Mounting evidence suggests that hierarchical psychopathology factors underlie psychiatric comorbidity. However, the exact neurobiological characterizations of these multilevel factors remain 144 elusive. In this study, leveraging the brain-behaviour 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-behaviour 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 (NP) 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.
Xie et al. (Tue,) studied this question.