Dissociating the Link of Neural Correlates of Inhibition to the Degree of Substance Use and Substance-Related Problems: A Preregistered, Multimodal, Combined Cross-sectional and Longitudinal Study

Abstract

BackgroundFrontal hypoactivation during inhibition is a promising phenotype for substance use disorders (SUDs), but studies comparing individuals with SUDs with unaffected individuals have reported inconsistent results. This may result from distinctive associations of neural correlates of inhibition with the degree of substance use and the severity of substance-related problems—two correlated but distinct facets of SUDs—reflecting a potentially disregarded confounding effect. This preregistered study tested whether frontal hypoactivation during inhibition is specifically linked to substance-related problems in SUDs beyond the degree of substance use. MethodsA stop signal task during functional magnetic resonance imaging, trait self-control, substance use, and substance-related problems in the past 12 months were assessed in 121 (poly)substance users. One hundred seven participants completed a 1-year follow-up. We examined the association between multimodal indicators of inhibition (neural activation in regions of interest, inhibitory performance, trait self-control) and substance-related problems while controlling for the degree of substance use. ResultsRight inferior frontal gyrus hypoactivation explained variance in substance-related problems beyond the degree of substance use, while hyperactivation in the same region explained variance in the degree of substance use beyond the effects of substance-related problems, both cross-sectionally (problems: Bonferroni-Holm–corrected p = .048; use: p < .01) and prospectively (problems at trend level: p = .096; use: p = .01). Trait and behavioral inhibition were unrelated to problems beyond the effects of substance use (ps > .05). ConclusionsWe demonstrated that frontal hypoactivation during inhibition specifically relates to substance-related problems. Interestingly, increased activity may even represent a resilience factor in substance use without SUDs. Future studies should distinguish between processes linked to the degree of substance use and substance-related problems to advance understanding of why some substance users develop SUDs and others do not.