Review
Neurobiology in primary headaches

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Abstract

Primary headaches such as migraine and cluster headache are neurovascular disorders. Migraine is a painful, incapacitating disease that affects a large portion of the adult population with a substantial economic burden on society. The disorder is characterised by recurrent unilateral headaches, usually accompanied by nausea, vomiting, photophobia and/or phonophobia. A number of hypothesis have emerged to explain the specific causes of migraine. Current theories suggest that the initiation of a migraine attack involves a primary central nervous system (CNS) event. It has been suggested that a mutation in a calcium gene channel renders the individual more sensitive to environmental factors, resulting in a wave of cortical spreading depression when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Genom wide scans have been performed in migraine with susceptibility regions on several chromosomes some are associated with altered calcium channel function. With positron emission tomography (PET), a migraine active region has been pointed out in the brainstem. In cluster headache, PET studies have implicated a specific active locus in the posterior hypothalamus. Both migraine and cluster headache involve activation of the trigeminovascular system. In support, there is a clear association between the head pain and the release of the neuropeptide calcitonin gene-related peptide (CGRP) from the trigeminovascular system. In cluster headache there is, in addition, release of the parasympathetic neuropeptide vasoactive intestinal peptide (VIP) that is coupled to facial vasomotor symptoms. Triptan administration, activating the 5-HT1B/1D receptors, causes the headache to subside and the levels of neuropeptides to normalise, in part through presynaptic inhibition of the cranial sensory nerves. These data suggest a central role for sensory and parasympathetic mechanisms in the pathophysiology of primary headaches. The positive clinical trial with a CGRP receptor antagonist offers a new promising way of treatment.

Introduction

The primary headaches include migraine, tension-type headache (TTH), cluster headache, other trigeminal autonomic cephalalgias and other headaches [147]. Tension-type headache is the most common of these in the general population, however, since little data exist for a neurovascular component, we have only described those briefly below [5]. Migraine headaches are ascribed as neurovascular disorders which world-wide afflict up to 15–20% of the general population. The socio-economic implications are extensive with considerable impact on productivity and quality of life. In Europe alone, it is calculated that 600,000 days of work are lost daily. Migraine, which is the most common type, is characterised by attacks of moderate to severe headache that last for 4–72 h, often unilateral, pulsating and associated with photophobia/phonophobia and/or nausea/vomiting [146]. In migraine with aura, the headache is preceded by transient focal neurological symptoms, most often contralaterally [84].

Cluster headache is another of the primary headaches; it has a distinct clinic with devastating pain. Some of the features of cluster headache overlap with those of other primary vascular headaches. The pain usually occurs around the eye and is described as retro-orbital or temporal. This implies involvement of the ophthalmic (first) division of the trigeminal nerve. In addition to the pain, there are signs of parasympathetic overactivity, e.g., lacrimation, nasal congestion and injection of the eye. Short-lasting headaches associated with autonomic symptoms may sometimes be confused with cluster headache. Although the exact causes of the primary headaches remain unknown, some pieces of the pathophysiological puzzle are starting to fall into place, particularly after a series of elegant positron emission tomography (PET) studies [132], [133], [134]. During the last 20 years, there has been a heated debate whether the primary headaches are neurogenic or vascular in origin. However, current molecular and functional studies suggest a way to incorporate the different aspects into an integrated hypothesis as neurovascular headaches [39], [84], [156].

In susceptible individuals, changes in environmental or physiological states are known to trigger the migraine headache. Migraine susceptibility has been linked to mechanisms regulating central sensitization. The systems that govern neuronal excitability involve homeostatic mechanisms and intracellular signalling pathways. The demonstration that mutations in the calcium channel gene CACNA1A, in approximately 50% of families suffering from the rare and severe familial hemiplegic migraine (FHM), has offered some hope that there is a molecular genetic cause also of the more common types of migraine [150], [188]. However, it is well recognised that the central nervous system (CNS) is devoid of sensory pain receptors, and intracranially, it is only blood vessels in the dura and the circle of Willis that are supplied with sensory nerves and receptors that can respond to thermal, mechanical or distensional stimuli [146], [159].

Section snippets

Where does the attack start?

Some researchers have suggested that migraine is a disease comprised of two main subtypes, migraine with aura and migraine without aura. In the former, the aura is characterized most often by visual field disturbances, but sometimes also by additional somatosensory disturbances. In these patients, changes in cortical blood flow correlate with areas of hypoperfusion, but no subsequent spreading from the area of hypoperfusion can be demonstrated, possibly because these patients have been studied

The ion channel connection

Clinical studies have revealed that migraine patients usually have a family history [84]. In the two main types of migraine, with aura and without aura, the familial aggregation cannot be explained by simple mendelian inheritance patterns. FHM is the only variety of migraine in which a mendelian type of inheritance has been clearly established. A few years ago, a candidate region on chromosome 19 was identified as a gene that encodes an α1 A subunit of a voltage-gated P/Q-type calcium channel

Nerves in the walls of intracranial vessels

Since intracranial vessels are the only source for eliciting intracranial pain and in particular referred pain [159], the understanding of the vascular innervation by autonomic and sensory nerves is a prerequisite for the understanding of intracranial pain as it occurs in primary headaches. The intracranial blood vessels are supplied with nerve fibers that emanate from cell bodies in ganglia belonging to the sympathetic, parasympathetic and sensory nervous systems (Fig. 1) [92]. In addition,

Trigeminal ganglion stimulation

The trigeminal system provides an important pain-transmitting link from the cranial vasculature to the CNS. In laboratory animals, the sensory pathway has no resting tonic influence on regional cerebral blood flow or regional cerebral metabolism [49], [136], whereas stimulation of the trigeminal ganglion increases intracranial blood flow in part via CGRP release [60], [79]. In humans, unilateral stimulation of the trigeminal ganglion results in increased bilateral cortical blood flow, slightly

Central mechanisms in headache

Once the trigeminovascular reflex is initiated, resulting in an antidromic activation which involves release of CGRP, the central part of this pathway, the TNC and/or its reciprocal parts at the C1 and C2 levels, are also activated (Fig. 3). Experiments in laboratory animals as well as in humans, have shown that direct stimulation of either the superior sagittal sinus or the trigeminal ganglion results in activation of cells in this region [75], [78]. This phenomenon may be shared by several of

Central sensitization

Reduced habituation of event-related potentials (ERPs) and enhanced contigent negative variation (CNV) appear to be a unique characteristic of migraine with and without aura [141], [175]. Thus, there is evidence of cortical hyperexcitability and lack of habituation to repetitive stimuli in the migraine brain. Furthermore, this phenomenon can be normalised by treatment with beta-blockers, calcium channel blockers, aspirin and 5-HT1 receptor agonists that show anti-migraine efficacy [174].

Peripheral sensitization

In many patients, pain of long duration often seems to be associated with a sensitized pain system in which there is a facilitated impulse signalling in nociceptive nerve fibres. A new load activating already sensitized fibres may in these patients result not only in increased pain but also in an increased receptive field. Such observations have been made by headache researchers since decades; hypersensitivity of the skin of the face or scalp, neck muscle tenderness and hyperalgesia [169].

Summary

Current data provide a model in which a central “generator” or an “active region”, different in migraine and in cluster headache, is activated. Following alteration of cerebral blood vessel tone, the trigeminovascular reflex is initiated to counter-balance cerebrovascular constriction in part via release of CGRP and VIP. The study of neuropeptide levels in migraine and cluster headache provides a link between the clinical and the basic research, work that is crucial for the understanding of the

Uncited reference

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Acknowledgements

The studies of the authors' reviewed here have in part been supported by the Swedish Research Council (project no. 5958).

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