Tracking the flow of cerebrospinal fluid reveals an unprecedented view of the brain's glymphatic system

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by Michaela Martinez, Duke University

edited by Lisa Lock, reviewed by Robert Egan

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A cross-section through the brain reveals the symmetric architecture of the vascular network (cyan-green) and the tracer highlighting the glymphatic system (red-yellow) along the brain's surface and drainage routes—imaged through the intact skull with 3D-PAULM. Credit: Duke University

Biomedical engineers at Duke University have developed a technique to noninvasively visualize the brain's waste-removal system in unprecedented detail. This new imaging approach allows researchers to examine how this system is altered by conditions including ischemic stroke, aging and anesthesia in animal models, providing new insights into a system increasingly linked to neurodegenerative disease and brain health. This work is published in the journal Science Advances.

Often described as the brain's cleaning system, the glymphatic system uses cerebrospinal fluid (CSF) to flush out metabolic waste, damaged or harmful proteins, and other cellular debris that accumulates during normal brain activity. This process is particularly active during sleep and is key to maintaining brain health and function. Disruptions to glymphatic function have also been linked to aging, stroke, traumatic brain injury and neurodegenerative diseases such as Alzheimer's disease.

"When we're sleeping, it's like a garbage truck going through our neighborhood and collecting all the garbage cans," said Junjie Yao, the Jeffrey N. Vinik Associate Professor of Biomedical Engineering at Duke. "The longer and better we sleep, the more garbage it can collect. The brain can remove this waste when we're awake, but it's much more active when we're asleep."

A three-dimensional 3D-PAULM rendering of a whole mouse brain, imaged non-invasively through the intact skull. Super-resolution ultrasound localization microscopy maps the brain’s vasculature (depth-encoded, warm colors superficial to cool colors deep), while photoacoustic tomography tracks a tracer moving through the glymphatic waste-clearance system (red to yellow). Credit: Duke University

A clearer view of glymphatic flow

Despite its importance, the glymphatic system was discovered only in 2012, and many aspects of its operation remain poorly understood. Part of the reason for this lack of knowledge has been how difficult it is to see the system in action.

Existing imaging technologies, including PET scans, MRIs, transcranial fluorescence imaging and two-photon microscopy, can help researchers visualize the brain. These tools, however, are often invasive or lack the depth and resolution necessary to study glymphatic transport throughout the entire brain.

"The glymphatic system clears waste through spaces that surround blood vessels and weave between brain cells, making it extremely difficult to visualize," said Yao.

Yao and Pengfei Song, an associate professor in Duke BME, hope to change that with 3D-PAULM, a hybrid imaging technology that relies on both light and sound to capture the flow of the CSF across the brain's vascular network.

Yao's expertise in 3D photoacoustic tomography provided a way to track glymphatic flow. The technique uses pulses of laser light and a specialized near-infrared tracer injected into the cerebrospinal fluid. As the tracer molecules move through the brain, they absorb the laser pulses and generate ultrasonic signals that reveal the fluid's location and movement deep within tissue.

The team paired this technique with Song's ultrasound localization microscopy, which allowed the researchers to visualize blood vessels throughout the brain and track blood flow in unprecedented detail. This marriage of technologies allowed the team to generate highly detailed maps of the brain's vascular network while simultaneously monitoring glymphatic transport.

Together, the approach enabled continuous, noninvasive, whole-brain imaging of the glymphatic system through the intact skull of a living mouse for the first time.

What changed in stroke, aging and sleep

To test their technique, the team used 3D-PAULM to monitor how the glymphatic system changed in specific disease states and conditions. In an ischemic stroke model, the team observed that CSF flow following a stroke was restricted, suggesting that strokes may impair the brain's ability to clear waste far beyond the injury site. In aging mice, the researchers observed reduced fluid transport and disruptions in key glymphatic pathways, indicating that the system becomes less efficient over time.

The researchers also compared glymphatic activity during natural sleep and under anesthesia. While previous studies have often relied on anesthetized animals to study glymphatic transport, the new imaging platform revealed that fluid flow remained relatively slow under anesthesia.

"We found that there was a clear difference between the glymphatic flow when an animal was sleeping compared to when they were put to sleep using anesthesia," said Yao. "It showed us that real sleep was the only thing that could actually improve that waste removal."

Clues for Alzheimer's and beyond

While the study demonstrates the potential of 3D-PAULM as a powerful new tool for glymphatic research, the team is already looking ahead to see how the technique could help illuminate the glymphatic system's role in neurodegenerative diseases.

"The glymphatic system clears away misfolded proteins associated with Alzheimer's disease, but when the system is damaged, those proteins can build up," said Yao. "Given this system's importance for brain health, we hope this technology will help us learn more about these diseases and contribute to the development of targeted therapies for Alzheimer's and other brain disorders."

Publication details

Nanchao Wang et al, Noninvasive whole-brain imaging of glymphatic dynamics, Science Advances (2026). DOI: 10.1126/sciadv.aee4926

Journal information: Science Advances

Key medical concepts

Glymphatic SystemAlzheimer's Disease

Clinical categories

NeurologySleep & RecoveryDiagnostic radiology Provided by Duke University Who's behind this story?

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