Disrupted development of neural connections by alcohol initiation in adolescence

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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.