded sustained motor improvements. Future trials should stratify by distal extension and physiology.

Over the past 2 decades, transcranial direct current stimulation has attracted substantial interest as an adjunctive strategy to enhance poststroke motor recovery. In addition to its potential neuromodulatory effects on motor cortical networks, transcranial direct current stimulation devices are low-cost, easy to use, and compatible with concurrent rehabilitation. Yet, despite its promise, several barriers hinder translation into routine clinical practice, including neutral results from several recently completed multicenter trials, such as TRANSPORT2 (Transcranial Direct Current Stimulation for Post-Stroke Motor Recovery). Moving forward, progress will depend on addressing issues in 3 broad domains: device-related (stimulation parameters and montage), disease-related (patient characteristics and timing), and trial design (outcomes, analytical approaches, adjunctive therapy, and trial infrastructure). In this topical review, we critically examine these challenges and outline strategies to refine transcranial direct current stimulation application, with the goal of more effectively leveraging its neuromodulation properties to promote neuroplasticity and enhance motor recovery after stroke.

INTRODUCTION:Millions of stroke survivors in the US have sensory-motor impairments that significantly impact quality of life and place a long-term burden on families, communities, and the healthcare system. Neurorehabilitation aims to improve function, typically through repetitive practice of movements and task-related activities where doses are regularly titrated by skilled clinicians. Unfortunately, these highly intensive, skilled interventions are challenging to implement at the scale needed to serve the needs of stroke survivors. Rehabilitation technologies have long promised to be the workforce multiplier to normalize this large supply-demand mismatch in the U.S. healthcare system. Extensive investigations into rehabilitation devices have revealed myriad benefits. While rehab technologies have the potential to improve function, these inferences are largely derived from academic clinical studies which, while useful for exploring efficacy, do not represent marketplace (ie, commercial) conditions where interventions must operate to serve the larger population. METHODS:Here, we present data from the first nationwide direct-to-consumer deployment of 2 home-based rehabilitation robotic systems. RESULTS:Analysis of 3182 device deployments from August 2019 to June 2024 reveal surprising patterns in usage and compliance. We investigate the effects of socio-economic status, sex, rural-urban classification, and engagement on long-term utilization. Finally, we provide preliminary dose-response insights. DISCUSSION AND CONCLUSIONS:We discuss the influence of market forces on commercial delivery of care to inform stakeholders of the challenges faced translating interventions to the consumer. Overall, we aim to derive lessons that can guide future implementations and improve the inclusivity and effectiveness of rehabilitation technologies deployed at scale.

OBJECTIVES: Vagus nerve stimulation (VNS) paired with rehabilitation improves short-term upper extremity (UE) function in people with chronic ischemic stroke. Because sustained improvements are needed for people with stroke, we examined the long-term effects of Paired VNS on impairment, activity, participation, and quality of life. METHODS: This is a post hoc analysis of 2-year data of the triple-blind, sham-controlled, randomized VNS-REHAB pivotal trial. After receiving the full therapeutic protocol with either real (Active) or sham (Control) VNS, participants continued self-activated active stimulation for at least 2 years. The Fugl-Meyer Assessment-Upper Extremity (FMA-UE), Wolf Motor Function Test (WMFT), participation, and quality of life outcomes were assessed at multiple time points. RESULTS: < 0.001) from baseline. There were significant improvements from baseline in 5 of 7 participation and quality of life measures at 2 years. Improvements were retained at 3 years among a subset of participants (n = 16). DISCUSSION: The sustained improvements in UE impairment and function for at least 2 years make this an important treatment option for a defined subset of individuals with chronic arm and hand deficits after ischemic stroke. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov/study/NCT03131960.

OBJECTIVES:Vagus nerve stimulation (VNS) paired with rehabilitation improves short-term upper extremity (UE) function in people with chronic ischemic stroke. Because sustained improvements are needed for people with stroke, we examined the long-term effects of Paired VNS on impairment, activity, participation, and quality of life. METHODS:This is a post hoc analysis of 2-year data of the triple-blind, sham-controlled, randomized VNS-REHAB pivotal trial. After receiving the full therapeutic protocol with either real (Active) or sham (Control) VNS, participants continued self-activated active stimulation for at least 2 years. The Fugl-Meyer Assessment-Upper Extremity (FMA-UE), Wolf Motor Function Test (WMFT), participation, and quality of life outcomes were assessed at multiple time points. RESULTS:Pooled 2-year outcome data were available from 49 participants. At the 2-year point, FMA-UE scores improved 7.51 points (95% CI 5.80-9.22; p < 0.001), and WFMT scores improved 0.63 points (0.50-0.75; p < 0.001) from baseline. There were significant improvements from baseline in 5 of 7 participation and quality of life measures at 2 years. Improvements were retained at 3 years among a subset of participants (n = 16). DISCUSSION:The sustained improvements in UE impairment and function for at least 2 years make this an important treatment option for a defined subset of individuals with chronic arm and hand deficits after ischemic stroke. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov/study/NCT03131960.

Parkinson’s disease disrupts motor control across multiple body parts, yet the neural mechanisms underlying these impairments remain incompletely defined. We compared resting-state functional connectivity in people with mild-to-moderate Parkinson’s disease ( n = 58) and neurotypical older adults ( n = 24), focusing on regions implicated in internally generated (IG) and externally generated (EG) movement pathways. For our analysis, we leveraged the reproducible NeuroMark independent component template and motor effector-specific mapping of primary motor cortex (M1). Our results reveal both increased and decreased connectivity patterns in Parkinson’s disease: M1 subregions associated with control of the leg, hand, and larynx showed robust increases in connectivity exclusively with cerebellar territories, particularly Crus II and Lobules VIIIa/VIIIb. The postcentral gyrus (primary somatosensory cortex) showed primarily increased connectivity with cerebellar regions and the insula. In contrast, the caudate nucleus displayed a mixed profile, with increased connectivity to the superior temporal gyrus and decreased connectivity to the superior medial frontal gyrus and cerebellar Crus II. Our motor effector-specific analysis of disease severity scores (MDS-UPDRS) in people with Parkinson’s disease revealed mild impairments across all categories (leg, hand, larynx) but disproportionately greater hand-related deficits, suggesting that some of the observed M1 connectivity differences may be influenced by these behavioral asymmetries. These anatomically precise, effector-specific alterations suggest compensatory recruitment of cerebellar circuits in Parkinson’s disease and provide a framework for targeting motor subcircuits in rehabilitation, including dance-based interventions.

BackgroundThe Wolf Motor Function Test (WMFT) is a well-recognized measure for assessing upper extremity motor function in stroke rehabilitation. However, prolonged administration time limits the WMFT in clinical use.ObjectiveThis study aimed to reduce the number of WMFT tasks using machine learning and explore its measurement structure and psychometric properties, using data from 3 stroke rehabilitation trials that together engaged 543 participants with a wide range of motor impairment during subacute and chronic recovery phases.MethodsWMFT performance time data were converted to rates and outliers were eliminated using multivariate normality tests. Random forest regression with the elbow method was employed to determine the optimal number of items in the WMFT. Further, a machine learning technique with cross-validation and bootstrapping was used to select items. We used confirmatory factor analysis to determine the measurement structure of the original and shortened version of WMFT. Psychometric properties of the shortened version were also assessed.ResultsMachine learning-based item reduction identified 4 items (Hand to Table, Hand to Box, Extend Elbow Without Weight, and Lift Can) as representative tasks. Factor analysis revealed a 2-factor structure for both original and shorten versions, comprising non-manipulative/transport and manipulative/dexterity factors. WMFT-4 showed strong convergent validity with WMFT-15 (R = 0.98, P < .001) and moderate cross-domain validity with the Fugl-Meyer Assessment of Upper Extremity (FMA-UE) (R = 0.523, P < .001), comparable to the original WMFT-15 (R = 0.526, P < .001).ConclusionThe streamlined WMFT-4 enhances the feasibility of the WMFT for both clinical and research settings while maintaining its original measurement characteristics.

BACKGROUND:Infants and toddlers with perinatal arterial ischemic stroke face a high risk for lifelong neuromotor impairments and multiple disabilities. Phase 3 clinical trial evidence is urgently needed to identify efficacious treatment to improve outcomes. METHODS:The I-ACQUIRE Phase 3 trial (Perinatal Arterial Stroke: A Multisite RCT of Intensive Infant Rehabilitation) is a 15-site randomized clinical trial of 2 dosages of I-ACQUIRE, a multicomponent, therapist-delivered intervention including key components of constraint-induced movement therapy compared with usual and customary treatment. The trial recruited children 8 to 36 months old with parent-reported perinatal arterial ischemic stroke, hemiparesis, good health, and no prior botulinum toxin or constraint-induced movement therapy. Central 1:1:1 randomization assigned children to High-dose I-ACQUIRE (6-hour sessions, 5 days/wk, 4 weeks), Moderate-dose I-ACQUIRE (3-hour sessions, 5 days/wk, 4 weeks), and Usual and Customary Treatment. Blinded assessments at baseline, end-of-treatment, and 6-months later include the Emerging Behaviors Scale (success defined as % with gains ≥7 points), the primary outcome for unilateral skills on the paretic arm-and-hand; and the Mini-Assisting Hand Assessment, the secondary outcome for bimanual activities. Parents also rate children's motor skills, treatment responses, and stress. Statistical analyses include 2-sample binomial tests for group differences and linear mixed regression models. The registered trial adheres to international trial reporting guidelines and has a parent council. RESULTS:This study protocol describes intervention components plus training and monitoring of treatment fidelity. The trial recruited N=216 children; 198 completed baseline assessments, and 168 (85 boys and 83 girls) qualified for the modified intent-to-treat sample. The mean age was 18.0 (SD=7.6) months. A majority had right-sided paresis (70%); 51% had seizures/epilepsy. Children varied widely in functional classification levels and parent ratings. CONCLUSIONS:The trial sets a unique high threshold for efficacy and proposes sensitivity and exploratory analyses to consider differential response patterns to treatment. If 1 or both I-ACQUIRE dosages lead to significant improvements, then Phase 3 evidence will assist in infant/toddler rehabilitation decision-making. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03910075.

BACKGROUND:Persistent upper extremity (UE) impairment is common after stroke. Durable treatment benefits for chronic ischemic stroke are needed. The purpose of this report is to determine the long-term effects of vagus nerve stimulation paired with rehabilitation on impairment, activity, and participation in people with UE impairment after ischemic stroke. METHODS:This is a post hoc analysis of data from the VNS-REHAB (A Pivotal Randomized Study Assessing Vagus Nerve Stimulation [VNS] During Rehabilitation for Improved Upper Limb Motor Function After Stroke) randomized clinical trial. Here, we report unblinded, partial crossover, and pooled 1-year outcomes. Initially, 108 participants across 19 sites with chronic ischemic stroke and moderate-to-severe UE impairment were enrolled in VNS-REHAB. Participants received 18 sessions of in-clinic intensive task-specific rehabilitation and 3 months of self-initiated home-based exercise with either real (active) or sham (control) vagus nerve stimulation. Thereafter, Control participants crossed over to receive in-clinic therapy paired with active stimulation. All participants performed home-based exercises paired with self-initiated active stimulation for 1 year. The Fugl-Meyer Assessment UE, Wolf Motor Function Test, and participation outcomes were assessed through 12 months. RESULTS:Seventy-four participants (69%; 51 male; age, mean±SD, 59.6±8.9) completed 1-year follow-up and provided pooled data through 1 year. At 1 year, compared with baseline, there were improvements in impairment (Fugl-Meyer Assessment UE, 5.23 [95% CI, 4.08-6.39]; P<0.001) activity (Wolf Motor Function Test, 0.50 [95% CI, 0.41-0.59]; P<0.001) and patient-reported outcomes (Motor Activity Log-Quality of Movement: 0.64 [95% CI, 0.46-0.82], P<0.001; Motor Activity Log-Amount of Use: 0.64 [95% CI, 0.46-0.82], P<0.001; Stroke Impact Scale-Activities of Daily Living: 7.43 [95% CI, 5.09-9.77], P<0.001; Stroke Impact Scale-Hand: 17.89 [95% CI, 14.16-21.63], P<0.001; EQ-5D: 5.76 [95% CI, 2.08-9.45], P<0.05; and Stroke Specific-Quality of Life: 0.29 [95% CI, 0.19-0.39], P<0.001) compared with baseline. CONCLUSIONS:People treated with paired vagus nerve stimulation maintained improvements in UE impairment, activity, participation, and quality-of-life measures at 1 year. Paired vagus nerve stimulation is a Food and Drug Administration-approved, beneficial treatment option for long-term benefit in individuals with chronic UE limitations after ischemic stroke. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03131960.

Background: Recent findings suggest increased excitatory heteronymous feedback from quadriceps onto soleus may contribute to abnormal coactivation of knee and ankle extensors after stroke. However, there is lack of consensus on whether persons post-stroke exhibit altered heteronymous reflexes and, when present, the origin of increased excitation (i.e. increased excitation alone and/or decreased inhibition). This study examined heteronymous excitation and inhibition from quadriceps onto soleus in paretic, nonparetic, and age-matched control limbs to determine whether increased excitation was due to excitatory and/or reduced inhibitory reflex circuits. A secondary purpose was to examine whether heteronymous reflex magnitudes were related to clinical measures of lower limb recovery, walking-speed, and dynamic balance. Methods: Heteronymous excitation and inhibition from quadriceps onto soleus were examined in fourteen persons post-stroke and fourteen age-matched unimpaired participants. Heteronymous feedback was elicited by femoral nerve and quadriceps muscle stimulation in separate trials while participants tonically activated soleus at 20% max. Fugl-Myer assessment of lower extremity, 10-meter walk test, and Mini-BESTest were assessed in stroke survivors. Results: Heteronymous excitation and inhibition onsets, durations, and magnitudes were not different between paretic, nonparetic or age-matched unimpaired limbs. Quadriceps stimulation elicited excitation that was half the magnitude of femoral nerve stimulation. Femoral nerve elicited paretic limb heteronymous excitation was positively correlated with walking speed but did not reach significance because only a subset of paretic limbs exhibited excitation (n = 8, Spearman r = 0.69, P = 0.058). Conclusions: Heteronymous feedback from quadriceps onto soleus assessed in a seated posture was not impaired in persons post-stroke. Despite being unable to identify whether reduced inhibition contributes to abnormal excitation reported in prior studies, our results indicate quadriceps stimulation may allow a better estimate of heteronymous inhibition in those that exhibit exaggerated excitation. Heteronymous excitation magnitude in the paretic limb was positively correlated with self-selected walking speed suggesting paretic limb excitation at the higher end of a normal range may facilitate walking ability after stroke. Future studies are needed to identify whether heteronymous feedback from Q onto SOL is altered after stroke in upright postures and during motor tasks as a necessary next step to identify mechanisms underlying motor impairment.

Heteronymous reflexes from quadriceps can increase and/or decrease soleus activity; yet few studies have examined factors influencing reflex strength. This study examined the independent influence of limb loading, posture, and task context on heteronymous feedback from quadriceps onto soleus. The influence of limb loading and posture was determined by comparing femoral nerve elicited heteronymous excitation and inhibition of soleus in a semi-recumbent position with and without 50% body weight limb loading and while standing with back support (n = 16). Task context was examined by comparing heteronymous reflex magnitudes while standing with back support to maintaining an unsupported squat posture which requires tonic soleus activity to maintain the posture (n = 12). Heteronymous inhibition decreased by 20% with limb loading in both semi-recumbent and standing postures, while excitation remained unchanged suggesting that limb loading, rather than postural orientation, independently modulates heteronymous inhibition. Inhibition decreased by 50% and excitation by 90% when maintaining the squat posture compared to supported standing, The pronounced suppression of both excitation and inhibition during the squat is considered a task-appropriate reflex modulation that aids in maintaining the posture. The results of this study highlight an important modulatory influence of limb loading afferents and task context on heteronymous reflex circuits.

Background:Enhancing the efficacy of gait rehabilitation is an important area of need as most persons with a history of stroke continue to experience gait deficits following discharge from rehabilitation. Incorporating gamification and real-time biofeedback into gait retraining may provide benefits by increasing engagement and salience of stepping practice to target specific gait parameters, maximizing therapeutic impact on walking function. The objective of this study was to evaluate the feasibility and preliminary effects of a novel, customized, gamified gait biofeedback interface specifically designed to enhance propulsion during gait training. Methods:A repeated-measures design was used to compare 3 speed-matched treadmill walking bouts: (1) walking without biofeedback (noBF); (2) walking while receiving simple, real-time audiovisual conventional biofeedback (cBF); and (3) walking while receiving gamified, real-time audiovisual biofeedback (gBF). Gait biomechanics, physiological intensity, and self-reports of task workload, user experience, and engagement were obtained from 15 participants (9 able-bodied, 6 post-stroke). Results:Compared to noBF, both gBF and cBF showed significantly greater increases in peak anterior ground reaction force, trailing limb angle, and ankle moment of the targeted leg during biofeedback exposure (Min. 3) and during the post-test without biofeedback exposure (Post), with moderate to large effect sizes. Compared to walking without biofeedback, both biofeedback conditions induced significantly greater physiological intensity (heart rate and rating of perceived exertion). NASA-Task Load Index results showed that gBF induced a higher workload than cBF for mental demand, temporal demand, performance, frustration, and effort. Also, gBF was rated higher in the novelty component of the User Experience Questionnaire. Conclusions:This preliminary study confirmed the feasibility of real-time gamified gait biofeedback, suggesting that gBF can induce similar enhancements in gait biomechanics and physiological intensity as cBF, while promoting greater task load and mental demand during walking practice. This work lays foundations for future studies that further refine and customize the game design, as well as evaluate the effects of gBF in larger samples and greater training dosage. Trial registration:This study was registered on ClinicalTrials.gov (NCT04013971) and all study procedures were approved by the human subjects review board (IRB00106866). The study started 04/04/2022 and ended 03/31/2023.

OBJECTIVE:Common data elements (CDEs) help harmonize data collection across clinical trials and observational studies, allowing for cross-study and cross-condition comparisons. Although CDEs exist for multiple clinical conditions and diseases, this work was extended only recently to neurorehabilitation research. DESIGN:Subgroups of clinical neurorehabilitation investigators operationalized a domain definition, selected applicable CDEs from 23 existing National Institute of Neurological Disorders and Stroke (NINDS) CDE projects and National Institutes of Health (NIH) CDE repositories, and identified areas needing further development. The subgroups also reviewed public comments on the NeuroRehab-specific CDEs, which were provided from September 1, 2021 to October 7, 2021. In March 2022, version 1.0 of the NeuroRehab CDEs was completed and can be found on the NINDS CDE website: https://www.commondataelements.ninds.nih.gov/. SETTING:NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Center for Medical Rehabilitation Research identified NeuroRehab CDEs across 12 different research domains: (1) assessments and examinations; (2) comorbid and behavioral conditions; (3) motor function; (4) treatment/intervention data: therapies; (5) treatment/intervention data: devices; (6) cognitive; (7) communication; (8) emotion/behavior/neuropsychology; (9) activities of daily living/instrumental activities of daily living; (10) quality of life; (11) participation; and (12) infant and pediatrics. Within each domain, corresponding subdomain experts identified instruments with good psychometric measurement properties. PARTICIPANTS:One hounded twenty experts (N=120) in rehabilitation across the 12 identified research domains and 2 cochairs with rehabilitation and measurement expertise provided oversight. INTERVENTIONS:Not applicable. MAIN OUTCOME MEASURES:CDEs from 23 existing NINDS CDE projects and NIH CDE repositories. RESULTS:Clinical investigators recommended NeuroRehab CDEs within 3 dimensions of the NINDS CDE classifications: Core, (Disease) Core, and Supplemental-Highly Recommended. Most measures were categorized as Supplemental-Highly Recommended; few were identified as Core or Disease Core. The subgroups also identified measurement gap areas to guide future initiatives because NeuroRehab CDEs will be developed in the future. CONCLUSIONS:These efforts are designed to accelerate rehabilitation research in neurologic disorders by allowing for cross-study and cross-condition comparisons and to encourage new CDE development.

ObjectiveTo evaluate differences in upper extremity (UE) segment-specific (proximal or distal segment) recovery after Vagus nerve stimulation (VNS) paired with UE rehabilitation (Paired-VNS) compared to rehabilitation with sham-VNS (Control). We also assessed whether gains in specific UE segments predicted clinically meaningful improvement.DesignThis study reports on a secondary analysis of the randomized, triple-blinded, sham-controlled pivotal VNS-REHAB trial. A Rasch latent regression was used to determine differences between Paired-VNS and Controls for distal and proximal UE changes after in-clinic therapy and 3-months later. Subsequently, we ran a random forest model to assess candidate predictors of meaningful improvement. Each item of the Fugl-Meyer Assessment-Upper Extremity and Wolf Motor Function Test was evaluated as a predictor of response to treatment.SettingData analyzed in this study were obtained from the completed VNS-REHAB trial. Participants received intensive UE rehabilitation from physical and occupational therapists in an outpatient setting for 6 weeks, followed by a home-based exercise program.ParticipantsDataset included 108 participants with chronic ischemic stroke and moderate-to-severe UE impairments.InterventionsN/AMain Outcome MeasuresFugl-Meyer Assessment-Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT)ResultsDistal UE improvement was significantly greater in the Paired-VNS group compared to Controls immediately post-therapy (95% CI [0.27-0.73], p≤0.001) and after 3-months (95% CI [0.16-0.75], p=0.003). Both groups showed similar improvement in proximal UE at both time points. A subset of both distal and proximal items from the FMA-UE and WMFT were predictors of meaningful improvement.ConclusionsPaired-VNS improved distal UE impairment in chronic stroke to a greater degree than intensive rehabilitation alone. Proximal improvements were equally responsive to either treatment. Given that meaningful UE recovery is predicted by improvements across both proximal and distal segments, Paired-VNS may facilitate improvement that is otherwise elusive.

Background and purpose: Implantable vagus nerve stimulation (VNS) paired with volitional upper extremity rehabilitation can improve impairment and function among moderately to severely impaired, chronic stroke survivors. This study is a retrospective analysis of the in-clinic rehabilitation phase of the blinded, placebo-controlled, randomized pivotal VNS-REHAB trial to determine whether dosing parameters during in-clinic paired VNS therapy were associated with responder status and whether covariates might impact that determination. Methods: Data were limited to 53 participants in the active VNS group who had received VNS implants prior to undergoing 6 weeks of in-clinic rehabilitation paired with VNS. Tasks were standardized across all participants. Dosing parameters included number of stimulations and task time. The primary outcome was the Fugl-Meyer Upper Extremity Assessment (FMA-UE), evaluated at the end of 6 weeks (Post-1). Participants were classified a priori as responders based on an improvement of ≥6 points on the FMA-UE from baseline to Post-1. Results: Dosing parameters were not associated with FMA-UE responder status at the end of 6 weeks. Covariates including age, gender, paretic hand, baseline severity, and chronicity of stroke were also not significant associations of response. Discussion and Conclusions: While responders to VNS could be defined, therapy dosing and participant attributes did not provide greater specification for association of responder status. Limitations of this study include small sample size and non-linearity of the FMA-UE. Future studies will include reassessing responder categorization using more linear scales and examining stroke lesion characteristics to determine whether these measures are more sensitive to dosing parameters. Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://www.w3.org/1999/xlink).

Heteronymous inhibition between lower limb muscles is primarily attributed to recurrent inhibitory circuits in humans but could also arise from Golgi tendon organs (GTOs). Distinguishing between recurrent inhibition and mechanical activation of GTOs is challenging because their heteronymous effects are both elicited by stimulation of nerves or a muscle belly above motor threshold. Here, the unique influence of mechanically activated GTOs was examined by comparing the magnitude of heteronymous inhibition from quadriceps (Q) muscle belly stimulation onto ongoing soleus (SOL) EMG at five Q stimulation intensities (1.5-2.5x motor threshold) before and after an acute bout of stimulation-induced Q fatigue. Fatigue was used to decrease Q stimulation evoked force (i.e., decreased GTO activation) despite using the same pre-fatigue stimulation currents (i.e., same antidromic recurrent inhibition input). Thus, a decrease in heteronymous inhibition after Q fatigue and a linear relation between stimulation-evoked torque and inhibition both before and after fatigue would support mechanical activation of GTOs as a source of inhibition. A reduction in evoked torque but no change in inhibition would support recurrent inhibition. After fatigue, Q stimulation-evoked knee torque, heteronymous inhibition magnitude, and inhibition duration were significantly decreased for all stimulation intensities. In addition, heteronymous inhibition magnitude was linearly related to twitch-evoked knee torque before and after fatigue. These findings support mechanical activation of GTOs as a source of heteronymous inhibition along with recurrent inhibition. The unique patterns of heteronymous inhibition before and after fatigue across participants suggest the relative contribution of GTOs and recurrent inhibition may vary across persons.

Background: Persistent post-stroke impairment of the arm and hand is debilitating after stroke. Pairing vagus nerve stimulation (VNS) with upper extremity (UE) rehabilitation improves such deficits after 5 months and was approved by the FDA in 2021. Here, we present 1-year outcomes from the VNS-REHAB pivotal trial. Methods: Stroke participants with moderate-to-severe UE impairment were randomized to task-specific rehabilitation plus either active VNS (n=53, VNS) or sham VNS (n=55, Control). After baseline assessment (Pre-therapy), both groups did 6 wk. of in-clinic therapy followed by a 3-mo. home exercise program combined with active or sham VNS (post90). Controls then crossed over to receive 6 wk. of active VNS followed by a 3-mo. home exercise program (Cross-over post90). Both groups continued active VNS with a home exercise program through 1 year, after which change from Pre-therapy baseline in Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT) scores were obtained. To determine whether participants made additional gains, 1 year outcome scores (n=70) were also compared to post90 (n=38, VNS) and Cross-over post90 (n=32, Control) scores. Data was available from 74 participants at one year, with others not available mainly due to COVID-19. Results: At 1-year, both FMA-UE and WMFT scores improved from Pre-therapy baseline by 5.3±6.9 (CI=3.7-6.9, p<0.001) and 0.51±0.52 (CI=0.39-0.63, p<0.001) points, respectively. FMA-UE change at 1-year was not significantly different from the post90 (VNS) and Cross-over post90 (control) timepoints (n=70, mean difference: -0.3±4.1, CI=-1.3-0.67, p=0.52), but WMFT was, by an additional 0.09 points (n=70, mean difference: 0.09±0.35, CI=0.01-0.18, p=0.03), indicating that participants either improved or maintained motor gains through 1 year. Conclusion: Improvements in arm and hand function with VNS were maintained at 1-year follow-up, supporting use of VNS paired with rehabilitation as a long-term treatment option for individuals with post-stroke UE impairment. Limitations include sample size and lack of details of therapeutic regimens over the long term. Future studies and an ongoing clinical registry will explore the long-term impact of active VNS in real-world settings.

OBJECTIVE:Vagus nerve stimulation (VNS) paired with rehabilitation therapy improved motor status compared to rehabilitation alone in the phase III VNS-REHAB stroke trial, but treatment response was variable and not associated with any clinical measures acquired at baseline, such as age or side of paresis. We hypothesized that neuroimaging measures would be associated with treatment-related gains, examining performance of regional injury measures versus global brain health measures in parallel with clinical measures. METHODS:Baseline magnetic resonance imaging (MRI) scans in the VNS-REHAB trial were used to derive regional injury measures (extent of injury to corticospinal tract, the primary regional measure; plus extent of injury to precentral gyrus and postcentral gyrus; lesion volume; and lesion topography) and global brain health measures (degree of white matter hyperintensities, the primary global brain measure; plus volumes of cerebrospinal fluid, cortical gray matter, white matter, each thalamus, and total brain). Eight clinical measures assessed at baseline were also evaluated (treatment group, age, race, gender, paretic side, pre-stroke dominant hand, time since stroke, and baseline Fugl-Meyer upper extremity score). Bivariate analyses compared each measure with the primary trial end point (change in Fugl-Meyer upper extremity score from baseline to end of 6 weeks of treatment) across all subjects, with secondary analyses examining trial groups separately. RESULTS:MRIs were available from 80 patients (age = 59.8 ± 9.5 years, 29 women). Across all patients, less white matter hyperintensities (r = -0.25, p = 0.028) at baseline was associated with larger Fugl-Meyer score change. In the VNS group, less white matter hyperintensities (r = -0.37, p = 0.018) and larger ipsilesional thalamus volume (r = 0.33, p = 0.046) were each associated with larger Fugl-Meyer score change. Analysis of covariance (ANCOVA) analyses tested the interaction that each baseline measure had with treatment group and found that the model examining white matter hyperintensities had a significant interaction term, indicating 2.3 less change in Fugl-Meyer Upper Extremity (FM-UE) points in the VNS group relative to the control group for each point increase in modified Fazekas scale. INTERPRETATION:Neuroimaging measures are associated with extent of gains on the primary endpoint of a phase III stroke recovery trial. Among the neuroimaging measures examined, a measure of global brain health (extent of white matter hyperintensities) was better at explaining the change in arm impairment as compared with measures of regional injury; this was true when examining all study subjects as well as only those in the VNS group and is consistent with the global mechanism of action that VNS has throughout the cerebrum. Future studies can evaluate additional measures that further predict response to VNS therapy. The current findings suggest that individual patient neuroimaging results may be useful for a personalized medicine approach to stroke recovery therapeutics. ANN NEUROL 2025;97:709-719.

BACKGROUND:Changes in regional levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may indicate the potential for favorable responses to the treatment of stroke affecting the upper extremity. By selectively altering GABA levels during training, we may induce long-term potentiation and adjust excitatory/inhibitory balance (E/I balance). However, the impact of this alteration may be limited by neural damage or aging. Aerobic exercise has been shown to increase GABA levels in the sensorimotor cortex and improve motor learning by widening the dynamic range of E/I balance. The cross-sectional project, Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke (EASE), is designed to assess the functional relevance of changes in GABA concentration within the sensorimotor cortex before and after an acute aerobic exercise session. METHODS/DESIGN:EASE will enroll 30 participants comprised of healthy younger adults (18-35 years; n = 10), older adults (60+ years; n = 10), and persons with chronic stroke (n = 10) affecting distal upper extremity function. We will use resting magnetic resonance spectroscopy to measure all participants' GABA levels at rest before and after aerobic exercise. In addition, we will employ functional magnetic resonance spectroscopy using motor skill acquisition and recall tasks in healthy adults. We hypothesize that acute aerobic exercise will increase resting sensorimotor GABA concentration and that higher GABA resting levels will predict better motor learning performance on measures taken both inside and outside the magnet. We also hypothesize that a higher dynamic range of GABA during task-based spectroscopy in healthy adults will predict better motor skill acquisition and recall. DISCUSSION:The EASE project will evaluate the effect of acute exercise on GABA levels as a biomarker of upper extremity motor skill learning with two populations (aging adults and those with chronic stroke). We predict that acute exercise, higher sensorimotor GABA levels, and broader dynamic range will be related to better motor skill acquisition.

Background Vagus nerve stimulation (VNS) combined with rehabilitation is a Food and Drug Administration approved intervention for moderate to severe upper extremity deficits in chronic ischemic stroke patients. Previous studies demonstrated that VNS improves upper extremity motor impairments, using the Fugl Meyer Assessment of Upper Extremity (FMA-UE); however, delineating where these improvements occur, and the role of VNS dosage parameters were not reported. Objective This study explored the relationship between dosing (time over which task repetitions were executed and number of VNS stimulations) and changes within proximal and distal components of the FMA-UE. Methods Participants underwent VNS implantation, with 1 group receiving VNS paired with rehabilitation (Active VNS) and the other group receiving rehabilitation with sham stimulation (Controls). Both groups received 6 weeks of in-clinic therapy followed by a 90-day at-home, self-rehabilitation program. Participants who completed at least 12 of 18 in-clinic sessions were included in the analyses (n = l06). Pearson correlations and analysis of covariance were used to investigate the relationship between dosing and FMA-UE outcome change along with the effect of covariates including baseline severity, time since stroke, age, and paretic side. Results Compared to Controls, active VNS favorably influenced distal function with sustained improvement after the home program. Significant improvements were observed in only distal components (FMdist) at both post day-1 (1.80 points, 95% Cl [0.85, 2.73], P < .001) and post-day 90 (1.62 points, 95% CI [0.45, 2.80], P < .007). Conclusions VNS paired with rehabilitation resulted in significant improvements in wrist and hand impairment compared to Controls, despite similar in-clinic dosing across both groups. NCT03131960