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.

Keywords: Addiction; Adolescence; Children of alcoholics; Cognitive control; Reward; Striatum; Substance use disorder; Substance use risk; fMRI; meta-Analysis.

Fig. 1.

A) Primary meta-analysis of all studies and all foci of substance use risk (peak coordinate, LPI MNI -8, 10, 4). B) Increased activation associated with substance use risk (peak coordinate, LPI MNI 26, 8, −4). Statistical maps displayed over Montreal Neurological Institute-152 template in neurological view. All results FWER p < .05 with single voxel p < .01. Scale bar (weighted % of studies with activation difference) refers to the relative proportion of studies with a risk difference, weighted by the square root of the study sample size (see description in Methods section).

Fig. 2.

Results from prospective prediction and family history of SUD studies in striatal clusters defined from primary meta-analysis (‘all studies’, A) and from ‘risk > non-risk’ studies (B). Y-axes (weighted % of studies with activation difference) refers to the relative proportion of studies with a risk difference, weighted by the square root of the study sample size (see description in Methods section). Cluster displayed in yellow to denote the proportion of studies with activation differences was calculated across the cluster.

Fig. 3.

Top panel displays results from substance use risk studies with and without externalizing disorders in striatal clusters defined from the primary ’all studies’ meta-analysis (A) and from ’risk > non-risk’ studies (B). Bar plots display proportion of studies with activation differences calculated across the cluster, weighted by the square root of the sample size. Striatal images below show that for the primary meta-analysis (A), studies where substance use risk included externalizing disorders were significantly more likely (FDR-corrected) to report activation differences in the striatum. Scale bar below refers to voxel p-value from chi-square analysis comparing activation difference versus no activation difference in substance use risk and substance use risk with externalizing analysis (yellow, p > .05; orange, p < .05, uncorrected, red, FDR-corrected (q) < 0.05 within striatal mask). C and D display the same information for the analysis where studies including externalizing disorders in substance use risk definitions were aggregated with studies not excluding other psychopathology or where externalizing psychopathology was matched across groups. Statistical maps displayed over Montreal Neurological Institute-152 template in neurological view.

Fig. 4.

Conjunction of significant (FWER p < .05 with single voxel p < .01) clusters across sensitivity analyses (n = 3) for ‘all studies’ (A) and ‘risk > non-risk’ (B). Statistical maps displayed over Montreal Neurological Institute-152 template in neurological view. See Results section in main text and Supplemental S12 for individual sensitivity analyses.