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

Abstract

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.

Closed-loop transcutaneous auricular vagus nerve stimulation for the improvement of upper extremity motor function in stroke patients: a study protocol

“…Nor have studies provided direct clinical evidence for the benefits of pairing taVNS with movement by decoding EMG signals during motor training. Previous studies have indicated that pairing VNS (10)(11)(12) or taVNS (27,28,30) 27) highlighted the benefits of movement-synchronized taVNS by decoding EMG signals compared to simple combination of taVNS and movements. However, their study was not designed with a sham control group and the number of subjects per group was limited to less than 10.…”

“…Nor have studies provided direct clinical evidence for the benefits of pairing taVNS with movement by decoding EMG signals during motor training. Previous studies have indicated that pairing VNS ( 10 – 12 ) or taVNS ( 27 , 28 , 30 ) with rehabilitative training can enhance motor function recovery. Whereas a study by Wu et al ( 31 ) demonstrated that taVNS treatment prior to regular motor training could improve motor functions.…”

“…Recent studies on rat models of stroke ( 4 – 9 ) and stroke patients ( 10 – 12 ) have demonstrated positive effects of VNS on motor rehabilitation. The study by Dawson et al ( 10 – 12 ) using a randomized double-blind approach showed that the efficacy of VNS paired with motor training was two to three times than that of sham VNS combined with motor training on the upper extremity rehabilitation in ischemic stroke patients. Several mechanisms have been proposed to elucidate the rehabilitative effects of VNS on stroke.…”

tVNS in Stroke: A Narrative Review on the Current State and the Future

“…The VNS-REHAB study subgroup analysis indicated no significant difference in the mean FMA-UE score improvement in subgroups divided by age (<62 versus ≥62), sex, stroke severity (FMA-UE score ≤34 versus >34), time since stroke (≤2 years versus >2 years), side of paresis, or presence/absence of cortical involvement. 67 These results are promising that invasive VNS paired with rehabilitation is potentially beneficial to a variety of stroke patients. Furthermore, the VNS-REHAB study did not include individuals with very severe strokes (FMA-UE <20), infratentorial stroke, intracerebral hemorrhage or those with multiple infarcts.…”

Case Report: The Rehabilitation of a Patient with Acute Transverse Myelitis after COVID-19 Vaccination

“…This pathway can also be activated via non-invasive Vagus Nerve Stimulation (nVNS) [ 15 ], which could turn out to be a true game changer not only in etiologic rehabilitation [ 16 ] but also in symptomatic rehabilitation, notably acting on motor rehabilitation [ 17 ] and pain [ 18 ].…”