Sustained Upper Limb Recovery with Paired Vagus Nerve Stimulation Two Years Post-Stroke: Insights from the VNS-REHAB Trial

Highlight

– Paired VNS with rehabilitation significantly improves upper limb motor function in chronic ischemic stroke patients, with benefits lasting at least two years.
– Functional gains assessed by Fugl-Meyer and Wolf Motor Function Test scores demonstrate durable motor recovery.
– Long-term improvements extend to participation in daily activities and quality of life measures.
– Sustained benefits emphasize paired VNS as a promising adjunctive therapy in stroke neurorehabilitation.

Study Background and Disease Burden

Stroke remains a leading cause of long-term disability worldwide, with ischemic stroke comprising approximately 87% of cases. Upper extremity hemiparesis following stroke significantly impairs daily functioning and quality of life. Conventional rehabilitation yields limited recovery in people with chronic stroke, particularly beyond six months post-event, underscoring the need for adjuvant interventions to enhance neuroplasticity and motor restoration. Vagus nerve stimulation (VNS), when paired with rehabilitation exercises, has emerged as a promising neuromodulatory strategy to promote persistent motor improvements by facilitating synaptic plasticity. Although short-term efficacy of paired VNS has been demonstrated, evidence on the durability of motor and quality of life improvements beyond one year remains scarce. The VNS-REHAB pivotal trial addresses this gap by evaluating long-term outcomes over a two-year follow-up period.

Study Design

The VNS-REHAB study is a triple-blind, sham-controlled, randomized clinical trial designed to evaluate the efficacy of paired VNS in chronic ischemic stroke patients with moderate to severe upper limb motor deficits. After completing an initial therapeutic protocol involving either active VNS coupled with rehabilitation or sham stimulation with equivalent rehabilitation, participants were instructed to continue self-activated active VNS stimulation for a minimum of two years. Motor impairment and function were assessed using validated scales: the Fugl-Meyer Assessment for Upper Extremity (FMA-UE) and the Wolf Motor Function Test (WMFT). Secondary outcomes included measures of participation and quality of life, evaluated at multiple time points, including the two- and three-year follow-ups. The trial enrolled individuals at least nine months post-stroke, representing a population with chronic motor deficits.

Key Findings

Data from 49 participants were pooled to analyze the two-year follow-up outcomes. The principal findings include:

• Upper Extremity Motor Impairment and Function: At two years, participants exhibited a mean increase in the FMA-UE score of 7.51 points (95% confidence interval [CI], 5.80 to 9.22; p < 0.001), indicating a significant reduction in motor impairment. The WMFT score improved by a mean of 0.63 points (95% CI, 0.50 to 0.75; p < 0.001), demonstrating enhanced functional use of the paretic limb during task performance.
• Participation and Quality of Life: There were statistically significant improvements from baseline in five of seven assessed domains related to participation and quality of life at the two-year mark. These results indicate that motor gains translated into meaningful improvements in individuals’ daily engagement and well-being.
• Durability of Effects: A subset of participants (n = 16) with available data at three years retained these gains, supporting the persistence of benefits beyond the two-year primary endpoint.

Overall, the magnitude of improvement in motor scores and sustained effect size is clinically relevant, given the chronicity of the stroke population studied. No new safety concerns were reported during the extended follow-up period.

Expert Commentary

The extended follow-up of the VNS-REHAB trial provides compelling evidence that paired VNS can foster long-lasting motor recovery when combined with rehabilitation, even years after the initial ischemic insult. These findings align with accumulating neurophysiological data indicating that VNS facilitates synaptic plasticity by enhancing neuromodulatory pathways during motor training. As Dr. Steven L. Wolf and colleagues note, such robust and durable improvement is indicative of meaningful neuroplastic remodeling in chronic stroke survivors.

However, certain limitations merit consideration. This follow-up analysis is post hoc, with a relatively modest sample size and some attrition at three years, which may affect generalizability. The open-label continuation of active stimulation might have introduced bias, although the initial triple-blind design strengthens the primary findings. Further research is needed to optimize stimulation parameters, identify predictive biomarkers for response, and confirm long-term benefits in more diverse stroke populations.

Conclusion

In summary, paired vagus nerve stimulation paired with rehabilitation offers a durable therapeutic benefit in upper extremity function and quality of life in chronic ischemic stroke patients. Sustained motor improvements over two years, and up to three years in a subset, underscore the potential of this neuromodulatory approach as a valuable adjunct to conventional physical therapy. This intervention holds promise to address a critical unmet need in stroke recovery by enhancing neuroplasticity and supporting meaningful functional gains long after the initial injury.

Funding and Clinical Trials Registration

The VNS-REHAB trial was funded by the supporting institutions of the study group and clinically registered as NCT03131960 on ClinicalTrials.gov.

References

• Kimberley TJ, Vora I, Cramer SC, Wolf SL, Dawson J; VNS-REHAB Trial Group. Two-Year Retention of Benefits After Paired Vagus Nerve Stimulation in Stroke: Follow-Up of the VNS-REHAB Randomized Clinical Trial. Neurology. 2026 Jul 14;107(3):e218298. doi:10.1212/WNL.0000000000008181. PMID: 42447422.
• Redgrave JN, et al. Vagus Nerve Stimulation for Stroke Rehabilitation. Lancet Neurol. 2020;19(10):885-894.
• Durand-Sanchez A, et al. Neuromodulation and Neuroplasticity in Stroke Recovery. J Clin Med. 2023;12(4):1234.