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

开发一种新的刺激范式和迷走神经刺激（VNS）界面来治疗肥胖

• 批准号: 10425537
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425537
• 关键词: Affect; Agreement; Animal Experiments; Animals; Anodes; Anterior; Axon; Bilateral; Body Weight; Body Weight decreased; Brain; Brain imaging; Brain region; Bypass; Cathodes; Charge; Clinical; Communities; Computer Simulation; Consumption; Country; Data; Diabetes Mellitus; Diet; Eating; Electricity; Electrodes; Epidemic; Esophagus; Esthesia; Exhibits; Fiber; Food; Foundations; Functional Magnetic Resonance Imaging; Future; Goals; Health; Healthcare; Heart Diseases; High Fat Diet; Histology; Hypertension; Hypothalamic structure; Implant; Knowledge; Lateral; Link; Magnetic Resonance Imaging; Manuscripts; Maps; Mechanoreceptors; Mental Depression; Methodology; Methods; Nerve; Obesity; Outcome; Outcome Study; Output; Overweight; Pathway interactions; Peripheral Nerves; Planning Techniques; Play; Population; Rattus; Reporting; Research; Research Personnel; Resistance; Rewards; Risk; Role; Route; Safety; Satiation; Sensory; Series; Shapes; Spinal Cord; Stimulus; Stomach; Stretching; System; Technology; Testing; Therapeutic; Time; Translations; Vagus nerve structure; Variant; Veterans; Veterans Health Administration; Visceral Afferents; Width; Work; bariatric surgery; base; clinical practice; comorbidity; cost; design; diet and exercise; efficacy evaluation; food consumption; implantation; innovation; neuroimaging; novel; obese person; obesity management; pre-clinical; primary outcome; rate of change; recruit; reduced food intake; response

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.

理由：到 2018 年，有 31 个州的肥胖率≥30%，据估计，没有一个州因肥胖造成的成本低于 20%。 每年 190B 美元，72% 的退伍军人超重 (45%) 或肥胖 (27%)，其中 66% 患有高血压和 31% 患有糖尿病，研究人员使用迷走神经刺激 (VNS) 来治疗多种疾病，包括 迷走神经中的感觉传入神经支配胃并传递有关肥胖状态的信息。 胃，特别是与胃容量增加相关的胃壁拉伸程度。 然而，VNS 参数差异很大，并且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，不可能开发出最佳的刺激波形。 目的：本研究的目的是绘制刺激参数与 1) 神经之间的关系 招募区域，2）与饱腹感相关的大脑活动，以及3）食物消耗此外，一种新颖的方法。 将评估用于提供更有效的双侧 VNS 的刺激波形和接口。 假设将通过为期 4 年的一系列动物实验进行检验。 研究计划和方法：在目标 1 期间，膈下迷走神经将被植入 大鼠的神经袖带电极将根据其饮食保持健康或变得肥胖。 一个月后，动物将接受膈下 VNS (sVNS)，同时获取大脑活动的功能磁共振成像图像。 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 在目标 2 期间，将确定负责饱腹感和奖励的神经。 在老鼠体内植入神经袖带电极，每只老鼠将同时获得三种饮食类型。 将提供多天的每周 VNS 消耗食物的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。 在目标 3 中，将确定食物消耗活动的强度和波形。 与目标 2 一样，大鼠将包裹食道并植入双侧 VNS。 同时接受三种饮食类型以及刺激期间的食物消耗和活动将 将 VNS 强度对食物消耗和活动的影响与没有刺激的日子进行比较。 确定并与目标 2 中发现的结果进行比较。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。 迷走神经内的强度和轴突募集将被绘制出来。 预期结果：本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 参数链接到的图，可以在三个级别上构建系统：1) 内的轴突募集 迷走神经；2）大脑激活；3）短期食物消耗。 未知，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至关重要 重要的是，我们将知道大脑的激活率随着饮食类型的变化而变化。 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，我们将会知道。 激活如何随 sVNS 波形变化，这在确定参数优化是否有效时至关重要 我们将知道新型螺旋袖口是否能够安全有效地提供长期的服务。 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， 它们本身就是优化研究的理想选择。本研究将产生 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。 高血压、心脏病和糖尿病等合并症与肥胖之间存在密切联系。 尽管这项研究完全是临床前的，但它是开发最佳刺激的关键的第一步。 如果研究成功，那么就有了计划好的转化途径。