Connectivity between the BNST and insula during prolonged alcohol withdrawal inhumans

项目摘要 酒精使用障碍(AUD)影响着1600多万美国人，给这些人带来了沉重的负担 受影响的是医疗保健系统和经济。尽管治疗有效，但大多数患者 复发，无法取得长期治疗成功。鉴于复发率很高，干预措施 旨在防止复发的措施具有很高的潜在影响。对动物模型和人类的研究表明 清醒的早期阶段以过度觉醒、焦虑和抑郁为特征。这些症状是 被认为是神经适应性变化的结果，这种变化发生在对长期饮酒的反应中，并可以持续 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 由负面强化驱动，饮酒是通过消除负面影响来强化的。因此，PW是一种 高风险的恢复期，因为它将消极强化与过度觉醒、焦虑和高 对压力的敏感性。在啮齿动物中，终纹床核(BNST)被认为是一种 焦虑和压力敏感的关键大脑区域，特别是在长时间戒断的情况下。新的 在一种长期戒断的动物模型中的发现表明，脑岛向BNST的投射是 焦虑和抑郁的表型通常在戒断期间观察到。我们的初步数据显示 在人类中，脑岛和BNST也是相连的。半岛是一个复杂的地区，有着异质的 结构、功能和连通性。到目前为止的研究结果表明，前脑岛参与了情绪和 奖赏，而后脑岛参与自主活动的感知。此外，前面和前面的 岛后有明显的神经环路。当前项目的目标是确定 在人类长期戒断的过程中，BNST-岛的连通性会发生变化。三个相互关联的目标是 提出要实现这一目标。具体目标1将建立BNST-Island结构的规范模式 健康人的连通性(扩散张量成像)和静息状态的功能连通性。一个前部 而岛叶的后部分割将被用来确定更精确的BNST-半岛连接模式。 特殊目标2和3将比较禁欲(PW)30-180岁的AUD患者和健康对照组(HC)。 特定目标2将测试BNST-半岛结构和静息状态功能连通性的变化 PW组与HC组比较。具体目标3将调查BNST-AILAY基于任务的功能连接 在与HC相比，PW组在压力较小的任务中。假设是1)前岛 将与BNST有更强的结构和功能连接，而不是后岛2) 与HC组相比，PW组BNST-前岛连接性更强。这项研究的结果 将通过阐明PW中涉及的神经机制来填补关键的知识空白，这可以用来 指导未来AUDS的预防和治疗目标。

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 region, with a heterogeneous structure, function, and connectivity. 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.