Measuring Gray Matter and White Matter Damage in MS: Why This is Not Enough

INTRODUCTION Over the past years, progress in cerebral magnetic resonance imaging (MRI) technology has increased the possibilities to quantify MS-related tissue changes, starting from lesion assessment in the white matter (WM) to the quantification of microstructural changes of the whole brain (1). This was expected to give full insight into the causes of MS patients’ deficits but despite all achievements, the current plethora of MRI metrics still provides no complete explanation for the clinical condition on a group (2) and even less so on an individual level. However, within the scope of personalized medicine, this remains an important goal to better understand and ultimately minimize the functional impact of MS-related tissue damage. In this context, functional cerebral changes including adaptation and plasticity are strong contributors to the apparent clinical consequences of MS and are likely to explain part of the “morphologicalclinical gap” (3), notwithstanding ongoing controversies what patient deficits to consider and how to assess them. Against this background, we critically review the development and current state of techniques to assess gross MS-related morphologic damage and their contribution to understand the clinical consequences of MS (disability, and also cognitive problems and fatigue) and the obvious modulating roles of cerebral adaptation and plasticity as unraveled by functional MRI (fMRI). From existing data, we suggest that it is unlikely to ever achieve a satisfactory level of explanation and prediction of an individual patient’s condition-based solely on morphologic information, although such insights might be better suited to define disease progression than clinical assessment.