Grey Matter Volume in Substance Use: A Preregistered, Dimensional Approach to Disentangle Substance Use and Disorder Severity.

This preregistered study investigates whether altered grey matter volume (GMV) in the insula and ventromedial prefrontal/anterior cingulate cortex (vmPFC/ACC) - regions commonly implicated in substance use disorder (SUD) - is associated with the degree of substance use or with the severity of substance-related problems, two distinct but correlated facets of SUD. Baseline structural MRI and behavioural assessment of substance use, substance-related problems (i.e., DSM-5 disorder severity) and negative urgency were conducted in 134 (poly-)substance users. At 1-year follow-up, behavioral assessments were repeated in 120 participants. Linear regression analyses tested associations between GMV in predefined regions (insula, vmPFC and ACC) and (1) degree of use, (2) substance-related problems and (3) substance-related problems controlled for use. Mediation analyses tested whether negative urgency mediated the problem-specific associations. GMV in all regions negatively related to substance-related problems and use (p < 0.05). Controlled for use, GMV in the insula and vmPFC (p < 0.05) but not ACC (p = 0.06) related to substance-related problems. Follow-up results revealed differential patterns, but when controlling for use, GMV reductions at baseline did not significantly relate to follow-up substance-related problems (insula: p = 0.06; ACC/vmPFC: p > 0.23). Negative urgency related to GMV in the vmPFC (p = 0.02) and mediated the association between vmPFC volume and substance-related problems controlled for use (indirect effect: CI [-0.12, -0.02]). We demonstrate that smaller GMV in the vmPFC and insula specifically relates to substance-related problems beyond substance use, albeit with distinct predictive value for prospective symptom development. This highlights the importance of distinguishing between the two facets of SUD to understand why some substance users develop SUD.