Disentangling Brain-Psychopathology Associations: A Systematic Evaluation of Transdiagnostic Latent Factor Models

Identifying robust brain-psychopathology associations with neuroimaging remains difficult, in part due to substantial heterogeneity within and comorbidity between diagnostic categories. Transdiagnostic latent factor models aim to address this structure by separating shared and unique symptom variance. However, it remains unclear whether latent factor modeling translates into stronger and more interpretable brain-psychopathology associations within contemporary whole-brain prediction frameworks. Using two large developmental cohorts, we systematically compared transdiagnostic bifactor models, correlated factor models, and typical summary scores derived from the Child Behaviour Checklist (CBCL) in their reliability and multivariate associations with whole-brain structure (MRI) and function (resting-state fMRI). General psychopathology, internalising, externalising, and attention dimensions could be significantly predicted from resting-state connectivity but not cortical thickness. We found no consistent evidence that latent factors (bifactor or correlated factor models) strengthened reliability or brain-psychopathology associations, relative to summary scores. Neural signatures were also highly consistent across all scoring methods, with triple network (DMN, FPN, CO) involvement in general, internalizing, and externalising psychopathology. Bifactor scores did, however, display more distinct neural signatures between general, internalising, and externalising dimensions than did summary or correlated factor scores. Collectively, results suggest that additional phenotypic modelling of psychopathology alone does not systematically strengthen the predictive utility of neuroimaging, possibly reflecting fundamental limits on the amount of explainable symptom variance by brain features. While latent factor models may aid in distinguishing neural correlates between constructs, improving phenotypic assessment may be necessary for improvements to brain-psychopathology association strength.