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

依据：到2018年，31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。研究人员使用迷走神经刺激（VNS）治疗多种疾病，包括 肥胖迷走神经中的感觉传入神经支配胃并传递关于胃的状态的信息。 胃，特别是与胃体积增加相关的胃壁拉伸程度。 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。 直到参数到结果的关系被映射，开发最佳的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）神经之间的关系 招募，2）与饱腹感相关区域的大脑活动，以及3）食物消耗。此外，一部小说 将评估用于提供更有效双侧VNS的刺激波形和接口。许多 将在4年内通过一系列动物实验对假设进行检验。 研究计划和方法：在目标1期间，将植入小脑下迷走神经， 大鼠神经袖状电极。老鼠将保持健康或变得肥胖，这取决于它们的饮食。一次 月，动物将接受脑下VNS（sVNS），同时获得脑活动的fMRI图像。 VNS强度、VNS波形、饮食类型和时间对大脑关键区域激活的影响 而对自己的付出和回报，也是有责任的。在Aim 2期间，小脑下迷走神经将被切断。 在大鼠体内植入神经袖状电极。大鼠将同时获得三种饮食类型。每个 一周VNS将提供多天。消费的食物数量和类型以及总体 将大鼠在刺激期间的活动与没有刺激的日子进行比较。VNS的影响 将确定对食物消耗和活动影响的强度和波形。在Aim 3期间， 包裹食道并输送双侧VNS。与目标2一样，大鼠将 同时获得三种饮食类型以及刺激期间的食物消耗和活动将 与没有刺激的日子相比。VNS强度对食物消耗和活动的影响将 确定并与目标2中发现的那些进行比较。食管对扩张的抵抗力和组织学将 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 将绘制迷走神经内的强度和轴突募集。 预期结果：本研究提供了必要的数据，以促进了解sVNS如何影响 通过生成将sVNS参数链接到以下各项的映射，在三个水平上建立了一个系统： 迷走神经; 2）大脑激活;和3）短期食物消耗。这些地图目前 对于sVNS参数优化至关重要，而sVNS参数优化本身对于成功的临床治疗至关重要。 部署.重要的是，我们将知道大脑激活的变化率作为饮食类型的函数。 这种变化率对于了解MRI是否以及何时可用于优化至关重要。便应当心 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可以安全有效地提供长期的 双侧sVNS，这对于扩大小型临床前动物的可搜索参数空间至关重要， 它们本身是优化研究的理想选择。本研究将产生4份手稿。 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 合并症包括高血压、心脏病和糖尿病。肥胖和肥胖之间有很强的联系， 萧条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第一步 波形如果研究成功，那么就有了一个计划的翻译途径。

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.