Primary headache disorders: From pathophysiology to neurostimulation therapies

Abstract

Primary headache disorders including migraine, cluster headache, and tension-type headache are among the most common disabling diseases worldwide. The unclear pathogenesis of primary headache disorders has led to high rates of misdiagnosis and limited available treatment options. In this review, we have summarized the pathophysiological factors for a better understanding of primary headache disorders. Advances in functional neuroimaging, genetics, neurophysiology have indicated that cortical hyperexcitability, regional brain dysfunction, central sensitization and neuroplasticity changes play vital roles in the development of primary headache disorders. Moreover, we have also discussed a series of neurostimulation approaches with their stimulation mechanism, safety and efficacy for prevention and treatment of primary headache disorders. Noninvasive or implantable neurostimulation techniques show great promise for treating refractory primary headache disorders.

Keywords: Cluster headache; Migraine; Neurostimulation; Primary headache disorders.

Fig. 1

Basic mechanisms of migraine. Both physiological and environmental factors would trigger dysfunction or abnormal activation in cortex and related brain regions, which aggravates trigeminal sensitization induced by repeated nociceptive inputs, release of nociceptive molecules and other neural symptoms. Abbreviations: CGRP, calcitonin gene-related peptide; NO, nitric oxide; ATP, adenosine triphosphate.

Fig. 2

Anatomical components in the pathogenesis of cluster headache. Vascular changes in the cavernous sinus loggia led to a third-order sympathetic nerve lesion, followed by activation of the superior cervical ganglion, resulting in a partial Horner's syndrome such as miosis and ptosis. This pathway is not shown in the schematic. Modified after ref. [43] Abbreviations: ACC, anterior cingulate cortex; AMY, amygdala; C1, dorsal horns of C1; C2, dorsal horns of C2; HYP, hypothalamus; PFC, prefrontal cortex; S1, primary sensory cortex; SN, suprachiasmatic nucleus; SSN, superior salivatory nucleus; SPG, sphenopalatine ganglion; THA, thalamus; TNC, trigeminal nucleus caudalis.