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

项目总结/摘要 创伤性脑损伤（TBI）仍然是全球死亡和残疾的主要原因。的 疾病控制中心估计，仅在美国，每年约有250万人 2010年，283，000人因TBI住院治疗，52，000人死亡。TBI包含一组复杂的 病理生理学阶段，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）通过向迷走神经传递电脉冲来激活副交感神经。 神经已经显示出减少促炎反应，增加去甲肾上腺素浓度， 减弱谷氨酸介导的兴奋性毒性，并改善BBB功能，从而改善认知功能 和运动功能的变化使用非侵入性VNS（nVNS）治疗的最新临床试验 偏头痛和创伤后应激障碍已显示出有效。此外，nVNS还具有 在缺血性和出血性中风的临床前模型中显示出改善结果。我们的初步 在大鼠TBI模型中使用nVNS治疗的数据表明脑损伤体积减小， 焦虑，但需要进一步的调查，以更好地了解nVNS治疗的真正影响， 改善TBI的结果。 在这里，我们建议进行为期2年的研究，以确定五nVNS在TBI大鼠模型的影响。 我们的主要假设是nVNS治疗将减少脑损伤体积，从而改善认知功能。 功能性成果。此外，我们假设这种症状的减少反映了BBB的减少， 通过神经成像，组织学， 和生物化学研究。对于拟议的项目，我们打算在急性环境中提供nVNS治疗， 在第1天（受伤后1或6小时内）提供5次2x2-min（4分钟）刺激，间隔10分钟 onset）使用γ Core装置（electroCore Inc.，NJ）。gammaCore是一款手持设备（大小为 移动的电话）的非侵入性设备，具有良好的安全记录。值得注意的是，gammaCore 该设备已经被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 创伤性脑损伤因此，迫切需要安全有效的治疗方法来提高服务的生活质量 受创伤性脑损伤影响的成员和平民，并促进更好的恢复和重返社区 在他们受伤之后。这一建议通过提供必要的信息，对脑损伤领域具有重要意义。 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.