Fractional anisotropy (FA) informs on the anisotropy of the cellular structures averaged over the entire voxel scale (sometimes called macroscopic anisotropy). While it does capture some sense of cell anisotropy, it also confounds this anisotropy with the orientational configuration of these cells. For instance, white matter is made of axonal fiber populations whose orientational configurations can greatly vary, from the single-fiber-population corpus callosum to the more complex crossings found in the corona radiata. In a single-fiber-population tissue, the anisotropy of the voxel-averaged tissue (macroscopic anisotropy) roughly coincides with that of the underlying fiber population (microscopic anisotropy). However, in more complex crossing configurations, the voxel-averaged tissue looks isotropic from a diffusion standpoint, because diffusion occurs in several spatial directions at the same time. This explains why FA tends to vanish in crossing areas and is overall an imperfect marker of white matter integrity. This problem also extends to tumorous tissue made of elongated cells, such as meningiomas, certain high-grade gliomas, and most breast tumors. Finally, grey matter does feature a certain degree of microscopic anisotropy, which is missed by FA.
Using multidimensional diffusion MRI, it is possible to measure microscopic fractional anisotropy (µFA), i.e., a measure of microscopic anisotropy unimpeded by orientational order. It has recently been shown to correlate with clinical scores in multiple sclerosis and Parkinson, and used to differentiate cortex and white matter in malformations of cortical development associated with epilepsy.