Hierarchical neurocognitive model of externalizing and internalizing comorbidity

Abstract Mounting evidence suggests that hierarchical psychopathology factors underlie psychiatric comorbidity. However, the exact neurobiological characterizations of these multilevel factors remain elusive. Here, 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 2 neural factors underlying externalizing and internalizing symptoms, which were reproducible across 6 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 findings, we propose a hierarchical neurocognitive model of comorbid psychopathology (NeuroHiP) from preadolescence to adulthood, comprising a general neuropsychopathological factor (manifested as inefficient executive control) and two stratified factors of 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.