Neurovascular Coupling and Subclinical White Matter Alterations in Young Adults with Migraine without Aura: A Multimodal MRI and Machine Learning Study.

RATIONALE AND OBJECTIVES: Young adults with migraine without aura (MwoA) may exhibit subtle white matter abnormalities, but their relationships with neurovascular measures, neurotransmitter distributions, and clinical burden remain unclear. We investigated these multimodal imaging associations in MwoA. MATERIALS AND METHODS: A total of 130 patients with MwoA and 110 healthy controls (HCs) were enrolled. Multimodal magnetic resonance imaging (MRI) was used to quantify white matter hyperintensity volume, free water (FW) fraction, peak width of skeletonized mean diffusivity (PSMD), and global neurovascular coupling (NVC); the regional measure was the cerebral blood flow (CBF)/fractional amplitude of low-frequency fluctuations (fALFF) ratio. Regional CBF/fALFF ratio alterations were spatially correlated with canonical neurotransmitter maps. Correlation, chain mediation, and machine-learning analyses were performed. RESULTS: Relative to HCs, patients with MwoA showed increased global FW fraction and PSMD and reduced global NVC. Decreased regional CBF/fALFF ratios involved sensorimotor, striatal, and cingulate regions. The spatial pattern of NVC abnormalities was positively associated with 5-HT1A, D1, DAT, and GABAergic maps, and negatively associated with D2 and noradrenaline transporter maps. FW fraction, PSMD, and regional CBF/fALFF ratio alterations were associated with migraine-related clinical indices. Random forest yielded the numerically highest area under the curve (0.866). Exploratory mediation analysis indicated that FW and PSMD statistically accounted for part of the association between regional CBF/fALFF ratios and clinical severity. CONCLUSION: Young adults with MwoA exhibited subtle white matter microstructural abnormalities, reduced global NVC, and altered regional CBF/fALFF ratios. These cross-sectional findings suggest a potentially clinically relevant multimodal imaging pattern but require longitudinal and independent validation.