Neural correlates of human fear conditioning and sources of variability in 2199 individuals
Joaquim Raduà, Hannah S. Savage, Enric Vilajosana, Alec J. Jamieson, Birgit Abler, Fredrik Åhs, Tom Beckers, Narcı́s Cardoner, Josh M. Cisler, Juliana Belo 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.M. 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 Rodrigo Bazán, Emma E. Biggs, Marta Cano, Pamela Chavarría-Elizondo, Samuel E. Cooper, Udo Dannlowski, Víctor De la 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 Kühn, Franziska Labrenz, Shmuel Lissek, Martín Lotze, Ulrike Lueken, Jürgen Margraf, Ignacio Martínez‐Zalacaín, Robert Moeck, Jayne Morriss, María Ortuño, Andre Pittig, Daniel Porta‐Casteràs, Jan Richter, Isabelle C. Ridderbusch, Winfried Rief, Kati Roesmann, Jörgen Rosén, Alena Russmann, Rachel Sjouwerman, Jennifer Spohrs, Andreas Ströhle, Benjamin Suarez‐Jimenez, Ulrich Martin, Hans‐Ulrich Wïttchen, Xi Zhu, Lea Waller, Henrik Walter, Paul M. Thompson, Janna Marie Bas‐Hoogendam, Nynke A. Groenewold, Dan J. Stein, Nic JA van der Wee, Joseph E. Dunsmoor, André F. Marquand, Ben J. Harrison, Miquel À. Fullana
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. A large brain imaging study of over 2000 people worldwide shows that fear conditioning engages brain regions linked to emotion and attention, with differences in individuals with anxiety or depression and strong influences from task design.