Update on the pathophysiology of cluster headache: imaging and neuropeptide studies

Objective: Cluster headache (CH) is the most severe primary headache condition. Its pathophysiology is multifaceted and incompletely understood. This review brings together the latest neuroimaging and neuropeptide evidence on the pathophysiology of CH. Methods: A review of the literature was conducted by searching PubMed and Web of Science. The search was conducted using the following keywords: imaging studies, voxel-based morphometry, diffusion-tensor imaging, diffusion magnetic resonance imaging, tractography, connectivity, cerebral networks, neuromodulation, central modulation, deep brain stimulation, orexin-A, orexin-B, tract-based spatial statistics, single-photon emission computer tomography studies, positron-emission tomography, functional magnetic resonance imaging, magnetic resonance spectroscopy, trigeminovascular system, neuropeptides, calcitonin gene-related peptide, neurokinin A, substance P, nitric oxide synthase, pituitary adenylate cyclase-activating peptide, vasoactive intestinal peptide, neuropeptide Y, acetylcholine, noradrenaline, and ATP. "Cluster headache" was combined with each keyword for more relevant results. All irrelevant and duplicated records were excluded. Search dates were from October 1976 to May 2018. Results: Neuroimaging studies support the role of the hypothalamus in CH, as well as other brain areas involved in the pain matrix. Activation of the trigeminovascular system and the release of neuropeptides play an important role in CH pathophysiology. Among neuropeptides, calcitonin gene-related peptide, vasoactive intestinal peptide, and pituitary adenylate cyclase-activating peptide have been reported to be reliable biomarkers for CH attacks, though not specific for CH. Several other neuropeptides are involved in trigeminovascular activation, but the current evidence does not qualify them as reliable biomarkers in CH. Conclusion: CH has a complex pathophysiology and the pain mechanism is not completely understood. Recent neuroimaging studies have provided insight into the functional and structural network bases of CH pathophysiology. Although there has been important progress in neuropeptide studies, a specific biomarker for CH is yet to be found.