Why diffusion tensor MRI does well only some of the time: variance and covariance of white matter tissue microstructure attributes in the living human brain.

Fundamental to increasing our understanding of the role of white matter microstructure in normal/abnormal function in the living human is the development of MR-based metrics that provide increased specificity to distinct attributes of the white matter (e.g., local fibre architecture, axon morphology, and myelin content). In recent years, different approaches have been developed to enhance this specificity, and the Tractometry framework was introduced to combine the resulting multi-parametric data for a comprehensive assessment of white matter properties. The present work exploits that framework to characterise the statistical properties, specifically the variance and covariance, of these advanced microstructural indices across the major white matter pathways, with the aim of giving clear indications on the preferred metric(s) given the specific research question. A cohort of healthy subjects was scanned with a protocol that combined multi-component relaxometry with conventional and advanced diffusion MRI acquisitions to build the first comprehensive MRI atlas of white matter microstructure. The mean and standard deviation of the different metrics were analysed in order to understand how they vary across different brain regions/individuals and the correlation between them. Characterising the fibre architectural complexity (in terms of number of fibre populations in a voxel) provides clear insights into correlation/lack of correlation between the different metrics and explains why DT-MRI is a good model for white matter only some of the time. The study also identifies the metrics that account for the largest inter-subject variability and reports the minimal sample size required to detect differences in means, showing that, on the other hand, conventional DT-MRI indices might still be the safest choice in many contexts.