Toward Closed-Loop Control of Homeostatic Blood Pressure Following Spinal Cord Injury

理由：大约42,000名退伍军人患有脊髓损伤(SCI)。对于这些人中65%患有 胸(T)脊柱6节段以上的脊髓损伤，低血压和高血压都是常见的合并症。SCI在T6以上 增加自主神经反射障碍(AD)的风险，因为中枢下行控制更大 内脏神经(GSN)丧失，随之而来的是控制腹部内脏血管的能力。 GSNs中不受控制的反射亢进可以演变为AD诱发的高血压，这是一个重大的风险 并使中风的风险增加高达400%。相反，内脏色调不足会导致 低血压和57%的人群经历了直立性低血压(OH)。OH与最多一个 认知功能下降65%。一种植入式系统，可提供适当的电刺激或 内脏神经阻断可以治疗这两种情况。 目的：内脏大神经是恢复正常动脉血压(BPart)的主要靶点。 调节这些神经的活动可能提供一种新的、即时的、急性的方法来预防这两种情况 低血压(目标1)和高血压(目标2)。我们的长期目标是开发一种闭环式、可植入的 在SCI患者中将BPart保持在健康范围内的系统，其中中央控制 腹部的血管系统已经受损。为了推进这一目标，我们需要更清楚地了解 脊髓损伤后内脏神经对腹部血管系统的控制。 研究计划和方法：我们将在已建立的啮齿动物T3脊髓上进行临床前试验 显示BPart调节受损的横断面模型。在这两个目标中，动脉血压和腹部 血流量(BFabd)将被监测。在目标1中，将应用内脏神经刺激(SPN)，而 在AIM 2期间，将应用内脏神经阻滞(SpNB)。SPN和SpNB对BPart和BFabd的影响 在广泛的频率范围内将被确定。将绘制一条剂量-反应曲线，以表达 脊髓损伤后BPart和BFabd随SPN和SpNB频率的变化这将被执行 适用于单侧和双侧SPN和SpNB。每条神经对整体变化的相对贡献 BPart和BFabd将确定。 预期结果：这项概念验证研究是开发新的干预和治疗的重要第一步 准备必要的技术和监管活动，使其进入第一次人体试验，并最终 关键临床试验。这项研究将产生足够的数据来创建一份功绩评估，从而开发真正的- 用于在BPart发生短暂但较大变化时控制BPart的时间、闭环和完全可植入的系统 患有慢性脊髓损伤的动物，包括年龄较大的动物，这些动物包括所有退伍军人。这是我们的长期目标 目标是将这一系统翻译给遭受脊髓损伤并经历反复和严重创伤的退伍军人 低血压和/或高血压。我们预计这一尖顶将产生一份出版物。 退伍军人的好处：数千名退伍军人的脊髓损伤在T6以上，并经历过低和/或 高血压。严重的、急性的低血压或高血压在没有适当和立即的情况下可能危及生命。 治疗。这项概念验证研究是开发新干预措施和准备的重要第一步 用于必要的技术和监管活动，使其进入第一次人体试验，并最终发挥关键作用 临床试验。成功将意味着患者有了一种替代疗法，可能会消除对慢性 药物疗法。

Rationale: Approximately 42,000 Veterans have a spinal cord injury (SCI). For the 65% of these individuals with an SCI above thoracic (T) spinal level 6, both hypo- and hypertension are common comorbidities. SCI above T6 increases the risk for autonomic dysreflexia (AD) because the central descending control over the greater splanchnic nerves (GSNs) is lost, and with it the ability to control the abdominal splanchnic vasculature. Uncontrolled hyperreflexia in the GSNs can evolve to AD-induced hypertension, which is a significant risk in this population and increases the risk of stroke by up to 400%. Conversely, insufficient splanchnic tone leads to hypotension and 57% of this population experience orthostatic hypotension (OH). OH is associated with up to a 65% reduction in cognitive function. An implantable system that delivers the appropriate electrical stimulation or block to the splanchnic nerves could treat both conditions. Objective: The greater splanchnic nerves are primary targets for restoring healthy arterial blood pressure (BPart). Modulating activity in these nerves may provide a novel, immediate, and acute means to prevent both hypotension (Aim 1) and hypertension (Aim 2). Our long-term goal is to develop a closed-loop, implantable system that maintains BPart within a healthy range in individuals with SCI in which central control over the abdominal vasculature has been compromised. To advance this goal, we require a clearer understanding of splanchnic nerve control of the abdominal vasculature following loss of central control due to SCI. Research Plan and Methodology: We will conduct pre-clinical trials in an established rodent T3 spinal transection model that displays impaired regulation of BPart. In both aims, arterial blood pressure and abdominal blood flow (BFabd) will be monitored. During Aim 1, splanchnic nerve stimulation (SpNS) will be applied whereas during Aim 2, splanchnic nerve block (SpNB) will be applied. The effect of SpNS and SpNB on BPart and BFabd over a broad range of frequencies will be determined. A dosage-response curve will be developed that expresses the changes in BPart and BFabd as a function of SpNS and SpNB frequencies following SCI. This will be performed for both unilateral and bilateral SpNS and SpNB. The relative contribution of each nerve to overall changes in BPart and BFabd will be determined. Expected Outcomes: This proof-of-concept study is an important first step in developing a new intervention and preparing for the technical and regulatory activities necessary to move it into first-in-human trials and ultimately pivotal clinical trials. This study will generate sufficient data to create a Merit Review that will develop the real- time, closed-loop, and fully implantable system for controlling BPart during transient but large changes in BPart in animals with a chronic SCI, including older animals that capture the full Veteran population. It is our long-term goal to translate this system to Veterans who have sustained an SCI and experience recurring and severe hypotension and/or hypertension. We anticipate that this SPiRE will generate one publication. Benefits to Veterans: Several thousand Veterans have an SCI above T6 and experience hypo- and/or hypertension. Severe, acute hypo- or hypertension can be life-threatening without proper and immediate treatment. This proof-of-concept study is an important first step in developing a new intervention and preparing for the technical and regulatory activities necessary to move it into first-in-human trials and ultimately pivotal clinical trials. Success will mean that patients have an alternative therapy that may obviate the need for a chronic drug regimen.