The causes of migraines – the most important theories



This section will not only offer you a brief insight into the history of research into the causes of migraines. Above all, it is intended to give you an overview of the current status of migraine research. This is not just of purely academic interest. There is a much more concrete reason why we continue to research: Only those who understand the causes down to the last detail can develop therapies that attack the causes directly with minimal side effects and defeat the pain.

What people thought back then

Headache disorders, including migraines, are as old as humanity itself. The earliest evidence dates back to around 6,000 years before our era. Possibly the so-called trepanations – holes carved into the skull – were intended to allow the painful evil spirit to escape. Not everyone will have survived this martial therapy back then. But there are numerous skull finds in which the edges of the bones have grown together again, so the “patients” must have survived. The treatment with leeches to extract poisons, which is still sometimes carried out by alternative practitioners today, is based on exactly these ancient ideas.

About evil spirits and “nervous storms”

The Sumerians 4,000 years ago believed that migraines were the work of evil spirits and recommended prayers to the god Horus as therapy. The Greek physician Aretaeus of Cappadocia (1st century BC) assumed that migraines were caused by colds and drying out of the body. Other supposed explanations that have accumulated in antiquity and the Middle Ages: constipation of the senses, flooding of the stomach and intestines with bile, imbalance of the four humors blood, black and yellow bile and mucus.

While the British doctor Thomas Willis recognized in the 17th century that a narrowing or widening of the blood vessels was causally involved in the development of migraines, concepts emerged again in the 19th century that make us smile today. Masturbation, “bad” hereditary influences, sources of infection, inflammation of the eyes and the like were blamed for migraines.

But one work from the 19th century was truly groundbreaking, as it not only provided a perceptive overview of the milestones in the history of ideas about the origin of migraine, but also contained the explanatory concepts that are still valid today: Edward Liveing's book “On Megrim, Sick” published in 1873. Headache, and some allied disorders.” In this work, Liveing ​​discusses, among other things, the theory of circulatory disorders as the cause of migraines and also brings forward a new theory: migraines as a result of “nervous storms” – excessive discharges of cranial nerves. You can see how far ahead of its time Liveing ​​was by the fact that some doctors are still arguing about whether changes to the blood vessels or changes to the nervous system (“nervous storm”) are the primary cause of migraines .

Migraine pain put to the test

If we step on a thumbtack barefoot, we know what to expect: at first it hurts sharply, then shortly afterwards it feels dull and burning. Most of us also know what a leg cramp or a joint sprain feels like: also anything but pleasant.

These two types of pain are referred to as “somatic pain”. If it is caused on the skin (tack), it is called “surface pain”. If it arises in the muscles, joints, bones or connective tissue, it is called “deep pain”.

If we want to know where we stepped on the thumbtack, we have no difficulty finding the injured area - the pain is easily localized. Even if you have a leg cramp or a sprained joint, we can immediately find the source of the pain. Things look completely different with so-called “visceral” pain.

Hide-and-seek pain

Thalamic infarction

Thalamic infarction

“Viscera” is Latin and, according to Duden, means the “organs located inside the skull, chest, abdominal and pelvic cavities”. We also call pain that occurs on or in these organs “visceral pain” or medically “visceral pain”. Based on this definition, it is actually clear what it is: For example, the pain of appendicitis, biliary or intestinal colic, pleurisy or even a heart attack.

Visceral pain has three typical characteristics in common: it often radiates to distant skin areas or muscles, it leads to excessive pain sensitivity of the affected organ system and/or the skin area into which the pain radiates, and visceral pain is particularly common with vegetative symptoms such as sweating, paleness, increased blood pressure, muscle tension, nausea and/or vomiting.

We find these signs, for example, in an acute heart attack: The severe and devastating pain in the heart behind the breastbone often radiates into the shoulders (especially the left one) and the left arm. But the pain can also be localized in the lower jaw, upper abdomen or on the back between the shoulder blades. The organ itself, as well as the affected skin areas, are more sensitive to pain, and the complexion is pale gray and pale. Nausea and vomiting, cold sweats on the forehead and upper lip, and there may even be a sudden collapse of the circulatory system are common.

Qualities of migraine pain

Although brain tissue is of course injured to a greater or lesser extent during every brain operation, anesthesia is generally not necessary. Reason: The brain tissue is insensitive to pain. Given the excruciating pain in the head caused by migraines, this statement seems strange to say the least. Apparently something happens during a migraine attack that makes the otherwise pain-insensitive structures of the brain extremely sensitive. We will try to narrow down this “something” in more detail in the following sections.

But this is first and foremost about pain and its qualities. Until recently, migraines were referred to as deep pain. Today we know that the term “visceral pain” fits migraines far better. Migraine pain is often difficult to localize and radiates to distant areas - in the case of migraines, usually to the neck muscles. It also shows that migraine pain can be accompanied by numerous vegetative symptoms: nausea and vomiting, sensitivity to light and noise, pale skin, freezing, shivering, trembling and much more.

Migraine as a circulatory disorder?

There are a few reasons why one might suspect changes in the blood flow to the brain - i.e. too much or too little pressure in the blood vessels - as the cause of migraines:

  • The migraine headache is throbbing and worsens with each pulse beat.
  • Headaches also occur with other disorders of the blood vessels in the brain - such as stroke, high blood pressure or inflammation of the blood vessels.
  • The brain itself is not sensitive to pain. But the blood vessels of the brain do.
  • Certain drugs, the so-called triptans, which influence the width of the cerebral vessels and thus the blood flow, can effectively stop a migraine attack.
  • During the aura phase, there is reduced blood flow in the cerebral cortex in the area of ​​the back of the head. The interesting thing: This area is responsible, among other things, for vision. And as you have already learned, the aura symptoms are mostly visual in nature.

Side effect, not cause

At first glance, the connections between changes in blood flow in the brain and migraines are entirely plausible: each of the five points taken individually is absolutely correct. But the conclusion that migraine is a purely vascular disease (in the blood vessels) is still unlikely.

Let's take a closer look at point 5. There is no question that the aforementioned reduced blood flow occurs during the aura. It has been proven using numerous methods. But if we look at the course of cerebral blood flow in different types of migraine - with aura, without aura - we immediately see that this cannot be the explanation for the migraine itself. Because with migraines without aura there is no change in blood flow in the head. The migraine pain can therefore have nothing to do with blood circulation, even if points 1 to 4 above seem to be strong indications.

But what about the aura? Is it at least triggered by the changes in blood flow? Not even that is clear. Whether it can be responsible depends on how severe the reduced blood flow is in the affected area of ​​the brain. If it is actually 50 percent - as the supporters of the so-called vascular hypothesis claim - this would result in a lack of oxygen for the brain cells, which could certainly lead to the aura symptoms. However, if blood flow drops by a maximum of 25 percent - as the proponents of the neurogenic (nerve-caused) hypothesis assume - this would not be enough to explain the effects.

No matter how the discussion turns out in the end: Changes in the size of the veins in the brain alone cannot be considered as the primary cause of migraines. Regardless of the severity of the changes in blood circulation, we can only regard them as accompanying symptoms.

Migraine as inflammation?

If we have injured ourselves on a thorn while gardening and foreign bodies such as bacteria have possibly penetrated the wound, or if we have lain in the sun for too long without protection, the typical signs of inflammation appear: the affected area reddens and swells , becomes hot and painful.

In both cases (thorn, sunburn), body tissue is injured, and the ensuing inflammatory response is nothing other than the body's normal way of repairing the injury. This releases messenger substances (so-called inflammatory mediators), which ensure greater blood flow to the area (redness), make the blood vessels more permeable so that more immune cells and tissue water can escape (swelling), and accelerate the metabolism at the site of the event (heat ) and increase pain sensitivity. So it is a sensible process that, on the one hand, creates the conditions for the necessary repairs and at the same time warns us through the pain not to put further strain on the injured area.

Special case of neurogenic inflammation

However, an inflammatory reaction can also be caused by nerves - hence the term "neurogenic inflammation" - without there being any tissue damage or infection with bacteria. In this case, increased nerve activity triggers the release of inflammatory messengers. As with any other inflammation, these cause increased blood flow in the blood vessels of the meninges, make the veins more permeable and increase pain sensitivity in the area. Applied to migraines, the neurogenic inflammation model can explain why the blood vessels in the brain are so sensitive to pain that the pain increases with every pulse beat.

Partial explanation yes, cause no

What is certain is that neurogenic inflammation is an important mechanism for the body to ward off damage. However, it is uncertain whether it actually plays an important role in migraines. However, the concept of neurogenic inflammation offers meaningful explanations for some aspects of migraine, which is why it actually has a high priority in modern migraine models. However, the cause of migraines in the sense of a factor X, which gives us answers to all open questions, is definitely not neurogenic inflammation.

Brain under high voltage

Particularly effective triggers of migraine attacks are sudden changes in the normal rhythm of life. It appears that these changes cause a temporary disruption to the normal flow of information. It is a particular achievement of the Belgian migraine researcher Jean Schoenen and his colleagues to have made this special willingness to change processing of stimuli visible through laboratory measurements in 1984. This involves a special recording of brain waves, an electro-encephalography (EEG), during which patients have to pay attention to certain stimuli and react.

Get ready to accelerate

What is examined under laboratory conditions is well known to us from everyday life: a driver has to stop at a red light. He has no idea how long the traffic light has been red and therefore doesn't know exactly when the yellow phase will come. He therefore stays in a phase of medium readiness and watches closely to see whether the traffic light changes. As soon as the traffic light shows yellow, the driver knows that after a few seconds it will turn green and that he then has to release the clutch and accelerate. The driver is now particularly concentrated, mentally preparing for his task and carrying out it immediately after the green light changes. During the phase of increased readiness immediately before the action is carried out, the brain has to be particularly active: it has to plan the action in advance so that it can be carried out immediately, and it has to take into account an internal clock in order to be able to estimate the time between the yellow and green phases .

Migraine patients act differently

This special willingness can now be made visible in the EEG. Of course, you don't build street lights in the laboratory. But the principle is the same. The usual procedure, for example, is for the patient connected to the EEG to put on headphones and closed glasses with built-in lights. The patient is told that, for example, three seconds after a cue (such as a short click) is heard in the headphones, the light in the glasses lights up. As soon as this light signal comes, the patient should press a button.

In order to get meaningful results, this process is usually repeated at least 30 times. The pause between the individual measurements varies in length, so that the patient never knows exactly when the next cue will come. The individual measurements are averaged using a computer, and the magnitude of the electrical voltage shift in the EEG can be determined very precisely based on the average values.

It turns out that the brains of migraine sufferers react differently to such tasks than the brains of healthy people or people with other types of headaches. There are two abnormalities:

  • The voltage shift in the EEG - i.e. the zigzag lines on the paper or monitor - is significantly larger than in other people.
  • While in healthy people the voltage shift becomes increasingly smaller after several measurements, it remains high in migraine patients.

These measurements are important evidence that the brains of migraine patients obviously react particularly actively to stimuli. But that's not all: While in healthy people the attention decreases more and more when the stimulus is repeated several times, the brain of the migraine patient remains constantly at maximum readiness. The brain apparently cannot “switch off” and is literally constantly under “high voltage”. Interestingly, successful treatment of patients with medications to prevent migraines - so-called beta-receptor blockers - can normalize this altered electrical behavior of the brain.

Practical: Modern model of migraine development

Migraine researchers have accumulated a lot of knowledge over the last 100 years. The many individual findings - along with numerous others, the already mentioned facts about the vascular theory, neurogenic inflammation and the excessive activity of the brain in migraine sufferers - are astonishing. However, this accumulation of knowledge also presents a major problem: the large amount of data makes it increasingly difficult to understand the processes.

What is certain is that it is not a single factor that causes migraines. But I would like to offer you a theory that incorporates as much of the data found as possible. Although many of the assumptions of this migraine theory are not yet fully supported by research data, this model can put a number of individual findings into a meaningful relationship with one another. I call it the “neurological-behavioral migraine theory.”

The beginning of the migraine attack

According to this migraine theory, migraine sufferers have an innate peculiarity in how they process stimuli in the brain - it is constantly under “high voltage”. If certain triggering factors (so-called trigger factors) occur too quickly, too suddenly, for too long or too intensely, a cascade of physiological changes, some of which occur simultaneously, is set in motion in the migraine sufferer, which ultimately causes the migraine attack. The trigger factors are, in a sense, the straw that breaks the camel's back.

Which trigger factors are decisive in the respective situation can only be predicted in a small proportion of patients. Examples include external stimuli such as stress, noise, irregularities in the sleep-wake rhythm or daily routine, as well as certain foods. Internal factors can also trigger an attack: changes in hormone levels, hunger or changes in metabolism, for example due to medication.

Flooding with neurotransmitters

The fundamentally increased activity of the brain plus trigger factor(s) now leads to sudden and excessive activation in the brain. Within a very short time, far too many neurotransmitters are released, especially the mood-controlling hormone (“happiness hormone”) serotonin and other excitatory neurotransmitters. The brain misinterprets the excessive release of messenger substances as the body's reaction to poisoning. The logical consequence is the activation of protective reflexes in the form of nausea and vomiting. However, these are biologically pointless, since the excessive activation of the neurotransmitters was ultimately not initiated by real poisoning via ingestion, but rather by the excessive processing of stimuli, and the excessive concentration of the neurotransmitters in the brain cannot be eliminated by vomiting. The result is senseless nausea, nausea and vomiting.

The emergence of the aura symptoms

At the same time, the excessively released excitatory neurotransmitters can trigger a so-called “spreading depression” - in a region of the cerebrum that is responsible for processing sensory impressions. “Spreading depression” means something like “spreading depression (of nerve cells)”. It is this that can produce the aura symptoms in migraine sufferers. The respective brain cells are initially overexcited and then fall into a state of reduced activity. This disruption of the nerve cells and the associated reduced blood flow spreads across the brain area at a speed of three to six millimeters per minute. This is exactly the speed that the aura symptoms also show when they spread. The nerve cells at the propagation front always fire like wildly, only to fall into a state of lethargy after the front advances. This is most obvious in the form of the aura that is characterized by abnormal sensations: the aura begins, for example, with a tingling sensation in the fingertips. Over the course of 30 to 60 minutes, the tingling sensation travels up the arm to the tongue, following the path marked by the disrupted brain cells in the cerebral cortex. After the tingling sensation, a numbness often remains, which corresponds to the dampened excitement of the brain cells and, like the other aura symptoms, eventually disappears.

The pain sets in

Spreading depression leads to a disruption in electrolyte concentrations (e.g. the mineral magnesium) in and between the cells. The result is that neighboring pain receptors are excited and are thus able to transmit pain. It takes around 30 to 60 minutes for inflammatory messenger substances to be released and cause neurogenic inflammation in the area of ​​the blood vessels in the meninges. Because the inflammation spreads in the blood vessels - and therefore also the sensitivity to pain - the consequences of the inflammation add up both spatially and temporally: The migraine pain typically spreads across different areas of the head and increases in intensity over time.

This lasts until the body's compensation mechanisms take effect. This includes the breakdown of the neurotransmitters released in the initial phase and the activation of the body's own pain defense systems. It can take several hours, or in individual cases up to three days, for these mechanisms to be able to compensate for the dysregulation in the central nervous system.

With or without aura?

The mechanisms that lead to migraine with or without aura have not yet been clearly established. A possible explanation is that the processes described in migraines with aura initially occur much faster and thus lead to relevant blood flow changes in the central nervous system, which can be responsible for the formation of the aura. In contrast, in migraine without aura, a very slow, gradually developing mechanism could be set in motion, the disruption of which does not lead to a noticeable change in blood flow, but does subsequently also release the inflammation-causing nerve messengers and lead to pain induction in the area of ​​the blood vessels in the meninges.

Radio interference in the brain

Of course, the messenger substances released in excess at the beginning of the attack also have to be broken down again. But due to the rapid breakdown of these messenger substances, a phase of messenger substance exhaustion follows - the stores of the important nerve messenger substances are initially empty and have to be replenished. But without messenger substances there is no or no correct conduction of stimuli in the brain. Consequence: Global information processing in the brain is disrupted.

The brain stem is also affected

The result of the inflammation initiated by excessive release of neurotransmitters is also an activation of nerve centers in the brainstem. This means that areas of the body that were not initially involved can also be included in the experience of pain. These include in particular the shoulder and neck muscles as well as areas of the skull that are not directly affected by the neurogenic inflammation.

This sensory overload could also explain why normally non-painful stimuli are experienced as extremely unpleasant during the migraine attack, particularly in the form of hypersensitivity to light and noise. Therapeutic maneuvers, such as massages, heat applications or trigger point injections in the area of ​​the head and neck muscles, can reduce the permanent subthreshold stimulation influence in the brain stem and are therefore experienced by migraine patients as pleasant, but without changing the persistence of the migraine attack. The influence of mental mechanisms on migraine occurrence - in particular cognitions, emotions, abilities to actively respond to stimuli (e.g. stress management), and psychological relaxation - can be understood by activating the body's own pain control systems.