Spatiotemporal Brain Imaging of Alcohol Effects on Inhibitory Control

描述(申请人提供)：行政职能容易受到酒精中毒的影响，因为它干扰了目标导向的行为，评估相互冲突的要求的能力， 抑制冲动反应，优化行为。这些损伤可能会导致自我约束能力下降，导致饮酒和依赖程度增加。酒精消费模式和依赖风险的特点是个体间的差异，因为环境与遗传易感性相互作用，如酗酒家族史。多巴胺能系统通过奖赏调节调节成瘾行为的形成和维持。然而，多巴胺能对自上而下的调节影响及其与酒精和冲动特征的相互作用的神经功能基础还知之甚少。这个项目的总体目标是使用多模式成像来检查在抑制控制和酒精挑战期间高危人群中基因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，调节与抑制性控制和酒精中毒相关的DA和GABA。在我们的初步研究中，所提出的范例招募了对感兴趣的基因类型敏感的前额叶回路。我们的多模式方法包括功能磁共振成像(FMRI)，它提供与冲突诱导任务相关的活动的空间地图，而出色的时间分辨率的脑磁图和脑成像(MEG/EEG)阐明了酒精相关异常的时间和振荡动力学。与我们的fMRI研究相结合，解剖受限的脑磁图方法表明，在冲突处理过程中，前扣带皮质(ACC)特别容易受到酒精影响。酒精减弱了估计为ACC的theta振荡。此外，酒精对ACC和外侧前额叶皮质(PFC)之间的振荡同步性的调节失调，这可能是抑制控制受损的基础。我们的初步数据表明，决策、反应抑制和错误处理的前额叶神经功能系统与中毒过程中COMT Val158Met的功能性多态存在不同的关联。考虑到这些相互作用的贡献，我们建议在有积极和消极酗酒家族史的个人中获得一套丰富的补充措施。在酒精挑战期间，将获得抑制控制和新奇加工的行为和多模式神经成像指标，并将作为与DA和GABA信号和性格特征相关的遗传标记的函数进行分析。信息的汇合将被单独和协同分析，并将提供多维的洞察，实时了解酒精诱导的抑制控制损害的基本机制，作为家族史和基因构成的函数，并对个性化预防策略和药物遗传学产生影响。

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.