Subcortical nuclei and glymphatic system alterations in migraine with aura: a comparative 7T multimodal MRI analysis.

backgroundAlthough cortical spreading depression is well-established in migraine with aura (MA), the potential involvement of subcortical nuclei and the glymphatic system (GS) in its pathogenesis—and their utility in distinguishing MA from migraine without aura (MO)—remains poorly investigated. Therefore, we employed multimodal 7T MRI—integrating functional, structural, quantitative susceptibility mapping (QSM), and GS metrics (perivascular space (PVS) morphology, choroid plexus volume, and analysis along the perivascular space (ALPS) index)—to enhance the understanding of MA and to characterize alterations specific to MA relative to MO and healthy controls (HCs).

methodsIn this cross-sectional study, 7T MRI scans were acquired from 35 MA patients, 45 MO patients, and 39 HCs. Group differences were evaluated using general linear models adjusted for age, anxiety, and depression scores (and intracranial volume when evaluating volumetric measures), with false discovery rate (FDR) correction. Partial correlation analyses were performed between abnormal imaging metrics and clinical parameters.

resultsBoth MA and MO showed lower regional homogeneity (ReHo) in the hippocampus(L), thalamus(R), and pallidum(R) compared to HCs (PFDR<0.05). In the volumetric comparisons, MO patients tended to have smaller volumes (especially in the amygdala) than HCs (PFDR<0.05) whereas MA patients showed relatively preserved volumes in these regions. QSM revealed higher iron content in the cortical nuclei of the amygdala in MA compared to MO, while MO had lower iron content relative to HCs (PFDR<0.05). Glymphatic dysfunction was prominent in MA, demonstrated by a lower right ALPS index compared to HCs and enlarged PVS compared to MO. Negative correlations were observed between QSM values of Corticoamygdaloid-transition(R) and headache intensity (r = -0.637, P < 0.001). Although GS metrics did not correlate with clinical parameters, higher amygdalar QSM related to shorter PVS length (cortical nucleus(R): r = − 0.606, P = 0.010), indicating iron–glymphatic coupling.

conclusionsOur findings demonstrate that MA is distinctly characterized by glymphatic dysfunction and aberrant iron deposition in the amygdala, suggesting a novel iron-glymphatic interplay in its pathogenesis. 7T MRI provides compelling evidence that MA and MO are distinct neurobiological entities and establishes robust imaging biomarkers for their differentiation, paving the way for future subtype-specific therapeutics.