Chronobiology and cluster headache: insights into a hypothalamic disorder

Purpose of review Cluster headache is a disorder which has been shown to have both a circadian and a circannual pattern. This review gives an overview of the chronobiology of cluster headache summarizing recent findings on structural variations with a focus on the hypothalamus and the implication of the molecular clock and circadian and circannual variations in gene expression. Recent findings Recent imaging studies using high-resolution structural and functional MRI have highlighted subtle hypothalamic alterations in cluster headache, specifically at the microstructural and connectivity level rather than clear macrostructural changes. Diffusion-based measures reveal altered fractional anisotropy and diffusivity in the hypothalamus, suggesting modified neuronal connectivity that may relate to attack frequency. In parallel, experimental data suggest significant differences in pain perception between day and night, which correlate to circadian oscillations of gene expression, and several drugs used for cluster headache have been reported to alter the molecular clock. Summary The striking circadian and circannual phenotype of cluster headache opens for the possibility of clock-modulating therapy. The potential to pharmacologically target the molecular clock mechanism is supported by experimental data from mice demonstrating substantial effects of standard cluster headache treatments on the molecular clock.