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

backgroundCocaine 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.

methodsWe 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.

resultsWe 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

conclusionsAltogether, 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.