Meal-Triggered Vagal Nerve Stimulation for Obesity

 描述（由申请人提供）：在美国，肥胖及其合并症每年导致约40万人死亡，花费超过1400亿美元。然而，目前肥胖症的治疗选择非常有限。迷走神经刺激（VNS）作为治疗肥胖症的潜在疗法 已经在实验室和临床环境中进行了探索。然而，缺乏系统的研究调查各种刺激参数和配置对食物摄入量和体重的影响。因此，目前没有临床相关的方法可用。在这个项目中，我们提出了一种创新的VNS方法，通过优化方法和提供食物摄入后自动输送电刺激来治疗肥胖。我们在肥胖大鼠中的初步数据已经证明了显著的和临床相关的体重减轻，归因于食物摄入的抑制。该项目的主要目的是证明建议的VNS用于治疗肥胖症的大型动物模型中使用植入式脉冲发生器的可行性。具体目标如下：1）获得VNS抑制猪肥胖模型中食物摄入的最有效参数。2）研究慢性迷走神经刺激参数对猪肥胖症的治疗效果和安全性，并探讨迷走神经刺激与自主神经功能、胃运动、胃促食欲素、胃促生长素、胰高血糖素样肽-1和多肽YY等胃肠激素的作用机制;将按需膳食触发VNS方法在减轻体重方面的性能与传统VNS进行比较; 3）开发算法并使用其检测食物摄入并在膳食摄入时自动启动VNS。它将根据食物摄入后自主功能的变化进行设计。将使用从刺激电极获得的心率变异性信号的频谱分析来评估自主神经功能。我们组建了一个全面而有竞争力的团队，拥有神经调节、软件和设备开发、肥胖和手术方面的专业知识。该小组还包括一名咨询统计员。该项目的完成将证明所提出的治疗肥胖症的方法的可行性。

 DESCRIPTION (provided by applicant): Obesity and its co-morbidities cause about 400,000 deaths and cost more than $140 billion per year in USA. However, current treatment options for obesity are very limited. Vagal nerve stimulation (VNS) as a potential therapy for treating obesity has been explored in both laboratory and clinical settings. However, there is lack of systematic studies investigating the effects of various stimulation parameters and configurations on food intake and body weight. Consequently, no clinically relevant methodologies are currently available. In this project, we propose an innovative method of VNS for treating obesity by optimizing methodologies and providing automated delivery of electrical stimulation upon food ingestion. Our preliminary data in obese rats have demonstrated a significant and clinically relevant weight loss, attributed to the inhibition in food intake. The main aim of this project is o prove the feasibility of the proposed VNS for treating obesity in a large animal model of obesity using an implantable pulse generator. Specific objectives are as follows: 1) to derive most effective parameters for VNS to inhibit food intake in a swine model of obesity. Experiments are designed to obtain most effective stimulation frequencies, pulse width and stimulation configurations; 2) to study the efficacy and safety of chronic VNS using optimized stimulation parameters in treating obesity in pigs and also to explore possible mechanisms involving autonomic functions, gastric motility and gastrointestinal hormones, such as orexigenic hormone, ghrelin, and anorexigenic hormones, glucagon-like peptide-1 and polypeptide YY; The performance of on-demand meal-triggered VNS method in reducing body weight will be compared with the conventional VNS; 3) to develop an algorithm and use it to detect food intake and automatically initiate VNS upon meal ingestion. It will be designed based on changes in autonomic functions upon food intake. The autonomic functions will be assessed using spectral analysis of the heart rate variability signal that is obtained from stimulation electrodes. A comprehensive and competitive team has been assembled with expertise in neuromodulation, software and device development, obesity, and surgery. A consulting statistician is also included in the team. The accomplishment of this project will prove the feasibility of the proposed method for treating obesity.