An intriguing article (very long) read at your own risk.

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Posted by drummer ( on April 15, 2000 at 08:12:38:

What Causes Migraine and What Can We Do About It?

Lars Edvinsson, MD, PhD

Migraine-like symptoms have been reported in the literature for more than 2000 years, and a number of different theories have been advanced to explain this symptomatology.

Hippocrates, writing as early as 400 BC, was the first to depict the visual symptoms of migraine. Of his own attacks, he described a shining light -- usually located in the right eye -- followed by violent pain beginning in the temples and eventually reaching the entire head and neck.

During the 17th century, Thomas Willis noted the importance of the vasculature in many cases of migraine. He was well aware that migraine, despite the severity of its attacks, was benign, had hereditary aspects, and was dependent on changes in season, atmospheric pressure, and diet.

Thomas Willis described the circle of Willis in 1664 and observed the presence of nerve fiber profiles on the walls of brain vessels. His view was that headache symptoms were related to slowly developing vasospasms that began at the peripheral ends of the vasculature.

Another important aspect of the pathophysiology of migraine emerged during the 19th century, when Edward Liveing attributed migraine to a brain dysfunction caused by "nerve storms" originating within the brain itself. Liveing believed that there was a relationship between migraine and epilepsy, and that both were caused by central nervous system (CNS) discharges.

In more recent times, further information about the pathophysiology of migraine headache has been learned through the study of cluster headache, which may share a similar neurobiology. Cluster headache is a distinct, although rare, clinical and epidemiologic entity. The pain it causes is devastating, and the syndrome is so unique and rewarding to manage that physicians with an interest in head pain must be acquainted with the condition. The etiology and pathophysiology of cluster headache is unknown, and some of its features may overlap with those of other primary vascular headaches such as migraine. Pain is usually centered around the eye and is reported as retro-orbital or temporal. This implies involvement of the ophthalmic (first) division of the trigeminal nerve. Given the location of the pain, there are signs of parasympathetic overactivity (eg, lacrimation, nasal congestion, and injection of the eye).

During the past 20 years, there has been a heated debate as to whether the primary headaches are neurogenic or vascular in origin. Current molecular and functional studies suggest a way to incorporate both of these aspects into an integrated hypothesis of the pathophysiology of migraine and cluster headache.

Sensory Nerves
Classic studies by Ray and Wolff demonstrated that the large cerebral arteries at the base of the brain as well as the meningeal (dural) arteries and veins were sensitive to noxious stimuli. This directed interest to the wall of the intracranial vessels as the putative source of headache. When the first series of selective vertebral angiographic studies were performed, all patients who received an injection of contrast media to the intracranial vessels via the vertebral artery complained of acute headache. Even visual phenomena resembling the aura in migraine and some associated facial symptoms were described.

Although alcohol and vasodilators such as nitroglycerine and histamine can induce bilateral pulsating headache (rarely accompanied by nausea, photo- and phonophobia in healthy subjects), migraine-like episodes can be triggered by alcohol and vasodilators in migraine sufferers or in cluster headache patients. Therefore, it seems clear that sensory nerves should be found on the intracranial vessels.

The first detailed study of the innervation of the human cerebral circulation focused on the "classic" autonomic transmitters noradrenaline and acetylcholine.

Schematic demonstration of the perivascular innervation of intracranial vessels and their neuronal messengers. For explanation of abbreviations, see text.
The sympathetic nervous system arises in hypothalamic neurons, passes to the intermediolateral cell column of the spinal cord and synapses, and then proceeds out to the superior cervical ganglion. Here the sympathetic nerves again synapse and give rise to the fibers that innervate the intracranial vessels. This system contains the transmitters noradrenaline, neuropeptide Y (NPY), and possibly adenosine triphosphate (ATP), and is a vasoconstrictor pathway.

The parasympathetic nervous system, which mediates vasodilation, arises from cell bodies in the superior salivatory nucleus (SSN), passes with fibers of the facial nerve (cranial nerve VII) and synapses in the sphenopalatine and otic ganglia. In some species, microganglia are also found on the internal carotid artery. This system uses the "classic" neurotransmitter acetylcholine. In addition, several vasoactive neuropeptides, such as vasoactive intestinal peptide (VIP), peptide histidine isoleucine, pituitary adenylate cyclase activating peptide (PACAP), and helospectin are found in this system. The discoveries that neurons use nitric oxide (NO) and that almost all of the parasympathetic ganglia contain NO have raised widespread interest in the role of NO in the cerebral circulation.

The trigeminal system, a vasodilator pathway via antidromic release upon activation, is the sensory system that innervates cranial vessels and dura mater via its first ophthalmic division. The cell bodies are bipolar and located in the trigeminal ganglion. They make functional first-order connections with neurons in the trigeminal nucleus caudalis and in its related extension down to the C2 level. Calcitonin gene-related peptide (CGRP), substance P, and neurokinin A are present in this system, and there is a minor population of cell bodies in the sensory system containing NO, PACAP-, dynorphin-, and galanin-positive cells.

Neurotransmitter Release
With precise knowledge of the organization of the sensory and autonomic nerves around the intracranial vessels, one can study their putative involvement in primary headache attacks by analyzing neurotransmitter release into cranial venous outflow.

Trigeminal Ganglion Stimulation
The trigeminal system provides the only known pain-sensitive innervation of the cranial vasculature by virtue of the central convergence of trigeminal and upper cervical pain inputs, at the level of second-order neurons. Studies have examined what takes place when these pathways are activated in animals and have shown that they have no resisting tonic influence on regional cerebral blood flow or regional metabolism, and that trigeminal ganglion stimulation enhances intracranial blood flow. In humans, stimulation of the trigeminal ganglion results in increased bilateral cortical blood flow, which is slightly more ipsilateral than contralateral in nature. Patients under treatment for trigeminal neuralgia are noted to flush ipsilaterally to the side of stimulation.

Cluster Headache
Cluster headache is an ideal condition to examine in that it is a well-described, clear-cut clinical syndrome. Thus, we examined patients with episodic cluster headache, upon fulfilling the criteria of the International Headache Society (IHS), during acute spontaneous attacks of headache to determine the local cranial release of neuropeptides. During the attacks, the levels of CGRP and VIP were markedly raised, while there were no changes in NPY or substance P. Treatment with oxygen or subcutaneous sumatriptan reduced the CGRP levels to normal, while opiate administration did not alter the peptide levels.

These data demonstrate activation of the trigeminovascular system and the cranial parasympathetic nervous system in an acute attack of cluster headache. It is particularly noteworthy that all subjects had release of VIP. This is in concert with the facial symptoms well known to the symptomatology of this disorder. Furthermore, it was shown that both oxygen and sumatriptan, while aborting the attacks, terminated the activity in the trigeminovascular system.

This agrees well with the results of others demonstrating release of CGRP in nitroglycerine-elicited attacks of cluster headache. Calcitonin gene-related peptide was found to be augmented in the external jugular vein ipsilateral to the pain side in cluster headache patients during the active period and was further elevated at the peak of the provoked attack. Complete reversal occurred during both the spontaneous and the sumatriptan-induced remission. Interestingly, nitroglycerine neither provoked a cluster headache attack nor altered CGRP levels in patients outside of their cluster bout. In addition, there were no alterations in substance P levels.

Thus, CGRP, which marks the trigeminovascular system, and VIP, which marks parasympathetic activity, are both elevated in the cranial venous blood of patients with an acute spontaneous attack of cluster headache. The termination of the attack with either sumatriptan or oxygen causes normalization of the CGRP levels, reflecting cessation of activity in the trigeminovascular system, whereas pain relief after administration of an opiate agonist apparently terminates the pain of the attack but does not immediately end the trigeminovascular activity. The finding of both CGRP and VIP in the cranial venous blood suggests that there is activation of a brain stem reflex, the afferent arc of which is the trigeminal nerve, and the efferent arc, the cranial parasympathetic outflow from cranial nerve VII.

In the early part of a migraine or cluster headache attack, the sensory nerves in the cerebral blood vessels are activated and antidromically release CGRP. These nerves, which originate in the first division of the trigeminal ganglion (TG), also project into the trigeminal nucleus caudalis (TNC). From this region a signal is transmitted to the cerebrum.

Central Mechanisms
Once the trigeminovascular reflex is initiated with an antidromic release of CGRP, the central part of this pathway -- the trigeminal nucleus caudalis (TNC) and/or its reciprocal parts at the C1 and C2 vertebra levels -- is probably activated (Figure 2). Direct stimulation of either the superior sagittal sinus or the trigeminal ganglion results in activation of cells in this region.

This characteristic may be shared by several of the primary headache forms. In this group of disorders at least 2 questions remain:

How is the reflex initiated?
What is the role of the TNC?

The introduction of the triptans represented a remarkable breakthrough in headache therapy and has served to highlight the importance of the 5-HT1B/1D agonist class of drugs in the acute treatment of migraine and cluster headache. These drugs are thought to act mainly as vasoconstrictors (to limit overdistension of the large circle of Willis arteries) via 5-HT1B receptors and to inhibit sensory nerve activity (documented by normalization of CGRP release) via 5-HT1D receptors.

When zolmitriptan appeared, a novel approach could be examined. In anesthetized cats, the stimulated release of CGRP and VIP as markers for activation of the trigeminal and facial nerves, respectively, was studied.[23] Following trigeminal ganglion stimulation, the concentrations of CGRP and VIP rose significantly. The concentrations of NPY and beta-endorphin remained unchanged, implying that peptide release was specifically related to trigeminovascular activation. Following intravenous administration of zolmitriptan, the concentrations of CGRP and VIP returned to near-normal levels.

These results reinforce the notion that zolmitriptan, like other members of the 5HT1B/1D agonist drug class, acts at prejunctional receptors on trigeminal afferents to inhibit CGRP release. However, inhibition of VIP release cannot be explained by a peripheral inhibitory action of zolmitriptan and implies that the drug acts in the brain stem to block reflex activation of the facial nerve.

Autoradiographic studies using labeled zolmitriptan and sumatriptan have subsequently confirmed the presence of 5-HT1B/1D receptors in discrete brain stem nuclei involved in cranial nociceptive processing.[24] Specific in vitro binding of radiolabel was examined in transverse sections of the brain stem and the C1-C2 regions of the cervical spinal cord. The binding was markedly heterogeneous, with the highest densities of binding observed in the TNC, the nucleus tractus solitarius of the brain stem, and in the dorsal horns of the C1 and C2 cervical spinal cord. Blockade experiments confirmed that the radiolabel was not binding to either 5-HT1A or 5-HT1F sites and provided evidence that 5-HT1B/1D receptors are discretely localized in central trigeminal (and other) sites that are likely to be activated during migraine, and that triptans can indeed access these sites after systemic administration.

A Link to the Cerebral Circulation
A possible way to link the early observed alterations in the intracranial circulation to the genetic theory of migraine is via the observation that a genetically reduced number of calcium channels may more easily be activated (due to altered membrane potential) and result in excitation of PAG, raphe nuclei, or locus ceruleus neurons in situations where these neurons are exposed to excessive stress.

The putative migraine generator is depicted in the brain stem and related to the periaqueductal gray area (PAG), raphe nuclei and, locus ceruleus. It is hypothesized that this generator activates centers in the cerebrum and possibly the cerebral blood vessels.
Proof of the involvement of brain stem nuclei in migraine first came from Weiller and colleagues, who studied unilateral acute migraine attacks with positron emission tomography (PET). During attacks, increased blood flow was observed in the cerebral hemispheres, in cingulate, auditory, and visual association cortices, and in the brain stem regions. However, only the brain stem activation persisted after the injection of sumatriptan, which induced complete relief from headache as well as from phono- and photophobia. These findings support the idea that the pathogenesis of migraine is related to an imbalance in the activity of brain stem nuclei regulating nociception and vascular control, and even associated symptoms such as emesis. The precise neurons involved are not known because the PET method does not have the ability to image them.

Although reductions in regional cerebral blood flow are known to occur in relation to migraine headache, the pattern of the alterations in blood flow has not been precisely delineated. Olesen and colleagues[26] observed a pattern of localized reductions in flow that appeared to spread contiguously along the cerebral cortex in patients with migraine attacks. This pattern of "spreading oligemia" or "spreading hypoperfusion" has been apparent only in patients who have migraine headache with aura. Areas of hypoperfusion have been demonstrated tomographically with intravenous or inhaled tracers in patients with spontaneous migraine headaches, but no subsequent spreading of the area of hypoperfusion has been demonstrated, possibly because these patients were studied late in the course of their attacks. As a rule, the hypoperfusion is ipsilateral to the headache pain and contralateral to the symptoms of aura. Two unexplained cases of bilateral blood flow changes have been documented. These observations have now been reported in one subject who by chance suffered a migraine attack during a series of blood flow measurements with PET. The headache was associated with bilateral hypoperfusion, which started in the occipital lobes and spread anteriorly into the temporal and parietal lobes, providing unequivocal high-resolution evidence of the spreading nature of hypoperfusion associated with a spontaneous migraine attack.

Several research groups have observed that the involvement spreads contiguously across the cortical surface at a relatively constant rate, sparing the cerebellum, basal ganglia, and thalamus, and ultimately spanning the vascular distributions of 4 major cerebral arteries. Given that extensive serotonergic afferent neurons from nuclei of the median and dorsal raphe supply the small blood vessels of the brain, it seemed possible that the changes observed in cortical blood flow might be mediated neuronally through projections from these nuclei.

A plausible explanation for the blood flow changes is that they are the result of spreading depression -- a transient marked reduction in electrical activity in gray matter seen in animal studies -- that advances contiguously across the cortical surface. The rate of advance is consistent with the spread of symptoms observed during migraine with aura and is associated with decreases in blood flow. Spreading depression can move transcallosally to homologous regions of the opposite hemisphere in animals, and transcallosal spread could account for the bilaterality observed at the onset of the headache.

Recent PET studies on cluster headache have reported blood flow changes that suggest, in part, a response that is not primarily generated by the pain. In this study, the anterior cingulate cortex was activated, as would be expected, as part of the affective response. Activation was also seen in the frontal cortex, and insulae and ventroposterior thalamus contralateral to the side of the pain. The only activated area that is particular to cluster headache is the ipsilateral hypothalamus gray matter region. This region is important in the control of circadian rhythm of neurons and thus can be linked to the neurohormonal imbalance seen in cluster headache. This raises the possibility that the pathophysiology of cluster headache is driven partially or entirely from the CNS. Thus, the key pathophysiologic process that takes place in cluster headache has recently been outlined.

Elements of a neurobiologically based explanation for cluster headache. Pain afferents from the trigeminovascular system transverse the ophthalmic division of the trigeminal nerve, taking signals from the cranial vessels and dura mater. These synapse in the trigeminal nucleus caudalis and then project to the thalamus (ventroposterior) and lead to activation in cortical areas, including frontal cortex, insulae, and cingulate cortex, resulting in pain. There is a reflex activation of the parasympathetic outflow via the facial nerve, predominantly through the pterygopalatine (sphenopalatine) ganglion, which acts as a positive feedback system to dilate the vessels further and irritate trigeminal endings. This autonomic activation leads to lacrimation, reddening of the eye, and nasal congestion, while a local third-order sympathetic nerve lesion caused by carotid swelling results in a partial Horner's syndrome. The key CNS site for triggering the pain and controlling the cycling aspects is in the posterior hypothalamic gray matter region, shown now to be active on PET scans in patients.

The most curious feature of the disorder is its episodic nature, from which the very apt name is derived. The headaches turn on and off like clockwork, respecting some daily (circadian) rhythm that has the stamp of the biological clock. Moreover, the remarkable half-yearly, yearly, or even biennial cycling of the bouts is one of the most fascinating cycling processes of human biology. These processes implicate involvement of at least the suprachiasmatic region, and the unravelling of their neurobiology will tell us much about human biological clocks.

Recent imaging using PET in 9 patients during acute attacks of cluster headache have demonstrated unilateral activation in the hypothalamic gray ipsilateral to the headache side only during the pain. Thus, it is highly likely that the fundamental driving process arises in diencephalic pacemakers. While migraine and cluster headache share much in the expression of the pain, their underlying generation distinguishes them. Indeed, it is the CNS's triggering or driving process that ultimately characterizes many of the primary headache syndromes. By contrast, PET scans of capsaicin-induced pain showed no hypothalamic activation, despite the fact that severe first-division pain is turned on by capsaicin. The capsaicin experiment did demonstrate flow changes in an area consistent with the cavernous sinus/carotid artery, just as there are flow changes in the vessels in cluster headache. This implies that the activation of the carotid does not relate specifically to cluster headache, but that it is a trigeminovascular autonomic reflex to first-division pain. The flow changes are, therefore, epiphenomena of the trigeminal activation, not part of the disease generation process in cluster headache.

The current data provide a model in which a central "generator," different in migraine and in cluster headache, is activated. Following alteration of cerebral blood vessel tone, the trigeminovascular reflex is initiated as a counterbalancing measure (in part via release of CGRP and/or VIP). The study of neuropeptide levels in migraine and cluster headache is now providing the link between the clinical and research work that is so crucial if the basic pathophysiology of the problem is to be determined. In migraines both with and without aura, marked changes in cranial levels of CGRP indicating activation of the trigeminal system have been observed. These levels are rendered normal by the highly effective antimigraine agent sumatriptan coincident with the relief of the headache. Similarly, CGRP is released with trigeminal activation in studies on animals and, at least for the cat, the changes are also inhibited by triptans.
The activation of TNC provides the central link to nociception, pain development, and other associated symptoms. Hypothetically, intense activation of the central pain pathways may also involve the superior salivatory nucleus (SSN), resulting in parasympathetic VIP release and expression of additional facial symptoms.

This way of connecting known facts may be useful in our future work to explore the neural innervation of the cerebral and extracerebral vessels, which, along with pharmacologic studies of the transmitters involved, should permit both a better understanding of the pathogenesis of migraine and better treatment.


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