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[Preprint]. 2025 Jul 1:rs.3.rs-6866544.

doi: 10.21203/rs.3.rs-6866544/v1.

Brain Age Prediction in Generalized Anxiety Disorder using a Convolutional Neural Network

Corey Richier^{1

2}, André Zugman², Anita Harrewijn^{2

3}, Elise M Cardinale^{2

4}, Parmis Khosravi², Moji Aghajani⁵, Willem B Bruin⁵, Kevin Hilbert⁶, Narcis Cardoner^{7

8

9}, Daniel Porta-Casteràs⁷, Marta Cano^{7

8

9}, Savannah Gosnell¹⁰, Ramiro Salas¹⁰, Andrea P Jackowski¹¹, Pedro M Pan¹¹, Giovanni A Salum¹², Karina S Blair¹³, James R Blair¹⁴, Mohammed R Milad¹⁵, Katie L Burkhouse¹⁶, K Luan Phan¹⁷, Heidi K Schroeder¹⁸, Jeffrey R Strawn¹⁸, Katja Beesdo-Baum¹⁹, Neda Jahanshad²⁰, Sophia I Thomopoulos²⁰, Jared A Nielsen^{21

22

23}, Jordan W Smoller²², Jair C Soares²⁴, Benson Mwangi²⁴, Mon-Ju Wu²⁴, Giovana B Zunta-Soares²⁴, Michal Assaf^{25

26}, Gretchen J Diefenbach^{26

27}, Paolo Brambilla^{28

29}, Eleonora Maggioni²⁸, David Hofmann³⁰, Thomas Straube³⁰, Carmen Andreescu³¹, Rebecca B Price^{31

32}, Gisele G Manfro³³, Federica Agosta^{34

35}, Elisa Canu³⁴, Camilla Cividini^{34

35}, Massimo Filippi^{34

35

36

37

38}, Milutin Kostić^{39

40}, Ana Munjiza Jovanovic³⁹, Brenda Benson², Gabrielle F Freitag², Ellen Leibenluft², Grace V Ringlein^{2

41}, Kathryn Werwath⁴², Hannah Zwiebel², Hans J Grabe^{43

44}, Sandra Van der Auwera^{43

44}, Katharina Wittfeld⁴³, Henry Völzke⁴⁵, Robin Bülow⁴⁶, Nicholas L Balderston⁴⁷, Monique Ernst⁴⁸, Lilianne R Mujica-Parodi⁴⁹, Helena van Nieuwenhuizen⁵⁰, Hugo D Critchley⁵¹, Elena Makovac⁵², Matteo Mancini⁵³, Frances Meeten⁵⁴, Cristina Ottaviani^{55

56}, Gregory A Fonzo⁵⁷, Martin P Paulus⁵⁸, Murray B Stein⁵⁹, Raquel E Gur⁶⁰, Ruben C Gur⁶⁰, Antonia N Kaczkurkin⁶¹, Bart Larsen^{60

62}, Theodore D Satterthwaite⁶⁰, Jennifer Harper⁶³, Michael T Perino⁶³, Chad M Sylvester⁶³, Qiongru Yu⁶³, Patrick McClure⁶⁴, Francisco Pereira⁶⁴, Ulrike Lueken⁶⁵, Dick J Veltman⁶⁶, Paul M Thompson²⁰, Nynke A Groenewold⁶⁷, Janna Marie Bas-Hoogendam^{68

69

70}, Dan J Stein^{71

67}, Nic J A Van der Wee^{68

70}, Anderson M Winkler^{2

72}, Daniel S Pine², Chelsea K Sawyers^{2

73}

Affiliations

¹ Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
² Emotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
³ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands.
⁴ Department of Psychology, The Catholic University of America.
⁵ Leiden University, Institute of Education & Child Studies, Section Forensic Family & Youth Care.
⁶ Department of Psychology, HMU Health and Medical University Erfurt, Erfurt, Germany.
⁷ Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.
⁸ Centro de Investigación Biomédica En Red en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁹ Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
¹⁰ Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
¹¹ LiNC, Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil.
¹² Section on Negative Affect and Social Processes, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
¹³ Center for Neurobehavioral Research, Boys Town National Research Hospital, Boys Town, NE, USA.
¹⁴ Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
¹⁵ Department of Psychiatry, NYU School of Medicine, New York University, New York, NY, USA.
¹⁶ Department of Psychology, Penn State University, University Park, PA, USA.
¹⁷ Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA.
¹⁸ Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
¹⁹ Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
²⁰ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
²¹ Center for Brain Science & Department of Psychology, Harvard University, Cambridge, MA, USA.
²² Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
²³ Psychology Department & Neuroscience Center, Brigham Young University.
²⁴ Center 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.
²⁵ Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
²⁶ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
²⁷ Anxiety Disorders Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
²⁸ Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²⁹ Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
³⁰ Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.
³¹ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
³² Department Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
³³ Anxiety Disorder Program, Hospital de Clínicas de Porto Alegre, Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
³⁴ Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁵ Vita-Salute San Raffaele University, Milan, Italy.
³⁶ Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁷ Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁸ Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁹ Institute of Mental Health, University of Belgrade, Belgrade, Serbia.
⁴⁰ Department of Psychiatry, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁴¹ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴² Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
⁴³ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁴⁴ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
⁴⁵ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁶ Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Center for Neuromodulation in Depression and Stress, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁸ Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
⁴⁹ Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
⁵⁰ Department of Physics, Stony Brook University, Stony Brook, NY, USA.
⁵¹ Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.
⁵² Department of Psychology, Brunel University London.
⁵³ "Enrico Fermi" Research Center, Rome, Italy.
⁵⁴ Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵⁵ Department of Psychology, Sapienza University of Rome, Rome, Italy.
⁵⁶ IRCCS Santa Lucia Foundation.
⁵⁷ Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
⁵⁸ Laureate Institute for Brain Research, Tulsa, OK, USA.
⁵⁹ Department of Psychiatry, School of Medicine and Herbert Wertheim School of Public Health, University of California, San Diego, La Jolla, CA, USA.
⁶⁰ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
⁶¹ Department of Psychology, Vanderbilt University, Nashville, TN, USA.
⁶² Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
⁶³ Department of Psychiatry, Washington University, St. Louis, MO, USA.
⁶⁴ Machine Learning Core, National Institute of Mental Health, Bethesda, MD, USA.
⁶⁵ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Mental Health (DZPG), partner site Berlin-Potsdam.
⁶⁶ Department of Psychiatry, Amsterdam UMC, location VUMC, Amsterdam, The Netherlands.
⁶⁷ Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁶⁸ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁶⁹ Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, The Netherlands.
⁷⁰ Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
⁷¹ South African Medical Research Council Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁷² University of Texas Rio Grande Valley, Brownsville, TX, USA.
⁷³ Division of Child and Adolescent Psychiatry, Department of Psychiatry, Virginia Commonwealth University.

PMID: 40630531
PMCID: PMC12236912
DOI: 10.21203/rs.3.rs-6866544/v1

Brain Age Prediction in Generalized Anxiety Disorder using a Convolutional Neural Network

Corey Richier et al. Res Sq. 2025.

[Preprint]. 2025 Jul 1:rs.3.rs-6866544.

doi: 10.21203/rs.3.rs-6866544/v1.

Authors

Affiliations

¹ Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
² Emotion and Development Branch, National Institute of Mental Health, Bethesda, MD, USA.
³ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands.
⁴ Department of Psychology, The Catholic University of America.
⁵ Leiden University, Institute of Education & Child Studies, Section Forensic Family & Youth Care.
⁶ Department of Psychology, HMU Health and Medical University Erfurt, Erfurt, Germany.
⁷ Sant Pau Mental Health Research Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.
⁸ Centro de Investigación Biomédica En Red en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
⁹ Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
¹⁰ Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.
¹¹ LiNC, Department of Psychiatry, Federal University of São Paulo, São Paulo, Brazil.
¹² Section on Negative Affect and Social Processes, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
¹³ Center for Neurobehavioral Research, Boys Town National Research Hospital, Boys Town, NE, USA.
¹⁴ Child and Adolescent Mental Health Center, Copenhagen University Hospital - Mental Health Services CPH, Copenhagen, Denmark.
¹⁵ Department of Psychiatry, NYU School of Medicine, New York University, New York, NY, USA.
¹⁶ Department of Psychology, Penn State University, University Park, PA, USA.
¹⁷ Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, USA.
¹⁸ Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA.
¹⁹ Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
²⁰ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, CA, USA.
²¹ Center for Brain Science & Department of Psychology, Harvard University, Cambridge, MA, USA.
²² Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
²³ Psychology Department & Neuroscience Center, Brigham Young University.
²⁴ Center 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.
²⁵ Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
²⁶ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
²⁷ Anxiety Disorders Center, Institute of Living, Hartford Hospital, Hartford, CT, USA.
²⁸ Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
²⁹ Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
³⁰ Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.
³¹ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
³² Department Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
³³ Anxiety Disorder Program, Hospital de Clínicas de Porto Alegre, Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
³⁴ Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁵ Vita-Salute San Raffaele University, Milan, Italy.
³⁶ Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁷ Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁸ Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
³⁹ Institute of Mental Health, University of Belgrade, Belgrade, Serbia.
⁴⁰ Department of Psychiatry, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁴¹ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴² Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
⁴³ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁴⁴ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
⁴⁵ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
⁴⁶ Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
⁴⁷ Center for Neuromodulation in Depression and Stress, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁸ Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, Bethesda, MD, USA.
⁴⁹ Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA.
⁵⁰ Department of Physics, Stony Brook University, Stony Brook, NY, USA.
⁵¹ Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.
⁵² Department of Psychology, Brunel University London.
⁵³ "Enrico Fermi" Research Center, Rome, Italy.
⁵⁴ Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
⁵⁵ Department of Psychology, Sapienza University of Rome, Rome, Italy.
⁵⁶ IRCCS Santa Lucia Foundation.
⁵⁷ Department of Psychiatry and Behavioral Sciences, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
⁵⁸ Laureate Institute for Brain Research, Tulsa, OK, USA.
⁵⁹ Department of Psychiatry, School of Medicine and Herbert Wertheim School of Public Health, University of California, San Diego, La Jolla, CA, USA.
⁶⁰ Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
⁶¹ Department of Psychology, Vanderbilt University, Nashville, TN, USA.
⁶² Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
⁶³ Department of Psychiatry, Washington University, St. Louis, MO, USA.
⁶⁴ Machine Learning Core, National Institute of Mental Health, Bethesda, MD, USA.
⁶⁵ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Mental Health (DZPG), partner site Berlin-Potsdam.
⁶⁶ Department of Psychiatry, Amsterdam UMC, location VUMC, Amsterdam, The Netherlands.
⁶⁷ Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁶⁸ Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
⁶⁹ Department of Developmental and Educational Psychology, Institute of Psychology, Leiden University, Leiden, The Netherlands.
⁷⁰ Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
⁷¹ South African Medical Research Council Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁷² University of Texas Rio Grande Valley, Brownsville, TX, USA.
⁷³ Division of Child and Adolescent Psychiatry, Department of Psychiatry, Virginia Commonwealth University.

PMID: 40630531
PMCID: PMC12236912
DOI: 10.21203/rs.3.rs-6866544/v1

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, p < .001) and evidence for greater variability in PAD of those with GAD over 25 years of age. No relationships between PAD and clinical or demographic measures were found. To conclude, using large training and testing samples, the study found no significant association between GAD and PAD, although individuals with GAD had greater heterogeneity in brain-predicted age.

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Figures

**Figure 1**
Overview of the CNN Model Architecture. *Note*. The CNN architecture was designed with four input channels for gray and white matter segmentations, as well as the T1-weighted and Jacobian images. The model consists of five repeated convolutional blocks, each containing 3D convolutional layers, batch normalization, ReLU activations and max pooling. The number of filters used in each block are denoted above. After the last convolutional block, the model includes a flattened layer.

**Figure 2**
Model Ensemble Procedure *Note*. Procedure for generating average predictions for the model ensemble. Eight splits of the training data were created, which used a different 90/10% split of training to validation data. Each of these splits was given to a unique instantiation of the model with identical architecture but instantiated with random weights.

**Figure 3**
Scatter Plot of True Age vs. Predicted Age Sorted By Diagnostic Status

**Figure 4**
Violin Plot of Variance in PAD across Age and Diagnostic Groups

See this image and copyright information in PMC

References

1. Szuhany K.L. and Simon N.M., Anxiety Disorders: A Review. JAMA, 2022. 328(24): p. 2431–2445. - PubMed
1. Wittchen H.-U., Generalized anxiety disorder: prevalence, burden, and cost to society. Depression and Anxiety, 2002. 16(4): p. 162–171. - PubMed
1. Kessler R.C., et al. , Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 2005. 62(6): p. 617. - PMC - PubMed
1. Kessler R.C., et al. , Lifetime Prevalence and Age-of-Onset Distributions of DSM-IV Disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry, 2005. 62(6): p. 593. - PubMed
1. Cole J.H., et al. , Predicting brain age with deep learning from raw imaging data results in a reliable and heritable biomarker. NeuroImage, 2017. 163: p. 115–124. - PubMed

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This is a preprint.

Brain Age Prediction in Generalized Anxiety Disorder using a Convolutional Neural Network

Affiliations

Brain Age Prediction in Generalized Anxiety Disorder using a Convolutional Neural Network

Authors

Affiliations

Abstract

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous