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）幸存者将无法恢复有意识的行为。幸存者将继续生活在严重意识受损（SIC）的状态中，因为几乎没有改善功能的治疗方法。我们的长期目标是开发安全诱导和调节神经活动的治疗方法，从而改善严重TBI患者的功能，而R21解决了这一需求，迈出了开发稳健和安全治疗方法的第一步。R21的研究目的是检查重复性经颅磁刺激（rTMS）联合金刚烷胺（TMS +金刚烷胺）相对于单独rTMS和单独金刚烷胺对慢性SIC状态患者的安全性和有效性。假设提供rTMS+金刚烷胺将提供一种安全的协同效应，诱导或加速功能恢复。这一假设是基于(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通性以及白色纤维束完整性的机制相关，(b)多巴胺（DA）与常见TBI损伤之间的关系，(c) DA在介导意识中的作用，(d) DA与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，(g) rTMS和金刚烷胺与上调脑源性神经营养因子的关系。其基本原理是将rTMS与金刚烷胺配对将对促进有意识行为的因素产生互补和协同作用。这项R21研究有可能为研究人群提供新的治疗方法，并推动TBI神经康复领域的发展。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)表征治疗前和治疗后的神经变化。Aim 1是基于我们关于金刚烷胺的初步安全数据和安全数据。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，rTMS单独和金刚烷胺单独。目标2和目标3的分析包括根据神经行为生长轨迹、大脑区域内和区域之间的平均神经激活量和连通性以及纤维束方向性指数来比较这些治疗组。研究结果将促进对rTMS +金刚烷胺如何安全地使神经行为获益的认识。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。这个项目是创新的，因为rTMS单独作为严重TBI的神经治疗是新颖的，因为药物与rTMS的联合从未作为潜在的神经治疗进行过研究。这项提议的研究意义重大，因为它有望扩大对金刚烷胺如何增加rTMS效应以及这与功能的关系的理解。这些贡献将导致开发治疗方案的复杂的病人群体很少或没有治疗方案存在。

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.