Structural brain differences associated with panic disorder: an ENIGMA-Anxiety Working Group mega-analysis of 4924 individuals worldwide

Neuroanatomical findings on panic disorder (PD) are typically difficult to replicate, with inconsistent effects. These concerns prompted a paradigm shift towards large-scale collaborations, focused on harmonized data extraction and processing for robust examination of PD brain correlates. Hence, leveraging the largest-ever multi-site neuroimaging database on PD (Age: 10-66 years; global sites: 28), compiled by the ENIGMA-Anxiety Working Group, we report on cortical and subcortical differences in individuals with PD (N = 1146) versus healthy controls (HC: N = 3778). The analyses revealed lower thickness and smaller cortical surface area within fronto-temporo-parietal regions in PD (Cohen's ds: -0.08-0.13), along with lower thalamic and caudate volumes (Cohen's ds: -0.07-0.12). Diagnosis-by-age<sup>2</sup> interactions (Cohen's ds: 0.07-0.12) revealed lower thickness in individuals with PD compared to HC in certain regions during adulthood (25-55 years), with relative absence of such differences during youth (<25 years) or late adulthood (>55 years). Finally, patient subgroup analyses showed that early disease onset (≤21 years) in PD was associated with larger lateral ventricles (Cohen's ds: 0.31-0.38), whilst no medication, comorbidity, or severity effects were found. These findings lend support to neurocircuitry models of PD, which postulate differences within fronto-striato-limbic circuits and temporo-parietal regions. Moreover, findings highlight the potential importance of abnormal development and aging in neuroanatomical differences related to PD. Given its unprecedented scale, the current study is an important milestone towards identifying the structural brain correlates of PD.

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Journal
Molecular Psychiatry
Published
2026-01-13
DOI
https://doi.org/10.1038/s41380-025-03376-4
Primary Topic
Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Type
article
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article

Structural brain differences associated with panic disorder: an ENIGMA-Anxiety Working Group mega-analysis of 4924 individuals worldwide

Karen S. Mitchell, Fabian Breuer, Pavel Rjabtsenkov, Gregory A. Fonzo et al.
Molecular Psychiatry
Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
article

Structural brain differences associated with panic disorder: an ENIGMA-Anxiety Working Group mega-analysis of 4924 individuals worldwide

Karen S. Mitchell, Fabian Breuer, Pavel Rjabtsenkov, Gregory A. Fonzo, Elisabeth Johanna Leehr, Claire E. Marino, Giovana B. Zunta Soares, Isabelle C. Ridderbusch, Katharina Dohm, Jared A. Nielsen, Ardesheer Talati, Benjamin Suarez‐Jimenez, Till Langhammer, David Hofmann, Angelika Erhardt, Nili Solomonov, Spiro P. Pantazatos, Katharina Koch, Eleonora Maggioni, Dan J. Stein, Dick J Veltman, Susanne Meinert, Moji Aghajani, Yunbo Yang, Kevin Hilbert, Udo Dannlowski, Laura K. M. Han, Andre [UNIFESP] Zugman, Robin Bülow, Nic J. A. van der Wee, Daniel S. Pine, Takeshi Asami, Randy L. Buckner, Jair C. Soares, Brenda W.J.H. Penninx, Sophia I. Thomopoulos, Thomas Dresler, Benson Mwangi, Andrea Reinecke, Patricia Ohrmann, Odile A. van den Heuvel, Thomas Straube, Anderson M. Winkler, Henry Völzke, Katharina Domschke, Natalia Chechko, Theodore D. Satterthwaite, Barbara Milrod, Francesco Benedetti, Nynke A. Groenewold, Elisabeth Schrammen, Max A. Laansma, Martin P. Paulus, Carlos E. Vazquez, Hannah Meinert, Dominik Grotegerd, Benjamin Straube, Jordan W. Smoller, Sang-Hyuk Lee, Philipp G. Sämann, Paolo Brambilla, Sara Poletti, Robert J. R. Blair, Ruben C. Gur, Raquel E. Gur, Willem B. Bruin, Monica E. Calkins, Hans J. Grabe, Paul M. Thompson, Murray B. Stein, Joscha Böhnlein, Mon-Ju Wu
article en

Abstract

Neuroanatomical findings on panic disorder (PD) are typically difficult to replicate, with inconsistent effects. These concerns prompted a paradigm shift towards large-scale collaborations, focused on harmonized data extraction and processing for robust examination of PD brain correlates. Hence, leveraging the largest-ever multi-site neuroimaging database on PD (Age: 10-66 years; global sites: 28), compiled by the ENIGMA-Anxiety Working Group, we report on cortical and subcortical differences in individuals with PD (N = 1146) versus healthy controls (HC: N = 3778). The analyses revealed lower thickness and smaller cortical surface area within fronto-temporo-parietal regions in PD (Cohen's ds: -0.08-0.13), along with lower thalamic and caudate volumes (Cohen's ds: -0.07-0.12). Diagnosis-by-age<sup>2</sup> interactions (Cohen's ds: 0.07-0.12) revealed lower thickness in individuals with PD compared to HC in certain regions during adulthood (25-55 years), with relative absence of such differences during youth (<25 years) or late adulthood (>55 years). Finally, patient subgroup analyses showed that early disease onset (≤21 years) in PD was associated with larger lateral ventricles (Cohen's ds: 0.31-0.38), whilst no medication, comorbidity, or severity effects were found. These findings lend support to neurocircuitry models of PD, which postulate differences within fronto-striato-limbic circuits and temporo-parietal regions. Moreover, findings highlight the potential importance of abnormal development and aging in neuroanatomical differences related to PD. Given its unprecedented scale, the current study is an important milestone towards identifying the structural brain correlates of PD.

Molecular Psychiatry
Brigham Young University (US), South African Medical Research Council (ZA), University of Southern California (US), Leiden University (NL), University of Copenhagen (DK), National Institutes of Health (US), Albert Einstein College of Medicine (US), Allen Institute for Brain Science (US), RELX Group (Netherlands) (NL), University of Bonn (DE), Harvard University (US), Vita-Salute San Raffaele University (IT), University of Hildesheim (DE), University of Cape Town (ZA), University of Freiburg (DE), Philipps University of Marburg (DE), The University of Melbourne (AU), Forschungszentrum Jülich (DE), University of Milan (IT), University of Erfurt (DE), Cornell University (US), University of Applied Sciences Leiden (NL), University of Münster (DE), University of Würzburg (DE), Universitätsmedizin Greifswald (DE), University Hospital Bonn (DE), Columbia University Irving Medical Center (US), Leiden University Medical Center (NL), Mental Health Services (DK), Harvard University Press (US), Oxford Health NHS Foundation Trust (GB), The University of Texas Rio Grande Valley (US), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Warneford Hospital (GB), New York Psychoanalytic Society and Institute (US), University of California San Diego (US), Humboldt-Universität zu Berlin (DE), University of Oxford (GB), Massachusetts General Hospital (US), Orygen Youth Health (AU), NeuroDevelopment Center (US), Amsterdam Neuroscience (NL), Orygen (AU), Diversitech (United States) (US), Brain (Germany) (DE), German Center for Infection Research (DE), Athinoula A. Martinos Center for Biomedical Imaging (US), IRCCS Ospedale San Raffaele (IT), Jülich Aachen Research Alliance (DE), CHA University Bundang Medical Center (KR), STZ eyetrial (DE), Max Planck Institute of Psychiatry (DE), CHA University (KR), Amsterdam University Medical Centers (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), National Institute of Mental Health (US), Laureate Institute for Brain Research (US), Weill Cornell Medicine (US), New York State Psychiatric Institute, HMU Health and Medical University Erfurt (DE), University of Rochester (US), FH Münster University of Applied Sciences (DE), Adelphi University (US), University of Pennsylvania (US), University of Tübingen (DE), The University of Texas at Austin (US), Vrije Universiteit Amsterdam (NL), University of Tulsa (US), University of Amsterdam (NL), RWTH Aachen University (DE), Yokohama City University (JP), The University of Texas Health Science Center at Houston (US), Politecnico di Milano (IT)
U.S. Department of Health and Human Services, Carnegie Corporation of New York, Massachusetts General Hospital, University of Southern California, Brigham Young University, University of Pennsylvania, Harvard University, University of Rochester, University of Texas at Austin, Philipps-Universität Marburg, National Alliance for Research on Schizophrenia and Depression, Università degli Studi di Milano, McGovern Medical School, Amsterdam University Medical Centers, University of Oxford, South African Medical Research Council, Deutsche Forschungsgemeinschaft, ZonMw, Vrije Universiteit Amsterdam, Bundesministerium für Bildung und Forschung, Albert-Ludwigs-Universität Freiburg, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Max-Planck-Gesellschaft, Westfälische Wilhelms-Universität Münster, Centre d'Imagerie BioMédicale, University of Cape Town, RWTH Aachen University, Rheinische Friedrich-Wilhelms-Universität Bonn, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, CHA University, Siemens Healthineers, Amsterdam Neuroscience, National Institutes of Health, Weill Cornell Medical College, University of California, San Diego, Institute for Translational Neuroscience, Perelman School of Medicine, University of Pennsylvania, Dell Medical School, University of Texas at Austin, Department of Psychology, Harvard University, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Laureate Institute for Brain Research, University of Tulsa, Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg, National Institute of Mental Health
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Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
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