White matter microstructural alterations in episodic cluster headache outside attacks: a tract-based spatial statistics study.

backgroundCluster headache (CH) is a highly disabling primary headache disorder increasingly conceptualized as a disorder of distributed brain networks rather than an isolated trigeminovascular dysfunction. While structural and functional MRI studies have demonstrated persistent brain alterations outside the ictal phase, the role of white matter microstructural changes supporting network-level dysfunction remains incompletely understood.

methodsWe investigated cerebral white matter microstructure in 27 patients with episodic CH examined during the bout outside active attacks using diffusion tensor imaging and tract-based spatial statistics (TBSS). Fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were compared between patients and healthy controls (N = 20) on a whole-brain white matter skeleton. Associations between diffusion metrics and clinical variables were explored using an ANCOVA-based TBSS framework.

resultsCompared with controls, patients with episodic CH showed widespread white matter microstructural alterations, characterized by reduced FA and AD and increased MD in multiple clusters involving long-range associative and projection pathways connecting frontal, parietal, temporal, subcortical, and cerebellar regions. No significant associations were observed between diffusion metrics and clinical variables, including disease duration, attack frequency, and pain intensity. DISCUSSION: White matter alterations predominantly affected pathways supporting large-scale pain-related and cognitive-affective networks, including fronto-parietal, thalamo-cortical, and cerebello-thalamo-cortical connections. These findings are consistent with a network-based model of CH and integrate coherently with recent multimodal MRI evidence of cortical thickness and functional connectivity alterations observed outside attacks in a largely overlapping cohort.

conclusionsOur results provide evidence of persistent white matter microstructural abnormalities in episodic CH outside the ictal phase, supporting the concept of CH as a disorder of distributed brain networks. White matter alterations may represent a structural substrate underlying enduring network dysfunction predisposing patients to recurrent attacks.