Longitudinal Associations Between White Matter Microstructure and Psychiatric Symptoms in Youth

Objective: Associations between psychiatric problems and white matter (WM) microstructure have been reported in youth. Yet, a deeper understanding of this relation has been hampered by a dearth of well-powered longitudinal studies and a lack of explicit examination of the bidirectional associations between brain and behavior. We investigated the temporal directionality of WM microstructure and psychiatric symptom associations in youth. Method: In this observational study, we leveraged the world's largest single- and multi-site cohorts of neurodevelopment: the Generation R (GenR) and Adolescent Brain Cognitive Development Studies (ABCD) (total n scans = 11,400; total N = 5,700). We assessed psychiatric symptoms with the Child Behavioral Checklist as broad-band internalizing and externalizing scales, and as syndrome scales (eg, Anxious/Depressed). We quantified WM with diffusion tensor imaging (DTI), globally and at a tract level. We used cross-lagged panel models to test bidirectional associations of global and specific measures of psychopathology and WM microstructure, meta-analyzed results across cohorts, and used linear mixed-effects models for validation. Results: We did not identify any longitudinal associations of global WM microstructure with internalizing or externalizing problems across cohorts (confirmatory analyses) before, and after multiple testing corrections. We observed similar findings for longitudinal associations between tract-based microstructure with internalizing and externalizing symptoms, and for global WM microstructure with specific syndromes (exploratory analyses). Some cross-sectional associations surpassed multiple testing corrections in ABCD, but not in GenR. Conclusion: Uni- or bi-directionality of longitudinal associations between WM and psychiatric symptoms were not robustly identified. We have proposed several explanations for these findings, including interindividual differences, the use of longitudinal approaches, and smaller effects than expected. Study registration information: Bidirectionality Brain Function and Psychiatric Symptoms; https://doi.org/10.17605/OSF.IO/PNY92