In vivo observation and biophysical interpretation of time-dependent diffusion in human white matter
Open accessAbstract
The presence of micrometer-level restrictions leads to a decrease of diffusion coefficient with diffusion time. Here we investigate this effect in human white matter in vivo. We focus on a broad range of diffusion times, up to 600 ms, covering diffusion length scales up to about 30 μm. We perform stimulated echo diffusion tensor imaging on 5 healthy volunteers and observe a relatively weak time-dependence in diffusion transverse to major fiber tracts. Remarkably, we also find notable time-dependence in the longitudinal direction. Comparing models of diffusion in ordered, confined and disordered media, we argue that the time-dependence in both directions can arise due to structural disorder, such as axonal beads in the longitudinal direction, and the random packing geometry of fibers within a bundle in the transverse direction. These time-dependent effects extend beyond a simple picture of Gaussian compartments, and may lead to novel markers that are specific to neuronal fiber geometry at the micrometer scale.
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Restricted and hindered diffusion mechanisms coexist within each voxel, generating non-Gaussian and time-dependent diffusion behavior.
“These mechanisms coexist within each voxel, generating non-Gaussian and time-dependent diffusion behavior (Fieremans et al., 2016; Novikov et al., 2019).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Fieremans et al., 2016
The Introduction links observed time dependence to non-Gaussian diffusion and argues that disordered hindrances and restrictions are likely contributors in human white matter. It does not establish that both mechanisms coexist within each voxel; the Discussion > Longitudinal Diffusion says the intra- and extra-axonal contributions cannot yet be separated. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHuman white-matter diffusivity depends on diffusion time, supporting the idea that axonal packing, extra-axonal disorder, restrictions, and exchange contribute to the measured signal.
“Later work showed that human white-matter diffusivity depends on diffusion time, supporting the idea that axonal packing, extra-axonal disorder, restrictions, and exchange contribute to the measured signal (Fieremans et al., 2016).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Fieremans et al., 2016
The Abstract and Conclusions report time-dependent diffusivity in human white matter and interpret it in terms of axonal packing, extra-axonal disorder, and restrictions along fibers. The Discussion’s “Potential confounding effects” section says exchange could affect the measured signal, but does not establish it as a contributor to the observed time dependence; the authors note that modeling this effect is beyond the study’s scope. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFree-water correction, multi-shell acquisition, and joint structural-functional modeling are already making diffusion MRI less reliant on a few oversimplified scalar summaries.
“Free-water correction, multi-shell acquisition, and joint structural–functional modeling are already making diffusion MRI less reliant on a few oversimplified scalar summaries (Assaf et al., 2019; Fieremans et al., 2016).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Fieremans et al., 2016
The Methods and Results describe varying diffusion time and fitting biophysical models to white-matter measurements, supporting the broader move beyond a few scalar summaries. But the Methods > In vivo measurements reports b = 0 and b = 500 s/mm² acquisitions, not multi-shell acquisition; the paper does not describe free-water correction or joint structural–functional modeling. Page numbers are unavailable in our copy. (LLM, conf=0.86)
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“These mechanisms coexist within each voxel, generating non-Gaussian and time-dependent diffusion behavior ( Fieremans et al., 2016; Novikov et al., 2019).”
- Authors
- Fieremans, E., Burcaw, L. M., Lee, H.-H., Lemberskiy, G., Veraart, J., & Novikov, D. S.
- Affiliations
- New York University (US)
- University of Antwerp (BE)
- Corresponding author
- Fieremans, Els
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 129
- Pages
- 414-427
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC4803645
- OpenAlex
- W2282437794
- Cited by
- 181
- References
- 3
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 18 · 2023: 9 · 2022: 16 · 2021: 19 · 2020: 27 · 2019: 16 · 2018: 23 · 2017: 24 · 2016: 7
- FWCI
- 20.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Christopher Glielmi
- Thorsten Feiweier
- Raymond and Beverly Sackler Laboratories for Convergence of Physical, Engineering, and Biomedical Sciences
- Litwin Foundation for Alzheimer's Research
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS088040)
- Fund for Scientific Research-Flanders (12S1615N)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Physical Sciences › Physics and Astronomy › Nuclear and High Energy Physics › NMR spectroscopy and applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- time-dependent diffusion, diffusion tensor imaging, stimulated echo, diffusion coefficient, structural disorder, confined diffusion, diffusion in disordered media
- MeSH terms
- Adult, Brain, Brain Mapping, Female, Humans, Image Processing, Computer-Assisted, Male, Diffusion Tensor Imaging, White Matter
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