Sensitivity to Intravenous Ethanol: Neuroimaging and Behavioral Phenotypes

描述(由申请人提供)：酒精敏感性的个体差异是酒精依赖的最广泛研究的内在表型之一。然而，对与酒精敏感相关的大脑机制知之甚少。对人类酒精敏感性表型的研究往往依赖于自我报告的测量方法和传统的口服酒精给药范例，这两者都可能引入相当大的测量误差，从而降低了检测遗传和神经相关性的敏感性。这项拟议的研究将在酒精挑战范例的背景下检查酒精敏感性的神经标记物，该范例结合了高度受控的静脉注射乙醇。这项建议的主要目标包括a)开发我们的方法来整合功能磁共振成像和输液；b)检查在这一背景下研究酒精敏感性的神经相关性的可行性；以及c)估计效应大小，以便为未来的研究提供能量分析。大量饮酒的年轻人将参加两个输液会议：基线“适应”会议和功能磁共振会议。基于生理的药代动力学模型将在15分钟内建立0.06 1 0.005 g%的峰值目标血酒精浓度。该BAC将保持(夹持)90分钟。酒精敏感性指数将包括传统的自我报告测量；输液期间的心率反应；以及整个疗程中主观醉酒(刺激/镇静)的一系列测量。我们将考察这些指标与任务中大胆反应的关系，这些任务涉及激励动机和认知控制网络，纳入了BAC时间进程中的重复评估。传统的和基于大脑的酒精敏感度测量都将与自我报告的饮酒有关。通过研究急性酒精暴露背景下的神经表型，我们希望确定与传统测量方法相比，可能对遗传变异和行为结果更敏感的基于大脑的酒精敏感性表型。) 公共卫生相关性：对酒精的生理敏感性被证明可以预测未来的酒精依赖风险。然而，对与酒精敏感相关的大脑机制知之甚少。这项研究旨在检验基于大脑的酒精敏感性测量，这些测量可以作为酒精依赖风险的生物标记物。

DESCRIPTION (provided by applicant): Individual variability in alcohol sensitivity is among the most widely studied endophenotypes for alcohol dependence. However, little is known about brain mechanisms relevant for alcohol sensitivity. Research on human alcohol sensitivity phenotypes has often relied on self-report measures and conventional oral alcohol administration paradigms, both of which may introduce considerable measurement error, thus decreasing sensitivity for detecting genetic and neural correlates. The proposed study will examine neural markers of alcohol sensitivity in the context of an alcohol challenge paradigm that incorporates highly controlled intravenous ethanol infusion. The broad aims of this proposal include a) developing our approach for integrating fMRI and infusion; b) examining feasibility of studying neural correlates of alcohol sensitivity in this context; and c) estimating effect sizes to inform power analyses for future studies. Heavy-drinking young adults will participate in two infusion sessions: a baseline "acclimation" session and an fMRI session. Physiologically- Based Pharmacokinetic (PBPK) modeling will be used to establish a peak target blood alcohol concentration (BAC) of 0.06 1 0.005 g% within 15 minutes. This BAC will be maintained (clamped) for 90 minutes. Alcohol sensitivity indices will include traditional self-report measures; heart rate response during infusion; and serial measures of subjective intoxication (stimulation/sedation) across the session. We will examine these indicators in relation to BOLD responses during tasks that engage incentive motivation and cognitive control networks, incorporating repeated assessments across the BAC time course. Both traditional and brain-based measures of alcohol sensitivity will be examined in relation to self-reported drinking. By examining neural phenotypes in the context of acute alcohol exposure, we hope to identify brain-based alcohol sensitivity phenotypes that are potentially more sensitive to genetic variation and to behavioral outcomes as compared to traditional measures. ) PUBLIC HEALTH RELEVANCE: Physiological sensitivity to alcohol is demonstrated to predict future risk for alcohol dependence. However, little is known about brain mechanisms relevant for alcohol sensitivity. This research aims to examine brain-based measures of alcohol sensitivity that could be useful as biomarkers for the risk for alcohol dependence.