Linking Functional impact and Microstructural properties of fiber tract demyelination and remyelination in a rodent model of multiple sclerosis

Ziel

Multiple sclerosis (MS) is a diffuse inflammatory and neurodegenerative disease of the central nervous system. Neuroinflammation destroys the myelin sheaths wrapped around the axons and may lead to axon degeneration. Repair processes trigger re-myelinisation. Myelin loss delays or blocks signal propagation along axons in white matter tracts, impairing neuronal integration within the affected brain network. The exact relationship between the amount of axonal de- and re-myelination and the resulting network dysfunction is still poorly understood. Using a rat MS model, I will bridge the scales from the cellular to the network level, to disentangle how myelin loss and axonal degeneration leads to network dysfunction. My approach integrates three lines of research: (i) I will prospectively perform diffusion MRI and quantitative MRI to assess the temporal dynamics of microstructural changes in axon diameter and myelin content in the lesioned white matter tract. Leveraging state-of-art expertise at DRCMR, I will optimize MR sequences and biophysical models to create an optimized axon diameter and myelin mapping framework. (ii) In parallel, I will perform resting-state and task-based functional MRI to trace the resulting changes in functional connectivity at the network level. (iii) Building on my expertise, I will combine functional MRI with optogenetics and simultaneous intracellular calcium (and trans-membrane voltage) recording to characterize in detail the functional impact of axonal damage in the lesioned white matter tract on well-defined cell circuits in the inter-connected cortical areas. This unique multimodal approach will yield novel MRI-based biomarkers that are sensitive and specific to primary demyelination and axonal degeneration on the one hand and reparatory processes such as remyelination on the other hand. These biomarkers will have great potential for monitoring disease activity, informing personalized treatment in patients with MS.