Connectivity between the BNST and insula during prolonged alcohol withdrawal inhumans

人类长期戒酒期间 BNST 和岛叶之间的连接

• 批准号: 10066255
• 负责人: Elizabeth Flook
• 金额: $ 3.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2023-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066255
• 关键词: Acute; Affect; Alcohol withdrawal syndrome; Alcoholism; Alcohols; American; Animal Model; Anterior; Anxiety; Attention; Brain; Brain region; Cocaine; Complex; Couples; Data; Diagnosis; Diffusion Magnetic Resonance Imaging; Drug Metabolic Detoxication; Emotional; Emotions; Excision; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Healthcare Systems; Homeostasis; Human; Insula of Reil; Intervention; Knowledge; Lead; Lesion; Literature; Mediating; Mental Depression; Mental Health; Morbidity - disease rate; Negative Reinforcements; Neurons; Patients; Pattern; Perception; Phenotype; Precipitating Factors; Predisposition; Prevention; Recovery; Relapse; Reporting; Research; Research Personnel; Rest; Rewards; Rodent; Role; Sampling; Smoking; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Symptoms; Testing; Time; Withdrawal; addiction; alcohol abuse therapy; alcohol use disorder; base; chronic alcohol ingestion; comorbidity; disability; drinking; effective therapy; high risk; image archival system; mortality; negative affect; neural circuit; neuroadaptation; neurobiological mechanism; neuroimaging; neuromechanism; prevent; relapse patients; relapse prediction; relapse risk; relating to nervous system; response; reward circuitry; sobriety; success; targeted treatment; tractography

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.

项目摘要 酒精使用障碍（AUD）影响超过1600万美国人，对那些人造成了重大负担 受影响的，医疗保健系统和经济。尽管有效治疗，大多数患者 复发，无法实现长期治疗成功。鉴于复发率很高，干预措施 这种旨在防止复发具有很高的潜在影响。动物模型和人类的研究表明 清醒的早期阶段的特征是超出症，焦虑和抑郁。这些症状是 被认为是由于响应慢性饮酒而发生的神经适应性变化而导致的，并且可以持续存在 在初始排毒成阶段后，被称为长时间戒断（PW）。在PW期间，复发通常是 由负强化驱动，在消除负面影响的情况下，饮酒得到加强。因此，PW是 高风险的恢复时期，因为它与高伴，焦虑和高 压力的敏感性。在啮齿类 焦虑和压力敏感性的至关重要的大脑区域，尤其是在长时间戒断期间。新的 长时间戒断的动物模型中的发现表明，对BNST的岛屿预测是 焦虑和抑郁表型通常在此戒断期间观察到。我们的初步数据显示 绝缘和BNST也与人类有关。绝缘是一个复杂的区域，具有异质性 结构，功能和连接。迄今为止的调查结果表明，前岛参与情感和 奖励虽然后岛涉及自主活动的感知。此外，前部和 后绝缘具有明显的神经循环。当前项目的目的是确定 在长时间退出期间，人类的BNST-insula连通性发生了变化。三个相互关联的目的是 提议实现这一目标。特定目标1将建立BNST-Insula结构的规范模式 连通性（扩散张量成像）和健康人的静止状态功能连通性。前 岛的后部分裂将用于确定BNST-insula连通性的更精确的模式。 具体目的2和3将比较30-180（PW）的AUD患者与健康对照（HC）。 特定的目标2将测试BNST-Insula结构和静止状态功能连接的变化 与HC相比，PW组。特定的目标3将研究基于任务的BNST-INSULA功能连接 与HC相比，在PW组的轻度压力任务中。假设是1）前绝缘 与BNST具有更强的结构和功能连接性，而不是后岛的2） 与HC相比，PW组的BNST-ter-per interial Insula连通性将更强。这项研究的结果 通过阐明PW中涉及的神经机制，将填补关键的知识差距 指导未来的预防和治疗AUD的目标。