Longitudinal White Matter Diffusion Alterations in Medication Overuse Headache Before and After Medication...

Background and Objectives: The pathophysiology of medication overuse headache (MOH) remains incompletely understood, and advanced neuroimaging methods such as Diffusion Tensor Imaging (DTI) may help clarify the structural white matter (WM) changes associated with chronic analgesic overuse. The objective of this study was to identify WM microstructural alterations in patients with MOH, both before and after discontinuation of the overused medication, compared with healthy controls (HC), utilizing whole-brain and region-of-interest (ROI)-restricted tract-based spatial statistics (TBSS). Materials and Methods: Twenty-three patients with MOH, diagnosed according to ICHD (3rd edition) criteria, and 23 demographically matched HC underwent 3-Tesla DTI. Whole-brain and ROI-restricted TBSS analyses of fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD) and radial diffusivity (RD) were performed to assess global and tract-specific white matter microstructural alterations. In the MOH group, DTI was repeated at follow-up after withdrawal of the overused medication, initiation of alternative treatment, and clinical improvement (MOH-DW). Sixteen patients and 16 controls were included in the final analysis after exclusions for pregnancy, loss to follow-up, or technical issues. Results: Whole-brain TBSS revealed no statistically significant group differences. ROI-restricted analysis revealed a marked increase in fractional anisotropy (FA) and axial diffusivity (AD) in the MOH group relative to the HC group within the left anterior limb of the internal capsule, the body of the corpus callosum, and the right superior corona radiata. Concurrently, higher mean diffusivity (MD) was observed in the left anterior limb of the internal capsule. At the follow-up assessment, FA and AD remained significantly higher than in healthy controls in the anterior limb of the internal capsule and superior corona radiata, whereas the group difference in the corpus callosum was no longer statistically significant. As the direct within-subject comparison between pre- and post-withdrawal measurements did not reach significance in any region, this may reflect the loss of a detectable group difference rather than confirmed within-subject reversibility. Conclusions: MOH may be associated with WM microstructural changes characterized predominantly by increased, rather than decreased, diffusion anisotropy and axial diffusivity in tracts relevant to pain processing. The disappearance of the significant group difference in the corpus callosum at follow-up raises the hypothesis that this may be compatible with a dynamic and potentially reversible microstructural process; however, because medication withdrawal occurred concurrently with the introduction of alternative treatment, this finding cannot be attributed specifically to withdrawal. Given the modest sample size and the absence of correction across the 27 ROI analyses tested, these exploratory findings are preliminary and warrant confirmation in larger, independent longitudinal cohorts.