Left middle frontal gyrus response to inhibitory errors in children prospectively predicts early problem substance use

Background: A core vulnerability trait for substance use disorder (SUD) is behavioral disinhibition. Error processing is a central aspect of inhibitory control that determines adaptive adjustment of performance; yet it is a largely overlooked aspect of disinhibition as it relates to risk for SUD. We investigated whether differences in brain activation during both successful and failed inhibition predicts early problem substance use. Method: Forty-five 9-12 year olds underwent a functional MRI scan during a go/no-go task. They were then followed over approximately 4 years, completing assessments of substance use. Externalizing behavior was measured at ages 3-8, 9-12 and 11-13. Participants with drug use or problem alcohol use by ages 13-16 (n= 13; problem-user group) were individually matched by gender, age, and family history of alcoholism with non-substance-using children (n= 13; non-user group). The remaining 19 participants provided an independent sample from which to generate unbiased regions-of-interest for hypothesis testing in the problem-user and non-user groups. Results: No differences were observed between groups in activation during correct inhibition compared with baseline. A significant difference arose in left middle frontal gyrus (LMFG) activation during failed inhibition compared with correct inhibition, with the problem-user group demonstrating blunted activation. The problem-user group also had more externalizing problems at ages 11-13. Logistic regression found that activation of LMFG significantly predicted group membership over and above externalizing problems. Conclusions: Blunted LMFG activation during performance errors may underlie problems adapting behavior appropriately, leading to undercontrolled behavior, early problem substance use and increased risk for SUD.