Fig. 9

Comparisons of the classical hypothesis, the glymphatic hypothesis and a scheme based on current evidence. They each summarise processes that may be important in extravascular supply and removal of solutes. a In the classical hypothesis [59, 63, 138] ISF is produced by secretion across the blood–brain barrier and flows out of the parenchyma along “preferred routes” including periarterial spaces, white matter tracts, subependymal spaces and possibly perivenous spaces. Solute movement within interstitial spaces is by diffusion. The velocity of the flow within the interstitium is too small to produce observable movements of solutes. b In the glymphatic hypothesis [11, 36] CSF enters the parenchyma via periarterial routes, flows into the interstitial spaces where it mixes with ISF and sweeps solutes to perivenous spaces. ISF flows out of the parenchyma along perivenous spaces. In simple extensions of the hypothesis, outflow may also occur via white matter tracts and subependymal spaces. c Scheme based on current evidence of possible processes involved in supply and removal of solutes in the brain parenchyma. Solutes may move in both directions via periarterial spaces and possibly also via perivenous spaces. There may or may not be net inflow along periarterial spaces and outflow along perivenous spaces. There are also other routes for outflow of fluid and efflux of solutes including white matter tracts and subependymal spaces (compare [34]). Fluid flow may be important in efflux of solutes via extravascular pathways but the flow velocity in interstitial spaces is too small to produce observable movements of solutes. Contrary to what is inferred in many figures portraying the glymphatic circulation, e.g. Fig. 1, there is no sweeping of solutes towards perivenous spaces. In all three schemes solutes emerging from the parenchyma by extravascular routes may be delivered directly to lymph or to CSF. From CSF they can leave the brain via lymph or possibly blood flow