6. Abstract This application is in response to RFA AA-07-006 entitled, ?Impact of adolescent drinking on the developing brain (R21).? To address the Phase I goals of this RFA, we propose a two-year longitudinal study to directly investigate the effect of adolescent alcohol abuse on brain development. Although early childhood has long been identified as a period of cortical overproduction and pruning in response to environmental demands, recent research (Giedd, et al., 1999) has identified a second surge of gray matter growth beginning just prior to puberty and followed by volume reduction throughout adolescence. This overgrowth-pruning process is thought to be the mechanism by which neural circuits attune themselves to environmental demands, and in adolescence it is most pronounced in the frontal gray matter, an area crucial for executive control. Decision making, planning, and inhibition of inappropriate social behavior are all behavioral control functions associated with frontal lobe development as well as resistance to substance abuse. In short, the period during which adolescents are most attuned to environmental input to shape frontocortical connections and develop a complex biosocial behavioral repertoire also comprises the period during which young people are most at risk of initiating use of alcohol, a known neurotoxin. We propose to investigate the effects of alcohol on the brain during this unique stage of neurodevelopment, seeking to differentiate alcohol's effects from premorbid risk factors that predispose to alcohol abuse. Our participants will be adolescents from 12 to 16 years of age, recruited in three groups. We will recruit a control group of non-drinking, but high-risk participants (HR; N = 10) and a group of healthy, normal control participants (HC; N = 10) matched for age and gender. A third group will be adolescents entering treatment for chronic alcohol abuse (CAA N = 20). It is expected that as many as half of the subjects in the CAA group will relapse during the course of this study. In that case, we will have two self- selected subgroups, CAA who maintain abstinence (CAA-ab) and CAA who relapse (CAA-re). To study brain changes, we will analyze neuropsychological variables, structural neuroimaging [magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and morphometric assessment (MR)], and functional neuroimaging [electroencephalography (EEG) and magnetoencephalography (MEG)] with respect to alcohol use variables such as length and degree. All measures will be assessed at three time points (baseline, 1 month, and 6 months). This project will yield new knowledge of normal and alcohol-impaired adolescent neurodevelopment via multimodal assessment of healthy brain growth, brain growth under alcohol stress and recovery from that stress, and brain growth in those at high risk for drinking. This interdisciplinary project closely follows the guidelines set out in the 2005 NIH Roadmap. 7. Project Narrative The adverse effects of chronic and binge alcohol exposure on adult brain and behavioral function are relatively well understood, but much less is known about the consequences of alcohol exposure for brain development and functioning in adolescents. Brain structure, cognitive ability, and emotional functioning mature concurrently throughout adolescence. Strong associations of brain abnormality and neurocognitive impairment with adolescent drinking suggest that alcohol exposure may exert a uniquely detrimental influence during this period of dynamic development, but little is known about the possible long-term effects. This study addresses that gap in our knowledge. By serially neuroimaging brain structure and function in adolescents with alcohol use disorders and of adolescents with no diagnosis, we will be able to track brain changes over time and document resultant behavioral problems.
