Most studies of the impact of alcohol dependence on the brain have examined individuals in treatment. They may embody a bias, called """"""""Berkson?s fallacy"""""""", if the association between variables (e.g., alcoholism and brain atrophy or brain function) differ between the population of alcoholics in treatment and alcoholics in the general population. We hypothesize that treatment-naive alcoholics have less psychiatric comorbidity compared to treatment samples, and that this reduced psychiatric morbidity is associated with a lessened severity of impairments in brain structure and function. The major goals of the proposed research are to determine: 1) whether treatment-naive alcoholics differ in brain structure and function from alcoholics recruited from treatment centers, 2) whether treatment-naive alcoholics differ from alcoholics recruited from treatment centers in the presence and severity of comorbid mood and externalizing disorder symptoms and traits, 3) what factors are associated with impairments in brain structure and function in treatment-naive alcoholics and in alcoholics drawn from treatment centers (including presence and severity of comorbid mood, anxiety, and externalizing disorder symptoms and traits, presence of the APOE-4 allele, premorbid headsize as a measure of functional reserve (as indexed by intracranial vault volume on MRI), and the frequency (and severity) of withdrawal symptoms), 4) whether males and females differ in these comparisons, and 5) to follow the treatment-naive alcoholics for future longitudinal assessment of factors that predict the course of their alcoholism (especially the seeking of treatment, and changes in brain structure and function). We will study 380 subjects over five years: 220 treatment-naive alcohol-dependent subjects, 80 alcohol-dependent subjects in outpatient treatment, and 80 lifetime light/non-drinker controls. The treatment sample will be drawn from outpatient treatment centers. The treatment-naive sample will be recruited from the Marin County First Offender Drinking Driver (FODD) program. The light/non-drinker controls will be recruited from the community. Brain structure will be examined using MRI, and will include segmentation of the brain into its? component tissue classes, delineation of specific structures (e.g., the hippocampus, cerebellum, and corpus callosum), and transformation of the images into a standard coordinate system (to facilitate analysis of regional cortical volume differences). Functional assessment will include neuropsychological and behavioral testing and electrophysiological recordings, focusing on inhibitory/disinhibitory processes, executive functions, visuospatial abilities, gait and balance, and processing and memory of emotional stimuli.
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