Cocaine use severity and cerebellar gray matter are associated with reversal learning deficits in cocaine-dependent individuals

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Abstract

Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning-sensitive regions. Cocaine-targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine-dependent individuals (CDIs) varying on levels of cocaine exposure in comparison with healthy controls (HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task (PRLT) and were subsequently scanned in a 3-Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and then must learn to respond according to the opposite, previously irrelevant, stimulus-reward pairing. Performance measures were errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel-based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter.

Perseveration after negative feedback -when punishment prevails over reward- is a central aspect of cocaine addiction. This study examined whether frontal cortical, insular and cerebellar gray matter volumes are associated with severity of cocaine use and behavioral perseveration among individuals with cocaine dependence. We show that severity of cocaine use is dosage-dependently negatively associated with gray matter volumes in the cerebellum. Further, the gray matter volume of a partially overlapping cerebellar cluster is negatively associated with perseveration after negative feedback. Right insular volumes correlated with a behavioral measure of feedback tracking. These findings highlight an important role of the cerebellum on perseverative behavior in cocaine addiction.

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