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

项目摘要/摘要。3%-5%的成年人患有颅内动脉瘤1和蛛网膜下腔 由破裂的动脉瘤引起的出血(SAH)与10%-25%的死亡率有关 另外30%的患者患有永久性残疾2。炎症起着核心作用，是导致发病率的主要原因 与SAH有关。尽管了解炎症在SAH后发病率中的重要作用，但 目前的障碍是没有有效的方法来调节有害的炎症反应。 SAH后的患者。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)提供了一种新颖的， 免疫调节的非药理学方法。研究表明，VNS可以减少全身性 炎症标记物3和VNS已在治疗关节炎等炎症性疾病方面取得早期成功。 败血症5，炎症性肠病6，7。我们的长期目标是将非侵入性使用 经皮耳廓迷走神经刺激术(TaVNS)降低术后并发症及改善预后 自发性SAH。为实现这一目标，本应用程序的总体目标是：(I) 演示TAVNS对以下患者血液和脑脊液中一项关键炎症标志物的影响 SAH，以及(Ii)确定taVNS是否通过以下方式减少SAH炎症介导的后遗症的发生率 一项前瞻性随机对照试验。我们的中心假设是在急性期实施taVNS 自发性蛛网膜下腔出血将减弱预期的出血炎症反应，并将减少 与炎症介导的临床终点(即血管痉挛、脑积水)相关的发病率。我们的 假设是基于我们的团队在SAH队列中应用taVNS的初步发现而形成的 导致脑脊液中白细胞计数、肿瘤坏死因子-α和IL-6减少的患者以及早期证据 减少血管痉挛和慢性脑积水。在这个初步数据的指引下，我们将测试我们的中央 假说的具体目的如下：1)定义经皮耳迷走神经 刺激对蛛网膜下腔出血所致炎症标志物--肿瘤坏死因子-α的影响 脑脊液(CSF)，2)确定SAH后的taVNS减少血管造影血管痉挛，以及3) 确定SAH后的taVNS可减少慢性脑积水。我们将进行随机对照 关于动脉瘤性蛛网膜下腔出血患者的研究，我们将测试每天两次的taVNS治疗是否与 假手术会改变这些生理和临床终点。这个项目具有创新性，因为它不同于 利用一种新的非侵入性神经调节方法及其已知的抗肿瘤药物的药理现状 炎症作用改变SAH的病理生理学。一种新的有效干预措施的发展 SAH的研究将具有重要意义，因为这项工作将为发展非侵入性 TAVNS以减少SAH后发病率的社会和个人负担。

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.