Myelin g Ratios: The Model Is in the Details

In contemporary myelin biology, there is a growing trend to prioritize faster, more convenient methodologies for evaluating white matter structure over quality of the analysis. This shift is often accompanied by less attention to the mechanistic foundations of the methods in preclinical and clinical research. To address such worrisome trends, the current article assesses three approaches for estimating the myelin g ratio from electron microscopy data, which is the gold standard approach to measure the impacts of neuropathology and treatment strategies on white matter integrity. Of the mathematical models examined, two are consistent with and equivalent to the linear relation defined by the axon versus fiber diameter plot (the principal data). The final model is the canonical almost universally accepted approach to measuring g ratios. This model is demonstrated to be internally inconsistent and discordant with the axon versus fiber diameter relation and can lead to inaccurate conclusions about myelin integrity. Furthermore, the increasing interest in non-invasive neuroimaging approaches to measure g ratios clinically in both physiologic and pathophysiologic studies necessitates calibration with electron microscopy-derived g ratios. In this vein, mathematical models applicable to these methodologies are concordant; thus, magnetic resonance imaging holds significant promise for accurate determination of myelin integrity in patients. On the other hand, the metrics measurable by this voxel-based technology may preclude application to gray matter myelin and perhaps limit its use to linearly-organized white matter tracts.