Developing a novel stimulus paradigm and interface of vagal nerve stimulation (VNS) to treat obesity

理由：到2018年，31个州的肥胖率≥为30%，而无肥胖率为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。研究人员使用迷走神经刺激(VNS)来治疗许多疾病，包括 肥胖。迷走神经中的感觉神经传入支配胃，并传递有关胃电状态的信息 胃，特别是胃壁伸展的程度与胃容量的增加有关。 然而，VNS参数变化很大，刺激参数的变化如何改变结果尚不清楚。 在绘制出参数与结果的关系之前，开发最佳刺激波形是不可能的。 目的：本研究的目的是绘制刺激参数与1)神经的关系图 招募，2)与饱腹感相关的区域的大脑活动，以及3)食物消耗。更进一步，一部小说 将评估用于提供更有效的双边VNS的刺激波形和接口。数不胜数 假说将通过为期4年的一系列动物实验进行验证。 研究计划和方法：在目标1期间，将在隔下迷走神经上植入 大鼠神经袖带电极。老鼠将保持健康或变得肥胖，这取决于它们的饮食。每小时一次 一个月后，动物将接受隔膜下迷走神经刺激(SVNS)，同时获得大脑活动的fMRI图像。 VNS强度、VNS波形、饮食类型和时间对关键区域脑激活的影响 对满足感和奖励负责的人将被确定。在《目标2》中，横隔膜下迷走神经 在大鼠体内植入神经袖带电极。这些老鼠将同时获得三种饮食类型。每个人 每周的VNS将提供多天。食物的消耗量和种类，以及总体 大鼠在刺激期间的活动将与没有刺激的日子进行比较。VNS的影响 将确定食品消费和活动的强度和波形。在《目标3》中，一款新奇的手铐 包裹在食道上的双侧迷走神经将被植入。与目标2一样，老鼠将拥有 同时获得三种饮食类型以及在刺激日期间的食物消耗和活动将 与没有刺激的日子相比。VNS强度对食物消费和活动的影响将是 测定并与AIM 2中发现的那些进行比较。食道的抗扩张性和组织学 用于评估植入物在6个月后是否仍然安全。此外，VNS刺激之间的映射 迷走神经内的强度和轴突招募将被绘制成地图。 预期结果：这项研究提供了必要的数据，以帮助理解sVNS如何影响 通过生成将sVNS参数链接到以下各项的映射来实现三个级别的系统：1)在 迷走神经；2)大脑激活；3)短期食物摄入。这些地图，目前是 未知，是sVNS参数优化的关键，而sVNS参数优化本身对临床成功至关重要 部署。重要的是，我们将知道大脑中的激活随着饮食类型的变化而变化的速度。 这一变化速度对于了解是否以及何时可以使用MRI进行优化至关重要。我们会知道的 激活如何随sVNS波形变化，这在确定参数优化是否 与波形无关。我们将知道一种新型的螺旋袖带是否能安全有效地提供长期 双边sVNS，这对于扩大临床前小动物的可搜索参数空间至关重要， 它们本身就是优化研究的理想选择。这项研究将产生4份手稿。 对退伍军人的好处：关于肥胖，72%的退伍军人超重或肥胖。肥胖有几个原因 并发症包括高血压、心脏病和糖尿病。肥胖和肥胖之间有很强的联系 抑郁症。尽管这项研究完全是临床前研究，但它是开发最佳刺激的关键的第一步。 波形。如果研究成功，那么就有了一条计划好的翻译途径。

Rationale: By 2018, 31 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. Researchers use vagal nerve stimulation (VNS) to treat a number of conditions, including obesity. Sensory afferents in the vagus nerves innervate the stomach and relay information about the state of the stomach, particularly the degree of stomach wall stretch associated with increased stomach volume. However, VNS parameters vary widely and it is unknown how changes in stimulus parameters alter outcomes. Until the parameter-to-outcome relationship is mapped, developing optimal stimulus waveforms is impossible. Objective: The objectives of this study are to map the relationship between stimulus parameters and 1) nerve recruitment, 2) brain activity in regions associated with satiety, and 3) food consumption. Further, a novel stimulus waveform and interface for delivering more effective bilateral VNS will be evaluated. Numerous hypotheses will be tested through a series of animal experiments over a period of 4 years. Research Plan and Methodology: During Aim 1, the subdiaphragmatic vagus nerve will be implanted with a nerve cuff electrode in rats. The rats will remain healthy or become obese depending on their diet. Once per month, the animal will receive subdiaphragmatic VNS (sVNS) while an fMRI image of brain activity is acquired. The effects of VNS intensity, VNS waveform, diet type, and time on activation of the brain in key regions responsible for satiety and reward will be determined. During Aim 2, the subdiaphragmatic vagus nerve will be implanted with a nerve cuff electrode in rats. The rats will have simultaneous access to three diet types. Each week VNS will be provided for multiple days. The amount and type of food consumed as well as the overall activity of the rat during days of stimulation will be compared to days without stimulation. The effects of VNS intensity and waveform on food consumption and activity will be determined. During Aim 3, a novel cuff that wraps around the esophagus and delivers bilateral VNS will be implanted. As with Aim 2, the rats will have simultaneous access to three diet types and both food consumption and activity during days of stimulation will be compared to days without stimulation. The effects of VNS intensity on food consumption and activity will be determined and compared to those found in Aim 2. Esophageal resistance to distension and histology will be used to assess if the implant remains safe after 6 months. Additionally, the map between VNS stimulus intensity and axon recruitment within the vagus nerve will be mapped. Expected Outcomes: This study provides the necessary data to facilitate understanding how sVNS effects the system at three levels by generating a map that links sVNS parameters to: 1) axon recruitment within the vagus nerves; 2) brain activation; and 3) short-term food consumption. These maps, which are currently unknown, are critical for sVNS parameter optimization, which, itself, is critical for successful clinical deployment. Importantly, we will know at what rate activation in the brain changes as a function of diet type. This rate of change will be critical to understand if and when MRI can be used for optimization. We will know how activation changes with sVNS waveform, which is critical when determining if parameter optimization is independent of waveform. We will know if a novel helical cuff can safely and effectively provide long-term bilateral sVNS, which is critical for expanding the searchable parameter space in small pre-clinical animals, which are, themselves, ideal for optimization studies. This study will produce 4 manuscripts. Benefit to Veterans: With regard to obesity, 72% of Veterans are overweight or obese. Obesity has several comorbidities including hypertension, heart disease, and diabetes. There is a strong link between obesity and depression. Although this study is entirely preclinical, it is a critical first step in developing optimal stimulus waveforms. If the study is successful, then there is a planned pathway to translation.