Noninvasive Vagus Nerve Stimulation for Treatment of Brain Injury (nVNS-TBI) in Rats

项目概要/摘要 创伤性脑损伤（TBI）仍然是全世界死亡和残疾的主要原因。的 疾病控制中心估计，仅在美国，每年就有大约 250 万人 人们遭受创伤性脑损伤，导致 283,000 人住院治疗，52,000 人死亡。 TBI 包含一个复杂的集合 病理生理阶段，包括血管损伤、血脑屏障（BBB）功能障碍、轴突损伤 剪切、细胞兴奋性毒性、神经炎症、颅内压升高、游离氧的释放 如果不预防或治疗，自由基、酸中毒和缺氧/缺血会导致进一步的脑损伤。 通过向迷走神经刺激 (VNS) 传递电脉冲来激活副交感神经 神经已被证明可以减少促炎反应，增加去甲肾上腺素浓度， 减弱谷氨酸介导的兴奋性毒性，改善 BBB 功能，从而改善认知能力 TBI 后的运动功能和运动功能。最近使用非侵入性 VNS (nVNS) 治疗的临床试验 偏头痛和创伤后应激障碍已被证明有效。此外，nVNS 有 已被证明可以改善缺血性和出血性中风的临床前模型的结果。我们的初步 在大鼠 TBI 模型中使用 nVNS 疗法的数据表明，脑损伤体积减少，并且 焦虑，但需要进一步研究以更好地了解 nVNS 治疗对患者的真正影响 改善 TBI 的结果。 在这里，我们建议进行一项为期 2 年的研究，以确定 5 种 nVNS 对 TBI 大鼠模型的影响。 我们的主要假设是 nVNS 治疗将减少大脑病变体积，从而改善认知能力 和功能结果。此外，我们假设症状的减轻反映了 BBB 的减少 通过神经影像学、组织学、 和生化研究。对于拟议的项目，我们打算通过以下方式在急性环境中提供 nVNS 治疗： 在第一天（受伤后 1 或 6 小时内）提供 5 次 2x2 分钟（4 分钟）刺激，间隔 10 分钟 使用 gammaCore 设备（新泽西州 electroCore Inc.）。 gammaCore 是一个手持设备（大小为 手机）具有良好安全记录的非侵入性设备。值得注意的是，gammaCore 该设备已获得 FDA 批准用于治疗偏头痛。 迄今为止，临床试验未能产生有效的治疗方法来对抗这种疾病的破坏性影响 创伤性脑损伤。因此，迫切需要安全有效的治疗来提高服务的生活质量 受 TBI 影响的成员和平民，并促进更好的康复和社区重新融入 他们受伤后。该提案通过提供必要的信息对脑损伤领域具有重要意义 有关开展有关 nVNS 使用的更大规模临床前和临床研究的信息。

Project Summary/Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. The Center for Disease Control estimates that each year in the United States alone, approximately 2.5 million people sustain a TBI, resulting in 283,000 hospitalizations and 52,000 deaths. TBI encompasses a complex set of pathophysiological stages, including damage to blood vessels, blood-brain barrier (BBB) dysfunction, axonal shearing, cellular excitotoxicity, neuroinflammation, the rise of intracranial pressure, the release of oxygen free radicals, acidosis, and hypoxia/ischemia that lead to further brain damage if not prevented or treated. Parasympathetic activation by vagus nerve stimulation (VNS) via delivering electric impulses to the nerve has been shown to reduce proinflammatory responses, increase norepinephrine concentrations, attenuate glutamate-mediated excitotoxicity, and improve BBB function leading to improvement in cognitive and motor functions following TBI. Recent clinical trials on the use of non-invasive VNS (nVNS) to treat migraine headaches and post-traumatic stress disorders have shown to be effective. Furthermore, nVNS has been shown to improve outcomes in preclinical models of ischemic and hemorrhagic strokes. Our preliminary data for the use of nVNS therapy in a rat TBI model indicates a reduction of the brain lesion volume and anxiety, but further investigations are needed to better understand the true impact of the nVNS therapy on improving the outcome of TBI. Here we propose to conduct a 2-year study to determine the effect of five nVNS in a rat model of TBI. Our primary hypothesis is that nVNS treatment will reduce in brain lesion volume leading to improved cognitive and functional outcomes. Further, we hypothesize that this reduction of symptoms reflects a decrease in BBB dysfunction and proinflammatory processes related to TBI as assessed through neuroimaging, histological, and biochemical studies. For the proposed project, we intend to deliver nVNS therapy in acute settings by delivering five 2x2-min (4 minutes) stimulations, 10 minutes apart on day 1 (within 1 or 6 hours from injury onset) using the gammaCore device (electroCore Inc., NJ). The gammaCore is a handheld (the size of a mobile phone) non-invasive device with a good safety record. It is important to note that the gammaCore device is already FDA-approved for migraine headaches. To date, clinical trials have failed to produce effective treatments to combat the devastating effects of TBI. Therefore, safe and effective treatments are desperately needed to improve the quality of life of service members and civilian populations affected by TBI and promote better recovery and community re-integration after their injury. This proposal has important implications for the field of brain injury by providing necessary information for launching larger preclinical and clinical studies on the use of nVNS.