Researchers at the McKelvey School of Engineering at Washington University in St. Louis have discovered a groundbreaking method to influence the glymphatic system in the brain using non-invasive and non-pharmaceutical techniques. The glymphatic system, akin to the lymphatic system in the body, is responsible for clearing waste and distributing nutrients in the brain. Dysfunction of this system is associated with various brain diseases, including neurodegenerative disorders and stroke.
The team, led by Hong Chen, an associate professor of biomedical engineering, conducted experiments in mice and published their findings in the Proceedings of the National Academy of Sciences. They demonstrated that focused ultrasound combined with circulating microbubbles, a technique termed FUSMB, can enhance glymphatic transport in the brain.
Focused ultrasound has the ability to penetrate the scalp and skull to reach specific regions within the brain. Previous studies by Chen’s team revealed that microbubbles injected into the bloodstream can amplify the effects of ultrasound waves on blood vessels, generating a pumping effect that aids the accumulation of agents delivered nasally, such as drugs or gene therapy treatments.
In their latest research, the scientists administered a tracer intranasally and then utilized focused ultrasound waves directed at the thalamus, a deep brain region, after injecting microbubbles intravenously. Through 3D imaging of the brain tissue, they observed that FUSMB enhanced the transport of the tracer in the perivascular space.
The team compared these results with three control groups that received various combinations of focused ultrasound, microbubbles, and the tracer. The control groups exhibited lower tracer accumulation, confirming that the enhanced transport was a direct result of the FUSMB technique.
To further validate their findings, the researchers employed FUSMB treatment after directly injecting the tracer into the cerebral spinal fluid, a common yet invasive method. They discovered that FUSMB also increased tracer transport along the vessels at the targeted brain site, demonstrating a two- to threefold improvement compared to the non-targeted side.
Regardless of whether the tracers were delivered intranasally or injected, FUSMB consistently enhanced glymphatic transport. The team utilized confocal microscopy imaging and brain-tissue clearing techniques to provide direct evidence of FUSMB’s ability to improve glymphatic transport of labeled protein agents in mice.
Additionally, the researchers investigated the impact of FUSMB on various types of vessels, including arterioles, capillaries, and venules, involved in the transport of the tracer. They observed improved glymphatic transport in both arterioles and capillaries, regardless of the delivery method. Notably, fluorescence intensity was higher along arterioles compared to capillaries and venules.
This groundbreaking study paves the way for using ultrasound in conjunction with microbubbles as a non-invasive and non-pharmacological approach to manipulate glymphatic transport. The activation of microbubbles by focused ultrasound shows promise in enhancing waste clearance in the brain and potentially mitigating brain diseases resulting from glymphatic system dysfunction.
The researchers plan to further explore the application of this non-invasive method for brain waste clearance in the treatment of neurodegenerative diseases like Alzheimer’s and Parkinson’s.