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Reduced glymphatic clearance in early psychosis

Molecular Psychiatry volume 30, pages 4665–4676 (2025)Cite this article

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Abstract

Psychosis involves neuroinflammation and oxidative stress, both affecting the glymphatic system, the lymphatic-like, fluid-transport system in the brain. However, it is unclear whether early psychosis is related to impairments in glymphatic functions. In resting-state fMRI, it has been recently established in a number of neurodegenerative diseases that the coupling relationship between cortical blood-oxygen-level-dependent (BOLD) signal and ventricular cerebrospinal fluid (CSF) flow is associated with brain waste clearance, a key glymphatic function that has not been examined in psychosis or any other psychiatric populations. In a large dataset (total n = 137, age = 23.86 ± 4.16), we demonstrated that glymphatic clearance marked by BOLD-CSF coupling was weaker and more delayed in patients with early psychosis compared to healthy controls. BOLD-CSF coupling also varied between the non-affective and affective psychosis groups with group differences most prominent in high-order but not low-order cortical regions. Finally, reduced global BOLD-CSF coupling was associated with cognitive decline and more severe psychotic symptoms. We provided novel evidence highlighting dysregulated coupling between cortical activity and macroscopic CSF flow as a biomarker for early psychosis. Similar to recent observations in neurodegenerative disorders, the association between reduced BOLD-CSF coupling and psychotic symptoms suggested that waste clearance is disrupted in psychosis which shed light on the pathophysiology of this disease from a glymphatic point of view.

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Fig. 1: Characterizing BOLD-CSF coupling in HCP-EP dataset.
Fig. 2: gBOLD-CSF coupling strength is associated with age and varies between diagnoses.
Fig. 3: The gBOLD-CSF coupling strength associated with sMRI morphological changes.
Fig. 4: Regional BOLD-CSF coupling strength is associated with morphological changes in low-order brain network.
Fig. 5: The coupling strength and time lags between vBOLD and CSF signals.
Fig. 6: Regression analysis between low-order/high-order/global brain regions of BOLD-CSF coupling and clinical assessments in HCs and psychotic patients.
Fig. 7: Reproducibility of BOLD-CSF coupling across independent datasets.

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Data availability

Data used in the preparation of this article were obtained from the Human Connectome Project for Early Psychosis (HCP-EP) database (https://nda.nih.gov/general-query.html?q=query=featured-datasets:Connectomes%20Related%20to%20Human%20Disease).

Code availability

All analyses used open-source software with URL links already included in Methods. Code used in the analyses described in this paper will be made available upon acceptance of the manuscript.

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Acknowledgements

This study was supported by the University of Macau (MYRG-GRG2023-00038-FHS, and MYRG-GRG2024-00259-FHS), and the Macao Science and Technology Development Fund (FDCT 0014/2024/RIB1, 0015/2023/ITP1).

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Authors and Affiliations

  1. Faculty of Health Sciences, University of Macau, Macau SAR, China

    Lin Hua, Xinglin Zeng & Zhen Yuan

  2. Center for Cognitive and Brain Sciences, University of Macau, Macau SAR, China

    Lin Hua, Xinglin Zeng, Kaixi Zhang, Zhiying Zhao & Zhen Yuan

  3. Brainstem Imaging Laboratory, Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Lin Hua

  4. Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Xinglin Zeng

  5. Center for Addiction and Mental Health, Toronto, ON, Canada

    Kaixi Zhang

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Contributions

LH: conceptualization, data curation, methodology, software, data analysis, visualization, writing—original draft, writing—review and editing, visualization. XZ: software, data analysis. KZ: data curation, data analysis. ZZ: conceptualization, data curation, methodology, funding acquisition, project administration, writing and editing. ZY: supervision, funding support, writing and editing.

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Correspondence to Zhiying Zhao or Zhen Yuan.

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All participants provided their written informed consent to participate in the HCP-EP, and the HCP-EP was reviewed and approved by the Human Connectome Project. And, all methods used in this study were performed in accordance with the relevant guidelines and regulations.

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Hua, L., Zeng, X., Zhang, K. et al. Reduced glymphatic clearance in early psychosis. Mol Psychiatry 30, 4665–4676 (2025). https://doi.org/10.1038/s41380-025-03058-1

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