NEUROPHYSIOLOGY IN CHILDREN AT HIGH RISK FOR ALCOHOLISM

描述（由申请人提供）：酗酒者的一些电生理学特征[例如，事件相关电位（ERP）的低P3振幅]已经通过其高风险（HR）后代表现出来，并且被认为是发展酒精使用障碍（AUD）的倾向的生物标志物。最近开发的时间-频率方法揭示事件相关振荡（ERO）的基础ERPs，并提供了一个窗口到神经网络功能，表明额叶功能障碍的酗酒者和HR.P3振幅已被发现与酗酒者的冲动水平，和个人的冲动表现减少激活额区。HR个体的电生理和功能成像研究强烈暗示额叶功能受损和额顶叶回路的脆弱性。拟议的项目计划通过实施神经生理学，神经心理学和神经影像学方法评估反应激活/抑制的范例，进一步评估酗酒者的年轻成年HR后代的去抑制和额叶功能障碍。新的时间频率的方法最近在我们的实验室和那些正在开发中允许调查潜在的神经振荡和它们的同步在几个频带（δ，θ，α，β和γ）在早期和晚期处理的认知任务。据推测，HR将利用类似的网络进行认知处理的不同方面，而不是专门的网络来优化性能，并且他们的神经网络可能无法有效同步。这可能是由于神经组装的无效交联，以及树突缺失、中间神经元架构或远程通讯受损的结构基础，正如记录白色物质病理学的研究所表明的那样，从而影响了整个大脑区域的前馈和反馈机制。为了补充电生理学研究，将使用相同的Go/NoGo和赌博任务进行结构/功能（fMRI）成像，以了解（额叶）回路并定位与反应抑制，错误/结果评估和奖励处理相关的网络损伤。为了补充酗酒者和HR的静息EEG相干性发现，将实施弥散张量成像（DTI）以检查髓鞘形成与相干性的差异。高级回归和分类方法将用于研究电生理指标、结构/功能指标、冲动性之间的关系，以确定在预测风险或保护方面最重要的指标，并确定或多或少可能发生AUD和相关疾病的亚组。电生理表型不仅提供了生物脆弱性标志物，以确定那些在风险中，但也提供了一些致病的病理生理过程中涉及的发展AUD相关的疾病的见解。来自多个领域的研究结果将对参与风险的认知，行为和神经责任以及从风险饮酒到依赖的过渡具有重要意义，并在治疗和预防方案中具有实用性。

DESCRIPTION (provided by applicant): Some electrophysiological characteristics of alcoholics [e.g., low P3 amplitude of the Event-Related Potential (ERP)] are already manifested by their high risk (HR) offspring and are considered to be biological markers of a predisposition to develop alcohol use disorders (AUDs). Recently developed time-frequency methods reveal event-related oscillations (EROs) that underlie ERPs, and provide a window into neuronal network functioning, suggesting frontal lobe dysfunction in alcoholics and HR. P3 amplitude has been found to be related to level of impulsivity in alcoholics, and individuals with increased impulsivity manifest reduced activation in frontal areas. Electrophysiological and functional imaging studies of HR individuals strongly implicate impaired frontal lobe functioning and vulnerability in fronto-parietal circuits. The proposed project plans to further evaluate disinhibition and frontal lobe dysfunction in young adult HR offspring of alcoholics by implementing paradigms that assess response activation/inhibition with neurophysiological, neuropsychological and neuroimaging methods. Novel time-frequency methods recently developed in our laboratory and those under development allow the investigation of underlying neural oscillations and their synchrony in several frequency bands (delta, theta, alpha, beta, and gamma) during early and late processing of cognitive tasks. It is hypothesized that HR will utilize similar networks for different aspects of cognitive processing, instead of specialized networks to optimize performance, and that their neural networks may not synchronize effectively. This may be due to ineffective cross-linking of neural assemblies, with structural bases in dendritic loss, impairment in interneuron architecture or long-range communication, as indicated by studies documenting white matter pathologies, thus affecting feedforward and feedback mechanisms across brain regions. To complement electrophysiological studies, structural/functional (fMRI) imaging using the same Go/NoGo and gambling tasks will be implemented to understand the (frontal) circuits and localize network impairments that are associated with response inhibition, error/outcome evaluation and reward processing. To supplement resting EEG coherence findings in alcoholics and HR, Diffusion Tensor Imaging (DTI) will be implemented to examine differences in myelination with respect to coherence. Advanced regression and classification methods will be used to investigate the relationships between electrophysiological measures, structural/functional indices, impulsivity, to identify those that are most important in predicting risk or protection, and to identify subgroups more or less likely to develop AUDs and related disorders. Electrophysiological phenotypes not only provide biological vulnerability markers to identify those at risk, but also provide insight into some causative pathophysiological processes involved in the development of AUD related disorders. Findings from multiple domains will have important implications for cognitive, behavioral and neural liabilities involved in risk and the transition from risk drinking to dependence, with utility in treatment and prevention protocols.