Remediation of Impaired Self-Regulation in Patients with Mild TBI

描述(由申请人提供)： 我们控制冲动的能力使我们能够计划未来，在分心的情况下保持我们的注意力，并管理我们的情绪。自我调节的失败是轻度创伤性脑损伤(MTBI)以及包括药物滥用和创伤后应激障碍在内的共生疾病的重要组成部分。由于自我调节在日常生活中的重要性，损伤对患有mTBI的退伍军人的生活产生了深远的影响，他们抱怨决策能力差，注意力分散，情绪难以控制。由于护理障碍，包括这些症状的严重性，他们的家偏远，以及对披露他们的缺陷程度的担忧，这些退伍军人中的许多人很难参加咨询和认知康复来解决这些问题。在这种情况下，有效的辅助药物来改善自我调节对于加强这些退伍军人控制症状和从事行为治疗的能力是重要的。不幸的是，很少有药物对mTBI患者的认知问题有效，目前的药物对许多症状和许多退伍军人都不有效。该应用程序的目的是开发用于治疗自我调节受损的辅助药物选择。为此，我们将使用功能磁共振来识别相关的大脑网络，以及我们的初步数据表明将改善大脑功能的药物托卡彭。具体地说，自律缺陷被认为是由于自上而下控制的失败--即更高层次的目标限制冲动、习惯和其他更“受刺激驱动”的反应的能力。来自多个领域的汇聚数据表明，大脑中自上而下的控制反映在前额叶皮质影响其他大脑区域活动的能力上。鉴于对自我调节障碍的新治疗方法的明显需要，这种从大脑到行为的映射确定了自我调节失败的潜在生物标记物，并指向开发治疗的战略。正如我们在研究中详细描述的那样，我们的工作和其他报告都表明，托卡彭可能通过增加额叶皮质中的多巴胺含量来改善前额叶皮质影响其他脑区的能力。因此，我们建议直接测试以下假设，即患有mTBI的退伍军人的自我调节缺陷是自上而下控制减弱的结果，并且托卡彭的应用将改善自我调节。我们将在一项随机、双盲、安慰剂控制的翻译功能磁共振研究中使用三项与临床相关的任务，分别解决行为、认知和情绪自我调节：平衡短期和长期目标的财务决策任务，要求受试者关注某些对象而不是其他对象的注意力任务，以及解决情绪-认知交互作用的情绪调节任务。通过测试易于处理的假设，这些研究解决了认知康复和心理治疗领域取得进展的关键障碍。通过使用脑成像来评估Tolcapone对与相关任务相关的脑活动的影响，我们获得了可以指导药物治疗或其他治疗发展的作用机制。因此，这项建议代表了一种创新、务实的方法来解决一个问题-mTBI后的自我调节困难-这个问题很普遍，没有得到充分的治疗，退伍军人迫切需要新的治疗方法。

DESCRIPTION (provided by applicant): Our ability to regulate our impulses enables us to plan for the future, to maintain our focus in th face of distractions, and to manage our emotions. Failures of self-regulation are an important component of mild traumatic brain injury (mTBI) and co-occurring disorders, including substance abuse and PTSD. Because of the importance of self-regulation in our daily lives, impairments have profound effects on the lives of Veterans with mTBI, who complain of poor decision making, diminished concentration, and difficult-to-control emotions. Due to barriers to care including the severity of these symptoms, the remoteness of their homes, and concerns about disclosing the extent of their deficits, many of these Veterans are poorly able to participate in counseling and cognitive rehabilitation to address these issues. In such circumstances, effective adjunctive medications to improve self-regulation are important to reinforce the ability of these Veterans to manage their symptoms and to engage in behavioral therapies. Unfortunately, very few medications are effective for cognitive issues in patients with mTBI, and current agents are not effective for many symptoms and for many Veterans. The purpose of this application is to develop adjunctive medication options for the treatment of impaired self-regulation. To this end, we will use functional MRI to identify relevant brain networks, and a medication, tolcapone, that our preliminary data suggests will improve brain function. Specifically, self-regulatory deficits ae thought to emerge from failures of top- down control - i.e. the ability of higher-order goals to constrain impulses, habits, and other more "stimulus-driven" responses. Convergent data from multiple fields argue that top-down control in the brain is reflected in the ability of prefrontal cortex to influence activity in other brain regions. Given the clear need for new therapeutic approaches to self-regulatory impairments, this mapping from brain to behavior identifies a potential biomarker for self-regulatory failure, and points toward a strategy for developing treatments. As we detail in our study, both our work and other reports suggest that tolcapone may improve the ability of prefrontal cortex to influence other brain areas by increasing the amount of dopamine in the frontal cortex. Thus, we propose to directly test the hypotheses that self-regulatory deficits in Veterans with mTBI result from diminished top-down control, and that administration of tolcapone will improve self-regulation. We will employ three clinically-relevant tasks within a randomized, double-blind, placebo- controlled translational functional MRI study to address behavioral, cognitive, and emotional self-regulation, respectively: a financial decision-making task that balances short-term and long-term goals, an attentional task that requires subjects to pay attention to some objects but not to others, and an emotion regulation task that addresses emotion-cognition interactions. By testing tractable hypotheses, these studies address a critical barrier to progress in the fields of cognitive rehabilitation and psychotherapy. By using brain imaging to evaluate the influence of tolcapone on brain activity related to relevant tasks, we gain insights into mechanism of action that can guide the development of treatments, whether pharmacological or otherwise. This proposal thus represents an innovative, pragmatic approach to a problem - self-regulatory difficulty after mTBI - that is widespread, under-treated, and for which Veterans desperately want new therapies.