Extracellular space structure revealed by diffusion analysis
Open accessAbstract
The structure of brain extracellular space resembles foam. Diffusing molecules execute random movements that cause their collision with membranes and affect their concentration distribution. By measuring this distribution, the volume fraction (alpha) and the tortuosity (lambda) can be estimated. The volume fraction indicates the relative amount of extracellular space and tortuosity is a measure of hindrance of cellular obstructions. Diffusion measurements with molecules or =3000 Mr show more hindrance, but molecules of 70000 Mr can move through the extracellular space. During stimulation, and in pathophysiological states, alpha and lambda change, for example in severe ischemia alpha = 0.04 and lambda = 2.2. These data support the feasibility of extrasynaptic or volume transmission in the extracellular space.
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The ECM comprises approximately 20% of the brain's volume.
“This matrix comprises approximately 20% of the brain's volume (Nicholson and Sykova, 1998)”
From Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity (2016) · cites this paper as Nicholson and Sykova, 1998
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Ruoslahti, E. (1996) · Glycobiology · doi:10.1093/glycob/6.5.489 · Cited by 467 · see citing works
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Landgraf, R., & Neumann, I. D. (2004) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2004.05.001 · Cited by 1,059 · see citing works
Thorne, R. G., & Nicholson, C. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509425103 · Cited by 641 · see citing works
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Scofield, M. D., Heinsbroek, J. A., Gipson, C. D., Kupchik, Y. M., Spencer, S., Smith, A. C. W., Roberts-Wolfe, D., & Kalivas, P. W. (2016) · Pharmacological Reviews · doi:10.1124/pr.116.012484 · Cited by 598 · see citing works
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“Restricted diffusion refers to confinement by boundaries within the diffusion time, whereas hindered diffusion describes slowed but unconfined motion through complex, tortuous environments ( Nicholson & Phillips, 1981; Nicholson & Sykov á , 1998; Nilsson et al., 2013).”
- Authors
- Nicholson, C., & Syková, E.
- Affiliations
- NYU Langone Health (US)
- Charles University (CZ)
- Venue
- Trends in Neurosciences
- Publisher
- Elsevier BV
- Published
- 1998-05
- Volume
- 21
- Issue
- 5
- Pages
- 207-215
- ISSN
- 0166-2236 (ISSN-L)
- OpenAlex
- W2082969312
- Cited by
- 914
- References
- 1
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 29 · 2023: 24 · 2022: 33 · 2021: 21 · 2020: 28 · 2019: 26 · 2018: 29 · 2017: 40 · 2016: 28 · 2015: 22 · 2014: 30 · 2013: 40 · 2012: 45
- FWCI
- 9.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Trends in Neurosciences (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50ns034115-05)
- National Institute of Neurological Disorders and Stroke (NS34115, NS-28642, R01NS028642)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- extracellular space, diffusion analysis, volume fraction, tortuosity, molecular diffusion, anisotropy, ischemia, volume transmission
- MeSH terms
- Animals, Brain, Brain Injuries, Cerebral Cortex, Corpus Callosum, Diffusion, Extracellular Space, Humans
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