Proposal 1 The first proposal (Fig. 7a) was that secretion of fluid by the blood–brain barrier provides a small pressure gradient for outflow of ISF along preferential routes (see [83, 126, 127, 129, 130]). These routes could be perivascular spaces or the extracellular spaces parallel to the axons in nerve fibre tracts. When this proposal was put forward more than 30 years ago (see e.g. [83]) it was believed that the half-life for clearance of marker solutes by outflow was of the order of 12 h. However, all of these early studies were performed on animals anaesthetized using barbiturates. Using either conscious animals or those anaesthetized with ketamine/zylazine or halothane, the half-lives are much shorter, 2–4 h [25, 62, 85, 131]. Perivascular efflux of solutes is considerably faster than envisaged by Cserr and coworkers. It should also be pointed out that Proposal 1 does not and was never intended to provide any explanation for the rapid influx of solutes. In Proposal 1 (and in Proposal 3, see below) the solutes are swept out of the parenchyma by the flow through the perivascular system. Estimates of the flow rate required to eliminate substances at the observed rates can be calculated from their clearances1 CLperivascular=rateofelimination/cisfand the assumption that the concentration of the solute is the same in ISF and the outflow. Then because elimination is by outflow2 rateofelimination=rateofoutflow×concentration in outflowand substituting that into the definition of clearance,3 CLperivascular=rateofoutflow×concentration in outflow/cisf,which, because the concentration in the outflow is the same as cisf, becomes4 CLperivascular=rateofoutflow.