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

基本信息

项目摘要

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.
依据:肥胖影响≥30%的美国人口,包括退伍军人,相关成本估计为 1900亿美元/年研究人员使用迷走神经刺激(VNS)来治疗包括肥胖在内的多种疾病。 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。期望 当双侧应用VNS时,结果最大化,当VNS 应用于次表层。然而,VNS参数变化很大,并且不知道如何变化 在刺激参数改变结果。直到参数与结果的关系被映射, 最佳刺激波形是不可能的。大鼠实验可以促进这些地图的发展,但 在具有目前可用的袖带的大鼠中,双侧小脑下VNS(sVNS)是困难的/不可能的, 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 招募和大脑激活与一种新的螺旋袖口,消除了食管狭窄的风险。的 本研究的次要目的是证明新型螺旋套囊用于以下方面是有效和安全的: 急性和存活实验,包括使用强磁场进行MRI的实验。 将通过为期2年的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,sVNS参数与轴突之间的关系 将对招聘进行映射以生成招聘表面。比较将包括单侧与双侧 sVNS;通过传统袖带输送的sVNS与通过新型螺旋袖带输送的sVNS; 手术时间与长期随访时的sVNS。将确定慢性高葡萄糖饮食的影响。 在Aim 2期间,sVNS参数与大脑关键区域的激活/抑制之间的关系被观察到。 与饱腹感和食物奖励相关的大脑将使用11.1 T fMRI进行映射。在目标3期间, 将通过检查所需的压力来确定长期植入的新型袖带的机械效应 扩张食管,并通过显微镜分析迷走神经。 预期成果:这项概念验证研究是开发新界面的关键第一步, 解决了当前可用技术的几个限制。我们希望这款新颖的袖带会很简单 2)双侧募集支配胃的大部分靶轴突,而没有明显的脱靶 影响; 3)对小脑下迷走神经不造成或造成最小程度的损伤; 4)对小脑下迷走神经不造成或造成最小程度的风险 食管狭窄; 5)在fMRI期间没有显示出发热迹象; 6)没有将伪影引入fMRI数据。 这项研究将产生数据,以促进了解单侧和双侧sVNS如何影响系统, 通过生成将sVNS参数链接到以下各项的图来实现两个水平:1)轴突募集和2)脑 activation.这些目前未知的标测图对于sVNS参数优化至关重要, 对于成功的临床部署至关重要。我们预计,该SPiRE将产生一个出版物, 一个专利。我们的长期目标是将最佳刺激参数, 界面的个人谁没有失去重量在传统的减肥方案。 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, 萧条虽然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 波形如果研究成功,则成功优化sVNS参数的机会为 因此,将这项技术应用于临床的机会大大增加。

项目成果

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MATTHEW Anthony SCHIEFER其他文献

MATTHEW Anthony SCHIEFER的其他文献

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{{ truncateString('MATTHEW Anthony SCHIEFER', 18)}}的其他基金

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:
    10597120
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Toward Closed-Loop Control of Homeostatic Blood Pressure Following Spinal Cord Injury
脊髓损伤后稳态血压的闭环控制
  • 批准号:
    10311117
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Design and Application of Custom Waveforms to Restore and Control Satiety
恢复和控制饱腹感的定制波形的设计和应用
  • 批准号:
    10390275
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Design and Application of Custom Waveforms to Restore and Control Satiety
恢复和控制饱腹感的定制波形的设计和应用
  • 批准号:
    9795377
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Design and Application of Custom Waveforms to Restore and Control Satiety
恢复和控制饱腹感的定制波形的设计和应用
  • 批准号:
    10011592
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Neural Interface and Control Design to Restore Sensation in Amputees
用于恢复截肢者感觉的神经接口和控制设计
  • 批准号:
    8278363
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Neural Interface and Control Design to Restore Sensation in Amputees
用于恢复截肢者感觉的神经接口和控制设计
  • 批准号:
    8499094
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:

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