Problematic alcohol use and hippocampal volume in a female sample: Disentangling cause from consequence using a co-twin control study design

Background: Although there is extensive evidence that problematic alcohol use is associated with smaller hippocampal volume, the typical cross-sectional study design cannot determine whether hippocampal deviations reflect pre-existing liability toward problematic alcohol use or instead reflect an alcohol exposure-related effect. We used the co-twin control study design, which capitalizes upon differences within a twin pair in levels of drinking, to differentiate pre-existing liability from an effect of alcohol exposure. Methods: The sample included 100 female twins, prospectively assessed from ages 11 to 24. Problematic alcohol use was assessed dimensionally and included indicators of quantity, frequency, and density of alcohol use and intoxication. Hippocampal volume was assessed using magnetic resonance imaging. Results: Problematic alcohol use (proximal and cumulative) was associated with significantly smaller left and right hippocampal volume. Follow-up co-twin control analyses that partitioned individual-level alcohol effects into pre-existing, familial liability and non-shared alcohol exposure-related effects indicated that this association reflected alcohol exposure. Greater alcohol using twins had smaller hippocampal volume relative to lesser alcohol using co-twins, beyond effects of their shared genetic and environmental liability toward problematic alcohol use. Results held accounting for recent alcohol use, other substance use, externalizing and internalizing psychopathology, personality traits, trauma exposure, and menstrual phase. Conclusions: The association between problematic alcohol use and smaller hippocampal volume likely reflects an alcohol exposure-related effect. Differentiating pre-existing brain deviations that confer risk for problematic alcohol use from those that reflect effects of alcohol on the brain will inform etiological models of addiction and further prevention and intervention efforts.