Both noise‐floor and tissue compartment difference in diffusivity contribute to FA dependence on b‐value in diffusion MRI

Noninvasive diffusion magnetic resonance imaging (dMRI) has been widely employed in both clinical and research settings to investigate brain tissue microstructure. Despite the evidence that dMRI‐derived fractional anisotropy (FA) correlates with white matter properties, the metric is not specific. Recent studies have reported that FA is dependent on the b‐value, and its origin has primarily been attributed to either the influence of microstructure or the noise‐floor effect. A systematic investigation into the inter‐relationship of these two effects is however still lacking. This study aims to quantify contributions of the reported differences in intra‐ and extra‐neurite diffusivity to the observed changes in FA, in addition to the noise in measurements. We used in‐vivo and post‐mortem human brain imaging, as well as numerical simulations and histological validation, for this purpose. Our investigations reveal that the percentage difference of FA between b‐values (pdFA) has significant positive associations with neurite density index (NDI), which is derived from in‐vivo neurite orientation dispersion and density imaging (NODDI), or Bielschowsky's silver impregnation (BIEL) staining sections of fixed post‐mortem human brain samples. Furthermore, such an association is found to be varied with Signal‐to‐Noise Ratio (SNR) level, indicating a nonlinear interaction effect between tissue microstructure and noise. Finally, a multicompartment model simulation revealed that these findings can be driven by differing diffusivities of intra‐ and extra‐neurite compartments in tissue, with the noise‐floor further amplifying the effect. In conclusion, both the differences in intra‐ and extra‐neurite diffusivity and noise‐floor effects significantly contribute to the FA difference associated with the b‐value.