Perivascular pumping in the mouse brain: Realistic boundary conditions reconcile theory, simulation, and experiment

Abstract

Cerebrospinal fluid (CSF) flows through the perivascular spaces surrounding cerebral arteries. Revealing the mechanisms driving its flow would bring improved understanding of brain waste transport and insights for disorders including Alzheimer’s disease, stroke, and traumatic brain injury. In vivo CSF velocity measurements in mice have been used to argue that flow is driven primarily by the pulsatile motion of artery walls — perivascular pumping. However, fluid dynamics theory and simulation have predicted that perivascular pumping produces flows differing from in vivo observations starkly, particularly in the phase and relative amplitude of flow oscillation. Here we show that coupling theoretical and simulated flows to realistic end boundary conditions, using resistance and compliance values measured in mice, results in velocities that match observations closely in phase, relative amplitude of oscillation, and mean flow speed. This new, quantitative agreement among theory, simulation, and in vivo measurement further supports the idea that perivascular pumping is a primary CSF driver in physiological conditions. Significance Statement The brain is immersed in cerebrospinal fluid, whose flow has long been thought to remove metabolic wastes and transport neurotransmitters, in addition to offering a potential path for drug delivery. Fluid has been hypothesized to enter the deep brain along spaces that surround arteries, but the mechanisms driving flow there have been debated. Experiments suggest artery wall pulsation drives the fluid in healthy conditions, but theories and simulations have predicted that wall-driven flows would have stronger oscillations and different phase than what is observed. We show that coupling those predictions to a simple but realistic model of the rest of the fluid pathway reconciles the differences, so that theory, simulation, and experiment agree.