Brain microstructure by multi-modal MRI: Is the whole greater than the sum of its parts?

The MRI signal is dependent upon a number of sub-voxel properties of tissue, which makes it potentially able to detect changes occurring at a scale much smaller than the image resolution. This "microstructural imaging" has become one of the main branches of quantitative MRI. Despite the exciting promise of unique insight beyond the resolution of the acquired images, its widespread application is limited by the relatively modest ability of each microstructural imaging technique to distinguish between differing microscopic substrates. This is mainly due to the fact that MRI provides a very indirect measure of the tissue properties in which we are interested. A strategy to overcome this limitation lies in the combination of more than one technique, to exploit the relative contributions of differing physiological and pathological substrates to selected MRI contrasts. This forms the basis of multi-modal MRI, a broad concept that refers to many different ways of effectively combining information from more than one MRI contrast. This paper will review a range of methods that have been proposed to maximise the output of this combination, primarily falling into one of two approaches. The first one relies on data-driven methods, exploiting multivariate analysis tools able to capture overlapping and complementary information. The second approach, which we call "model-driven", aims at combining parameters extracted by existing biophysical or signal models to obtain new parameters, which are believed to be more accurate or more specific than the original ones. This paper will attempt to provide an overview of the advantages and limitations of these two philosophies.