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

通过迷走神经刺激的靶向神经可塑性改善脊髓损伤后的泌尿功能障碍

• 批准号: 10785466
• 负责人: Ana Hernandez-Reynoso
• 金额: $ 10.88万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-26 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10785466
• 关键词: Accelerated Executive Review; Acceleration; Affect; Animals; Ataxia; Behavioral; Bladder; Bladder Control; Breakthrough device; Catheterization; Cervical; Cervical spinal cord injury; Clinical Research; Clinical Trials; Data; Death Rate; Development; Devices; Disinhibition; Electric Stimulation; Engineering; Ensure; Forelimb; Functional disorder; Goals; Hand functions; Home; Human; Implant; Individual; Injury; Intake; Intervention; Kidney Diseases; Label; Liquid substance; Lower urinary tract; Measurement; Medicine; Mentors; Micturition Reflex; Modeling; Modification; Motor; Movement; Muscle; Nervous System Trauma; Neural Pathways; Neuromodulator; Neuronal Plasticity; Neurons; Obstruction; Operative Surgical Procedures; Overactive Bladder; Participant; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Persons; Pharmacologic Substance; Phase; Phase II Clinical Trials; Pilot Projects; Population; Prevalence; Process; Pseudorabies; Quadriplegia; Quality of life; Rattus; Recovery; Recurrence; Rehabilitation therapy; Reporting; Residual state; Risk; Sacral Region; Sensory; Sphincter; Spinal cord injury; Structure; Surveys; Symptoms; Synapses; System; Technology; Time; Tissues; Training; Translating; Translational Research; Translations; Upper Extremity; Urethral sphincter; Urinary Incontinence; Urinary tract infection; Urodynamics; Vagus nerve structure; arm function; awake; bioelectronics; career; catalyst; design; detrusor muscle; implantation; improved; mortality; neural; neuromechanism; neuroregulation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical research; recruit; research clinical testing; restoration; restraint; safety and feasibility; side effect; skills; stroke rehabilitation; success; symptomatic improvement; translational scientist; urinary; urine overflow incontinence; vagus nerve stimulation

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.

项目总结：泌尿功能障碍的恢复通常是康复的前25%优先事项， 在脊髓损伤（SCI）后的个体中，通常排名高于上肢功能的恢复。然而，在这方面， 目前的治疗主要限于包括间歇性导管插入术的保守方法， 行为改变，如液体摄入管理，但这些干预措施只能缓解症状 并且与复发性尿路感染、肾脏疾病和高死亡率相关。而其他 药物和手术治疗可能适用于某些特定主诉的患者， 膀胱过度活动症，开发新的治疗方法来改善和恢复SCI后的膀胱功能， 明确的重要性。 迷走神经刺激（VNS）与康复配对是一种神经调节技术， 在神经损伤（包括不完全SCI）后恢复运动和感觉功能的巨大潜力。VNS 通过定时释放神经调质促进神经可塑性变化，从而增强恢复。这里我们 我首次提出，在不完全SCI后将VNS与膀胱功能配对的策略，以改善 泌尿功能障碍的症状。我们的初步结果支持使用这种技术来恢复膀胱 SCI后的功能 我们建议同时进行临床和临床前研究，以加速技术转化。要求1 (K99阶段）利用了一项单独的、正在进行的临床试验（NCT 04288245），该试验有15名参与者， 已植入VNS系统并愿意参与新的治疗方法。这一目标将证明 迷走神经刺激联合膀胱功能治疗可以提高SCI患者的排尿效率。实现 为此，我们将修改VNS系统的接口（ReStore VNS系统; FDA批准用于上肢 目前正在进行SCI后上肢康复的2期临床试验） 以允许与自主膀胱排尿配对，并在当前植入的个体中进行初步研究。目的2 优化VNS输送时机，配合膀胱功能的不同阶段，以改善排尿 在大鼠模型中的有效性（子目标2.1，K99/R 00阶段），并表征了背后的作用机制 这些变更（子目标2.2，R 00阶段）。 在Hernandel-Reynoso博士的职业生涯中，她广泛研究了电刺激的使用， 靶向周围神经系统作为泌尿功能障碍的新治疗，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。 本提案的两个目的的结果将支持提交R 01，以进行独立的临床研究。 审判，并作为催化剂的候选人达到独立作为一个翻译研究员在神经 工程和生物电子医学领域。

项目成果

NeurostimML: A machine learning model for predicting neurostimulation-induced tissue damage.

NeurostimML：一种用于预测神经刺激引起的组织损伤的机器学习模型。

• DOI: 10.1101/2023.10.18.562980
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Li,Yi;Frederick,RebeccaA;George,Daniel;Cogan,StuartF;Pancrazio,JosephJ;Bleris,Leonidas;Hernandez-Reynoso,AnaG
• 通讯作者: Hernandez-Reynoso,AnaG