A woman with migraine with her head in her hands, and a human brain with green arrows showing the progress of a migraine attack.
Asger Hee Stjernholm, MSc

What Happens in the Brain During a Migraine?

Until the 20th century it was a mystery what caused migraine and what happened in the body during an attack. However, in recent years scientists have discovered many of the mechanisms that are involved when migraine attacks start and develop. This article will describe the most important of these mechanisms.

Picturing a migraine attack

The brain works through many extremely complicated biochemical and electrical mechanisms, many of which are not even completely understood by science – so it is no surprise that a description of what happens in the brain during a migraine attack is complicated! This article will try to make the process as clear as understandable as possible, even if you do not know a lot about cells and chemistry.

To start off, it can be helpful to use a mental picture that illustrates what is going on when migraine attacks are triggered: imagine a large troupe of gymnasts doing a dance routine to music, on a slick hardwood floor. The dancers are listening to music for their cues of when to do which dance move.

Now imagine that each dancer is holding in her left hand a fist full of small marble balls. When she dances, sometimes she drops one of the marbles on the floor by accident but quickly picks it up again and puts it back in her left hand with the others. Now imagine what happens if a dancer becomes tired and doesn’t have the energy to pick up the marbles as quickly, or she starts dancing much wilder so that more marbles drop on the floor.
After a while of this, there will be many more marbles around her feet than normal, making it likely that she will suddenly slip on one of them. As she falls to the floor, all the marbles in her hand spill out on the floor where they roll out among the feet of the dancers next to her.
When that happens, those dancers have to start picking up marbles at a much faster rate. If not, they will fall as well and drop their own marbles, starting a chain reaction spreading like ripples through the dance troupe.

This wave of falling dancers is of course a bit silly, but the process has some similarity to the kind of chain reaction that takes place in the brain when a migraine attack is triggered, as we will see when we now dive into the actual biology of a migraine attack.

The brain before a migraine attack

The figure below illustrates the normal brain, showing nerve cells surrounded by extracellular fluid (ECF).
An illustration of the normal brain, with nerve cells surrounded by the extracellular fluid (ECF). The brain is surrounded by the brain membrane, and lying on top of this membrane are the arteries supplying the brain with blood. The arteries have pain receptors. The concentration of K+ is high inside the cells and low outside in the ECF. For Na+, it is the other way around.

The entire brain with all its neurons and ECF is covered by a membrane (a bit like plastic wrap covering a head of cabbage). Running on the outside of this membrane are the arteries that supply the brain with oxygen and blood sugar. The nerve cells in the brain cannot feel pain, but the arteries have pain-sensing nerve endings in them, so-called pain receptors.

In the normal case illustrated in the picture above, the concentration of K+ is very large inside the nerve cells, but very low outside in the ECF. For Na+ it is the other way around.

When a nerve cell sends a signal (also known as “firing”), some of the K+ inside leaks out of the cell into the ECF, and some of the Na+ outside leaks into the cell. In our dancer example, this is similar to how the dancer from time to time drops a marble on the floor.

The normal inside/outside concentrations are kept stable by microscopic Na+/K+ “pumps” in the nerve cell’s walls. These pumps are all the time pumping K+ out of the ECF and into the cells, and Na+ in the other direction. In our dancefloor example, these pumps are like the dancer continually picking up the marbles that she drops.

A migraine attack is triggered

There is a lot of evidence that migraine attacks are triggered when the concentration of K+ in the ECF becomes too high. This corresponds to the situation where the dancer has dropped so many marbles around her feet that she ends up slipping on one of them. This increase in K+ in the ECF can happen for a number of reasons:

  • If the Na+/K+-pumps are not being supplied with enough oxygen and/or blood sugar, K+ cannot be pumped out of the ECF fast enough and the concentration of K+ in the ECF will increase . This can happen if the arteries supplying this part of the brain are very contracted so that too little blood flow is coming through, starving the Na+/K+-pumps of the oxygen and blood sugar that is normally being delivered in sufficient amounts by the blood. If it is too long since you’ve eaten a meal, your blood sugar may also be so low that the Na+/K+-pumps are not getting the energy they need to remove K+ from the ECF at a fast enough rate.
  • If the nerve cells have been firing at a very high frequency for a very long time, K+ in the ECF will increase (remember that some K+ flows out into the ECF every time the nerve cell sends a signal). This can happen when you have been very stressed for a long time or have not had enough sleep.
  • If too little K+ is being removed by the blood flow that normally helps “sweep up” some of the excess K+ in the ECF. This happens if the blood flow to that part of the brain is insufficient.

The picture below shows the situation where a lot of K+ has leaked out of a nerve cell, so that the concentration of K+ in the ECF around that cell has become too high:

An illustration of the normal brain, with nerve cells surrounded by the extracellular fluid (ECF). The brain is surrounded by the brain membrane, and lying on top of this membrane are the arteries supplying the brain with blood.Too much K+ has entered the extracellular fluid around the nerve cell to the left.


A chain reaction begins

When the concentration of K+ in the ECF becomes very high, it can trigger a chain reaction known as Cortical Spreading Depression (CSD), somewhat like the wave of falling dancers in the example. CSD moves as a slow wave along the surface of the brain at a speed of about three millimeters per minute:
Two human brains next to each other. Part of them is colored blue in order to indicate the progression of Cortical Spreading Depression.

When the CSD wave arrives at a nerve cell, its normal Na+ and K+ concentration differences break down, which again makes CSD spread further.

The next step of this vicious cycle happens, when enough K+ has entered the ECF around a nerve cell. The excess K+ acts as a key which unlocks a specific type of channel in the wall of the nerve cell:

This type of channel (called the NMDA channel) has its “keyhole” on the outside of the cell, so K+ can’t unlock it when it is inside the cell. When the NMDA channel opens, a lot of Na+ is able to enter the cell from the ECF:

When this large number of Na+ molecules enter the molecule it becomes depolarized (illustrated in the figure above by the color change of the nerve cell), meaning that it loses its normal “battery charge” and cannot work properly again before it has been recharged by its Na+/K+-pumps.

Importantly, the opening of the NMDA channels also allows even more K+ to escape into the ECF (in the example this corresponds to the dancer dropping all her marbles on the floor when she falls):

The inside of the nerve cell is now extremely low in K+ (indicated by the orange color in the figure above) and the ECF around the cell has a very high K+ concentration. This excess K+ spreads through the ECF to the neighboring nerve cells (like the marbles rolling out on the floor to where the neighboring dancers are standing), which triggers opening of NMDA channels in the neighboring cells, which – repeating the process which happened in the first nerve cell – allows K+ to flow out of and Na+ to flow into these neighboring cells, depolarizing them:

This chain reaction spreads from nerve cell to nerve cell, opening NMDA channels, strongly depolarizing each cell in turn and overturning the normal concentrations of Na+ and K+. It is this late part of the CSD chain reaction which in some migraine patients is experienced as a migraine “aura”, because of the way that CSD disrupts the cells’ normal function.

The headache begins

At the end of the CSD chain reaction, all the nerve cells in that part of the brain may be affected (i.e. all the dancers may have fallen):
Since there are no pain receptors on the inside of the brain’s membrane, the migraine patient doesn’t normally feel pain at this point of the migraine attack. Unfortunately, the CSD process releases a lot of molecules that are able to trigger pain outside the brain’s membrane, including K+ as well as other substances. As the attack develops, these molecules spread across the brain membrane in greater and greater numbers, reaching the pain receptors in the brain’s arteries (see the figure below). Using our dancer example, the comparison could be that the music at this point starts to be drowned out by the moaning of the fallen dancers, so that the dancers that are still standing can no longer follow the music to do the correct moves!

As illustrated in the figure above, the pain receptors react to the arrival of the pain-producing molecules by sending out pain signals. These signals travel through the nerves down to the brain stem and back up to the part of the brain that is responsible for registering pain – at which point the headache phase of the migraine attack starts. At some of the “relay stations” on this path of the pain signal, other nerve cells are activated that cause the non-pain migraine symptoms, such as nausea and light/sound sensitivity.

Sensitization

Unfortunately, this is not always the end of the process. When the pain receptors are activated they start to release inflammation molecules, among them the substance known as CGRP:

CGRP causes inflammation, which further worsens and prolongs the attack. At this point, so-called sensitization may occur, meaning that the pain receptors and the brain become even more sensitive, which makes the pain and other migraine symptoms even worse.

Healing begins

As the attack develops, the brain is at the same time working on normalizing itself by removing pain-causing molecules and trying to re-balance the Na+/K+-concentrations. In our dancer example, we can picture the dancers slowly getting to their feet and start picking up all the marbles they dropped.

This normalizing work is done most effectively while you are sleeping, which is why sleep is one of the best remedies for a migraine attack. Unfortunately, it may still take a long time for the attack’s chain reactions to burn themselves out, and for the body to recover.

Summing up

Migraine attacks are triggered when brain cells lose their normal inside/outside balance of potassium and sodium, for example by being starved of oxygen. This leads to a chain reaction in the brain called Cortical Spreading Depression (CSD) that causes even more brain cells to destabilize and release pain-triggering molecules.

When enough brain cells have been hit by the CSD wave, so many of the pain-triggering molecules build up that they spread out through the brain’s membranes, after a while reaching the pain receptors on the outside surface of the brain. This causes the migraine headache.

Because the breakdown in the brain’s normal balance is so drastic and so many pain-triggers are released, it can takes days to restore the brain to its normal state.

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