No Detectable Hippocampal Subfield Volume Differences in Medication-Free Episodic Cluster Headache During Active Bouts: A 3 T MRI Cross-Sectional Study

Background: Cluster headache is a severe primary headache disorder in which neuroimaging studies have suggested involvement of hypothalamic, limbic, and pain-related networks. Although hippocampal abnormalities have been reported in some studies, volumetric findings remain inconsistent and may depend on disease state, treatment exposure, chronicity, and imaging methodology. We explored whole hippocampus and hippocampal subfield volumes in medication-free patients with episodic cluster headache scanned interictally during an active bout. Methods: In this cross-sectional case–control study, 26 patients with episodic cluster headache (eCH) and 20 age- and sex-matched healthy controls underwent 3 T brain MRI. Patients were scanned during an active bout but outside acute headache attacks and had not received preventive treatment for at least three months before MRI acquisition. Automated hippocampus segmentation and subfield volumetry were performed using FreeSurfer 7.4.1, followed by visual quality control by two neuroradiologists. Group comparisons were adjusted for age, sex, and total intracranial volume. Multiple comparisons were addressed using Bonferroni correction for whole hippocampal volumes and false discovery rate (FDR) correction for subfield and clinical analyses. Results: No significant differences were detected between eCH patients and healthy controls in whole hippocampus or hippocampal subfield volumes after correction for multiple comparisons. Descriptive analyses showed numerically higher volumes in patients across several regions, but these effects were small to moderate and did not reach statistical significance. Exploratory analyses showed a nominal association between right fimbria volume and pain intensity; however, this association did not survive FDR correction. Conclusions: This study found no evidence of detectable hippocampal macrostructural differences in medication-free eCH patients scanned interictally during active bouts using 3 T MRI-based subfield volumetry. These null findings should not be interpreted as proof of preserved hippocampal structure, but rather as absence of measurable volumetric alterations within the limits of the present sample size, acquisition protocol, and analytical framework. Longitudinal and multimodal studies, including in-bout and out-of-bout assessments, higher-resolution imaging, and neuropsychological covariates, are needed to clarify whether hippocampal involvement in eCH is structural, microstructural, functional, or state-dependent.