Diffusion in Brain Extracellular Space

By E. Sykova, C. Nicholson. Physiological Reviews, 2008

1,414 citations recorded by the source corpus.

Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecules in the brain. Deviations from the equation reveal loss of molecules across the blood-brain barrier, through cellular uptake, binding or other mechanisms. Early diffusion measurements used radiolabeled sucrose and other tracers. Presently, the real-time iontophoresis (RTI) method is employed for small ions and the integrative optical imaging (IOI) method for fluorescent macromolecules, including dextrans or proteins. Theoretical models and simulations of the ECS have explored the influence of ECS geometry, effects of dead-space microdomains, extracellular matrix and interaction of macromolecules with ECS channels. Extensive experimental studies with the RTI method employing the cation tetramethylammonium (TMA) in normal brain tissue show that the volume fraction of the ECS typically is about 20% and the tortuosity about 1.6 (i.e. free diffusion coefficient of TMA is reduced by 2.6), although there are regional variations. These parameters change during development and aging. Diffusion properties have been characterized in several interventions, including brain stimulation, osmotic challenge and knockout of extracellular matrix components. Measurements have also been made during ischemia, in models of Alzheimer's and Parkinson's diseases and in human gliomas. Overall, these studies improve our conception of ECS structure and the roles of glia and extracellular matrix in modulating the ECS microenvironment. Knowledge of ECS diffusion properties are valuable in contexts ranging from understanding extrasynaptic volume transmission to the development of paradigms for drug delivery to the brain.

Subfields: Nuclear and High Energy Physics, Radiology, Nuclear Medicine and Imaging, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/05cd8d711b6a72b9851e57af300e449b27b7d508

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Citations in the corpus

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Imaging brain microstructure with diffusion MRI: practicality and applications (2019, background): “Invasive microscopy techniques suggest that the fraction of ECS in adult brain of various non‐human species is 15‐35%.(60) However, neither electron nor light microscopy can provide reliable measurements of ECS fraction, because chemicals used in the processing of the tissue for the display introduc”
A new look at cerebrospinal fluid circulation (2014, neutral): “(reviewed by [92] ).”
The blood-brain barrier: an engineering perspective (2013, background): “The extracellular volume fluctuates during normal brain function and decreases during development and aging (Sykova and Nicholson, 2008; Kroeger et al., 2010).”
Revisiting the concept of CNS immune privilege (2015, background): “For larger molecules, simple diffusion is not efficient enough to drain molecules from the deep brain parenchyma into the CSF [28].”
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White matter characterization with diffusional kurtosis imaging (2011, methodology): “89 has been found for the corpus callosum of adult rat brain using the standard iontophoresis method with tetramethylammonium (TMA) as probing molecule (Syková and Nicholson, 2008) (this value is derived from the reported value of 1.”
Physiological roles of aquaporin-4 in brain. (2013, background): “Obviously, changes in extracellular volume and tortuosity will affect diffusion and clearance of signal molecules and other solutes (180).”
Apparent Fibre Density: A novel measure for the analysis of diffusion-weighted magnetic resonance images (2012, methodology): “We investigated in vivo human data acquired from 15 healthy control subjects (as described in the AFD voxel-based analysis of Motor Neurone Disease section below) to determine if the observed radial DW signal is approximately 80% of the b=0 signal based on the expected 20% extra-cellular volume frac”
Physiology of Astroglia. (2018, neutral): “Synaptic transmission evokes rapid and considerable (5–30%) reduction in the extracellular volume (430, 1710).”