Structural connectome architecture and biological vulnerability shape cortical atrophy in cocaine use disorder

Background: Cocaine use disorder (CUD) is highly prevalent and characterized by widespread gray matter atrophy across the cerebral cortex. Yet, it remains unclear whether and how connectome-based circuits and biological features shape these structural abnormalities. Methods: We mapped cortical atrophy patterns in CUD (discovery cohort: N = 53; replication cohort: N = 74; controls: N = 364) onto the brain’s structural connectome, functional connectivity, transcriptomic similarity and receptor similarity architecture. Using a multimodal and multiscale connectivity-based framework, we identified CUD epicenters and evaluated their spatial correspondence with therapeutic brain stimulation targets and individual variations in clinical symptoms. Results: We found that CUD-related regional atrophy is constrained by the white matter (WM) structural connectome. Along these WM pathways, regions that share similar haemodynamic activity and molecular features are more likely to exhibit convergent atrophy profiles. By integrating the structural connectome with multiple connectivity blueprints, we subsequently identified CUD epicenters and revealed that the prefrontal and visual cortices serve as core systems. Furthermore, we linked these epicenters to cortical transcriptomic patterns and receptor architectures, identifying synaptic and neural homeostasis-related gene enrichment and the strongest spatial correspondence with serotonergic (5-HT_1B/5-HT₄) and dopaminergic (D₂) receptors. Finally, we demonstrated that the spatial distribution of these epicenters correlates with cocaine craving-response maps derived from repeated transcranial magnetic stimulation and can track individual variations in clinical behavioural representations, suggesting their potential as targets for therapeutic intervention. Conclusions: Altogether, our findings establish a structurally constrained framework for the spread of pathology underlying cortical atrophy in CUD, where initial perturbations propagate via structural connectome pathways to vulnerable regions shaped by neural activity and molecular landscapes.