This R21 application, in response to RFA-AA-07-006, proposes to initiate a project to determine the effects of alcohol exposure on the developing brain during adolescence. The study examines brain areas that are actively developing during adolescence, involved in psychological regulation, response to rewards, thought to be vulnerable to dysmaturation by alcohol exposure, and evaluate with contemporary neuroimaging techniques. An accelerated longitudinal design will be utilized. A representative community sample will be identified, recruited and screened, and a stratified sample of 160 adolescents ages 12 through 15 years old will be selected. Subject stratification will be based on age, gender and race. A substantial proportion of the sample will be recruited prior to the initiation of alcohol use, and our prior longitudinal study using similar methods indicates that the sample will show sufficient variability in alcohol use trajectories for the study aims to be fulfilled. The neurodevelopmental evaluation will focus on structures and circuits subserving psychological regulation and responses to rewards, including the prefrontal cortex, amygdala, hippocampus and ventral striatum, as well as associated white mater. The project will specifically examine the organization of white matter areas serving the frontal cortex by diffusion tensor imaging (DTI), prefrontal and amygdalar activation by functional magnetic resonance imaging (fMRI) during tasks involving emotional responses to affectively-laden faces, regional activation to a task requiring inhibition of pre-potent oculomotor responses in an anti-saccade task, and responses to systematically varied reward contingencies. Psychological dysregulation constructs measured will include behavioral undercontrol, negative emotionality, and executive cognitive functioning. We hypothesize that neurodevelopmental maturation indicators will be systematically and significantly correlated to behavioral indicators of psychological dysregulation and parental alcohol use disorders. Anticipating the utilization of these data in a larger study, we predict that the maturation of these neural structures and circuits will be adversely affected by adolescent alcohol exposure. The study will also consider environmental and genetic factors. In addition to demographic characteristics, environmental influences considered will include parent involvement, traumatic experiences, and neighborhood context. The project will collect DNA for studies of genetic polymorphisms associated with neurobiological endophenotypes and alcohol involvement trajectories. The R21 data collection will provide sufficient data to determine relationships among neurodevelopmental maturation in early adolescence, psychological dysregulaiton and AUD risk. In addition to providing the initial cohorts for a definitive study on the effects of alcohol exposure on adolescent brain development, the R21 project will facilitate the refinement of recruitment procedures and will collect data needed for statistical power calculations and sample size estimates. ? ? Project Narrative: This R21 project will initiate a study to determine the effects of alcohol exposure on adolescent brain development. The study will involve a representative sample of 160 adolescents in an accelerated longitudinal design examining ages 12 through 18 years. Neural circuits known to be involved in psychological regulation and reward responses are hypothesized to be particularly vulnerable to alcohol effects and will be assessed with innovative neuroimaging methods. ? ? ?
