Targeted Neuroplasticity via vagus nerve stimulation to improve urinary dysfunction after spinal cord injury

项目摘要：恢复排尿功能障碍往往是#年康复工作的前25%优先事项。 个人脊髓损伤(SCI)后，往往排名高于上肢功能恢复。然而， 目前的治疗大多局限于保守的方法，包括间歇性导尿和 行为改变，如液体摄入管理，但这些干预只提供症状缓解 并与反复的尿路感染、肾脏疾病和高死亡率有关。而其他人 药物和手术治疗可能适用于某些有特殊症状的患者，例如 脊髓损伤后膀胱过度活动，改善和恢复膀胱功能的新疗法的发展 显而易见，这很重要。 迷走神经刺激(VNS)结合康复是一种神经调节技术，已经证明 在神经损伤，包括不完全性脊髓损伤后恢复运动和感觉功能的巨大潜力。VNS 通过定时释放可促进恢复的神经调节剂来促进神经可塑性变化。在这里我们 首次提出不完全性脊髓损伤后VNS与膀胱功能配对的改善策略 排尿功能障碍的症状。我们的初步结果支持使用这项技术修复膀胱 脊髓损伤后的功能。 我们建议同时进行临床和临床前研究，以加快技术转化。目标1 (K99阶段)利用单独的、正在进行的临床试验(NCT04288245)，该试验有15名参与者，他们拥有 VNS系统已经植入，并愿意参与新的治疗方法。这一目标，将证明 脊髓损伤后VNS治疗配合膀胱功能治疗可提高排尿效率。要实现 为此，我们将修改VNS系统的界面(恢复VNS系统；FDA-清除上肢 中风后康复，目前正在进行脊髓损伤后上肢康复的第二阶段临床试验) 允许配对自愿性膀胱排尿，并在目前植入的个体中进行先导性研究。目标2 优化配对不同阶段膀胱功能的VNS的时机，以改善排尿 在大鼠模型中的效率(子目标2.1，K99/R00阶段)，并表征了背后的作用机制 这些变化(次级目标2.2，R00阶段)。 在赫尔南德斯-雷诺索博士的职业生涯中，她对电刺激的使用进行了广泛的研究 以周围神经系统为靶点的尿路功能障碍的新疗法，以及 外周和中枢神经接口。因此，她是完成这项提议的理想人选。 这项提案的两个目标的结果将支持提交R01进行独立临床试验 试验，并充当催化剂，使候选人作为神经领域的翻译研究人员获得独立 工程和生物电子医药领域。

Project summary: Restoration of urinary dysfunction is often in the top 25% priority for rehabilitation in individuals after spinal cord injury (SCI), often ranking higher than restoration of upper limb function. However, current treatments are mostly limited to conservative approaches consisting of intermittent catheterization and behavioral changes such as fluid intake management, but these interventions only provide symptomatic relief and are associated with recurrent urinary tract infections, kidney disease, and high mortality rates. While other pharmaceutical and surgical treatments may be available for some patients with specific complaints such as overactive bladder, the development of novel therapies to improve and restore bladder function after SCI is of clear importance. Vagus nerve stimulation (VNS) paired with rehabilitation is a neuromodulation technology that has demonstrated great potential at restoring motor and sensory function after neurological injury, including incomplete SCI. VNS promotes neuroplastic changes by the timed-release of neuromodulators that can enhance recovery. Here we propose for the first time, a strategy of pairing VNS with bladder function after incomplete SCI to improve symptoms of urinary dysfunction. Our preliminary results support the use of this technology to restore bladder function after SCI. We propose to conduct clinical and preclinical research concurrently to accelerate technology translation. Aim 1 (K99 phase) leverages a separate, ongoing clinical trial (NCT04288245) that has 15 participants, who have the VNS system already implanted and willing to partake in novel therapy approaches. This aim, will demonstrate that VNS therapy paired with bladder function can improve voiding efficiency in humans after SCI. To achieve this, we will modify the interface of the VNS system (ReStore VNS system; FDA-cleared for upper limb rehabilitation after stroke and currently undergoing phase 2 clinical trials for upper limb rehabilitation after SCI) to allow pairing with volitional bladder voiding and conduct a pilot study in currently implanted individuals. Aim 2 optimizes the timing of delivery VNS paired with different stages of the bladder function to improve voiding efficiency in the rat model (sub-Aim 2.1, K99/R00 phase) and characterizes the mechanisms of action behind those changes (sub-Aim 2.2, R00 phase). During Dr. Hernandez-Reynoso’s career, she has extensively investigated the use of electrical stimulation targeted to the peripheral nervous system as a novel treatment of urinary dysfunction, and the development of peripheral and central neural interfaces. As such, she is the ideal candidate to carry this proposal to completion. Results from both aims of this proposal will support the submission of an R01 to conduct an independent clinical trial, and act as a catalyst for the candidate to reach independence as a translational researcher in the neural engineering and bioelectronic medicines field.