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

Abstract

Introduction: Pairing vagus nerve stimulation with traditional rehabilitation therapies results in improved motor recovery in people with stroke. However, this approach has not yet been studied in people with spinal cord injury (SCI). Motor recovery continues to be challenging after SCI, and there is a need for innovative research strategies to enhance motor recovery after SCI. Hence, this pilot randomized controlled trial aims to evaluate the safety, feasibility, and potential efficacy of pairing vagus nerve stimulation (VNS) with rehabilitation therapy to restore the motor function of the paretic upper limbs in people with cervical SCI.

Methods and analysis: In this triple-blind, randomized, sham-controlled pilot study, 8 adults with chronic incomplete SCI will be implanted with a VNS device and randomly assigned to either active VNS (0.8 mA) control VNS (0.0 mA) paired with upper limb rehabilitation. Each participant will undergo 18 in-clinic therapy sessions over 6 weeks, each lasting 120 min and delivered three times per week. Following the in-clinic phase, participants will continue with a 90-day home exercise program. Participants in both groups will receive similar goal-directed and intense upper limb rehabilitation. The therapy is focused on active movements, task specificity, high number repetitions, variable practice, and active participant engagement. Post-treatment assessment will occur immediately after in-clinic therapy and at 30 and 90 days of follow-up. After completion of blinding at 90 days follow-up, participants in the control group will be offered 6 weeks of in-clinic active VNS (0.8 mA) paired with rehabilitation. The safety of pairing VNS with rehabilitation will be assessed by the occurrence of adverse events in each group, and feasibility by the number of treatment sessions and follow-up visits attended and the number of dropouts. Potential efficacy will be assessed by measuring the change in Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) performance from baseline to immediately after in-clinic therapy and to 90 days. Secondary clinical outcome measures are the Toronto Rehabilitation Institute Hand Function Test, Capabilities of Upper Extremity Questionnaire, Spinal Cord Injury Independence Measure-III self-care subscore, and Spinal Cord Injury-Quality of Life scale.

Ethics and dissemination: The trial protocol was approved by the Institutional Review Board of UTHealth (HSC-MS-22-0579). We anticipate publishing the results in a peer-reviewed journal within 1 year of study completion.

Clinical trial registration: ClinicalTrials.gov, NCT05601661.

Keywords: motor recovery; rehabilitation; spinal cord injury; upper extremity; vagus nerve stimulation.

Figure 1

Study flow.

Figure 2

Vagus nerve stimulation (VNS) with rehabilitation. (a) In-clinic rehabilitation session set-up. The therapist is shown holding the VNS trigger button, which delivers a VNS pulse when the participant performs the task-specific movements. Also depicted in the figure is the wireless transmitter on the table connected to the notebook via a USB cable. When the therapist presses the VNS trigger button, the wireless transmitter sends a signal to the implanted device, which stimulates the left vagus nerve via a cuff electrode in the participant’s neck. (b) Possible mechanism for VNS paired with movement. Stimulation of the vagus nerve stimulates the deep brain cholinergic nucleus basalis and noradrenergic locus coeruleus neurons (base of green arrow). Stimulation of the vagus nerve during task-specific movements modulates the activity of the motor cortex (blue and red area) in a task-specific manner. Reprinted with permission from Kimberley et al. (37).