Design and Application of Custom Waveforms to Restore and Control Satiety

恢复和控制饱腹感的定制波形的设计和应用

• 批准号: 9795377
• 负责人: MATTHEW Anthony SCHIEFER
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795377
• 关键词: 3-Dimensional; Abdominal Pain; Acute; Animal Experiments; Animals; Axon; Body Weight; Body Weight decreased; Body mass index; Chronic; Clinical; Code; Communities; Comorbidity; Computer Simulation; Country; Cross-Over Studies; Custom; Cutaneous; Diabetes Mellitus; Diet; Dyspepsia; Eating; Eating Behavior; Electric Stimulation; Electricity; Electrodes; Elements; Engineering; Ensure; Epidemic; Eructation; Esthesia; Fatty acid glycerol esters; Goals; Grant; Health; High Fat Diet; Histology; Human; Hypertension; Implant; Implanted Electrodes; Individual; Institution; Knowledge; Lead; Learning; Libraries; Location; Mental Depression; Mentors; Methods; Modeling; Nausea; Nerve; Neurons; Obesity; Operating Rooms; Operative Surgical Procedures; Outcome; Output; Overweight; Paresthesia; Patients; Pattern; Peripheral; Peripheral Nerves; Pharmaceutical Preparations; Planning Techniques; Population; Procedures; Rattus; Reporting; Research; Research Personnel; Risk; Satiation; Sensory; Series; Signal Transduction; Spinal Cord; Spinal nerve structure; Splanchnic Nerves; Stimulus; Stomach; Surgical complication; Tactile; Techniques; Testing; Texas; Therapeutic; Time; Touch sensation; Training; Universities; Variant; Veterans; Visceral; Vomiting; Weight; Weight Gain; Work; autonomic nerve; career; cost; design; experimental study; food consumption; healing; healthy weight; implantation; improved; insight; nerve supply; neural patterning; neuromechanism; neuroregulation; next generation; novel; obesity treatment; preclinical efficacy; pressure; recruit; relating to nervous system; response; side effect; skills; success

Rationale: By 2014, 22 states had an obesity rate ≥30% and none <20%. Costs due to obesity are estimated at $190B/yr. 72% of Veterans are overweight (45%) or obese (27%), of which 66% have hypertension and 31% have diabetes, the two most common comorbidities associated with obesity. Researchers use vagal nerve stimulation (VNS) to treat a number of conditions, including obesity. The vagal nerve is the parasympathetic branch of stomach innervation whereas the lesser-studied splanchnic nerve provides sympathetic innervation. Splanchnic nerve stimulation (SpNS) has also been used to treat obesity. Sensory afferents in these nerves relay information about the state of the stomach. How and why VNS and SpNS work remain unknown. Stimulus parameters vary widely and are often accompanied by side-effects. The limited success and undesired side effects are hypothesized to be due to the stimulus waveform. This grant seeks to understand the neural population code associated with stomach distension. It also assesses the effect of novel VNS and SpNS waveforms designed to mimic the neural population code and reduce side-effects on body weight in obese rats. Objective: The objectives of this study are to 1) elucidate the neural mechanisms underlying obesity and 2) develop and assess the effects of novel stimuli on eating behavior in obese rats. Numerous hypotheses will be tested through a series of animal experiments over a 4 year time period. Research Plan and Methodology: During Aim 1, in a series of non-survival experiments, the vagal and splanchnic nerves will be implanted with electrodes in rats. The rats will be healthy or made overweight or obese using a moderate or high-fat diet. The animal’s stomach will be distended with an intragastric balloon to mimic food consumption. Intragastric pressure will be recorded. Nerve recordings will provide insight to the neural response in the two nerves to stomach filling. The effect of diet and body mass index (BMI) on discharge pattern will be assessed. During Aim 2, in a series of survival experiments, nerve cuff electrodes will be implanted around the vagal and splanchnic nerves of rats. The rats will be either a healthy weight or obese. After healing, the rats will receive VNS, SpNS, or both using either standard time-invariant or novel time-variant waveforms. A time-variant waveform will be developed from recorded neural patterns and histology obtained in Aim 1 using 3D finite element models. Effects of stimulus location and waveform type on weight and activity will be determined over a 20-week period. Histology will be conducted to assess the effects of stimulus on nerve health. Immediate and Long-Term Career Goals: The immediate career goal is to become immersed within the field of obesity research and expand scientific understanding of how electrical stimulation applied to autonomic nerves can be used to reduce body weight. The long-term career goal is to become an independent clinical researcher with a lab at the LSCDVAMC that focuses on understanding and controlling the neural mechanism associated with obesity. Additional goals include 1) continuing to contribute to the local and national VA research community in the field of neural engineering and 2) advancing the body of scientific knowledge of how to interface with and control neurons in a manner that leads to natural outcomes. Future research will make extensive use of computer simulations, animal experiments, and human trials. Patterned nerve stimulation will be an expertise. Candidate Training: This CDA2 provides protected time to develop the following new skills: acute and chronic animal studies; animal surgeries; intraneural and extraneural nerve recording, processing, and analysis; electrode implantation; autonomic neuromodulation; clinical and surgical treatments of obesity;

理由：到 2014 年，有 22 个州的肥胖率≥30%，没有一个州的肥胖率低于 20%。估计肥胖造成的成本 $190B/年。 72% 的退伍军人超重 (45%) 或肥胖 (27%)，其中 66% 患有高血压和 31% 患有糖尿病，这是与肥胖相关的两种最常见的合并症。研究人员利用迷走神经 神经刺激（VNS）可治疗多种疾病，包括肥胖症。迷走神经是 胃神经支配的副交感神经分支，而研究较少的内脏神经提供 交感神经支配。内脏神经刺激（SpNS）也已用于治疗肥胖。感官 这些神经中的传入神经传递有关胃状态的信息。 VNS 和 SpNS 如何以及为何发挥作用 仍然未知。刺激参数变化很大，并且常常伴有副作用。有限的 假设成功和不良副作用是由于刺激波形造成的。这笔赠款旨在 了解与胃扩张相关的神经群体代码。它还评估了小说的效果 VNS 和 SpNS 波形旨在模仿神经群体代码并减少对身体的副作用 肥胖大鼠的体重。 目的：本研究的目的是 1) 阐明肥胖背后的神经机制；2) 开发并评估新刺激对肥胖大鼠饮食行为的影响。将会有许多假设 经过四年多的一系列动物实验测试。 研究计划和方法：在目标 1 期间，在一系列非生存实验中，迷走神经和 老鼠的内脏神经将被植入电极。老鼠会健康或超重或 使用中度或高脂肪饮食的肥胖者。动物的胃将通过胃内气球扩张以 模仿食物消耗。将记录胃内压力。神经记录将提供洞察力 两条神经对胃充盈的神经反应。饮食和体重指数 (BMI) 对健康的影响 将评估放电模式。在目标 2 期间，在一系列生存实验中，神经袖带电极将 植入大鼠迷走神经和内脏神经周围。老鼠的体重要么是健康的，要么是肥胖的。 愈合后，大鼠将接受 VNS、SpNS 或两者均使用标准时不变或新型时变 波形。时变波形将从记录的神经模式和组织学中获得 目标 1 使用 3D 有限元模型。刺激位置和波形类型对体重和活动的影响 将在 20 周内确定。将进行组织学评估刺激对 神经健康。 近期和长期职业目标：近期职业目标是融入该领域 肥胖研究并扩大对电刺激如何应用于自主神经的科学理解 神经可以用来减轻体重。长期职业目标是成为一名独立的临床医生 LSCDVAMC 实验室的研究员，专注于理解和控制神经机制 与肥胖有关。其他目标包括 1) 继续为地方和国家 VA 做出贡献 神经工程领域的研究界，以及 2）推进科学知识体系的发展 以产生自然结果的方式与神经元交互并控制神经元。未来的研究将使得 广泛使用计算机模拟、动物实验和人体试验。图案化的神经刺激将 成为专家。 候选人培训：此 CDA2 提供受保护的时间来发展以下新技能：急性和慢性 动物研究；动物手术；神经内和神经外神经记录、处理和分析； 电极植入；自主神经调节；肥胖症的临床和外科治疗；