NEUROMODULATION THERAPY FOR FECAL INCONTINENCE

描述（由申请人提供）：大便失禁（FI）影响8- 15%的美国人口，主要是妇女和老年人，以及45%的养老院居民。它严重损害生活质量，造成重大的卫生保健负担。FI的特征是骨盆底明显的神经肌肉功能障碍，包括双侧腰肛肠和骶肛肠神经病变以及感觉运动功能障碍。这种多因素病因提示下胃肠道神经支配的神经可塑性改变可能在FI的发病机制中起重要作用。FI治疗进展的一个关键障碍是缺乏对治疗如何影响FI的核心病理生理机制的理解，以及缺乏基于机制的非侵入性治疗。我们的目标是通过开发调节周围和中枢神经元扰动的疗法来解决FI问题，从而改善内脏运动控制和感觉运动功能障碍，并了解这些治疗的神经生物学基础。我们的中心假设是一种新的非侵入性治疗，包括经腰椎磁刺激（rTLMS）和经骶骨磁刺激（rTSMS）联合治疗，将通过增强外周和中枢神经兴奋性来显著改善FI，并通过增强肛门肌肉力量、改善粪便感知和改善直肠容量来提供多维治疗效果。我们的方法是基于我们的初步研究表明，重复经腰磁刺激（rTLMS）和经骶磁刺激（rTSMS）改善肛肠疼痛和神经病变，并诱导中枢神经可塑性改变。我们的目标是1)解决我们关于外周和中枢神经肠轴的知识的重大差距，以及传入和传出神经信号的扰动如何影响FI；2)开发一种新的重复磁法治疗FI

DESCRIPTION (provided by applicant): Fecal Incontinence (FI) affects 8-15 % of the US population, predominantly women and elderly, and 45% of nursing home residents. It significantly impairs quality of life and poses a major health care burden. FI is characterized by significant neuromuscular dysfunction of the pelvic floor that includes bilateral lumbo-anorectal and sacro-anorectal neuropathy and sensori-motor dysfunction. This multifactorial etiology suggests that maladaptive neuroplastic changes in the neural innervation of lower gastrointestinal tract could play a significant role in the pathogenesis of FI. A critical barrier o progress in the treatment of FI is the lack of understanding of how treatments affect the core pathophysiological mechanisms of FI and the absence of mechanistically based non-invasive therapies. Our goal is to address the problem of FI by developing therapies that modulate peripheral and central neuronal perturbations and thereby improve visceromotor control and sensori-motor dysfunctions, and to understand the neurobiologic basis of these treatments. Our central hypothesis is that a novel non-invasive treatment, consisting of combined translumbar magnetic stimulation (rTLMS) and transsacral magnetic stimulation (rTSMS), will significantly improve FI by enhancing peripheral and central neural excitability and will provide a multidimensional therapeutic effect by enhancing anal muscle strength, improving stool perception and improving rectal capacity. Our approach is based on our preliminary studies which suggest that repetitive translumbar magnetic stimulation (rTLMS) and transsacral magnetic stimulation (rTSMS) improve anorectal pain and neuropathy and induce central neuroplastic changes. Our objectives are to 1) address the significant gap in our knowledge regarding the peripheral and central neuroenteric axis and how perturbations in the afferent and efferent neural signaling can affect FI; 2) develop a new treatment for FI with repetitive magnetic stimulation and determine the feasibility, safety and optimal frequency setting of rTLMS and rTSMS; 3) determine the mechanistic basis for this neuromodulation therapy; 4) identify if the locus for improvement lies in the afferent or efferent signaling or both. Our expected outcomes include development of new treatment approaches for FI which are mechanistically based, effective, safe, low cost, less invasive, low risk and less dependent on patient compliance. The impact of our project include a new non-invasive treatment modality for FI, a scientific basis for the development of this treatment and improved understanding of the peripheral and central neuroenteric axis in FI.