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: 10390275
• 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 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390275
• 关键词: 3-Dimensional; Abdominal Pain; Acute; Animal Experiments; Animals; Axon; Body Weight; Body Weight decreased; Body mass index; Chronic; Clinical; Code; Communities; 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; comorbidity; cost; design; experimental study; food consumption; healing; healthy weight; implantation; improved; insight; nerve supply; neural patterning; neuromechanism; neuroregulation; next generation; novel; obese patients; 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;

依据：到2014年，22个州的肥胖率≥30%，没有一个州低于20%。估计肥胖造成的费用 1900亿美元/年。72%的退伍军人超重（45%）或肥胖（27%），其中66%患有高血压， 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）治疗包括肥胖在内的多种疾病。迷走神经是 胃神经支配的副交感分支，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）也已用于治疗肥胖症。感官 这些神经中的传入神经传递关于胃的状态的信息。VNS和SpNS如何以及为什么工作 仍然未知。刺激参数变化很大，往往伴随着副作用。有限 成功和不希望的副作用被假设是由于刺激波形。该补助金旨在 了解与胃扩张相关的神经群体编码。并对小说的效果进行了评价 VNS和SpNS波形旨在模拟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）阐明肥胖的神经机制和2） 开发和评估新刺激对肥胖大鼠进食行为的影响。许多假设将 在4年的时间内通过一系列动物实验进行测试。 研究计划和方法：在目标1期间，在一系列非存活实验中，迷走神经和 将电极植入大鼠内脏神经。这些老鼠将是健康的或超重的， 使用中等或高脂肪饮食的肥胖症。用胃内球囊扩张动物的胃， 模仿食物消耗。将记录胃内压。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 将评估放电模式。在Aim 2期间，在一系列生存实验中，神经袖带电极将 植入大鼠的迷走神经和内脏神经周围。大鼠将是健康体重或肥胖。 愈合后，大鼠将接受VNS，SpNS，或两者使用标准的时不变或新的时变 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使用三维有限元模型。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。将进行组织学检查以评估刺激对 神经健康 近期和长期职业目标：近期职业目标是沉浸在该领域中 肥胖研究和扩大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 LSCDVAMC实验室的研究人员，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 研究社区在神经工程领域和2）推进身体的科学知识如何 以一种自然的方式与神经元连接并控制它们。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。模式神经刺激将 成为一种专长。 候选人培训：该CDA 2提供保护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;

项目成果

Bilateral Subdiaphragmatic Vagal Nerve Stimulation Using a Novel Waveform Decreases Body Weight, Food Consumption, Adiposity, and Activity in Obesity-Prone Rats.

• DOI: 10.1007/s11695-023-06957-w
• 发表时间: 2024-01
• 期刊: OBESITY SURGERY
• 影响因子: 2.9
• 作者: Leinen, Monique;Grandy, Elise F.;Gebel, Lourdes M. Ubeira;Santana, Tahimi Machin;Rodriguez, Amanda L.;Singh, Sundip K.;Fernandez, Michael I.;Dalugdug, Justin C.;Garcia-Colon, Elaine M.;Lybeshari, Kamela;Alexander, Daniel R.;Maura, Maria I.;Gonzalez, Maria D. Cabrera;De Paula Cunha Almeida, Caroline;Anyaso-Samuel, Samuel;Datta, Somnath;Schiefer, Matthew A.
• 通讯作者: Schiefer, Matthew A.

Both high fat and high carbohydrate diets impair vagus nerve signaling of satiety.

高脂肪和高碳水化合物饮食都会损害迷走神经的饱腹感信号传导。

• DOI: 10.1038/s41598-021-89465-0
• 发表时间: 2021-05-17
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Loper H;Leinen M;Bassoff L;Sample J;Romero-Ortega M;Gustafson KJ;Taylor DM;Schiefer MA
• 通讯作者: Schiefer MA