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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Kimberly V Blake - , University of Cape Town (Author)
  • Kevin Hilbert - , HMU Health and Medical University (Author)
  • Jonathan C Ipser - , University of Cape Town (Author)
  • Laura K M Han - , University of Melbourne (Author)
  • Janna Marie Bas-Hoogendam - , Leiden University (Author)
  • Fredrik Åhs - , Mid Sweden University (Author)
  • Jochen Bauer - , University of Münster (Author)
  • Katja Beesdo-Baum - , Chair of Behavioral Epidemiology (Author)
  • Johannes Björkstrand - , Lund University (Author)
  • Laura Blanco-Hinojo - , Hospital del Mar (Author)
  • Joscha Böhnlein - , University of Münster (Author)
  • Robin Bülow - , Greifswald University Hospital (Author)
  • Marta Cano - , Sant Pau Research Institute (Author)
  • Narcis Cardoner - , Sant Pau Research Institute (Author)
  • Xavier Caseras - , Cardiff University (Author)
  • Udo Dannlowski - , C-I-R-C Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (Author)
  • Mats Fredrikson - , Uppsala University (Author)
  • Liesbet Goossens - , Maastricht University (Author)
  • Hans J Grabe - , Greifswald University Hospital (Author)
  • Dominik Grotegerd - , University of Münster (Author)
  • Tim Hahn - , University of Münster (Author)
  • Alfons Hamm - , University of Greifswald (Author)
  • Ingmar Heinig - , Chair of Clinical Psychology and Behavioral Neuroscience (Author)
  • Martin J Herrmann - , University Hospital of Würzburg (Author)
  • David Hofmann - , University of Münster (Author)
  • Hamidreza Jamalabadi - , Center for Mind, Brain and Behavior (CMBB) (Author)
  • Andreas Jansen - , University of Marburg, Center for Mind, Brain and Behavior (CMBB) (Author)
  • Merel Kindt - , Amsterdam University Medical Centers (UMC) (Author)
  • Tilo Kircher - , Center for Mind, Brain and Behavior (CMBB) (Author)
  • Anna L Klahn - , University of Gothenburg (Author)
  • Katja Koelkebeck - , University Hospital Bielefeld (Author)
  • Axel Krug - , University of Bonn Medical Center (Author)
  • Elisabeth J Leehr - , University of Münster (Author)
  • Martin Lotze - , Greifswald University Hospital (Author)
  • Juergen Margraf - , Ruhr University Bochum (Author)
  • Markus Muehlhan - , MSH Medical School Hamburg (Author)
  • Igor Nenadić - , University of Marburg, Center for Mind, Brain and Behavior (CMBB) (Author)
  • Wenceslao Peñate - , University of La Laguna (Author)
  • Andre Pittig - , University of Göttingen (Author)
  • Jens Plag - , HMU Health and Medical University (Author)
  • Jesús Pujol - , Hospital del Mar (Author)
  • Jan Richter - , University of Hildesheim (Author)
  • Isabelle C Ridderbusch - , Center for Mind, Brain and Behavior (CMBB) (Author)
  • Francisco Rivero - , European University of the Canary Islands (Author)
  • Axel Schäfer - , University of Marburg (Author)
  • Judith Schäfer - , Chair of Behavioral Epidemiology (Author)
  • Anne Schienle - , University of Graz (Author)
  • Elisabeth Schrammen - , University of Münster (Author)
  • Koen Schruers - , Maastricht University (Author)
  • Esther Seidl - , SBA Research (Author)
  • Rudolf M Stark - , Justus Liebig University Giessen (Author)
  • Benjamin Straube - , University of Marburg (Author)
  • Thomas Straube - , University of Münster (Author)
  • Andreas Ströhle - , Charité – Universitätsmedizin Berlin (Author)
  • Boris Suchan - , Ruhr University Bochum (Author)
  • Lea Teutenberg - , Center for Mind, Brain and Behavior (CMBB) (Author)
  • Sophia I Thomopoulos - , Keck School of Medicine at University of Southern California (Author)
  • Carlos Ventura-Bort - , University of Potsdam (Author)
  • Renee M Visser - , Amsterdam University Medical Centers (UMC) (Author)
  • Henry Völzke - , Greifswald University Hospital (Author)
  • Albert Wabnegger - , University of Graz (Author)
  • André Wannemüller - , Amsterdam University Medical Centers (UMC) (Author)
  • Julia Wendt - , University of Potsdam (Author)
  • Hans-Ulrich Wittchen - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Katharina Wittfeld - , Greifswald University Hospital (Author)
  • Yunbo Yang - , University of Hildesheim (Author)
  • Anna Zilverstand - , University of Minnesota (Author)
  • Peter Zwanzger - , Hospital of the Ludwig-Maximilians-University (LMU) Munich (Author)
  • Lianne Schmaal - , University of Melbourne (Author)
  • Moji Aghajani - , Leiden University (Author)
  • Daniel S Pine - , National Institutes of Health (NIH) (Author)
  • Paul M Thompson - , Keck School of Medicine at University of Southern California (Author)
  • Nic J A van der Wee - , Leiden University (Author)
  • Dan J Stein - , University of Cape Town (Author)
  • Ulrike Lueken - , Charité – Universitätsmedizin Berlin (Author)
  • Nynke A Groenewold - , University of Cape Town (Author)

Abstract

Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, limited brain age research has been conducted in anxiety disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group. 3D brain structural MRI scans from 17 international samples (600 SPH individuals, of whom 504 formally diagnosed and 96 questionnaire-based cases; 1134 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-effects models examined group differences in brain-PAD and moderation by age. 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). 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 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.

Details

Original languageEnglish
Article numbere70595
JournalHuman brain mapping
Volume47
Issue number10
Publication statusPublished - Jul 2026
Peer-reviewedYes

External IDs

Scopus 105043884401
ORCID /0000-0002-9687-5527/work/220697305
ORCID /0000-0002-7762-4327/work/220700499

Keywords

Keywords

  • Adult, Aged, Aging/pathology, Brain/diagnostic imaging, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Phobic Disorders/diagnostic imaging, Young Adult, brain age, machine learning, neuroimaging, mega-analysis, brain morphometry, phobic disorders