Supplementation with Amino Acid Rehabilitative Therapy in TBI (SmART-TBI): A Randomized Placebo-Controlled Trial to Improve Sleep

过去，轻度创伤性脑损伤（mTBI）影响了60%以上的OEF/OIF退伍军人 十年来，超过20%的退伍军人被诊断为脑震荡后综合征。可以说是最 脑震荡后的致残症状是睡眠-觉醒和认知障碍。睡眠，认知功能， 相关症状通常在mTBI后>10-15年保持受损。这些症状不仅 他们自己非常难以相处，但睡眠和认知不良也会干扰持续的 这些措施包括采取康复干预措施，防止重返平民生活和重返有酬就业。最 mTBI后睡眠-觉醒和认知功能障碍的现有疗法仅仅是症状性的， 还具有低功效和/或患者可接受性。因此，迫切需要确定机制- 基于mTBI后睡眠和认知问题的干预措施，以促进最佳康复 功能性成果。 我们的长期目标是实施脑生物活性药物干预，以解决睡眠和 mTBI患者的认知障碍。此应用程序的总体目标，代表了我们的 实现这一目标的第一步是测试一种非常有前途的治疗方法的可行性和有限的疗效， 在膳食补充剂中，支链氨基酸（BCAA;即，亮氨酸、异亮氨酸和缬氨酸），以治疗 mTBI患者的睡眠障碍有令人信服的科学先例和安全数据支持 BCAA治疗mTBI退伍军人的测试。我们的临床前数据表明， BCAA的作用，作为兴奋性神经递质谷氨酸的前体，恢复平衡， mTBI中睡眠和认知功能障碍的脑回路内的兴奋到抑制。23 -26 这些数据，我们还精心绘制了最佳剂量，持续时间和给药途径， 此外，我们现在有一项双盲、安慰剂对照研究的初步数据显示， 饮食BCAA补充剂，而不是安慰剂，显着改善退伍军人自我报告的睡眠。 其他研究小组已经在多种条件下在人类中使用膳食BCAA补充剂， 剂量高达60克/天，持续时间长达12个月，几乎没有副作用。 我们的中心假设是，BCAA膳食补充剂将改善退伍军人的睡眠质量， mTBI。作为检验这一假设的第一步，我们提出了一个长期的可行性，可接受性， BCAA对睡眠影响的有限有效性研究，将采用随机、安慰剂对照和双盲试验， 瞎了患有mTBI的退伍军人将被随机分配接受BCAA，剂量为20、40或60克/天，口服 (PO)或安慰剂（每组n=50）治疗12周。可行性、可接受性和有限的有效性结局 基于睡眠（例如，自我报告、连续体动记录和夜间多导睡眠记录）。 我们希望这些结果将为未来的最佳研究方法和设计提供信息， 大规模随机对照试验，包括确定BCAA的适当剂量和持续时间， 改善睡眠和潜在的mTBI退伍军人亚群，可能受到不同的影响， 支链氨基酸。我们还打算利用这项工作来产生关于支链氨基酸对认知和整体影响的假设。 生活质量的措施，为今后的研究提供信息。

Mild traumatic brain injury (mTBI) has impacted over 60% of all OEF/OIF Veterans over the past decade, and over 20% of these Veterans carry a diagnosis of postconcussion syndrome. Arguably the most disabling postconcussion symptoms are sleep-wake and cognitive disturbances. Sleep, cognitive function, and related symptoms often remain impaired >10-15 years following mTBI. Not only are these symptoms themselves exceedingly difficult to live with, but poor sleep and cognition also interfere with ongoing rehabilitation interventions, and prevent reintegration into civilian life and return to gainful employment. Most existing therapies for sleep-wake and cognitive dysfunction following mTBI are merely symptomatic, and they also suffer from low efficacy and/or patient acceptability. Thus, there is an urgent need to identify mechanism- based interventions for sleep and cognitive problems following mTBI, in order to facilitate optimal rehabilitation and functional outcomes. Our long-term goal is to implement a brain-bioactive pharmacological intervention to address sleep and cognitive disturbance in individuals with mTBI. The overall objective of this application, which represents our first step towards this goal, is to test the feasibility and limited efficacy of a highly promising therapy consisting of a dietary supplement, branched chain amino acids (BCAA; i.e., leucine, isoleucine, and valine), to treat sleep disturbances in individuals with mTBI. There is compelling scientific precedent and safety data to support the testing of BCAA therapy in Veterans with mTBI. Our preclinical data has shown that the mechanism of action for BCAA, acting as a precursor to the excitatory neurotransmitter glutamate, restores the balance of excitation to inhibition within the dysfunctional brain circuits for both sleep and cognition in mTBI.23-26 With these data, we have also meticulously mapped the optimal dosing, duration, and route of administration in mice.27 Further, we now have pilot data from a double-blinded, placebo-controlled study showing that 3 weeks of dietary BCAA supplementation, but not placebo, significantly improved self-reported sleep in Veterans. Other research groups have used dietary BCAA supplementation in humans across multiple conditions at doses up to 60 grams/day and durations up to 12 months with few to no side effects.32-49 Our central hypothesis is that BCAA dietary supplementation will improve sleep quality in Veterans with mTBI. As a first step towards testing this hypothesis, we propose a long-term feasibility, acceptability, and limited efficacy study of BCAA's effects on sleep that will be randomized, placebo-controlled, and double- blinded. Veterans with mTBI will be randomly assigned to receive BCAA at 20, 40 or 60 grams/day per oral (PO) or a placebo (n=50 per group) for 12 weeks. Feasibility, acceptability, and limited efficacy outcomes based on sleep (e.g., self-report, continuous actigraphy, and overnight polysomnography) will be assessed. We expect that these results will inform the optimal study methodology and design for a future, full- scale randomized controlled trial, including the identification of the proper dose and duration of BCAA to improve sleep and the potential subpopulations of Veterans with mTBI that may be differentially affected by BCAA. We also intend to use this work to generate hypotheses on the effect of BCAA on cognition and overall quality of life measures to inform future research.