Enhanced distribution of molecules in the brain due to oscillations of the interstitial flow

TL;DR

This paper models how oscillatory interstitial fluid flow, driven by cardiac and respiratory cycles, enhances molecular dispersion in the brain, potentially explaining high-volume molecular transmission observed in MRI studies.

Contribution

It introduces a novel oscillatory random walk model to quantify molecule spread due to pulsatile flow in brain interstitial spaces, incorporating cardiac and respiratory effects.

Findings

Oscillatory flow induces significant effective diffusivity.

Cardiac and respiratory cycles enhance molecular dispersion.

Model explains high-volume transmission observed in MRI studies.

Abstract

MRI measurements from a decade-old study of the physical properties of brain tissue observed a dynamic, pulsating fluid flow in the interstitial spaces of the brain attributed to the cardiac cycle. The effects of this cyclic flow pattern on the spatial distribution of molecules in the brain are modeled in this paper. The effects of oscillatory flow on the dispersion or volumetric transmission of a molecule that is advected by this flow is modeled by a mechanism hitherto neglected in the literature. An oscillatory random walk model is used to estimate the spread or effective diffusivity due to the oscillatory advection. Then, respiration effects are also estimated and the additional dispersion of molecules due to this are calculated in our model. Our model indicates that the observed oscillatory flow in the interstitial spaces due to cardiac as well as respiratory pulsatility can induce an effective diffusivity when the spread of the molecule is observed over times long compared with a cycle of the oscillation. This would help explain the high-volume transmission within the interstitium or brain parenchyma found in MRI measurements of a marker infused into the cerebrospinal fluid in human subjects that is well above what would be expected. Interstitial spaces should be viewed as a region of dynamic oscillatory flow driven by cardiac and respiratory cycles. This oscillatory flow could result in a significant dispersion of molecules and explain the higher-than-expected effective diffusion suggested in human studies. It may be possible to augment or slow this flow and concomitant spread by applying external forces.