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Perceiving traumatic brain injury from glymphatic system

Molecular Psychiatry (2025)Cite this article

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Abstract

Traumatic brain injury (TBI) is a complex and often-devastating condition. This disease involves damage to cerebral structures: meninges (dura, arachnoid, pia), cerebral cortex, white matter tracts, and deeper structures (basal ganglia, brainstem), along with mechanisms including contusions, hematomas (epidural/subdural), diffuse axonal injury from shear forces, secondary edema compromising blood-brain barrier, and ischemia/hemorrhage caused by vascular disruption. The pathophysiological process of TBI above varies significantly among individuals. However, prevalent TBI treatments still focus on symptomatic management, such as surgical intervention represented by craniotomy, medical management represented by osmotic agents for cerebral edema, supportive care represented by oxygen therapy, and adjuvant therapies represented by hypothermia. Worse still, traditional therapies often yield unfavorable outcomes and indulge the potential onset of long-term neurodegenerative diseases (NDDs). On the other side, Glymphatic System (GS), discovered as a clearance system in the brain, has made tremendous progress over the past decade. Dysfunction of the GS has been implicated in various central nervous system (CNS) diseases including TBI. The discovery of the GS offers new perspectives for the pathophysiological process of TBI, particularly unveiling the truth of the development of diphasic brain edema following TBI. Impressively, with the GS maturing, unprecedented therapeutic strategies ensue. For instance, the GS might explain sleep deprivation after TBI strikes in part and strongly validate the prospect of sleep therapy, then provide insights into the enigma of sleep. Also, nor-adrenergic inhibition facilitates CSF-ISF exchange and glymphatic outflow, significantly attenuating brain edema. AQP4, the guardian and regulator of brain capacity at the end-foot of astrocyte, which can modulate its array and amounts aligning with nor-adrenergic signal, is indispensable in this process. Moreover, neurons have gained prominence in the brain’s clearance system. Exploring the relationship between the GS and TBI will likely to blaze the new trail for advancing our understanding of TBI.

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Fig. 1: Schematic diagram of the current understanding of Glymphatic System.
Fig. 2: Mechanism diagram of brain edema formation at two-time points.
Fig. 3: Mechanism diagram of why sleep disturbance impedes TBI recovery.
Fig. 4: Mechanism diagram of vascular dynamics, as well as the function mechanism of multisensory stimulation.

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Data availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. However, relevant searching criteria pertinent to the specific part in this review are available from the corresponding author on reasonable request.

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Acknowledgements

This research was supported by National High Level Hospital Clinical Research Funding (2022-PUMCH-C-032), Science and Technology Major Project of Stroke Prevention and Treatment of the NHC-Million Disability Reduction Initiative (2024PSPT0903102), CAMS Innovation Fund for Medical Sciences (2024-I2M-C&T-B-022), Peking Union Medical College Hospital Postdoctoral Incubation Fund (kyfyjj202401), and Beijing Science and Technology Innovation Foundation for University students (2024dcxm047). The formats in this review were supported by biorender. The views expressed in this Review are those of the authors and do not necessarily represent the official policy or position of the Department of Neurosurgery, Peking Union Medical College Hospital. The funding source had no input in the conception or preparation of this Review.

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  1. Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Zeyi Yang, Pengtao Li & Junji Wei

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Data acquisition, Mechanism concept and diagram, review writing: ZYY; Revised version: PTL; Source of funds: JJW. All authors have read and approved the manuscript.

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Correspondence to Junji Wei.

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Yang, Z., Li, P. & Wei, J. Perceiving traumatic brain injury from glymphatic system. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03126-6

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