Resting-state fMRI analysis of functional connectivity and temporal dynamics differences between cocaine users and healthy controls

Understanding alterations in functional connectivity among individuals with substance use disorder (SUD) is critical for elucidating the neural mechanisms underlying addiction. In this study, we applied Energy Landscape Analysis (ELA), an energy-based machine learning method, to examine whole-brain functional connectivity differences between SUD patients and healthy controls (HCs). A key methodological challenge in ELA lies in the selection of appropriate Regions of Interest (ROIs) from comprehensive brain atlases. To address this, we employed seed-based connectivity analysis to identify task-relevant ROIs, thereby overcoming the limitation of focusing on a restricted subset of regions. The dataset comprised 53 cocaine users (CUs) and 52 age- and sex-matched HCs, with functional MRI data preprocessed using the CONN toolbox. ROI-to-ROI seed-based connectivity was computed through first- and second-level analyses. ELA revealed that HCs exhibited stronger positive connectivity between cerebellar and visual regions, whereas CUs showed stronger positive connectivity between the cerebellum and the inferior temporal gyrus (temporooccipital part; toITG). Seven low-energy connectivity states were identified that differentiated the two groups. In these states, the cerebellum and toITG demonstrated antagonistic activation patterns, while the cerebellum and visual cortex co-activated in HCs. Temporal dynamics analyses further indicated that HCs visited these low-energy states more frequently, driven by shorter dwell times but higher transition rates. These findings suggest that cocaine addiction may reflect a weakening of adaptive, protective ("guardian") connectivity patterns, rather than an increased propensity to remain in maladaptive connectivity states. Collectively, these results highlight key network-level distinctions between HCs and CUs and offer new insights into the neurobiological mechanisms of cocaine addiction.