The mechanisms behind perivascular fluid flow

Abstract

Flow of cerebrospinal fluid (CSF) in perivascular spaces (PVS) is one of the key concepts involved in theories concerning clearance from the brain. Experimental studies have demonstrated both net and oscillatory movement of microspheres in PVS (Mestre et al. (2018), Bedussi et al. (2018)). The oscillatory particle movement has a clear cardiac component, while the mechanisms involved in net movement remain disputed. Using computational fluid dynamics, we computed the CSF velocity and pressure in a PVS surrounding a cerebral artery subject to different forces, representing arterial wall expansion, systemic CSF pressure changes and rigid motions of the artery. The arterial wall expansion generated velocity amplitudes of 60-260 µm/s, which is in the upper range of previously observed values. In the absence of a static pressure gradient, predicted net flow velocities were small (<0.5 µm/s), though reaching up to 7 µm/s for non-physiological PVS lengths. In realistic geometries, a static systemic pressure increase of physiologically plausible magnitude was sufficient to induce net flow velocities of 20-30 µm/s. Moreover, rigid motions of the artery added to the complexity of flow patterns in the PVS.Our study demonstrates that the combination of arterial wall expansion, rigid motions and a static CSF pressure gradient generates net and oscillatory PVS flow, quantitatively comparable with experimental findings. The static CSF pressure gradient required for net flow is small, suggesting that its origin is yet to be determined.

Brain solute transport is more rapid in periarterial than perivenous spaces

“…We let the flow be driven by a constant pressure gradient ∂p ∂z = 1.46 mmHg/m. Even though such a gradient has only been reported as a pulsatile gradient [25], static gradients of this magnitude have been shown to create net velocities of around 20 µm/s in the PVS [16] in agreement with experimental observations of injected microspheres in pial PVS. We also conducted experiments with a lower pressure gradient: ∂p ∂z = 0.01 mmHg/m [25] corresponding to the third circulation's production of CSF alone [26].…”

“…Local arterial wall pulsations can induce a small net flow, of 0.1 µm/s over a 5 mm long PVS or up to 7 µm/s in very long (100 mm) PVSs [16]. On the other hand, tracer infusions increase the intracranial pressure (ICP) [11], and may also give rise to a small but longlasting ICP gradient [37].…”

“…We thus omit bifurcations and the curvature of the vessel. However, as PVS flow has a very low Reynolds number (Re < 0.01), and as we have previously shown that bifurcations do not introduce complex flow patterns in the PVS [16], we therefore consider this simplification to be reasonably valid. The concentration threshold used to render volumetric images was arbitrarily set; a change in this value would not alter our conclusions, but would shift the arrival time of tracer shown in Figures 7-8.…”

Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection

“…Characterizing the flow, however, is easier than determining its driver. Although arterial pulsation has long been considered as a possible driving mechanism for the bulk flow (Bilston et al, 2003;Hadaczek et al, 2006;Wang and Olbricht, 2011;Iliff et al, 2013;Thomas, 2019;Daversin-Catty et al, 2020), that notion remains controversial (Diem et al, 2017;Kedarasetti et al, 2020a;van Veluw et al, 2020), and other mechanisms are possible.…”

Fast uncertainty quantification of tracer distribution in the brain interstitial fluid with multilevel and quasi Monte Carlo

“…Mathematical modeling is therefore a compelling tool to investigate CSF/IFS-exchange related to brain clearance or drug delivery. Computational studies [11][12][13] investigating CSF flow in paravascular spaces (PVS) have not been able to reproduce the average flow velocities reported in experimental studies with microspheres. 14,15 Within the interstitium, both experimental, 7 and computational 16 studies have concluded that diffusion dominates convection.…”