Design and Application of Custom Waveforms to Restore and Control Satiety

理由：到2014年，22个州的肥胖率≥为30%，无肥胖率为20%。估计因肥胖而产生的成本 1,900亿美元/年。72%的退伍军人超重(45%)或肥胖(27%)，其中66%有高血压和 31%的人患有糖尿病，这是与肥胖有关的两种最常见的并发症。研究人员使用迷走神经 神经刺激(VNS)可治疗包括肥胖在内的多种疾病。迷走神经是 胃神经的副交感神经分支，而较少研究的内脏神经提供 交感神经支配。内脏神经刺激(SPNS)也被用于治疗肥胖症。感官 这些神经中的传入传递有关胃状态的信息。VNS和SPN的工作方式和原因 仍然不为人所知。刺激参数变化很大，而且经常伴随着副作用。有限的 成功和不受欢迎的副作用被假定是由于刺激波形。这笔赠款旨在 了解与胃扩张相关的神经种群编码。它还评估了小说的效果 VNS和SPNS波形旨在模拟神经种群编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)阐明肥胖的神经机制；2) 开发和评估新刺激对肥胖大鼠进食行为的影响。许多假说将会是 在四年的时间里，通过一系列动物实验进行了测试。 研究计划和方法：在目标1中，在一系列非存活实验中，迷走神经和 内脏神经将在大鼠体内植入电极。这些老鼠要么健康，要么超重，要么 使用中等或高脂肪饮食的肥胖。动物的胃会用胃内气球扩张到 模仿食物消费。记录胃内压。神经记录将为我们提供对 这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 将对放电模式进行评估。在目标2中，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。这些老鼠要么体重正常，要么肥胖。 愈合后，大鼠将接受VNS和/或SPN，使用标准时不变或新时变 波形。将从记录的神经模式和组织学中获得时变波形 目的1采用三维有限元模型。刺激位置和波形类型对体重和活动度的影响 将在20周内确定。将进行组织学检查，以评估刺激对 神经健康。 近期和长期的职业目标：近期的职业目标是沉浸在这个领域 肥胖症研究和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。长期的职业目标是成为一名独立的临床医生 LSCDVAMC实验室的研究人员，专注于了解和控制神经机制 与肥胖有关。其他目标包括1)继续为地方和国家退伍军人管理局作出贡献 神经工程领域的研究共同体和2)促进关于如何 以一种导致自然结果的方式与神经元交互并进行控制。未来的研究将使 广泛使用计算机模拟、动物实验和人体试验。模式化的神经刺激将 成为一名专家。 应聘者培训：此CDA2提供了有保护的时间来培养以下新技能：急性和慢性 动物研究；动物外科；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；肥胖的临床和外科治疗；

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;