Pudendal neuromodulation for incontinence and sphincter dyssynergia after spinal injury

Dignify Therapeutics, Llc, Research Triangle Park NC

Investigators

Abstract

Spinal cord injury (SCI) frequently produces severe, life-long bladder and bowel dysfunction that result in urinary and fecal incontinence, as well as sphincter dyssynergia that causes urinary retention and fecal impaction. Current standard of care for incontinence consists of adult diapers, while bladder and bowel voiding require multiple-times-daily catheterization of the bladder and regular digital extraction of feces. Diapers are odiferous, catheters induce frequent urinary tract infections, and digital bowel programs are time-consuming and stigmatizing for the individual and/or their caregiver. For most people with SCI, bladder and bowel dysfunction impacts their professional and social lives more than their inability to walk. In this application, we propose that currently available, programmable, implantable pulse generators (IPGs), interfaced with electrodes placed bilaterally on the pudendal nerves, can offer people with SCI a remedy for both incontinence and sphincter dyssynergia. The pudendal nerve provides efferent innervation to the urethral and anal rhabdosphincters that produces contractions and prevents the leakage of urine and feces through the urethra and anal canal, respectively. In this application, we focus on improving urinary function and propose that stimulation of the pudendal nerve at low frequencies (LFS) will produce urethral sphincter contractions that resist flow of urine and prevent urinary incontinence. We further propose that LFS will also activate pudendal afferent fibers to suppress bladder overactivity through spinal mechanisms. When voiding is desired, we propose that brief (2-5 min), intermittent (4-5/day), pudendal nerve stimulation at high (kHz) frequencies (KHFS) will occlude pudendal nerve action potentials and prevent sphincter dyssynergia to allow voiding. Unilateral stimulation of the pudendal nerve was found clinically safe and efficacious for treating various urogenital dysfunctions, but bilateral stimulation, which is necessary to fully contract the sphincter, has not been attempted. Specific Aim 1 will establish the most efficient LFS pulse characteristics needed to provide maintained urethral sphincter contractions to prevent leakage of urine during periods of elevated bladder pressure (Storage Mode). Specific Aim 2 will explore whether the LFS pulse characteristics that activate efferent fibers, to contract the sphincter, can also provide effective stimulation of the afferent fibers, to inhibit bladder overactivity. Specific Aim 3 will establish if the same electrodes used for LFS can also deliver KHFS to block pudendal nerve activity, relax the sphincter, and facilitate voiding (Voiding Mode). Phase 2 studies using implanted IPGs for long-term behavioral studies of urinary function in a preclinical, translational model of chronic SCI will also establish if the device simultaneously improves bowel function.