Steven L. Wolf

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.

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. 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. 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). 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. ClinicalTrials.gov/study/NCT03131960.

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.

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: The 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. Objective: This 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. Methods: WMFT 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. Results: Machine 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). Conclusion: The streamlined WMFT-4 enhances the feasibility of the WMFT for both clinical and research settings while maintaining its original measurement characteristics.

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 P P P P P P 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 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).

The evidence-based quantification of the relation between changes in movement quality and functionality can assist clinicians in achieving more effective structuring or adapting of therapy. In this paper, clinicians rated task, segment, and composite movement feature performance for 478 videos of stroke survivors executing upper extremity therapy tasks. We used the clinician ratings to develop a Hierarchical Bayesian Model (HBM) with task, segment, and composite layers for computing the statistical relation of movement quality changes to function. The model was enhanced through a detailed correlation graph (Δ HBM ) that links computationally extracted kinematics with clinician-rated composite features for different task-segment combinations. Utilizing the weights and correlation graphs, we finally derive reverse cascading probabilities of the proposed HBM from kinematics to composite features, segments, and tasks. In a test involving 98 cases where clinician ratings differed, the HBM resolved 95% of these discrepancies. The model effectively aligned kinematic data with specific task-segment combinations in over 90% of cases. Once the HBM is expanded and refined through additional data it can be used for the automated calculation of statistical relations between changes in kinematics and performance of functional tasks and the generation of therapy assessment recommendations for clinicians. While our work primarily focuses on the upper extremities of stroke survivors, the HBM can be adapted to many other neurorehabilitation contexts.

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 (FM_dist) 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

Excitatory feedback from muscle spindles, and inhibitory feedback from Golgi tendon organs and recurrent inhibitory circuits are widely distributed within the spinal cord to modulate activity between human lower limb muscles. Heteronymous feedback is most commonly studied in humans by stimulating peripheral nerves, but the unique effect of non-spindle heteronymous feedback is difficult to determine due to the lower threshold of excitatory spindle axons. A few studies suggest stimulation of the muscle belly preferentially elicits non-spindle heteronymous feedback. However, there remains a lack of consensus on the differential effect of nerve and muscle stimulation onto the H-reflex, and the relation of the heteronymous effects onto H-reflex compared to that onto ongoing EMG has not been determined. In this cross-sectional study, we compared excitatory and inhibitory effects from femoral nerve and quadriceps muscle belly stimulation onto soleus H-reflex size in 15 able-bodied participants and in a subset also compared heteronymous effects onto ongoing soleus EMG at 10% and 20% max. Femoral nerve stimulation elicited greater excitation of the H-reflex compared to quadriceps stimulation. The differential effect was also observed onto ongoing soleus EMG at 20% max but not 10%. Femoral nerve and quadriceps stimulation elicited similar inhibition of the soleus H-reflexes, and these results were better associated with soleus EMG at 20%. The results support surface quadriceps muscles stimulation as a method to preferentially study heteronymous inhibition at least in healthy adults. The primary benefit of using muscle stimulation is expected to be in persons with abnormal, prolonged heteronymous excitation. These data further suggest heteronymous feedback should be evaluated with H-reflex or onto ongoing EMG of at least 20% max to identify group differences or modulation of heteronymous feedback in response to treatment or task.