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Migraine is a crippling illness for those who suffer. Despite the ‘background noise’, there has also been considerable and valuable research effort in this field — if one combs the literature hard enough to find it. Even so, the international migraine scene tends to be dominated by large set-piece meetings, weak on innovative science, and strong on drug-trial reports. This approach may be good for the market analysts but does little for our understanding of migraine. The Migraine Trust therefore decided that a ‘brain-storming’ type of meeting might be timely, to try to decide what path precisely future directions might follow.

The migraine attack may start in the brain and affect the vascular system secondarily. Feedback from vessels to the brain completes a vicious circle. In the internal carotid circulation, the phase of constriction is associated with neurological symptoms. There may be a diffuse ischaemia of the brain or a progressive, slow march of oligaemia that correlates with spreading depression.

This chapter focuses on the development of clinical neurology. Clinical neurology was early combined with psychiatry in the 19th century and only began to emerge as a separate specialty around 1900. In North America, the Neurological Unit of the Boston City Hospital was one of the early seeding places for the new discipline. At midcentury, a succession of neurologists in Boston, including Stanley Cobb, Tracy Putnam, Derek Denny-Brown, Raymond Adams, and C. Miller Fisher, laid the basis for modern clinical neurology as an independent discipline. The first effective drug for treatment of epilepsy was introduced. Spreading cortical depression was discovered and linked to migraine. The role of dopamine and the substantia nigra in Parkinson's disease was recognized.

Besides pain, Parkinson's disease represents an excellent model to study the neurobiological mechanisms of the placebo effect. The placebo effect in Parkinson's disease is mediated by dopamine release in the striatum and is associated to changes in activity of neurons in the subthalamic nucleus. The therapeutic effects of deep brain stimulation are powerfully modulated by placebos as well. As to migraine, although migraine clinical trials show very high rates of improvement in those patients who received placebo, the underlying mechanisms are not known. Many other neurological diseases, like epilepsy, show improvements in placebo groups, but the mechanisms are completely unknown.

The anxiogenic effect may be relevant to migraine, as anxiety or stress are candidates for precipitating attacks of migraine, and it is therefore of great interest that Brewerton et al. recently reported that m-CPP precipitated headache in both control and migrainous subjects with a significantly greater incidence in the latter group. Seven out of eight of them reported that the headaches could not be distinguished from their naturally occurring symptoms, except possibly for the absence of prodromal signs. This work and findings of the current study may suggest new avenues for migraine research. At the least, they raise a number of questions. This chapter summarizes the evidence that the anxiogenic effect of m-CPP is mediated by 5-HTlc receptors, that it is not merely a consequence of the hypolocomotor effect of m-CPP, and that it may also have implications for the mechanism and treatment of migraine.

This chapter asks: What is migraine? The word ‘migraine’ needs clarifying because it can be used in two senses: clinical attacks and the underlying migraine processes. This chapter describes the clinical phenomena of migraine (first in outline and then in detail), followed by the life-cycle of migraine in individuals, and ends with some implications of clinical migraine on possible mechanisms. The chapter tries to define migraine more strictly, the novel feature of this definition being that it includes timing, which has been incorporated in the International Headache Society's (IHS) Classification. This chapter describes five phases of migraine attack.

For any hypothesis to be truly satisfying, it must be compatible with all the known facts. The manifestations of migraine are so diverse that one must resist the temptation to seize on some and reject others in an attempt to justify a tenuous theory. Certain symptoms that can be recognized within the conceptual framework of migraine may be present in some episodes and not others, and may recur in certain phases of each attack but not in others. Each of these symptoms or groups of symptoms may have a different neurovascular basis.

Several methods for measuring regional cerebral blood flow (rCBF) are now available. Each method and equipment has its own advantages and drawbacks. The xenon-133 (133Xe) inhalation or injection techniques and the recording of rCBF with systems of stationary or rotating γ-radiation detectors have, until now, been the most useful methods for studying migraine patients. With these methods it is possible to repeat measurements before, during, and after a migraine attack in the same patient and, thereby, to elucidate the course of dynamic rCBF changes. Almost all the rCBF studies referred to in this chapter were carried out with the 133Xe technique.

Regardless of the many considerations, GR43175 has been shown to be effective when administered subcutaneously and orally as well as when administered intravenously in the treatment of acute migraine. It is now in phase III clinical trials and promises to provide a major breakthrough in migraine therapy. Importantly, further studies on its clinical mechanism of action are in progress and they will, it is hoped, be invaluable in elucidating the pathogenesis of migraine and vascular headache.

There can be no doubt that migraine is associated with changes in the cephalic (cerebral and non-cerebral) circulation; the doubts, however, concern the cause and nature of such changes. In a majority of migraine patients with ‘aura’, the cerebral blood flow decreases, but in ‘classical’ migraine patients both decreases and increases have been reported. In the non-cerebral cephalic circulation, vasodilatation and increased pulsations are observed principally on the side of the migraine headache, but the idea of simple vasodilatation is paradoxical to the facial pallor and laxity of tissues usually noticed during the headache. To resolve this paradox, Heyck suggested that vasodilatation involves cephalic arteriovenous anastomoses.

This chapter discusses some aspects of the biochemistry of migraine predisposition, and indicate how some of the initiating factors may interact with the central monoamine systems. Professor Lance and others have discussed persuasively how these centres (particularly the raphe nuclei and locus coeruleus) may be involved in the generation of a migraine attack. It is likely that the more we understand about individual vulnerability, the more we may be able to tailor specific treatment to particular patients.

A recent method of preventing migraine attack has been tried on patients with premonitory symptoms, for example, irritability, excitement, euphoria, or food cravings that occur as long as twenty-four hours before the attack; these patients have been given domperidone, a dopamine D2 receptor antagonist, which is anti-emetic (that is, relieving nausea and vomiting) and gastro-kinetic (that is, stimulating the stomach and opening the pyloric spincter so that oral medication can be absorbed by the small gut). With premonitory symptoms of more than six hours, it can be effective in preventing migraine attacks. There is still no general agreement as to how migraine is best treated, largely because of the fact that many drugs which are used have not been scientifically evaluated by methodologically sound clinical trials.

Headache is among the most fascinating and most common of medical problems. It can be a manifestation of a disease process in its own right, without a clearly defined other cause (primary headaches such as migraine, tension-type headache, or cluster headache), or headache can be due to a defined other disease process, such as that associated with infection, brain tumour, or head trauma. This chapter discusses the common biology of pain processing for headache, since it is likely to be shared to some extent by most forms of headache. It then presents the unique biology that underlies migraine as a form of primary headache that exemplifies some of the basic principles of headache biology.

The chapter begins with a description of the characteristics that make visual stimuli uncomfortable to look at. It is shown that certain spatial and temporal periodicity, and strong colour contrast are responsible for discomfort. These particular characteristics are rare in the natural images to which the human visual system has adapted and, perhaps for this reason, natural images are generally more comfortable than those that are unnatural. Text has the characteristics of an uncomfortable image, and there are simple steps that can be taken to reduce the discomfort. Uncomfortable (and unnatural) visual stimulation gives rise to strong physiological excitation in the visual cortex of the brain and some people are far more susceptible to such strong excitation than others. Individuals with migraine are among those who are most susceptible. The excitation induced by strong visual stimulation can be reduced by coloured filters individually chosen to reduce discomfort, and other coloured filters are without effect. The benefits of coloured filters on reading speed, on accommodation and on other higher perceptual function can be understood as due to a reduction of over-excitation, with implications for treatment in a variety of medical conditions in which the cortex is hyperexcitable, and with implications also for the idiosyncratic manner in which colour is coded within the higher levels of the visual system. There are large individual differences in the colours optimal for therapy.

This chapter provides information on the epidemiology of headache, with major sections devoted to migraine and tension-type headache. The clinical features of each headache type are discussed, and details of International Headache Society (IHS) criteria are described. This is followed by a summary of studies related to the incidence and prevalence, and a description of how headache frequency varies by age, sex, race, and geographic region. The chapter provides a summary of risk factors for headache, in addition to describing triggering factors among headache sufferers. The final section is devoted to a discussion of the impact of headaches, including frequency, severity, and health-related quality of life.

Pregnancy is characterized by profound metabolic and physiological alterations involving virtually every organ system. Among apparently healthy women, the metabolic challenges, or “stress test” of pregnancy may contribute to adverse perinatal and neonatal outcomes, and may also unmask susceptibility for maternal chronic disorders. Available clinical and epidemiologic data are supportive of the hypothesis that common medical complications of pregnancy including gestational diabetes mellitus, and hypertensive disorders of pregnancy may represent, at least for some women, their underlying risk for developing related chronic medical conditions as they age. This chapter first provides a brief overview of maternal metabolic, physiological, and anatomical changes during pregnancy. These are followed by a review of selected maternal pre-gestational chronic medical conditions and those arising during pregnancy. The chapter closes with a discussion of the influence of other factors, including intimate partner violence, on maternal physical and mental well-being.