Amantadine + rTMS as a Neurotherapeutic for Disordered Consciousness after TBI

描述（由申请人提供）：三分之一的严重创伤性脑损伤（TBI）幸存者将无法恢复意识行为。幸存者将继续生活在严重的意识障碍（SIC）状态中，因为很少或没有改善功能的治疗。我们的长期目标是开发安全诱导和调节神经活性的治疗方法，从而改善严重TBI患者的功能，而R21通过向开发稳健和安全的治疗方法迈出第一步来满足这一需求。R21研究目的是检查重复经颅磁刺激（rTMS）联合金刚烷胺（TMS +金刚烷胺）相对于单独使用rTMS和单独使用金刚烷胺治疗SIC慢性状态患者的安全性和有效性。假设rTMS+金刚烷胺的提供将提供诱导或加速功能恢复的安全但协同作用。该假设基于（a）初步数据，表明部分改善的神经行为功能与rTMS诱导的神经活动和连接以及改善的白色纤维束的完整性在机制上相关，（B）多巴胺（DA）和常见TBI损伤之间的关系，（c）DA在介导意识中的作用，（d）DA和rTMS靶向通路之间的共性，（e）金刚烷胺的临床疗效和安全性，（f）金刚烷胺的作用机制，和（g）rTMS和金刚烷胺与上调脑源性神经营养因子之间的关联。其基本原理是，配对rTMS与金刚烷胺将有一个互补和协同作用的因素，促进有意识的行为。这项R21研究有可能为研究人群提供新的治疗方法，并推动TBI神经康复领域的发展。具体目标是：（1）证明rTMS+金刚烷胺是安全耐受的，（2）确定rTMS+金刚烷胺的神经行为效应，和（3）表征治疗前和治疗后神经系统的神经变化。目标1基于我们的初步安全性数据和金刚烷胺的安全性数据。为了解决目标2和3，我们使用重复测量基线对照设计，随机治疗顺序产生三个治疗组; rTMS +金刚烷胺，单独rTMS和单独金刚烷胺。目的2和3的分析涉及根据神经行为生长轨迹、脑区内和脑区之间的平均神经激活和连接量以及纤维束方向性指数比较这些治疗组。研究结果将进一步了解rTMS +金刚烷胺如何安全地实现神经行为增益。研究结果将用于选择和改进治疗方法，以便在未来的有效性试验中进行检查。该项目具有创新性，因为rTMS单独作为重度TBI的神经治疗剂是新颖的，并且因为药物与rTMS的组合从未被检查为潜在的神经治疗剂。拟议的研究意义重大，因为它有望扩大对金刚烷胺如何增加rTMS效应以及如何与功能相关的理解。这些贡献将导致为几乎没有治疗选择的复杂患者群体开发治疗选择。

DESCRIPTION (provided by applicant): One-third of severe traumatic brain injury (TBI) survivors will not recover conscious behavior. Survivors will continue to live in states of seriousy impaired consciousness (SIC) because there are few to no treatments that improve function. Our long-term goal is to develop treatments that safely induce and modulate neural ac- tivity resulting in improved function for persons incurring severe TBI and this R21 addresses this need by tak-ing the first step toward developing a robust and safe treatment. The R21 research objective is to examine the safety and efficacy of repetitive transcranal magnetic stimulation (rTMS) combined with Amantadine (TMS + Amantadine) relative to rTMS Alone and Amantadine Alone for persons in chronic states of SIC. The hypothesis is that provision of rTMS+Amantadine will provide a safe yet synergistic effect that induces or ac- celerates functional recovery. This hypothesis is based on (a) preliminary data indicating partially improved neurobehavioral functioning mechanistically related to rTMS-induced neural activity and connectivity as well as improved integrity of white fiber tracts, (b) relationship between dopamine (DA) and common TBI impairments, (c) role of DA in mediating consciousness, (d) the commonality between and DA and rTMS-targeted pathways, (e) clinical efficacy and safety of Amantadine, (f) mechanisms of action of Amantadine, and (g) the association between rTMS and Amantadine with up-regulating brain derived neurotrophic factor . The rationale is that pairing rTMS with Amantadine will have a complementary and synergistic effect on factors promoting conscious behavior. This R21 research has the potential to provide new treatments for the study population and to advance the field of TBI neurorehabilitation. The specific aims are to: (1) Demonstrate that rTMS+Amantadine is safely tolerated, (2) Determine neurobehavioral effect of rTMS+Amantadine, and (3) Characterize pre-and post-treatment neural changes in neural. Aim 1 is based on our preliminary safety data and safety data regarding Amantadine. To address Aims 2 & 3 we use a repeated measures baseline control design with randomized treatment orders yielding three treatment groups; rTMS + Amantadine, rTMS Alone and Amantadine Alone. Analyses for Aims 2 and 3 involve comparing these treatment groups according to neurobehavioral growth trajectories, mean amount of neural activation and connectivity within and between brain regions, and indices of fiber tract directionality. Findings will advance knowledge about how rTMS + Amantadine safely enable neurobehavioral gains. Findings will be used to select and refine treatments to be examined in a future effectiveness trial. This project is innovative because rTMS alone as a neurotherapeutic for severe TBI is novel and because the combination of a drug with rTMS has never been examined as a po- tential neurotherapeutic. The proposed research is significant because it is expected to expand understanding of how Amantadine adds to the rTMS effect and how this relates to functioning. These contributions will lead to developing treatment options for a complex patient population for whom few to no treatment options exist.