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的神经科学模型假设自上而下的皮质控制网络和皮质下的动机和奖励网络之间的不平衡，导致自知力受损和强迫寻求药物的行为(Koob和Volkow，2010)。白质束是这一概念化的关键元素，它形成了使神经元之间进行交流的连接结构。白质损伤是AUD的一个标志性损伤，在尸检和活体研究中都发现了大量的体积损失(Kril和Halliday，1999；Monnig等人，正在审查-c；Oscar-Berman和Marinkovic，2007；Sullivan，2000)。弥散张量成像(DTI)是磁共振成像(MRI)的一种应用，它可以量化脑白质的完整性，比简单的体积测量产生更丰富的信息。几项DTI调查发现澳元失调症患者的奖励和自我调节网络异常(Harris等人，2008年；Monnig等人，审查中--a；Monnig等人，审查中-b；Pfefferbaum等人，2009年；Yeh等人，2009年)。这些发现可能尤其有问题，因为对AUD的心理社会干预通常依赖于自我反思、费力的信息处理和对奖励的重新评估尽管之前的调查提供了AUD脑白质异常的明确证据，但其原因和相关性仍不清楚。申请人最近对AUD白质体积的荟萃分析表明，寻求治疗和戒酒时间较短的人萎缩更严重，从而将AUD的严重程度和最近的饮酒行为与脑白质损害联系起来(Monnig等人，正在审查-c)。当前项目的目标是在261名酗酒者的代表性样本中测试和推广这些发现。这些人在酒精摄入量、饮酒的健康后果以及他们对AUD的心理结构的认同程度(例如，对饮酒的失控)方面差异很大。来自这个样本的神经成像和行为数据驻留在一个现有的数据集中，我可以通过与主要赞助人肯特·E·哈奇森博士的合作来访问这个论文提案。拟议的项目将使用结构方程模型来确定酗酒者脑白质损伤的关键心理、行为和生物标志。接下来，将使用分层线性模型检验长期饮酒与白质异常之间的关系的中介、适度和适度中介。最后，将评估脑白质异常与认知之间的联系，以确定脑白质损伤的功能后果。从临床评估中识别与酒精相关的脑损伤标记物有助于将研究结果转化为现实世界的干预措施。这个项目将有助于理解白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。 公共卫生相关性：这项研究将通过系统地测试酒精消费、AUD严重性的心理结构以及与酒精相关的健康后果的生物标记物如何影响白质完整性，有助于神经科学对AUD的理解。它的最终目的是阐明酒精相关的损害如何发生在奖励和自我调节的白质网络中，以及这种损害可能如何影响功能结果。

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.