Brain Stimulation in Animal Models of Recovery from Acute Brain Injury

总结 创伤性脑损伤（TBI）是美国的一个主要公共卫生问题，占所有损伤相关疾病的30 死亡和7%的幸存者长期功能性残疾。目前，530万美国人生活在 TBI导致的永久性功能性残疾，估计终身护理费用为400万美元， 人.迫切需要新的有效的TBI治疗方法，特别是对于晚期或恢复期。 经颅直流电刺激（tDCS）已经成为一种有前景的治疗方法，并且已经 最近被研究作为TBI的临床干预。然而，由于缺乏控制动物， 研究中，有许多重要的问题需要解决，以确定tDCS在TBI中的效用， 并完善干预措施以优化长期结果。这些问题包括： 干预和刺激极性。tDCS是否刺激内源性 恢复和修复机制，在未来的研究中可以有针对性地进一步提高有效性， TBI幸存者中的tDCS。本提案中的工作将解决这些关键的未回答的问题， 为临床干预措施的评价和未来发展奠定基础。我们的中心假设是tDCS 在TBI后的恢复期应用可改善长期神经功能恢复， 内源性神经干细胞（NSC）向梗死周围区域的迁移增加， 脑血流量（CBF）。将使用TBI的小鼠控制的皮质撞击模型，并且重复tDCS 在TBI后一周和三周应用治疗。Specific Aim 1将使用一组先进的 神经行为测试，用于评估刺激参数和极性以及干预时间对 tDCS对神经系统结局的纵向改善。具体目标2将使用遗传标记方法 评估tDCS对内源性细胞迁移追踪和长期表型命运作图的影响， 神经干细胞及其后代。具体目标3将使用光学成像技术来评估 tDCS对局部和微血管脑循环的影响。总之，这些研究将提供一个有价值的基础， 为了更好地理解tDCS在恢复大脑中的作用，并为未来的临床改进 应用.

SUMMARY Traumatic brain injury (TBI) is a major public health problem in the U.S. which causes 30% of all injury related deaths and 7% long-term functional disabilities in survivors. Currently, 5.3 million Americans are living with permanent functional disabilities resulting from TBI with an estimated lifetime care cost of $4 million per person. New, effective treatments for TBI, especially for the late or recovery phase are urgently needed. Transcranial direct current stimulation (tDCS) has emerged as a promising therapeutic approach, and has recently been investigated as a clinical intervention for TBI. However, due to a lack of controlled animal studies, there are many important questions that need to be addressed to determine the utility of tDCS in TBI, and to refine the intervention to optimize long-term outcomes. These questions include the time windows for intervention and stimulus polarity for application. It is also unknown whether tDCS stimulates endogenous recovery and repair mechanisms that could in future studies be targeted to further enhance the effectiveness of tDCS in TBI survivors. The work in this proposal will address these key unanswered questions, to provide a basis for evaluation and future development of clinical interventions. Our central hypothesis is that tDCS applied in the recovery phase after TBI improves long-term neurologic recovery and is associated with increased migration of endogenous neuronal stem cells (NSC) to peri-infarct regions, and sustained increases in cerebral blood flow (CBF). A mouse controlled cortical impact model of TBI will be used, and repetitive tDCS treatment applied at one and three weeks after TBI. Specific Aim 1 will use a battery of advanced neurobehavioral tests for evaluation stimulus parameters and polarity and intervention time to the effects of tDCS on longitudinal improvement of neurological outcome. Specific Aim 2 will use a genetic labeling approach to assess the effects of tDCS on the migration tracking and long term phenotypic fate mapping of endogenous neural stem cells and their progeny. Specific Aim 3 will use optical imaging techniques to assess effects of tDCS on regional and microvascular cerebral circulation. Together, these studies will provide a valuable basis for improved understanding of the effects of tDCS in recovering brain, and for future refinement clinical applications.