Alterations in the interstitial microenvironment across headache phases and clinical phenotypes in migraine: A multimodal diffusion MRI study

AimProcesses related to glymphatic function and fluid exchange may contribute to migraine pathophysiology. We used multimodal diffusion MRI to investigate perivascular diffusivity and the interstitial microenvironment in migraine and to assess differences across migraine phases and clinical phenotypes.MethodsWe enrolled 120 migraine participants and 52 healthy controls (HC) who underwent 3 T MRI. Participants were classified as episodic migraine (EM, n = 93) or chronic migraine with medication-overuse headache (CM-MOH, n = 25), and by headache status as migraine with headache (MwH, n = 25) or headache-free migraine (MwoH, n = 95). Two CM participants without MOH were excluded from phenotype analyses. Diffusion-derived metrics included diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) and neurite orientation dispersion and density imaging-derived white matter intracellular (IVF) and extracellular volume fractions (EVF). Group comparisons and correlations were assessed using pBonferroni-corrected < 0.05. Voxel-wise IVF and EVF analyses were performed using tract-based spatial statistics with threshold-free cluster enhancement (pFWE-corrected < 0.05).ResultsNo DTI-ALPS differences were observed between migraine and HC or across subgroups. No significant IVF or EVF differences emerged between the migraine group and HC, between EM and HC, or between EM and CM-MOH. In contrast, CM-MOH participants showed reduced EVF and increased IVF versus HC (pFWE-corrected < 0.05). Similar alterations were observed in MwH versus HC and MwoH (pFWE-corrected < 0.05). Changes involved the corpus callosum, anterior thalamic radiation, cingulum, and optic radiations. No significant associations with clinical variables emerged, except a weak association between longer disease duration and lower EVF (r = -0.3, pBonferroni-corrected=0.04).ConclusionsMultimodal diffusion MRI revealed subgroup-specific differences in compartmental volume fractions, with reduced EVF and increased IVF, in individuals with migraine. These findings suggest possible alterations in the interstitial microenvironment that vary with headache phase and disease burden, rather than representing a stable trait. Whether such compartmental shifts influence interstitial transport or glymphatic-related processes remains speculative and warrants further investigation.