Ten years of study has resulted in considerable but fragmented knowledge about regional cerebral blood flow in migraine with aura (classic migraine). In the present study, the number of repeatedly studied patients (n = 63) was large enough to determine statistically significant sequences of events and statistically significant spatial relations. The first observable event was a decrease of regional cerebral blood flow posteriorly in one cerebral hemisphere. Further development of this pathological process was accompanied by the aura symptoms. Thereafter headache occurred while regional cerebral blood flow remained decreased. During the headache phase, regional cerebral blood flow gradually changed from abnormally low to abnormally high without apparent change in headache. In some patients headache disappeared while regional cerebral blood flow remained increased. Although regional cerebral blood flow reduction and aura symptoms in the great majority of patients were unilateral, one-third had bilateral headache. Unilateral headache usually localized to the side on which regional cerebral blood flow was reduced and from which the aura symptoms originated (i.e., aura symptoms were perceived to occur contralaterally but presumably originated in the hypoperfused hemisphere). Our results suggest a simple model for migraine attacks: A pathological disturbance in one cerebral hemisphere causes the aura symptoms and after a time delay, it also causes the headache by stimulating local vascular nociceptors. Bilateral headache caused by a unilateral cerebral disturbance may be explained by recent neuroanatomical and neurophysiological findings.

Timing and topography of cerebral blood flow, aura, and headache during migraine attacks.

Primary headache syndromes, such as cluster headache and migraine, are widely described as vascular headaches, although considerable clinical evidence suggests that both are primarily driven from the brain. The shared anatomical and physiologic substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine and in the hypothalamic gray in cluster headache. These areas are involved in the pain process in a permissive or triggering manner rather than as a response to first-division nociceptive pain impulses. In a positron emission tomography study in cluster headache, however, activation in the region of the major basal arteries was observed. This is likely to result from vasodilation of these vessels during the acute pain attack as opposed to the rest state in cluster headache, and represents the first convincing activation of neural vasodilator mechanisms in humans. The observation of vasodilation was also made in an experimental trigeminal pain study, which concluded that the observed dilation of these vessels in trigeminal pain is not inherent to a specific headache syndrome, but rather is a feature of the trigeminal neural innervation of the cranial circulation. Clinical and animal data suggest that the observed vasodilation is, in part, an effect of a trigeminoparasympathetic reflex. The data presented here review these developments in the physiology of the trigeminovascular system, which demand renewed consideration of the neural influences at work in many primary headaches and, thus, further consideration of the physiology of the neural innervation of the cranial circulation. We take the view that the known physiologic and pathophysiologic mechanisms of the systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to emphasize the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Moreover, the syndromes can be understood only by a detailed study of the cerebrovascular physiologic mechanisms that underpin their expression.

https://journals.sagepub.com/doi/pdf/10.1097/00004647-199902000-00001

The Trigeminovascular System in Humans: Pathophysiologic Implications for Primary Headache Syndromes of the Neural Influences on the Cerebral Circulation:

Basic mechanisms in vascular headache.

Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat.

An understanding of migraine must be based on data concerning the anatomy and physiology of the pain-sensitive intracranial structures. Stimulation of the superior sagittal sinus produces changes in brain blood flow and changes in neuropeptide levels similar to those seen in humans during migraine. To better understand the anatomy of the central ramifications of pain-sensitive intracranial structures we have examined the distribution of c-fos immunoreactivity in the monkey when the sinus is stimulated. Six adult Macaca nemestrina monkeys were anaesthetised. The superior sagittal sinus was isolated after a midline craniotomy and a paraffin well created. At 24 h after completion of the surgery the sinus was stimulated electrically for 1 h and the brain subsequently removed and processed for c-fos. In control animals in which the sinus was isolated but not stimulated there was a small amount of c-fos expression in the caudal brainstem and upper cervical spinal cord. Stimulation of the superior sagittal sinus evoked expression of c-fos in the caudal superfical laminae of the trigeminal nucleus and in superficial laminae of the dorsal horn of the C1 level of the upper cervical spinal cord. A lesser amount of c-fos was seen at C2 while no significant labelling above control was observed at C3. These data, while largely confirming the results from the cat concerning the central distribution trigeminovascular afferents, underscore a possibly unique specialisation of trigeminovascular afferents at the C1 level. Given the close evolutionary relationship of the monkey to man it is likely that the cells described in this study represent for primates the nucleus that mediates the pain of migraine.

The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c‐fos immunocytochemical study

Two or three or sometimes more fine intracavernous branches were traced from the ophthalmic nerve using serial section reconstruction and induced nerve degeneration. They joined the cavernous plexus and were distributed forward with autonomic nerves to the adventitia of the internal carotid artery, emerging from the sinus with the artery. A strong recurrent branch from the plexus joined the abducent nerve, passed back and left the nerve at pontine level to innervate the basilar artery and the caudal circle of Willis. The recurrent nerve was absent from one side of two animals and showed asymmetry in others. No branch issued intracranially to the plexus from the maxillary nerve, but in the pterygopalatine fossa the orbitociliary branch of the maxillary nerve gave off one or two filaments that re-entered the cranial cavity through the medial infraorbital fissure and joined the cavernous plexus. Their content augmented the ophthalmic afferent distribution. All plexus branches with trigeminal fibres also contained autonomic fibres. The results show, firstly, that the cavernous plexus consists of a mixture of sensory and autonomic nerves (sympathetic and parasympathetic) and, secondly, that afferents of the internal carotid artery and rostral circle of Willis and those to the basilar artery and caudal circle of Willis are distributed separately.

T Simons

Papers

Trigeminal nerve pathways to the cerebral arteries in monkeys.