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Excessive interstitial free-water in cortical gray matter preceding accelerated volume changes in individuals at clinical high risk for psychosis

Molecular Psychiatry (2024)Cite this article

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Abstract

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development.

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Fig. 1: Estimation of iFW.
Fig. 2: Baseline and longitudinal changes in iFW and volume.
Fig. 3: Correlations between baseline measures and clinical scores.

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Data availability

The dataset is available per request. Please request an access through e-mail: ofer@bwh.harvard.edu.

Code availability

Our iFW code is available per request. Please request an access through e-mail: ofer@bwh.harvard.edu.

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Acknowledgements

This work was funded by the following National Institutes of Health (NIH) grants: R01 MH108574, R01 MH111448, R01 MH074794, U24 MH124629.

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Authors and Affiliations

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

    Kang Ik K. Cho, Johanna Seitz-Holland, Martha E. Shenton & Ofer Pasternak

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

    Fan Zhang, Martha E. Shenton & Ofer Pasternak

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

    Nora Penzel, Johanna Seitz-Holland, Martha E. Shenton & Ofer Pasternak

  4. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yingying Tang, Tianhong Zhang, Lihua Xu & Jijun Wang

  5. Brain Science and Technology Research Center, Shanghai Jiao Tong University, Shanghai, China

    Yingying Tang, Lihua Xu & Jijun Wang

  6. Department of Psychology, Florida A&M University, Tallahassee, FL, USA

    Huijun Li

  7. The Massachusetts Mental Health Center, Public Psychiatry Division, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA

    Matcheri Keshavan & William S. Stone

  8. Department of Psychology, Northeastern University, Boston, MA, USA

    Susan Whitfield-Gabrieli

  9. The McGovern Institute for Brain Research and the Poitras Center for Affective Disorders Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Susan Whitfield-Gabrieli

  10. The Department of Psychiatry, Veterans Affairs Boston Healthcare System, Brockton Division, Brockton, MA, USA

    Margaret Niznikiewicz

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  15. Ofer Pasternak
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Contributions

KC and OP: Development of the idea, method, analysis, interpretation of the results, and writing the manuscript; FZ: Development of the idea, method, and analysis; NP and JS: Development of the idea, method, analysis, and interpretation of the results; YT, TZ, LX, HL, KM, SWG, MN, WS, JW, MS: Data collection and interpretation of the results.

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Correspondence to Jijun Wang or Ofer Pasternak.

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Cho, K.I.K., Zhang, F., Penzel, N. et al. Excessive interstitial free-water in cortical gray matter preceding accelerated volume changes in individuals at clinical high risk for psychosis. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02597-3

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