Cluster headache pathophysiology: What we have learned from advanced neuroimaging

BACKGROUND: Although remarkable progress has been achieved in understanding cluster headache (CH) pathophysiology, there are still several gaps about the mechanisms through which independent subcortical and cortical brain structures interact with each other. These gaps could be partially elucidated by structural and functional advanced neuroimaging investigations. OBJECTIVE: Although we are aware that substantial achievements have come from preclinical, neurophysiological, and biochemical experiments, the present narrative review aims to summarize the most significant findings from structural, microstructural, and functional neuroimaging investigations, as well as the consequent progresses in understanding CH pathophysiological mechanisms, to achieve a comprehensive and unifying model. RESULTS: Advanced neuroimaging techniques have contributed to overcoming the peripheral hypothesis that CH is of cavernous sinus pathology, in transitioning from the pure vascular hypothesis to a more comprehensive trigeminovascular model, and, above all, in clarifying the role of the hypothalamus and its connections in the genesis of CH. CONCLUSION: Altogether, neuroimaging findings strongly suggest that, beyond the theoretical model of the “pain matrix,” the model of the “neurolimbic pain network” that is accepted in migraine research could also be extended to CH. Indeed, although the hypothalamus’ role is undeniable, the genesis of CH attacks is complex and seems to not be just the result of a single “generator.” Cortical‐hypothalamic‐brainstem functional interconnections that can switch between out‐of‐bout and in‐bout periods, igniting the trigeminovascular system (probably by means of top‐down mechanisms) and the consensual trigeminal autonomic reflexes, may represent the “neuronal background” of CH.