Potentially traumatic events and substance use predict changes in resting state functional connectivity in early adolescence

Potentially traumatic events (PTEs) and substance use (SU) are commonly endorsed in early adolescence, a crucial period for neurodevelopment. PTEs and SU are precipitating events in the etiological development of comorbid posttraumatic stress disorder (PTSD) and substance use disorder (SUD). Separately, they have been shown to alter within- and between-network connectivity in the three brain networks posited by Menon’s Theory of Psychopathology: the default mode network (DMN), fronto-parietal network (FPN), and salience network (SN). While comorbid PTSD+SUD in adulthood shows shared neural underpinnings, this is less clear in adolescence. We analyzed the effects of PTEs and SU (all use, alcohol/cannabis/nicotine only, and stimulant or sedative use) on resting state functional connectivity (rsFC) in 9-15 year olds from the Adolescent Brain Cognitive Development (ABCD) Study. Fixed effects panel models were fit to assess the effects of PTEs and SU on between-network (FPN-SN rsFC, DMN-SN rsFC, and FPN-DMN rsFC) and within-network (FPN rsFC, SN rsFC, and DMN rsFC) connectivity measured across three timepoints spanning two years. PTEs were the most reliable predictor prospectively, with significant effects of PTEs observed for both between- and within-network rsFC. Alcohol and nicotine use predicted higher within-network DMN and FPN rsFC, but lower DMN-SN connectivity, while cannabis use predicted lower within-network SN connectivity and moderated PTE effects in SN and DMN-SPN connectivity. Evidence for PTEs and SU interactively predicting rsFC was supported with sex-specific effects (males showed a steeper decline in SN and DMN-SN connectivity when PTEs and SU were combined, and females showed stronger positive DMN connectivity when alcohol and PTEs were combined). Results suggest that the observed changes in resting state functional connectivity are related to exposure to PTEs, SU, and their interaction rather than the typically observed neurodevelopmental changes during adolescence, highlighting a critical period for early intervention to prevent rsFC changes following PTEs and SU in early adolescence.