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[Preprint]. 2025 Mar 20:2025.03.19.25323474.

doi: 10.1101/2025.03.19.25323474.

Brain Aging in Specific Phobia: An ENIGMA-Anxiety Mega-Analysis

Kimberly V Blake¹, Kevin Hilbert², Jonathan C Ipser¹, Laura K M Han³, Janna Marie Bas-Hoogendam^{4

5

6}, Fredrik Åhs⁷, Jochen Bauer⁸, Katja Beesdo-Baum⁹, Johannes Björkstrand¹⁰, Laura Blanco-Hinojo¹¹, Joscha Böhnlein¹², Robin Bülow¹³, Marta Cano¹⁴, Narcis Cardoner¹⁴, Xavier Caseras¹⁵, Udo Dannlowski¹², Mats Fredrikson¹⁶, Liesbet Goossens¹⁷, Hans J Grabe¹⁸, Dominik Grotegerd¹², Tim Hahn¹², Alfons Hamm¹⁹, Ingmar Heinig²⁰, Martin J Herrmann²¹, David Hofmann²², Hamidreza Jamalabadi^{23

24}, Andreas Jansen^{23

24}, Merel Kindt²⁵, Tilo Kircher^{23

24}, Anna L Klahn²⁶, Katja Koelkebeck²⁷, Axel Krug^{23

24}, Elisabeth J Leehr¹², Martin Lotze²⁸, Juergen Margraf²⁹, Markus Muehlhan^{30

31}, Igor Nenadić^{23

24}, Wenceslao Peñate³², Andre Pittig³³, Jens Plag³⁴, Jesús Pujol¹¹, Jan Richter³⁵, Isabelle C Ridderbusch^{23

24}, Francisco Rivero³⁶, Axel Schäfer^{37

38}, Judith Schäfer²⁰, Anne Schienle³⁹, Elisabeth Schrammen¹², Koen Schruers¹⁷, Esther Seidl⁴⁰, Rudolf M Stark⁴¹, Benjamin Straube⁴², Thomas Straube²¹, Andreas Ströhle⁴³, Lea Teutenberg^{23

24}, Sophia I Thomopoulos⁴⁴, Carlos Ventura-Bort⁴⁵, Renee M Visser²⁵, Henry Völzke⁴⁶, Albert Wabnegger³⁹, Julia Wendt⁴⁷, Hans-Ulrich Wittchen⁴⁸, Katharina Wittfeld¹⁸, Yunbo Yang⁴⁹, Anna Zilverstand⁵⁰, Peter Zwanzger⁵¹, Lianne Schmaal³, Moji Aghajani⁵², Daniel S Pine⁵³, Paul M Thompson⁴⁴, Nic J A van der Wee^{5

6}, Dan J Stein^{1

54}, Ulrike Lueken^{55

56}, Nynke A Groenewold¹

Affiliations

¹ Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
² Department of Psychology, Health and Medical University Erfurt, Erfurt, Germany.
³ Centre for Youth Mental Health, University of Melbourne, Orygen, Parkville, VIC, Australia.
⁴ Department of Developmental and Educational Psychology Leiden University, Leiden, The Netherlands.
⁵ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
⁷ Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
⁸ University Clinic for Radiology, University of Münster, Münster, Germany.
⁹ Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Dresden, Germany.
¹⁰ Department of Psychology, Lund University, Lund, Sweden.
¹¹ MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.
¹² Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹³ Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹⁴ Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.
¹⁵ Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
¹⁶ Department of Psychology, Uppsala University, Uppsala, Sweden.
¹⁷ Department of Psychiatry and Neuropsychology, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹⁹ Institute of Psychology, University of Greifswald, Greifswald, Germany.
²⁰ Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
²¹ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
²² Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany.
²³ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
²⁴ Center for Mind, Brain and Behavior (CMBB), Marburg, Germany.
²⁵ University of Amsterdam, Amsterdam, The Netherlands.
²⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁷ LVR-University Hospital Essen, Medical Faculty, Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany.
²⁸ Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
²⁹ Mental Health Research and Treatment Center, Ruhr-Universitaet Bochum, Bochum, Germany.
³⁰ Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany.
³¹ ICAN Institute of Cognitive and Affective Neuroscience, MSH Medical School Hamburg, Hamburg, Germany.
³² Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, Spain.
³³ Translational Psychotherapy, Institute of Psychology, University of Göttingen, Göttingen, Germany.
³⁴ Faculty of Medicine, Institute for Mental Health and Behavioral Medicine, HMU Health and Medical University Potsdam, Potsdam, Germany.
³⁵ Institute of Psychology, University of Hildesheim, Hildesheim, Germany.
³⁶ Universidad Europea de Canarias, La Orotava, Spain.
³⁷ Bender Institute of Neuroimaging, Justus Liebig University Giessen, Giessen, Germany.
³⁸ Center for Mind, Brain and Behavior, Philipps-University Marburg, Marburg, Germany.
³⁹ University of Graz, Graz, Austria.
⁴⁰ SBA Research, Vienna, Austria.
⁴¹ Department of Psychotherapy and Systems Neuroscience, Justus Liebig University Giessen, Giessen, Germany.
⁴² Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁴³ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁴⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, California, CA, USA.
⁴⁵ Department of Psychology, University of Potsdam, Potsdam, Germany.
⁴⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Department of Biological Psychology and Affective Science, Faculty of Human Sciences, University of Potsdam, Potsdam, Germany.
⁴⁸ Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.
⁴⁹ Department of Experimental Psychopathology, Institute for Psychology, Hildesheim University, Hildesheim, Germany.
⁵⁰ Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
⁵¹ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany.
⁵² Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, The Netherlands.
⁵³ Emotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
⁵⁴ SA-MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
⁵⁵ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁵⁶ German Center for Mental Health (DZPG), partner site Berlin/Potsdam, Germany.

PMID: 40166564
PMCID: PMC11957081
DOI: 10.1101/2025.03.19.25323474

Brain Aging in Specific Phobia: An ENIGMA-Anxiety Mega-Analysis

Kimberly V Blake et al. medRxiv. 2025.

[Preprint]. 2025 Mar 20:2025.03.19.25323474.

doi: 10.1101/2025.03.19.25323474.

Authors

Affiliations

¹ Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
² Department of Psychology, Health and Medical University Erfurt, Erfurt, Germany.
³ Centre for Youth Mental Health, University of Melbourne, Orygen, Parkville, VIC, Australia.
⁴ Department of Developmental and Educational Psychology Leiden University, Leiden, The Netherlands.
⁵ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
⁷ Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
⁸ University Clinic for Radiology, University of Münster, Münster, Germany.
⁹ Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, TUD - Dresden University of Technology, Dresden, Germany.
¹⁰ Department of Psychology, Lund University, Lund, Sweden.
¹¹ MRI Research Unit, Department of Radiology, Hospital del Mar, Barcelona, Spain.
¹² Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹³ Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
¹⁴ Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.
¹⁵ Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
¹⁶ Department of Psychology, Uppsala University, Uppsala, Sweden.
¹⁷ Department of Psychiatry and Neuropsychology, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁸ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹⁹ Institute of Psychology, University of Greifswald, Greifswald, Germany.
²⁰ Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
²¹ Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany.
²² Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany.
²³ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
²⁴ Center for Mind, Brain and Behavior (CMBB), Marburg, Germany.
²⁵ University of Amsterdam, Amsterdam, The Netherlands.
²⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁷ LVR-University Hospital Essen, Medical Faculty, Department of Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany.
²⁸ Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
²⁹ Mental Health Research and Treatment Center, Ruhr-Universitaet Bochum, Bochum, Germany.
³⁰ Department of Psychology, Faculty of Human Sciences, MSH Medical School Hamburg, Hamburg, Germany.
³¹ ICAN Institute of Cognitive and Affective Neuroscience, MSH Medical School Hamburg, Hamburg, Germany.
³² Department of Clinical Psychology, Psychobiology and Methodology, University of La Laguna, La Laguna, Spain.
³³ Translational Psychotherapy, Institute of Psychology, University of Göttingen, Göttingen, Germany.
³⁴ Faculty of Medicine, Institute for Mental Health and Behavioral Medicine, HMU Health and Medical University Potsdam, Potsdam, Germany.
³⁵ Institute of Psychology, University of Hildesheim, Hildesheim, Germany.
³⁶ Universidad Europea de Canarias, La Orotava, Spain.
³⁷ Bender Institute of Neuroimaging, Justus Liebig University Giessen, Giessen, Germany.
³⁸ Center for Mind, Brain and Behavior, Philipps-University Marburg, Marburg, Germany.
³⁹ University of Graz, Graz, Austria.
⁴⁰ SBA Research, Vienna, Austria.
⁴¹ Department of Psychotherapy and Systems Neuroscience, Justus Liebig University Giessen, Giessen, Germany.
⁴² Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁴³ Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁴⁴ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, California, CA, USA.
⁴⁵ Department of Psychology, University of Potsdam, Potsdam, Germany.
⁴⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Department of Biological Psychology and Affective Science, Faculty of Human Sciences, University of Potsdam, Potsdam, Germany.
⁴⁸ Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany.
⁴⁹ Department of Experimental Psychopathology, Institute for Psychology, Hildesheim University, Hildesheim, Germany.
⁵⁰ Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
⁵¹ Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany.
⁵² Institute of Education & Child Studies, Section Forensic Family & Youth Care, Leiden University, Leiden, The Netherlands.
⁵³ Emotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
⁵⁴ SA-MRC Unit on Risk and Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
⁵⁵ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁵⁶ German Center for Mental Health (DZPG), partner site Berlin/Potsdam, Germany.

PMID: 40166564
PMCID: PMC11957081
DOI: 10.1101/2025.03.19.25323474

Abstract

Introduction: Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, brain age research in psychiatry has primarily examined mood and psychotic disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group.

Methods: 3D brain structural MRI scans from 17 international samples (600 SPH individuals, of whom 504 formally diagnosed and 96 questionnaire-based cases; 1,134 controls; age range: 22-75 years) were processed with FreeSurfer. Brain age was estimated from 77 subcortical and cortical regions with a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as brain age minus chronological age. Linear mixed-effect models examined group differences in brain-PAD and moderation by age.

Results: No significant group difference in brain-PAD manifested (β _diagnosis (SE)=0.37 years (0.43), p=0.39). A negative diagnosis-by-age interaction was identified, which was most pronounced in formally diagnosed SPH (β _{diagnosis-by-age}=-0.08 (0.03), pFDR=0.02). This interaction remained significant when excluding participants with anxiety comorbidities, depressive comorbidities, and medication use. Post-hoc analyses revealed a group difference for formal SPH diagnosis in younger participants (22-35 years; β _diagnosis=1.20 (0.60), p<0.05, mixed-effects d (95% confidence interval)=0.14 (0.00-0.28)), but not older participants (36-75 years; β _diagnosis=0.07 (0.65), p=0.91).

Conclusions: Brain aging did not relate to SPH in the full sample. However, a diagnosis-by-age interaction was observed across analyses, and was strongest in formally diagnosed SPH. Post-hoc analyses showed a subtle advanced brain aging in young adults with formally diagnosed SPH. Taken together, these findings indicate the importance of clinical severity, impairment and persistence, and may suggest a slightly earlier end to maturational processes or subtle decline of brain structure in SPH.

Keywords: Phobic disorders; brain age; brain morphometry; machine learning; mega-analysis; neuroimaging.

PubMed Disclaimer

Conflict of interest statement

Disclosures HJG has received travel grants and speakers honoraria from Neuraxpharm, Servier, Indorsia and Janssen Cilag. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

**Figure 1.**
Chronological age plotted against predicted brain age in the full sample. Note. SPH, specific phobia. Diagonal dashed line represents the line of identity (x = y).

See this image and copyright information in PMC

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This is a preprint.

Brain Aging in Specific Phobia: An ENIGMA-Anxiety Mega-Analysis

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Brain Aging in Specific Phobia: An ENIGMA-Anxiety Mega-Analysis

Authors

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Abstract

Conflict of interest statement

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