Structural brain network organization and aggressive behavior in schizophrenia: a mega-analysis of 2260 patients and 3058 healthy controls from the ENIGMA-Schizophrenia Working Group

Background: Although most individuals with schizophrenia do not show aggressive behavior, rates are higher than in the general population. Identifying the neurobiological correlates of aggression may inform prevention. Methods: We included 2260 individuals with schizophrenia spectrum disorders and 3058 healthy controls (HC) from 26 sites in the ENIGMA-Schizophrenia Working Group. The former were classified as showing at least moderate aggression (SZ+A; N = 231) or not (SZ−A; N = 2029) based on symptom rating scales. Structural covariance networks were constructed from cortical and subcortical volumes. We examined global and nodal network topology, as well as density within six large-scale brain networks and between each network and the rest of the brain. Metrics were summarized as the area under the curve (AUC) across a prespecified range of densities ( K = 0.10–0.25, Δ K = 0.01). Group differences were assessed using pairwise permutation tests with Benjamini–Hochberg correction for multiple comparisons. Results: Global and nodal network topology did not differ significantly between SZ+A and HC. Network–rest density of the salience network (SN) was higher in SZ+A than in HC, although this difference did not survive multiple-comparison correction (ΔAUC = 0.018, p BH = .083). In exploratory subgroup analyses, higher SN network–rest density was observed only in SZ+A with high delusion severity (ΔAUC = 0.021, p = .007). By contrast, SZ−A demonstrated extensive alterations in global network topology compared with SZ+A and HC, alongside selective alterations in nodal topology and large-scale network density compared with HC. Results were broadly consistent across sensitivity analyses using alternative definitions of aggression and adjusting for current antipsychotic dose. Conclusions: SZ+A was characterized by fewer—not more—abnormalities in structural covariance network organization than SZ−A, which may reflect etiological heterogeneity. In SZ+A with high delusion severity, higher network–rest density of the SN may point to aberrant salience processing in aggressive behavior.

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Journal
medRxiv
Published
2026-10-26
DOI
https://doi.org/10.64898/2026.10.22.26363656
Primary Topic
Schizophrenia research and treatment
Type
preprint
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preprint

Structural brain network organization and aggressive behavior in schizophrenia: a mega-analysis of 2260 patients and 3058 healthy controls from the ENIGMA-Schizophrenia Working Group

Stefan Ehrlich, Edith Pomarol‐Clotet, Jessica A. Turner, David Tomeček et al.
medRxiv
Schizophrenia research and treatment
preprint

Structural brain network organization and aggressive behavior in schizophrenia: a mega-analysis of 2260 patients and 3058 healthy controls from the ENIGMA-Schizophrenia Working Group

Stefan Ehrlich, Edith Pomarol‐Clotet, Jessica A. Turner, David Tomeček, Kira Flinkenflügel, Martijn P. van den Heuvel, Philipp Homan, Filip Španiel, Godfrey D. Pearlson, Andrea de Bartolomeis, Raymond M. Salvador, Paola Dazzan, Janik Goltermann, Elysha Ringin, Will Woods, Young‐Chul Chung, Peter V Kochunov, Jim van Os, Dominik Grotegerd, Qian Hui Chew, Jun Soo Kwon, Kelly Rootes-Murdy, Mario Tranfa, Susanne L. Meinert, Matthew Edward Hughes, Robin M. Murray, Matthias Kirschner, Giuseppe Pontillo, Fabrizio Piras, Oliver Gruber, Benedicto Crespo‐Facorro, Bin Wan, Vince D. Calhoun, Philip J. Sumner, Stefan Kaiser, Adrian Raine, Amalia Guerrero‐Pedraza, Minah Kim, Adrian Preda, Rachel M. Brouwer, Thomas Nickl‐Jockschat, Marc Fischer, Annarita Barone, Yann Quidé, Andriana Karuk, Sean P. Carruthers, Felice Iasevoli, Patricia Segura, Henk S. Temmingh, Florian Thomas‐Odenthal, Minji Ha, Giacomo Cecere, Neeltje E.M. van Haren, Daniela Vecchio, Mariateresa Ciccarelli, Soyolsaikhan Odkhuu, Igor Nenadić, Paolo Fusar‐Poli, Jelle Lamsma, Derin J. Cobia, Wiepke Cahn, Frederike Stein, Mihai Avram, Carl M. Sellgren, Alexander S. Tomyshev, Udo Dannlowski, Tilo T. J. Kircher, В. Г. Каледа, Amanda Rodrigue, Simon Červenka, И. С. Лебедева, Kang Sim, Susan Lee Rossell, David C. Glahn, Sirio Cocozza, Rosanne Picotin, Tiago Reis Marques, Freda Scheffler, Tamsyn E. Van Rheenen, Katharina Brosch, Bernd Krämer, Stefan Borgwardt, Antonín Škoch, Wolfgang Omlor, Melissa J. Green, Theo G.M. van Erp, Sunah Choi, Arturo Brunetti, Rebekka Lencer, Nerisa Banaj, Dominic Arold, Marta Di Forti, Liyi Elliot Hong, Maria Lee, A. Ferrari, Simone Elia, Rafael Romero-Garcia, Dana Nguyen, Lei Wang
preprint en

Abstract

Background: Although most individuals with schizophrenia do not show aggressive behavior, rates are higher than in the general population. Identifying the neurobiological correlates of aggression may inform prevention. Methods: We included 2260 individuals with schizophrenia spectrum disorders and 3058 healthy controls (HC) from 26 sites in the ENIGMA-Schizophrenia Working Group. The former were classified as showing at least moderate aggression (SZ+A; N = 231) or not (SZ−A; N = 2029) based on symptom rating scales. Structural covariance networks were constructed from cortical and subcortical volumes. We examined global and nodal network topology, as well as density within six large-scale brain networks and between each network and the rest of the brain. Metrics were summarized as the area under the curve (AUC) across a prespecified range of densities ( K = 0.10–0.25, Δ K = 0.01). Group differences were assessed using pairwise permutation tests with Benjamini–Hochberg correction for multiple comparisons. Results: Global and nodal network topology did not differ significantly between SZ+A and HC. Network–rest density of the salience network (SN) was higher in SZ+A than in HC, although this difference did not survive multiple-comparison correction (ΔAUC = 0.018, p BH = .083). In exploratory subgroup analyses, higher SN network–rest density was observed only in SZ+A with high delusion severity (ΔAUC = 0.021, p = .007). By contrast, SZ−A demonstrated extensive alterations in global network topology compared with SZ+A and HC, alongside selective alterations in nodal topology and large-scale network density compared with HC. Results were broadly consistent across sensitivity analyses using alternative definitions of aggression and adjusting for current antipsychotic dose. Conclusions: SZ+A was characterized by fewer—not more—abnormalities in structural covariance network organization than SZ−A, which may reflect etiological heterogeneity. In SZ+A with high delusion severity, higher network–rest density of the SN may point to aberrant salience processing in aggressive behavior.

medRxiv
Brigham Young University (US), Boston Children's Hospital (US), Georgia Institute of Technology (US), Seoul National University (KR), Emory University (US), University of Cape Town (ZA), Philipps University of Marburg (DE), The University of Melbourne (AU), Jeonju National University of Education (KR), Georgia State University (US), King's College London (GB), Utrecht University (NL), University of Zurich (CH), University of California, Irvine (US), Heidelberg University (DE), University of Münster (DE), Seoul National University Hospital (KR), The Ohio State University Wexner Medical Center (US), Karolinska Institutet (SE), University Medical Center Utrecht (NL), UNSW Sydney (AU), University Hospital of Geneva (CH), Fidmag Sisters Hospitallers (ES), Hospital Mare de Déu de la Mercè (ES), Instituto de Biomedicina de Sevilla (ES), Center for Translational Research in Neuroimaging and Data Science (US), Stockholm Health Care Services (SE), Institute of Mental Health (SG), Institute for Community Living (US), Fondazione Santa Lucia (IT), Boston Children's Museum (US), Mental Health Research Center of Russian Academy of Medical Sciences (RU), Istituti di Ricovero e Cura a Carattere Scientifico (IT), National Institute of Mental Health (CZ), Hartford Financial Services (United States) (US), Swinburne University of Technology (AU), University of Naples Federico II (IT), Technische Universität Dresden (DE), Universidad de Sevilla (ES), University of Pennsylvania (US), Jeonbuk National University (KR), Vrije Universiteit Amsterdam (NL), The University of Texas Health Science Center at Houston (US), University of Lübeck (DE), Otto-von-Guericke-Universität Magdeburg (DE)
Schizophrenia research and treatment
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