Chronic Electrical Stimulation to Reduce Bladder Hyperreflexia after SCI

描述（由申请人提供）： 目的和研究目标：脊髓损伤（SCI）等疾病引起的神经源性膀胱可能对患者及其家人造成毁灭性影响，导致高昂的费用 对个人和社会的影响。这项研究计划的长期目标是开发神经假体，以长期恢复SCI患者的泌尿系统。神经源性膀胱可导致反射性膀胱活动，其可导致尿失禁、肾损伤和自主神经反射障碍。研究设计和方法：本研究建议使用慢性电刺激生殖神经（GN），以减少SCI患者的上运动神经元膀胱后遗症。还将对不完全SCI患者的GN进行急性电刺激，以确定该先前未研究的人群亚组的耐受性和有效性。GN的电刺激提供了一种立即的、可逆的方法来电关闭不想要的上运动神经元神经源性膀胱后遗症。我们已经在动物模型和一个慢性人类模型中证明，这种方法减少了目标反射，并有可能恢复反射。具体来说，我们将确定这种方法在人类中产生SCI中的尿液的长期安全性和有效性。将表面电极放置在阴茎干上以刺激GN，并且在十周研究期间每两周进行一次尿动力学研究以获得膀胱容量的估计值。将在慢性试验受试者刺激开始前的尿动力学研究（UDS）中或在对不完全SCI受试者进行的单次尿动力学研究中获得有效GN刺激的刺激参数。刺激的有效性将根据UDS期间所有受试者膀胱容量的增加来确定。慢性测试将测量慢性刺激的临床和膀胱压力影响。在间歇性导尿的患者中，预期刺激可减少失禁发作的次数和严重程度，并增加液体摄入量和减少导尿频率;液体和导尿频率改变了用于减少SCI患者尿失禁的常见临时措施。在留置导尿管的患者中，预期可减少膀胱痉挛的次数和强度以及留置导尿管患者的平均膀胱压力。临床意义：基础科学家和医生之间的这一合作项目的成功完成将证明通过外周传入神经的电刺激产生慢性震颤的有效性。这具有直接的临床潜力，并将为启动旨在为非侵入性器械进行临床试验的工作提供理由。 除了用于膀胱扩张的非侵入性表面刺激之外，这些结果可以转化为长期植入的医疗设备。这项研究的长期目标是开发一种植入式刺激器，通过导线连接到放置在相应传入神经附近的电极。克利夫兰FES中心拥有开发植入器械的技术和专业知识。未来的项目将开发植入系统，包括使用放置在本研究中确定的解剖目标附近的经皮电极进行确认。从该项目中获得的信息将为开发和测试植入系统奠定基础，从而在下一个项目中实现首批植入，并生成数据以支持FDA批准和临床试验。 公共卫生相关性： 虽然大约11%的美国人是退伍军人，但美国脊髓损伤（SCI）患者中有25%是退伍军人。神经源性膀胱是脊髓损伤常见的神经系统并发症。除了是一个衰弱和昂贵的条件，神经源性膀胱妥协的能力，是生产力在工作场所，从事社会或休闲活动，追求教育，并参与其他活动与独立和富有成效的生活方式。神经源性膀胱经常导致其他泌尿系统并发症，如尿失禁、尿路感染、肾损伤和随后的肾透析或肾移植，这可能导致反复和昂贵的住院治疗。该项目通过提供减少膀胱过度活动的方法直接解决神经性膀胱的问题。这种方法比现有的设备侵入性更小，预计将扩大能够受益于神经刺激系统以恢复膀胱功能的个人群体。

DESCRIPTION (provided by applicant): Objectives and Research Aims: Neurogenic bladder resulting from disorders such as spinal cord injury (SCI) can have a devastating impact on patients and their families, resulting in a high cost to the individual and to society. The long-term goal of this research program is to develop neural prostheses to chronically restore urinary continence in persons with SCI. Neurogenic bladder can result in reflex bladder activity that can result in urinary incontinence, renal damage and autonomic dysreflexia. Research Design and Methods: This study proposes using chronic electrical stimulation of the genital nerve (GN) to produce a decrease in upper motor neuron bladder sequelae in persons with SCI. Acute electrical stimulation of the GN in persons with incomplete SCI will also be conducted to determine tolerance and effectiveness in this previously unstudied human population subset. Electrical stimulation of the GN provides an immediate, reversible approach to electrically shutting down unwanted upper motor neuron neurogenic bladder sequelae. We have demonstrated in animal models and one chronic human model that this approach reduces the target reflexes and has potential to restore continence. Specifically, we will determine chronic safety and efficacy of this approach in humans to produce urinary continence in SCI. Surface electrodes will be placed on the shaft of the penis to stimulate the GN, and urodynamic studies will be conducted every two weeks over the course of the ten week study to obtain estimates of bladder capacity. Stimulus parameters for effective GN stimulation will be obtained at the urodynamic study (UDS) prior to stimulation initiation in chronic testing subjects, or at the single urodynamic study conducted for subjects with incomplete SCI. The effectiveness of stimulation will be determined based upon the increase in bladder capacity in all subjects during UDS. Chronic testing will measure the clinical and bladder pressure impact of the chronic stimulation. In persons who intermittently catheterize, stimulation is anticipated to decrease the number and severity of incontinent episodes, as well as increased fluid intake and decreased catheterization frequency; fluid and catheterization frequency changes common temporizing measures utilized to decrease urinary incontinence in SCI. In persons with indwelling catheters it is expected to reduce the number and intensity of bladder spasms as well as average bladder pressures in persons with indwelling catheters. CLINICAL SIGNIFICANCE: Successful completion of this collaborative project between basic scientists and physicians will demonstrate the efficacy of producing chronic continence via electrical stimulation of peripheral afferent nerves. This has immediate clinical potential and wil provide justification for initiating work aimed at producing clinical trials for a non-invasive devce. In addition to non-invasive surface stimulation for bladder continence, these results can be translated into a chronically implanted medical device. A long term goal of this research is to develop an implanted stimulator, connected by a lead to an electrode placed near the corresponding afferent nerve. The Cleveland FES Center has the technology and expertise to develop the implanted device. Future projects will develop the implanted system, including validation using percutaneous electrodes placed near the anatomical targets identified in this study. The information obtained from this project will lay the groundwork for developing and testing an implanted system, leading to the first implants during the next project and generating data to support FDA approval and clinical trials. PUBLIC HEALTH RELEVANCE: Although about 11% of Americans are veterans, 25% of all individuals with spinal cord injuries (SCIs) in the US are veterans. Neurogenic bladder is a common neurologic complication associated with SCI. In addition to being a debilitating and costly condition, neurogenic bladder compromises the ability to be productive in the workplace, engage in social or leisure activities, pursue an education, and participate in other activities associated with an independent and productive lifestyle. Neurogenic bladder frequently leads to other urologic complications, such as incontinence, urinary tract infection, renal damage and consequent renal dialysis or transplantation which can lead to recurrent and costly hospitalization. This project directly addresses the problem of neurogenic bladder by providing a means to reduce bladder over-activity. This approach is less invasive than existing devices and is expected to expand the population of individuals able to benefit from neural stimulation systems to restore bladder function.