Two structural neuroimaging studies in adults with Major Psychoses and Alcohol Dependence

Sex differences in the neuroanatomical correlates of Alcohol Dependence: findings from the ENIGMA Addiction Working group BACKGROUND: Male and female alcohol users show different patterns of alcohol use (e.g., age of onset, dosage) and related disorders which are likely to be influenced by neurobiological factors. However, the role of sex in the neuroanatomical correlates of alcohol dependence remains poorly examined and results are often contradictory. Discrepancies between studies may be partially due to methodological issues (i.e., small samples size and a male sampling bias) as well as to the lack of a statistically valid approach to analyse and model the effect of sex. AIMS: 1) To measure group and group-by-sex differences in the neuroanatomy of alcohol-dependent participants (AD) and HC and explore the role of the severity of use, in a large and well-characterised sample. We focused on regions of interest (ROIs) mostly found impaired in AD including, orbitofrontal cortex (OFC), hippocampus, amygdala, nucleus accumbens, caudate, putamen, globus pallidus, thalamus, corpus callosum, cerebellum as well as global brain volumes (i.e., Grey Matter (GM), White Matter (WM), cerebrospinal fluid (CSF)). In line with previous studies, we hypothesized that all ROIs considered as well as total GM and WM may be smaller in AD versus HC and would be accompanied by CSF increases. Moreover, we expected to find group-by-sex effects in OFC, hippocampus, corpus callosum and global brain volumes. METHODS: We pooled behavioural and MRI data from 10 research sites of the ENIGMA Addiction Working Group. In total, 326 HC (99 females) and 683 AD (329 females) were included in the analysis. First, ROIs were extracted using standard pipelines from Freesurfer v 5.3. Second, mixed-effect models were run to test the impact of the following variables on the ROIs (i) group, sex, and group-by-sex; (ii) monthly standard drinks (all p≤ .05, False Discovery Rate (FDR) corrected). All models were adjusted for major confounders including, assessment site, age, education and intracranial volume (ICV). RESULTS: AD versus HC showed smaller GM volumes of the hippocampus, putamen, globus pallidus, thalamus, corpus callosum and cerebellum, accompanied by whole brain GM and WM shrinkage. Group-by-sex interactions were observed in the amygdala, (i.e., males AD < males HC) and cerebellar GM (i.e., females AD < females HC). Within the group of male AD, smaller amygdala volumes were predicted by greater alcohol use (all p < .05, FDR corrected). CONCLUSION: In a large and well-characterised sample we confirmed that alcohol dependence is associated with neuroanatomical alterations mostly distributed in mesocorticolimbic and cerebellar circuitry which play a critical role in memory, impulse control, emotions regulation and salience attribution. These processes are commonly found altered in addiction. Furthermore, we observed, for the first time, group-by-sex interactions in the amygdala (male AD < male HC) and the cerebellum (more reduced in female AD < female HC), corroborating the hypothesis that sex plays a role in the effect of alcohol dependence on brain structures. While the exact mechanism underlying sex differences in the brain morphology of AD is unknown, both preclinical and clinical studies suggest the influence of gonadal and stress hormones that modulate alcohol’s psychoactive effects via affecting brain receptors in a sex-specific manner. Longitudinal designs and comprehensive standardised assessments of alcohol dependence and relevant psychosocial outcomes will be necessary to shed some light on the mechanisms underlying sex differences in trajectories in and out of alcohol dependence related psychosocial / treatment outcomes.