Neuroplastic effects of changes in cocaine use intensity on resting-state functional connectivity of the brain: a longitudinal study

Background: Chronic cocaine use is associated with physical, neuropsychiatric, and social consequences. While cocaine‑induced neuroplasticity is well-studied in animal models, less is known about recovery of the human brain after prolonged exposure. This longitudinal functional MRI (fMRI) study therefore examined whether (1) whole‑brain and fronto‑striatal resting‑state functional connectivity (rsFC) are modulated by reduced cocaine use and (2) baseline fronto‑striatal rsFC predicts future cocaine intake in individuals with chronic cocaine use (ICCU). Methods: We analysed rsFC data from 32 ICCU (15 sustained users [SU], 17 decreased users [DU]) and 38 matched cocaine‑naive controls (CNC) collected at baseline and long-term follow-up (median interval: 10.3 months). Whole‑brain rsFC was compared between ICCU and CNC and fronto‑striatal rsFC was examined within ICCU subgroups. Additionally, we tested whether baseline rsFC predicted future cocaine use and intensity or craving. Results: At TP1, no striatal‑prefrontal rsFC differences emerged between SU and DU. At TP2, SU exhibited widespread whole‑brain hyperconnectivity versus CNC and stronger striatal rsFC (pallidum/nucleus accumbens to superior frontal gyrus; caudate anti‑correlation to inferior frontal gyrus) versus DU (rm‑ANCOVA, p<0.05, cluster‑corrected). Baseline TP1 striatal‑prefrontal rsFC significantly predicted TP2 cocaine use (R²=0.892; caudate fronto‑striatal connectivity surviving FDR correction), whereas the craving model showed high in‑sample fit (R²=0.975) but no single seed survived FDR correction. Conclusion: Our findings indicate that altered rsFC in ICCU reflects widespread network disruption, while rsFC changes partially normalize toward control‑like patterns with reduced cocaine use. Finally, fronto‑striatal rsFC might be useful to predict cocaine use trajectories for individualized treatment of cocaine use disorder.