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

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.

Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice

“…Cerebellar pathology and cognitive inflexibility co-occur in neuropsychiatric disorders including autism (Hughes et al, 1994, Hill, 2004, Fatemi et al, 2012), schizophrenia (Pantelis et al, 1999, Andreasen and Pierson, 2008, Floresco et al, 2009, Leeson et al, 2009), and drug addiction (Woicik et al, 2011, Fatemi et al, 2012, McCracken and Grace, 2013, Moreno-Lopez et al, 2015, Verdejo-Garcia et al, 2015, Miquel et al, 2016). Findings from the present study suggest that the nature of these relationships may be causal.…”

“…Deficits in this fundamental cognitive ability are proposed to underlie the maladaptive behaviors which characterize a wide range of neuropsychiatric disorders including autism (Hughes et al, 1994, Hill, 2004), schizophrenia (Pantelis et al, 1999, Floresco et al, 2009, Leeson et al, 2009), and drug addiction (Woicik et al, 2011, McCracken and Grace, 2013, Moreno-Lopez et al, 2015, Verdejo-Garcia et al, 2015, Miquel et al, 2016). Although cognitive flexibility is often discussed as a unitary construct, it can be subdivided into at least two dissociable cognitive processes.…”

The effects of N -Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study

“…Task-based fMRI and volumetric VBM analyses have implicated regions of the cerebellum, and its connectivity with the striatum, in various forms of learning such as implicit motor learning (Tzvi et al, 2014) and reversal learning (Moreno-López et al, 2015). The cerebellum plays a role in reactive ‘on-line’ error correction in movement (Doya, 2000) and motor learning (Bastian, 2006).…”

Addiction and dopamine: sex differences and insights from studies of smoking

“…Stimulant users are more impulsive than healthy control subjects, and show a negative correlation between impulsivity and striatal D2-type receptor availability (e.g., [33,34]). Conversely, cognitive control, measured in tests of motor response inhibition [35–37] and cognitive flexibility [38,39], show weaknesses in substance abusers, and positive correlations of striatal D2-type receptor availability with performance on relevant tests in healthy controls is disrupted in stimulant users [40,41]. …”