NEUROCOGNITIVE CONSEQUENCES OF UNDERAGE DRINKING

描述（由申请人提供）：拟议研究的总体目标是在控制预先存在的遗传和环境背景因素的情况下，研究青少年酒精暴露对额叶脑功能的影响。我们假设前额叶介导的执行和认知控制功能特别容易受到酒精的影响，因为它们在青春期持续发展。动物研究表明，青少年接触酒精会对大脑和行为产生持久的影响，然而，人体研究非常少，而且在很大程度上仅限于病例对照设计，排除了酒精使用后果和饮酒前存在的脆弱性因素之间的区别。拟议的研究将通过实施双胎对照设计来解决这一基本限制，该设计基于对青春期酒精暴露的双胞胎的比较。研究的具体目的是：1)检查青少年酒精暴露与神经认知功能之间的关联，并确定这些关联在多大程度上取决于开始使用酒精的年龄、暴露程度和最近使用酒精的情况；2)使用双胎对照方法将酒精暴露的后果与先前存在的缺陷分离开来；3)研究生物相关遗传多态性在个体对酒精暴露对神经认知功能有害影响的易感性中的作用（基因暴露相互作用）。这些目标将通过一项跨学科的研究来实现，该研究整合了认知神经科学、双胞控制和药物遗传学方法，并使用假设驱动的依赖性措施选择，这些措施在以前的研究中与前额叶皮层的特定区域相关联，并挖掘执行功能的特定方面，包括动作监测、反应抑制、奖惩处理、决策制定和执行注意力。研究样本将包括280名年龄在18-22岁之间的双胞胎，他们有不同程度的酒精暴露。样本将从申请人和共同调查人员正在进行的流行病学双胞胎研究中抽取，并根据已有的酒精和烟草使用史数据选择双胞胎。拟议的研究应该增加我们对未成年人饮酒对与成瘾脆弱性相关的神经和认知过程的长期影响的理解。酒精使用，包括酗酒，在青少年和青少年中仍然很普遍。动物和人类研究表明，青春期饮酒会干扰正常的大脑发育，影响以后的认知功能和行为。然而，酒精对神经机制的影响仍然知之甚少，神经机制是人类高级认知功能的基础，如自我控制和决策。通过解决这一重要问题，这项研究将增加我们对未成年人饮酒的长期认知和行为后果及其神经生物学基础的理解。研究中获得的知识可用于制定针对未成年人饮酒的更好的预防和干预策略。

DESCRIPTION (provided by applicant): The overall goal of the proposed study is to examine the consequences of adolescent alcohol exposure on frontal brain function, while controlling for pre-existing genetic and environmental background factors. We hypothesize that prefrontally mediated executive and cognitive control functions can be particularly vulnerable to alcohol effects due to their continuing development during adolescence. Animal studies suggest that adolescent exposure to alcohol can produce long-lasting impact on the brain and behavior, however, human studies are very scarce and have been largely limited to a case-control design that precludes the discrimination between the consequences of alcohol use and pre-existing vulnerability factors predating the onset of drinking. The proposed study will address this fundamental limitation by implementing a co-twin control design based on the comparison of twins concordant or discordant for alcohol exposure during adolescence. Specific aims of the study are: 1) to examine associations between adolescent alcohol exposure and neurocognitive functioning and to determine the extent to which these associations depend on the age of onset of alcohol use, the extent of exposure, and recency of alcohol use, 2) to isolate consequences of alcohol exposure from pre-existing deficits using the co-twin control approach, and 3) to examine the role of biologically relevant genetic polymorphisms in individual susceptibility to deleterious effects of alcohol exposure on neurocognitive functioning (gene by exposure interaction). These aims will be achieved through an interdisciplinary study integrating cognitive neuroscience, co-twin control, and pharmacogenetic approaches and using a hypothesis-driven selection of dependent measures that have been linked to specific regions of the prefrontal cortex in previous studies and tap into specific aspects of executive functioning including action monitoring, response inhibition, reward and punishment processing, decision making, and executive attention. The study sample will include 280 twins (age 18-22) with varying degree of alcohol exposure. The sample will be drawn from ongoing epidemiological twin studies of the applicant and co-investigators, with selection of twin pairs based on already available data on the history of alcohol and tobacco use. The proposed study should increase our understanding of long-term consequences of underage drinking for neural and cognitive processes relevant to addiction vulnerability. Alcohol use, including heavy drinking episodes, continues to be common among adolescents and. Animal and human research suggests that alcohol exposure during adolescence can interfere with normal brain development and affect cognitive function and behavior later in life. However, little is still known about the effects of alcohol on neural mechanisms that underlie higher cognitive functions such as self-control and decision making in humans. By addressing this important issue, this study will increase our understanding of long-term cognitive and behavioral consequences of underage drinking and their neurobiological basis. The knowledge gained in the study can be used for the development of better prevention and intervention strategies aimed at underage drinking.