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Characterization of the extracellular free water signal in schizophrenia using multi-site diffusion MRI harmonization

Molecular Psychiatry volume 28, pages 2030–2038 (2023)Cite this article

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Abstract

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15–58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70–0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32–0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes.

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Fig. 1: Age-related whole brain white matter FW trajectories.
Fig. 2: Effect size at each age of coefficient v2 from the quadratic model.

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Code availability

Our multi-site diffusion MRI harmonization software is available in GitHub: https://github.com/pnlbwh/dMRIharmonization.

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Acknowledgements

We gratefully acknowledge funding provided by the following National Institutes of Health (NIH) grants: R01 MH102377, K24 MH110807 (PI: MK), R01 MH119222 (PI: YR), R03 MH110745, K01 MH115247-01A1 (PI: AEL), U01 MH109977, U24 MH124629-01 (PI: MES), R01 MH108574 (PI: OP), MRC G0500092 (PI: AJ), R01MH076995 (PI: PRS), P30MH090590, P50MH080173 (PI: AKM), R01MH077862 (PI: JAS). We also acknowledge funding provided by the Brigham and Women’s Hospital Program for Interdisciplinary Neurosciences through a gift from Lawrence and Tina Rand (PI: SC-K), Swiss National Science Foundation (SNF) grant 152619 (PI: SW), Harvard Medical School Department of Psychiatry Livingston Award (JS-H) and three Brain and Behavior Research Foundation NARSAD Young Investigator Awards (PIs: SC-K, AEL, JS-H).

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Author notes

  1. These authors contributed equally: Suheyla Cetin-Karayumak, Amanda E. Lyall.

  2. These authors jointly supervised this work: Ofer Pasternak, Marek Kubicki.

Authors and Affiliations

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

    Suheyla Cetin-Karayumak, Amanda E. Lyall, Maria A. Di Biase, Johanna Seitz-Holland, Sinead Kelly, Martha E. Shenton, Yogesh Rathi, Ofer Pasternak & Marek Kubicki

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

    Amanda E. Lyall, Johanna Seitz-Holland, Martha E. Shenton, Yogesh Rathi, Ofer Pasternak & Marek Kubicki

  3. Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia

    Maria A. Di Biase

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

    Fan Zhang, Martha E. Shenton, Yogesh Rathi, Ofer Pasternak & Marek Kubicki

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

    Sinead Kelly & Matcheri Keshavan

  6. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    Doron Elad

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

    Godfrey Pearlson

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

    Carol A. Tamminga

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

    John A. Sweeney

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

    Brett A. Clementz

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

    David Schretlen

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

    Katharina Stegmayer & Sebastian Walther

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

    Jungsun Lee

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

    Tim Crow & Anthony James

  15. Centre for Addiction and Mental Health, Toronto, ON, Canada

    Aristotle Voineskos

  16. Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA

    Robert W. Buchanan

  17. Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Philip R. Szeszko

  18. Mental Illness Research, Education, and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA

    Philip R. Szeszko

  19. The Feinstein Institutes for Medical Research and Zucker Hillside Hospital, Glen Oaks, NY, USA

    Anil K. Malhotra

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  1. Suheyla Cetin-Karayumak
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  26. Marek Kubicki
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Contributions

SC-K carried out the analysis, drafted the manuscript; AEL helped interpreting findings, drafted the manuscript; MADB helped in writing; JS-H helped in collecting clinical data; FZ helped in developing FW software; SK helped in collecting BICEPS, BSNIPS; DE helped in FW analysis; GP, CAT, JAS, BAC, DS, KS, SW, JL, TC, AJ, AV, RWB, PRS, AKM, MK and MES collected multi-site datasets; YR helped in running harmonization; OP and MK conceived of the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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Correspondence to Suheyla Cetin-Karayumak.

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Cetin-Karayumak, S., Lyall, A.E., Di Biase, M.A. et al. Characterization of the extracellular free water signal in schizophrenia using multi-site diffusion MRI harmonization. Mol Psychiatry 28, 2030–2038 (2023). https://doi.org/10.1038/s41380-023-02068-1

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