Cluster headache: from treatment to pathophysiology.

This key note lecture illustrates the role of clinical developments in stimulating research and discovery in the area of the pathophysiology of cluster headache (CH) and other trigeminal autonomic cephalalgias (TACs), reviewing the physiological, biochemical and neuroimaging data that have suggested involvement of the hypothalamus in CH pathogenesis. These findings suggested the use of deep brain stimulation as a treatment for chronic drug-resistant CH. The typical circadian and circannual periodicity of CH attacks were the fundamental clinical characteristics that shifted focus from peripheral hypotheses to the idea of central origin for this headache form. Functional neuroimaging demonstrated that TACs are associated with activation of the posterior hypothalamus and there is clinical evidence that patients who suffer from CH have altered biological rhythms. Furthermore, the principal seat of biorhythm regulation - the hypothalamus - is known to have a modulatory role on nociceptive and autonomic pathways, specifically trigemino-vascular nociceptive pathways. Future research will elucidate why neuromodulatory approaches are effective in CH and other TACs, determine whether the hypothalamus is itself the generator of CH attacks, or whether it is activated in response to a generator situated elsewhere, and identify pharmacological treatments that directly target the hypothalamus.