Mechanically manipulate glymphatic transportation by ultrasound combined with microbubbles

Abstract

The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transportation is believed to be driven by the perivascular pumping effect generated by arterial wall pulsation induced by the cardiac cycle. Ultrasound sonication of circulating microbubbles in the cerebral vasculature induces volumetric expansion and contraction of microbubbles that push and pull on the vessel wall to generate a microbubble pumping effect. The objective of this study was to evaluate whether glymphatic transportation can be mechanically manipulated by focused ultrasound (FUS) sonication of microbubbles. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as a fluid tracer followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected microbubbles. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the perivascular space into the interstitial space. This study revealed that ultrasound combined with circulating microbubbles could noninvasively enhance glymphatic transportation in the brain. Significance StatementThe glymphatic system is a waste clearance system in the brain analogous to the lymphatic system in peripheral organs. Glymphatic system impairment might contribute to brain disease pathologies, including those in neurodegenerative diseases, traumatic brain injury, and stroke. This study revealed that ultrasound could mechanically enhance glymphatic transportation. This result opens opportunities for using ultrasound to probe the role of the glymphatic system in brain function and brain diseases. Findings from this study suggest that ultrasound can be utilized as a noninvasive/nonpharmacological approach to mitigate brain diseases caused by impaired glymphatic function.