Meta-analysis and review of functional neuroimaging differences underlying adolescent vulnerability to substance use

Abstract Adolescence is increasingly viewed as a sensitive period in the development of substance use disorders (SUDs). Neurodevelopmental ‘dual-risk’ theories suggest adolescent vulnerability to problematic substance use is driven by an overactive reward drive mediated by the striatum, and poor cognitive control mediated by the prefrontal cortex. To this end, there has been a growing number of neuroimaging studies examining cognitive and affective neural systems during adolescence for markers of vulnerability to problematic substance use. Here, we perform a coordinate-based meta-analysis on this emerging literature. Twenty-two task-based voxelwise fMRI studies with activation differences associated with substance use vulnerability, representative of approximately 1092 subjects, were identified through a systematic literature search (PubMed, Scopus) and coordinates of activation differences (N ​= ​190) were extracted. Adolescents were defined as ‘at-risk’ for problematic substance use based on a family history of SUD or through prospective prediction of substance use initiation or escalation. Multilevel kernel density analysis was used to identify the most consistent brain regions associated with adolescent substance use vulnerability. Across the included studies, substance use vulnerability was most reliably associated with activation differences in the striatum, where at-risk adolescents had hyper-activation in the dorsal subdivision (putamen). Follow-up analyses suggested striatal differences were driven by tasks sharing a motivational and/or reward component (e.g., monetary incentive) and common across subgroups of substance use risk (family history and prospective prediction studies). Analyses examining the role of psychiatric comorbidity revealed striatal activation differences were significantly more common in samples whose definition of substance use risk included cooccurring externalizing psychopathology. Furthermore, substance use risk meta-analytic results were no longer significant when excluding these studies, although this may reflect limitations in statistical power. No significant activation differences were observed in prefrontal cortex in any analysis. These results suggest striatal dysfunction, rather than prefrontal, may be a more primary neural feature of adolescent vulnerability to problematic substance use, possibly through a dimension of individual variability shared with externalizing psychopathology. However, our systematic literature search confirms this is still an emerging field. More studies, increased data sharing, and further quantitative integration are necessary for a comprehensive understanding of the neuroimaging markers of adolescent substance use risk.