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）对急性脑缺血的治疗潜力。颈部传入迷走神经纤维的电刺激已被证明可以激活脑干迷走神经中枢，诱导抗兴奋毒性和抗炎机制，并增加脑血流量（CBF）。使用外科植入电极（cVNS）刺激颈迷走神经是fda批准的一种治疗癫痫和抑郁症患者的方法。最近的研究表明，cVNS对缺血性中风动物模型的组织损伤和运动功能丧失也有实质性的保护作用。在缺血后2.5小时内启动cVNS，在各种局灶性脑缺血大鼠模型和有合并症的动物中，可将梗死面积减少约50%。这种保护机制尚不清楚，但初步发现表明它与脑血流无关。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不适用于人类急性中风病例。在这个应用中，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；(2)使用针电极刺激外耳皮肤组织的迷走神经耳分支。颈椎和耳穴tVNS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技术在局灶性缺血中的疗效；(2)描述tVNS治疗的最佳时间窗；(3)研究tVNS和tPA合用在脑缺血中的安全性和有效性。我们将确定颈部tVNS和耳部tVNS对梗死面积（通过生命染色评估）和运动功能（通过行为测试和握力测量评估）的影响。为了确定它们的安全性，我们将在刺激后立即监测生理参数（如动脉血压、心率、心率变异性和呼吸频率），并在治疗后随访动物长达1周。在另一组动物中，为了验证脑干迷走神经中枢的激活，我们将执行c

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.