Reproducible grey matter patterns index a multivariate, global alteration of brain structure in schizophrenia and bipolar disorder

The IMAGEMEND Consortium, Karolinska Schizophrenia Project (KaSP) Consortium

Research output: Contribution to JournalArticleAcademicpeer-review


Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.

Original languageEnglish
Article number12
Pages (from-to)1-13
Number of pages13
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 17 Jan 2019


We thank all the patients and healthy volunteers for their willingness to participate in the study. We also wish to express our appreciation to the KaSP research nurses. We would further like to thank Dr. Axel Schaefer and Marina Cariello for their assistance with this study. This study was supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602450 (IMAGEMEND, IMAging GENetics for MENtal Disorders) and the Deutsche Forschungsgemeinschaft (DFG), SCHW 1768/1-1. A.M.-L. was supported by the Deutsche Forschungsgemeinschaft (DFG) (Collaborative Research Center SFB 636, subproject B7); the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Programme (BMBF Grant 01ZX1314A and 01ZX1314G); and the Innovative Medicines Initiative Joint Undertaking (IMI) under Grant Agreements no 115300 (European Autism Interventions—A Multicentre Study for Developing New Medications) and no 602805 (European Union-Aggressotype). This study made use of the Dutch sample of the International Multicentre persistent ADHD CollaboraTion (IMpACT). IMpACT unites major research centres working on the genetics of ADHD persistence across the lifespan and has participants in the Netherlands, Germany, Spain, Norway, the United Kingdom, the United States, Brazil, and Sweden. The Dutch IMpACT node is supported by grants from the Netherlands Organisation for Scientific Research (NWO; grants 433-09-229 and 016-130-669 to BF), from the European Community’s Seventh Framework Programme (FP7/2007-2013) (grant agreements no 278948 (TACTICS), no 602450 (IMAGEMEND), and no 602805 (Aggressotype)) and Horizon 2020 Programme (grant agreements no 643051 (MiND) and no 667302 (CoCA)). This research also receives funding from the European College of Neuropsychopharmacology (ECNP) Network ‘ADHD across the Lifespan’ and the National Institutes of Health (NIH) Consortium grant U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centers of Excellence. The NeuroIMAGE study, also contributing data to this study, represents the longitudinal follow-up of the Dutch subsample of the International Multicentre ADHD Genetics (IMAGE) project. PIs of NeuroIMAGE are Jan Buitelaar and Barbara Franke (Radboud University Medical Center, Nijmegen), Jaap Oosterlaan and Dirk Heslenfeld (Vrije Universiteit Medical Centre, Amsterdam), and Pieter Hoekstra and Catharina Hartman (University Medical Centre Groningen). NeuroIMAGE is supported by grants from The Netherlands Organization for Health Research and Development (ZonMw 60-60600-97-193), the Netherlands Organization for Scientific Research (NWO, grants 1750102007010, 433-09-242 and 056-13-015), and by the European Community’s Seventh Framework Programme (FP7/ 2007-2013) under grant agreement number 278948 (TACTICS), 602450 (IMAGEMEND), 602805 (AGGRESSOTYPE), 603016 (MATRICS), and Horizon 2020 (grant agreement 643051 (MiND) and 642996 (BRAINVIEW) research programmes. T.P.G. acknowledges funding from The Research Council of Norway (grant #223273) and the KG Jebsen Foundation. J.O. acknowledges funding by NIH Grant R01MH62873, NWO Large Investment Grant 1750102007010 and an NWO Brain & Cognition grant (056-24-011), the European Union 7th Framework programs AGGRESSOTYPE (602805) and MATRICS (603016), and by grants from Radboud University Medical Center, University Medical Center Groningen and Accare, and Vrije Universiteit Amsterdam. L.F. acknowledges funding by Söderbergs Königska Stiftelse, Stockholm County Council (ALF, PPG). H.F.B. acknowledges funding by Söderbergs Königska Stiftelse, Centre for Psychiatry Research (post doc stipendium). S.C. acknowledges funding by The Swedish Research Council (523-2014-3467) and the Stockholm County Council (20160328). P.K. acknowledges funding by the DFG (KI 576/14-2). T.K. acknowledges funding by the Research Council of Norway (grants #213837 and #223273 to PI Ole Andreassen). J.H. acknowledges funding by the Wellcome Trust as well as the MRC. D.J.F.d.Q acknowledges funding by the Swiss National Science Foundation. G.P. acknowledges funding by Fondazione CON IL SUD, and Hoffmann-La Roche. PB was partially supported by grants from the Italian Ministry of Health (RF-2011-02352308). P.M.T. acknowledges funding by NIH grant U54 EB020403. F.D. acknowledges funding by the German Federal Ministry of Education and Research (BMBF) grant 01ZX1314A/01ZX1614A. A.R. acknowledges funding by the “Capitale Umano ad Alta Qualificazione” grant awarded by Fondazione Con Il Sud. E.G.J. acknowledges funding by the Swedish Research Council, a regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet, and the HUBIN project. The HUBIN and KaSP studies were supported by the Swedish Research Council. A.M.-L. has received consultant fees from Blueprint Partnership, Boehringer Ingelheim, Daimler und Benz Stiftung, Elsevier, F. Hoffmann-La Roche, ICARE Schizophrenia, K. G. Jebsen Foundation, L.E.K Consulting, Lundbeck International Foundation (LINF), R. Adamczak, Roche Pharma, Science Foundation, Synapsis Foundation – Alzheimer Research Switzerland, System Analytics, and has received lectures including travel fees from Boehringer Ingelheim, Fama Public Relations, Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Janssen-Cilag, Klinikum Christophsbad, Göppingen, Lilly Deutschland, Luzerner Psychiatrie, LVR Klinikum Düsseldorf, LWL PsychiatrieVerbund Westfalen-Lippe, Otsuka Pharmaceuticals, Reunions i Ciencia S. L., Spanish Society of Psychiatry, Südwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. J.K.B. has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Roche, Medice and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. A.B. is a stockholder of Roche and has received lecture fees from Otsuka. M.Z. has received unrestricted scientific grants from German Research Foundation (DFG), and Servier; further speaker and travel grants were provided by Otsuka, Servier, Lundbeck, Roche, Ferrer and Trommsdorff. S.C. has received grant support from AstraZeneca as a co-investigator, and has served as a one-off speaker for Otsuka-Lundbeck and Roche Pharmaceuticals. SCs spouse is an employee of SOBI pharmaceuticals. G.P. was an academic supervisor of a Hoffmann-La Roche collaboration grant (years 2015-16). B.F. has received educational speaking fees from Shire and Medice. All other authors declare no potential conflicts of interest.

FundersFunder number
European Union-Aggressotype
Söderbergs Königska Stiftelse, Centre for Psychiatry Research
National Institutes of Health
National Institute of Biomedical Imaging and BioengineeringU54EB020403
F. Hoffmann-La Roche
Stiftelsen Kristian Gerhard JebsenR01MH62873, 056-24-011
Wellcome Trust
Horizon 2020 Framework Programme
Chiropractic and Osteopathic College of Australasia
Seventh Framework Programme602805, 602450, 642996, 278948, 643051, 603016
Medical Research Council
Deutsche ForschungsgemeinschaftSFB 636, SCHW 1768/1-1
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Bundesministerium für Bildung und Forschung01ZX1314G, 01ZX1314A
Ministero della SaluteRF-2011-02352308, 01ZX1314A/01ZX1614A
Nederlandse Organisatie voor Wetenschappelijk Onderzoek016-130-669, 1750102007010, 433-09-242, 056-13-015, 433-09-229
Karolinska Institutet
Stockholms Läns Landsting
VetenskapsrådetKI 576/14-2, 213837, 523-2014-3467, 20160328
Norges forskningsråd223273
Radboud Universitair Medisch Centrum
Fondazione CON IL SUD
Horizon 2020
European College of Neuropsychopharmacology
Stiftelsen Söderström Königska Sjukhemmet
Innovative Medicines Initiative115300


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