Knowledge of the brain’s waste removal mechanism may provide insight into brain disorders

The glymphatic system in the brain, like the lymphatic system in the body, distributes nutrients and other essential compounds and eliminates metabolic waste. Weaknesses in this framework might add to mental illnesses like neurodegenerative illnesses and stroke.

The McKelvey School of Engineering at Washington University in St. Louis has developed a focused ultrasound-based, non-pharmaceutical method for influencing glymphatic transport, paving the way for further research into brain diseases and brain function. The consequences of the work are distributed in the Procedures of the Public Foundation of Sciences on May 15.

The first direct evidence that focused ultrasound, combined with circulating microbubbles—a technique they call FUSMB—could mechanically enhance glymphatic transport in the mouse brain was discovered by Hong Chen and her team, which also included Dezhuang (Summer) Ye, a postdoctoral research associate, and Si (Stacie) Chen, a former postdoctoral research associate. Hong Chen is an associate professor of biomedical engineering in McKelvey Engineering and of

“Intranasal administration offers a novel, non-invasive technique to study the glymphatic system in intact brains. This strategy to studying glymphatic transport has the potential to be applied to the research of glymphatic function in people, which is presently constrained by the lack of non-invasive methods to reach the glymphatic system.”

Hong Chen, associate professor of biomedical engineering in McKelvey Engineering

Focused ultrasound can precisely target a specific area of the brain and penetrate the scalp and skull to reach the brain. In previous research, Chen’s group discovered that microbubbles injected into the bloodstream amplify the effects of ultrasound waves on the blood vessels and generate a pumping effect, which aids in the accumulation of drugs or gene therapy treatments delivered intravenously in the brain.

Chen stated, “A novel, non-invasive route to investigate the glymphatic pathway in intact brains is provided by intravenous delivery.” This course for exploring glymphatic transport can possibly be used in the investigation of glymphatic capability in people, which is as of now restricted by the shortfall of painless ways to deal with accessing the glymphatic framework.”
In the new examination, the group administered a fluorescently named tracer intranasally. After injecting microbubbles intravenously, they then gave focused ultrasound waves to the thalamus, which is located deep inside the brain. They discovered that FUSMB enhanced the transport of the tracer in the perivascular space when they conducted 3D imaging of the treated side’s brain tissue.

They compared this to three control groups that received focused ultrasound, microbubbles, and the tracer in various combinations. The team was able to confirm that the enhanced tracer transport was the result of the focused ultrasound with microbubbles because all of the mice in the three control groups showed lower tracer accumulation.

To additionally approve their outcomes, they utilized the FUSMB treatment in the wake of infusing the tracer straightforwardly into the cerebral spinal fluid, an obtrusive yet generally utilized strategy. When compared to the non-targeted side, they discovered that FUSMB also increased the transport of tracers along the vessels at the focused-ultrasound-targeted brain site by approximately two to threefold.

Ye stated, “FUSMB consistently improved glymphatic transport, whether tracers were delivered via the intranasal or injected route.” Our review utilizing confocal microscopy imaging combined with cerebrum tissue clearing got immediate proof that unequivocally demonstrated that FUSMB improved the glymphatic transport of a named protein specialist in mice.”

Additionally, the team looked into a variety of vessels, such as arterioles, capillaries, and venules, that aid in the intranasal and injected delivery of the tracer for FUSMB-enhanced transport. With both types of delivery, they observed enhanced glymphatic transport of the tracer in both capillaries and arterioles. They discovered that arterioles had a higher fluorescence intensity than capillaries and venules.

Ye stated, “This study opens new opportunities for a non-invasive and non-pharmacological approach to manipulating glymphatic transport using ultrasound combined with microbubbles.” Focused ultrasound-activated microbubbles have the potential to improve brain waste clearance and possibly reduce the risk of brain diseases brought on by glymphatic system dysfunction.

According to Chen, the group will now concentrate on implementing this non-pharmacological and non-invasive method for clearing out brain waste in order to possibly combat neurodegenerative diseases like Alzheimer’s and Parkinson’s.

More information: Dezhuang Ye et al, Mechanically manipulating glymphatic transport by ultrasound combined with microbubbles, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2212933120

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