Design and testing of a novel circumesophageal cuff for chronic bilateral subdiaphragmatic vagal nerve stimulation (sVNS)

用于慢性双侧膈下迷走神经刺激（sVNS）的新型环食管套囊的设计和测试

• 批准号: 10702126
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702126
• 关键词: Acute; Address; Adoption; Affect; Animal Experiments; Animal Model; Area; Axon; Bilateral; Body Weight; Body Weight decreased; Brain; Brain region; Cardiac Output; Cervical; Charge; Chronic; Clinic; Clinical; Communication; Country; Dangerousness; Data; Development; Diabetes Mellitus; Diet; Dorsal; Elasticity; Electric Stimulation; Electricity; Electrodes; Emerging Technologies; Epidemic; Esophageal Stenosis; Esophagus; Exposure to; Failure; Feasibility Studies; Fiber; Food; Functional Magnetic Resonance Imaging; Future; Gastric Balloon; Glucose; Goals; Health; Heart Diseases; Heating; Hypertension; Implant; Individual; Ingestion; Intestines; Left; Legal patent; Letters; Link; Location; Longterm Follow-up; Magnetic Resonance Imaging; Maps; Mechanics; Mechanoreceptors; Medical Device; Mental Depression; Methodology; Microscopic; Morphologic artifacts; Motivation; Nerve; Neuronal Plasticity; Obesity; Operative Surgical Procedures; Organ; Outcome; Overweight; Pattern; Perception; Pharmaceutical Preparations; Population; Publications; Rattus; Regimen; Reporting; Research; Research Personnel; Rewards; Risk; Rodent; Rodent Model; Safety; Satiation; Sensory; Series; Stenosis; Stimulus; Stomach; Stretching; Surface; System; Technology; Testing; Therapeutic; Time; Tissues; Translating; Translations; Vagus nerve structure; Veterans; Veterans Health Administration; Visceral Afferents; Weight; bariatric surgery; clinical practice; comorbidity; cost estimate; density; design; diet and exercise; driving force; experimental study; food consumption; imaging study; magnetic field; minimal risk; non-invasive imaging; novel; obesity management; pre-clinical; pressure; recruit; side effect; success; tool; vagus nerve stimulation

Rationale: Obesity affects ≥30% of the U.S. population, including Veterans, with related costs estimated at $190B/yr. Researchers use vagus 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. Desired outcomes are maximized when VNS is applied bilaterally and off-target effects are minimized when VNS is applied at the subdiaphragmatic level. 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. Experiments in rats could facilitate development of these maps, but bilateral subdiaphragmatic VNS (sVNS) is difficult/impossible in rats with currently available cuffs, which carry an inherent risk of esophageal stenosis. Objective: The primary objective of this study is to map the relationship between sVNS parameters, nerve recruitment, and brain activation with a novel helical cuff that eliminates the risk of esophageal stenosis. The secondary objective of this study is to demonstrate that the novel helical cuff is effective and safe for use in both acute and survival experiments, including experiments that use strong magnetic fields for MRI. Hypotheses will be tested through a series of animal experiments over a period of 2 years. Research Plan and Methodology: During Aim 1, the relationship between sVNS parameters and axon recruitment will be mapped to generate recruitment surfaces. Comparisons will include unilateral vs. bilateral sVNS; sVNS delivered through a traditional cuff vs. sVNS delivered through the novel helical cuff; sVNS at the time of surgery vs. sVNS at long-term follow-up. The effect of a chronic high glucose diet will be determined. During Aim 2, the relationship between sVNS parameters and brain activation/inhibition in key regions of the brain associated with satiety and food-based reward will be mapped using an 11.1 T fMRI. During Aim 3, the mechanical effects of a chronically-implanted novel cuff will be determined by examining the pressure required to distend the esophagus and through microscopic analysis of the subdiaphragmatic vagus nerves. Expected Outcomes: This proof-of-concept study is a critical first step in developing a new interface that addresses several limitations with currently-available technology. We expect that the novel cuff will 1) be easy to implant; 2) bilaterally recruit most of the target axons innervating the stomach without apparent off-target effects; 3) cause no or minimal damage to the subdiaphragmatic vagus nerves; 4) cause no or minimal risk of esophageal stenosis; 5) show no signs of heating during fMRI; 6) not introduce artefacts into the fMRI data. This study will generate data to facilitate understanding how unilateral and bilateral sVNS effects the system at two levels by generating a map that links sVNS parameters to: 1) axon recruitment and 2) brain activation. These maps, which are currently unknown, are critical for sVNS parameter optimization, which, itself, is critical for successful clinical deployment. We anticipate that this SPiRE will generate one publication and one patent. It is our long-term goal to translate optimal stimulus parameters and possibly the novel interface to individuals who have failed to lose weight under traditional weight loss regimens. 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 the chance of successful optimization of sVNS parameters is dramatically increased and, as such, the chance of translating this technology to the clinic.

理由：肥胖影响 ≥30% 的美国人口，包括退伍军人，相关成本估计为 $190B/年 研究人员使用迷走神经刺激 (VNS) 来治疗多种疾病，包括肥胖症。 迷走神经中的感觉传入神经支配胃并传递有关胃状态的信息 胃，特别是与所需胃体积增加相关的胃壁拉伸程度。 当双侧应用 VNS 时，结果最大化；当 VNS 联合应用时，脱靶效应最小化。 然而，VNS 参数变化很大，并且尚不清楚如何变化。 刺激参数会改变结果，直到绘制出参数与结果的关系为止。 最佳刺激波形是不可能的，但在大鼠身上进行的实验可以促进这些图的开发。 对于目前可用的袖带的大鼠来说，双侧膈下 VNS (sVNS) 是困难/不可能的，袖带携带 食管狭窄的固有风险。 目的：本研究的主要目的是绘制 sVNS 参数、神经 新型螺旋袖带可消除食管狭窄的风险，从而进行脑募集和激活。 本研究的次要目的是证明新型螺旋袖带可有效且安全地用于 急性实验和生存实验，包括使用强磁场进行 MRI 的实验。 假设将通过为期两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，sVNS参数和轴突之间的关系 将绘制招募图以生成招募面，比较将包括单边与双边。 sVNS；通过传统袖带递送的 sVNS 与通过新型螺旋袖带递送的 sVNS； 手术时间与长期随访时的 sVNS 的影响将被确定。 在目标 2 期间，sVNS 参数与大脑关键区域的激活/抑制之间的关系 在目标 3 期间，将使用 11.1 T fMRI 绘制与饱腹感和食物奖励相关的大脑图谱。 长期植入的新型袖带的机械效应将通过检查所需的压力来确定 扩张食道并通过显微镜分析膈下迷走神经。 预期成果：这项概念验证研究是开发新界面的关键的第一步， 解决了当前可用技术的一些限制，我们预计新型袖带将 1) 变得简单。 植入；2)双侧募集大部分支配胃的目标轴突，没有明显的脱靶 影响； 3) 对膈下迷走神经没有造成或最小程度的损害； 4) 不会造成或最小程度的风险； 食管狭窄；5) 在功能磁共振成像期间没有显示加热迹象；6) 不在功能磁共振成像数据中引入伪影。 这项研究将生成数据，以帮助了解单边和双边 sVNS 如何影响系统 通过生成将 sVNS 参数链接到以下两个级别的图：1) 轴突募集和 2) 大脑 这些目前未知的映射对于 sVNS 参数优化至关重要，其中， 本身对于成功的临床部署至关重要，我们预计该 SPiRE 将发表一份出版物。 和一项专利是我们的长期目标是转化最佳刺激参数以及可能的新颖性。 与那些在传统减肥方案下减肥失败的人建立联系。 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，则 sVNS 参数成功优化的机会为 显着增加了将该技术转化为临床的机会。