White Matter Micro-Structure Characterization 

Diffusion magnetic resonance imaging (MRI) became one of the most popular magnetic resonance imaging techniques to study brain macro-structure, pathophysiology and even micron-scale structure (1,2). DTI is the state-of-the-art methodology in white mater mapping. DTI characterizes white matter based on the measurement of water molecules motion in multiple directions and assessment of motional anisotropy (3,4). DTI enables quantification of the motional anisotropy of water molecules and can provide images with high contrast to white matter.

The composite hindered and restricted model of diffusion (CHARMED) is an expansion of DTI method that relates the measured signal to tissue compartment (5,6). Under this approach it is hypothesized that the geometry of the tissue affects the diffusivity of water molecules. It is assumed that in white matter restricted diffusion occurs within the axonal space while hindered diffusion occurs elsewhere. By separating the contribution of restricted diffusion to overall diffusion MRI signal CHARMED allows enhanced characterization of the axonal water compartment. Therefore, one of the advantages of CHARMED is that it is possible to estimate different physical/geometrical properties for each of the components (hindered and restricted) such as the diffusivity of the extra-axonal matrix (diffusivity of the hindered part), the axonal density (the volume fraction of the restricted part) (Figure 1), and the fiber directions (the orientation density function of the restricted part).

The axon diameter distribution is an important histological morphological feature of white matter. The estimation of this parameter is done today with histological procedures. With an expansion to the CHARMED framework, called AxCaliber, the estimation of the axon diameter distribution is feasible (7,8). The idea behind AxCaliber is that each axon size will experience restricted diffusion at a different diffusion time. For example, axon with a diameter of 1m will experience restricted diffusion already at very short diffusion times while a large axon will experience restricted diffusion only when the diffusion time will be increased.

By acquiring a multi-diffusion time CHARMED data set it is possible to accurately estimate the axon diameter distribution function with the AxCaliber framework. The AxCaliber framework was verified on excised samples of optic and sciatic nerves. It was found that the AxCaliber diameter distribution functions were in good agreement with the histological ones. In addition, AxCaliber was performed in-vivo in the rat (Figure 2) and human brain (Figure 3) revealing the regional difference in ADD along the corpus callosum. With the geometrical model approach (as in CHARMED and AxCaliber) it is possible to use diffusion MRI to extract compartment specific information and thus turning it into a microstructural probe that actually serves as a virtual histological tool.


1. Jones DK. Diffusion MRI : theory, methods, and application. New York: Oxford University Press.
2. Johansen-Berg H, Behrens TEJ. Diffusion MRI : from quantitative measurement to in-vivo neuroanatomy. Amsterdam ; Boston: Elsevier/Academic Press; 2009.
3. Basser PJ, Mattiello J, LeBihan D. MR diffusion tensor spectroscopy and imaging. Biophys J 1994;66(1):259-267.
4. Basser PJ. Inferring microstructural features and the physiological state of tissues from diffusion-weighted images. NMR Biomed 1995;8(7-8):333-344.
5. Assaf Y, Freidlin RZ, Rohde GK, Basser PJ. New modeling and experimental framework to characterize hindered and restricted water diffusion in brain white matter. Magn Reson Med 2004;52(5):965-978.
6. Assaf Y, Basser PJ. Composite hindered and restricted model of diffusion (CHARMED) MR imaging of the human brain. Neuroimage 2005;27(1):48-58.
7. Assaf Y, Blumenfeld-Katzir T, Yovel Y, Basser PJ. AxCaliber: a method for measuring axon diameter distribution from diffusion MRI. Magn Reson Med 2008;59(6):1347-1354.
8. Barazany D, Basser PJ, Assaf Y. In vivo measurement of axon diameter distribution in the corpus callosum of rat brain. Brain 2009;132(Pt 5):1210-1220.

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