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Quantitative magnetization transfer and g-ratio imaging of white matter myelin in early psychotic spectrum disorders

Molecular Psychiatry volume 30, pages 2739–2747 (2025)Cite this article

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Abstract

Myelin abnormalities in white matter have been implicated in the pathophysiology of psychotic spectrum disorders (PSD), which are characterized by brain dysconnectivity as a core feature. Among evidence from in vivo MRI studies, diffusion imaging findings have largely supported disrupted white matter integrity in PSD; however, they are not specific to myelin changes. Using a multimodal imaging approach, the current study aimed to further delineate myelin and microstructural changes in the white matter of a young PSD cohort. We utilized quantitative magnetization transfer (qMT) imaging combined with advanced diffusion imaging to estimate specific myelin-related biophysical properties in 51 young adult PSD patients compared with 38 age-matched healthy controls. The macromolecular proton fraction (MPF) obtained from qMT was used as a specific marker of myelin content. Additionally, MPF was employed along with diffusion metrics of axonal density (vic) and extra-cellular volume fraction to derive the g-ratio, a measure of relative myelin sheath thickness defined as the ratio of inner to outer axonal diameter. Compared to controls, we observed a widespread MPF reduction and localized g-ratio increase in patients, primarily those with a diagnosis of schizophrenia or depressive schizoaffective disorder. No between-group differences were noted in vic, suggesting similar axonal densities across groups. Correlation analysis revealed that lower MPF was significantly related to poorer working memory performance in PSD, while the HC group showed a positive association for working memory with both g-ratio and vic. The pattern of changes observed in our multimodal imaging markers suggests that PSD, depending on symptomatology, is characterized by specific alterations in white matter integrity and myelin-axonal geometry of major white matter tracts, which may impact working memory function. These findings provide a more detailed view of myelin-related white matter changes in early stages of PSD.

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Fig. 1: Multimodal imaging processing pipeline.
Fig. 2: Differences in MRI metrics between patient groups and healthy controls (HC).
Fig. 3: Correlations between MRI metrics and behavioral measurements in the PSD and HC groups.

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Acknowledgements

This work was supported by the National Institutes of Health (R01MH108962 to ML and R01EB027087 to AS) and the Radiology Department at the NYU Grossman School of Medicine. We acknowledge Dr. Pippa Storey for providing the magnetization transfer imaging sequence for this study. We thank Research Match and NAMI for supporting our recruitment efforts, and we extend our sincere gratitude to our participants for their contribution.

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Authors and Affiliations

  1. Department of Radiology, NYU Grossman School of Medicine, New York, NY, USA

    Yu Veronica Sui & Mariana Lazar

  2. Department of Psychiatry, Northwell Zucker Hillside Hospital, Glen Oaks, NY, USA

    Hilary Bertisch

  3. Department of Psychiatry, NYU Grossman School of Medicine, New York, NY, USA

    Donald C. Goff

  4. Nathan Kline Institute, Orangeburg, NY, USA

    Donald C. Goff

  5. Department of Radiology, University of Wisconsin – Madison, Madison, WI, USA

    Alexey Samsonov

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  1. Yu Veronica Sui
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  5. Mariana Lazar
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Contributions

The study was conceptualized by YVS and ML. Recruitment of participants and clinical assessment were conducted with the help of HB and DCG. AS provided expertise in MRI pulse sequence and quantitative parametric mapping. Imaging data acquisition and processing, and statistical analysis were performed by YVS and ML. YVS drafted the original manuscript, with all coauthors involved in manuscript review and editing.

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Correspondence to Yu Veronica Sui or Mariana Lazar.

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The study was approved by the Institutional Review Board of the NYU Grossman School of Medicine. All participants provided written informed consent and were given a full explanation of the research protocol before being enrolled in the study.

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Sui, Y.V., Bertisch, H., Goff, D.C. et al. Quantitative magnetization transfer and g-ratio imaging of white matter myelin in early psychotic spectrum disorders. Mol Psychiatry 30, 2739–2747 (2025). https://doi.org/10.1038/s41380-024-02883-0

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