Migraine and the pharmaceutical industry

The biology of migraine

Three factors complicate any attempt to explain migraine. Firstly, it is a collection of symptoms that appear to affect not only the head but various parts of the body such as the limbs (tingling and other abnormal sensory feelings called paraesthesia), gastric tract disturbances, and in some people neurological disturbances, including various forms of aura. Secondly, it seems to have a remarkably wide range of trigger factors which vary from person to person. Thirdly, the range and severity of the symptoms and their duration vary between people. Any attempt to explain migraine has to unite these different aspects.

Brain structure and function

To begin with, it is necessary to consider briefly some aspects of the brain and how it works. Central to migraine are two structures lying deep within the brain called the thalamus and hypothalamus (labelled TH and HyT in the figure on page 18). The former is the processing centre for most of the senses and is linked with emotional centres and those concerned with the highest human activities in the cortex (creativity, speech, written word, etc.). The hypothalamus regulates body temperature, sleep-wake patterns, many hormonal and glandular activities, and that part of the nervous system not under your direct control (called the autonomic nervous system – e.g. heart rate and blood pressure, movement of the gut, control of urinary urge, etc). It is also concerned in emotional feelings such as pleasure, pain, anger, fear and love.

From the thalamus, nerve connections run upwards to the higher brain centres in the cortex. Others run downwards into the brain stem, where they engage with distinct clusters of nerve cells called nuclei. One of these lies at the root of the trigeminal nerve, whose branches supply and receive nerve signals from the external blood vessels feeding the face and scalp and the internal blood vessels feeding the brain. Branches of this nerve end in the smaller blood vessels in the membranes below the skull. Nerves from the hypothalamus run upwards to the higher emotional centres and also down to nuclei in the brain stem concerned with pain perception. Near to the pain nucleus is another, whose function is to damp down pain sensations. Hypothalamic nerves also trigger other nuclei which cause symptoms such as nausea and gastric discomfort.

This description shows how the processing centres of the brain are linked in two-way traffic to the higher cortex and numerous clusters of cells in the brain stem concerned with blood vessel ‘tone’, pain and ‘gut’ reaction.

The migraine attack

Armed with this background information, we can try to understand how a migraine starts and evolves – though much of this remains unproven in a strict scientific sense.

One widely held view is that migraine is a reaction in nerves and blood vessels to internal or external trigger factors. At the outset of an attack, it is supposed that the trigger factors cause an over-excitation in some part of the brain. The area affected may differ according to the trigger, but could be concerned with the senses (vision, sound, touch), emotions such as stress, or with internal biological control (e.g. sleep rhythm, hormonal changes). The over-excitation leads to a contraction of blood vessel walls and an initial decrease in blood flow which spreads, wave-like, slowly through the brain, especially the cortex – a process called cortical spreading depression. Brain scanning studies have sometimes shown a decreased blood flow of as much as 40 per cent. The spreading wave of decrease in blood flow may result in the pre-headache symptoms such as dietary intolerance, aversion to light and sound, and possibly aura.

Another consequence of the over-excitation is that nerve signals reach the thalamus and hypothalamus.

In the case of the hypothalamus, signals are then sent down the brain stem to the visceral nucleus, which in turn triggers sensations of nausea in the stomach and intestines.

By contrast, nerve signals from the thalamus activate the trigeminal nucleus and impulses are sent along the trigeminal nerve to the arteries feeding the face and the brain. These enlarge with increased blood flow (dilatation), causing facial flushing and sensations of throbbing.

• Enlargement of the internal blood vessels has three consequences:
• raised metabolic activity in the brain,
• leakage of fluids from the blood into the arterial walls and surrounding tissues causing local pressure – called sterile inflammation, and
• squeezing and stretching of pain receptors.

These events result in further nerve signals travelling to the pain nuclei in the brain stem, where the sensation of pain is processed. In people with migraine, it is suggested that the nearby nucleus whose normal function is to damp down pain perception works less well and hence they experience a more severe headache than in other people. The pain is not consciously felt in the brain stem, but in an area near the frontal cortex which can be visualised by Positron Emission Tomography (PET) scanning.

A further intriguing detail needs to be introduced here, namely the fact that the brain itself lacks pain receptors. So where does migraine pain arise? Between the skull and the brain tissue are three meningeal membranes (which become inflamed in meningitis) called the dura mater, the arachnoid membrane, with a spongy space below it criss-crossed by strands of tissue, and the pia mater. These three membranes are rich in blood vessels and pain receptors and are the physical site of the nerve impulses that cause migraine pain.

The importance of the brain stem in processing and relaying pain messages during an attack is supported by the results from recent specialised PET scans showing raised blood flow and much increased activity in the brain stem on the opposite side to the headache.

The migraine aura

Of all the premonitory signs in migraine, the most vivid is undoubtedly the migraine aura and this has attracted much research because of its spectacular and frightening nature.

It has been proposed that the aura is related to the initial contraction of brain blood vessels which occur in the early stages of migraine. The decrease in blood flow starts at the back of the brain, where visual images are processed and then progresses forward, spreading over the cortex at a speed of about 2-3mm per minute. It has been suggested that this travelling wave corresponds to the nervous excitation in the visual cortex and marks the moving front of the aura. As the wave passes, there is a temporary period of impaired vision and then a more general depression of nervous activity which persists during the headache phase.

The demonstration of travelling waves of nerve activity in migraine led to the suggestion of parallels between migraine, epilepsy and some other long-term disorders of the nervous system. In epilepsy, there are rapid waves of discharge that cause absences of consciousness or epileptic seizures. It is perhaps significant that some medicines used in epilepsy also appear to have beneficial effects in migraine.

Scientists at SmithKline Beecham have developed a model system in which a wave of activity (called cortical spreading depression) can be induced and visualised by advanced scanning techniques. This is an important new model of the human condition and will greatly help in the search for new migraine medicines.