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

Understanding the neurobiological basis of mental health disorders and their symptoms is a central goal of research in psychiatry. Yet, 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. This can potentially yield more reliable and neurobiologically-relevant dimensions of psychopathology. However, the extent to which latent factor models improve brain-psychopathology associations remains largely unclear. Using two large developmental cohorts, we 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). We found no consistent evidence that latent factors (bifactor or correlated factor models) strengthened reliability or brain-psychopathology associations, relative to summary scores. Whole-brain predictive models revealed broadly distributed neural signatures that were highly similar between corresponding factor and summary score constructs, with general psychopathology factors and total problem summary scores approaching numerical equivalence. Bifactor scores did, however, display more distinct neural signatures between general, internalising, and externalising dimensions than did summary or correlated factor scores. These results suggest that phenotypic modelling of psychopathology alone does not systematically strengthen the predictive utility of psychiatric 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.