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Abstract Walking slowly after stroke reduces health and quality of life. This multi-site, prospective, interventional, 2-arm randomized controlled trial (NCT04121754) evaluated the safety and efficacy of an autonomous neurorehabilitation system (InTandemTM) designed to use auditory-motor entrainment to improve post-stroke walking. 87 individuals were randomized to 5-week walking interventions with InTandem or Active Control (i.e., walking without InTandem). The primary endpoints were change in walking speed, measured by the 10-meter walk test pre-vs-post each 5-week intervention, and safety, measured as the frequency of adverse events (AEs). Clinical responder rates were also compared. The trial met its primary endpoints. InTandem was associated with a 2x larger increase in speed (Δ: 0.14 ± 0.03 m/s versus Δ: 0.06 ± 0.02 m/s, F(1,49) = 6.58, p = 0.013), 3x more responders (40% versus 13%, χ2(1) ≥ 6.47, p = 0.01), and similar safety (both groups experienced the same number of AEs). The auditory-motor intervention autonomously delivered by InTandem is safe and effective in improving walking in the chronic phase of stroke.

Traumatic brain injury (TBI) impairs sensory–motor functions, with debilitating consequences on postural control and balance, which persist during the chronic stages of recovery. The Timed Up and Go (TUG) test is a reliable, safe, time-efficient, and one of the most widely used clinical measures to assess gait, balance, and fall risk in TBI patients and is extensively used in inpatient and outpatient settings. Although the TUG test has been used extensively due to its ease of performance and excellent reliability, limited research has been published that investigates the relationship between TUG performance and quantitative biomechanical measures of balance. The objective of this paper was to quantify the relationship between biomechanical variables of balance and the TUG scores in individuals with chronic TBI. Regression models were constructed using six biomechanical variables to predict TUG scores. The model that conservatively removed gait speed (i.e., TUG-1/GS) gave the best results, achieving a root-mean-square error of ∼±2 s and explaining over 69% of the variability.

Acquired brain injury (ABI) is a leading cause of ambulation deficits in the United States every year. ABI (stroke, traumatic brain injury and cerebral palsy) results in ambulation deficits with residual gait and balance deviations persisting even after 1 year. Current research is focused on evaluating the effect of robotic exoskeleton devices (RD) for overground gait and balance training. In order to understand the device effectiveness on neuroplasticity, it is important to understand RD effectiveness in the context of both downstream (functional, biomechanical and physiological) and upstream (cortical) metrics. The review identifies gaps in research areas and suggests recommendations for future research. We carefully delineate between the preliminary studies and randomized clinical trials in the interpretation of existing evidence. We present a comprehensive review of the clinical and pre-clinical research that evaluated therapeutic effects of RDs using various domains, diagnosis and stage of recovery.

Abstract Background Atypical walking in the months and years after stroke constrain community reintegration and reduce mobility, health, and quality of life. The ReWalk ReStore™ is a soft robotic exosuit designed to assist the propulsion and ground clearance subtasks of post-stroke walking by actively assisting paretic ankle plantarflexion and dorsiflexion. Previous proof-of-concept evaluations of the technology demonstrated improved gait mechanics and energetics and faster and farther walking in users with post-stroke hemiparesis. We sought to determine the safety, reliability, and feasibility of using the ReStore™ during post-stroke rehabilitation. Methods A multi-site clinical trial (NCT03499210) was conducted in preparation for an application to the United States Food and Drug Administration (FDA). The study included 44 users with post-stroke hemiparesis who completed up to 5 days of training with the ReStore™ on the treadmill and over ground. In addition to primary and secondary endpoints of safety and device reliability across all training activities, an exploratory evaluation of the effect of multiple exposures to using the device on users’ maximum walking speeds with and without the device was conducted prior to and following the five training visits. Results All 44 study participants completed safety and reliability evaluations. Thirty-six study participants completed all five training days. No device-related falls or serious adverse events were reported. A low rate of device malfunctions was reported by clinician-operators. Regardless of their reliance on ancillary assistive devices, after only 5 days of walking practice with the device, study participants increased both their device-assisted (Δ: 0.10 ± 0.03 m/s) and unassisted (Δ: 0.07 ± 0.03 m/s) maximum walking speeds (P’s

Stroke commonly results in gait deficits which impacts functional ambulation and quality of life. Robotic exoskeletons (RE) for overground walking are devices that are programmable to provide high dose and movement-impairment specific assistance thus offering new rehabilitation possibilities for recovery progression in individuals post stroke. The purpose of this investigation is to present preliminary utilization data in individuals with acute and chronic stroke after walking overground with an RE. Secondary analysis on a subset of individuals is presented to understand the mechanistic changes due to RE overground walking. Thirty-eight participants with hemiplegia secondary to stroke were enrolled in a clinical trial conducted at eight rehabilitation centers. Data is presented for four sessions of overground walking in the RE over the course of 2 weeks. Participants continued their standard of care if they had any ongoing therapy at the time of study enrollment. Gait speed during the 10 Meter Walk Test, Gait deviations and the Functional Ambulation Category (FAC) data were collected before (baseline) and after (follow-up) the RE walking sessions. Walking speed significantly increased between baseline and follow-up for participants in the chronic (p

Introduction: Innovative motor therapies have attempted to reduce upper extremity impairment after stroke but have not made substantial improvement as over 50% of people post-stroke continue to have sensorimotor deficits affecting their self-care and participation in daily activities. Intervention studies have focused on the role of increased dosing, however recent studies have indicated that timing of rehabilitation interventions may be as important as dosing and importantly, that dosing and timing interact in mediating effectiveness. This study is designed to empirically test dosing and timing.Methods and Analysis: In this single-blinded, interventional study, subjects will be stratified on two dimensions, impairment level (Fugl-Meyer Upper Extremity Assessment (FM) and presence or absence of Motor Evoked Potentials (MEPs) as follows; (1) Severe, FM score 10–19, MEP+, (2) Severe, FM score 10–19, MEP–, (3) Moderate, FM score 20–49, MEP+, (4) Moderate, FM score 20–49, MEP–. Subjects not eligible for TMS will be assigned to either group 2 (if severe) or group 3 (if moderate). Stratified block randomization will then be used to achieve a balanced assignment. Early Robotic/VR Therapy (EVR) experimental group will receive in-patient usual care therapy plus an extra 10 h of intensive upper extremity therapy focusing on the hand using robotically facilitated rehabilitation interventions presented in virtual environments and initiated 5–30 days post-stroke. Delayed Robotic/VR Therapy (DVR) experimental group will receive the same intervention but initiated 30–60 days post-stroke. Dose-matched usual care group (DMUC) will receive an extra 10 h of usual care initiated 5–30 days post-stroke. Usual Care Group (UC) will receive the usual amount of physical/occupational therapy.Outcomes: There are clinical, neurophysiological, and kinematic/kinetic measures, plus measures of daily arm use and quality of life. Primary outcome is the Action Research Arm Test (ARAT) measured at 4 months post-stroke.Discussion: Outcome measures will be assessed to determine whether there is an early time period in which rehabilitation will be most effective, and whether there is a difference in the recapture of premorbid patterns of movement vs. the development of an efficient, but compensatory movement strategy.Ethical Considerations: The IRBs of New Jersey Institute of Technology, Rutgers University, Northeastern University, and Kessler Foundation reviewed and approved all study protocols. Study was registered in https://ClinicalTrials.gov (NCT03569059) prior to recruitment. Dissemination will include submission to peer-reviewed journals and professional presentations.

Stroke is the leading cause of severe disability in adults resulting in mobility, balance, and coordination deficits. Robotic exoskeletons (REs) for stroke rehabilitation can provide the user with consistent, high dose repetition of movement, as well as balance and stability. The goal of this intervention study is to evaluate the ability of a RE to provide high dose gait therapy and the resulting effect on functional recovery for individuals with acute stroke. The investigation included a total of 44 participants. Twenty-two participants received RE gait training during inpatient rehabilitation (RE+SOC Group), and a matched sample of 22 individuals admitted to the same inpatient rehabilitation facility-receiving conventional standard of care treatment (SOC group). The effect of RE training was quantified using total distance walked during inpatient rehabilitation and functional independence measure (FIM). The total distance walked during inpatient rehabilitation showed a significant difference between the SOC and RE+SOC groups. RE+SOC walked twice the distance as SOC during the same duration (time spent in inpatient rehabilitation) of training. In addition, the average change in motor FIM showed a significant difference between the SOC and RE+SOC groups, where the average difference in motor FIM was higher in RE+SOC compared to the SOC group. The results suggest that RE provided increased dosing of gait training without increasing the duration of training during acute stroke rehabilitation. The RE+SOC group increased their motor FIM score (change from admission to discharge) compared to SOC group, both groups were matched for admission motor FIM scores suggesting that increased dosing may have improved motor function.

There is limited research on sensory acuity i.e., ability to perceive external perturbations via body-sway during standing in individuals with a traumatic brain injury (TBI). It is unclear whether sensory acuity diminishes after a TBI and if it is a contributing factor to balance dysfunction. The objective of this investigation is to first objectively quantify the sensory acuity in terms of perturbation perception threshold (PPT) and determine if it is related to functional outcomes of static and dynamic balance. Ten individuals with chronic TBI and 11 age-matched healthy controls (HC) performed PPT assessments at 0.33, 0.5, and 1 Hz horizontal perturbations to the base of support in the anterior-posterior direction, and a battery of functional assessments of static and dynamic balance and mobility [Berg balance scale (BBS), timed-up and go (TUG) and 5-m (5MWT) and 10-m walk test (10MWT)]. A psychophysical approach based on Single Interval Adjustment Matrix Protocol (SIAM), i.e., a yes-no task, was used to quantify the multi-sensory thresholds of perceived external perturbations to calculate PPT. A mixed-design analysis of variance (ANOVA) and post-hoc analyses were performed using independent and paired t-tests to evaluate within and between-group differences. Pearson correlation was computed to determine the relationship between the PPT and functional measures. The PPT values were significantly higher for the TBI group (0.33 Hz: 2.97 ± 1.0, 0.5 Hz: 2.39 ± 0.7, 1 Hz: 1.22 ± 0.4) compared to the HC group (0.33 Hz: 1.03 ± 0.6, 0.5 Hz: 0.89 ± 0.4, 1 Hz: 0.42 ± 0.2) for all three perturbation frequencies (p < 0.006 post Bonferroni correction). For the TBI group, the PPT for 1 Hz perturbations showed significant correlation with the functional measures of balance (BBS: r = −0.66, p = 0.037; TUG: r = 0.78, p = 0.008; 5MWT: r = 0.67, p = 0.034, 10MWT: r = 0.76, p = 0.012). These findings demonstrate that individuals with TBI have diminished sensory acuity during standing which may be linked to impaired balance function after TBI.

Background. Acquired brain injury (ABI) is one of the leading causes of motor deficits in children and adults and often results in motor control and balance impairments. Motor deficits include abnormal loading and unloading, increased double support time, decreased walking speed, control, and coordination. These deficits lead to diminished functional ambulation and reduced quality of life. Robotic exoskeletons (RE) for motor rehabilitation can provide the user with consistent, symmetrical, goal-directed repetition of movement, as well as balance and stability. Purpose. The goal of this preliminary prospective before and after study is to evaluate the therapeutic effect of RE training on the loading/unloading and spatial-temporal characteristics in adolescents and young adults with chronic ABI. Method. Seven participants diagnosed with ABI between the ages of 14 and 27 years participated in the study. All participants received twelve 45 minute sessions of RE gait training. The bilateral loading (linearity of loading and rate of loading), speed, step length, swing time, stance time, and total time were collected using Zeno™ walkway (ProtoKinetics, Havertown, PA, USA) before and after RE training. Results. Results from the study showed improved step length, speed, and an overall progression towards healthy bilateral loading, with linearity of loading showing a significant therapeutic effect (p

Foot drop is one of the most common secondary conditions associated with hemiplegia post stroke and cerebral palsy (CP) in children, and is characterized by the inability to lift the foot (dorsiflexion) about the ankle. This investigation focuses on children and adolescents diagnosed with brain injury and aims to evaluate the orthotic and therapeutic effects due to continuous use of a foot drop stimulator (FDS). Seven children (10 ± 3.89 years) with foot drop and hemiplegia secondary to brain injury (stroke or CP) were evaluated at baseline and after 3 months of FDS usage during community ambulation. Primary outcome measures included using mechanistic (joint kinematics, toe displacement, temporal-spatial asymmetry), and functional gait parameters (speed, step length, time) to evaluate the orthotic and therapeutic effects. There was a significant correlation between spatial asymmetry and speed without FDS at 3 months (r = 0.76, p < 0.05, df = 5) and no correlation between temporal asymmetry and speed for all conditions. The results show orthotic effects including significant increase in toe displacement (p < 0.025 N = 7) during the swing phase of gait while using the FDS. A positive correlation exists between toe displacement and speed (with FDS at 3 months: r = 0.62, p > 0.05, without FDS at 3 months: r = 0.44, p > 0.05). The results indicate an orthotic effect of increased dorsiflexion and toe displacement during swing with the use of the FDS in children with hemiplegia. Further, the study suggests that there could be a potential long-term effect of increased dorsiflexion during swing with continuous use of FDS.

Background: Robotic exoskeleton (RE) based gait training involves repetitive task-oriented movements and weight shifts to promote functional recovery. To effectively understand the neuromuscular alterations occurring due to hemiplegia as well as due to the utilization of RE in acute stroke, there is a need for electromyography (EMG) techniques that not only quantify the intensity of muscle activations but also quantify and compare activation timings in different gait training environments.Purpose: To examine the applicability of a novel EMG analysis technique, Burst Duration Similarity Index (BDSI) during a single session of inpatient gait training in RE and during traditional overground gait training for individuals with acute stroke.Methods: Surface EMG was collected bilaterally with and without the RE device for five participants with acute stroke during the normalized gait cycle to measure lower limb muscle activations. EMG outcomes included integrated EMG (iEMG) calculated from the root-mean-square profiles, and a novel measure, BDSI derived from activation timing comparisons.Results: EMG data demonstrated volitional although varied levels of muscle activations on the affected and unaffected limbs, during gait with and without the RE. During the stance phase mean iEMG of the soleus (p = 0.019) and rectus femoris (RF) (p = 0.017) on the affected side significantly decreased with RE, as compared to without the RE. The differences in mean BDSI scores on the affected side with RE were significantly higher than without RE for the vastus lateralis (VL) (p = 0.010) and RF (p = 0.019).Conclusions: A traditional amplitude analysis (iEMG) and a novel timing analysis (BDSI) techniques were presented to assess the neuromuscular adaptations resulting in lower extremities muscles during RE assisted hemiplegic gait post acute stroke. The RE gait training environment allowed participants with hemiplegia post acute stroke to preserve their volitional neuromuscular activations during gait iEMG and BDSI analyses showed that the neuromuscular changes occurring in the RE environment were characterized by correctly timed amplitude and temporal adaptations. As a result of these adaptations, VL and RF on the affected side closely matched the activation patterns of healthy gait. Preliminary EMG data suggests that the RE provides an effective gait training environment for in acute stroke rehabilitation.

BackgroundA foot drop stimulator (FDS) is a rehabilitation intervention that stimulates the common peroneal nerve to facilitate ankle dorsiflexion at the appropriate time during post-stroke hemiplegic gait. Time–frequency analysis (TFA) of non-stationary surface electromyograms (EMG) and spectral variables such as instantaneous mean frequency (IMNF) can provide valuable information on the long-term effects of FDS intervention in terms of changes in the motor unit (MU) recruitment during gait, secondary to improved dorsiflexion.ObjectiveThe aim of this study was to apply a wavelet-based TFA approach to assess the changes in neuromuscular activation of the tibialis anterior (TA), soleus (SOL), and gastrocnemius (GA) muscles after utilization of an FDS during gait post-stroke.MethodsSurface EMG were collected bilaterally from the TA, SOL, and GA muscles from six participants (142.9 ± 103.3 months post-stroke) while walking without the FDS at baseline and 6 months post-FDS utilization. Continuous wavelet transform was performed to get the averaged time–frequency distribution of band pass filtered (20–300 Hz) EMGs during multiple walking trials. IMNFs were computed during normalized gait and were averaged during the stance and swing phases. Percent changes in the energies associated with each frequency band of 25 Hz between 25 and 300 Hz were computed and compared between visits.ResultsAveraged time–frequency representations of the affected TA, SOL, and GA EMG show altered spectral attributes post-FDS utilization during normalized gait. The mean IMNF values for the affected TA were significantly lower than the unaffected TA at baseline (p = 0.026) and follow-up (p = 0.038) during normalized stance. The mean IMNF values significantly increased (p = 0.017) for the affected GA at follow-up during normalized swing. The frequency band of 250–275 Hz significantly increased in the energies post-FDS utilization for all muscles.ConclusionThe application of wavelet-based TFA of EMG and outcome measures (IMNF, energy) extracted from the time–frequency distributions suggest alterations in MU recruitment strategies after the use of FDS in individuals with chronic stroke. This further establishes the efficacy of FDS as a rehabilitation intervention that may promote motor recovery in addition to treating the secondary complications of foot drop due to post-stroke hemiplegia.

The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit.