Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure

Abstract

Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at least in isolation) to draw strong reverse inferences about white matter microstructure, but based on the continued application and interpretation of these metrics in the broader biomedical/neuroscience literature, it appears that this has perhaps not yet become common knowledge among diffusion imaging end-users. Therefore, this paper will briefly discuss the complex biophysical underpinnings of these measures in the context of crossing fibers, provide some intuitive “thought experiments” to highlight how conventional interpretations can lead to incorrect conclusions, and suggest that future studies refrain from using (over-interpreting) FA, AD, and RD values as standalone biomarkers of cerebral white matter microstructure.

An ALE meta-analytic review of musical expertise

“…Hence, some works reported co-occurrent patterns of increase and decrease of grey matter (GM) volumes when comparing musicians to non-musicians 23 , 24 , and other research highlighted negative correlations between GM volumes and musical expertise 24 , 25 . Similarly, investigations focusing on white matter (WM) reported increased fractional anisotropy (i.e., a WM micro-structural organisation measure informing about the diffusion within the predominant direction in a given pathway 26 ) in expert musicians as compared to non-musicians in the corticospinal tract 27 , 28 , internal capsule bundles 29 and corpus callosum 30 , while others found reduced fractional anisotropy and increased radial diffusivity 31 . fMRI studies are similarly characterized by variegated observations, with musicianship being exclusively associated with stronger activity in, e.g., either premotor cortices 32 , right auditory cortex 33 , or prefrontal cortex 34 , ultimately failing to converge into a common functional network for music expertise.…”

Individual differences in slow wave sleep architecture relate to variation in white matter microstructure across adulthood

“…We used a range of diffusion metrics (FA, MD, RD, AD) to probe different aspects of white matter microstructure. While specific biological interpretation of diffusion metrics can be challenging, particularly in regions of crossing fibers ( Figley et al, 2022 ), our findings suggest a consistent picture of altered white matter microstructure across widely distributed regions.…”

Comparison of Olfactory Tract Diffusion Measures Between Early Stage Parkinson’s Disease Patients and Healthy Controls Using Ultra-High Field MRI

“…The positive correlation found in this study between MDS-UPDRSIII (ON-medication) and FA of the OT paradoxically suggests that OT integrity increases with PD severity. However, due to the presence of many crossing fibers in the white matter, FA can also increase as a result of disproportionate degradation of one or more of these fiber bundles, even despite an actual decrease in local fiber den-sity and myelination [10,37]. This would indicate that the white matter fibers in the OT are less complex as PD severity increases, while myelin and axons are preserved.…”