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

项目摘要/摘要 创伤性脑损伤(TBI)仍然是世界范围内死亡和残疾的主要原因。这个 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28.3万人住院和5.2万人死亡。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 剪切、细胞兴奋性毒性、神经炎症、颅内压升高、氧自由释放 自由基、酸中毒和缺氧/缺血，如果不预防或治疗，会导致进一步的脑损伤。 迷走神经刺激(VNS)通过将电脉冲传递到 神经已被证明可以减少促炎反应，增加去甲肾上腺素浓度， 减轻谷氨酸介导的兴奋性毒性，改善血脑屏障功能，从而改善认知能力 脑外伤后的运动功能。非侵入性迷走神经刺激(NVNS)治疗的最新临床试验 偏头痛和创伤后应激障碍已被证明是有效的。此外，nVNS还拥有 在缺血性和出血性中风的临床前模型中，已被证明可以改善预后。我们的预赛 在大鼠颅脑损伤模型中使用nVNS治疗的数据表明，脑损伤体积和 焦虑，但还需要进一步的研究，以更好地了解nVNS治疗对 改善颅脑损伤的转归。 在这里，我们建议进行一项为期两年的研究，以确定五个NVNS在脑外伤大鼠模型中的效果。 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，我们假设这种症状的减少反映了血脑屏障的减少。 通过神经影像、组织学等方法评估与脑外伤相关的功能障碍和促炎过程 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情况下提供nVNS治疗 提供五次2x2分钟(4分钟)刺激，第一天相隔10分钟(受伤后1小时或6小时内 使用GammaCore设备(电子核心公司，新泽西州)。GammaCore是一种手持设备(大小为 移动电话)具有良好安全记录的非侵入性设备。需要注意的是，GammaCore 该设备已经被FDA批准用于偏头痛。 到目前为止，临床试验还没有产生有效的治疗方法来对抗肺炎的破坏性影响 TBI。因此，迫切需要安全有效的治疗来提高服务的生活质量 成员和受TBI影响的平民人口，促进更好的恢复和社区重新融合 在他们受伤后。这一提议对脑损伤领域具有重要意义，因为它提供了必要的 关于启动关于nVNS使用的更大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.