Biophysical mechanisms of MRI signal frequency contrast in multiple sclerosis

Abstract

Phase images obtained with gradient echo MRI provide image contrast distinct from T1-and T2-weighted images. It is commonly assumed that the local contribution to MRI signal phase directly relates to local bulk tissue magnetic susceptibility. Here, we use Maxwell's equations and Monte Carlo simulations to provide theoretical background to the hypothesis that the local contribution to MRI signal phase does not depend on tissue bulk magnetic susceptibility but tissue magnetic architecture-distribution of magnetic susceptibility inclusions (lipids, proteins, iron, etc.) at the cellular and subcellular levels. Specifically, we show that the regular longitudinal structures forming cylindrical axons (myelin sheaths and neurofilaments) can be locally invisible in phase images. Contrary to an expectation that the phase contrast in multiple sclerosis lesions should always increase in degree along with worsening of lesion severity (which happens for all known MR magnitude-based contrast mechanisms), we show that phase contrast can actually disappear with extreme tissue destruction. We also show that the phase contrast in multiple sclerosis lesions could be altered without loss of nervous system tissue, which happens in mild injury to the myelin sheaths or axonal neurofilaments. Moreover, we predict that the sign of phase contrast in multiple sclerosis lesions indicates the predominant type of tissue injury-myelin damage (positive sign) vs. axonal neurofilament damage (negative sign). Therefore, our theoretical and experimental results shed light on understanding the relationship between gradient echo MRI signal phase and multiple sclerosis pathology.RI has played a revolutionary role in enhancing knowledge in biology and medicine. Numerous MRI techniques have been developed over the years to aid physicians and scientists in understanding tissue structure and function in health and disease. One MRI technique that has been of increasing interest in recent years relies on phase images obtained by gradient echo (GE) MRI. It was shown that phase images provide image contrast distinct from T1-weighted (T1W) and T2-weighted (T2W) images (1-6). However, the sources of phase contrast have not been completely understood and are a subject of intense debate. Myelin was proposed as one of the main contributors to MR signal phase in white matter (7), and it was shown that demyelination leads to a loss of phase contrast between white matter (WM) and gray matter (GM) (8,9). This finding could have been explained by the difference in tissue cellular/ molecular content (iron, lipids, and proteins) between GM and WM. However, it was also reported that phase contrast is practically absent between WM and CSF (cerebrospinal fluid) (3, 6), despite substantial differences in their molecular content. Iron was shown to play an important role in formation of phase contrast in iron-rich areas, such as caudate, putamen, and globus pallidus (10-13). However, experimental data on the role of iron in WM is controversial; although a decrease of the phas...

A modulated closed form solution for quantitative susceptibility mapping — A thorough evaluation and comparison to iterative methods based on edge prior knowledge

“…The phase contrast changes are dependent from the underlying structural change; myelination damage could lead to hyper-intensities (positive contrast) while axonal damage could lead to hypo-intensities (negative contrast) (Yablonskiy et al, 2012), in our study all lesions showed a positive phase and susceptibility contrast. Moreover, in multiple sclerosis lesions where there are changes/ damage/injury of the myelin sheet, without loss of the tissue, could make them visible in the phase contrast map without being visible neither on the R 2 ⁎ nor on the magnitude (Yablonskiy et al, 2012). This is the case of the lesion pointed with the red arrow which has been hypothesized to correspond mild or early multiple sclerosis lesions.…”

“…It has been shown that tissue damage due to multiple sclerosis leads to the loss of macromolecules (myelin sheaths of the white matter axons) and therefore to a R 2 ⁎ hypo-intensities (negative contrast), reduction of the R 2 ⁎ relaxation rate (Yablonskiy et al, 2012), which were clearly visible (green and blue arrow in Fig. 8).…”

“…More recently it was proposed (He and Yablonskiy, 2009) and demonstrated (Luo et al, 2013;Wharton and Bowtell, 2013;Yablonskiy et al, 2012) that the microstructural compartmentalization in the organization of lipids on the cellular and subcellular level (e.g. lipids, proteins) has a dominant effect on the contrast observed between white and gray matter in phase imaging.…”

Studying cyto and myeloarchitecture of the human cortex at ultra-high field with quantitative imaging: R1, R2* and magnetic susceptibility

“…Myelin content does contribute to the gray and white matter contrast in phase imaging (C. Liu et al, 2011;Lodygensky et al, 2012) yet, not only is the myelin susceptibility anisotropic, its contribution to the measured phase images is driven by the microstructural compartmentalization of lipid organization and its orientation in respect to the static magnetic field (He and Yablonskiy, 2009;Luo et al, 2014;Wharton and Bowtell, 2013;Yablonskiy et al, 2012). These mechanisms are not taken into account in the COSMOS formalism, but they should only be dominating factors in regions where tissue is highly anisotropic (unlike grey matter).…”

Phase White Matter Signal Abnormalities in Patients with Clinically Isolated Syndrome and Other Neurologic Disorders

“…[11][12][13][14][15] However, factors other than nonheme iron may influence the observed WM-SA signal, such as changes in myelin, deoxyhemoglobin, and inflammation. 11,[16][17][18][19] Therefore, because there are a multitude of effects, it is not fully known to what extent they each individually influence SWI-filtered phase changes. Phase changes may signal early WM-SA development 17,20 in that these phase WM-SAs may appear initially but then disappear as the pathology advances.…”