A multi-modal framework for characterizing myelin microstructure

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Magnetic resonance imaging (MRI) shows great promise for characterizing brain microstructure during development, aging, disease, and treatment. However, with its current resolution (on the order of millimeters), MRI remains a blunt tool that provides only a birds-eye view of the complex network of fibers (on the order of micrometers) that make up the bulk of white matter in the brain. The last ten years have seen tremendous advances in the field of quantitative magnetic resonance imaging (qMRI), enabling us to glean microstructural information on a scale that is orders of magnitude smaller than the native MRI resolution. Being able to do so will increase our understanding of brain development and become an invaluable tool for diagnosis and treatment of neurodegenerative disorders.******The fibers in white matter consist of axons, most of which are wrapped in a myelin sheath that enables fast conduction of information. I have recently proposed a novel biophysical model of white matter relating the microstructural features, such as the relative myelin thickness (g-ratio), to macroscopic quantities such as the myelin volume fraction (MVF) and the axon volume fraction (AVF). Other researchers have independently confirmed the theoretical soundness of the model, so the next step is to use this model to increase the specificity of MRI in characterizing myelin microstructure.******I propose combining quantitative MRI biomarkers to make it possible to decouple the contribution of axons from the contribution of myelin to the MR signal. Incorporating the individual MR biomarkers in a multi-modal framework will greatly increase the specificity of MRI to the microstructural features of myelin, making it possible to measure for the first time the myelin thickness (g-ratio) non-invasively. The methodology will be tested in mouse demyelination models, before translating it to clinical studies in multiple sclerosis. ******Measuring myelin thickness in multiple sclerosis will give neurologists a real-time tool for tracking the progression of a lesion during demyelination and remyelination, which would be extremely valuable in the development and evaluation of new therapeutic agents that promote remyelination. Along the way, many small discoveries will be made that lead toward better and more relevant quantitative MR protocols. The multi-modal framework proposed in this grant will contribute to expanding the qMRI toolbox, giving scientists new tools to attack a range of basic science and clinical questions related to brain microstructure.