White Matter Integrity and Chronic Poststroke Upper Limb Function: An ENIGMA Stroke Recovery Analysis.

BACKGROUND: Integrity of the corticospinal tract (CST) is an important biomarker for upper limb motor function following stroke. However, when structurally compromised, other tracts may become relevant for compensation or recovery of function. METHODS: We used the ENIGMA Stroke Recovery data set, a multicenter, retrospective, and cross-sectional collection of patients with upper limb impairment during the chronic phase of stroke to test the relevance of tracts in individuals with less and more severe (laterality index of CST fractional anisotropy ≥0.25) CST damage in an observational study design. White matter integrity was quantified using fractional anisotropy for the CST, the superior longitudinal fascicle, and the callosal fibers interconnecting the primary motor cortices between hemispheres. Optic radiations served as a control tract as they have no a priori relevance for the motor system. Pearson correlation was used for testing correlation with upper limb motor function (Fugl-Meyer upper extremity). RESULTS: From 1235 available data sets, 166 were selected (by imaging, Fugl-Meyer upper extremity, covariates, stroke location, and stage) for analyses. Only individuals with severe CST damage showed a positive association of fractional anisotropy in both callosal fibers interconnecting the primary motor cortices (r[21]=0.49; P=0.025) and superior longitudinal fascicle (r[21]=0.51; P=0.018) with Fugl-Meyer upper extremity. CONCLUSIONS: Our data support the notion that individuals with more severe damage of the CST depend on residual pathways for achieving better upper limb outcome than those with less affected CST.

Variation of body weight supported treadmill training parameters during a single session can modulate muscle activity patterns in post-stroke gait.

Evidence supporting the benefits of locomotor training (LT) to improve walking ability following stroke are inconclusive and could likely be improved with a better understanding of the effects of individual parameters i.e., body weight support (BWS), speed, and therapist assistance and their interactions with walking ability and specific impairments. We evaluated changes in muscle activity of thirty-seven individuals with chronic stroke (> 6 months), in response to a single session of LT at their self-selected or fastest-comfortable speed (FS) with three levels of BWS (0%, 15%, and 30%), and at FS with 30% BWS and seven different combinations of therapist assistance at the paretic foot, non-paretic foot, and trunk. Altered Muscle Activation Pattern (AMAP), a previously developed tool in our lab was used to evaluate the effects of LT parameter variation on eight lower-extremity muscle patterns in individuals with stroke. Repeated-measures mixed-model ANOVA was used to determine the effects of speed, BWS, and their interaction on AMAP scores. The Wilcoxon-signed rank test was used to determine the effects of therapist-assisted conditions on AMAP scores. Increased BWS mostly improved lower-extremity muscle activity patterns, but increased speed resulted in worse plantar flexor activity. Abnormal early plantar flexor activity during stance decreased with assistance at trunk and both feet, exaggerated plantar flexor activity during late swing decreased with assistance to the non-paretic foot or trunk, and diminished gluteus medius activity during stance increased with assistance to paretic foot and/or trunk. Therefore, different sets of training parameters have different immediate effects on activation patterns of each muscle and gait subphases.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

The ENIGMA Stroke Recovery Working Group: Big data neuroimaging to study brain-behavior relationships after stroke.

The goal of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well-powered meta- and mega-analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large-scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.

Muscle contributions to pre-swing biomechanical tasks influence swing leg mechanics in individuals post-stroke during walking.

BACKGROUND: Successful walking requires the execution of the pre-swing biomechanical tasks of body propulsion and leg swing initiation, which are often impaired post-stroke. While excess rectus femoris activity during swing is often associated with low knee flexion, previous work has suggested that deficits in propulsion and leg swing initiation may also contribute. The purpose of this study was to determine underlying causes of propulsion, leg swing initiation and knee flexion deficits in pre-swing and their link to stiff knee gait in individuals post-stroke. METHODS: Musculoskeletal models and forward dynamic simulations were developed for individuals post-stroke (n = 15) and healthy participants (n = 5). Linear regressions were used to evaluate the relationships between peak knee flexion, braking and propulsion symmetry, and individual muscle contributions to braking, propulsion, knee flexion in pre-swing, and leg swing initiation. RESULTS: Four out of fifteen of individuals post-stroke had higher plantarflexor contributions to propulsion and seven out of fifteen had higher vasti contributions to braking on their paretic leg relative to their nonparetic leg. Higher gastrocnemius contributions to propulsion predicted paretic propulsion symmetry (p = 0.005) while soleus contributions did not. Higher vasti contributions to braking in pre-swing predicted lower knee flexion (p = 0.022). The rectus femoris had minimal contributions to lower knee flexion acceleration in pre-swing compared to contributions from the vasti. However, for some individuals with low knee flexion, during pre-swing the rectus femoris absorbed more power and the iliopsoas contributed less power to the paretic leg. Total musculotendon work done on the paretic leg in pre-swing did not predict knee flexion during swing. CONCLUSIONS: These results emphasize the multiple causes of propulsion asymmetry in individuals post-stroke, including low plantarflexor contributions to propulsion, increased vasti contributions to braking and reliance on compensatory mechanisms. The results also show that the rectus femoris is not a major contributor to knee flexion in pre-swing, but absorbs more power from the paretic leg in pre-swing in some individuals with stiff knee gait. These results highlight the need to identify individual causes of propulsion and knee flexion deficits to design more effective rehabilitation strategies.

Altered muscle activation patterns (AMAP): an analytical tool to compare muscle activity patterns of hemiparetic gait with a normative profile.

BACKGROUND: Stroke survivors often have lower extremity sensorimotor impairments, resulting in an inability to sufficiently recruit muscle activity at appropriate times in a gait cycle. Currently there is a lack of a standardized method that allows comparison of muscle activation in hemiparetic gait post-stroke to a normative profile. METHODS: We developed a new tool to quantify altered muscle activation patterns (AMAP). AMAP accounts for spatiotemporal asymmetries in stroke gait by evaluating the deviations of muscle activation specific to each gait sub-phase. It also recognizes the characteristic variability within the healthy population. The inter-individual variability of normal electromyography (EMG) patterns within some sub-phases of the gait cycle is larger compared to others, therefore AMAP penalizes more for deviations in a gait sub-phase with a constant profile (absolute active or inactive) vs variable profile. EMG data were collected during treadmill walking, from eight leg muscles of 34 stroke survivors at self-selected speeds and 20 healthy controls at four different speeds. Stroke survivors' AMAP scores, for timing and amplitude variations, were computed in comparison to healthy controls walking at speeds matched to the stroke survivors' self-selected speeds. RESULTS: Altered EMG patterns in the stroke population quantified using AMAP agree with the previously reported EMG alterations in stroke gait that were identified using qualitative methods. We defined scores ranging between ±2.57 as "normal". Only 9% of healthy controls were outside "normal" window for timing and amplitude. Percentages of stroke subjects outside the "normal" window for each muscle were, Soleus = 79%; 73%, Medial Gastrocnemius = 62%; 79%, Tibialis Anterior = 62%; 59%, and Gluteus Medius = 48%; 51% for amplitude and timing component respectively, alterations were relatively smaller for the other four muscles. Paretic-propulsion was negatively correlated to AMAP scores for the timing component of Soleus. Stroke survivors' self-selected walking speed was negatively correlated with AMAP scores for amplitude and timing of Soleus but only amplitude of Medial gastrocnemius (p < 0.05). CONCLUSIONS: Our results validate the ability of AMAP to identify alterations in the EMG patterns within the stroke population and its potential to be used to identify the gait phases that may require more attention when developing an optimal gait training paradigm. TRIAL REGISTRATION: ClinicalTrials.gov NCT00712179 , Registered July 3rd 2008.

Corticospinal tract lesion load: An imaging biomarker for stroke motor outcomes.

OBJECTIVE: The aim of this work was to investigate whether an imaging measure of corticospinal tract (CST) injury in the acute phase can predict motor outcome at 3 months in comparison to clinical assessment of initial motor impairment. METHODS: A two-site prospective cohort study followed up a group of first-ever ischemic stroke patients using the Upper-Extremity Fugl-Meyer (UE-FM) Scale to measure motor impairment in the acute phase and at 3 months. A weighted CST lesion load (wCST-LL) was calculated by overlaying the patient's lesion map on magnetic resonance imaging with a probabilistic CST constructed from healthy control subjects. Regression models were fit to assess the predictive value of wCST-LL and compared with initial motor impairment. RESULTS: Seventy-six patients (37 from cohort 1 and 39 from cohort 2) completed the study. wCST-LL as well as assessment of motor impairment (UE-FM) in the acute phase correlated with motor impairment (UE-FM) at 3 months in both cohort 1 (R(2) = 0.69 vs. R(2) = 0.67; p = 0.43) and cohort 2 (R(2) = 0.69 vs. R(2) = 0.62; p = 0.25). In the severely impaired subgroup (defined as UE-FM ≤ 10 at baseline), wCST-LL correlated with outcomes significantly better than clinical assessment (R(2) = 0.47 vs. R(2) = 0.11; p = 0.03). In the nonseverely impaired subgroup, stroke patients recovered approximately 70% of their maximal recovery potential. All stroke patients in both cohorts had poor motor outcomes at 3 months (defined as UE-FM ≤ 25) when wCST-LL was ≥ 7.0 cc (positive predictive value was 100%). INTERPRETATION: wCST-LL, an imaging biomarker determined in the acute phase, can predict poststroke motor outcomes at 3 months, especially in patients with severe impairment at baseline.

Locomotor Adaptability Task Promotes Intense and Task-Appropriate Output From the Paretic Leg During Walking.

OBJECTIVE: To test the hypothesis that participants with stroke will exhibit appropriate increase in muscle activation of the paretic leg when taking a long step with the nonparetic leg compared to during steady-state walking, with a consequent increase in biomechanical output and symmetry during the stance phase of the modified gait cycle. DESIGN: Single-session observational study. SETTING: Clinical research center in an outpatient hospital setting. PARTICIPANTS: Adults with chronic poststroke hemiparesis (N=15). INTERVENTIONS: Participants walked on an instrumented treadmill while kinetic, kinematic, and electromyogram data were recorded. Participants performed steady-state walking and a separate trial of the long-step adaptability task in which they were instructed to intermittently take a longer step with the nonparetic leg. MAIN OUTCOME MEASURES: Forward progression, propulsive force, and neuromuscular activation during walking. RESULTS: Participants performed the adaptability task successfully and demonstrated greater neuromuscular activation in appropriate paretic leg muscles, particularly increased activity in paretic plantarflexor muscles. Propulsion and forward progression by the paretic leg were also increased. CONCLUSIONS: These findings support the assertion that the nonparetic long-step task may be effective for use in poststroke locomotor rehabilitation to engage the paretic leg and promote recovery of walking.

Dimensionality and Item-Difficulty Hierarchy of the Lower Extremity Fugl-Meyer Assessment in Individuals With Subacute and Chronic Stroke.

OBJECTIVE: To investigate the dimensionality and item-difficulty hierarchy of the Fugl-Meyer Assessment of the lower extremity (FMA-LE). DESIGN: Secondary analyses of data pooled from 4 existing datasets: a phase III randomized controlled trial investigating the effectiveness of body weight support and a treadmill for rehabilitation of walking poststroke, and 3 cross-sectional studies investigating the link between impaired motor performance poststroke and walking. SETTING: University research centers and rehabilitation centers. PARTICIPANTS: A pooled sample of individuals with a stroke (N=535, men=313; mean age ± SD, 61.91±12.42y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Confirmatory factor analyses (CFA) and Rasch residual principal component analysis (PCA) investigated the dimensionality of the FMA-LE. The Rasch analysis rating scale model investigated item-difficulty hierarchy of the FMA-LE. RESULTS: The CFA showed adequate fit of a 3-factor model, with 2 out of 3 indices (CFA=.95; Tucker-Lewis Index=.94; root mean square error of approximation=.124) showing good model fit. Rasch PCA showed that removal of the reflex and coordination items explained 90.8% of variance in the data, suggesting that the abnormal synergy items contributed to the measurement of a unidimensional construct. However, rating scale model results revealed deviations in the item-difficulty hierarchy of the unidimensional abnormal synergy items from the originally proposed stepwise sequence of motor recovery. CONCLUSIONS: Our findings suggest that the FMA-LE might represent a multidimensional construct, challenging the use of a total score of the FMA-LE to predict lower extremity motor recovery. Removal of the misfit items resulted in creation of a unidimensional scale composed of the abnormal synergy items. However, this unidimensional scale deviates from the originally proposed hierarchical ordering.

Persistent racial disparity in stroke hospitalization and economic impact in young adults in the buckle of stroke belt.

BACKGROUND AND PURPOSE: Mounting evidence points to a decline in stroke incidence. However, little is known about recent patterns of stroke hospitalization within the buckle of the stroke belt. This study aims to investigate the age- and race-specific secular trends in stroke hospitalization rates, inpatient stroke mortality rates, and related hospitalization charges during the past decade in South Carolina. METHODS: Patients from 2001 to 2010 were identified from the State Inpatient Hospital Discharge Database with a primary discharge diagnosis of stroke (International Classification of Diseases, Ninth Revision codes: 430-434, 436, 437.1). Age- and race-stroke-specific hospitalization rates, hospital charges, charges associated with racial disparity, and 30-day stroke mortality rates were compared between blacks and whites. RESULTS: Of the 84,179 stroke hospitalizations, 31,137 (37.0%) were from patients aged<65 years and 29,846 (35.5%) were blacks. Stroke hospitalization rates decreased in the older population (aged≥65 years) for both blacks and whites (P<0.001) but increased among the younger group (aged<65 years; P=0.004); however, this increase was mainly driven by a 17.3% rise among blacks (P=0.001), with no difference seen among whites (P=0.84). Of hospital charges totaling $2.77 billion, $453.2 million (16.4%) are associated with racial disparity (79.6% from patients aged<65 years). Thirty-day stroke mortality rates decreased in all age-race-stroke-specific groups (P<0.001). CONCLUSIONS: The stroke hospitalization rate increased in the young blacks only, which results in a severe and persistent racial disparity. It highlights the urgent need for a racial disparity reduction in the younger population to alleviate the healthcare burden.

Compensatory increase in ipsilesional supplementary motor area and premotor connectivity is associated with greater gait impairments: a personalized fMRI analysis in chronic stroke.

Background: Balance and mobility impairments are prevalent post-stroke and a large number of survivors require walking assistance at 6 months post-stroke which diminishes their overall quality of life. Personalized interventions for gait and balance rehabilitation are crucial. Recent evidence indicates that stroke lesions in primary motor pathways, such as corticoreticular pathways (CRP) and corticospinal tract (CST), may lead to reliance on alternate motor pathways as compensation, but the current evidence lacks comprehensive knowledge about the underlying neural mechanisms. Methods: In this study, we investigate the functional connectivity (FC) changes within the motor network derived from an individualized cortical parcellation approach in 33 participants with chronic stroke compared to 17 healthy controls. The correlations between altered motor FC and gait deficits (i.e., walking speed and walking balance) were then estimated in the stroke population to understand the compensation mechanism of the motor network in motor function rehabilitation post-stroke. Results: Our results demonstrated significant FC increases between ipsilesional medial supplementary motor area (SMA) and premotor in stroke compared to healthy controls. Furthermore, we also revealed a negative correlation between ipsilesional SMA-premotor FC and self-selected walking speed, as well as the Functional Gait Assessment (FGA) scores. Conclusion: The increased FC between the ipsilesional SMA and premotor regions could be a compensatory mechanism within the motor network following a stroke when the individual can presumably no longer rely on the more precise CST modulation of movements to produce a healthy walking pattern. These findings enhance our understanding of individualized motor network FC changes and their connection to gait and walking balance impairments post-stroke, improving stroke rehabilitation interventions.

The evolution of neuromodulation for chronic stroke: From neuroplasticity mechanisms to brain-computer interfaces.

Stroke is one of the most common and debilitating neurological conditions worldwide. Those who survive experience motor, sensory, speech, vision, and/or cognitive deficits that severely limit remaining quality of life. While rehabilitation programs can help improve patients' symptoms, recovery is often limited, and patients frequently continue to experience impairments in functional status. In this review, invasive neuromodulation techniques to augment the effects of conventional rehabilitation methods are described, including vagus nerve stimulation (VNS), deep brain stimulation (DBS) and brain-computer interfaces (BCIs). In addition, the evidence base for each of these techniques, pivotal trials, and future directions are explored. Finally, emerging technologies such as functional near-infrared spectroscopy (fNIRS) and the shift to artificial intelligence-enabled implants and wearables are examined. While the field of implantable devices for chronic stroke recovery is still in a nascent stage, the data reviewed are suggestive of immense potential for reducing the impact and impairment from this globally prevalent disorder.

A novel biomechanical indicator for impaired ankle dorsiflexion function during walking in individuals with chronic stroke.

BACKGROUND: Ankle dorsiflexion function during swing phase contributes to foot clearance and plays an important role in walking ability post-stroke. Commonly used biomechanical measures such as foot clearance and ankle joint excursion have limited ability to accurately evaluate impaired dorsiflexor function. RESEARCH QUESTION: Can ankle angular velocity and acceleration be used as reliable measurers of dorsiflexion function in post-stroke gait? METHODS: Using linear regression and Pearson's correlation we retrospectively compared peak ankle angular velocity (AωP), peak ankle angular acceleration (AαP), peak dorsiflexion angle (DFAP) and peak foot clearance (FCLP) as direct measures for swing phase dorsiflexor function in 60 chronic stroke survivors. Intraclass correlation coefficient (ICC) analysis was used for test-retest reliability of AωP and AαP. RESULTS: Linear regression models revealed that AωP, AαP, DFAP, FCLP had a significant relationship (p < 0.05) with impaired dorsiflexion function. AαP and DFAP accounted for the most variance of dorsiflexion function. AωP, AαP, FCLP, correlated significantly with all clinical outcome measures of walking ability. DFAP had a positive correlation only with FMA-LE. Post-hoc William's t-tests, used to compare the magnitude of difference between two non-independent correlations, revealed that the correlation between all clinical measures and DFAP were significantly weaker than with AωP and AαP. Correlation between FMA-LE and FCLP was weaker than with AωP and AαP. Excellent test-retest reliability for both AωP (ICC = 0.968) and AαP (ICC = 0.947) was observed. SIGNIFICANCE: These results suggest that DFAP may only be associated with dorsiflexion function during non-task specific isolated movements, but not during walking. FCLP is associated with dorsiflexion function and walking ability measures but not as strongly as AωP and AαP possibly because FCLP is influenced by contribution from hip and knee joint movements. Therefore, AωP and AαP are reliable measures and represent dorsiflexion function more accurately than DFAP, and FCLP.

Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp ) , segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, Klk15 G224D/+ mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support Kallikrein gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.

Modular control of varied locomotor tasks in children with incomplete spinal cord injuries.

A module is a functional unit of the nervous system that specifies functionally relevant patterns of muscle activation. In adults, four to five modules account for muscle activation during walking. Neurological injury alters modular control and is associated with walking impairments. The effect of neurological injury on modular control in children is unknown and may differ from adults due to their immature and developing nervous systems. We examined modular control of locomotor tasks in children with incomplete spinal cord injuries (ISCIs) and control children. Five controls (8.6 ± 2.7 yr of age) and five children with ISCIs (8.6 ± 3.7 yr of age performed treadmill walking, overground walking, pedaling, supine lower extremity flexion/extension, stair climbing, and crawling. Electromyograms (EMGs) were recorded in bilateral leg muscles. Nonnegative matrix factorization was applied, and the minimum number of modules required to achieve 90% of the "variance accounted for" (VAF) was calculated. On average, 3.5 modules explained muscle activation in the controls, whereas 2.4 modules were required in the children with ISCIs. To determine if control is similar across tasks, the module weightings identified from treadmill walking were used to reconstruct the EMGs from each of the other tasks. This resulted in VAF values exceeding 86% for each child and each locomotor task. Our results suggest that 1) modularity is constrained in children with ISCIs and 2) for each child, similar neural control mechanisms are used across locomotor tasks. These findings suggest that interventions that activate the neuromuscular system to enhance walking also may influence the control of other locomotor tasks.

Locomotor rehabilitation of individuals with chronic stroke: difference between responders and nonresponders.

OBJECTIVES: To identify the clinical measures associated with improved walking speed after locomotor rehabilitation in individuals poststroke and how those who respond with clinically meaningful changes in walking speed differ from those with smaller speed increases. DESIGN: A single group pre-post intervention study. Participants were stratified on the basis of a walking speed change of greater than (responders) or less than (nonresponders) .16m/s. Paired sample t tests were run to assess changes in each group, and correlations were run between the change in each variable and change in walking speed. SETTING: Outpatient interdisciplinary rehabilitation research center. PARTICIPANTS: Hemiparetic subjects (N=27) (17 left hemiparesis; 19 men; age: 58.74±12.97y; 22.70±16.38mo poststroke). INTERVENTION: A 12-week locomotor intervention incorporating training on a treadmill with body weight support and manual trainers accompanied by training overground walking. MAIN OUTCOME MEASURES: Measures of motor control, balance, functional walking ability, and endurance were collected at pre- and postintervention assessments. RESULTS: Eighteen responders and 9 nonresponders differed by age (responders=63.6y, nonresponders=49.0y, P=.001) and the lower extremity Fugl-Meyer Assessment score (responders=24.7, nonresponders=19.9, P=.003). Responders demonstrated an average improvement of .27m/s in walking speed as well as significant gains in all variables except daily step activity and paretic step ratio. Conversely, nonresponders demonstrated statistically significant improvements only in walking speed and endurance. However, the walking speed increase of .10m/s was not clinically meaningful. Change in walking speed was negatively correlated with changes in motor control in the nonresponder group, implying that walking speed gains may have been accomplished via compensatory mechanisms. CONCLUSIONS: This study is a step toward discerning the underlying factors contributing to improved walking performance.

Interhemispheric Asymmetries in Intracortical Facilitation Correlate With Fatigue Severity in Individuals With Poststroke Fatigue.

PURPOSE: Poststroke fatigue (PSF) contributes to increased mortality and reduces participation in rehabilitative therapy. Although PSF's negative influences are well known, there are currently no effective evidence-based treatments for PSF. The lack of treatments is in part because of a dearth of PSF pathophysiological knowledge. Increasing our understanding of PSF's causes may facilitate and aid the development of effective therapies. METHODS: Twenty individuals, >6 months post stroke, participated in this cross-sectional study. Fourteen participants had clinically relevant pathological PSF, based on fatigue severity scale (FSS) scores (total score ≥36). Single-pulse and paired-pulse transcranial magnetic stimulation were used to measure hemispheric asymmetries in resting motor threshold, motor evoked potential amplitude, and intracortical facilitation (ICF). Asymmetry scores were calculated as the ratios between lesioned and nonlesioned hemispheres. The asymmetries were then correlated (Spearman rho) to FSS scores. RESULTS: In individuals with pathological PSF (N = 14, range of total FSS scores 39-63), a strong positive correlation (rs = 0.77, P = 0.001) between FSS scores and ICF asymmetries was calculated. CONCLUSIONS: As the ratio of ICF between the lesioned and nonlesioned hemispheres increased so did self-reported fatigue severity in individuals with clinically relevant pathological PSF. This finding may implicate adaptive/maladaptive plasticity of the glutamatergic system/tone as a contributor to PSF. This finding also suggests that future PSF studies should incorporate measuring facilitatory activity and behavior in addition to the more commonly studied inhibitory mechanisms. Further investigations are required to replicate this finding and identify the causes of ICF asymmetries.

Transcranial Direct Current Stimulation Electrode Montages May Differentially Impact Variables of Walking Performance in Individuals Poststroke: A Preliminary Study.

PURPOSE: Transcranial direct current stimulation (tDCS) has mixed effects on walking performance in individuals poststroke. This is likely the result of variations in tDCS electrode montages and individualized responses. The purpose of this study was to quantify the effects of a single session of tDCS using various electrode montages on poststroke walking performance. METHODS: Individuals with chronic stroke ( n = 16) participated in a double-blind, randomized cross-over study with sham stimulation and three tDCS electrode montages. Gait speed, paretic step ratio, and paretic propulsion were assessed prestimulation and poststimulation at self-selected and fastest comfortable speeds. Changes in muscle activation patterns with self-selected walking were quantified by the number of modules derived from nonnegative matrix factorization of EMG signals for hypothesis generation. RESULTS: There was no significant effect of active stimulation montages compared with sham. Comparisons between each participant's best response to tDCS and sham show personalized tDCS may have a positive effect on fastest comfortable overground gait speed ( P = 0.084), paretic step ratio ( P = 0.095) and paretic propulsion ( P = 0.090), and self-selected paretic step ratio ( P = 0.012). Participants with two or three modules at baseline increased module number in response to the all experimental montages and sham, but responses were highly variable. CONCLUSIONS: A single session of tDCS may affect clinical and biomechanical walking performance, but effects seem to be dependent on individual response variability to different electrode montages. Findings of this study are consistent with responses to various tDCS electrode montages being the result of underlying neuropathology, and the authors recommend examining how individual factors affect responses to tDCS.

A novel biomechanical indicator for impaired ankle dorsiflexion function during walking in individuals with chronic stroke.

Ankle dorsiflexion function during swing phase of the gait cycle contributes to foot clearance and plays an important role in walking ability post-stroke. Commonly used biomechanical measures such as foot clearance and ankle joint excursion have limited ability to accurately evaluate dorsiflexor function in stroke gait. We retrospectively evaluated ankle angular velocity and ankle angular acceleration as direct measures for swing phase dorsiflexor function in post-stroke gait of 61 chronic stroke survivors. Our linear regression models revealed that peak ankle angular velocity (AAV P ), peak ankle angular acceleration (AAA P ), peak dorsiflexion angle (DFA P ) and peak foot clearance (FCL P ) during swing had a significant relationship (p < 0.05) with impaired dorsiflexion function. AAA P and DFA P accounted for the most variance of dorsiflexion function. Additionally, AAV P , AAA P , FCL P during swing, correlated significantly with all clinical outcome measures of walking ability. DFA P during swing had a positive correlation only with FMA-LE. Post-hoc William's t -tests, used to compare the magnitude of difference between two non-independent correlations, revealed that the correlation between all clinical measures and DFA P were significantly weaker than with AAV P and AAA P . We also found that correlation between FMA-LE and FCL P was weaker than with AAV P and AAA P . We found an excellent test-retest reliability for both AAV P (ICC = 0.968) and AAA P (ICC = 0.947). These results suggest that DFA P may only be associated with non-task specific isolated dorsiflexion movement, but not during walking. FCL P is associated with dorsiflexion function and walking ability measures but not as strongly as AAV P and AAA P possibly because FCL P is influenced by contribution from hip and knee joint movements during walking. Therefore, we believe that AAV P and AAA P both can be used as reliable measures of impaired dorsiflexion function in post-stroke gait.

Vagus Nerve Stimulation Paired With Rehabilitation for Upper Limb Motor Impairment and Function After Chronic Ischemic Stroke: Subgroup Analysis of the Randomized, Blinded, Pivotal, VNS-REHAB Device Trial.

BACKGROUND: Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke. OBJECTIVE: We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury. METHODS: Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in impairment measured by the Fugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of 6-weeks in-clinic therapy. We explored the effect of VNS treatment by sex, age (≥62 years), time from stroke (>2 years), severity (baseline FMA-UE score >34), paretic side of body, country of enrollment (USA vs UK) and presence of cortical involvement of the index infarction. We assessed whether there was any interaction with treatment. FINDINGS: The primary outcome increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (P = .001, between group difference 2.6, 95% CI 1.03-4.2). The between group difference was similar across all subgroups and there were no significant treatment interactions. There was no important difference in rates of adverse events across subgroups. CONCLUSION: The response was similar across subgroups examined. The findings suggest that the effects of paired VNS observed in the VNS-REHAB trial are likely to be consistent in wide range of stroke survivors with moderate to severe upper extremity impairment.