Understand migraine pathophysiology and allodynia

by admin | Jun 29, 2021 | Migraine

Pathophysiology: What Happens in Your Brain During a Migraine

First, what is pathophysiology? Pathophysiology refers to the changes that occur in the body’s systems, resulting in abnormal function, as a result of an illness, a disease, or an abnormal condition such as migraine. Scientists are constantly learning new information about what happens in your brain at the start of a migraine and during a headache.

Most of us have probably heard about changes in blood vessels associated with migraine headaches. It might seem that blood vessels constrict during a migraine—that would seem logical, wouldn’t it? And so they do, some of them—but the entire situation is not as simple as originally thought.

Initially, it was thought that the blood vessels on the surface of your brain dilate, and with each heartbeat, the blood surging through throws the dilated blood vessel wall up against your skull, resulting in that throbbing pounding pain you are so familiar with. And migraines were termed “vascular headaches”. Recently, that phenomenon has been thrown into doubt, although various experts disagree. Certainly, though, it is not as simple as just blood vessel changes.

Migraine mostly happens within your brain. Several things happen at the beginning of a migraine attack, and we are not yet sure exactly what happens first, or whether one leads to another.

CHANGES IN YOUR BRAIN—CORTICAL SPREADING DEPRESSION

We know that there are waves of electrical changes that go across the brain, starting at the back and moving slowly towards the front. First there is a wave of excitation, followed by what is called spreading cortical depression. This has been known since the 1940s, when it was discovered in rabbits by a Brazilian neurologist named Leão, although it wasn’t immediately associated with migraine at that time. Interestingly, though, there was another neurologist at about that time (named Lashley) who tracked the spread of his own visual auras, and found that they moved at about 2-3 mm/minute. This is about the same speed as cortical spreading depression.

We have since made an association between cortical spreading depression and migraine aura. And, in fact, we have been able to demonstrate very slow changes moving across the brain during migraine aura on both blood oxygen level dependent (BOLD) MRI studies and magnetoencephalography. These changes move at a rate consistent with the speed of cortical spreading depression. Although most of these studies have been done in migraine with aura, there is one PET study done in a single patient who has migraine without aura showing slowing of blood flow in a similar pattern, suggesting that cortical spreading depression may occur in migraine without aura as well. Obviously, it is much harder to study in migraine without aura, as it is more difficult to determine when the beginning of the attack is in order to test it.

Recent studies of blood vessels in the brain during cortical spreading depression show that there is constriction of the blood vessels as the waves of spreading depression pass over the brain. There is also a drop in oxygenation of that segment of the brain as a consequence. Yes, you’re right—that’s not a good thing. Fortunately, it does not last long until the wave passes along.

Brainstem Activation

There is also evidence of brainstem activation at the beginning of a migraine. Areas of the brainstem show up as brightly active on PET scans in the beginning of a migraine attack. These studies have indicated that brainstem activation occurs in both migraine with and without aura.

If you like, take a look at diagrams of the brainstem and other brain areas.

So is this what causes the pain? Well, yes and no. We know that these areas of the brainstem—the raphé nucleus, and the locus cœruleus—are important in the maintenance of mood and the processing of pain. Other brainstem areas, the substantia nigra and the red nucleus, were previously thought to be more important for normal movement, and we have found recently that they have a role in headache pain as well.

But that’s not the whole migraine pain story. We still haven’t gotten to the inside of your head, really. Everything we have talked about so far has happened at the base of the brain or on its surface. And we haven’t really covered that in detail yet.

EXCITABLE NEURONS

Based on research, the best understanding we now have is that migraine arises from abnormally excitable neurons in the brain and trigeminal nerve. What causes the neurons to be abnormally excitable? Various things can do this, including low magnesium, abnormal calcium channels on the surface of the neuron, mitochondrial abnormalities, or other inherited brain chemical abnormalities. The newest things in the migraine story are the glia—the support cells in the brain—which also appear to have a role in transmitting pain, perhaps moreso in chronic headache, although their story is still being determined.

The trigeminal nerves start in the brainstem in the trigeminal nucleus caudalis, and travel to your face, teeth, eyes, sinuses, and forehead. They also go to the blood vessels on the surface of the brain. So, now we have excitable neurons, and (maybe) dilating blood vessels. These make up what we call the trigeminovascular system, or trigeminovascular theory of migraine.

Now, why “maybe”? A recent study has shown that this may not actually be the case, and that “vascular” headaches may not even be vascular at all! A study in Brain conducted by Schoonman et al induced experimental migraine in both migraine sufferers and control subjects with intravenous nitroglycerine. The controls developed dilation of the meningeal vessels (the ones on the surface of the brain); the migraineurs did not.

This result casts some doubt on the trigeminovascular theory, particularly if these results are replicated by other similar studies.

While there is still some controversy over the “vascular” part of migraine, the situation was recently summed up by Dr. Andrew Charles, UCLA migraine researcher. Dr. Charles indicated that while it is clear that vascular changes occur in migraine, it does not mean migraine is triggered by vascular processes, and that the dilation of blood vessels is neither necessary nor sufficient for causing migraine pain.

According to existing trigeminovascular theory, once the messages come from the activated cells in the trigeminal nucleus in the brainstem, and travel to the trigeminal nerves that go to the dural blood vessels on the brain’s surface, it causes dilation. However, the trigeminal activation also causes the release of brain chemicals called neuropeptides (substance P, CGRP or calcitonin gene-related peptide, neurokinin A, 5HT or serotonin, and noradrenalin.)

ALLODYNIA

The release of these chemicals causes inflammation, and what is called peripheral sensitization. This is most likely what results in the throbbing pain most people experience. As the attack progresses, something can occur called central sensitization. When this occurs, it causes what is known as cutaneous allodynia. This means that things that are usually just a normal touch are now felt as painful. Many headache patients with allodynia cannot continue to wear earrings, necklaces or neckties, or their glasses. Some find that they cannot lie down on the side of the head pain, or report that “even their hair hurts.” Up to 80% of migraine sufferers are affected by some degree of cutaneous allodynia, and it generally occurs in the late stages of a migraine attack when the pain is severe. This is why it is important to treat early when the pain is mild or moderate.

When central sensitization becomes advanced, it can involve areas beyond the head, and simple touch on the arms or shoulder can be perceived as painful. For example, I am aware of one migraine sufferer who is bothered by the seams in her clothing during such an attack. At this stage of the migraine, migraine-specific medication is less likely to be helpful, and studies have shown that while they will reduce the pain and relieve the throbbing, they cannot abort the attack, and allodynic pain remains as well as other migraine symptoms.

In late-stage migraine, other medications may be necessary in order to end the attack. We do not yet have migraine-specific medications designed for the late stage of the migraine attack, although research into migraine pathophysiology is ongoing. As we learn more, it should lead to better developments in the treatment of migraine.

References:

1. Leão, APP. Spreading depression of activity in the cerebral cortex. J. Neurophysiol. 1944; 7:359-90.

2. Leão, APP, Morison, RS. Propagation of spreading cortical depression. Neurophysiol.1945; 8:33-45.

3. Lashley K. Patterns of cerebral integration indicated by scotomas of migraine. Arch. Neurol. Psychiatry 1941; 46: 331-339.

4. Charles A, Brennan K. Cortical Spreading Depression—New Insights and Persistent Questions. Cephalalgia. 2009;29(10):1115 -1124.

5. Malick A, Burstein R. Peripheral and central sensitization during migraine. Funct. Neurol. 2000;15 Suppl 3:28-35.

6. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Annals of Neurology. 1981; 9,344-352.

7. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123 ( Pt 8):1703-1709.

8. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann. Neurol. 2000;47(5):614-624.

9. Charles, A. Intercellular calcium waves in glia. Glia. 1998; 24:39-49.

10. Schoonman GG, van der Grond J, Kortmann C, et al. Migraine headache is not associated with cerebral or meningeal vasodilatation—a 3T magnetic resonance angiography study. Brain. 2008;131(8):2192 -2200.

11. Hadjikhani N,   Sanchez del Rio M,   Wu  O, Schwartz  D, Bakker D, Fischl B, Kwong KK, Cutrer, FM, Rosen BR, Tootell RBH, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. PNAS. 2011;  ,9:4687-4692.

by Christina Peterson, M.D.

Updated June 29, 2021