Alpha and beta/low-gamma frequency bands may have distinct neural origin and function during post-stroke walking.

Plantarflexors provide propulsion during walking and receive input from both corticospinal and corticoreticulospinal tracts, which exhibit some frequency-specificity that allows potential differentiation of each tract's descending drive. Given that stroke may differentially affect each tract and impair the function of plantarflexors during walking; here, we examined this frequency-specificity and its relation to walking-specific measures during post-stroke walking. Fourteen individuals with chronic stroke walked on an instrumented treadmill at self-selected and fast walking speed (SSWS and FWS, respectively) while surface electromyography (sEMG) from soleus (SOL), lateral gastrocnemius (LG), and medial gastrocnemius (MG) and ground reaction forces (GRF) were collected. We calculated the intermuscular coherences (IMC; alpha, beta, and low-gamma bands between SOL-LG, SOL-MG, LG-MG) and propulsive impulse using sEMG and GRF, respectively. We examined the interlimb and intralimb IMC comparisons and their relationships with propulsive impulse and walking speed. Interlimb IMC comparisons revealed that beta LG-MG (SSWS) and low-gamma SOL-LG (FWS) IMCs were degraded on the paretic side. Intralimb IMC comparisons revealed that only alpha IMCs (both speeds) exhibited a statistically significant difference to random coherence. Further, alpha LG-MG IMC was positively correlated with propulsive impulse in the paretic limb (SSWS). Alpha and beta/low-gamma bands may have a differential functional role, which may be related to the frequency-specificity of the underlying descending drives. The persistence of alpha band in plantarflexors and its strong positive relationship with propulsive impulse suggests relative alteration of corticoreticulospinal tract after stroke. These findings imply the presence of frequency-specific descending drives to walking-specific muscles in chronic stroke.

Computerized Adaptive Testing for the Berg Balance Scale Improves Measurement Efficiency Without Compromising Precision in People With Stroke.

OBJECTIVE: Objectives of this study were to confirm the Berg Balance Scale's (BBS) measurement properties and unidimensionality with an item response theory analysis in persons with subacute and chronic stroke and examine the precision and efficiency of computerized adaptive testing (CAT). METHODS: Data were obtained from 519 ambulatory persons with subacute and chronic stroke in 2 retrospective databases. A principal component analysis (PCA) of residuals was used to evaluate unidimensionality. BBS fit to a rating scale model versus a partial credit model was examined and item parameters were generated for CAT calibration. Person measures from all 14 items were defined as actual balance ability. BBS CAT simulations were used to examine changes in measurement precision with increasing number of items administered and a precision-based stopping rule (0.5 logit standard error (SE) threshold). RESULTS: A PCA of residuals supports the BBS's unidimensionality and Rasch analysis supports using the rating scale model for measurement. Maximum precision for BBS CAT was SE = 0.40 logits when administering all items. BBS CAT estimated balance ability was highly correlated with actual ability when 4 or more items were administered (r > 0.9). Precision was within 0.5 logits when 5 or more items were administered (SE < 0.48 logits). BBS CAT estimated balance ability was highly correlated with actual ability (r = 0.952) using a precision-based stopping rule. The average number of items administered with the precision-based stopping rule was 5.43. CONCLUSION: The BBS is sufficiently unidimensional and the rating scale model can be used for measurement. BBS CAT is efficient and replicates the full instrument's reliability when measuring balance ability in ambulatory persons with subacute and chronic stroke. Future work should aim to enhance the interpretability of measures to facilitate clinical decision making. IMPACT STATEMENT: BBS CAT provides an efficient way of measuring balance ability for individuals in stroke rehabilitation giving clinicians more time with patients.

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.

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.

Data-driven biomarkers outperform theory-based biomarkers in predicting stroke motor outcomes.

Chronic motor impairments are a leading cause of disability after stroke. Previous studies have predicted motor outcomes based on the degree of damage to predefined structures in the motor system, such as the corticospinal tract. However, such theory-based approaches may not take full advantage of the information contained in clinical imaging data. The present study uses data-driven approaches to predict chronic motor outcomes after stroke and compares the accuracy of these predictions to previously-identified theory-based biomarkers. Using a cross-validation framework, regression models were trained using lesion masks and motor outcomes data from 789 stroke patients (293 female/496 male) from the ENIGMA Stroke Recovery Working Group (age 64.9±18.0 years; time since stroke 12.2±0.2 months; normalised motor score 0.7±0.5 (range [0,1]). The out-of-sample prediction accuracy of two theory-based biomarkers was assessed: lesion load of the corticospinal tract, and lesion load of multiple descending motor tracts. These theory-based prediction accuracies were compared to the prediction accuracy from three data-driven biomarkers: lesion load of lesion-behaviour maps, lesion load of structural networks associated with lesion-behaviour maps, and measures of regional structural disconnection. In general, data-driven biomarkers had better prediction accuracy - as measured by higher explained variance in chronic motor outcomes - than theory-based biomarkers. Data-driven models of regional structural disconnection performed the best of all models tested (R2 = 0.210, p < 0.001), performing significantly better than predictions using the theory-based biomarkers of lesion load of the corticospinal tract (R2 = 0.132, p< 0.001) and of multiple descending motor tracts (R2 = 0.180, p < 0.001). They also performed slightly, but significantly, better than other data-driven biomarkers including lesion load of lesion-behaviour maps (R2 =0.200, p < 0.001) and lesion load of structural networks associated with lesion-behaviour maps (R2 =0.167, p < 0.001). Ensemble models - combining basic demographic variables like age, sex, and time since stroke - improved prediction accuracy for theory-based and data-driven biomarkers. Finally, combining both theory-based and data-driven biomarkers with demographic variables improved predictions, and the best ensemble model achieved R2 = 0.241, p < 0.001. Overall, these results demonstrate that models that predict chronic motor outcomes using data-driven features, particularly when lesion data is represented in terms of structural disconnection, perform better than models that predict chronic motor outcomes using theory-based features from the motor system. However, combining both theory-based and data-driven models provides the best predictions.

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.

Left or right ear? A neuroimaging study using combined taVNS/fMRI to understand the interaction between ear stimulation target and lesion location in chronic stroke.

BACKGROUND: Implanted vagus nerve stimulation (VNS) and transcutaneous auricular VNS (taVNS) have been primarily administered clinically to the unilateral-left vagus nerve. This left-only convention has proved clinically beneficial in brain disorders. However, in stroke survivors, the presence of a lesion in the brain may complicate VNS-mediated signaling, and it is important to understand the laterality effects of VNS in stroke survivors to optimize the intervention. OBJECTIVE: To understand whether taVNS delivered to different ear targets relative to the lesion (ipsilesional vs contralesional vs bilateral vs sham) impacts blood oxygenation level dependent (BOLD) signal propagation in stroke survivors. METHODS: We enrolled 20 adults with a prior history of stroke. Each participant underwent a single visit, during which taVNS was delivered concurrently during functional magnetic resonance imaging (fMRI) acquisition. Each participant received three discrete active stimulation conditions (ipsilesional, contralesional, bilateral) and one sham condition in a randomized order. Stimulation-related BOLD signal changes in the active conditions were compared to sham conditions to understand the interaction taVNS and laterality effects. RESULTS: All active taVNS conditions deactivated the contralesional default mode network related regions compared to sham, however only ipsilesional taVNS enhanced the activations in the ipsilesional visuomotor and secondary visual cortex. Furthermore, we reveal an interaction in task activations between taVNS and cortical visuomotor areas, where ipsilesional taVNS significantly increased ipsilesional visuomotor activity and decreased contralesional visuomotor activity compared to sham. CONCLUSION: Laterality of taVNS relative to the lesion is a critical factor in optimizing taVNS in a stroke population, with ipsilesional stimulation providing largest direct brain activation and should be explored further when designing taVNS studies in neurorehabilitation.

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.

Transcranial Direct Current Stimulation for Chronic Stroke: Is Neuroimaging the Answer to the Next Leap Forward?

During rehabilitation, a large proportion of stroke patients either plateau or begin to lose motor skills. By priming the motor system, transcranial direct current stimulation (tDCS) is a promising clinical adjunct that could augment the gains acquired during therapy sessions. However, the extent to which patients show improvements following tDCS is highly variable. This variability may be due to heterogeneity in regions of cortical infarct, descending motor tract injury, and/or connectivity changes, all factors that require neuroimaging for precise quantification and that affect the actual amount and location of current delivery. If the relationship between these factors and tDCS efficacy were clarified, recovery from stroke using tDCS might be become more predictable. This review provides a comprehensive summary and timeline of the development of tDCS for stroke from the viewpoint of neuroimaging. Both animal and human studies that have explored detailed aspects of anatomy, connectivity, and brain activation dynamics relevant to tDCS are discussed. Selected computational works are also included to demonstrate how sophisticated strategies for reducing variable effects of tDCS, including electric field modeling, are moving the field ever closer towards the goal of personalizing tDCS for each individual. Finally, larger and more comprehensive randomized controlled trials involving tDCS for chronic stroke recovery are underway that likely will shed light on how specific tDCS parameters, such as dose, affect stroke outcomes. The success of these collective efforts will determine whether tDCS for chronic stroke gains regulatory approval and becomes clinical practice in the future.

Acetabular Wall Weakening in Total Hip Arthroplasty: A Pilot Study.

Total hip arthroplasty is a widely performed operation allowing disabled patients to improve their quality of life to a degree greater than any other elective procedure. Planning for a THA requires adequate patient assessment and preoperative characterizations of acetabular bone loss via radiographs and specific classification schemes. Some surgeons may be inclined to ream at a larger diameter thinking it would lead to a more stable press-fit, but this could be detrimental to the acetabular wall, leading to intraoperative fracture. In the attempt to reduce the incidence of intraoperative fractures, the current study aims to identify how increased reaming diameter degrades and weakens the acetabular rim strength. We hypothesized that there is proportionality between the reaming diameter and the reduction in acetabular strength. To test this hypothesis, this study used bone surrogates, templated from CT scans, and reamed at different diameters. The obtained bone surrogate models were then tested using an Intron 8874 mechanical testing machine (Instron, Norwood, MA) equipped with a custom-made fixture. Analysis of variance (ANOVA) was used to identify differences among reamed diameters while linear regression was used to identify the relationship between reamed diameters and acetabular strength. We found a moderate correlation between increasing reaming diameter that induced thinning of the acetabular wall and radial load damage. For the simplified acetabular model used in this study, it supported our hypothesis and is a promising first attempt in providing quantitative data for acetabular weakening induced by reaming.

Association of Brain Age, Lesion Volume, and Functional Outcome in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS: We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS: We examined 963 patients across 38 cohorts. Greater lesion damage was associated with older brain age (ß = 0.21; 95% CI 0.04-0.38, p = 0.015), which in turn was associated with poorer outcomes, both in the sensorimotor domain (ß = -0.28; 95% CI -0.41 to -0.15, p < 0.001) and across multiple domains of function (ß = -0.14; 95% CI -0.22 to -0.06, p < 0.001). Brain age mediated 15% of the impact of lesion damage on sensorimotor performance (95% CI 3%-58%, p = 0.01). Greater brain resilience explained why people have better outcomes, given matched lesion damage (odds ratio 1.04, 95% CI 1.01-1.08, p = 0.004). DISCUSSION: We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

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.

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 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.

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.

The relationship between motor pathway damage and flexion-extension patterns of muscle co-excitation during walking.

Background: Mass flexion-extension co-excitation patterns during walking are often seen as a consequence of stroke, but there is limited understanding of the specific contributions of different descending motor pathways toward their control. The corticospinal tract is a major descending motor pathway influencing the production of normal sequential muscle coactivation patterns for skilled movements. However, control of walking is also influenced by non-corticospinal pathways such as the corticoreticulospinal pathway that possibly contribute toward mass flexion-extension co-excitation patterns during walking. The current study sought to investigate the associations between damage to corticospinal (CST) and corticoreticular (CRP) motor pathways following stroke and the presence of mass flexion-extension patterns during walking as evaluated using module analysis. Methods: Seventeen healthy controls and 44 stroke survivors were included in the study. We used non-negative matrix factorization for module analysis of paretic leg electromyographic activity. We typically have observed four modules during walking in healthy individuals. Stroke survivors often have less independently timed modules, for example two-modules presented as mass flexion-extension pattern. We used diffusion tensor imaging-based analysis where streamlines connecting regions of interest between the cortex and brainstem were computed to evaluate CST and CRP integrity. We also used a coarse classification tree analysis to evaluate the relative CST and CRP contribution toward module control. Results: Interhemispheric CST asymmetry was associated with worse lower extremity Fugl-Meyer score (p = 0.023), propulsion symmetry (p = 0.016), and fewer modules (p = 0.028). Interhemispheric CRP asymmetry was associated with worse lower extremity Fugl-Meyer score (p = 0.009), Dynamic gait index (p = 0.035), Six-minute walk test (p = 0.020), Berg balance scale (p = 0.048), self-selected walking speed (p = 0.041), and propulsion symmetry (p = 0.001). The classification tree model reveled that substantial ipsilesional CRP or CST damage leads to a two-module pattern and poor walking ability with a trend toward increased compensatory contralesional CRP based control. Conclusion: Both CST and CRP are involved with control of modules during walking and damage to both may lead to greater reliance on the contralesional CRP, which may contribute to a two-module pattern and be associated with worse walking performance.

Low Mortality of Orthopedic Trauma Patients With Asymptomatic COVID-19: A Level I Trauma Center Pandemic Experience.

Background: Early (2020) reports on mortality in patients with coronavirus disease 2019 (COVID-19) who underwent orthopedic surgery ranged from 20.5% to 56%, but these studies included elderly patients with multiple comorbidities. The mortality rate for younger and asymptomatic COVID-19-positive patients undergoing orthopedic surgery after high-energy trauma is underreported. The purpose of this study was to compare the 30-day mortality of asymptomatic COVID-19-positive patients and COVID-19-negative patients surgically treated for orthopedic trauma at a Level I trauma center during the coronavirus pandemic. A secondary objective was to compare the patients' postoperative hospital course and length of stay. Methods: This study is a single-center retrospective review of all patients who underwent an orthopedic surgical procedure at a Level I trauma center during a 3-month period early in the COVID-19 pandemic. All patients received a preoperative nasopharyngeal swab to determine COVID-19 infection status. Preoperative demographic variables, perioperative and postoperative mortality within 30 days, length of stay, and intensive care unit days were compared between COVID-19-positive and COVID-19-negative patients. Results: Of the 471 total patients, 13 were COVID-19-positive and 458 were COVID-19-negative prior to surgery. The average age of all patients was 40.5 ± 19.8 years. The mortality rate in the COVID-19-positive group was 0% vs 0.7% in the COVID-19-negative group, with no significant difference between groups (P=0.77). The COVID-19-positive group vs the COVID-19-negative group had no significant difference in hospital length of stay (7.4 days vs 4.4 days, respectively, P=0.12). Conclusion: Asymptomatic COVID-19-positive orthopedic trauma patients treated with surgery at a Level I trauma center in a 3-month period during the COVID-19 pandemic had a 0% mortality rate, and we found no differences between COVID-19-positive and COVID-19-negative patients with respect to mortality and hospital length of stay.

A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms.

BACKGROUND: Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These "long COVID" symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively. METHODS: We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020-2021) and equipment being shipped to individuals' homes. This trial was registered on ClinicalTrials.gov under the identifier: NCT04638673 registered November 20, 2020. RESULTS: Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. CONCLUSIONS: This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.