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Abstract

Subcortical white matter (SWM) is a thin layer of white matter (WM) residing just below the cortex. Its structure, metabolism and function differ substantially from deep WM. Importantly, SWM incorporates short association fibers, the intra-hemispheric connections between adjacent gyri, referred to as U-fibers. Despite their importance for cortico-cortical connectivity little is known about the distribution of U-fibers in humans mainly due to the lack of appropriate imaging methods. SWM mapping by structural magnetic resonance imaging (MRI), came into reach only very recently by the availability of ultra high resolution MRI vivo required to image this ultra-thin, geometrically complex structure. No study has explored this potential so far and the underlying biophysical MR contrast mechanisms in SWM are still unclear. Herein, we investigate multiple MR contrasts in human SWM with high-resolution in-vivo 7T MRI. We demonstrate that the transverse relaxation rate (R2), effective transverse relaxation rate (R2)* and magnetic susceptibility are increased in SWM exhibiting strong contrast to both adjacent grey matter (GM) and deep WM. Combination of increased R2* and increased susceptibility points toward an elevated levels of paramagnetic iron as a driving contrast mechanism. This hypothesis was tested in a post-mortem human brain sample with 7T MRI, classical histology and quantitative iron and myelin mapping. Quantitative iron maps were obtained at scales ranging from 1 to 100μm by proton induced X-ray emission (PIXE) and Laser Ablation Inductively Coupled Plasma Mass Spectroscopic Imaging (LA ICP MSI). Elevated iron level in oligodendrocytes and iron-rich fibers in SWM was confirmed as the dominant contrast mechanism. In addition, we showed that SWM contrast in MRI vanished after de-ironing the brain tissue sample in deferroxamine solution. We therefore conclude that the SWM appearance in MR images is solely driven by elevated iron concentration. Furthermore, using a novel SWM segmentation method we demonstrated that SWM contrast is not uniform across the brain. U-fiber-rich frontal, temporal and parietal association areas showed higher SWM contrast, while primary motor, sensory and auditory areas with high intracortical myelination showed lower SWM contrast. This suggests that iron accumulation in SWM is area-dependent and might reflect U-fiber density and distinct myelination patterns of overlying cortical areas. These new findings are of paramount importance and may pave the way for future in-vivo segmentation strategies for this crucial white matter structure and for potential non-invasive U-fiber density mapping in humans.