ArticleResearch square2025
Brain Age Prediction in Generalized Anxiety Disorder using a Convolutional Neural Network.
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91 authors.
Corey RichierDepartment of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
André ZugmanEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.ORCID 0000-0002-6126-7759
Anita HarrewijnEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Elise M CardinaleEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Parmis KhosraviEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Moji AghajaniLeiden University, Institute of Education & Child Studies, Section Forensic Family & Youth Care.ORCID 0000-0003-2040-4881
Willem B BruinLeiden University, Institute of Education & Child Studies, Section Forensic Family & Youth Care.ORCID 0000-0002-0672-8903
Kevin HilbertDepartment of Psychology, HMU Health and Medical University Erfurt, Erfurt, Germany.ORCID 0000-0002-7986-4113
Narcis CardonerSant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.ORCID 0000-0001-9633-0888
Daniel Porta-CasteràsSant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.ORCID 0000-0002-3921-3607
Marta CanoSant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.ORCID 0000-0003-0675-9483
Savannah GosnellMenninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
Ramiro SalasMenninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.ORCID 0000-0002-1105-566X
Andrea P JackowskiLiNC, Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil.ORCID 0000-0001-8842-5406
Pedro M PanLiNC, Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil.ORCID 0000-0002-1943-6520
Giovanni A SalumSection on Negative Affect and Social Processes, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Karina S BlairCenter for Neurobehavioral Research, Boys Town National Research Hospital, Boys Town, NE, USA.
James R BlairChild and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.ORCID 0000-0002-6377-2361
Mohammed R MiladDepartment of Psychiatry, NYU School of Medicine, New York University, New York, NY, USA.
Katie L BurkhouseDepartment of Psychology, Penn State University, University Park, PA, USA.
K Luan PhanDepartment of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA.
Heidi K SchroederDepartment of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
Jeffrey R StrawnDepartment of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
Katja Beesdo-BaumBehavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
Neda JahanshadImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
Sophia I ThomopoulosImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
Jared A NielsenCenter for Brain Science & Department of Psychology, Harvard University, Cambridge, MA, USA.ORCID 0000-0002-2717-193X
Jordan W SmollerDepartment of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Jair C SoaresCenter Of Excellence On Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID 0000-0002-5466-5628
Benson MwangiCenter Of Excellence On Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Mon-Ju WuCenter Of Excellence On Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID 0000-0002-0540-8027
Giovana B Zunta-SoaresCenter Of Excellence On Mood Disorders, Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Michal AssafOlin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.ORCID 0000-0001-5307-1986
Gretchen J DiefenbachDepartment of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
Paolo BrambillaDepartment of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.ORCID 0000-0002-4021-8456
Eleonora MaggioniDepartment of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.ORCID 0000-0003-4331-4029
David HofmannInstitute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.ORCID 0000-0003-3494-634X
Thomas StraubeInstitute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.
Carmen AndreescuDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.ORCID 0000-0003-3767-5127
Rebecca B PriceDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Gisele G ManfroAnxiety Disorder Program, Hospital de Clínicas de Porto Alegre, Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.ORCID 0000-0002-0109-7591
Federica AgostaNeuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID 0000-0003-3121-4979
Elisa CanuNeuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Camilla CividiniNeuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Massimo FilippiNeuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.ORCID 0000-0002-5485-0479
Milutin KostićInstitute of Mental Health, University of Belgrade, Belgrade, Serbia.
Ana Munjiza JovanovicInstitute of Mental Health, University of Belgrade, Belgrade, Serbia.
Brenda BensonEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Gabrielle F FreitagEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Ellen LeibenluftEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Grace V RingleinEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Kathryn WerwathPsychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Hannah ZwiebelEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Hans J GrabeDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Sandra Van der AuweraDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.ORCID 0000-0002-1757-7768
Katharina WittfeldDepartment of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.ORCID 0000-0003-4383-5043
Henry VölzkeInstitute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Robin BülowInstitute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.ORCID 0000-0003-1884-5784
Nicholas L BalderstonCenter for Neuromodulation in Depression and Stress, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-8565-1544
Monique ErnstSection on Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
Lilianne R Mujica-ParodiDepartment of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
Helena van NieuwenhuizenDepartment of Physics, Stony Brook University, Stony Brook, NY, USA.
Hugo D CritchleyDepartment of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.ORCID 0000-0002-2445-9284
Elena MakovacDepartment of Psychology, Brunel University London.
Matteo Mancini"Enrico Fermi" Research Center, Rome, Italy.
Frances MeetenDepartment of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Cristina OttavianiDepartment of Psychology, Sapienza University of Rome, Rome, Italy.ORCID 0000-0002-5240-4387
Gregory A FonzoDepartment of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA.ORCID 0000-0002-0213-1034
Martin P PaulusLaureate Institute for Brain Research, Tulsa, OK, USA.ORCID 0000-0002-0825-3606
Murray B SteinDepartment of Psychiatry, School of Medicine and Herbert Wertheim School of Public Health, University of California, San Diego, La Jolla, CA, USA.ORCID 0000-0001-9564-2871
Raquel E GurDepartment of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
Ruben C GurDepartment of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-4082-8502
Antonia N KaczkurkinDepartment of Psychology, Vanderbilt University, Nashville, TN, USA.ORCID 0000-0002-0943-3094
Bart LarsenDepartment of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0001-7896-4342
Theodore D SatterthwaiteDepartment of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
Jennifer HarperDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Michael T PerinoDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Chad M SylvesterDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Qiongru YuDepartment of Psychiatry, Washington University, St. Louis, MO, USA.
Patrick McClureMachine Learning Core, National Institute of Mental Health, Bethesda, MD, USA.
Francisco PereiraMachine Learning Core, National Institute of Mental Health, Bethesda, MD, USA.
Ulrike LuekenDepartment of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Mental Health (DZPG), partner site Berlin-Potsdam.ORCID 0000-0003-1564-4012
Dick J VeltmanDepartment of Psychiatry, Amsterdam UMC, location VUMC, Amsterdam, The Netherlands.
Paul M ThompsonImaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
Nynke A GroenewoldDepartment of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.ORCID 0000-0002-0865-8427
Janna Marie Bas-HoogendamDepartment of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.ORCID 0000-0001-8982-1670
Dan J SteinSouth African Medical Research Council Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.ORCID 0000-0001-7218-7810
Nic J A Van der WeeDepartment of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
Anderson M WinklerEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Daniel S PineEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
Chelsea K SawyersEmotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.ORCID 0000-0001-9704-6555
Funding
fMRI Studies Of Pediatric Mood And Anxiety DisordersZIAMH002781 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI PINE, DANIEL · 2009 to 2025
$41.5MPenn Mental Health AIDS Research CenterP30MH097488 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI Karine Dube, Kelly L Jordan-Sciutto · 2013 to 2026
$23.5MIntramural NIH HHS ZIA MH002781NIMH NIH HHS P30 MH097488
Abstract
Higher predicted brain age difference has been associated with several psychiatric disorders. Generalized anxiety disorder (GAD) is associated with markers of accelerated aging. In this study, we determined brain predicted age difference (PAD) in individuals with GAD and healthy controls (HC) as well as group differences in PAD variability using voxel-wise structural MRI. The training dataset included 3,511 controls, and the testing dataset included 1,595 individuals with GAD and 4,552 HC from the ENIGMA-Anxiety GAD Working Group. A convolutional neural network model using four input modalities per subject and a model ensemble approach was used to predict brain age. The PAD was then calculated by subtracting chronological age. Model performance was consistent with other image-based brain age prediction models with similar accuracy across the training set (mean absolute error (MAE) = 2.95 years) and HC in the testing set (MAE = 2.94). We found no evidence of accelerated brain aging in individuals with GAD, though we did find evidence for greater variation in PAD for individuals with GAD (Levene's test: W = 442.98,
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