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

腰骶部硬膜外刺激功能标测用于脊髓损伤后膀胱功能的恢复

• 批准号: 10455251
• 负责人: SUSAN J HARKEMA
• 金额: $ 120万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455251
• 关键词: Functional; Mapping; Lumbosacral; Epidural; Stimulation

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.

项目摘要/摘要 该功能性膀胱映射研究的总体目的是确定脊髓的附向 刺激（SCES）配置（阳极/阴极选择，振幅，频率和脉冲宽度） 可以促进膀胱储存（CAPACE）的神经控制和后效率的腰s骨水平 脊髓损伤（SCI）。 涉及到SCI后膀胱功能障碍的销售Medtronic设备的新型临床应用 映射（人类和动物）和培训（人类）经验解决西弗勒斯的几个特定目标 SPARC计划计划每RFA-RM-15-018，包括有关功能连接的神经电路图 （AIM 1），与刺激有关的神经塑料（膀胱训练实验-AIM 2），可变性（动物对 - - 动物和患者对患者），以及研究哪些器官功能是由不同类型的刺激引起的。 （存储与识别和识别。对肠和性功能的任何其他影响）。 医疗保健系统，护理人员和社会的长期降低是 SCI戏剧性。 健康和适当的膀胱管理是必要的 尿路疾病是SCI个体需要的主要泌尿科护理的主要来源 大多数努力治疗症状，但不能改善膀胱管理的当前疗法。 SCI之后包括导管插入术，药理学和手术国际，功能电刺激 （外围）和尿道支架，但都具有有害的效果。 严重伤害的个体（AIS A和B）表明经历了广泛的膀胱功能 实施基于活动的康复，运动训练（LT），其中包括使用体重重的踏脚。 支持手动促进的跑步机。 完全瘫痪的人接收SCE与恢复的任务特定培训结合 站立和自愿运动，并在膀胱容量和效率上都表现出改善。 我们的最新飞行员还表明，仅SCE的囊andicate在膀胱功能上 提议确定在较低的存储和排放阶段中可以实现的功能增长 尿路功能是由于工作的结果。 相关的啮齿动物SCI模型。 随着时间的推移，随着SCES膀胱训练，SCES后SCE和SCE的增加。 该建议涉及临床医生和科学家的合作，并具有丰富的动物经验 和人类的SCI模型。 膀胱功能，神经调节，康复，工程和统计）至1）确定最佳 SCI研究参与者中存储和空隙的刺激参数Alreatady植入了SCESS Medtronic设备（L1-S1的16-电极阵列）量化每日膀胱训练的长期影响 使用最佳站点参数（所有相同的研究参与者）； 益处（膀胱用药使用，对尿路感染的感染率，间接心血管，肠和肠 性功能的好处）长期膀胱训练和4）用小动物模型解决 位置，病变严重性，慢性和性别。 Medtronic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 这将为将这种有希望的技术的权宜转换奠定基础 在SPARC倡议的下一阶段中具有SCI的个体，并同时使用A 大型动物SCI模型（PIG）目前正在肯塔基州脊髓绳研究中 中央。

项目成果

Mid-lumbar (L3) epidural stimulation effects on bladder and external urethral sphincter in non-injured and chronically transected urethane-anesthetized rats.

• DOI: 10.1038/s41598-023-39388-9
• 发表时间: 2023-07-28
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Medina-Aguinaga, Daniel;Hoey, Robert F.;Wilkins, Natasha L.;Ugiliweneza, Beatrice;Fell, Jason;Harkema, Susan J.;Hubscher, Charles H.
• 通讯作者: Hubscher, Charles H.

Bladder and bowel responses to lumbosacral epidural stimulation in uninjured and transected anesthetized rats.

• DOI: 10.1038/s41598-021-81822-3
• 发表时间: 2021-02-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hoey RF;Medina-Aguiñaga D;Khalifa F;Ugiliweneza B;Zdunowski S;Fell J;Naglah A;El-Baz AS;Herrity AN;Harkema SJ;Hubscher CH
• 通讯作者: Hubscher CH

Thoracolumbar epidural stimulation effects on bladder and bowel function in uninjured and chronic transected anesthetized rats.

• DOI: 10.1038/s41598-022-06011-2
• 发表时间: 2022-02-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hoey RF;Medina-Aguiñaga D;Khalifa F;Ugiliweneza B;Wang D;Zdunowski S;Fell J;Naglah A;El-Baz AS;Herrity AN;Harkema SJ;Hubscher CH
• 通讯作者: Hubscher CH

Restoration of autonomic cardiovascular regulation in spinal cord injury with epidural stimulation: a case series.

• DOI: 10.1007/s10286-020-00693-2
• 发表时间: 2021-04
• 期刊: Clinical autonomic research : official journal of the Clinical Autonomic Research Society
• 作者: Legg Ditterline BE;Aslan SC;Wang S;Ugiliweneza B;Hirsch GA;Wecht JM;Harkema S
• 通讯作者: Harkema S