Functional hyperemia drives fluid exchange in the paravascular space

Abstract

The brain lacks a conventional lymphatic system to remove metabolic waste. It has been proposed that fluid movement through the arteriolar paravascular space (PVS) promotes metabolite clearance. We performed simulations to understand how arteriolar pulsations and dilations, and brain deformability affect PVS fluid flow. In simulations with compliant brain tissue, arteriolar pulsations did not drive appreciable flows in the PVS. However, when the arteriole dilated as in functional hyperemia, there was a marked movement of fluid. Simulations suggest that functional hyperemia may also serve to increase fluid exchange between the PVS and the subarachnoid space. We measured blood vessels and brain tissue displacement simultaneously in awake, head-fixed mice using two-photon microscopy. These measurements showed that brain deforms in response to pressure changes in PVS, as predicted by simulations. Our results show that the deformability of the brain tissue needs to be accounted for when studying fluid flow and metabolite transport.Acknowledgements: This work was supported by NSF Grant CBET 1705854.

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

“…Probability density functions show that the delay times between the peaks in the cardiac cycle and the peaks in V rms are nearly identical for the two infusion methods. While we can not rule out other physiological mechanisms that might drive CSF flow, such as functional hyperemia 35 or vasomotion 15,36 , we conclude that the currently employed methods of tracer infusion are not responsible for the observed flows.…”

A network model of glymphatic flow under different experimentally-motivated parametric scenarios

“…Finally, we highlight that our model can be generalized to predict transport of dye, metabolic waste, drugs, or any other molecules due to advection-diffusion. Such future studies will contribute to the substantial ongoing debate regarding the nature of transport in penetrating PVSs ( 63–66 ).…”

“…In our model, CSF flow is driven by the simplest possible mechanism – an externally applied pressure drop across the entire network. However, other potential driving mechanisms (e.g., pressure gradients generated by arterial pulsations ( 14 ), functional hyperemia ( 66 ), or osmotic effects ( 22, 51, 67 )) could be tested with this network model approach by implementing pressure sources (i.e., “batteries”) throughout the network. In particular, incorporation of osmotic effects could be leveraged to investigate the mechanisms by which aquaporin-4 facilitates glymphatic flow ( 4, 23, 53,68 ), although there is some debate about this point ( 68,69 ).…”

Brain solute transport is more rapid in periarterial than perivenous spaces

“…As our simulated net flow was close to the experimentally observed range, we would expect to see but a minor additional effect of vessel wall pulsations or pulsatile pressure gradients on tracer trans-port. Similarly, by including brain compliance one could imagine a minor additional change in fluid velocities and dispersion [42].…”