Safety and feasibility of paired vagus nerve stimulation with rehabilitation for improving upper extremity function in people with cervical spinal cord injury: a pilot randomized controlled trial.

Background: Recovery of upper extremity function remains a major unmet need for individuals with chronic cervical spinal cord injury (SCI). Pairing vagus nerve stimulation (VNS) with task-specific rehabilitation has been shown to enhance neuroplasticity and motor recovery in stroke, but evidence in SCI is limited. Objective: To evaluate the safety and feasibility of pairing VNS with upper extremity rehabilitation in individuals with chronic cervical SCI, and to explore preliminary effects on upper extremity function. Methods: This single-site, triple-blind, randomized, sham-controlled pilot trial enrolled adults with chronic traumatic incomplete cervical SCI. All participants underwent implantation of a VNS device and were randomized 1:1 to receive active VNS paired with rehabilitation or sham VNS paired with rehabilitation. Participants completed 18 in-clinic rehabilitation sessions over 6-8 weeks, followed by a 90-day home-based exercise program. Primary outcomes were safety and feasibility; exploratory outcomes included standardized upper extremity motor measures and patient-reported experiences. The randomized design was intended to assess feasibility of trial procedures rather than estimate treatment effects. Results: Six participants were implanted and completed study procedures through 90-day follow-up. No serious adverse events, unanticipated adverse device effects, or unresolved surgery-related complications were observed. In-clinic therapy adherence was high, supporting the feasibility of the intervention. At the immediate post-intervention, all participants receiving active VNS demonstrated mild-to-moderate improvements in upper extremity motor function, whereas no improvements were observed in the sham group. At 90 days, two active VNS participants sustained these gains. Participants receiving active VNS reported subjective improvements in coordination, movement quality, and daily task performance. Conclusion: This pilot randomized trial demonstrates that pairing invasive VNS with upper extremity rehabilitation in individuals with chronic cervical spinal cord injury is safe, feasible, and well-tolerated. While clinical improvements were exploratory, positive participant-reported experiences and observed patterns of improvement support further investigation in larger trials designed to rigorously assess efficacy, durability, and optimal dosing parameters. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05601661.