Mechanisms of tracer transport in cerebral perivascular spaces

Tracers infused into the brain appear to be transported along channels surrounding cerebral blood vessels. Bulk fluid flow has been hypothesized in paravascular "glymphatic" channels (outer space between the pial membrane and astrocyte endfeet), as well as in the periarterial space (inner space between smooth muscle cells). The plausibility of net flow in these channels due to steady and oscillatory pressures is reviewed, as is that of transport by oscillatory shear-enhanced dispersion in the absence of net flow. Models including 1D branching networks of annular channels and an expanded compartmental model for humans both predict that flow driven by physiologic steady pressure differences is unlikely in both periarterial and paraarterial spaces, whether the spaces are open or filled with porous media. One exception is that a small additional steady pressure difference could drive paraarterial flow if the space is open. The potential that the tracer injection itself could present such a pressure difference is outlined. Oscillatory (peristaltic) wall motion alone has been found to be insufficient to drive significant forward flow. However, a number of hypothesized mechanisms that have yet to be experimentally verified in the brain may create directional flow in combination with wall motion. Shear-augmented dispersion due to oscillatory pressure in channels with a range of porosity has been modeled analytically. Enhancement of axial dispersion is small for periarterial channels. In open paraarterial channels, dispersion enhancement with optimal lateral mixing is large enough that it may explain observed tracer transport without net forward fluid flow.