Refining RDoC Using Individual-Level Task fMRI Factor Models Reveals Reproducible and Clinically Relevant Brain-Wide...

The Research Domain Criteria (RDoC) framework was introduced to guide psychiatric research using biologically grounded, dimensional constructs of mental function. However, its hierarchical domain structure remains largely unvalidated against individual-level brain and behavioral data. Building on prior group-level work, we applied a multi-stage validation framework to Human Connectome Project (HCP) task-fMRI data to test whether individual-level, data-driven models more accurately capture the organization of brain activity and behavior than RDoC-based models. Using confirmatory factor analysis in two independent cohorts, we found that data-driven bifactor models consistently outperformed RDoC-based models across multiple fit indices. The general factor derived from these models revealed a reproducible, low-dimensional axis spanning visual-attentional to default mode-auditory systems, aligning with canonical macroscale cortical gradients. Community detection further identified reproducible spatial motifs whose centroids corresponded to interpretable functional systems and whose alignment predicted individual performance on working memory and relational reasoning tasks. To assess whether these findings extended beyond neural data, we analyzed behavioral measures in HCP and in an independent transdiagnostic dataset (LA5c). In both datasets, data-driven behavioral models outperformed RDoC-based models, although the relative support for bifactor versus specific factor structure differed by dataset. Extending the neural analyses to LA5c, which included healthy controls and individuals with ADHD, bipolar disorder, and schizophrenia, showed that data-driven bifactor models generalized across diagnostic groups and that alignment with data-driven community centroids related to symptom severity, whereas RDoC-based representations showed weaker or no associations. Finally, topological analysis of task-evoked brain activity revealed that data-driven representations better captured the global organization of brain states than RDoC domains. Together, these findings demonstrate that individual-level, empirically derived models provide a more accurate, generalizable, and behaviorally relevant account of brain organization than the current RDoC framework. By integrating neural, behavioral, and clinical validation, this work advances precision neuroscience and supports the empirical refinement of dimensional psychiatric frameworks.