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.

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Publication Details

Journal
Nature Mental Health
Published
2026-02-13
DOI
https://doi.org/10.1038/s44220-025-00577-2
Primary Topic
Attention Deficit Hyperactivity Disorder
Type
article
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article

Hierarchical neurocognitive model of externalizing and internalizing comorbidity

Viola Kappel, Dongtao Wei, Betteke Maria van Noort, Lauren Robinson et al.
Nature Mental Health
Attention Deficit Hyperactivity Disorder
article

Hierarchical neurocognitive model of externalizing and internalizing comorbidity

Viola Kappel, Dongtao Wei, Betteke Maria van Noort, Lauren Robinson, Corinna Insensee, Wei Cheng, Juliane H. Fröhner, Sinéad King, Julia Sinclair, Patricia Conrod, Marina Bobou, A. Becker, Trevor W Robbins, E. Artiges, Jani Penttilä, Nick Ortiz, Yvonne Grimmer, Chen Shen, Chao Xie, Hugh P. Garavan, Rüdiger Brühl, Yupeng Zheng, Luise Poustka, Ulrike Schmidt, Yuzhu Li, Jianfeng Feng, Yuning Zhang, Tahmine Fadai, Hervé Lemaître, Tianye Jia, Herta Flor, Penny Gowland, Michael N. Smolka, Christian Büchel, Nilakshi Vaidya, Sylvane Desrivières, Henrik Walter, Maren Struve, Jean-Luc Martinot, Jeanne Winterer, Argyris Stringaris, Dimitri Papadopoulos Orfanos, Barbara J. Sahakian, Andreas Heinz, Hedi Kebir, M. John Broulidakis, Tobias Banaschewski, Peng Xie, Zuo Zhang, Jiang Qiu, Marie-Laure Paillère Martinot, Gareth J. Barker, Arun L. Bokde, Gunter Schumann, Robert Whelan
article en

Abstract

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.

Nature Mental HealthVol. 4(3)
University of Vermont (US), Physikalisch-Technische Bundesanstalt (DE), Centre National de la Recherche Scientifique (FR), Ministry of Education of the People's Republic of China (CN), Southwest University (CN), University of Nottingham (GB), Université de Bordeaux (FR), Inserm (FR), Universität Hamburg (DE), University of Mannheim (DE), King's College London (GB), South London and Maudsley NHS Foundation Trust (GB), Hong Kong University of Science and Technology (HK), Peking University (CN), Université Paris Cité (FR), Trinity College Dublin (IE), Heidelberg University (DE), University of Cambridge (GB), Fudan University (CN), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University Hospital Heidelberg (DE), Centre Hospitalier Universitaire Sainte-Justine (CA), Christian-Albrechts-Universität zu Kiel (DE), Humboldt-Universität zu Berlin (DE), University of Warwick (GB), Sorbonne Université (FR), University of Oxford (GB), Shanghai Institute for Science of Science (CN), Institut des Maladies Neurodégénératives (FR), MSB Medical School Berlin (DE), Faculty (United Kingdom) (GB), Assistance Publique – Hôpitaux de Paris (FR), Central Institute of Mental Health (DE), University Medical Center Hamburg-Eppendorf (DE), Universitätsmedizin Göttingen (DE), Pitié-Salpêtrière Hospital (FR), German Centre for Cardiovascular Research (DE), CEA Paris-Saclay (FR), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Etelä-Karjalan sosiaali ja terveyspiiri (FI), Huashan Hospital (CN), Shanghai Center for Brain Science and Brain-Inspired Technology (CN), University of Southampton (GB), University College London (GB), University of Göttingen (DE), Freie Universität Berlin (DE), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE), University of Birmingham (GB), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Chongqing Medical University (CN), Tsinghua University (CN)
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