Multimodal MRI of episodic cluster headache reveals frontal cortical alterations and network-level connectivity changes

Cluster headache (CH) is a primary headache disorder characterized by circadian rhythmicity and autonomic symptoms. While the posterior hypothalamus has been historically implicated, converging evidence now supports a distributed, network-level dysfunction involving cortical and subcortical regions. This study aimed to: (1) assess whole-brain cortical thickness alterations in episodic CH (eCH) during the bout period, (2) examine their associations with clinical burden, and (3) investigate resting-state functional connectivity patterns of cortical regions showing structural alterations. We investigated whole-brain cortical thickness and subcortical volumes in 26 patients with episodic CH scanned during the bout period but outside of attacks and 20 matched healthy controls (HC) using surface-based morphometry (FreeSurfer). Associations between cortical thickness and clinical variables (attack frequency, duration, disease history, and pain intensity) were assessed using general linear models corrected for multiple comparisons. Resting-state functional connectivity (FC) was further analyzed using seed-to-voxel correlations in the CONN toolbox, with seeds placed in cortical regions showing significant thinning. Compared with HC, eCH patients showed cortical thinning in the right inferior frontal gyrus (pars triangularis, BA45) and left superior frontal gyrus (BA9/10) (p < 0.05, Bonferroni correction). No significant subcortical volumetric differences were observed. Cortical thickness showed significant positive associations with clinical burden in associative parietal and occipital regions (p < 0.01, Bonferroni correction). Seed-based FC analyses revealed decreased coupling between the left superior frontal gyrus and right supramarginal cortex, but increased connectivity with the left precentral gyrus. Conversely, the right inferior frontal gyrus showed widespread hyperconnectivity with bilateral insulae, supramarginal, and sensorimotor cortices, and decreased connectivity with the right superior frontal region. These findings identify coexisting structural and functional alterations within frontal cortices and their distributed targets, suggesting a differential reorganization of frontal attentional and sensorimotor networks in eCH. The pattern of fronto-parietal disconnection and fronto-insular hyperconnectivity extends the network model of cluster headache beyond the well-established hypothalamic–thalamic dysregulation. Together, these results strengthen the concept of cluster headache as a network-level disorder involving both executive and sensorimotor control systems.