Disrupted development of neural connections by alcohol initiation in adolescence

描述(由申请人提供)：此申请是针对PA-09-097酒精、决策和青少年大脑发育(NIAAA)重新提交的R01提案。该项目利用了2004年开始的一项纵向大脑发育研究中的青少年现有纵向样本。参与者年龄在9岁到23岁之间，他们接受了广泛的结构神经成像方案，包括T1加权和扩散加权扫描，还完成了全面的行为测试组合和一套自我报告问卷。在研究登记时，大多数参与者都没有饮酒和吸毒。参与者在基线登记两年后使用与基线时类似的数据收集方法完成了一次后续评估。[自审查这项提案以来，对大约一半的样本完成了第三次评估浪潮]。在这里，需要资金对整个样本(n=170)进行另外两次纵向评估，其中许多已经随着时间的推移从不饮酒过渡到大量使用。到目前为止，在许多额叶调节的功能中发现了与年龄相关的改善，包括计划、延迟折扣、抑制控制和动机决策。这些功能与整个大脑中白质的完整性有关，尤其是在连接额叶和纹状体脑区的区域。初步研究结果表明，开始饮酒和/或随着时间的推移而增加饮酒的个体，表现出白质发育减少的迹象，特别是在提供参与高水平联想过程以及抑制性认知和行为控制的皮质区域(顶上、颞前、前额)之间连接的纤维通路方面。此外，酒精使用的纵向影响包括神经纤维的体积减少，这些神经纤维连接着参与调节激励-奖励激活的关键皮质下结构伏隔核，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质区域，内侧眼眶额叶皮质。[时间3的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、颞极皮质)的白质完整性降低，与从时间2到时间3酒精使用的增加有关。]额外的纵向评估将允许使用线性混合模型对青少年酒精开始对正在进行的神经连接发展的影响进行更复杂的建模，并对行为和大脑发育之间的联系以及酒精开始对它们的影响进行平行分析。在这项拟议的研究中，研究人员将能够通过结构磁共振、电生理学、静息状态功能磁共振和广泛的行为任务来评估大脑的连通性。因此，这项申请符合NIAAA的资助目标，因为酒精对发育中的大脑的影响问题的科学调查将得到推进。

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.