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Activity-dependent myelination is a fundamental mode of brain plasticity which significantly influences network function. We recently discovered that absence seizures, which occur in multiple forms of generalized epilepsy, can induce activity-dependent myelination, which in turn promotes further progression of epilepsy. Structural alterations of myelin are likely to be widespread, given that absence seizures arise from an extensive thalamocortical network involving frontoparietal regions of the bilateral hemispheres. However, the temporal course and spatial extent of myelin plasticity is unknown, due to limitations of gold-standard histological methods such as electron microscopy (EM). In this study, we leveraged magnetization transfer and diffusion MRI for estimation of g-ratios across major white matter tracts in a mouse model of generalized epilepsy with progressive absence seizures. EM was performed on the same brains after MRI. After seizure progression, we found increased myelination (decreased g-ratios) throughout the anterior portion (genu-to-body) of the corpus callosum but not in the posterior portion (body-splenium) nor in the fornix or the internal capsule. Curves obtained from averaging g-ratio values at every longitudinal point of the corpus callosum were statistically different with p < 0.001. Seizure-associated myelin differences found in the corpus callosum body with MRI were statistically significant (p = 0.0027) and were concordant with EM in the same region (p = 0.01). Notably, these differences were not detected by diffusion tensor imaging. This study reveals widespread myelin structural change that is specific to the absence seizure network. Furthermore, our findings demonstrate the potential utility and importance of MRI-based g-ratio estimation to non-invasively detect myelin plasticity. • MRI-derived g-ratios detect activity dependent myelination changes. • Widespread but seizure-network specific differences in g-ratio were observed. • G-ratio estimation was more sensitive to myelin changes than DTI alone. [ABSTRACT FROM AUTHOR]