Remediation of Impaired Self-Regulation in Patients with Mild TBI

轻度 TBI 患者自我调节受损的修复

• 批准号: 8989478
• 负责人: ANDREW S KAYSER
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989478
• 关键词: Address; Adjuvant Analgesic; Alcohol or Other Drugs use; Animals; Anxiety; Area; Attention; Behavior; Behavior Therapy; Behavioral; Behavioral Paradigm; Brain; Brain Mapping; Brain imaging; Brain region; Caring; Catechol O-Methyltransferase; Clinical; Cognition; Cognitive; Cognitive Therapy; Comorbidity; Counseling; Data; Decision Making; Development; Dopamine; Double-Blind Method; Emotional; Emotions; Equilibrium; Exclusion Criteria; FDA approved; Face; Failure; Functional Magnetic Resonance Imaging; Future; Goals; Habits; Home environment; Human; Impairment; Impulsivity; Informal Social Control; Measures; Mental Health; Motion; Neurocognitive; Patients; Pharmaceutical Preparations; Placebo Control; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Publishing; Quality of life; Randomized; Reporting; Severities; Stimulus; Substance abuse problem; Symptoms; Testing; Transcranial magnetic stimulation; Veterans; Work; associated symptom; behavioral impairment; clinically relevant; cognitive function; cognitive rehabilitation; daily functioning; discounting; distraction; dual diagnosis; emotion regulation; experience; financial decision making; frontal lobe; human subject; improved; inhibitor/antagonist; innovation; insight; mild traumatic brain injury; neuroimaging; neurophysiology; novel therapeutic intervention; novel therapeutics; potential biomarker; public health relevance; remediation; response; therapy development; tolcapone

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.

描述（由申请人提供）： 我们调节冲动的能力使我们能够为未来做计划，在面对分心时保持专注，并管理我们的情绪。自我调节失败是轻度创伤性脑损伤（mTBI）和并发症（包括药物滥用和PTSD）的重要组成部分。由于自我调节在我们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，注意力不集中，难以控制情绪。由于护理障碍，包括这些症状的严重程度，他们的家偏远，以及对披露他们的赤字程度的担忧，这些退伍军人中的许多人很难参与咨询和认知康复来解决这些问题。在这种情况下，有效的预防性药物，以提高自我调节是重要的，以加强这些退伍军人的能力，以管理他们的症状，并从事行为疗法。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无效。 本申请的目的是开发治疗自我调节受损的药物选择。为此，我们将使用功能性磁共振成像来识别相关的大脑网络，以及一种药物，托卡朋，我们的初步数据表明，它将改善大脑功能。具体来说，自我调节缺陷被认为是自上而下控制失败的结果，即高阶目标限制冲动、习惯和其他更多“刺激驱动”反应的能力。来自多个领域的趋同数据认为，大脑中自上而下的控制反映在前额叶皮层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确需求，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志物，并指出了开发治疗方法的策略。正如我们在研究中所详述的那样，我们的工作和其他报告都表明，托卡朋可能通过增加额叶皮层中多巴胺的含量来提高前额叶皮层影响其他大脑区域的能力。因此，我们建议直接测试的假设，即自我调节缺陷的退伍军人与mTBI的结果减少自上而下的控制，并管理托卡朋将提高自我调节。我们将在一项随机、双盲、安慰剂对照的翻译功能性MRI研究中采用三项临床相关任务，分别解决行为、认知和情绪自我调节问题：一个平衡短期和长期目标的财务决策任务，一个要求受试者注意一些物体而不注意其他物体的注意力任务，以及一个处理情绪-认知交互的情绪调节任务。 通过测试易处理的假设，这些研究解决了认知康复和心理治疗领域进展的关键障碍。通过使用脑成像来评估托卡朋对与相关任务相关的脑活动的影响，我们可以深入了解可以指导治疗发展的作用机制，无论是药理学还是其他方面。因此，这项提案代表了一种创新的，务实的方法来解决一个问题-mTBI后的自我调节困难-这是普遍的，治疗不足，退伍军人迫切需要新的疗法。