Reproducible Left Anterior-Superior Hypothalamic Enlargement in Episodic Migraine: Evidence from Two Independent Cohorts

Growing evidence implicates the hypothalamus as a key structure in migraine pathophysiology; however, our understanding of its precise role and of the specific nuclei involved remains limited. We combined MRI data from our laboratory with publicly available MRI datasets from OpenNeuro to examine hypothalamic subunit volumes in episodic migraine and to assess whether comparable alterations were observed in available chronic pain datasets. Structural MRI combined with an automated atlas-based segmentation algorithm was employed to investigate cross-sectional volumetric differences across 5 bilateral hypothalamic subunits in two independent migraine cohorts: DS1-MIG (DS1-MIG-base, n = 111 patients, n = 35 controls) and DS2-MIG (n = 28 patients, n = 31 controls). The adjusted volumes were compared between groups using MANOVA as an omnibus test, followed by Welch t-tests to test univariate follow-up. Longitudinal volumetric changes were additionally assessed in DS1-MIG participants with available follow-up scans using linear mixed models. To examine whether comparable hypothalamic alterations were observed in available clinical comparison datasets, the same cross-sectional pipeline was applied to two chronic pain datasets, one including patients with fibromyalgia (DS-FM, n = 33 patients, n = 33 controls) and the other including patients with trigeminal neuralgia (DS-TN, n = 119 patients, n = 55 controls). MANOVA revealed significant multivariate group differences in both independent migraine cohorts (DS1-MIG-base: p = .006 ; DS2-MIG: p = .008 ). Follow-up univariate analyses identified a consistent enlargement of the left anterior-superior subunit across both cohorts ( p_FDR = .023 in DS1-MIG-base and p_FDR = .046 in DS2-MIG), representing the only cross-cohort replication finding. Beyond this shared signature, DS2-MIG exhibited additional significant enlargements of the right anterior-inferior and right inferior tubular subunits. Longitudinal analyses in DS1-MIG showed no significant group-by-time interactions in hypothalamic subunit volumes over the available follow-up period. No significant volumetric alterations were detected in the fibromyalgia or trigeminal neuralgia cohorts, either in multivariate or univariate analyses. These findings provide evidence for subunit-specific hypothalamic structural alterations in migraine localized to the left anterior-superior hypothalamic subunit. The absence of detectable differential longitudinal change over the available follow-up period, together with the absence of comparable alterations in the available fibromyalgia and trigeminal neuralgia datasets, supports a migraine-related pattern of hypothalamic structural organization. However, this finding does not establish diagnostic specificity and should be confirmed in harmonized multi-diagnostic cohorts.