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Asymmetry, cytoarchitectonic morphology and genetics associated with Broca’s area in schizophrenia

Nature Mental Health volume 2, pages 310–319 (2024)Cite this article

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Abstract

A common hypothesis on the etiopathology of schizophrenia is that the failure of segregation of right from left hemisphere functions is a core deficit in psychosis. It has even been proposed that schizophrenia symptoms in general may reflect a hemispheric ‘dominance failure’ for language and that the corresponding predisposition is genetic. Here, we show that reduced asymmetries of cytoarchitectonic Broca’s subareas link to the degree of specific psychopathology and that specific gray matter reductions of subareas are related to a cognitive and a negative subtype of schizophrenia. Gene expression analyses indicate an upregulation of the MET gene in these particular areas, which has been implicated in neurodevelopment as well as neurocognition and influences the risk for schizophrenia. Our integrative findings suggest that variations of MET are associated with distinct structural alterations at the subregional level in key language regions, which may contribute to development of specific psychopathology in schizophrenia.

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Fig. 1: Volumetric differences in areas 44 and 45 between patients and healthy controls.
Fig. 2: Association between gray matter morphology and symptom dimensions.
Fig. 3: Three-dimensional visualization of the regional specification analysis.

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Data availability

COBRE data were obtained from the SchizConnect, a publicly available website (http://www.schizconnect.org/documentation#by_project). The COBRE dataset was downloaded from the Center for Biomedical Research Excellence in Brain Function and Mental Illness (COBRE) (https://coins.trendscenter.org/). Data from the other datasets are not publicly available for download, but access requests can be made to the respective study investigators: Aachen, B.D. (birgit.derntl@med.uni-tuebingen.de); Göttingen, O.G. (oliver.gruber@med.uni-heidelberg.de); Groningen, A.A. (a.aleman@umcg.nl); Utrecht, I.E.S. (isc.sommer@umcg.nl); Regensburg, corresponding author T.B.P.; Singapore, J.H.Z. (helen.zhou@nus.edu.sg). Requests for raw and analyzed data can be made to the corresponding author and will be promptly reviewed by the Ethics Committee at the University of Regensburg to verify whether the request is subject to any intellectual property or confidentiality obligations. The Jülich Brain Atlas is accessible at https://julich-brain-atlas.de and the BrainMap database is accessible at http://www.brainmap.org/.

Code availability

The ‘Dimensions and Clustering Tool for assessing schizophrenia Symptomatology’ (DCTS) is available at http://webtools.inm7.de/sczDCTS/, the Computational Anatomy Toolbox (CAT) at https://neuro-jena.github.io/cat/, the SPM12 software at https://www.fil.ion.ucl.ac.uk/spm/software/spm12/, G*Power software at http://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower, and the JuGEx toolbox at https://www.fz-juelich.de/de/inm/inm-1/leistungen/tools-services-und-forschungsdaten/jugex.

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Acknowledgements

This research project is supported by a grant from the START-Program of the Faculty of Medicine of the RWTH Aachen University (37/20; funded by the North Rhine-Westphalian Ministry of Culture and Science). J.H.Z. was supported by Yong Loo Lin School of Medicine, National University of Singapore.

Author information

Author notes

  1. Lydia Kogler

    Present address: Partner site Tübingen, German Center for Mental Health (DZPG), Tübingen, Germany

Authors and Affiliations

  1. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Medical Faculty, RWTH Aachen University, Aachen, Germany

    Saskia Zimmermann, Katrin Sakreida, Thomas Frodl, Stefan Heim & Timm B. Poeppl

  2. Institute of Neuroscience and Medicine, Structural and Functional Organization of the Brain (INM-1), Research Centre Jülich, Jülich, Germany

    Sebastian Bludau, Dominique I. Pelzer, Stefan Heim & Thomas W. Mühleisen

  3. Institute of Neuroscience and Medicine, Brain and Behaviour (INM-7), Research Centre Jülich, Jülich, Germany

    Julia A. Camilleri, Felix Hoffstaedter & Simon B. Eickhoff

  4. Institute of Systems Neuroscience, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Julia A. Camilleri & Simon B. Eickhoff

  5. Department of Neuroscience, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    André Aleman

  6. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

    Torsten Brückner, Elmar Frank, Thomas Frodl, Göran Hajak, Peter M. Kreuzer, Daniela Mirlach, Michael Landgrebe, Berthold Langguth, Julia Prasser, Martin Schecklmann & Timm B. Poeppl

  7. District Hospital Rehau, Rehau, Germany

    Torsten Brückner

  8. Department of Psychiatry and Psychotherapy, Tübingen Centre for Mental Health (TüCMH), Medical Faculty, University of Tübingen, Tübingen, Germany

    Birgit Derntl & Lydia Kogler

  9. Department of Psychiatry and Psychotherapy, Otto von Guericke University Magdeburg, Magdeburg, Germany

    Thomas Frodl

  10. FIDMAG Hermanas Hospitalarias Research Foundation, Sant Boi de Llobregat, Spain

    Paola Fuentes-Claramonte, María Ángeles García-León, Edith Pomarol-Clotet & Joan Soler-Vidal

  11. CIBERSAM (G15), Barcelona, Spain

    Paola Fuentes-Claramonte, María Ángeles García-León, Edith Pomarol-Clotet & Joan Soler-Vidal

  12. Section for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Heidelberg University, Heidelberg, Germany

    Oliver Gruber

  13. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Social Foundation Bamberg, Bamberg, Germany

    Göran Hajak

  14. Lille Neurosciences and Cognition, Plasticity and Subjectivity Team, Université de Lille, INSERM U-1172, Lille, France

    Renaud Jardri

  15. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, kbo-Lech-Mangfall-Klinik Agatharied Hausham, Hausham, Germany

    Michael Landgrebe

  16. West Region, Institute of Mental Health, Singapore, Singapore

    Kang Sim

  17. Universitat de Barcelona, Barcelona, Spain

    Joan Soler-Vidal

  18. Benito Menni Complex Asistencial en Salut Mental, Sant Boi de Llobregat, Spain

    Joan Soler-Vidal

  19. Department of Biomedical Science of Cells and Systems, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Iris E. Sommer

  20. Centre for Sleep and Cognition and Centre for Translational Magnetic Resonance Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Juan H. Zhou

  21. Cécile and Oskar Vogt Institute for Brain Research, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    Thomas W. Mühleisen

  22. Partner site Tübingen, German Center for Mental Health (DZPG), Tübingen, Germany

    Birgit Derntl

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Contributions

T.B.P., S.Z. and K. Sakreida designed the study. S.B.E. gave conceptual advice. A.A., T.B., B.D., E.F., T.F., P.F.-C., M.Á.G.-L., O.G., G.H., R.J., L.K., P.M.K., D.M., M.L., B.L., E.P.-C., J.P., M.S., K. Sim, J.S.-V., I.E.S., J.H.Z. and T.B.P. contributed data. S.Z. conducted the analyses under supervision by K. Sakreida and T.B.P. F.H. organized and preprocessed data of the replication sample. J.A.C. and S.B.E. provided the functional characterization. S.B., D.I.P. and T.W.M. advised on the gene expression analyses. S.Z. and T.B.P. wrote the paper. S.B., D.I.P., S.H., T.W.M. and S.B.E. discussed the results and implications. All authors commented on the paper at all stages.

Corresponding author

Correspondence to Timm B. Poeppl.

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Supplementary Methods, Results, Tables 1–16, Figs. 1–3 and References.

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Zimmermann, S., Sakreida, K., Bludau, S. et al. Asymmetry, cytoarchitectonic morphology and genetics associated with Broca’s area in schizophrenia. Nat. Mental Health 2, 310–319 (2024). https://doi.org/10.1038/s44220-023-00200-2

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