White Matter Integrity and Alcohol Use Disorders

描述（由申请人提供）：了解酒精使用障碍（AUD）的神经基础需要整合神经生理学，行为和心理学概念。AUD的神经科学模型表明，自上而下的皮层控制网络与皮层下的动机和奖励网络之间存在不平衡，导致洞察力受损和强迫性药物寻求行为（Koob和Koob，2010）。白色物质束形成了神经元之间能够进行通信的连接结构，是这种概念化的关键要素。白色物质损伤是AUD的标志性损伤，在死后和体内研究中都发现了大量的体积损失（Kril和Halliday，1999; Monnig等人，under review-c; Oscar-Berman and Marinkovic，2007; Sullivan，2000）.扩散张量成像（DTI）是磁共振成像（MRI）的一种应用，可量化白色物质的完整性，产生比简单的体积测量更丰富的信息。一些DTI研究已经发现患有AUD的个体的奖励和自我调节网络异常（Harris等人，2008; Monnig等人，在综述中-a; Monnig等人，正在审查中-b; Pfefferbaum等人，2009; Yeh等人，2009年）。这些发现可能是特别有问题的，因为心理社会干预的AUD通常依赖于自我反思，努力的信息处理，并重新评估奖励虽然以前的调查提供了明确的证据，白色物质异常的AUD，其原因和相关性仍然不清楚。申请人最近对AUD中的白色物质体积的荟萃分析表明，在寻求治疗和已经禁欲较短时间的那些人中萎缩更大，因此将AUD严重程度和最近的饮酒行为与白色物质损伤相关（Monnig等人，正在审查-c）。当前项目的目标是在261名重度饮酒者的代表性样本中测试和扩展这些发现。这些人的酒精摄入量、饮酒的健康后果以及他们对AUD心理结构的认同程度（例如，饮酒失控）。这个样本的神经影像学和行为学数据存在于一个现存的数据集中，我通过与主要发起人肯特E.哈奇森 拟议的项目将使用结构方程模型来确定酗酒者白色物质损害的关键心理，行为和生物标志物。接下来，将使用分层线性模型来检验慢性饮酒与白色物质异常之间的关系的中介、适度和适度中介。最后，将评价白色物质异常和认知之间的关联，以确定白色物质损伤的功能后果。从临床评估中识别酒精相关脑损伤的标志物可以增强将发现转化为现实世界的干预措施。这个项目将增加对白色物质网络受损引起的认知缺陷如何破坏AUD认知行为治疗的有效性的理解。 公共卫生相关性：本研究将通过系统地测试酒精消费、AUD严重程度的心理结构以及酒精相关健康后果的生物标志物如何影响白色物质完整性，有助于对AUD的神经科学理解。其最终目的是阐明如何酒精相关的损害发生在白色物质网络的奖励和自我调节，以及如何这种损害可能会影响功能的结果。

DESCRIPTION (provided by applicant): Understanding the neural basis of alcohol use disorders (AUD) requires integration of neurophysiology, behavior, and psychological concepts. Neuroscientific models of AUD posit an imbalance between top-down cortical control networks and subcortical networks of motivation and reward, leading to impaired insight and compulsive drug-seeking behavior (Koob and Volkow, 2010). White matter tracts, which form the connective structure enabling communication among neurons, are a critical element in this conceptualization. White matter damage is a hallmark injury of AUD, with substantial volume loss found in both postmortem and in vivo studies (Kril and Halliday, 1999; Monnig et al., under review-c; Oscar-Berman and Marinkovic, 2007; Sullivan, 2000). Diffusion tensor imaging (DTI), an application of magnetic resonance imaging (MRI), quantifies integrity of white matter, yielding richer information than simple volumetric measures. Several DTI investigations have found abnormality in reward and self-regulation networks in individuals with AUD (Harris et al., 2008; Monnig et al., under review-a; Monnig et al., under review-b; Pfefferbaum et al., 2009; Yeh et al., 2009). These findings may be especially problematic because psychosocial interventions for AUD typically rely on self-reflection, effortful information processing, and reevaluation of reward Although previous investigations provide clear evidence of white matter abnormality in AUD, its causes and correlates remain obscure. The applicant's recent meta-analysis of white matter volume in AUD indicated that atrophy was greater in those who were seeking treatment and who had been abstinent for shorter periods of time, thus relating AUD severity and recent drinking behavior to white matter damage (Monnig et al., under review-c). The goal of the current project is to test and extend these findings in a representative sample of 261 heavy drinkers. These individuals range widely in their alcohol intake, health consequences of drinking, and extent to which they identify with psychological constructs of AUD (e.g., loss of control over drinking). Neuroimaging and behavioral data from this sample reside in an extant dataset to which I have access for this dissertation proposal through collaboration with the primary sponsor, Dr. Kent E. Hutchison. The proposed project will use structural equation modeling to identify key psychological, behavioral, and biological markers of white matter damage in heavy drinkers. Next, mediation, moderation, and moderated mediation of the relationship between chronic drinking and white matter abnormality will be tested with hierarchical linear modeling. Finally, associations between white matter abnormality and cognition will be evaluated to determine the functional consequences of white matter damage. Identifying markers of alcohol- related brain damage from clinical assessments enhances the translation of findings to real-world interventions. This project will add to understanding of how cognitive deficits arising from compromise of white matter networks may undermine the effectiveness of cognitive-behavioral treatment for AUD. PUBLIC HEALTH RELEVANCE: This study will contribute to neuroscientific understanding of AUD by systematically testing how alcohol consumption, psychological constructs of AUD severity, and biomarkers of alcohol-related health consequences impact white matter integrity. Its ultimate aim is to elucidate how alcohol-related damage occurs in white matter networks underlying reward and self-regulation and how this damage may affect functional outcomes.