Altered functional diversity in alcohol use disorder: an edge-centric marker linked to neurochemical and transcriptional signatures.

BACKGROUND: Alcohol Use Disorder (AUD) is increasingly understood as a disorder of connectomic dysregulation. However, node-centric models fail to capture the brain's overlapping functional architecture. We employed an edge-centric framework to quantify functional diversity from overlapping communities and investigated its neurobiological basis in AUD.

METHODS: We analyzed resting-state fMRI data from 93 individuals with AUD and 91 matched healthy controls. We quantified nodal functional diversity using normalized entropy derived from overlapping edge communities. In this context, high diversity (entropy approaching 1) reflects flexible, multi-network engagement, while low diversity (entropy approaching 0) reflects functional specialization. A Partial Least Squares Discriminant Analysis (PLS-DA) identified the whole-brain functional diversity pattern maximizing group separation. This pattern was then correlated with normative neurotransmitter receptor and gene expression data.

RESULTS: A PLS component significantly separated the groups (p < 0.001). This pattern was defined by decreased functional diversity in the nucleus accumbens and globus pallidus, and increased functional generalization in the insula and inferior frontal gyrus. This AUD-related pattern was negatively predicted by D1 and NMDA receptor distributions and positively by the 5-HTT transporter. Spatially, this pattern correlated with genes enriched for "synapse structure" and "cellular responses to stress".

CONCLUSION: Our edge-centric approach identified a bidirectional reorganization of functional diversity in AUD. This pattern, reflecting a specialized striatum and generalized insula, is spatially anchored to core dopaminergic/glutamatergic receptor maps and genetic pathways for synaptic plasticity and cellular stress, highlighting functional diversity as a novel, multilevel biomarker for AUD.