Altered prefrontal signaling during inhibitory control in a salient drug context in human cocaine addiction

Drug addiction is characterized by impaired Response Inhibition and Salience Attribution (iRISA), where the salience of drug cues is postulated to overpower that of other reinforcers with a concomitant decrease in self-control. However, the neural underpinnings of the interaction between the salience of drug cues and inhibitory control in drug addiction remain unclear. We developed a novel stop-signal fMRI task where the stop-signal reaction time (SSRT—a classical inhibitory control measure) was tested under different salience conditions (modulated by drug, food, threat or neutral words) in individuals with cocaine use disorder (CUD; n=26) vs. demographically matched healthy control participants (HC; n=26). Despite similarities in drug cue-related SSRT and valence and arousal word ratings between groups, the dorsolateral prefrontal cortex (dlPFC) activity was diminished during the successful inhibition of drug versus food cues in CUD, and was correlated with lower frequency of recent use, lower craving, and longer abstinence (Z > 3.1, p < .05 corrected). Results suggest reduced involvement of cognitive control regions (e.g., dlPFC) during inhibitory control under a drug context, relative to an alternative reinforcer, in CUD. Supporting the iRISA model, these results elucidate the direct impact of drug-related cue-reactivity on the neural signature of inhibitory control in drug addiction.Significance statementExcessive salience attribution to drugs and related cues at the expense of nondrug reinforcers and cues and inhibitory control impairments are hallmark symptoms of drug addiction. Although these neuropsychological functions have been investigated independently, brain representations of their interaction are less clear. We illustrate that, despite matched behavioral performance and valence and arousal ratings, the dorsolateral prefrontal cortex—a key node of the cognitive control network also associated with craving—exhibits decreased signaling when successfully inhibiting responses to drug compared to nondrug (food) cues (words) in cocaine-addicted individuals. Modulating salience while taxing self-control permits the study of their combined impact, an ecologically valid examination of the addiction experience. Better understanding inhibitory control under drug cue-reactivity may refine targeted neuromodulatory interventions.