Intracranial cerebrospinal and interstitial fluid (ISF) flow and solute transport have important clinical implications, but limited in vivo access to the brain interior leaves gaping holes in human understanding of the nature of these neurophysiological phenomena. Models can address some gaps, but only insofar as model inputs are accurate. We perform a sensitivity analysis using a Monte Carlo approach on a lumped-parameter network model of cerebrospinal and ISF in perivascular and extracellular spaces in the murine brain. We place bounds on model predictions given the uncertainty in input parameters. Péclet numbers for transport in penetrating perivascular spaces (PVSs) and within the parenchyma are separated by at least two orders of magnitude. Low permeability in penetrating PVSs requires unrealistically large driving pressure and/or results in poor perfusion and are deemed unlikely. The model is most sensitive to the permeability of penetrating PVSs, a parameter whose value is largely unknown, highlighting an important direction for future experiments. Until the value of the permeability of penetrating PVSs is more accurately measured, the uncertainty of any model that includes flow in penetrating PVSs is so large that absolute numbers have little meaning and practical application is limited.
Bibliographical noteFunding Information:
This work was supported by the NIH National Institute on Aging through grant no. RF1AG057575 and by the Army Research Office through grant no. MURI W911NF1910280. J.T. is supported by a Career Award at the Scientific Interface from Burroughs Wellcome Fund. Acknowledgements
© 2022 The Author(s) Published by the Royal Society.
- Cerebrospinal fluid
- Computational modelling
- Glymphatic system
- Perivascular spaces
- Reduced-order modelling
- Sensitivity analysis
PubMed: MeSH publication types
- Journal Article