ArticlemedRxiv : the preprint server for health sciences2023
Two neurostructural subtypes: results of machine learning on brain images from 4,291 individuals with schizophrenia.
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107 authors at 20 institutions in 16 countries.
Yuchao JiangInstitute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai, China.
Cheng LuoThe Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, School of life Science and technology, University of Electronic Science and Technology of China, Chengdu, China.
Jijun WangShanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Lena PalaniyappanDouglas Mental Health University Institute, Department of Psychiatry, McGill University, Montréal, Canada.
Xiao ChangInstitute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai, China.
Shitong XiangInstitute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai, China.
Jie ZhangInstitute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai, China.
Mingjun DuanThe Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, School of life Science and technology, University of Electronic Science and Technology of China, Chengdu, China.
Huan HuangThe Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, School of life Science and technology, University of Electronic Science and Technology of China, Chengdu, China.
Christian GaserDepartment of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
Kiyotaka NemotoDepartment of Psychiatry, Division of Clinical Medicine, Institute of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
Kenichiro MiuraDepartment of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, 187-8553, Japan.
Ryota HashimotoDepartment of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, 187-8553, Japan.
Lars T WestlyeDepartment of Psychology, University of Oslo, Oslo, Norway.
Genevieve RichardDepartment of Psychology, University of Oslo, Oslo, Norway.
Sara Fernandez-CabelloDepartment of Psychology, University of Oslo, Oslo, Norway.
Nadine ParkerNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Ole A AndreassenNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Tilo KircherDepartment of Psychiatry and Psychotherapy, Philipps Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
Igor NenadićDepartment of Psychiatry and Psychotherapy, Philipps Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
Frederike SteinDepartment of Psychiatry and Psychotherapy, Philipps Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
Florian Thomas-OdenthalDepartment of Psychiatry and Psychotherapy, Philipps Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
Lea TeutenbergDepartment of Psychiatry and Psychotherapy, Philipps Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
Paula UsemannDepartment of Psychiatry and Psychotherapy, Philipps Universität Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
Udo DannlowskiInstitute for Translational Psychiatry, University of Münster, Münster, Germany.
Tim HahnInstitute for Translational Psychiatry, University of Münster, Münster, Germany.
Dominik GrotegerdInstitute for Translational Psychiatry, University of Münster, Münster, Germany.
Susanne MeinertInstitute for Translational Psychiatry, University of Münster, Münster, Germany.
Rebekka LencerInstitute for Translational Psychiatry, University of Münster, Münster, Germany.
Yingying TangShanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Tianhong ZhangShanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Chunbo LiShanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Weihua YuePeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, PR China.
Yuyanan ZhangPeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, PR China.
Xin YuPeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, PR China.
Enpeng ZhouPeking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, PR China.
Ching-Po LinInstitute of Neuroscience, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Shih-Jen TsaiDepartment of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
Amanda L RodrigueDepartment of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston MA, USA.
David GlahnDepartment of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston MA, USA.
Godfrey PearlsonOlin Neuropsychiatry Research Center, Institute of Living, Hartford, CT, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas of the Rio Grande Valley, Brownsville, TX, USA.
Andriana KarukFIDMAG Germanes Hospitalàries Research Foundation, Barcelona 08035, Spain.
Edith Pomarol-ClotetFIDMAG Germanes Hospitalàries Research Foundation, Barcelona 08035, Spain.
Raymond SalvadorFIDMAG Germanes Hospitalàries Research Foundation, Barcelona 08035, Spain.
Paola Fuentes-ClaramonteFIDMAG Germanes Hospitalàries Research Foundation, Barcelona 08035, Spain.
María Ángeles Garcia-LeónFIDMAG Germanes Hospitalàries Research Foundation, Barcelona 08035, Spain.
Gianfranco SpallettaNeuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, IRCCS Santa Lucia Foundation, Rome, Italy.
Fabrizio PirasNeuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, IRCCS Santa Lucia Foundation, Rome, Italy.
Daniela VecchioNeuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, IRCCS Santa Lucia Foundation, Rome, Italy.
Nerisa BanajNeuropsychiatry Laboratory, Department of Clinical Neuroscience and Neurorehabilitation, IRCCS Santa Lucia Foundation, Rome, Italy.
Jingliang ChengDepartment of MRI, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Zhening LiuNational Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
Jie YangNational Clinical Research Center for Mental Disorders, Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
Ali Saffet GonulEge University School of Medicine Department of Psychiatry, SoCAT Lab, Izmir, Turkey.
Ozgul UsluEge University Institute of Health Sciences Department of Neuroscience, Izmir, Turkey.
Birce Begum BurhanogluEge University Institute of Health Sciences Department of Neuroscience, Izmir, Turkey.
Aslihan Uyar DemirEge University School of Medicine Department of Psychiatry, SoCAT Lab, Izmir, Turkey.
Kelly Rootes-MurdyTri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) [Georgia State University, Georgia Institute of Technology, Emory University], Atlanta, GA, USA.
Vince D CalhounTri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) [Georgia State University, Georgia Institute of Technology, Emory University], Atlanta, GA, USA.
Kang SimWest Region, Institute of Mental Health, Singapore.
Melissa GreenSchool of Clinical Medicine, University of New South Wales, Sydney, Australia.
Yann QuidéSchool of Psychology, University of New South Wales, Sydney, Australia.
Young Chul ChungDepartment of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea.
Woo-Sung KimDepartment of Psychiatry, Jeonbuk National University Hospital, Jeonju, Korea.
Scott R SponheimMinneapolis VA Medical Center, University of Minnesota, Minneapolis, MN, USA.
Caroline DemroDepartment of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
Ian S RamsayDepartment of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
Felice IasevoliSection of Psychiatry - Department of Neuroscience - University "Federico II", Naples, Italy.
Andrea de BartolomeisSection of Psychiatry - Department of Neuroscience - University "Federico II", Naples, Italy.
Annarita BaroneSection of Psychiatry - Department of Neuroscience - University "Federico II", Naples, Italy.
Mariateresa CiccarelliSection of Psychiatry - Department of Neuroscience - University "Federico II", Naples, Italy.
Arturo BrunettiDepartment of Advanced Biomedical Sciences - University "Federico II", Naples, Italy.
Sirio CocozzaDepartment of Advanced Biomedical Sciences - University "Federico II", Naples, Italy.
Giuseppe PontilloDepartment of Advanced Biomedical Sciences - University "Federico II", Naples, Italy.
Mario TranfaDepartment of Advanced Biomedical Sciences - University "Federico II", Naples, Italy.
Min Tae M ParkDepartment of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.
Matthias KirschnerDivision of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, Switzerland.
Foivos GeorgiadisDepartment of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital University of Zurich, Switzerland.
Stefan KaiserDivision of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, Switzerland.
Tamsyn E Van RheenenMelbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne, Australia.
Susan L RossellCentre for Mental Health and Brain Sciences, School of Health Sciences, Swinburne University, Melbourne, Australia.
Matthew HughesCentre for Mental Health and Brain Sciences, School of Health Sciences, Swinburne University, Melbourne, Australia.
William WoodsCentre for Mental Health and Brain Sciences, School of Health Sciences, Swinburne University, Melbourne, Australia.
Sean P CarruthersCentre for Mental Health and Brain Sciences, School of Health Sciences, Swinburne University, Melbourne, Australia.
Philip SumnerCentre for Mental Health and Brain Sciences, School of Health Sciences, Swinburne University, Melbourne, Australia.
Elysha RinginNational Institute of Mental Health, Klecany, Czech Republic.
Filip SpanielNational Institute of Mental Health, Klecany, Czech Republic.
Antonin SkochNational Institute of Mental Health, Klecany, Czech Republic.
David TomecekNational Institute of Mental Health, Klecany, Czech Republic.
Philipp HomanPsychiatric Hospital, University of Zurich, Zurich, Switzerland.
Stephanie HomanDepartment of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital Zurich, Switzerland.
Wolfgang OmlorPsychiatric Hospital, University of Zurich, Zurich, Switzerland.
Giacomo CecerePsychiatric Hospital, University of Zurich, Zurich, Switzerland.
Dana D NguyenDepartment of Pediatrics, University of California Irvine, Irvine, California, USA.
Adrian PredaDepartment of Psychiatry and Human Behavior, University of California Irvine, Irvine, California, USA.
Sophia ThomopoulosImaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Neda JahanshadImaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Long-Biao CuiDepartment of Clinical Psychology, Fourth Military Medical University, Xi'an, PR China.
Dezhong YaoThe Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, School of life Science and technology, University of Electronic Science and Technology of China, Chengdu, China.
Paul M ThompsonImaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Jessica A TurnerPsychiatry and Behavioral Health, Ohio State Wexner Medical Center, Columbus, OH, USA.
Theo G M van ErpClinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine Hall, room 109, Irvine, CA, 92697-3950, USA.
Wei ChengInstitute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai, China.
ENIGMA Schizophrenia Consortium
ZIB Consortium
Jianfeng FengInstitute of Science and Technology for Brain Inspired Intelligence, Fudan University, Shanghai, China.
Federico II University Hospital · ITPhilipps University of Marburg · DEUniversity of Zurich · CHInstituto de Salud Carlos III · ESOslo University Hospital · NOSwinburne University of Technology · AUUniversity of Münster · DEEge University · TRFondazione Santa Lucia · ITFudan University · CNPeking University · CNShanghai Jiao Tong University · CNUniversity of Electronic Science and Technology of China · CNUniversity of California, Irvine · USUniversity of Minnesota · USUniversity of Southern California · USBoston Children's Hospital · USCentral South University · CNGeorgia Institute of Technology · USJeonbuk National University Hospital · KR
Funding
FUNCTION BIRNU24RR021992 · NCRR · UNIVERSITY OF CALIFORNIA-IRVINE · PI POTKIN, STEVEN G · 2006 to 2010
$25.0MSouth Texas Alzheimer's Disease Research CenterP30AG066546 · NIA · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Mohamad Habes · 2021 to 2026
$24.0MGenetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI SCOTT Loren POMEROY, MUSTAFA SAHIN · 2021 to 2026
$9.4MNEURAL MECHANISMS OF SCHIZOPHRENIAP20RR021938 · NCRR · THE MIND RESEARCH NETWORK · PI JUNG, REX · 2008 to 2011
$9.4MMining the Genomewide Scan: Genetic Profiles of Structural Loss in Schizophrenia: AD/ADRD supplementR01MH094524 · NIMH · THE MIND RESEARCH NETWORK · PI CALHOUN, VINCE D, TURNER, JESS · 2012 to 2021
$6.3MRio Grande Valley Alzheimer's Resource Center for Minority Aging Research: Partnerships for ProgressP30AG059305 · NIA · UNIVERSITY OF TEXAS RIO GRANDE VALLEY · PI Gladys E. Maestre · 2018 to 2026
$5.8MHuman Connectome Project for Early PsychosisU01MH109977 · NIMH · BRIGHAM AND WOMEN'S HOSPITAL · PI BREIER, ALAN, SHENTON, MARTHA E. · 2016 to 2020
$5.5MNeural Disconnection and Errant Visual Perception in Psychotic PsychopathologyU01MH108150 · NIMH · UNIVERSITY OF MINNESOTA · PI SPONHEIM, SCOTT R · 2016 to 2021
$5.0MENIGMA-COINSTAC-APOE2 Functional and structural connectome protective mechanisms for Alzheimer’s disease and mood disorders: Request for supplemental funds for NIH R01:1R01MH121246R01MH121246 · NIMH · OHIO STATE UNIVERSITY · PI CALHOUN, VINCE D, TURNER, JESS · 2019 to 2023
$5.0MGenetics of Brain Structure and FunctionR01MH078111 · NIMH · TEXAS BIOMEDICAL RESEARCH INSTITUTE · PI BLANGERO, JOHN · 2006 to 2014
$4.5MGenetics of Brain Structure and FunctionR01MH078143 · NIMH · YALE UNIVERSITY · PI GLAHN, DAVID C · 2006 to 2014
$4.3MGene Networks Influencing Psychotic Dysconnectivity in African AmericansR01MH106324 · NIMH · YALE UNIVERSITY · PI BLANGERO, JOHN, GLAHN, DAVID C · 2015 to 2019
$4.2MCSRD VA I01 CX000227NCRR NIH HHS P20 RR021938NCRR NIH HHS U24 RR021992NIA NIH HHS P30 AG059305NIA NIH HHS P30 AG066546NIA NIH HHS R01 AG058464NICHD NIH HHS P50 HD105351NIMH NIH HHS R01 MH056584NIMH NIH HHS R01 MH078111NIMH NIH HHS R01 MH078143NIMH NIH HHS R01 MH084803NIMH NIH HHS R01 MH094524NIMH NIH HHS R01 MH106324NIMH NIH HHS R01 MH121246NIMH NIH HHS R21 MH097196NIMH NIH HHS U01 MH108150NIMH NIH HHS U01 MH109977
Abstract
Machine learning can be used to define subtypes of psychiatric conditions based on shared clinical and biological foundations, presenting a crucial step toward establishing biologically based subtypes of mental disorders. With the goal of identifying subtypes of disease progression in schizophrenia, here we analyzed cross-sectional brain structural magnetic resonance imaging (MRI) data from 4,291 individuals with schizophrenia (1,709 females, age=32.5 years±11.9) and 7,078 healthy controls (3,461 females, age=33.0 years±12.7) pooled across 41 international cohorts from the ENIGMA Schizophrenia Working Group, non-ENIGMA cohorts and public datasets. Using a machine learning approach known as Subtype and Stage Inference (SuStaIn), we implemented a brain imaging-driven classification that identifies two distinct neurostructural subgroups by mapping the spatial and temporal trajectory of gray matter (GM) loss in schizophrenia. Subgroup 1 (n=2,622) was characterized by an early cortical-predominant loss (ECL) with enlarged striatum, whereas subgroup 2 (n=1,600) displayed an early subcortical-predominant loss (ESL) in the hippocampus, amygdala, thalamus, brain stem and striatum. These reconstructed trajectories suggest that the GM volume reduction originates in the Broca's area/adjacent fronto-insular cortex for ECL and in the hippocampus/adjacent medial temporal structures for ESL. With longer disease duration, the ECL subtype exhibited a gradual worsening of negative symptoms and depression/anxiety, and less of a decline in positive symptoms. We confirmed the reproducibility of these imaging-based subtypes across various sample sites, independent of macroeconomic and ethnic factors that differed across these geographic locations, which include Europe, North America and East Asia. These findings underscore the presence of distinct pathobiological foundations underlying schizophrenia. This new imaging-based taxonomy holds the potential to identify a more homogeneous sub-population of individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.
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artificial intelligencebrain gray matterENIGMAschizophreniastructural MRIsubtype
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