Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

Abstract

Recent years have seen an increased understanding of the importance of myelination in healthy brain function and neuropsychiatric diseases. Non-invasive microstructural magnetic resonance imaging (MRI) holds the potential to expand and translate these insights to basic and clinical human research, but the sensitivity and specificity of different MR markers to myelination is a subject of debate.To consolidate current knowledge on the topic, we perform a systematic review and meta-analysis of studies that validate microstructural imaging by combining it with myelin histology.We find meta-analytic evidence for correlations between myelin histology and markers from different MRI modalities, including diffusion-weighted imaging, relaxometry, quantitative susceptibility mapping and magnetization transfer imaging. Meta-analytic correlation effect sizes range widely, between R2 = 0.26 and R2 = 0.82. However, formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias, thus preventing the establishment of a single most sensitive strategy to measure myelin with MRI.To facilitate further progress, we provide a detailed characterisation of the studies in our analysis as an online resource. We also share a set of recommendations for future studies validating putative MR-based myelin markers and deploying them in vivo in humans.HighlightsSystematic review and meta-analysis of studies validating microstructural imaging with myelin histologyWe find many MR markers are sensitive to myelin, including FA, RD, MP, MTR, Susceptibility, R1, but not MDFormal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication biasResults emphasize the advantage of using multimodal imaging when testing hypotheses related to myelin in vivo in humans.

White matter microstructure across the adult lifespan: A mixed longitudinal and cross-sectional study using advanced diffusion models and brain-age prediction

“…While several of the advanced dMRI models showed comparable results to DTI in terms of age sensitivity, they also showed visibly different age trajectories (Figure 3 Although recent research has validated FA and RD metrics of DTI as being sensitive markers to myelin (Lazari & Lipp, 2020), caution must be exerted in interpreting specific underlying biology on the basis of DTI alone (Novikov et al, 2018). With this in mind, combining tissue models such as NODDI, WMTI, RSI, and SMT mc may hold promise in jointly reflecting measures more relatable to the neurobiological underpinnings of brain ageing.…”

DIffusion-Prepared Phase Imaging (DIPPI): quantifying myelin in crossing fibres

“…The axonal volume fraction can be estimated from diffusion MRI, using a multi-compartment fit to the diffusion-weighted signal 14-18 . A wide variety of different MRI modalities have been proposed to estimate the myelin volume fraction 19,20 . Most of these rely on directly imaging the myelin water, which can be distinguished from the rest of the water based on its short T 2 * using multi-echo spin-echo sequences 21–23 , its short T 2 * using multi-echo gradient-echo sequences 24,25 , its short T 1 using an inversion-recovery sequence 26 , or based on magnetisation transfer between the myelin macromolecules and water 27 .…”

“…It is also an average across fibre populations in voxels where multiple fibres cross each other, which is a common configuration in the human brain 29,30 . Furthermore, this approach relies on the accuracy of the volume fraction estimates 31 , which has been questioned for both the axonal volume fractions 32 and the myelin volume fractions 13,19,20 . Here we aim to overcome these limitations by proposing a novel sequence, which is directly sensitive to the g -ratio (rather than the volume fractions) and allows to distinguish between crossing fibres.…”

New insights into the dynamic development of the cerebral cortex in childhood and adolescence: Integrating macro- and microstructural MRI findings

“…T1w tissue contrasts and T1w/T2w ratio have both been presumed to indirectly reflect differences in intracortical (and subjacent white matter) myelin content (Glasser and Van Essen, 2011;Salat et al, 2009). Of note, while neuronal axons have diameters in the μm range, cortical microstructure is inferred from large tissue volumes, typically at about 1mm voxel resolution (Lazari and Lipp, 2020). Such inferences are possible as macromolecules in the myelin sheath, including cholesterol, have a major influence on T1 longitudinal-and T2 and T2* transverse relaxation times (Does, 2018;Koenig, 1991;Koenig et al, 1990).…”

“…Together, these findings demonstrate that intensity measures are by no means straightforward myelin proxies, and that histological validation studies are needed. Ideally by joint human post-mortem and MRI studies, where the tissue is processed both histologically as well as with neuroimaging, and where variance assessments control for confounders such as axon density and iron content (Lazari and Lipp, 2020). Other complicating factors, such as whether intensity measures capture the same underlying properties across the life-span and within and across brain matter, also need clarification.…”