The glymphatic system: Current understanding and modeling

Abstract

We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid and interstitial fluid around the brain, facilitating solute transport. Models enable hypothesis development and predictions of transport, with clinical applications including drug delivery, stroke, cardiac arrest, and neurodegenerative disorders like Alzheimer's disease. We sort existing models into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, and links to neuronal activity. Needs and opportunities for future work are highlighted wherever possible; new models, expanded models, and novel experiments to inform models could all have tremendous value for advancing the field.

Keywords: Neuroanatomy; Neuroscience; Systems biology.

Graphical abstract

Figure 1

Updated schematic description of the glymphatic system (2022) The glymphatic system supports the perivascular exchange of CSF and interstitial solutes throughout the CNS. This process occurs over macroscopic anatomical scales, within the perivascular influx of subarachnoid CSF into brain tissue organized along the scaffold of the arterial vascular network, and the efflux of interstitial solutes occurring toward cisternal CSF compartments associated with dural sinuses. (A) CSF influx into brain tissue occurs along perivascular pathway surrounding penetrating arteries (A1) and is driven in part by arterial pulsation (A2). Perivascular bulk flow and interstitial solute clearance are dependent upon the astroglial water channel AQP4 localized to perivascular astroglial endfeet surrounding the cerebral vasculature (A3). (B) Interstitial solute movement occurs through the combined effects of diffusion and advection. Advection is most rapid along privileged anatomical pathways, including intraparenchymal perivascular spaces (B1) and white matter tracts (B3), and supports the movement of large molecular weight solutes. Diffusion dominates the movement of small molecules, particularly within the wider interstitium (B2). (C) Interstitial solutes drain from the parenchyma along white matter tracts and draining veins towards sinus-associated cisternal CSF compartments (C1). CSF solutes are cleared from the cranium via uptake into meningeal lymphatic vessels, by efflux through dural arachnoid granulations, or through clearance along cranial or spinal nerve sheathes (C2).

Figure 2

Overview of experimental techniques that can inform glymphatic modeling ¹In spite of the mathematician Gelfand’s claim that “there is only one thing which is more unreasonable than the unreasonable effectiveness of mathematics in physics, and this is the unreasonable ineffectiveness of mathematics in biology”, the powerful mathematical methods developed with the understanding of inorganic matter are often surprisingly useful (Wigner, 1990).