Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130.
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63130.
Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2212933120. doi: 10.1073/pnas.2212933120. Epub 2023 May 15.
The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transport is believed to be driven by the perivascular pumping effect created by the pulsation of the arterial wall caused by the cardiac cycle. Ultrasound sonication of circulating microbubbles (MBs) in the cerebral vasculature induces volumetric expansion and contraction of MBs that push and pull on the vessel wall to generate a MB pumping effect. The objective of this study was to evaluate whether glymphatic transport can be mechanically manipulated by focused ultrasound (FUS) sonication of MBs. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as fluid tracers, followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected MBs. Intracisternal magna injection, the conventional technique used in studying glymphatic transport, was employed to provide a comparative reference. 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 (PVS) along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the PVS into the interstitial space. This study revealed that ultrasound combined with circulating MBs could mechanically enhance glymphatic transport in the brain.
类淋巴系统是一种用于清除废物的血管周围液体转运系统。类淋巴转运被认为是由动脉壁的搏动所产生的血管周围泵送效应驱动的，这种搏动是由心动周期引起的。在脑血管中超声处理循环微泡（MBs）会引起 MBs 的体积膨胀和收缩，从而推动和拉动血管壁，产生 MB 泵送效应。本研究的目的是评估通过聚焦超声（FUS）处理 MBs 是否可以机械地操纵类淋巴转运。使用荧光标记的白蛋白作为流体示踪剂，通过鼻内给药，在静脉注射 MBs 的情况下，对完整小鼠大脑中的类淋巴途径进行了研究，并在深部脑目标（丘脑）处进行了 FUS 超声处理。采用鞘内注射（intracisternal magna injection）作为传统技术，用于提供比较参考。对光学清除脑组织进行三维共聚焦显微镜成像显示，超声处理增强了荧光标记白蛋白示踪剂在沿微血管的血管周围空间（PVS）中的转运，主要是小动脉。我们还获得了 FUS 增强白蛋白示踪剂从 PVS 渗透到细胞间隙的证据。这项研究表明，超声联合循环 MBs 可以机械地增强大脑中的类淋巴转运。
