Pudendal neuromodulation for incontinence and sphincter dyssynergia after spinal injury

脊髓损伤(SCI)经常导致严重的、终生的膀胱和肠道功能障碍，导致 尿失禁和大便失禁，以及括约肌协同失调，导致尿潴留和粪便 影响。目前治疗大小便失禁的标准包括成人尿布，而膀胱和肠道排尿 需要每天多次进行膀胱导尿术，并定期以数字方式抽取粪便。尿布是 导尿管会导致频繁的尿路感染，而数字肠道程序很耗时 以及对个人和/或其照顾者的污名。对于大多数患有脊髓损伤、膀胱和肠道的人来说 功能障碍对他们职业和社交生活的影响比他们不能走路更大。 在本申请中，我们提出了当前可用的、可编程的、可植入的脉冲发生器(IPG)， 与放置在双侧阴部神经上的电极相接，可以为脊髓损伤患者提供治疗 大小便失禁和括约肌协同失调。阴部神经为尿路提供传出神经 和肛门横纹括约肌，产生收缩并防止尿液和粪便通过 分别为尿路和肛管。在此应用中，我们将重点放在改善排尿功能上，并提出 以低频(LFS)刺激阴部神经会产生尿道括约肌收缩， 防止尿流，防止尿失禁。我们进一步建议，LFS也将激活阴部 传入纤维通过脊髓机制抑制膀胱过度活动。当需要排空时，我们 建议短时(2-5分钟)、间歇性(4-5次/天)高频阴部神经刺激 (KHFS)将阻断阴部神经动作电位，并防止括约肌协同失调以允许排尿。 单侧阴部神经刺激在临床上被发现是安全和有效的治疗各种疾病 泌尿生殖功能障碍，但双侧刺激是完全收缩括约肌所必需的，但没有 有人试图这样做。 具体目标1将建立提供维持的尿路所需的最有效的LFS脉冲特征 括约肌收缩以防止膀胱压力升高期间的尿漏(存储模式)。 具体目标2将探索激活传出纤维的LFS脉冲特征是否会收缩 括约肌，也能有效刺激传入纤维，抑制膀胱过度活动。特定的 目标3将确定用于LFS的相同电极是否也可以提供KHFS来阻断阴部神经 活动，放松括约肌，促进排尿(排尿模式)。使用植入的IPG治疗的第二阶段研究 在慢性脊髓损伤的临床前、翻译模型中对尿功能的长期行为研究也将 确定该装置是否同时改善了排便功能。

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.