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.

Feasibility of transcutaneous spinal direct current stimulation combined with locomotor training after spinal cord injury.

STUDY DESIGN: Feasibility study, consisting of random-order, cross-over study of a single intervention session, followed by a parallel-arm study of 16 sessions. OBJECTIVES: To investigate the feasibility of a novel combinatorial approach with simultaneous delivery of transcutaneous spinal direct current stimulation (tsDCS) and locomotor training (tsDCS + LT) after spinal cord injury, compared to sham stimulation and locomotor training (sham + LT), and examine preliminary effects on walking function. SETTING: Clinical research center in the southeastern United States. METHODS: Eight individuals with chronic incomplete spinal cord injury (ISCI) completed the two-part protocol. Feasibility was assessed based on safety (adverse responses), tolerability (pain, spasticity, skin integrity), and protocol achievement (session duration, intensity). Walking function was assessed with the 10 m and 6 min walk tests. RESULTS: There were no major adverse responses. Minimal reports of skin irritation and musculoskeletal pain were consistent between groups. Average training peak heart rate as percent of maximum (mean(SD); tsDCS + LT: 66 (4)%, sham + LT: 69 (10)%) and Borg ratings of perceived exertion (tsDCS + LT: 17.5 (1.2), sham + LT: 14.4 (1.8)) indicate both groups trained at high intensities. Walking speed gains exceeded the minimal clinically important difference (MCID) in three of four who received tsDCS + LT (0.18 (0.29) m/s) and one of four in sham + LT (-0.05 (0.23) m/s). Gains in walking endurance exceeded the MCID in one of four in each group (tsDCS + LT: 36.4 (69.0) m, sham + LT: 4.9 (56.9) m). CONCLUSIONS: Combinatorial tsDCS and locomotor training is safe and feasible for individuals with chronic ISCI, even those with considerable walking impairment. Study outcomes support the need to investigate the efficacy of this approach.

Rehabilitation with accurate adaptability walking tasks or steady state walking: A randomized clinical trial in adults post-stroke.

OBJECTIVE: To assess changes in walking function and walking-related prefrontal cortical activity following two post-stroke rehabilitation interventions: an accurate adaptability (ACC) walking intervention and a steady state (SS) walking intervention. DESIGN: Randomized, single blind, parallel group clinical trial. SETTING: Hospital research setting. SUBJECTS: Adults with chronic post-stroke hemiparesis and walking deficits. INTERVENTIONS: ACC emphasized stepping accuracy and walking adaptability, while SS emphasized steady state, symmetrical stepping. Both included 36 sessions led by a licensed physical therapist. ACC walking tasks recruit cortical regions that increase corticospinal tract activation, while SS walking activates the corticospinal tract less intensely. MAIN MEASURES: The primary functional outcome measure was preferred steady state walking speed. Prefrontal brain activity during walking was measured with functional near infrared spectroscopy to assess executive control demands. Assessments were conducted at baseline, post-intervention (three months), and follow-up (six months). RESULTS: Thirty-eight participants were randomized to the study interventions (mean age 59.6 ± 9.1 years; mean months post-stroke 18.0 ± 10.5). Preferred walking speed increased from baseline to post-intervention by 0.13 ± 0.11 m/s in the ACC group and by 0.14 ± 0.13 m/s in the SS group. The Time × Group interaction was not statistically significant (P = 0.86). Prefrontal fNIRS during walking decreased from baseline to post-intervention, with a marginally larger effect in the ACC group (P = 0.05). CONCLUSIONS: The ACC and SS interventions produced similar changes in walking function. fNIRS suggested a potential benefit of ACC training for reducing demand on prefrontal (executive) resources during walking.

Cardiorespiratory Responses to Acute Intermittent Hypoxia in Humans With Chronic Spinal Cord Injury.

Brief exposure to repeated episodes of low inspired oxygen, or acute intermittent hypoxia (AIH), is a promising therapeutic modality to improve motor function after chronic, incomplete spinal cord injury (SCI). Although therapeutic AIH is under extensive investigation in persons with SCI, limited data are available concerning cardiorespiratory responses during and after AIH exposure despite implications for AIH safety and tolerability. Thus, we recorded immediate (during treatment) and enduring (up to 30 min post-treatment) cardiorespiratory responses to AIH in 19 participants with chronic SCI (>1 year post-injury; injury levels C1 to T6; American Spinal Injury Association Impairment Scale A to D; mean age = 33.8 ± 14.1 years; 18 males). Participants completed a single AIH (15, 60-sec episodes, inspired O2 ≈ 10%; 90-sec intervals breathing room air) and Sham (inspired O2 ≈ 21%) treatment, in random order. During hypoxic episodes: (1) arterial oxyhemoglobin saturation decreased to 82.1 ± 2.9% (p < 0.001); (2) minute ventilation increased 3.83 ± 2.29 L/min (p = 0.008); and (3) heart rate increased 4.77 ± 6.82 bpm (p = 0.010). Considerable variability in cardiorespiratory responses was found among subjects; some individuals exhibited large hypoxic ventilatory responses (≥0.20 L/min/%, n = 11), whereas others responded minimally (<0.20 L/min/%, n = 8). Apneas occurred frequently during AIH and/or Sham protocols in multiple participants. All participants completed AIH treatment without difficulty. No significant changes in ventilation, heart rate, or arterial blood pressure were found 30 min post-AIH p > 0.05). In conclusion, therapeutic AIH is well tolerated, elicits variable chemoreflex activation, and does not cause persistent changes in cardiorespiratory control/function 30 min post-treatment in persons with chronic SCI.

The 3-Meter Backward Walk Test (3MBWT): Reliability and validity in individuals with subacute and chronic stroke.

INTRODUCTION: Backward walking (BW) is an important gait adaptation and BW speed may be an important indicator of walking function and fall risk. However, the measurement characteristics of a standardized assessment of BW post-stroke have not been fully established. OBJECTIVES: To determine intra- and interrater reliability, concurrent validity and minimal detectable change (MDC) scores for the 3-Meter Backward Walk Test (3MBWT) post-stroke. METHODS: Thirty-four individuals with subacute and 29 individuals with chronic stroke participated. Two trials of comfortable BW was measured over a total distance of 5-meters, while speed was calculated during the middle 3-meters of the walking distance. Intra and interrater reliability were determined by comparing the two trials from one rater and simultaneous assessment of two raters, respectively. Two additional trials were performed and BW speed was calculated using 3MBWT and an instrumented walkway to determine concurrent validity. Intraclass correlation coefficients (ICC) estimated reliability and validity. The MDC was calculated from the standard error of measurement. RESULTS: Excellent ICC values were obtained for the 3MBWT in the subacute (interrater: ICC2,1 = 0.99; intrarater: ICC2,1 = 0.96; validity: ICC2,1 = 0.96) and chronic (interrater: ICC2,1 = 0.99; intrarater: ICC2,1 = 0.94; validity: ICC2,1 = 0.97) groups. The MDC was 0.07 m/s (subacute) and 0.11 m/s (chronic). CONCLUSIONS: Establishment of the 3MBWT as a reliable and valid measure in assessing BW speed is an important addition to the assessment toolbox for rehabilitation post-stroke.

The use of assisted technologies in early aggressive mobilization with an individual in a minimally conscious state: a case report.

INTRODUCTION: Early neurorehabilitation and passive, upright mobilization strategies have been shown to be beneficial for individuals with disorders of consciousness (DOC). However, literature is limited in illustrating the use of an early, aggressive program with an added focus on dynamic and active upright mobilization. The purpose of this case report is to describe a two-week aggressive, upright standing and walking program with an individual with traumatic brain injury in an acute inpatient rehabilitation setting. The case investigates the association between aggressive mobilization with changes in level of consciousness and daily cognitive, motor and communicative behaviours. CASE DESCRIPTION: A 30-year-old male classified in DOC as minimally conscious state (MCS) participated in an early upright mobilization program. The two-week intervention consisted of aggressive static/passive and dynamic/active upright mobilization activities, involving a multidisciplinary rehabilitation team. Expressive communication, motor responses and current level of consciousness were monitored and assessed twice a day. Additionally, the patient's activation and arousal were subjectively monitored during daily therapy sessions. RESULTS: Following the dynamic/active mobilization activities, the patient demonstrated improved expressive communication, motor scores and increased activation and arousal during the mobilizations. After the two-week intervention, he emerged from DOC. CONCLUSION: This case report illustrates intense, more active/dynamic upright mobilization with the use of assisted technologies provides promise as an effective intervention for improving communication, motor responses, arousal and level of consciousness in a patient in MCS. Initiating upright, active activity sooner in the recovery process, may lead to improved outcomes and quicker emergence.IMPLICATIONS FOR REHABILITATIONAggressive upright mobilization may be delivered safely to patients in DOC early in their rehabilitative care.Aggressive upright mobilization may be beneficial for patients in DOC.Higher intensity, more active/dynamic upright mobilization such as the use of Erigo®Pro + stepping and locomotor training on a treadmill with body weight support demonstrated positive outcomes with expressive communication, motor responses and arousal.Earlier initiation of aggressive mobilization may promote recovery.

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.

Clinical application of backward walking training to improve walking function, balance, and fall-risk in acute stroke: a case series.

Background: With limited inpatient rehabilitation (IR) length of stays for patients post-stroke, it is critical to maximize the effectiveness of interventions to address their balance and gait speed deficits. Backward walking (BW) is an emerging training approach; however, its application to patient populations consistent with those in IR is limited. Objectives: To describe the effects of an additional BW training program to standard IR care on balance, walking ability and fall-risk in a heterogenic caseload of adults <2 weeks post-stroke with a broad range of lesion locations and physical sequelae. Methods: Eight patients with first-time stroke (5 male; average age 66.5 ± 11.7 years; average stroke onset 7.6 ± 1.6 days; 6 right hemiparesis) participated in 10-daily sessions that included 20 min of over ground BW training for each session, in addition to standard IR. Standard outcome measures were used to assess balance, walking ability and fall-risk at admission and post-intervention. Results: All eight patients demonstrated improvements in all outcomes with a clinically meaningful increase in forward walking speed, as measured by 10MWT. Four participants exceeded fall-risk cut-off scores for all balance-related outcome measures. Conclusions: In a diverse patient population early after stroke, individuals successfully participated in an additional BW training program. Despite the patients' acuity and severe impairments in walking, significant gains in balance and walking function were noted. This program may be useful in improving outcomes with patient characteristics commonly seen in IR.