Microstructural damage of white-matter tracts connecting large-scale networks is related to impaired executive profile in alcohol use disorder

Alcohol Use Disorders (AUD) is associated with negative consequences on global functioning, likely reflecting chronic changes in brain morphology and connectivity. Previous attempts to characterize cognitive impairment in AUD addressed patients’ performance in single domains, without considering their cognitive profile as a whole. While altered cognitive performance likely reflects abnormal white-matter microstructural properties, to date no study has directly addressed the relationship between a proxy of patients’ cognitive profile and microstructural damage. To fill this gap we aimed to characterize the microstructural damage pattern, and its relationship with cognitive profile, in treatment-seeking AUD patients. Twenty-two AUD patients and 18 healthy controls underwent a multimodal MRI protocol including diffusion tensor imaging (DTI), alongside a comprehensive neurocognitive assessment. We used a principal component analysis (PCA) to identify superordinate components maximally explaining variability in cognitive performance, and whole-brain voxelwise analyses to unveil the neural correlates of AUD patients’ cognitive impairment in terms of different white-matter microstructural features, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). PCA revealed a basic executive component, significantly impaired in AUD patients, associated with tasks tapping visuo-motor processing speed, attention and working-memory. Within a widespread pattern of white-matter damage in patients, we found diverse types of relationship linking WM microstructure and executive performance: (i) in the whole sample, we observed a linear relationship involving MD/RD metrics within both ‘superficial’ white-matter systems mediating connectivity within large-scale brain networks, and deeper systems modulating their reciprocal connections; (ii) in AUD patients vs. controls, a performance-by-group interaction highlighted a MD/AD pattern involving two frontal white-matter systems, including the genu of corpus callosum and cingulum bundle, mediating structural connectivity among central executive, salience and default mode networks. Alterations of prefrontal white-matter pathways are suggestive of abnormal structural connectivity in AUD, whereby a defective interplay among large-scale networks underpins patients’ executive dysfunction. These findings highlight different directions for future basic and translational research aiming to tailor novel rehabilitation strategies and assess their functional outcomes.