Is solute movement within the extracellular spaces of brain gray matter brought about primarily by diffusion or flow? A commentary on “Analysis of convective and diffusive transport in the brain interstitium” Fluids and Barriers of the CNS (2019) 16:6 by L. Ray, J.J. Iliff and J.J. Heys

Solutes can enter and leave gray matter in the brain by perivascular routes. The glymphatic hypothesis supposes that these movements are a consequence of inward flow along periarterial spaces and an equal outward flow along perivenous spaces. The flow through the parenchyma between periarterial and perivenous spaces is the same as the inflow and the outflow. Ray et al. (Fluids Barriers CNS 16:6, 2019) have investigated how this flow could interact with diffusion using numerical simulations of real-time iontophoresis experiments that monitor the concentrations of tetramethylammonium ions (TMA(+)) injected into the parenchyma via iontophoresis. For this purpose they have devised a description of the parenchyma incorporating perivascular spaces. Their simulations show that superficial flow velocities of about 50 µm min(−1) are needed to produce changes in TMA(+) fluxes comparable to those accounted for by diffusion. In the glymphatic hypothesis the proposed flow through the parenchyma can be estimated from the clearance of solutes that are present in the perivenous outflow at the same concentration as in the interstitial fluid of the parenchyma. Reported clearances are approximately 1 µL min(−1) g(−1). This flow can be converted to a superficial flow velocity using the area available for the flow, which can be estimated using Ray et al.’s description of the tissue as 40 cm(2) g(−1). The best available estimate of the flow velocity is thus 0.25 µm min(−1) which is 200 times smaller than the flow that produces effects comparable to diffusion for TMA(+). Thus it follows in Ray et al.’s description of the parenchyma that diffusion rather than flow accounts for TMA(+) movements. Because the diffusion constant depends only weakly on molecular weight the same is expected to apply even for solutes somewhat larger than serum albumin.