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Elucidating the relationship between white matter structure, demographic, and clinical variables in schizophrenia—a multicenter harmonized diffusion tensor imaging study

Molecular Psychiatry volume 26, pages 5357–5370 (2021)Cite this article

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Abstract

White matter (WM) abnormalities are repeatedly demonstrated across the schizophrenia time-course. However, our understanding of how demographic and clinical variables interact, influence, or are dependent on WM pathologies is limited. The most well-known barriers to progress are heterogeneous findings due to small sample sizes and the confounding influence of age on WM. The present study leverages access to the harmonized diffusion magnetic-resonance-imaging data and standardized clinical data from 13 international sites (597 schizophrenia patients (SCZ)). Fractional anisotropy (FA) values for all major WM structures in patients were predicted based on FA models estimated from a healthy population (n = 492). We utilized the deviations between predicted and real FA values to answer three essential questions. (1) “Which clinical variables explain WM abnormalities?”. (2) “Does the degree of WM abnormalities predict symptom severity?”. (3) “Does sex influence any of those relationships?”. Regression and mediator analyses revealed that a longer duration-of-illness is associated with more severe WM abnormalities in several tracts. In addition, they demonstrated that a higher antipsychotic medication dose is related to more severe corpus callosum abnormalities. A structural equation model revealed that patients with more WM abnormalities display higher symptom severity. Last, the results exhibited sex-specificity. Males showed a stronger association between duration-of-illness and WM abnormalities. Females presented a stronger association between WM abnormalities and symptom severity, with IQ impacting this relationship. Our findings provide clear evidence for the interaction of demographic, clinical, and behavioral variables with WM pathology in SCZ. Our results also point to the need for longitudinal studies, directly investigating the casualty and sex-specificity of these relationships, as well as the impact of cognitive resiliency on structure-function relationships.

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Fig. 1: Association between white matter, age, and duration-of-illness.
Fig. 2: Association between white matter, symptom severity, and IQ (structural equation model).

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  • 02 February 2021

    The original version of this Article was updated shortly after publication following an error that resulted in the incorrect. Author name: It should be “These authors contributed equally: Matcheri Keshavan, Marek Kubicki,” but it is “These authors contributed equally: Matcheri Keshavan, Marek Kubick” (Kubicki versus Kubick). The HTML version was correct at the time of publication.

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Acknowledgements

We gratefully acknowledge funding provided by the following National Institutes of Health (NIH) grants: R01MH102377, K24MH110807 (PI: Dr MK), R01MH119222 (PI: Dr YR), R03 MH110745, K01 MH115247–01A1 (PI: Dr AL), VA Merit Award and U01 MH109977 (PI: Dr MS), R01MH108574 (PI: Dr OP), MRC G0500092 (PI: Dr AJ), R01MH076995 (PI: Dr PS), P50MH080173 (PI: Dr AKM), 1R01 MH102318-01A1 (PI: Dr RWB), R01MH092440, MH078113 (PI: Dr MK), MH077851 (PI: Dr CT), MH077945 (PI: Dr GP), MH077862 (PI: Dr JS), R21MH121704 (PI: Dr JL). We also acknowledge funding provided by the BWH Program for Interdisciplinary Neurosciences (through a gift from Lawrence and Tiina Rand), BBRF NARSAD Young Investigator grant (PI: Dr SCK), Swiss National Science Foundation (SNF) grant 152619 (PI: Dr SW) and National Research Foundation of Korea (NRF) grant NRF-2012R1A1A1006514 (PI: Dr JL).

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Author notes

  1. These authors contributed equally: Johanna Seitz-Holland, Suheyla Cetin-Karayumak

  2. These authors contributed equally: Matcheri Keshavan, Marek Kubicki

Authors and Affiliations

  1. Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Johanna Seitz-Holland, Suheyla Cetin-Karayumak, Amanda Lyall, James Levitt, Martha E. Shenton, Ofer Pasternak, Madhura Baxi, Sinead Kelly, Yogesh Rathi & Marek Kubicki

  2. Department of Psychiatry, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, USA

    Joanne D. Wojcik, Sinead Kelly, Raquelle Mesholam-Gately & Matcheri Keshavan

  3. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Amanda Lyall, Martha E. Shenton, Yogesh Rathi & Marek Kubicki

  4. VA Boston Healthcare System, Brockton, MA, USA

    James Levitt & Martha E. Shenton

  5. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Martha E. Shenton, Carl-Fredrik Westin, Yogesh Rathi & Marek Kubicki

  6. Graduate Program of Neuroscience, Boston University, Boston, MA, USA

    Madhura Baxi

  7. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Mark Vangel

  8. Department of Psychiatry, Yale University, New Haven, CT, USA

    Godfrey Pearlson

  9. Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA

    Carol A. Tamminga

  10. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA

    John A. Sweeney

  11. Department of Psychology and Neuroscience, Bio-Imaging Research Center, University of Georgia, Athens, GA, USA

    Brett A. Clementz

  12. Department of Psychiatry and Behavioral Sciences, Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    David Schretlen

  13. University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland

    Petra Verena Viher, Katharina Stegmayer & Sebastian Walther

  14. Department of Psychiatry, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

    Jungsun Lee

  15. Department of Psychiatry, SANE POWIC, Warneford Hospital, University of Oxford, Oxford, UK

    Tim Crow & Anthony James

  16. Center for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Aristotle Voineskos

  17. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Robert W. Buchanan

  18. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Philip R. Szeszko

  19. Mental Illness Research, Education and Clinical Center, James J. Peters VA Medical Center, Bronx, New York, NY, USA

    Philip R. Szeszko

  20. The Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA

    Anil K. Malhotra

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  1. Johanna Seitz-Holland
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Correspondence to Johanna Seitz-Holland.

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Seitz-Holland, J., Cetin-Karayumak, S., Wojcik, J.D. et al. Elucidating the relationship between white matter structure, demographic, and clinical variables in schizophrenia—a multicenter harmonized diffusion tensor imaging study. Mol Psychiatry 26, 5357–5370 (2021). https://doi.org/10.1038/s41380-021-01018-z

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