Targeted Neuroplasticity via vagus nerve stimulation to improve urinary dysfunction after spinal cord injury

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Project summary: Restoration of urinary dysfunction is often in the top 25% priority for rehabilitation in individuals after spinal cord injury (SCI), often ranking higher than restoration of upper limb function. However, current treatments are mostly limited to conservative approaches consisting of intermittent catheterization and behavioral changes such as fluid intake management, but these interventions only provide symptomatic relief and are associated with recurrent urinary tract infections, kidney disease, and high mortality rates. While other pharmaceutical and surgical treatments may be available for some patients with specific complaints such as overactive bladder, the development of novel therapies to improve and restore bladder function after SCI is of clear importance. Vagus nerve stimulation (VNS) paired with rehabilitation is a neuromodulation technology that has demonstrated great potential at restoring motor and sensory function after neurological injury, including incomplete SCI. VNS promotes neuroplastic changes by the timed-release of neuromodulators that can enhance recovery. Here we propose for the first time, a strategy of pairing VNS with bladder function after incomplete SCI to improve symptoms of urinary dysfunction. Our preliminary results support the use of this technology to restore bladder function after SCI. We propose to conduct clinical and preclinical research concurrently to accelerate technology translation. Aim 1 (K99 phase) leverages a separate, ongoing clinical trial (NCT04288245) that has 15 participants, who have the VNS system already implanted and willing to partake in novel therapy approaches. This aim, will demonstrate that VNS therapy paired with bladder function can improve voiding efficiency in humans after SCI. To achieve this, we will modify the interface of the VNS system (ReStore VNS system; FDA-cleared for upper limb rehabilitation after stroke and currently undergoing phase 2 clinical trials for upper limb rehabilitation after SCI) to allow pairing with volitional bladder voiding and conduct a pilot study in currently implanted individuals. Aim 2 optimizes the timing of delivery VNS paired with different stages of the bladder function to improve voiding efficiency in the rat model (sub-Aim 2.1, K99/R00 phase) and characterizes the mechanisms of action behind those changes (sub-Aim 2.2, R00 phase). During Dr. Hernandez-Reynoso’s career, she has extensively investigated the use of electrical stimulation targeted to the peripheral nervous system as a novel treatment of urinary dysfunction, and the development of peripheral and central neural interfaces. As such, she is the ideal candidate to carry this proposal to completion. Results from both aims of this proposal will support the submission of an R01 to conduct an independent clinical trial, and act as a catalyst for the candidate to reach independence as a translational researcher in the neural engineering and bioelectronic medicines field.