Remediation of Impaired Self-Regulation in Patients with Mild TBI

轻度 TBI 患者自我调节受损的修复

基本信息

批准号：
8595764
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
项目类别：
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/8595764
关键词：
Address Adjuvant Analgesic Alcohol or Other Drugs use Animals Anxiety Area Attention Behavior Behavior Therapy Behavioral Behavioral Paradigm Biological Markers 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 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 public health relevance remediation response therapy development tolcapone

项目摘要

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计划，保持面对分心并管理情绪的关注。自我调节失败是轻度脑损伤（MTBI）和同时发生疾病的重要组成部分，包括药物滥用和PTSD。由于自我调节在我们的日常生活中的重要性，障碍对退伍军人的生活产生了深远的影响，他们抱怨决策不力，集中注意力减少和难以控制的情绪。由于护理的障碍，包括这些症状的严重程度，其房屋的偏远以及对披露其缺陷程度的担忧，这些退伍军人中的许多人都能够参与咨询和认知康复来解决这些问题。在这种情况下，改善自我调节的有效辅助药物对于增强这些退伍军人管理症状和进行行为疗法的能力很重要。不幸的是，在MTBI患者中，很少有药物对认知问题有效，而目前的药物对于许多症状和许多退伍军人都无效。本应用的目的是开发辅助药物选择来治疗受损的自我调节。为此，我们将使用功能性MRI来识别相关的大脑网络，并使用我们的初步数据表明可以改善大脑功能的药物Tolcapone。具体而言，自我调节性缺陷AE被认为是由于上下控制的失败而出现的 - 即高阶目标约束冲动，习惯和其他更多“刺激驱动”的反应的能力。来自多个领域的收敛数据认为，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的活动的能力中。鉴于明确需要对自我调节损伤进行新的治疗方法，因此从大脑到行为的映射可以确定一种潜在的自我调节失败的生物标志物，并指向开发治疗的策略。正如我们在研究中详细介绍的那样，我们的工作和其他报告都表明，托尔卡酮可以通过增加额叶皮层中多巴胺的量来提高前额叶皮层影响其他大脑区域的能力。因此，我们建议直接测试由自上而下控制减少导致的退伍军人的自我调节缺陷的假设，而托尔卡酮的给药将改善自我调节。我们将在一个随机，双盲，由安慰剂控制的翻译功能MRI研究中采用三个相关的任务，分别解决行为，认知和情感自我调节：一种财务决策任务，平衡短期和长期目标，这是一种注意力，需要对象注意某些对象，但要对其他对象进行注意，并以情感的方式进行情感范围，并不是要对其进行情感调节。通过检验可牵引假设，这些研究涉及认知康复和心理治疗领域进步的关键障碍。通过使用脑成像来评估Tolcapone对与相关任务相关的大脑活动的影响，我们可以洞悉可以指导治疗发展的作用机理，无论是药理还是其他。因此，该提案代表了一种创新的，务实的方法 - MTBI之后的自我调节难度 - 广泛，处理不足，并且退伍军人迫切希望新疗法。