Paravascular spaces at the brain surface: Low resistance pathways for cerebrospinal fluid flow

Abstract

Clearance of waste products from the brain is of vital importance. Recent publications suggest a potential clearance mechanism via paravascular channels around blood vessels. Arterial pulsations might provide the driving force for paravascular flow, but its flow pattern remains poorly characterized. In addition, the relationship between paravascular flow around leptomeningeal vessels and penetrating vessels is unclear. In this study, we determined blood flow and diameter pulsations through a thinned-skull cranial window. We observed that microspheres moved preferentially in the paravascular space of arteries rather than in the adjacent subarachnoid space or around veins. Paravascular flow was pulsatile, generated by the cardiac cycle, with net antegrade flow. Confocal imaging showed microspheres distributed along leptomeningeal arteries, while their presence along penetrating arteries was limited to few vessels. These data suggest that paravascular spaces around leptomeningeal arteries form low resistance pathways on the surface of the brain that facilitate cerebrospinal fluid flow.

Keywords: Cerebrospinal fluid; fluid dynamics; interstitial fluid; intracranial pressure; paravascular space; subarachnoid space.

Figure 1.

Microspheres move along arteries. The cranial window (black circle in (a)) was made to image branches of the MCA. (b) A typical image of two microspheres moving close to the vessel wall (indicated by the white lines). A capillary crosses the MCA branch (black lines). The majority of the microspheres were found close to the vessel wall, suggesting that the paravascular space is around 20 µm in width at this level of the vascular tree (c). Only a few microspheres were observed at larger distance, presumably in the subarachnoid space (SAS). Data are mean ± SEM. Scale bar represents 50 µm. *p < 0.05 and **p < 0.01.

Figure 2.

Ensemble average of diameter, blood velocity, and microsphere position. The ensemble average was constructed from a typical recording over 2 s. All parameters showed a pulsatile pattern attributable to the heartbeat. The microspheres showed a to and fro movement during the cardiac cycle. Position of the microsphere indicates the deviation from the net forward trend.

Figure 3.

Microspheres oscillate in the paravascular space of leptomeningeal vessels. The microspheres moved along the vessels in an oscillatory manner. The frequency of the oscillations corresponded to the heart rate of the animal.

Figure 4.

Microsphere distribution around arteries, veins, and the SAS. (a, b) The SAS with microspheres (green arrows) around arteries (a), veins (v), and in the SAS. Microspheres were present at the surface, but did not follow the PVS along penetrating vessels at the dorsal side of the brain (a). However, they were present in the paravascular space of some parenchymal arteries at the ventral side of the brain (b). In (c), a large paravascular space is evident next to a leptomeningeal artery (white box). (d) Quantification of microspheres. Microspheres were observed more frequently around arteries as compared to veins. Total microsphere numbers were similar around arteries as compared to the SAS, which, however, occupied a much larger surface area. Blue: nuclear stain; green: microspheres; magenta: laminin; and red: Von Willebrand, to identify vessels and pial membranes. (a) Scale bar 200 µm and (b, c) scale bar 50 µm. Data are mean ± SEM; *p <  0.05.