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研究最广泛的酒精依赖内在表型之一。然而，对酒精敏感性相关的大脑机制知之甚少。人类酒精敏感性表型的研究往往依赖于自我报告的措施和传统的口服酒精管理模式，这两种可能会引入相当大的测量误差，从而降低检测遗传和神经相关的灵敏度。拟议的研究将在酒精挑战范式的背景下，结合高度控制的静脉乙醇输注检查酒精敏感性的神经标志物。该提案的主要目的包括：a）开发我们整合功能磁共振成像和输液的方法; B）在此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，为未来的研究提供信息。大量饮酒的年轻人将参加两个输液会议：基线“适应”会议和功能磁共振成像会议。基于生理学的药代动力学（PBPK）建模将用于在15分钟内建立0.06 ± 0.005g %的峰值目标血液酒精浓度（BAC）。将该BAC保持（夹紧）90分钟。酒精敏感性指数将包括传统的自我报告指标;输注期间的心率反应;以及整个疗程中主观中毒（刺激/镇静）的系列指标。我们将研究这些指标与BOLD反应在任务中，从事激励动机和认知控制网络，结合在BAC时间过程中的重复评估。传统的和基于大脑的酒精敏感性测量将被检查与自我报告的饮酒有关。通过在急性酒精暴露的背景下检查神经表型，我们希望确定基于大脑的酒精敏感性表型，与传统措施相比，这些表型对遗传变异和行为结果可能更敏感。) 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，对酒精敏感性相关的大脑机制知之甚少。这项研究的目的是检查基于大脑的酒精敏感性的测量，这些测量可以作为酒精依赖风险的生物标志物。

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.