The neurobiology of cluster headache

Handb Clin Neurol. 2021:182:401-414. doi: 10.1016/B978-0-12-819973-2.00027-7.


Cluster headache is a primary headache form occurring in paroxysmal excruciatingly severe unilateral head pain attacks usually grouped in periods lasting 1-2months, the cluster periods. A genetic component is suggested by the familial occurrence of the disease but a genetic linkage is yet to be identified. Contemporary activation of trigeminal and cranial parasympathetic systems-the so-called trigemino-parasympathetic reflex-during the headache attacks seem to cause the pain and accompanying oculo-facial autonomic phenomena respectively. At peripheral level, the increased calcitonin gene related peptide (CGRP) plasma levels suggests trigeminal system activation during cluster headache attacks. The temporal pattern of the disease both in terms of circadian rhythmicity and seasonal recurrence has suggested involvement of the hypothalamic biological clock in the pathophysiology of cluster headache. The posterior hypothalamus was investigate as the cluster generator leading to activation of the trigemino-parasympathetic reflex, but the accumulated experience after 20 years of hypothalamic electrical stimulation to treat the condition indicate that this brain region rather acts as pain modulator. Efficacy of monoclonal antibodies to treat episodic cluster headache points to a key role of CGRP in the pathophysiology of the condition.

Keywords: CGRP; Circadian and seasonal rhythmicity; Cluster headache; Deep brain stimulation; Headache; Hypothalamus; Neuromodulation; Neurovascular headache; Pain; Pathophysiology; Trigemino-parasympathetic reflex; Vasodilatation.

Publication types

  • Review

MeSH terms

  • Autonomic Nervous System
  • Cluster Headache*
  • Headache
  • Humans
  • Neurobiology
  • Pain