Hierarchical Neurocognitive Model of Externalizing and Internalizing Comorbidity

Res Sq [Preprint]. 2025 Jan 10:rs.3.rs-5397195. doi: 10.21203/rs.3.rs-5397195/v1.

ABSTRACT

Mounting evidence suggests hierarchical psychopathology factors underlying psychiatric comorbidity. However, the exact neurobiological characterizations of these multilevel factors remain elusive. In this study, leveraging the brain-behavior predictive framework with a 10-year longitudinal imaging-genetic cohort (IMAGEN, ages 14, 19 and 23, N = 1,750), we constructed two neural factors underlying externalizing and internalizing symptoms, which were reproducible across six clinical and population-based datasets (ABCD, STRATIFY/ESTRA, ABIDE II, ADHD-200 and XiNan, from age 10 to age 36, N = 3,765). These two neural factors exhibit distinct neural configurations: hyperconnectivity in impulsivity-related circuits for the externalizing symptoms and hypoconnectivity in goal-directed circuits for the internalizing symptoms. Both factors also differ in their cognitive-behavior relevance, genetic substrates and developmental profiles. Together with previous studies, these findings propose a hierarchical neurocognitive spectral model of comorbid mental illnesses from preadolescence to adulthood: a general neuropsychopathological (NP) factor (manifested as inefficient executive control) and two stratified factors for externalizing (deficient inhibition control) and internalizing (impaired goal-directed function) symptoms, respectively. These holistic insights are crucial for the development of stratified therapeutic interventions for mental disorders.

PMID:39866873 | PMC:PMC11760247 | DOI:10.21203/rs.3.rs-5397195/v1