Functional Mapping with Lumbosacral Epidural Stimulation for Restoration of Bladder Function After Spinal Cord Injury

项目摘要/摘要 这项功能性膀胱标测研究的总体目标是确定脊髓硬膜外 刺激(SCES)配置(阳极/阴极选择、幅度、频率和脉冲宽度) 腰骶水平可促进神经控制的膀胱存储(容量)和排尿效率后 脊髓损伤(SCI)。这项在人类和动物中平行进行的全面功能图谱研究 涉及一种上市的美敦力设备在治疗脊髓损伤后膀胱功能障碍方面的新临床应用。这个 测绘(人和动物)和训练(人)实验涉及以下几个具体目标 符合RFA-RM-15-018的SPARC计划计划，包括有关功能连接的神经电路图 (目标1)，与刺激有关的神经可塑性(膀胱训练实验-目标2)，可变性(动物到... 动物和病人对病人)，以及研究不同类型的刺激导致什么器官功能 (储存与排尿，并确定对肠道和/或性功能的任何额外影响)。 医疗保健系统、护理人员和社会成本的长期降低将是 太戏剧化了。脊髓损伤导致运动、感觉和自主神经功能受损，严重影响整体 健康和生活质量。脊髓损伤后合理的膀胱管理是降低高位膀胱癌风险的必要措施 尿路疾病是发病率的主要来源。脊髓损伤患者需要终生的泌尿外科护理，但 大多数努力是治疗症状，但不能改善内在功能。当前膀胱管理的治疗方法 脊髓损伤后包括插管、药物和手术干预、功能性电刺激。 (外周)，和尿路支架，但都有有害的影响。我们有来自多个国家的令人兴奋的数据 严重损伤(AIS A和B)的个人，表明在广泛的手术后膀胱功能改善 实施以活动为基础的康复、运动训练(LT)，其中包括利用体重进行步进 通过手动辅助在跑步机上提供支持。此外，我们还有一些耐人寻味的初步数据 接受SCES并结合康复的特定任务训练的完全瘫痪的个人 站立和自主活动，并显示出膀胱容量和排尿效率的改善。 我们最新的试验数据也表明，SCES单独对膀胱功能有直接好处。因此，我们 建议确定在Low的储存和排出阶段可以实现的功能收益 在患有脊髓损伤的人类和临床上，SCE激活了脊髓回路的尿路功能。 相关啮齿动物脊髓损伤模型。我们将检验一般假设，即膀胱容量和排尿效率 随着SCES损伤后SCES的增加，随着SCES膀胱训练时间的推移，SCES增加的程度更大。 这项建议涉及临床医生和在动物方面有丰富经验的科学家的合作。 和人体SCI模型。我们独特的方法将利用多学科团队的专业知识(在 膀胱功能、神经调节、康复、工程学和统计学)以1)确定最佳 已植入SCES的脊髓损伤研究参与者储存和排尿的刺激参数 美敦力装置(L1-S1的16电极阵列)；2)量化日常膀胱训练的长期效果 使用最佳刺激参数(所有相同的研究参与者)；3)测量次要刺激 好处(膀胱药物使用、尿路感染易感性、间接心血管、肠道和 性功能的益处)；以及4)用一个小动物模型说明 位置、病变严重程度、慢性和性别。我们的创新方法和新的应用 美敦力指定5-6-5设备将使我们能够确定膀胱功能所需的特定类型的SCE 这将为将这一前景看好的技术方便地翻译到更多的 在SPARC倡议的下一阶段，患有SCI的个人，使用 大动物脊髓损伤模型(猪)，目前正在肯塔基州脊髓研究中心开发 中心。

PROJECT SUMMARY/ABSTRACT The overall objective of this functional bladder mapping study is to identify the spinal cord epidural stimulation (scES) configurations (anode/cathode selection, amplitude, frequency and pulse width) at the lumbosacral level that can promote neural control of bladder storage (capacity) and voiding efficiency after spinal cord injury (SCI). This comprehensive functional mapping study in both humans and animals in parallel involves a novel clinical application of a marketed Medtronic device for bladder dysfunction after SCI. The mapping (human and animal) and training (human) experiments address several specific objectives of the SPARC Program initiative per RFA-RM-15-018 including neural circuit maps regarding functional connectivity (Aim 1), neural plasticity related to stimulation (bladder training experiments – Aim 2), variability (animal-to- animal and patient-to-patient), and research on what organ functions results from different types of stimulation (storage vs voiding and identifying any additional effects on bowel and/or sexual function). The long-term reduction in the cost to the health care system, care givers and society would be dramatic. SCI results in impairments of locomotor, sensory and autonomic functions, severely affecting overall health and quality of life. Proper bladder management post-SCI is necessary to decrease the risk of upper urinary tract disease, a major source of morbidity. Life-long urologic care is required for SCI individuals, yet most efforts treat symptoms but do not improve intrinsic function. Current therapies for bladder management after SCI include catheterization, pharmacologic and surgical interventions, functional electrical stimulation (peripheral), and urethral stents, but all have deleterious effects. We have exciting data from multiple individuals with severe injuries (AIS A and B) indicating improved bladder function after undergoing a widely implemented activity-based rehabilitation, locomotor training (LT), which includes stepping using body weight support on a treadmill with manual facilitation. In addition, we have intriguing preliminary data from several completely paralyzed individuals receiving scES in combination with task specific training that recovered standing and voluntary movement and showed improvements in both bladder capacity and voiding efficiency. Our most recent pilot data also indicate an immediate benefit of scES alone on bladder function. Thus, we propose to determine the functional gains that can be achieved in the storage and voiding phases of lower urinary tract function as a result of activation of spinal circuits with scES in humans with SCI and in a clinically- relevant rodent SCI model. We will test the general hypothesis that bladder capacity and voiding efficiency increases with scES post-SCI and to an even greater extent with scES bladder training over time. This proposal involves the collaboration of clinicians and scientists with extensive experience in animal and human SCI models. Our unique approach will utilize the expertise of a multi-disciplinary team (expertise in bladder function, neuromodulation, rehabilitation, engineering, and statistics) to 1) determine the optimal stimulation parameters for storage and voiding in SCI research participants already implanted with the scES Medtronic device (16-electrode array from L1-S1); 2) quantify the long-term effects of daily bladder training using optimal stimulation parameters (all the same research participants); 3) measurement of secondary benefits (bladder medication usage, susceptibility to urinary tract infections, indirect cardiovascular, bowel and sexual function benefits) of long-term bladder training; and 4) address with a small animal model the impact of location, lesion severity, chronicity and gender. Our innovative approach and novel application of this Medtronic Specify 5-6-5 device will allow us to determine specific types of scES needed for bladder function which will lay the groundwork for expedient translation of this promising technique to larger numbers of individuals with SCI in the next phase of the SPARC initiative, with additional refinement in parallel using a large animal SCI model (pig) that is currently under development within the Kentucky Spinal Cord Research Center.