TRANSLUMBOSACRAL NEUROMODULATION THERAPY FOR FECAL INCONTINENCE: RANDOMIZED TRIAL

经腰椎神经调节疗法治疗大便失禁： 随机试验 项目摘要/摘要： 大便失禁(FI)影响着4000万美国人，主要是妇女和老年人。这是一名少校 保健负担，严重损害生活质量和心理社会功能。FI的特点是 由多因素功能障碍引起的，包括腰骶神经病变、肛门直肠感觉运动 功能障碍和不适应盆底-脑神经支配。取得进展的一个关键障碍 FI的治疗缺乏随机对照试验，缺乏基于机制的非 修改疾病的侵入性治疗，以及对治疗效果缺乏了解 FI的病理生理学，正如专家在最近的NIDDK研讨会上强调的那样。因此，大多数 目前的补救措施仍然无效。我们的长期目标是解决缺乏 通过研究调节外周和中枢神经元的治疗方法有效治疗FI 从而改善感觉和内脏运动的控制，并理解 这些治疗的神经生物学基础。我们的中心假设是一种新颖的、非侵入性的 包括经腰骶神经调节疗法(TNT)的治疗，使用重复 磁刺激，将在短期和长期内显著提高FI，通过增强 神经兴奋性和诱导神经可塑性，从而提供了一种多维治疗 利益。我们的方法是基于令人信服的初步研究，该研究表明TNT在1赫兹 频率显著提高，通过增强双向肠道和大脑信号，肛门括约肌 强度和直肠感觉与5或15赫兹相比。我们的目标是1)调查 一种新的治疗方法TNT的有效性、安全性和最佳剂量，在假控制的随机剂量中- 132例FI患者的相关性研究；2)评估TNT的发病机制 传出脊柱-肛门直肠和传入盆底-脑信号和肛门直肠感觉-运动 功能；3)确定TNT的治疗反应和神经调节作用的持久性，以及 增强TNT是否通过增强的自适应能力提供增强的改进 神经可塑性，通过执行一项长期、假对照的随机试验。我们期望的是 结果包括证明TNT是一种耐用、有效、安全、基于机械的 非侵入性、低风险的FI治疗。我们项目的影响包括一种新的疾病 改良的非侵入性治疗FI，开发这种治疗的科学基础，以及 提高了对FI的病理生理学和FI的神经生物学机制的理解(S) TNT可以改变双向肠道和脑轴以及肛门直肠功能。归根结底，知识 由该项目产生的数据将为创新的、以证据为基础的 治疗FI的方法。

TRANSLUMBOSACRAL NEUROMODULATION THERAPY FOR FECAL INCONTINENCE: RANDOMIZED TRIAL PROJECT SUMMARY/ABSTRACT: Fecal Incontinence (FI) affects 40 million Americans, predominantly women and elderly. It is a major health care burden, significantly impairs quality of life and psychosocial function. FI is characterized by multifactorial dysfunction that includes lumbosacral neuropathy, anorectal sensori-motor dysfunction, and maladaptive pelvic floor-brain innervation. A critical barrier to progress in the treatment of FI is the lack of randomized controlled trials, absence of mechanistically based non- invasive therapies that modify disease, and a lack of understanding on how treatments affect pathophysiology of FI, as highlighted by experts at a recent NIDDK workshop. Consequently, most current remedies remain ineffective. Our long-term goal is to address the problem of lack of effective treatments for FI by investigating treatments that modulate peripheral and central neuronal perturbations and thereby improve sensory and visceromotor control, and to understand the neurobiologic basis of these treatments. Our central hypothesis is that a novel, non-invasive treatment consisting of Translumbosacral Neuromodulation Therapy (TNT), using repetitive magnetic stimulation, will significantly improve FI in the short-term and long-term, by enhancing neural excitability and inducing neuroplasticity, and thereby provide a multidimensional therapeutic benefit. Our approach is based on compelling preliminary study which showed that TNT at 1 Hz frequency, significantly improved FI, by enhancing bidirectional gut and brain signaling, anal sphincter strength and rectal sensation compared to 5 or 15 Hz. Our objectives are to 1) investigate the efficacy, safety and optimal dose of a new treatment, TNT, in a sham controlled, randomized dose- dependent study in 132 FI patients; 2) determine the mechanistic basis for TNT by assessing the efferent spino-anorectal and afferent pelvic floor-brain signaling, and anorectal sensori-motor function; 3) identify the durability of treatment response and neuromodulatory effects of TNT, and whether reinforcement TNT provides augmented improvement through enhanced adaptive neuroplasticity, by performing a long-term, sham controlled randomized trial. Our expected outcomes include the demonstration of TNT as a durable, efficacious, safe, mechanistically based, non-invasive, and low risk treatment for FI. The impact of our project includes a novel, disease modifying, non-invasive treatment for FI, a scientific basis for the development of this treatment, and improved understanding of the pathophysiology of FI and the neurobiologic mechanism(s) of how TNT modifies bidirectional gut and brain axes and anorectal function. Ultimately, the knowledge generated by this project will provide new avenues for the development of innovative, evidence-based therapies for FI.