Spatiotemporal Brain Imaging of Alcohol Effects on Inhibitory Control

描述（由申请人提供）：执行功能容易受到酒精中毒的影响，因为它会干扰目标导向的行为，评估冲突需求的能力， 抑制冲动反应，优化行为。这些损害可能导致自我克制能力下降，导致酗酒和依赖性增加。酒精消费模式和依赖风险的特点是个体间的变异性，因为环境与遗传易感性相互作用，如酗酒家族史。多巴胺能（DA）系统通过奖赏调节介导成瘾行为的发展和维持。然而，DA能影响自上而下的调节影响及其与酒精和冲动性状的相互作用的神经功能基础知之甚少。本项目的总体目标是使用多模态成像技术来研究在抑制控制和酒精挑战过程中处于危险中的人群中基因x环境相互作用的神经生物学基础。它的设计包括明确定义的功能多态性调节DA和GABA相关的抑制控制和酒精中毒。拟议的范例招募前额叶回路显示出敏感的基因型的兴趣，在我们的初步调查。 我们的多模态方法包括功能性磁共振成像（fMRI），提供空间地图的活动相关的冲突诱导任务，而出色的时间分辨率的磁和脑电图（MEG/EEG）阐明的时间和振荡动力学的酒精相关异常。与我们的功能磁共振成像研究，解剖学约束的MEG方法表明，前扣带皮层（ACC）是特别容易受到酒精的影响，在冲突处理。酒精会减弱ACC的theta振荡。此外，ACC和外侧前额叶皮质（PFC）之间的振荡同步性会因酒精而失调，这可能是抑制控制受损的基础。我们的初步数据表明，前额叶神经功能系统的决策，反应抑制和错误处理的差异与功能COMT Val 158 Met多态性在中毒。鉴于这些互动的贡献，我们建议获得一套丰富的补充措施，在个人与积极与消极的酗酒家族史。行为和多模态神经影像学措施的抑制控制和新奇的处理将在酒精的挑战，并将作为一个功能的遗传标记相关的DA和GABA信号和性格特征进行分析。信息的汇合将被单独分析，并在协同作用，并将提供多维的洞察基本机制，酒精诱导的障碍抑制控制在真实的时间作为一个功能的家族史和遗传组成，与个性化的预防策略和遗传药理学的影响。

DESCRIPTION (provided by applicant): Executive functions are vulnerable to alcohol intoxication as it interferes with goal-directed behavior, ability to evaluate conflicting demands, inhibit impulsive responses, and optimize behavior. These impairments may result in a decreased capacity to exert self-restraint, contributing to increased drinking and dependence. Patterns of alcohol consumption and the risk for dependence are characterized by inter individual variability as the environment interacts with genetic susceptibility such as family history of alcoholism. Dopaminergic (DA) system mediates development and maintenance of addictive behaviors via reward regulation. However, the neurofunctional basis of DA-ergic influence on the top-down regulatory influence and its interaction with alcohol and impulsivity traits is poorly understood. The overall goal of this project is to use the multimodal imaging to examine the neurobiological basis of gene x environment interactions in the population at risk during inhibitory control and alcohol challenge. Its design includes well-defined functional polymorphisms regulating DA and GABA that are relevant to inhibitory control and alcoholism. The proposed paradigms recruit prefrontal circuitry shown to be sensitive to genotypes of interest in our preliminary investigations. Our multimodal approach comprises functional magnetic resonance imaging (fMRI) that provides spatial maps of activity related to conflict-inducing tasks, whereas the excellent temporal resolution of magneto- and encephalography (MEG/EEG) elucidates the timing and the oscillatory dynamics of alcohol-related abnormalities. Converging with our fMRI studies, the anatomically-constrained MEG approach indicates that the anterior cingulate cortex (ACC) is especially vulnerable to alcohol effects during conflict processing. Alcohol attenuates theta oscillations estimated to the ACC. Furthermore, oscillatory synchrony between the ACC and lateral prefrontal cortex (PFC) is dysregulated by alcohol, possibly underlying impaired inhibitory control. Our preliminary data indicate that the prefrontal neurofunctional systems underlying decision making, response inhibition, and error processing are differentially associated with the functional COMT Val158Met polymorphism during intoxication. Given these interactive contributions, we propose to obtain a rich set of complementary measures in individuals with a positive vs. negative family history of alcoholism. Behavioral and multimodal neuroimaging measures of inhibitory control and novelty processing will be obtained during alcohol challenge and will be analyzed as a function of genetic markers relevant to DA and GABA signaling and dispositional traits. The confluence of information will be analyzed separately and in synergy and will provide multidimensional insight into the basic mechanisms underlying alcohol-induced impairment of inhibitory control in real time as a function of family history and genetic makeup, with implications for individualized prevention strategies and pharmacogenetics.