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

Joaquim Radua^#^{1

2

3}, Hannah S Savage^#^{4

5

6}, Enric Vilajosana^{1

2}, Alec Jamieson⁷, Birgit Abler⁸, Fredrik Åhs⁹, Tom Beckers^{10

11}, Narcís Cardoner^{12

13

14}, Josh M Cisler¹⁵, Juliana B Diniz¹⁶, Dominik R Bach^{17

18

19}, Sigrid Elsenbruch²⁰, Steven G Greening²¹, Daphne J Holt^{22

23

24}, Antonia N Kaczkurkin²⁵, Andreas Keil²⁶, Merel Kindt²⁷, Kathrin Koch²⁸, Kevin S LaBar²⁹, Charlene L Lam^{30

31}, Christine L Larson³², Tina B Lonsdorf^{33

34}, Christian J Merz³⁵, Katie A McLaughlin^{36

37}, Yuval Neria³⁸, Daniel S Pine³⁹, Carien M van Reekum⁴⁰, Alexander J Shackman^{41

42}, Carles Soriano-Mas^{3

43

44}, Victor I Spoormaker⁴⁵, Daniel M Stout^{46

47

48}, Benjamin Straube^{49

50}, Thomas Straube⁵¹, Lauri Tuominen⁵², Renée M Visser²⁷, Laura Ahumada²⁶, Volker Arolt^{53

54}, Marcelo C Batistuzzo^{16

55}, Paulo R Bazán⁵⁶, Emma E Biggs¹⁰, Marta Cano^{12

13}, Pamela Chavarría-Elizondo^{44

57}, Samuel E Cooper⁵⁸, Udo Dannlowski⁵³, Víctor de la Peña-Arteaga^{12

13

43}, Stephanie N DeCross³⁶, Katharina Domschke^{59

60}, Mana R Ehlers^{33

34}, John L Graner²⁹, Alfons O Hamm⁶¹, Martin J Herrmann⁶², Ashley A Huggins⁶³, Adriane Icenhour²⁰, Asier Juaneda-Seguí⁴⁴, Markus Junghoefer^{54

64}, Tilo Kircher^{49

50}, Katja Koelkebeck⁶⁵, Manuel Kuhn^{34

66

67}, Franziska Labrenz²⁰, Shmuel M Lissek⁶⁸, Martin Lotze⁶⁹, Ulrike Lueken^{60

70}, Jürgen Margraf⁷¹, Ignacio Martínez-Zalacaín^{44

72}, Robert Moeck⁵¹, Jayne Morriss⁷³, María Ortuño¹, Andre Pittig⁷⁴, Daniel Porta-Casteras¹², Jan Richter⁷⁵, Isabelle C Ridderbusch^{49

50}, Winfried Rief⁷⁶, Kati Roesmann^{64

77}, Jörgen Rosén⁷⁸, Alena N Rußmann^{34

79}, Rachel Sjouwerman^{34

80}, Jennifer Spohrs^{81

82}, Andreas Ströhle⁸³, Benjamin Suarez-Jimenez^{84

85}, Martin Ulrich⁸, Hans-Ulrich Wittchen⁸⁶, Xi Zhu^{38

87}, Lea Waller⁸³, Henrik Walter^{60

83}, Paul M Thompson⁸⁸, Janna Marie Bas-Hoogendam^{89

90

91}, Nynke A Groenewold⁹², Dan J Stein⁹³, Nic J Van der Wee^{90

91}, Joseph E Dunsmoor⁹⁴, Andre F Marquand^{4

5}, Ben J Harrison⁷, Miquel A Fullana^{95

96}

Affiliations

¹ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
² University of Barcelona, Barcelona, Spain.
³ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
⁴ Donders Institute of Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
⁵ Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁶ Institute of Cognitive Neuroscience, UCL, London, UK.
⁷ Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia.
⁸ Department of Psychiatry and Psychotherapy III, Ulm University Clinic, Ulm, Germany.
⁹ Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
¹⁰ Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium.
¹¹ Leuven Brain Institute, KU Leuven, Leuven, Belgium.
¹² Sant Pau Mental Health Group, Institut d'Investigació Biomèdica Sant Pau (IBB-Sant Pau), Barcelona, Spain.
¹³ Hospital de la Sant Creu i Sant Pau, Barcelona, Spain.
¹⁴ Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
¹⁵ Department of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas at Austin, Austin, TX, USA.
¹⁶ Department of Psychiatry, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
¹⁷ University of Bonn, Transdisciplinary Research Area "Life and Health", Hertz Chair for Artificial Intelligence and Neuroscience, Institute of Computer Science, Medical Faculty, Institute of Experimental Epileptology and Cognition Research, Bonn, Germany.
¹⁸ University Hospital Bonn, Department of Psychiatry and Psychotherapy, Bonn, Germany.
¹⁹ Department for Imaging Neuroscience, UCL Queen Square Institute of Neurology, University College, London, UK.
²⁰ Department of Medical Psychology and Medical Sociology, Medical Faculty, Ruhr University, Bochum, Germany.
²¹ Brain & Cognitive Sciences, Department of Psychology, University of Manitoba, Winnipeg, Canada.
²² Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA.
²³ Harvard Medical School, Boston, MA, USA.
²⁴ Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Psychology, Vanderbilt University, Nashville, TN, USA.
²⁶ Department of Psychology, University of Florida, Gainesville, FL, USA.
²⁷ Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.
²⁸ School of Medicine and Health, Technical University of Munich, Munich, Germany.
²⁹ Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
³⁰ Laboratory of Clinical Psychology & Affective Neuroscience, Department of Psychology, University of Hong Kong, Hong Kong, China.
³¹ State Key Laboratory of Brain and Cognitive Sciences, Hong Kong, China.
³² University of Wisconsin-Milwaukee, Department of Psychology, Milwaukee, WI, USA.
³³ Biological Psychology and Cognitive Neuroscience, Bielefeld University, Bielefeld, Germany.
³⁴ Institute for Systems Neuroscience, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
³⁵ Department of Cognitive Psychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany.
³⁶ Department of Psychology, Harvard University, Cambridge, MA, USA.
³⁷ Ballmer Institute for Children's Behavioral Health, University of Oregon, Eugene, OR, USA.
³⁸ Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.
³⁹ Section on Development and Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
⁴⁰ School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK.
⁴¹ Department of Psychology, Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD, USA.
⁴² Maryland Neuroimaging Center, University of Maryland, College Park, MD, USA.
⁴³ Department of Social Psychology and Quantitative Psychology, Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
⁴⁴ Psychiatry and Mental Health Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain.
⁴⁵ Max Planck Institute of Psychiatry, Munich, Germany.
⁴⁶ University of California, San Diego, CA, USA.
⁴⁷ VA San Diego Healthcare System, San Diego, CA, USA.
⁴⁸ Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
⁴⁹ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
⁵⁰ Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
⁵¹ Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.
⁵² University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
⁵³ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁵⁴ Otto-Creutzfeld-Center of Cognitive Neuroscience, University of Münster, Münster, Germany.
⁵⁵ Department of Methods and Techniques in Psychology, Pontifical Catholic University, São Paulo, Brazil.
⁵⁶ Radiology Institute, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
⁵⁷ Department of Clinical Sciences, School of Medicine, Universitat de Barcelona - UB, L'Hospitalet de Llobregat, Barcelona, Spain.
⁵⁸ Department of Psychiatry and Behavioral Sciences, University of Texas at Austin, Austin, TX, USA.
⁵⁹ Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁶⁰ German Center of Mental Health (DZPG), partner site Berlin/Potsdam, Berlin, Germany.
⁶¹ Department of Psychology, University of Greifswald, Greifswald, Germany.
⁶² Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
⁶³ Department of Psychology, University of Arizona, Tucson, AZ, USA.
⁶⁴ Institute for Biomagnetism and Biosignal analysis, University of Münster, Münster, Germany.
⁶⁵ Bielefeld University, Medical School and University Medical Center OWL, Protestant Hospital of the Bethel Foundation, Department of Psychiatry and Psychotherapy, Bielefeld, Germany.
⁶⁶ Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA, USA.
⁶⁷ Department of Psychiatry, Harvard Medical School, Cambridge, MA, USA.
⁶⁸ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
⁶⁹ Diagnostic Radiology, University Medicine Greifswald, Greifswald, Germany.
⁷⁰ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁷¹ Mental Health Research and Treatment Center, Ruhr-University Bochum (FBZ) and German Center for Mental Health (DZPG), partner site Bochum/Marburg, Bochum, Germany.
⁷² Radiology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
⁷³ School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK.
⁷⁴ Translational Psychotherapy, Institute for Psychology, University of Göttingen, Göttingen, Germany.
⁷⁵ Department of Experimental Psychopathology, University of Hildesheim, Hildesheim, Germany.
⁷⁶ Division of Clinical Psychology and Psychotherapy, University of Marburg, Marburg, Germany.
⁷⁷ Institute of Psychology, Clinical Psychology in Childhood and Adolescence, University of Osnabrück, Osnabrück, Germany.
⁷⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷⁹ Department of Psychology, Clinical Psychology and Neuroscience, University of Hamburg, Hamburg, Germany.
⁸⁰ Experimental Health Psychology, Maastricht University, Maastricht, The Netherlands.
⁸¹ Department of Child and Adolescent Psychiatry and Psychotherapy, Ulm University Medical Centre, Ulm, Germany.
⁸² Department of Psychiatry, Psychotherapy and Psychotraumatology Military Medical Centre, Ulm, Germany.
⁸³ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸⁴ Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA.
⁸⁵ Center for Visual Sciences, University of Rochester, Rochester, NY, USA.
⁸⁶ Psychiatric University Hospital, Ludwig-Maximilians-University München, München, Germany.
⁸⁷ New York State Psychiatric Institute, New York, NY, USA.
⁸⁸ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸⁹ Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, The Netherlands.
⁹⁰ Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
⁹¹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁹² Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹³ SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹⁴ Department of Neuroscience, University of Texas at Austin, Austin, TX, USA.
⁹⁵ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. mafullana@clinic.cat.
⁹⁶ Adult Psychiatry and Psychology Department, Institute of Neurosciences, Hospital Clinic, Barcelona, Spain. mafullana@clinic.cat.

^# Contributed equally.

PMID: 40849409
PMCID: PMC12375119
DOI: 10.1038/s41467-025-63078-x

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

Joaquim Radua et al. Nat Commun. 2025.

. 2025 Aug 23;16(1):7869.

doi: 10.1038/s41467-025-63078-x.

Authors

Affiliations

¹ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
² University of Barcelona, Barcelona, Spain.
³ Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
⁴ Donders Institute of Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
⁵ Department of Cognitive Neuroscience, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁶ Institute of Cognitive Neuroscience, UCL, London, UK.
⁷ Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia.
⁸ Department of Psychiatry and Psychotherapy III, Ulm University Clinic, Ulm, Germany.
⁹ Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
¹⁰ Faculty of Psychology and Educational Sciences, KU Leuven, Leuven, Belgium.
¹¹ Leuven Brain Institute, KU Leuven, Leuven, Belgium.
¹² Sant Pau Mental Health Group, Institut d'Investigació Biomèdica Sant Pau (IBB-Sant Pau), Barcelona, Spain.
¹³ Hospital de la Sant Creu i Sant Pau, Barcelona, Spain.
¹⁴ Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
¹⁵ Department of Psychiatry and Behavioral Sciences, Dell Medical School, University of Texas at Austin, Austin, TX, USA.
¹⁶ Department of Psychiatry, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
¹⁷ University of Bonn, Transdisciplinary Research Area "Life and Health", Hertz Chair for Artificial Intelligence and Neuroscience, Institute of Computer Science, Medical Faculty, Institute of Experimental Epileptology and Cognition Research, Bonn, Germany.
¹⁸ University Hospital Bonn, Department of Psychiatry and Psychotherapy, Bonn, Germany.
¹⁹ Department for Imaging Neuroscience, UCL Queen Square Institute of Neurology, University College, London, UK.
²⁰ Department of Medical Psychology and Medical Sociology, Medical Faculty, Ruhr University, Bochum, Germany.
²¹ Brain & Cognitive Sciences, Department of Psychology, University of Manitoba, Winnipeg, Canada.
²² Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA, USA.
²³ Harvard Medical School, Boston, MA, USA.
²⁴ Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Psychology, Vanderbilt University, Nashville, TN, USA.
²⁶ Department of Psychology, University of Florida, Gainesville, FL, USA.
²⁷ Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands.
²⁸ School of Medicine and Health, Technical University of Munich, Munich, Germany.
²⁹ Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
³⁰ Laboratory of Clinical Psychology & Affective Neuroscience, Department of Psychology, University of Hong Kong, Hong Kong, China.
³¹ State Key Laboratory of Brain and Cognitive Sciences, Hong Kong, China.
³² University of Wisconsin-Milwaukee, Department of Psychology, Milwaukee, WI, USA.
³³ Biological Psychology and Cognitive Neuroscience, Bielefeld University, Bielefeld, Germany.
³⁴ Institute for Systems Neuroscience, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
³⁵ Department of Cognitive Psychology, Institute of Cognitive Neuroscience, Ruhr University Bochum, Bochum, Germany.
³⁶ Department of Psychology, Harvard University, Cambridge, MA, USA.
³⁷ Ballmer Institute for Children's Behavioral Health, University of Oregon, Eugene, OR, USA.
³⁸ Department of Psychiatry, Columbia University Irving Medical Center, New York, NY, USA.
³⁹ Section on Development and Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
⁴⁰ School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK.
⁴¹ Department of Psychology, Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD, USA.
⁴² Maryland Neuroimaging Center, University of Maryland, College Park, MD, USA.
⁴³ Department of Social Psychology and Quantitative Psychology, Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
⁴⁴ Psychiatry and Mental Health Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge - IDIBELL, L'Hospitalet de Llobregat, Spain.
⁴⁵ Max Planck Institute of Psychiatry, Munich, Germany.
⁴⁶ University of California, San Diego, CA, USA.
⁴⁷ VA San Diego Healthcare System, San Diego, CA, USA.
⁴⁸ Center of Excellence for Stress and Mental Health, San Diego, CA, USA.
⁴⁹ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
⁵⁰ Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
⁵¹ Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.
⁵² University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
⁵³ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁵⁴ Otto-Creutzfeld-Center of Cognitive Neuroscience, University of Münster, Münster, Germany.
⁵⁵ Department of Methods and Techniques in Psychology, Pontifical Catholic University, São Paulo, Brazil.
⁵⁶ Radiology Institute, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
⁵⁷ Department of Clinical Sciences, School of Medicine, Universitat de Barcelona - UB, L'Hospitalet de Llobregat, Barcelona, Spain.
⁵⁸ Department of Psychiatry and Behavioral Sciences, University of Texas at Austin, Austin, TX, USA.
⁵⁹ Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
⁶⁰ German Center of Mental Health (DZPG), partner site Berlin/Potsdam, Berlin, Germany.
⁶¹ Department of Psychology, University of Greifswald, Greifswald, Germany.
⁶² Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
⁶³ Department of Psychology, University of Arizona, Tucson, AZ, USA.
⁶⁴ Institute for Biomagnetism and Biosignal analysis, University of Münster, Münster, Germany.
⁶⁵ Bielefeld University, Medical School and University Medical Center OWL, Protestant Hospital of the Bethel Foundation, Department of Psychiatry and Psychotherapy, Bielefeld, Germany.
⁶⁶ Center for Depression, Anxiety, and Stress Research, McLean Hospital, Belmont, MA, USA.
⁶⁷ Department of Psychiatry, Harvard Medical School, Cambridge, MA, USA.
⁶⁸ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
⁶⁹ Diagnostic Radiology, University Medicine Greifswald, Greifswald, Germany.
⁷⁰ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁷¹ Mental Health Research and Treatment Center, Ruhr-University Bochum (FBZ) and German Center for Mental Health (DZPG), partner site Bochum/Marburg, Bochum, Germany.
⁷² Radiology Department, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
⁷³ School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK.
⁷⁴ Translational Psychotherapy, Institute for Psychology, University of Göttingen, Göttingen, Germany.
⁷⁵ Department of Experimental Psychopathology, University of Hildesheim, Hildesheim, Germany.
⁷⁶ Division of Clinical Psychology and Psychotherapy, University of Marburg, Marburg, Germany.
⁷⁷ Institute of Psychology, Clinical Psychology in Childhood and Adolescence, University of Osnabrück, Osnabrück, Germany.
⁷⁸ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷⁹ Department of Psychology, Clinical Psychology and Neuroscience, University of Hamburg, Hamburg, Germany.
⁸⁰ Experimental Health Psychology, Maastricht University, Maastricht, The Netherlands.
⁸¹ Department of Child and Adolescent Psychiatry and Psychotherapy, Ulm University Medical Centre, Ulm, Germany.
⁸² Department of Psychiatry, Psychotherapy and Psychotraumatology Military Medical Centre, Ulm, Germany.
⁸³ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁸⁴ Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA.
⁸⁵ Center for Visual Sciences, University of Rochester, Rochester, NY, USA.
⁸⁶ Psychiatric University Hospital, Ludwig-Maximilians-University München, München, Germany.
⁸⁷ New York State Psychiatric Institute, New York, NY, USA.
⁸⁸ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸⁹ Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, The Netherlands.
⁹⁰ Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden, The Netherlands.
⁹¹ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁹² Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹³ SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁹⁴ Department of Neuroscience, University of Texas at Austin, Austin, TX, USA.
⁹⁵ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. mafullana@clinic.cat.
⁹⁶ Adult Psychiatry and Psychology Department, Institute of Neurosciences, Hospital Clinic, Barcelona, Spain. mafullana@clinic.cat.

^# Contributed equally.

PMID: 40849409
PMCID: PMC12375119
DOI: 10.1038/s41467-025-63078-x

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.

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Conflict of interest statement

Competing interests: Dr Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson,. Kanna, L’Oreal,Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. The other authors declare no competing interests.

Figures

**Fig. 1. Neural correlates and individual-level heterogeneity in human fear conditioning.**
Schematic indicating the levels of analysis (a). Significant brain functional activation (b) and deactivation (c) to the CS+ versus CS− determined by mega-analysis (n = 1888 healthy controls). Schematic of normative modelling framework (d). Normative probability maps illustrate the percentage of participants in the healthy control test sample who had positive (hot colours -right) or negative deviations (cool colours - left) >±2.6 within each voxel. Circle highlights frequent large deviations (both positive and negative) within the most ventral region of the vmPFC (e). AIC anterior insular cortex, AG angular gyrus, CN caudate nucleus, dACC dorsal anterior cingulate cortex, dlPFC dorsolateral prefrontal cortex, dPFC dorsal prefrontal cortex, dPons dorsal pons, dPrec dorsal precuneus, Hipp hippocampus, HYP hypothalamus, lOFC lateral orbitofrontal cortex, PCC posterior cingulate cortex, SI primary somatosensory cortex, SII secondary somatosensory cortex, SMA supplementary motor area, TG temporal gyrus, Thal thalamus, vmPFC ventromedial prefrontal cortex. Source data are provided as a Source Data file.

**Fig. 2. Robust influence of task variables on brain activation during fear conditioning.**
Maps show the influence of pre-task instructions about CS-US contingency (a), type of US (b), number of CS used in paradigm (i.e. multiple CS+ or CS- or single CS+ or CS-) (c), pairing rate (d), and potential US confounding in CS + > CS- contrast (e) on mean activation (left; mega-analysis linear mixed-effects models) and relation to predicted activation (right; normative model structure coefficients). For the mega-analysis, warm colours indicate positive correlations (i.e., higher variable values associated with greater activation), while cool colours indicate negative correlations (i.e., higher variable values associated with reduced activation). For normative modeling, structure coefficient maps show the correlation coefficients (rho) thresholded by their respective coefficients of determination (rho2 > 0.3) of selected task variables. This can be interpreted as showing how predicted activation to the CS + > CS- contrast relates to the task variables included in the building of the normative models. Positive correlations (warm colours) indicate greater activation for higher values of the input variable and negative correlations (cool colours) greater activation for lower values of the input variable (note that some variables are dummy coded, e.g., pre-task instructions, type of US). CS Conditioned Stimulus; US Unconditioned Stimulus. For Pairing Rate (RR) in linear mixed-effects models, the figure shows significant results in the ANOVA comparing four categories (RR30, RR50, RR62, RR100). For the results of post-hoc tests, see Supplementary Figs. S6 and S7. Source data are provided as a Source Data file.

**Fig. 3. Differences between individuals with anxiety-related and depressive disorders and healthy controls in human fear conditioning.**
Regions wherein individuals with anxiety-related and depressive disorders (n = 311) showed significantly increased functional activation to the CS+ versus CS − , as compared to healthy controls (a). Normative probability maps illustrate the percentage of participants in the sample (test controls – top; individuals with anxiety-related and depressive disorders – bottom) who had positive (hot colours – right) or negative deviations (cool colours – left) > ±2.6 within each voxel (b). Box plots show the distribution of the total number of large deviations (> ±2.6) per group. The centre line indicates the median; box bounds represent the 25 and 75th percentiles (interquartile range, IQR); whiskers extend to the smallest and largest values within 1.5 × IQR from the lower and upper quartiles. Sample sizes: control group n = 646; PTSD n = 55; OCD n = 68; GAD n = 48; SAD n = 31; total clinical group n = 202 (c). Normative probability maps illustrate the percentage of each clinical group who had positive (hot colours – right) or negative deviations (cool colours – left) > ±2.6 within each voxel (d). Confusion matrix for multi-class support vector machine differentiating patterns of deviations among clinical groups (e). ARDD anxiety-related and depressive disorders, GAD Generalised Anxiety Disorder, OCD Obsessive Compulsive Disorder, PTSD Post-traumatic Stress Disorder, SAD Social Anxiety Disorder. * = p < 0.05, ** = p < 0.01, *** = p < 0.0001. Kruskal–Wallis H-tests were used to test for main group effects (cases vs controls), with follow-up Mann–Whitney U tests false discovery rate (FDR) corrected at α = 0.05. Source data are provided as a Source Data file.

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References

1. Beckers, T. et al. Understanding clinical fear and anxiety through the lens of human fear conditioning. Nat. Rev. Psychol.2, 233–245 (2023). - PMC - PubMed
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Neural correlates of human fear conditioning and sources of variability in 2199 individuals

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources