Frontal cortical thinning and disease burden–related plasticity in episodic cluster headache: a whole-brain cortical and subcortical morphometry study

Background Cluster headache (CH) is a primary headache disorder characterized by severe unilateral pain and cranial autonomic symptoms. Although the posterior hypothalamus has been implicated as a key structure in CH pathophysiology, evidence suggests that this disorder involves widespread alterations in cortical and subcortical networks. This study investigated whole-brain cortical thickness and subcortical volumetric differences in patients with episodic CH (eCH) compared with healthy controls (HC) and examined associations with clinical burden. Methods Twenty-six patients with eCH and 20 age- and sex-matched HC underwent 3T MRI scanning during the bout period but outside attacks. Cortical thickness and subcortical volumes were analyzed using FreeSurfer. Group differences were tested with FDR-corrected vertex-wise and ROI-based analyses. Associations between cortical thickness, sub-cortical volumes, and clinical variables (attack frequency and duration, disease duration, and pain intensity) were evaluated using general linear models adjusted for age and sex. Results Compared with HC, patients with eCH exhibited significant cortical thinning in two clusters: the right pars triangularis (inferior frontal gyrus, BA45) and the left superior frontal gyrus (p < 0.05, FDR-corrected). Positive correlations between cortical thickness and clinical burden were observed in multimodal associative cortices, including inferior temporal, postcentral, superior parietal, supramarginal, inferior parietal, and lateral occipital regions (p < 0.01, FDR-corrected). No significant subcortical volumetric alterations or correlations with clinical variables were detected. Conclusions Our findings demonstrate frontal cortical thinning and disease burden–related cortical thickness increases in associative temporal, parietal and occipital cortices in eCH, supporting a two-level model of cortical alterations. Frontal cortical thinning may represent a trait-like abnormality affecting executive control hubs, whereas cortical thickening in associative regions may reflect dynamic plasticity in response to clinical burden. These results extend the evidence that CH is a network-level disorder and highlight the potential for cortical thickness measures to serve as neuroimaging biomarkers of disease progression.