A stabbing pain in the forehead, flashes of light in the field of vision: these sensations are a regular part of life for millions of people. About 10 percent of the world’s population suffers from migraines. They have been with us for thousands of years. Pliny the Elder, who wrote an encyclopedia in ancient Rome, described five different types of headache in his work “Naturalis historia,” including “temporum dolores,” a form that corresponds to the typical symptoms of migraine.
The question of where headaches come from has probably been around just as long. What structures trigger them? In the 1940s, Bronson Ray and Harold Wolff of Cornell University Medical College in New York seized an opportunity to get to the bottom of it: brain surgery in which patients remained awake to answer questions or undergo functional tests. In this way, surgeons can be sure not to remove tissue that is important for essential functions such as speech. The two doctors observed 30 such procedures at their hospital over a five-year period.
The two used mechanical, thermal, and chemical means to test various points inside the skull. They always asked the patients: ‘Does this hurt? And where do you feel the pain?’ Over time, the researchers found that the meninges are the only parts of our brain where we feel pain. Although the brain is essential for processing pain signals, it has no pain receptors. The meninges, on the other hand, are supplied by the two trigeminal (facial) nerves. These originate in the trigeminal ganglia at the base of the skull and extend into the meninges, where they branch out and nestle tightly against blood vessels.
The conclusion of the experiment was that the meninges are the primary pain-sensitive structures in our head. And this conclusion is still valid today. In 2018, French experts led by Denys Fontaine of the Université Cote d’Azur confirmed the results using modern methods. When they irritated the meninges, Ray and Wolff also asked the patients where exactly they felt the pain. None of the patients were able to localize the pain in the meninges. Instead, they felt pain in their temples and around their eyes – where migraine headaches are most common. This led to the theory that something activates the nerve endings in the meninges, which in turn causes the headache of a migraine attack.
Does it all start in the central nervous system?
It is possible that the hypothalamus, which regulates breathing, body temperature, and circadian rhythms, controls the onset of migraine attacks. This is because the structure is particularly active in the hours and days leading up to an attack. As the attack progresses through the nervous system, the pain fibers in the meninges are activated. This means that while the meninges are an important factor in triggering the headache phase of migraine, they are not the cause of the attacks. That is much more likely to be in the central nervous system. However, exactly what activates the pain fibers in the meninges is still not understood.
In the 1970s, researchers at Harvard Medical School in Boston suggested that localized inflammation in the meninges activates the nerves there in the long term, triggering migraine headaches. Inflammation is the body’s defense against pathogens. Unlike meningitis, however, migraine is not caused by viruses or bacteria. Instead, it is a sterile, neurogenic inflammation in which no pathogens are involved.
And this hypothesis is still considered the most likely scenario today. Trigeminal neurons, which extend their fibers into the meninges, play an important role. In a process called axon reflex, activated neurons release neuropeptides. These substances then trigger neurogenic inflammation. In the case of the meninges, this is the neuropeptide CGRP. Several observations suggest that it triggers migraine pain. For example, CGRP blockers can stop the pain in many patients. When the peptide is injected directly into the blood of patients, it triggers a migraine attack.
The neuropeptides released also cause the blood vessels around the neurons to dilate. However, whether and how this affects headaches is still controversial. It is thought that the nerve cells that wrap around the vessels are stretched and may be hypersensitive in migraine. It is also possible that immune cells are involved and increase this sensitivity.
But migraines could take a completely different course. There is some debate as to whether the pain actually originates in the brain. This means that the pain-generating networks in the cerebral cortex and thalamus could, in principle, cause us to feel pain at any time – without any external trigger. This is what people sometimes experience after a stroke: they feel pain in a part of their body where there is no injury. However, this is very rare and affects only a small number of people.
Flood of proteins
A strange phenomenon that often occurs during an attack may help solve the mystery of the pain’s origin. About one-third of migraine sufferers experience an aura before an attack begins. Many migraineurs report seeing strange flashes of light or colored spots, experiencing paraesthesia, or having difficulty speaking at the beginning of an attack. In the days leading up to a migraine attack, people may experience unusual fatigue, difficulty concentrating, or food cravings.
How these additional migraine symptoms occur is not fully understood. However, the meninges probably play a minor role (unlike in pain). One likely mechanism is a wave of neuronal activity in the cerebral cortex. Such a cortical spreading polarization spreads slowly, most often in the visual center, and triggers the various visual disturbances and prodromal symptoms.
A study conducted this year shows that such an event, in turn, can activate peripheral pain receptors in the meninges. Researchers at the University of Rochester Medical Center induced waves of depolarization in the brains of mice and observed that neurons released a variety of proteins into the cerebrospinal fluid (CSF). They then tracked how the fluid transported these substances to the trigeminal ganglion. The trigeminal ganglion, like the rest of the peripheral nervous system, lies outside the blood-brain barrier. However, a previously unknown gap in the protective barrier has now been discovered, through which the cerebrospinal fluid can flow directly into the ganglion. It is flooded with the protein cocktail released in the brain, primarily CGRP.
Could this mechanism also explain migraine pain in people without aura? It is conceivable because they also have elevated levels of CGRP in their cerebrospinal fluid. However, it should be noted that the protein level in the cerebrospinal fluid quickly normalizes after the activation wave. Therefore, other processes are likely to trigger the headache in later phases of migraine.
The results of the latest study show another mechanism that may contribute to the pain of migraine – but I don’t think it’s the only answer. The study also raises other questions, such as why migraine is primarily a headache. The trigeminal ganglion innervates most structures in the head – if it were simply bathed in CGRP and other substances in the cerebrospinal fluid, it should hurt everywhere: in the cornea of the eyes, in the mouth, in the skull bones, in the ears. It is therefore speculated that the ganglion is sensitized by the flood of CGRP, but that specific nerve endings in the meninges are activated, which ultimately leads to the headache.
Triptans work on many levels
Migraine is a spectrum and much more complicated than most people want to admit. Different mechanisms trigger headaches in different people, and they simply have a similar effect. Currently, the disease is categorized as migraine with aura or migraine without aura, with several types of migraine within each category. In some subgroups, migraine may be triggered by nerve injury, in others by central pain, and in many by activation of the trigeminal nerve. As a result, there will probably never be a single drug that works for all patients.
In fact, there is currently no treatment that specifically targets the trigeminal nerve. Triptans, which became available in the 1990s, were the first drugs developed specifically for migraine. Initially, they were used as vasoconstrictors, which means they counteract the dilation of blood vessels. Over the years, however, we have learned that triptans block the release of neuropeptides and thus stop neurogenic inflammation. Triptans therefore work on many levels, which is why they can be used relatively widely in the treatment of migraine.
Many of the drugs used were originally used to treat epilepsy and depression. This means that they can cause side effects in the central nervous system, such as slowing cognition or causing drowsiness. In the last decade, new drugs have come onto the market, mainly targeting CGRP. They block either the neuropeptide itself or the receptors to which it binds. For many people, these new drugs stop the attack. However, it is not known exactly where they work to block CGRP.
One clue comes from a specific class of drugs that block CGRP: monoclonal antibodies. These molecules are so large that they cannot cross the blood-brain barrier. Therefore, they reach the meninges, but presumably not the brain itself, or only in minute amounts. This supports the simple explanation that CGRP acts in the meninges. Accordingly, it is possible to develop targeted drugs that affect mechanisms in the meninges and do not need to enter the brain to be effective. The advantage of this approach is that such drugs would likely have significantly fewer side effects.