Transcutaneous vagus nerve stimulation in cerebral ischemia

描述（由申请人提供）：本提案的目的是研究经皮迷走神经刺激（tVNS）在急性脑缺血中的治疗潜力。颈部传入迷走神经纤维的电刺激已被证明可激活脑干迷走神经中枢，诱导抗兴奋性毒性和抗炎机制，并增加脑血流量（CBF）。使用手术植入电极（cVNS）刺激颈部迷走神经是FDA批准的用于一些癫痫和抑郁症患者的治疗。最近的研究表明，cVNS提供了实质性的保护，防止组织损伤和运动功能丧失的缺血性中风的动物模型，以及。cVNS在缺血后2.5小时开始时，在各种局灶性脑缺血大鼠模型和患有共病的动物中，可使梗死体积减少约50%。保护机制尚不清楚，但初步研究结果表明，它是CBF独立的。尽管缺血研究的结果非常令人鼓舞，但由于刺激的侵入性，cVNS不适用于人类急性卒中病例。在本申请中，我们提出了两种不同的tVNS方法来规避手术干预的问题：（1）使用最近可用的技术通过完整的皮肤刺激颈部迷走神经，以及（2）使用针电极刺激供应外耳皮区的迷走神经的耳分支。颈部和耳部tVNS已分别安全成功地用于打嗝和疼痛患者。我们的具体目标是：（1）确定tVNS技术治疗局灶性脑缺血的有效性;（2）描述tVNS治疗的最佳时间窗;（3）研究tVNS和tPA联合应用是否安全有效。我们将确定颈部tVNS和耳部tVNS对梗死面积（通过活体染色评估）和运动功能（通过行为测试和握力测量评估）的影响。为了确定其安全性，我们将监测生理参数（例如，动脉血压、心率、心率变异性和呼吸率），并将在治疗后1周内对动物进行随访。在另外一组动物中，为了验证脑干迷走神经中枢的激活，我们将进行c tVNS后Fos免疫组化。在确定颈部tVNS和耳部tVNS在特定目标1中的安全性和有效性后，我们将继续研究最安全和最有效的tVNS。为了确定缺血后tVNS的时间窗，我们在缺血后3小时或更长时间开始tVNS，并确定其对梗死面积的影响。我们还建议确定tPA和tVNS之间的相互作用。我们将检查tPA-tVNS联合给药对出血风险的影响。我们还将研究tVNS对tPA的时间窗和疗效的影响，使用多模式MR成像与分子血栓成像。拟议的研究将提供tVNS改善卒中结局的原则证据。如果成功，这些探索性研究的结果将用于不久的将来的翻译研究，旨在优化 tVNS治疗人类急性缺血性卒中

DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the therapeutic potential of transcutaneous vagus nerve stimulation (tVNS) in acute cerebral ischemia. Electrical stimulation of the afferent vagal fibers in the neck has been shown to activate the brainstem vagal centers, induce anti-excitotoxic and anti-inflammatory mechanisms, and increase cerebral blood flow (CBF). Stimulation of the cervical vagus nerve using surgically implanted electrodes (cVNS) is an FDA-approved treatment in some epilepsy and depression patients. Recent studies demonstrated that cVNS provides substantial protection against tissue injury and motor function loss in animal models of ischemic stroke as well. cVNS, when initiated up to 2.5 hours after ischemia, reduces infarct volume by approximately 50% in a variety of rat models of focal cerebral ischemia and in animals with comorbid conditions. The mechanism of protection is not clear yet, but initial findings suggest that it is CBF independent. Even though the findings of ischemia studies are quite encouraging, cVNS is not applicable to acute stroke cases in humans due to invasive nature of the stimulation. In this application, we propose two different tVNS approaches to circumvent the problem of surgical intervention: (1) to stimulate the cervical vagus nerve through the intact skin using a recently available technology and (2) to stimulate the auricular branch of the vagus nerve that supplies a dermatome in external ear using needle electrodes. Both cervical and auricular tVNS have been safely and successfully used in patients with hiccups and pain, respectively. Our specific aims are: (1) determine the efficacy of tVNS techniques in focal ischemia, (2) describe the optimal time window of tVNS treatment, (3) study whether concomitant application of tVNS and tPA is safe and effective in cerebral ischemia. We will determine the effects of cervical tVNS and ear tVNS on infarct size (as assessed by vital stain) and motor function (as assessed by behavioral tests and grip strength measurements). To determine their safety, we will monitor physiological parameters (e.g., arterial blood pressure, heart rate, heart rate variability, and respiration rate) during an immediately after stimulation and will follow-up animals up to 1 week after the treatment. In an additional group of animals, to verify the activation of brainstem vagal centers, we will perform c Fos immunohistochemistry after tVNS. After determining the safety and efficacy of neck tVNS and ear tVNS in specific aim 1, we will continue our studies with the safest and most efficacious tVNS. To determine the time window of tVNS after ischemia, we initiate tVNS 3 hours or more after ischemia and determine its effect on infarct size. We also propose to determine the interaction between tPA and tVNS. We will examine the effect of tPA - tVNS co-administration on risk of hemorrhage. We also will investigate the effect of tVNS on tPA's time window and efficacy using multi-modal MR imaging with molecular thrombus imaging. The proposed studies will provide the proof of principle that tVNS improves stroke outcome. If successful, the findings of these exploratory studies will be used in near future translational studies designed to optimize tVNS treatment for acute ischemic stroke in humans.