The pathophysiology of episodic cluster headache: Insights from recent neuroimaging research

Background: Cluster headache is a disorder characterized by intermittent, severe unilateral head pain accompanied by cranial autonomic symptoms. Most cases of CH are episodic, manifesting as “in-bout” periods of frequent headache separated by month-to-year-long “out-of-bout” periods of remission. Previous imaging studies have implicated the hypothalamus and pain matrix in the pathogenesis of episodic CH. However, the pathophysiology driving the transition between in- and out-of-bout periods remains unclear. Methods: The present study provides a narrative review of previous neuroimaging studies on the pathophysiology of episodic CH, addressing alterations in brain structures, metabolism, and structural and functional connectivity occurring between bout periods. Results: Although the precise brain structures responsible for episodic CH are unknown, major roles are indicated for the posterior hypothalamus (especially in acute attacks), the pain neuromatrix with an emphasis on central descending pain modulation, and non-traditional pain processing networks including the occipital, cerebellar, and salience networks. These areas are potentially related to dynamic transitioning between in- and out-of-bout periods. Conclusion: Recent progress in magnetic resonance imaging of episodic CH has provided additional insights into dynamic bout-associated structural and functional connectivity changes in the brain, especially in non-traditional pain processing network areas. These areas warrant future investigations as targets for neuromodulation in patients with CH.