Ultra-high-field (7.0 Tesla and above) MRI is now necessary to make the next step forward in understanding MS pathophysiology – YES

There has been growing interest in the use of magnetic resonance imaging (MRI) at ultra-high-field strength (7 Tesla (7T) and above) to probe disease mechanisms in the brain and spinal cord of patients with multiple sclerosis (MS). Higher spatial resolution and signal-to-noise ratio (SNR) images are the most attractive gains from 7T MRI that may be incorporated into MS clinical studies whenever applicable. Moreover, higher fields provide increased sensitivity to specific contrast mechanisms and agents, not otherwise exploitable at lower field strength.

Magnetic resonance (MR) images are derived from measurements of the macroscopic magnetization induced within tissues by an external magnetic field, and this increases in direct proportion to field strength. The use of higher fields also connotes the use of higher frequencies which produce larger detected signals in MRI coils. Thus, MR signal strengths increase dramatically at higher fields, and although these gains are partially offset by other changes, the overall SNR increases. At higher fields, also the effects of small variations in tissue susceptibility are magnified. As a result, small venous structures and iron deposits, for example, around lesions and in normal-appearing white matter and gray matter tissue, produce much greater changes in tissue contrast than at lower fields.

In general, the contrast at higher fields is different than at lower fields as relaxation times diverge. This contrast may depend on different underlying biophysical characteristics, providing new opportunities for visualization of pathological changes. For example, at high fields, the chemical exchange of protons between water and labile side groups in macromolecules and metabolites causes the relaxation time T2 to shorten and thus T2 variations reflect tissue composition in a different manner.

In the light of this notion, over the last decade, MS scientists focused on the use of 7T MRI to probe disease in small anatomical structure, like the brain cortex, the Virchow–Robin spaces, and the spinal cord. Cortical gray matter regions are especially vulnerable to MS disease because pathological changes from both white matter and subpial spaces can spread through the cortex. In vivo studies showed that up to about 90% of subpial cortical lesions detected on a T2* fast low angle shot spoiled gradient echo MRI at 7T (0.3 mm × 0.3 mm × 1 mm resolution) are not visible on a 3T double-inversion recovery MRI (0.8 mm × 0.8 mm × 3 mm resolution).¹ Yet, post-mortem studies proved that lesion size is a major determinant of cortical lesion visibility^2,3 with lesions smaller than 1.2 mm in diameter being undetected by even T2* gradient echo MRI (0.15 mm × 0.15 mm × 0.3 mm resolution) at 7T.² Undesirably, also much of the widespread MS-induced cortical pathology still remains undetected using multi-echo gradient echo (0.21 mm³ isotropic) 7T MRI,³ urging a scientific effort to overcome current limitations. T1-weighted MRI at 7T (acquired resolution 0.8 mm³) allowed to determine that MS patients have a higher count of Virchow–Robin spaces compared to non-MS people, overall indicative of underlying neurodegeneration.⁴ In the spinal cord, the increased resolution achievable with 7T imaging allows to reduce partial volume averaging effects, to increase white/gray matter differentiation, and to augment sensitivity to lesions. In a cohort of 15 MS patients, T2*-weighted images at 7T (0.3 mm × 0.3 mm × 4 mm resolution) showed 14 more spinal cord lesions than conventional T2-weighted clinical scans at 3T.⁵

As stated earlier, another important gain associated with 7T MRI is the ability of exploiting different mechanisms of contrast. Over the last few years, the characterization of iron as a tracer of MS pathology^1,6,7 was made possible by the use of susceptibility-based 7T MRI. The latter opened to the study of microglia activation in patients with MS and the in vivo identification of the so-called slowly expanding lesions,^1,6,7 till then characterized only pathologically.⁸ This new MRI approach will certainly change the way we measure MS disease progression and will extend the concept of disease activity beyond that of inflammation sustained by acute blood–brain barrier breakdown.

Combining the effects of increased resolution and susceptibility-based contrast allowed assessing the venous vasculature and its relation to parenchymal disease in patients with MS.⁹ With the notion that perivenular infiltrates and inflammation are key events in the formation of MS lesions, pursuing research targeting small vessel changes in MS has the potential to provide important insight into the disease mechanisms and evolution. The anatomical proximity between vasculature and lesions is also a possible tool to differentiate MS from several of its imitators.¹⁰

Last, but not least, technical innovations in image acquisition at 7T and—through it—the discovery of otherwise occult disease pathology will certainly help with the interpretation of lower resolution MR images, will provide new insights, and will allow correcting previously unidentified pitfalls.

For the near future, some of the works at 7T will remain in the exclusive realm of research. Due to its safety profile, 7T-based research studies will continue to apply only to selected patients. Due to its costs and the high-level requirements of its maintenance, 7T MRI will be available in only a few specialized MRI centers in the world. Together, these factors will limit its usage on patients in clinical practice. However, these constraints should not be taken as drawbacks and by no means should limit the expansion of MS research at 7T. Conversely, current limitations shall encourage research to alleviate safety issues at 7T, as done in the past when moving from 0.5T to 3T MRI.

As evident already, the use of 7T for clinical research will continue to increase our knowledge of the disease mechanisms of MS in a not otherwise achievable manner and shall be supported. More precise quantification and better characterization, made possible at 7T, are fundamental aspects of MS research and of that of other diseases. It is through improved understanding of diseases that novel treatments can be discovered, developed, and ultimately used to defeat them. It is in light of this basic scientific notion that 7T (and above) MRI now is necessary to take the next steps forward in understanding MS pathophysiology.