Analysis of transport in the brain

Abstract

Neurodegeneration is one of the most significant medical challenges facing our time, yet the gap between therapies and understanding of the inner workings of the brain is great. Impairment of waste clearance has been identified as one key underlying factor in the vulnerability of the brain to neurodegeneration, stimulating research towards understanding transport of molecules in the brain. Based on experimental findings, a unique-to-the-brain circulation has been proposed, the glymphatic system, where cerebrospinal fluid surrounding the brain moves into the brain along the periarterial space that surrounds cerebral arteries, flows through the interstitial space between brain cells, where cellular wastes reside, and carries waste out of the brain tissue along perivenous routes. However, current gaps in knowledge about the driving force for fluid flow have generated scientific skepticism, and an independent method for quantifying transport and demonstrating the presence or absence of convection is desirable. In this work, computational transport models are developed and used to analyze published experimental data to determine fundamental transport parameters for different aspects of the glymphatic circulation. Calculated transport parameters are compared to the known diffusivity of tracers through brain tissue to draw conclusions about the presence and significance of bulk flow, or convection. Based on these analyses, transport in the periarterial spaces surrounding major arteries is over 10,000 times faster than diffusion and in brain tissue, containing both periarterial and interstitial space, transport is around 10 times faster than diffusion alone (for characteristic transport lengths around 1 mm). Interstitial velocity is determined to be on the order of 0.01 mm/min, making convection in the interstitial spaces of the brain critical to the transport of large, slow-to-diffuse molecules implicated in neurodegeneration. Convection is demonstrated to be a significant mechanism of transport throughout the brain. Observations and analyses from this work contribute further evidence to a circulatory-like system in the brain with relatively rapid convection along periarterial space, branching throughout the brain tissue and slower convection across that tissue, in the interstitial spaces of the brain. Transport models developed in this work are demonstrated to be useful tools for gleaning further information from experimental data.