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

Significance Transport of nutrients and clearance of waste products are prerequisites for healthy brain function. It is still debated whether solutes are transported through the interstitial space by pressure-mediated bulk flow or by diffusion. Here we have simulated interstitial bulk flow within 3D electron microscope reconstructions of hippocampal tissue. We show that the permeability is one to two orders of magnitude lower than values typically seen in the literature, arguing against bulk flow as the dominant transport mechanism. Further, we show that solutes of all sizes are more easily transported through the interstitium by diffusion than by bulk flow. We conclude that clearance of waste products from the brain is largely based on diffusion of solutes through the interstitial space. The brain lacks lymph vessels and must rely on other mechanisms for clearance of waste products, including amyloid β that may form pathological aggregates if not effectively cleared. It has been proposed that flow of interstitial fluid through the brain’s interstitial space provides a mechanism for waste clearance. Here we compute the permeability and simulate pressure-mediated bulk flow through 3D electron microscope (EM) reconstructions of interstitial space. The space was divided into sheets (i.e., space between two parallel membranes) and tunnels (where three or more membranes meet). Simulation results indicate that even for larger extracellular volume fractions than what is reported for sleep and for geometries with a high tunnel volume fraction, the permeability was too low to allow for any substantial bulk flow at physiological hydrostatic pressure gradients. For two different geometries with the same extracellular volume fraction the geometry with the most tunnel volume had 36% higher permeability, but the bulk flow was still insignificant. These simulation results suggest that even large molecule solutes would be more easily cleared from the brain interstitium by diffusion than by bulk flow. Thus, diffusion within the interstitial space combined with advection along vessels is likely to substitute for the lymphatic drainage system in other organs.

[1]  Anders Logg,et al.  Automated Solution of Differential Equations by the Finite Element Method: The FEniCS Book , 2012 .

[2]  C. Nicholson,et al.  Diffusion in brain extracellular space. , 2008, Physiological reviews.

[3]  J. Humphrey,et al.  Interstitial transport and transvascular fluid exchange during infusion into brain and tumor tissue. , 2007, Microvascular research.

[4]  P. Basser Interstitial pressure, volume, and flow during infusion into brain tissue. , 1992, Microvascular research.

[5]  Alex J. Smith,et al.  Muddying the water in brain edema? , 2015, Trends in Neurosciences.

[6]  Michael Detmar,et al.  A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules , 2015 .

[7]  Gaute T. Einevoll,et al.  Electrodiffusive Model for Astrocytic and Neuronal Ion Concentration Dynamics , 2013, PLoS Comput. Biol..

[8]  T. Hughes,et al.  A new finite element formulation for computational fluid dynamics: V. Circumventing the Babuscka-Brezzi condition: A stable Petrov-Galerkin formulation of , 1986 .

[9]  E. Nagelhus,et al.  Physiological roles of aquaporin-4 in brain. , 2013, Physiological reviews.

[10]  P F Morrison,et al.  High-flow microinfusion: tissue penetration and pharmacodynamics. , 1994, The American journal of physiology.

[11]  N. Joan Abbott,et al.  Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology , 2004, Neurochemistry International.

[12]  S. Hladky,et al.  Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence , 2014, Fluids and Barriers of the CNS.

[13]  M. Nedergaard,et al.  Garbage Truck of the Brain , 2013, Science.

[14]  R O Weller,et al.  Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology , 2008, Neuropathology and applied neurobiology.

[15]  Timothy J Keyes,et al.  Structural and functional features of central nervous system lymphatics , 2015, Nature.

[16]  Maiken Nedergaard,et al.  Cerebral Arterial Pulsation Drives Paravascular CSF–Interstitial Fluid Exchange in the Murine Brain , 2013, The Journal of Neuroscience.

[17]  G. E. Vates,et al.  A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β , 2012, Science Translational Medicine.

[18]  Daniel J. R. Christensen,et al.  Sleep Drives Metabolite Clearance from the Adult Brain , 2013, Science.

[19]  G T Gillies,et al.  Distribution of macromolecular dyes in brain using positive pressure infusion: a model for direct controlled delivery of therapeutic agents. , 1998, Surgical neurology.

[20]  Jürgen Hennig,et al.  Ultra-fast magnetic resonance encephalography of physiological brain activity – Glymphatic pulsation mechanisms? , 2016, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  Alan S. Verkman,et al.  Spatial model of convective solute transport in brain extracellular space does not support a “glymphatic” mechanism , 2016, The Journal of general physiology.

[22]  N. Alperin,et al.  MR-Intracranial pressure (ICP): a method to measure intracranial elastance and pressure noninvasively by means of MR imaging: baboon and human study. , 2000, Radiology.

[23]  H F Cserr,et al.  Bulk flow of interstitial fluid after intracranial injection of blue dextran 2000. , 1974, Experimental neurology.

[24]  C. C. Law,et al.  ParaView: An End-User Tool for Large-Data Visualization , 2005, The Visualization Handbook.

[25]  P F Morrison,et al.  Convection-enhanced delivery of macromolecules in the brain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Nedergaard,et al.  Filtering the muddied waters of brain edema , 2015, Trends in Neurosciences.

[27]  Valentina Piserchia,et al.  Vascular Supply of the Cerebral Cortex is Specialized for Cell Layers but Not Columns. , 2015, Cerebral cortex.

[28]  A. Louveau,et al.  Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease? , 2016, Neuron.

[29]  C. Nicholson,et al.  Clearance systems in the brain-implications for Alzheimer disease. , 2015, Nature reviews. Neurology.

[30]  P. Agre,et al.  Specialized Membrane Domains for Water Transport in Glial Cells: High-Resolution Immunogold Cytochemistry of Aquaporin-4 in Rat Brain , 1997, The Journal of Neuroscience.

[31]  Vartan Kurtcuoglu,et al.  Glymphatic solute transport does not require bulk flow , 2016, Scientific Reports.

[32]  O. R. Blaumanis,et al.  Evidence for a ‘Paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space , 1985, Brain Research.

[33]  Josef Spacek,et al.  Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuropil , 2013, The Journal of comparative neurology.

[34]  R. Carare,et al.  Vascular basement membranes as pathways for the passage of fluid into and out of the brain Journal Item , 2018 .

[35]  Per Kristian Eide,et al.  Is ventriculomegaly in idiopathic normal pressure hydrocephalus associated with a transmantle gradient in pulsatile intracranial pressure? , 2010, Acta Neurochirurgica.