Neurovascular origin of primary headaches

This special issue is dedicated to neurovascular mechanisms in primary headaches. Primary headaches are recurrent headaches not caused by underlying disease or structural problems.¹ Migraine with or without aura affects 10% of world population and is by far the most common primary headache type in patients referred to neurologists.^2,3 Cluster headache occurs much less commonly and has unique features such circadian and circannual rhythmicity unlike any other primary headache.⁴

For more than 100 years, and particularly after the first report by Ray and Wolff⁵ in humans demonstrating that focal head pain may be elicited from both extra- and intracranial vessels, there has been an intense debate whether migraine and cluster headache are neurogenic or vascular in origin.⁶ All substances that can induce migraine and cluster headache are vasodilators, but the causal relationship between experimentally induced attacks and vasodilatation has not been fully clarified.⁷ Several studies have focused on the investigation of cerebral hemodynamics using different methods and headache provocation models using pharmacological triggers. The discovery of triptans⁸ and CGRP antagonists⁹ have revolutionized our understanding of the mechanisms underlying primary headaches and demonstrated the importance of neurovascular mechanisms in drug development.

Collectively, these data have led to a more integrated “neurovascular” theory that involves both vascular and neuronal components in pathophysiology of primary headaches.⁶

The collection of review articles and original research papers in this special Headache issue provides both an introduction for the uninitiated and an update for the well versed on neurovascular mechanisms in primary headache, with a critical review of different methods used to investigate neurovascular mechanisms. The review articles by Hansen et al.¹⁰ and Hoffman et al.¹¹ provide a comprehensive overview of the evidence for the neurovascular basis of migraine and cluster headaches, while Frederiksen et al.¹² put perivascular innervation and its role in the regulation of cerebral blood flow in the context of primary headaches. Reviews by Chong et al.¹³ and Schytz et al.¹⁴ cover cutting-edge application of MRI and optical imaging technologies in selected headache disorders. Last but not the least, original articles by expert groups connect several molecular mediators (e.g. RAMP1, CGRP, K_ATP) and physiological processes (central trigeminovascular projections, spreading depression) to neurovascular headaches.^15–20

Altogether our aim is to raise awareness for headache as a neurovascular disorder with mechanisms no less complex or fascinating than other neurovascular disorders such as stroke and brain injury.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.