Theoretical analysis of wake/sleep changes in brain solute transport suggests a flow of interstitial fluid

Clearance of protein waste products from the brain is accomplished by a combination of advection and diffusion in cerebrospinal fluid (CSF) and interstitial fluid (ISF). In the glymphatic model, there is a flow of ISF in the interstitial space, and both advection and diffusion occur there. Such a flow of ISF would be slow and difficult to detect directly, and its existence has proved controversial. Waste clearance has been shown to occur mainly during sleep, during which the volume of the interstitial space increases substantially due to ISF emitted from astrocytes. Here I show that this volume increase of the interstitial space, by itself, should lead to a slight reduction of diffusive transport, due to dilution of the waste solute, but to a significant increase in flow rate and advective transport, due to lowered hydraulic resistance. Thus, a flow of ISF together with the observed volume increase of the interstitial space might provide an important mechanism contributing to the enhanced clearance during sleep.