Disrupted development of neural connections by alcohol initiation in adolescence

描述（由申请人提供）：本申请是针对PA-09-097酒精、决策和青少年大脑发育（NIAAA）重新提交的R 01提案。该项目利用了从2004年开始参加纵向大脑发育研究的青少年的现有纵向样本。参与者年龄在9到23岁之间，接受了广泛的结构神经成像方案，包括T1加权和弥散加权扫描，还完成了全面的行为测试电池和一组自我报告问卷。大多数参与者在研究入组时没有酒精和药物使用。参与者在基线招募后两年内完成一次随访评估，使用与基线相似的数据收集方法。[自审查本提案以来，对大约一半的样本完成了第三轮评估]。在这里，资金要求进行两个额外的纵向评估的全部样本（n=170），其中许多人已经从没有酒精使用过渡到显着使用随着时间的推移。迄今为止，在许多额叶介导的功能中发现了与年龄相关的改善，包括计划、延迟折扣、抑制性控制和积极决策。这些功能与整个大脑的白色物质完整性有关，特别是在连接额叶和纹状体脑区的神经束内。初步研究结果表明，开始使用酒精和/或随着时间的推移增加使用酒精的个体显示出白色发育减少的迹象，特别是在涉及高级关联过程以及抑制性认知和行为控制的皮质区域（上级顶叶，前颞叶，前额叶）之间提供连接的纤维通路方面。此外，酒精使用的纵向影响包括减少神经纤维的数量，这些神经纤维连接参与介导激励-奖励激活的关键皮层下结构，丘脑核，以及参与对奖励线索的行为反应提供下行抑制控制的关键皮层区域，内侧眶额皮层。[时间3部分数据收集的初步发现包括与记忆过程直接相关的大脑区域（海马回，颞极皮层）的白色物质完整性降低，这与时间2到时间3的酒精使用量增加有关。]额外的纵向评估将允许一个更复杂的建模，使用线性混合模型，青少年饮酒开始对正在进行的神经连接发展的影响，同时并行分析行为和大脑发育之间的关联，以及饮酒开始如何影响他们。在拟议的研究中，研究人员将能够通过结构MRI，电生理学，静息状态fMRI和广泛的行为任务来评估大脑连接。因此，这项申请符合NIAAA的资助目标，因为酒精对大脑发育影响的科学探究将得到推进。

DESCRIPTION (provided by applicant): This application is a resubmitted R01 proposal in response to PA-09-097 Alcohol, Decision- Making, and Adolescent Brain Development (NIAAA). The project capitalizes upon an existing longitudinal sample of adolescents who were enrolled starting in 2004 in a longitudinal brain development study. Participants, ages 9 to 23, underwent an extensive structural neuroimaging protocol that included T1-weighted and diffusion-weighted scans, and also completed a comprehensive behavioral testing battery and a set of self- report questionnaires. Most participants were free of alcohol and drug use at study enrollment. Participants completed one follow-up assessment, two years after the baseline enrollment, using similar data collection methods as at baseline. [A third assessment wave was completed on approximately half the sample since this proposal was reviewed]. Here, funds are requested to conduct two additional longitudinal assessments of the full sample (n=170), many of whom have transitioned from no alcohol use to significant use over time. To date, found age-related improvements were found in numerous frontal lobe-mediated functions, including planning, delay discounting, inhibitory control, and motivated decision making. These functions are associated with white matter integrity throughout the brain, but particularly within tracts that connect the frontal lobe with striatal brain regions. Preliminary findings indicate that individuals who initiated alcohol use, and/or increased their use over time, showed signs of reduced white matter development, specifically with respect to fiber pathways that provide connectivity among cortical regions (superior parietal, anterior temporal, prefrontal) involved in high-level associative processes as well as inhibitory cognitive and behavioral control. Additionally, longitudinal effects of alcohol use include reduced volume of neural fibers connecting the key subcortical structure involved in mediating incentive-reward activation, the nucleus accumbens, with the key cortical region involved in providing descending inhibitory control over behavioral responses to reward cues, the medial orbitofrontal cortex. [Preliminary findings from the partial Time 3 data collection include reductions in white matter integrity of brain regions directly involved in memory processes (hippocampal gyrus, temporal polar cortex) in association with escalating alcohol use from Time 2 to Time 3.] Additional longitudinal assessment will permit a more sophisticated modeling, using linear mixed models, of the effects of adolescent alcohol initiation on ongoing neural connectivity development, together with parallel analyses on associations between behavioral and brain development and how alcohol initiation impacts them. Within the proposed study, the investigators will be able to assess brain connectivity via structural MRI, electrophysiology, resting state fMRI, and a broad range of behavioral tasks. Thus, this application meets NIAAA funding objectives, because the scientific inquiry into the question of alcohol's effects on the developing brain will be advanced.