Non-invasive vagus nerve stimulation to mitigate subarachnoid hemorrhage induced inflammation

无创迷走神经刺激减轻蛛网膜下腔出血引起的炎症

• 批准号: 10665166
• 负责人: Peter Brunner
• 金额: $ 23.33万
• 依托单位: WASHINGTON UNIVERSITY
• 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/10665166
• 关键词: Acute; Adult; Aneurysmal Subarachnoid Hemorrhages; Angiography; Anti-Inflammatory Agents; Antiinflammatory Effect; Arthritis; Attenuated; Automobile Driving; Blood; Brain; Brain hemorrhage; Central Nervous System; Cerebral Edema; Cerebrospinal Fluid; Cerebrovascular Spasm; Chronic; Clinical; Clinical Trials; Data; Development; Drainage procedure; Foundations; Functional disorder; Future; Goals; Hemorrhage; Hydrocephalus; IL18 gene; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-6; Intervention; Intracranial Aneurysm; Knowledge; Life; Macrophage; Mediating; Methodology; Methods; Mission; Morbidity - disease rate; National Institute of Neurological Disorders and Stroke; Nature; Nerve; Operative Surgical Procedures; Outcome; Outcome Study; Pathway interactions; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Physiological; Play; Public Health; Randomized, Controlled Trials; Research; Risk; Role; Rupture; Ruptured Aneurysm; Sepsis; Serum; Shunt Device; Subarachnoid Hemorrhage; Subarachnoid Space; T-Lymphocyte; TNF gene; Testing; Translating; Validation; Vasospasm; Ventricular; White Blood Cell Count procedure; Work; absorption; cohort; cytokine; disability; effective intervention; immunoregulation; implantation; improved outcome; inflammatory marker; innovation; interleukin-23; mortality; nervous system disorder; neuroregulation; novel; novel strategies; pharmacologic; prospective; randomized, controlled study; side effect; success; systemic inflammatory response; vagus nerve stimulation

Project Summary/Abstract. Between 3-5% of adults harbor an intracranial aneurysm1, and subarachnoid hemorrhages (SAH) resulting from ruptured aneurysms are associated with a mortality rate of 10-25% with an additional 30% of patients suffering permanent disability2. Inflammation plays a central role, driving the morbidity associated with SAH. Despite understanding the important role of inflammation in morbidity following SAH, the current barrier is that there is no effective methodology to modulate the deleterious inflammatory response in patients following SAH. Due to this gap, there is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a novel, non-pharmacologic approach to immunomodulation. Studies have demonstrated VNS to reduce systemic inflammatory markers3 and VNS has had early success treating inflammatory conditions such as arthritis4, sepsis5, and inflammatory bowel diseases6,7. Our long-term goal is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to reduce morbidity and improve outcomes in patients following spontaneous SAH. The overall objectives for this application in pursuit of achieving this goal are to (i) demonstrate the impact taVNS has on a key inflammatory marker in the blood and CSF in patients following SAH, and (ii) determine if taVNS reduces the incidence of inflammation-mediated sequelae of SAH by performing a prospective, randomized controlled trial. Our central hypothesis is that implementing taVNS in the acute period following spontaneous SAH will attenuate the expected inflammatory response to hemorrhage and will curtail morbidity associated with inflammatory-mediated clinical endpoints (i.e., vasospasm, hydrocephalus). Our hypothesis has been formulated based on preliminary findings where our team applied taVNS in a cohort of SAH patients leading to reductions in white blood cell count, TNF- α, and IL-6 in the CSF, as well as early evidence of decreased vasospasm and chronic hydrocephalus. Guided by this preliminary data, we will test our central hypothesis with the following specific aims: 1) Define the impact that transcutaneous auricular vagus nerve stimulation has on a key subarachnoid hemorrhage-induced inflammatory marker, TNF-α, in the serum and cerebrospinal fluid (CSF), 2) Determine that taVNS following SAH reduces angiographic vasospasm, and 3) Determine that taVNS following SAH reduces chronic hydrocephalus. We will perform a randomized controlled study on aneurysmal SAH patients where we will test whether twice daily treatment with taVNS compared to sham will alter these physiologic and clinical endpoints. This project is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti- inflammatory effects to alter the pathophysiology of SAH. The development of a new and effective intervention in SAH will be significant because this work will create the foundation of knowledge for advancing non-invasive taVNS to reduce the societal and personal burden of post-SAH morbidity.

项目概要/摘要。3-5%的成年人患有颅内动脉瘤1， 动脉瘤破裂导致的蛛网膜下腔出血（SAH）与10-25%的死亡率相关， 另外30%的永久性残疾患者2。炎症起着核心作用， 与SAH有关。尽管了解炎症在SAH后发病率中的重要作用， 目前的障碍是没有有效的方法来调节有害的炎症反应， SAH后患者。由于这一差距，迫切需要一种新的免疫调节方法， 可以安全、快速和有效地部署在SAH患者中。迷走神经刺激（VNS）提供了一种新的， 免疫调节的非药物方法。研究表明，VNS可以减少全身性 炎性标记物3和VNS已经在治疗炎性疾病如关节炎4方面取得了早期成功， 脓毒症5和炎症性肠病6，7。我们的长期目标是将非侵入性 经皮耳VNS（taVNS），以降低发病率并改善以下患者的结局 自发性SAH。为实现这一目标，本申请的总体目标是（i） 证明了taVNS对血液和CSF中的关键炎症标志物的影响， SAH，以及（ii）通过进行以下操作来确定taVNS是否降低炎症介导的SAH后遗症的发生率： 前瞻性随机对照试验我们的中心假设是在急性期实施taVNS 自发性SAH后，将减弱预期的对出血的炎症反应， 与炎症介导的临床终点相关的发病率（即，血管痉挛、脑积水）。我们 我们的研究小组在SAH队列中应用taVNS的初步研究结果为基础，提出了一个假设 导致CSF中白色血细胞计数、TNF- α和IL-6降低的患者，以及早期证据 减少血管痉挛和慢性脑积水。在这些初步数据的指导下，我们将测试我们的中央 假设有以下具体目标：1）定义经皮耳迷走神经的影响， 刺激对血清中关键的蛛网膜下腔出血诱导的炎症标志物TNF-α有影响， 脑脊液（CSF），2）确定SAH后taVNS减少血管造影性血管痉挛，和3） 确定SAH后taVNS可减少慢性脑积水。我们将进行一项随机对照 研究中，我们将测试每日两次taVNS治疗与 假手术将改变这些生理和临床终点。这个项目是创新的，因为它偏离了 药理学现状，利用一种新的非侵入性神经调节方法及其已知的抗- 炎症作用改变SAH的病理生理学。制定新的有效干预措施 在SAH中的作用将非常重要，因为这项工作将为推进非侵入性奠定知识基础 TAVNS可减轻SAH后发病的社会和个人负担。