TY - JOUR
T1 - Neural correlates of human fear conditioning and sources of variability in 2199 individuals
AU - Radua, Joaquim
AU - Savage, Hannah S.
AU - Vilajosana, Enric
AU - Jamieson, Alec
AU - Abler, Birgit
AU - Åhs, Fredrik
AU - Beckers, Tom
AU - Cardoner, Narcís
AU - Cisler, Josh M.
AU - Diniz, Juliana B.
AU - Bach, Dominik R.
AU - Elsenbruch, Sigrid
AU - Greening, Steven G.
AU - Holt, Daphne J.
AU - Kaczkurkin, Antonia N.
AU - Keil, Andreas
AU - Kindt, Merel
AU - Koch, Kathrin
AU - LaBar, Kevin S.
AU - Lam, Charlene L.
AU - Larson, Christine L.
AU - Lonsdorf, Tina B.
AU - Merz, Christian J.
AU - McLaughlin, Katie A.
AU - Neria, Yuval
AU - Pine, Daniel S.
AU - van Reekum, Carien M.
AU - Shackman, Alexander J.
AU - Soriano-Mas, Carles
AU - Spoormaker, Victor I.
AU - Stout, Daniel M.
AU - Straube, Benjamin
AU - Straube, Thomas
AU - Tuominen, Lauri
AU - Visser, Renée M.
AU - Ahumada, Laura
AU - Arolt, Volker
AU - Batistuzzo, Marcelo C.
AU - Bazán, Paulo R.
AU - Biggs, Emma E.
AU - Cano, Marta
AU - Chavarría-Elizondo, Pamela
AU - Cooper, Samuel E.
AU - Dannlowski, Udo
AU - de la Peña-Arteaga, Víctor
AU - DeCross, Stephanie N.
AU - Domschke, Katharina
AU - Ehlers, Mana R.
AU - Graner, John L.
AU - Sjouwerman, Rachel
AU - Et al.
N1 - Funding Information:
The research was supported by Secretaria d\u2019Universitats i Recerca del Departament d\u2019Economia i Coneixement de la Generalitat de Catalunya (No. 2021 SGR 1128, J.R.; M.A.F.), the Swedish Research Council (No. 2014-01160, F.\u00C5.), the European Research Council (No. 648176, T.B.; ERC-2018 CoG-816564, D.B.; 101001118, A.F.M.), the National Institute of Mental Health (No. R01MH119132 and MH108753, J.C.; R01MH095904 and K23MH076054, D.J.H.; R01MH125615, A.K.; R01-MH103291, K.A.M.; 1R61MH129559-02, Y.N.; R01-AA031261, A.S.; K01MH122774, X.Z.; R01MH131532, B.S.J; R01MH125615, L.A.), the German Research Foundation (No. 316803389 - SFB 1280, S.E., C.J.M. and A.I.; LO 1980/1-1 and CRC-TRR58 subproject B07, T.B.L.; LO 1980/4-1, T.B.L. and M.R.E.; 521379614 \u2013 TRR393, B.S., U.D. and T.K.; 44541416 CRC-TRR58 T.S., K.R., K.D. and M.J.; 442075332 (RU 5187) and 461947532 (RU 5389), U.L.; WA 1539/11-1, H.W.;), the Economic and Social Research Council UK (No. ES/W000776/1, D.B.), the NSERC Discovery (No. RGPIN-2021-02906, S.G.), the National Institute of Health (No. R01 MH106574, C.L.; R01 MH122387, J.D.), the United states-Israel binational science foundation and NIA (No. 2P30AG064198, Y.N.), the National Institute of Mental Health Intramural Research (No. ZIA-MH-002781, D.P.), the Biotechnology and Biological Sciences Research Council (No. BB/L02697X/1, C.vR.), NIAAA (No. R01-AA030042, A.S.), the Instituto de Salud Carlos III (ISCIII) (No. PI16/00889 and PI19/01171, C.S.M.; FI22/00219, M.O.), Fundaci\u00F3 Marat\u00F3 de TV3 (No. 202201-31, C.S.M.), Ag\u00E8ncia de Gesti\u00F3 d\u2019Ajuts Universitaris i de Recerca (No. 2021SGR01017, C.S.M.), the Ministerio de Ciencia, Innovaci\u00F3n y Universidades, Spain (No. PID2022-139081OB-C22, C.S.M.), the Department of Veteran Affairs (No. I01-CX002760, D.M.S.), the German Federal Ministry of Education and Research (No. 01EE1402E, B.S., T.K., A.P., U.D., K.D. and H-U.W.; 01EE2101, U.L.), Brain and Behavior Research Foundation NARSAD Young Investigator Award (X.Z.), \u201Cla Caixa\u201D Foundation (No. LCF/BQ/IN17/11620071, V.P.A.), Spanish Ministry of Science, Innovation and Universities (No. JDC2022\u2013048445-I, V.P.A), the National Eye Institute Core Grant (No. P30 EY001319, B.S.J.), the Medical Research Council (No. MR/J003980/1, J.M.), National Science Foundation Graduate Research Fellowship (No. DGE1745303, S.N.D.), the South African Medical Research Council (D.J.S.), the EU Innovative Medicines Initiative (IMI) 2 Joint Undertaking (IMI2 JU) (No. 101034377, NJVW), the Dutch Research Agenda (NeuroLabNL\u2013Small Projects for NWA routes 21/22) (No. NWA.1418.22.025, JM.B-H.), the Talent Acceleration grant (Medical Delta) (JM.B-H.), the NIH Big Data to Knowledge (BD2K) award (No. U54 EB020403 and R01MH131806, P.M.T.), the National Health and Medical Research Council of Australia (NHMRC) Project Grants (No. 1161897 and 1145010, B.J.H.).
Publisher Copyright:
© The Author(s) 2025.
PY - 2025/8/23
Y1 - 2025/8/23
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-025-63078-x
DO - 10.1038/s41467-025-63078-x
M3 - Article
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7869
ER -