Hierarchical neurocognitive model of externalizing and internalizing comorbidity
Year: 2026
Type: article
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.
Source: Nature Mental Health
Authors: Chao Xie, Shitong Xiang, Yueyuan Zheng, Chun Shen, Yuzhu Li, Wei Cheng, Nilakshi Vaidya, Zuo Zhang, Lauren Robinson, Jeanne Winterer, Yuning Zhang, Sinead King, Gareth J. Barker, Arun L. Bokde, Rüdiger Brühl, Hedi Kebir, Dongtao Wei, Eric Artiges, Marina Bobou, M. John Broulidakis, Tobias Banaschewski, Andreas Becker, Christian Büchel, Patricia Conrod, Tahmine Fadai, Herta Flor, Antoine Grigis, Yvonne Grimmer, Hugh Garavan, Penny Gowland, Andreas Heinz, Corinna Insensee, Viola Kappel, Hervé Lemaître, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Betteke Maria van Noort, Frauke Nees, Dimitri Papadopoulos Orfanos, Jani Penttilä, Luise Poustka, Juliane H. Fröhner, Ulrike Schmidt, Julia Sinclair, Michael N. Smolka, Argyris Stringaris, Maren Struve, Henrik Walter, Robert Whelan, Jiang Qiu, Peng Xie, Barbara J. Sahakian, Trevor W. Robbins, Sylvane Desrivières, Gunter Schumann, Jianfeng Feng, Tianye Jia, Betteke Maria van Noort, Gunter Schumann
Institutions: Shanghai Medical College of Fudan University, Fudan University, Tsinghua University, Hong Kong University of Science and Technology, Charité - Universitätsmedizin Berlin, King's College London, University of Birmingham, University of Oxford, Humboldt-Universität zu Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Freie Universität Berlin, University of Southampton, Trinity College Dublin, Physikalisch-Technische Bundesanstalt, Southwest University, École Normale Supérieure Paris-Saclay, Inserm, Université Paris Cité, Université Paris-Saclay, Trajectoires développementales & psychiatrie, Centre Borelli, University College London, Heidelberg University, Central Institute of Mental Health, Medizinische Fakultät Mannheim, Universitätsmedizin Göttingen, University of Göttingen, University Medical Center Hamburg-Eppendorf, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, University of Mannheim, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CEA Paris-Saclay - Etablissement de Saclay, CEA Paris-Saclay, University of Vermont, University of Nottingham, Deutsches Zentrum für Psychische Gesundheit, University of Tübingen, Centre National de la Recherche Scientifique, Université de Bordeaux, Institut des Maladies Neurodégénératives, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, MSB Medical School Berlin, Christian-Albrechts-Universität zu Kiel, University Hospital Schleswig-Holstein, Institut für Medizinische Psychologie, Ludwig-Maximilians-Universität München, University Hospital Heidelberg, Technische Universität Dresden, South London and Maudsley NHS Foundation Trust, The Affiliated Yongchuan Hospital of Chongqing Medical University, University of Cambridge, University of Warwick, Frontiers Center for Brain Science of the Ministry of Education
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Eli Lilly and Company, Fondation de l'Avenir pour la Recherche Médicale Appliquée, UK Research and Innovation, National Institute for Health and Care Research, King's College London, University of Oxford, European Commission, Science Foundation Ireland, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, Bundesministerium für Bildung und Forschung, Ministry of Science and Technology of the People's Republic of China, China Postdoctoral Science Foundation, Fondation pour la Recherche Médicale, Fondation de France, Fédération pour la Recherche sur le Cerveau, Mission Interministérielle de Lutte Contre les Drogues et les Conduites Addictives, National Institutes of Health, HORIZON EUROPE Framework Programme, Arts and Humanities Research Council, Medical Research Council, Economic and Social Research Council, National Natural Science Foundation of China-Yunnan Joint Fund, National Institute of Biomedical Imaging and Bioengineering
Awards: G1495243366, G1503502494, The Neurobiology of Voluntary Nicotine Abstinence: Genetics, Environment and Neurocognitive Endophenotypes, G1734063488, ENIGMA World Aging Center, G2593651357, G262382698, G2753678999, G2779700878, G2789362503, Depression in adolescents. Brain structure and myelination, translational markers., G291674040, G3148620967, G3160699921, G3350404865, Establishing causal relationships between biopsychosocial predictors and correlates of eating disorders and their mediation by neural pathways, Reducing the impact of major environmental challenges on mental health, G3762890544, G3799960043, G3861730116, G3921316769, G3957321765, G3986097662, G4038026799, G4175096997, G4199552044, G426824318, G4296709102, G434337789, G4401276296, G4430103938, G4649087444, G4656594441, G4846141755, G4880459266, G49163856, G5615130774, G5700399613, Human Brain Project Specific Grant Agreement 2, G5937087696, G6012606064, Verbundprojekt: Genetik der Alkoholsucht - Teilprojekt 1, 7, 8, 9, 11, 13, 14, 15, ENIGMA Center for Worldwide Medicine, Imaging & Genomics, Verbund AERIAL im Forschungsnetz für psychische Erkrankungen - Risikoprofile für Alkoholmissbrauch über die Lebensspanne und als Behandlungsergebnis, Eating Disorders: Delineating illness and recovery trajectories to inform personalised prevention and early intervention in young people (EDIFY), G6702880738, G6720995914, G6797292646, G680728828, G6900113999, G7257041843, G7500368295, G7578079922, Einflüsse von Drogenkonsum auf die Reifung des jugendlichen Gehirns, G8086339906, G8262056361, IMAC-MIND - Verbesserung der psychischen Gesundheit und Verringerung der Suchtgefahr im Kindes- und Jugendalter - TP1 Neurobehaviorale Risiko- und Resilienzprofile, TP2 Entwicklung von Screening und Präventionsinstrumenten, G84396891, G8533677071, Human Brain Project Specific Grant Agreement 3, Neurobiological underpinning of eating disorders: integrative biopsychosocial longitudinal analyses in adolescents, G88412094, G8846233336, G8847134549, Verbund AERIAL im Forschungsnetz für psychische Erkrankungen - Suchterkrankungen: Früherkennung und Intervention über die Lebensspanne, G9000046818, G9000049753, G9000210308
OpenAlex ID: W7128802529