Enhancing recovery of lower limb function after spinal cord injury

Spinal cord injury (SCI) is a debilitating neurological condition that impacts an estimated 250,000 individuals in the United States. Deficits in locomotion strongly contribute to post-SCI disability, and there are limited therapies to restore walking. The development of consistent, effective interventions to promote recovery of gait in individuals with SCI is of clear importance. It is widely recognized that approaches that facilitate synaptic plasticity in conjunction with rehabilitation hold promise to guide adaptive changes and improve recovery after incomplete SCI. We have developed one such strategy that uses electrical stimulation of the vagus nerve in the neck to drive precisely-timed release of neuromodulators. Coupling vagus nerve stimulation (VNS) with rehabilitation enhances synaptic plasticity and significantly improves recovery in multiple preclinical models of SCI. Moreover, a pivotal study demonstrates that VNS paired with upper limb rehabilitation promotes recovery of arm and hand function after chronic stroke, and promising preliminary clinical data indicates similar improvements in individuals with incomplete cervical SCI. Here, we seek to build on this success and translate a VNS therapy to restore gait after SCI. VNS therapy is based on coincident stimulation during specific rehabilitative exercises, thus the goal of UG3 phase of the proposed project is to finalize a system for closed-loop VNS triggering during lower limb rehabilitation. We will integrate an array of lower limb sensors with our VNS system and perform testing to ensure performance to relevant standards. Additionally, we will gain the necessary regulatory approvals for a subsequent study. Finally, we will perform a pilot study of this approach in individuals with SCI previously implanted with a VNS device as part of a separate study. In the UH3 phase of this project, we will perform a randomized, double-blinded, sham- controlled study to evaluate the utility of this strategy to improve recovery of gait in individuals with chronic incomplete SCI. Our team is seriously committed to clinical translation and has successfully performed multiple clinical trials using VNS paired with rehabilitation. Collectively, these aims represent an expeditious approach that balances the challenge of translation with achievable goals necessary for effective clinical investigation. Successful completion of these Aims will directly lead to a performance of a subsequent pivotal trial of this potential therapy in individuals with chronic SCI.