Neural correlates of human fear conditioning and sources of variability in 2199 individuals

Joaquim Radua, Hannah S. Savage, Enric Vilajosana, Alec Jamieson, Birgit Abler, Fredrik Åhs, Tom Beckers, Narcís Cardoner, Josh M. Cisler, Juliana B. Diniz, Dominik R. Bach, Sigrid Elsenbruch, Steven G. Greening, Daphne J. Holt, Antonia N. Kaczkurkin, Andreas Keil, Merel Kindt, Kathrin Koch, Kevin S. LaBar, Charlene L. Lam, Christine L. Larson, Tina B. Lonsdorf, Christian J. Merz, Katie A. McLaughlin, Yuval Neria, Daniel S. Pine, Carien M. van Reekum, Alexander J. Shackman, Carles Soriano-Mas, Victor I. Spoormaker, Daniel M. Stout, Benjamin Straube, Thomas Straube, Lauri Tuominen, Renée M. Visser, Laura Ahumada, Volker Arolt, Marcelo C. Batistuzzo, Paulo R. Bazán, Emma E. Biggs, Marta Cano, Pamela Chavarría-Elizondo, Samuel E. Cooper, Udo Dannlowski, Víctor Peña-Arteaga, Stephanie N. DeCross, Katharina Domschke, Mana R. Ehlers, John L. Graner, Alfons O. Hamm, Martin J. Herrmann, Ashley A. Huggins, Adriane Icenhour, Asier Juaneda-Seguí, Markus Junghoefer, Tilo Kircher, Katja Koelkebeck, Manuel Kuhn, Franziska Labrenz, Shmuel M. Lissek, Martin Lotze, Ulrike Lueken, Jürgen Margraf, Ignacio Martínez-Zalacaín, Robert Moeck, Jayne Morriss, María Ortuño, Andre Pittig, Daniel Porta-Casteras, Jan Richter, Isabelle C. Ridderbusch, Winfried Rief, Kati Roesmann, Jörgen Rosén, Alena N. Rußmann, Rachel Sjouwerman, Jennifer Spohrs, Andreas Ströhle, Benjamin Suarez-Jimenez, Martin Ulrich, Hans-Ulrich Wittchen, Xi Zhu, Lea Waller, Henrik Walter, Paul M. Thompson, Janna Marie Bas-Hoogendam, Nynke A. Groenewold, Dan J. Stein, Nic J. Wee, Joseph E. Dunsmoor, Andre F. Marquand, Ben J. Harrison and Miquel A. Fullana ()
Additional contact information
Joaquim Radua: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Hannah S. Savage: Radboud University
Enric Vilajosana: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Alec Jamieson: The University of Melbourne
Birgit Abler: Ulm University Clinic
Fredrik Åhs: Mid Sweden University
Tom Beckers: Faculty of Psychology and Educational Sciences
Narcís Cardoner: Institut d’Investigació Biomèdica Sant Pau (IBB-Sant Pau)
Josh M. Cisler: University of Texas at Austin
Juliana B. Diniz: Universidade de São Paulo
Dominik R. Bach: Institute of Experimental Epileptology and Cognition Research
Sigrid Elsenbruch: Ruhr University
Steven G. Greening: University of Manitoba
Daphne J. Holt: Massachusetts General Hospital
Antonia N. Kaczkurkin: Vanderbilt University
Andreas Keil: University of Florida
Merel Kindt: University of Amsterdam
Kathrin Koch: Technical University of Munich
Kevin S. LaBar: Duke University
Charlene L. Lam: University of Hong Kong
Christine L. Larson: Department of Psychology
Tina B. Lonsdorf: Bielefeld University
Christian J. Merz: Ruhr University Bochum
Katie A. McLaughlin: Harvard University
Yuval Neria: Columbia University Irving Medical Center
Daniel S. Pine: National Institute of Mental Health
Carien M. van Reekum: University of Reading
Alexander J. Shackman: University of Maryland
Carles Soriano-Mas: Instituto de Salud Carlos III (ISCIII)
Victor I. Spoormaker: Max Planck Institute of Psychiatry
Daniel M. Stout: University of California
Benjamin Straube: University of Marburg
Thomas Straube: University of Muenster
Lauri Tuominen: University of Ottawa Institute of Mental Health Research at the Royal
Renée M. Visser: University of Amsterdam
Laura Ahumada: University of Florida
Volker Arolt: University of Münster
Marcelo C. Batistuzzo: Universidade de São Paulo
Paulo R. Bazán: Universidade de São Paulo
Emma E. Biggs: Faculty of Psychology and Educational Sciences
Marta Cano: Institut d’Investigació Biomèdica Sant Pau (IBB-Sant Pau)
Pamela Chavarría-Elizondo: Institut d’Investigació Biomèdica de Bellvitge - IDIBELL
Samuel E. Cooper: University of Texas at Austin
Udo Dannlowski: University of Münster
Víctor Peña-Arteaga: Institut d’Investigació Biomèdica Sant Pau (IBB-Sant Pau)
Stephanie N. DeCross: Harvard University
Katharina Domschke: University of Freiburg
Mana R. Ehlers: Bielefeld University
John L. Graner: Duke University
Alfons O. Hamm: University of Greifswald
Martin J. Herrmann: University of Würzburg
Ashley A. Huggins: University of Arizona
Adriane Icenhour: Ruhr University
Asier Juaneda-Seguí: Institut d’Investigació Biomèdica de Bellvitge - IDIBELL
Markus Junghoefer: University of Münster
Tilo Kircher: University of Marburg
Katja Koelkebeck: Department of Psychiatry and Psychotherapy
Manuel Kuhn: University Medical Center Hamburg Eppendorf
Franziska Labrenz: Ruhr University
Shmuel M. Lissek: University of Minnesota
Martin Lotze: University Medicine Greifswald
Ulrike Lueken: partner site Berlin/Potsdam
Jürgen Margraf: partner site Bochum/Marburg
Ignacio Martínez-Zalacaín: Institut d’Investigació Biomèdica de Bellvitge - IDIBELL
Robert Moeck: University of Muenster
Jayne Morriss: University of Southampton
María Ortuño: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Andre Pittig: University of Göttingen
Daniel Porta-Casteras: Institut d’Investigació Biomèdica Sant Pau (IBB-Sant Pau)
Jan Richter: University of Hildesheim
Isabelle C. Ridderbusch: University of Marburg
Winfried Rief: University of Marburg
Kati Roesmann: University of Münster
Jörgen Rosén: Karolinska Institutet
Alena N. Rußmann: University Medical Center Hamburg Eppendorf
Rachel Sjouwerman: University Medical Center Hamburg Eppendorf
Jennifer Spohrs: Ulm University Medical Centre
Andreas Ströhle: Charité - Universitätsmedizin Berlin
Benjamin Suarez-Jimenez: University of Rochester Medical Center
Martin Ulrich: Ulm University Clinic
Hans-Ulrich Wittchen: Ludwig-Maximilians-University München
Xi Zhu: Columbia University Irving Medical Center
Lea Waller: Charité - Universitätsmedizin Berlin
Henrik Walter: partner site Berlin/Potsdam
Paul M. Thompson: University of Southern California
Janna Marie Bas-Hoogendam: Leiden University
Nynke A. Groenewold: University of Cape Town
Dan J. Stein: University of Cape Town
Nic J. Wee: Leiden University Medical Center
Joseph E. Dunsmoor: University of Texas at Austin
Andre F. Marquand: Radboud University
Ben J. Harrison: The University of Melbourne
Miquel A. Fullana: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Pavlovian fear conditioning is a fundamental process in both health and disease. We investigate its neural correlates and sources of variability using harmonized functional magnetic resonance imaging data from 2199 individuals across nine countries, including 1888 healthy individuals and 311 with anxiety-related or depressive disorders. Using mega-analysis and normative modeling, we show that fear conditioning consistently engages brain regions within the “central autonomic–interoceptive” or “salience” network. Several task variables strongly modulate activity in these regions, contributing to variability in neural responses. Additionally, brain activation patterns differ between healthy individuals and those with anxiety-related or depressive disorders, with distinct profiles characterizing specific disorders such as post-traumatic stress disorder and obsessive-compulsive disorder. While the neural correlates of fear conditioning are highly generalizable at the population level, variability arises from differences in task design and clinical status, highlighting the importance of methodological diversity in capturing fear learning mechanisms.

Date: 2025
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DOI: 10.1038/s41467-025-63078-x

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