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Migraines: Scientific searches for the cause

Feb 28, 2012

My guess is that some of you suffer migraines or know someone who does. A person close to me gets them. Luckily her new medication has been effective in eliminating the pain - so long as she takes a pill soon after an attack begins.

My laboratory studies brain dopamine and learning.  I'm not an expert on migraines.  But if I suffered migraines, I'd want to have an idea in my mind, a working model, of what's going on.  So I've done a quick review of some of the recent scientific literature on migraines.  As in any field of science, there are controversies over particular issues. However, it seems to me that the factors below are supported by the weight of the evidence. Below is the kind of model that I'd have in mind if I were suffering a migraine.  It’s not business, it’s personal.

1. Migraines are associated with the dilation of blood vessels.

In the illustration below you can see smooth muscle cells wrapping around an artery. Relaxation of these muscle cells causes the arteries to open wider, allowing more blood to flow.  Migraines are associated with abnormally large opening of arteries, that is, vasodilation. Most drugs that are vasodilators can trigger migraines.  Many medications that relieve migraine cause vasoconstriction or reduce vasodilation.

The cells lining the inner wall of the artery are the 'endothelium' (shown
in purple).  The smooth muscle wrapped around the endothelium can contract
to cause vasoconstriction, or relax to cause vasodilation. Vasodilation opens
the passage for more blood  to flow through.  Normally this occurs in arteries
serving areas of the body and the brain that need more oxygen and glucose 
at the moment. Migraines are associated with arterial dilation. But which 
arteries are dilated during migraine?
The evidence that vasodilation is a factor in migraines seems to me to be strong. In cases where vasodilation is induced on one side of the brain (unilateral), the migraine is only on that side of the brain. In cases where the vasodilation is on both sides of the brain, the migraine is on both sides.

The fact that caffeine can reduce migraine pain is probably because it's a vasoconstrictor. The fact that migraines can be aggravated some hours after drinking coffee is likely due to the rebound vasodilation that can occur after the caffeine has worn off.

2. Do migraines involve dilation of blood vessels in general, or is it the dilation of particular blood vessels that causes migraines? If they are particular blood vessels, are they blood vessels in the brain?

The answer to the first question is that migraines are believed to result from dilation of arteries (not veins). While arteries inside the brain (intracranial arteries) may be involved, the real culprits appear to be arteries just outside the brain (extracranial arteries).

Located between the brain and the skull are layers of tissue called meninges (yellowish and blue layers in the illustration below). The layers of tissue that comprise the meninges aren't part of the brain. They cushion the brain. They also contain arteries. Think of meninges as bubble wrap beneath the skull, protecting the fragile brain. The  arteries coursing through the meninges ('meningeal arteries') carry blood that nourishes the brain with oxygen and glucose. Meningeal arteries can become abnormally dilated, and this dilation is believed to be a trigger for migraine attacks.

Between the brain and the bone of the skull are layers of tissue
called the meninges (in blue and yellow here).
 As can be seen, arteries course trough the meninges.

3. Why does dilation of artieries within the meninges cause pain?
The meninges contain blood vessels, but they also contain pain-sensitive, or "nociceptive", neurons (not shown in the figure).  These nociceptive neurons monitor conditions surrounding the brain, including pressure within the skull.  When there is an abnormality, these neurons fire and transmit signals down to the brainstem (at the base of the brain), initiating neural activity that the brain interprets as pain.  One unresolved question is whether the abnormal dilation of the meningeal arteries is what causes the nearby nociceptive neurons to become activated and signal that there is abnormal pressure around the brain worthy of throbbing pain.

4. Does dilation of arteries within meninges really cause abnormally high activity in the nearby pain neurons?
This part of the story is still unclear. While the neurons in meninges have been observed to dilate reliably during migraine, they don’t dilate enormously – their circumference increases by about 12%. Should that be enough to trigger high activity in the nearby pain-sensitive neurons? Blood vessels can normally constrict and dilate over a pretty wide range during the day. It’s possible that migraine sufferers also have abnormally sensitive pain-transmitting neurons, permitting this small amount of artery dilation to set the pain signal in motion. Or, it may be that during vasodilation, migraine sufferers release particular factors from the blood into the meninges which cause stimulation of the pain-transmitting neurons.

5. What causes the vasodilation in the first place?
One highly-likely suspect is a molecule called CGRP. Here’s some evidence that incriminates CGRP as a culprit. CGRP is normally present in the brain, but during migraines, CGRP concentrations in the blood are much higher. Drugs that block receptors for CGRP (so that CGRP no longer has sites to bind and produce its effects) reduce migraine pain. Receptors for CGRP are in fact found on the smooth muscle cells surrounding arteries (including arteries in the meninges). It has been shown that CGRP causes dilation of the meningeal arteries.

Here’s the big one: migraine sufferers and non-migraine sufferers volunteered to receive CGRP itself (not the drug that blocks it, but the actual CGRP).  CGRP triggered migraines in both groups of volunteers. The migraine-sufferers say that the pain they suffer after taking CGRP is indistinguishable from their normal migraine pain. Finally, after taking CGRP and suffering a migraine, the migraine goes away when the volunteers take the drug that blocks CGRP receptors (CGRP is still in the system but no longer has receptors to bind to).

We know that CGRP causes dilation of the meningeal arteries, and causes migraine. But couldn’t the CGRP be causing headaches by dilating arteries within the brain itself? (Remember the meninges are just outside the brain, between the brain and the skull). No. In the subjects that volunteered to take CGRP and suffered migraines, the CGRP didn’t enter the brain, and so it couldn’t have caused the migraines by vasodilation of arteries in the brain. But it did reach the meninges.

It’s not certain, but there’s sure strong evidence that CGRP is a guilty party here, and that the meninges are the scene of the crime. One of the effective antimigraine medications, Sumatriptan, causes constriction of blood vessels in the meninges, but not within the brain. The thought is that CGRP is causing vasodilation in the meningeal arteries, and Sumatriptan reverses that effect by causing those same arteries to constrict.

Does CGRP cause migraine pain because it causes dilation of the meningeal arteries? Maybe.  But it also has other effects aside from vasodilation, and it acts in many regions of the brain, so this part of the story remains to be solved.  CGRP also probably isn’t the only culprit in triggering migraine attacks. For instance, another naturally-released neurochemical, nitric oxide, has been similarly implicated. 

The information above gives a general landscape of issues relevant to understanding migraines. There are many other questions to ask.  What are the newest avenues of research for coming up with more effective anti-migraine medication?  Will anti-CGRP drugs be effective?  How about non-drug approaches?  Have they been shown to be effective?

6/20/2012 follow-up post, "Five questions and answers about migraines"
8/9/2014 follow-up post on two anti-CGRP drugs on the horizon.