Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism

Abstract

A “glymphatic system,” which involves convective fluid transport from para-arterial to paravenous cerebrospinal fluid through brain extracellular space (ECS), has been proposed to account for solute clearance in brain, and aquaporin-4 water channels in astrocyte endfeet may have a role in this process. Here, we investigate the major predictions of the glymphatic mechanism by modeling diffusive and convective transport in brain ECS and by solving the Navier–Stokes and convection–diffusion equations, using realistic ECS geometry for short-range transport between para-arterial and paravenous spaces. Major model parameters include para-arterial and paravenous pressures, ECS volume fraction, solute diffusion coefficient, and astrocyte foot-process water permeability. The model predicts solute accumulation and clearance from the ECS after a step change in solute concentration in para-arterial fluid. The principal and robust conclusions of the model are as follows: (a) significant convective transport requires a sustained pressure difference of several mmHg between the para-arterial and paravenous fluid and is not affected by pulsatile pressure fluctuations; (b) astrocyte endfoot water permeability does not substantially alter the rate of convective transport in ECS as the resistance to flow across endfeet is far greater than in the gaps surrounding them; and (c) diffusion (without convection) in the ECS is adequate to account for experimental transport studies in brain parenchyma. Therefore, our modeling results do not support a physiologically important role for local parenchymal convective flow in solute transport through brain ECS.

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…It is becoming increasingly apparent that under normal conditions, such flows likely do not exist in the neuropil of the gray matter. Rather than a 'glymphatic' system as originally proposed [91,124,125], the weight of the evidence now suggests the existence of a perivascular fluid system for the CNS, with convective flow or dispersion along the perivascular spaces of larger vessels and then diffusion predominantly regulating CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, as now proposed by several groups [6,74,80,96,137,161,162,192]. It remains possible that pericapillary convection occurs in the basal lamina in addition to diffusion to formally link up the arteriolar and venular perivascular fluid compartments and allow a fully convective circulation pathway [74,137]; regardless, CSF/ISF exchange may at least partly occur through the neuropil of the gray matter at the capillary level by diffusion, as neurons and all the other constituents of the NVU are not located further than about 10-20 µm from the pericapillary spaces, a distance that has likely been optimized for the effective diffusion of glucose, oxygen, and countless other substances from the circulation [3,192].…”

“…The perivascular spaces (PVS) 1 of cerebral blood vessels have in recent years been the subject of increasing research focus as pathways for CSF/ISF exchange [1,74,89,91,95,112,137,138,162], but controversy exists over their precise role [58,77,96,161,162]. Indeed, the glial components (astrocyte foot processes) that provide the outer boundary of the PVS within the parenchyma have been proposed to serve a special function for CNS clearance and waste turnover, forming the basis for a so-called 'glymphatic' circulation [91,124] that may potentially allow a more complete exchange of CSF and ISF at both superficial and deep sites spanning the entire neural axis.…”

“…It has long been suggested that the reason diffusive transport is strongly favoured over flow in the brain ECS under most conditions is that the hydraulic resistance of such narrow spaces is too high for bulk flow to occur even in the presence of a significant pressure difference [60,80,192]. Recent modelling studies of tracer movement through the ECS have continued to suggest that flow in the ECS (as suggested by the 'glymphatic' hypothesis) is unlikely [80,96].…”

Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow

“…Although lymphatic vessels occur within the meninges (1, 2), they are absent from the brain's parenchyma. This raises the question of how waste products are cleared from the brain (3)(4)(5)(6)(7)(8). There is an urgent need to resolve this question, given the fact that several neurological disorders are associated with accumulation of toxic debris and molecules in the brain interstitium (9).…”

“…There are, however, controversies regarding the relative importance of advective versus diffusive transport within the interstitial space (3,5,7,8), and the idea that a hydrostatic pressure gradient can cause an advective flow within the interstitium has been questioned (3,5,6).…”