Triple Interactions Between the Environment, Brain, and Behavior in Children: An ABCD Study

Background Environmental exposures play a crucial role in shaping children's behavioral development. However, the mechanisms by which these exposures interact with brain functional connectivity and influence behavior remain unexplored. Methods We investigated the comprehensive environment-brain-behavior triple interactions through rigorous association, prediction, and mediation analyses, while adjusting for multiple confounders. Particularly, we examined the predictive power of brain functional network connectivity (FNC) and 41 environmental exposures for 23 behaviors related to cognitive ability and mental health in 7655 children selected from the ABCD study at both baseline and follow-up time. Results FNC demonstrated more predictability for cognitive abilities than mental health, with cross-validation from UK Biobank study (n= 20852), highlighting the importance of thalamus and hippocampus in longitudinal prediction, while FNC+environment demonstrated more predictive power than FNC in both cross-sectional and longitudinal prediction of all behaviors, especially for mental health (r = 0.32∼0.63). We found family and neighborhood exposures were common critical environmental influencers on cognitive ability and mental health, which can be mediated by FNC significantly. Healthy perinatal development was a unique protective factor for higher cognitive ability, whereas sleep problems, family conflicts and adverse school environments specifically increase risk of mental health. Conclusions This work revealed comprehensive environment-brain-behavior triple interactions based on ABCD study, identified cognitive control and default mode networks as the most predictive functional networks for a wide repertoire of behaviors, and underscored the long-lasting impact of critical environmental exposures on childhood development, in which sleep problem was the most prominent factor affecting the mental health.