Connectivity between the BNST and insula during prolonged alcohol withdrawal inhumans

项目摘要 酒精使用障碍（AUD）影响了超过1600万美国人，给他们造成了巨大的负担。 受影响的，医疗保健系统和经济。尽管治疗有效，但大多数患者 复发，无法实现长期治疗成功。鉴于复发率高，干预措施 旨在防止复发具有很大潜在影响。对动物模型和人类的研究表明， 清醒的早期表现为过度兴奋焦虑和抑郁这些症状 这被认为是由于长期饮酒引起的神经适应性变化， 在最初的戒毒后进入一个被称为长期戒断（PW）的阶段。在PW期间，复发通常是 由负强化驱动，即通过消除负面影响来强化饮酒。因此，PW是一个 高风险的恢复期，因为它结合了负强化与过度觉醒，焦虑和高 对压力的敏感性在啮齿类动物中，终纹床核（BNST）已被确定为一个神经元。 这是大脑中对焦虑和压力敏感的关键区域，特别是在长时间戒断期间。新 在长期戒断的动物模型中的发现表明，BNST的神经元投射是BNST的基础， 焦虑和抑郁表型通常在该停药期观察到。我们的初步数据显示 在人类中，BNST和BNST也有联系。中亚是一个复杂的、异质的地区。 迄今为止的研究结果表明，前额叶与情绪和奖励有关，而后额叶与情绪和奖励有关。 参与自主活动的感知。此外，前和后脊具有不同的 神经回路当前项目的目标是确定BNST-BNS连接的程度， 在人类中发生了改变为实现这一目标，提出了三个相互关联的目标。 具体目标1将建立BNST-BNT结构连接性（扩散张量）的规范模式 成像）和静息状态功能连接。前、后两部分 BNST将用于识别BNST-BNST连接的更精确模式。具体目标2和3将 将30-180戒断（PW）的AUD患者与健康对照（HC）进行比较。具体目标2将测试 与HC相比，PW组中BNST-STAT结构和静息态功能连接的改变。 具体目标3将调查在轻度压力任务中BNST-ESTA基于任务的功能连接， PW组与HC组相比。这些假设是：1）前牙槽骨将具有更强的结构和 与BNST的功能连接比后桥和2）BNST-前桥连接 与HC相比，PW组的强度更高。这项研究的结果将填补一个关键的知识空白， 阐明涉及PW的神经机制，可用于指导未来的预防目标 治疗AUD。所要求的补助金将减轻儿童保育费用上涨对儿童的影响， 实习生津贴儿童保育允许申请人全职工作，以实现本项目的目标。

Project Summary Alcohol use disorder (AUD) affects more than 16 million Americans, causing a substantial burden on those affected, the health care system, and the economy. Despite effective treatments, the majority of patients relapse and are unable to achieve long-term treatment success. Given the high rates of relapse, interventions that aim to prevent relapse have high potential impact. Research in both animal models and humans shows that early stages of sobriety are characterized by hyperarousal, anxiety, and depression. These symptoms are thought to result from the neuroadaptive changes that occur in response to chronic alcohol use and can persist after the initial detoxification into a stage known as prolonged withdrawal (PW). During PW, relapse is often driven by negative reinforcement, where drinking is reinforced by the removal of negative affect. Thus, PW is a high-risk period of recovery because it couples negative reinforcement with hyperarousal, anxiety, and high susceptibility to stress. In rodents, the bed nucleus of the stria terminalis (BNST) has been identified as a crucial brain region for both anxiety and stress-sensitivity, especially during prolonged withdrawal. New findings in an animal model of prolonged withdrawal suggest that insula projections to the BNST underlie the anxiety and depression phenotype typically observed during this withdrawal period. Our preliminary data show that the insula and BNST are also connected in humans. The insula is a complex, heterogeneous region. Findings to date show that the anterior insula is involved in emotion and reward while the posterior insula is involved in the perception of autonomic activity. Further, the anterior and posterior insula have distinct neurocircuits. The goal of the current project is to determine the extent to which BNST-insula connectivity is altered in humans during prolonged withdrawal. Three inter-related aims are proposed to achieve this goal. Specific Aim 1 will establish the normative pattern of BNST-insula structural connectivity (diffusion tensor imaging) and resting-state functional connectivity in healthy humans. An anterior and posterior division of the insula will be used to identify more precise patterns of BNST-insula connectivity. Specific Aims 2 and 3 will compare patients with AUD who are 30-180 abstinent (PW) to healthy controls (HC). Specific Aim 2 will test for alterations in BNST-insula structural and resting-state functional connectivity in the PW group compared to HC. Specific Aim 3 will investigate BNST-insula task-based functional connectivity during a mildly stressful task in the PW group compared to HC. The hypotheses are 1) that the anterior insula will have stronger structural and functional connectivity with the BNST than the posterior insula and 2) that BNST-anterior insula connectivity will be stronger in the PW group compared to HC. The results of this study will fill a critical knowledge gap, by elucidating the neural mechanisms involved in PW, which can be used to guide future targets for prevention and treatment of AUDs. The requested supplement will alleviate the impact of the rising cost of childcare on the trainee stipend. Childcare permits the applicant to work full-time towards achieving the aims of this project.