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意识受损的状态(原文如此)，因为很少或根本没有改善功能的治疗方法。我们的长期目标是开发安全地诱导和调节神经活动的治疗方法，从而改善遭受严重脑外伤患者的功能，而这款R21通过迈出开发稳健和安全治疗的第一步来满足这一需求。R21研究的目的是检验重复经颅磁刺激(RTMS)联合金刚烷胺(TMS金刚烷胺)相对于rTMS和金刚烷胺对慢性SIC患者的安全性和有效性。假说是，提供rTMS金刚烷胺将提供一种安全而又协同的效应，诱导或加速功能恢复。这一假说基于(A)初步数据显示部分神经行为功能改善与rTMS诱导的神经活动和连接以及改善白色纤维束的完整性有关，(B)多巴胺(DA)与常见的脑损伤之间的关系，(C)DA在调节意识中的作用，(D)DA和rTMS靶向通路的共性，(E)金刚烷胺的临床疗效和安全性，(F)金刚烷胺的作用机制，以及(G)rTMS和金刚烷胺与上调脑源性神经营养因子之间的关系。其基本原理是，将rTMS与金刚烷胺配对将对促进意识行为的因素具有互补和协同作用。这项R21研究有可能为研究人群提供新的治疗方法，并推动脑外伤神经康复领域的发展。其具体目的是：(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；(3)表征治疗前后神经功能的变化。AIM 1是基于我们的初步安全数据和有关金刚烷胺的安全数据。为了解决目标2和目标3，我们使用重复测量基线对照设计，随机处理顺序产生三个处理组：rTMS金刚烷胺、rTMS单独和单独金刚烷胺。AIMS 2和AIMS 3的分析包括根据神经行为生长轨迹、大脑区域内和脑区之间的平均神经激活量和连接量以及纤维束方向性指数来比较这些治疗组。这些发现将促进人们对rTMS金刚烷胺如何安全地实现神经行为收益的了解。研究结果将被用来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。这个项目是创新的，因为rTMS单独作为一种治疗重型脑外伤的神经治疗是新颖的，因为一种药物与rTMS的组合从未被作为潜在的神经治疗进行检验。这项拟议的研究具有重要意义，因为它有望扩大对金刚烷胺如何增加rTMS效应以及这如何与功能相关的理解。这些贡献将导致为复杂的患者群体开发治疗选择，对这些患者来说，治疗选择很少或根本没有。

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.