Understand migraine pathophysiology and allodynia

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

Chronic Migraine

What is Chronic Migraine?

What is chronic migraine? The International Headache Society’s International Classification of Headache Disorders, 3rd edition, has defined chronic migraine as 15 or more headache days a month that has lasted for three months or more, and that on eight or more days a month has the features of a migraine headache. 

What Causes Chronic Migraine?

Why some people get chronic migraine and some people don’t is not always entirely clear. There is some evidence that chronic migraine may be on a spectrum of headache frequency between episodic migraine (less than 15 days a month) and transformed migraine, which is migraine occurring very frequently, similar to chronic daily headache, but with clear migraine features to the headaches. Research into why headaches become chronic has shown the following risk factors for headache chronicization. This research did not focus on chronic migraine specifically, but looked at chronic daily headache.

Risk factors for chronic migrane are:

  • History of head or neck trauma
  • Female
  • Habitual snoring
  • Sleep apnea and other sleep disorders
  • Obesity
  • High caffeine intake
  • Smoking
  • Coexisting pain disorders
  • Overuse of pain medications
  • Major life changes (moving, getting married, etc.) were associated with the onset of chronic headache
1. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. Chronic migraine is an earlier stage of transformed migraine in adults. Neurology. 2005; 65(10): 1556-1561.
http://cep.sagepub.com/content/26/6/742.abstract [Accessed July 17, 2010].
3. Bigal M, Sheftell F, Rapoport A, Lipton R, Tepper S. Chronic Daily Headache in A Tertiary Care Population: Correlation Between the International Headache Society Diagnostic Criteria and Proposed Revisions of Criteria for Chronic Daily Headache. Cephalalgia. 2002:432 -438. Available at: http://cep.sagepub.com/content/22/6/432.abstract [Accessed July 17, 2010].
4. Scher AI, Stewart WF, Lipton RB. Caffeine as a risk factor for chronic daily headache: A population-based study. Neurology. 2004;63(11):2022-2027. Available at: http://www.neurology.org/cgi/content/abstract/63/11/2022 [Accessed July 17, 2010].
5. Scher A, Lipton R, Stewart W. Habitual snoring as a risk factor for chronic daily headache. Neurology. 2003;60(8):1366-1368. Available at: http://www.neurology.org/cgi/content/abstract/60/8/1366 [Accessed July 17, 2010].
6. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology. 2004;62(5):788-790. Available at: http://www.neurology.org/cgi/content/abstract/62/5/788 [Accessed July 17, 2010].
 
by Christina Peterson, M.D.
updated July 17, 2013

Delaying Migraine Treatment

Do you ever delay treating your migraines?

It’s a fairly common thing to do. You think to yourself, this one won’t be all that bad. I’ll: eat lunch, have a cup of coffee, lie down for half an hour, drink a glass of water or diet soda—whatever thing you think might work that’s never really worked before. But you have hope. You have hope that this time you can beat this thing, this space alien invading your brain.

Why do we do this? I’ve done it myself. It never works. And yet, there is that hope that we can be in control, and not the migraine. I have a colleague who believes that this mistaken belief is part of the migraine itself, that there is cognitive confusion altering good decision-making because of the early stages of the migraine process. If we were thinking clearly, we’d just take our medication. I’m not so sure it’s that clear-cut, although that may be the case for some people. There are also issues of weighing out the risk-to-benefit ratios of whether the adverse effects of medication are worth the severity of this headache. There is also the issue of whether you have enough medication to last all month, and if this headache is “medication-worthy” in light of that.

“Masking the Pain”

I have also had patients tell me they did not want to treat their migraines because they did not want to mask the pain. Now, frankly, this does not make sense. About the only situation I can think of in which this might make sense would be a disaster setting in which one had sustained a head injury and needed to be monitored without benefit of a CT, MRI, or an ICU. Morphine would be withheld so that mental status could be monitored until you could be evaluated in a hospital setting.

However, there is no medical rationale for not taking migraine medication. It will not mask any damage being done to the brain unless your headache is due to something other than a migraine, and something serious at that, in which case you need to be in the emergency department anyway. So, unless you have the red flags that indicate a serious underlying problem, go ahead and take your migraine medication. You do not get points for suffering!

There is also evidence to suggest that early treatment of migraine not only ends an attack sooner, but prevents the pain from becoming fully established.

Red Flags in Headache

Red flags that indicate something serious other than a migraine might be occurring are:

  • Significant fever with a headache (more than 99.5)
  • Stiff-as-a-board kind of stiff neck
  • Severe all-over muscle pains
  • Headache that comes on like a thunderclap
  • Worst headache of life
  • Significant change in headache (not just it used to be on the right, and now it’s on the left – that’s actually okay)
  • Any neurologic symptoms that are not part of your usual aura

If you have any of these, see your doctor or go to the emergency department for evaluation. It might not be anything serious, but better safe than sorry. And otherwise, treat your headaches. Unless you enjoy pain?

How to Know If Your Headache Is a Migraine?

The question of whether a headache is a migraine may seem obvious if you are an experienced migraine sufferer, but not everyone knows this stuff inside out. There is still confusion out there, and it’s always worth reviewing. Some people, for example, think that a migraine is defined by how bad the headache is. While a migraine is defined by moderate or severe pain, among other things, it does require other features to be a migraine headache and is not just a severe headache. And there are other types of severe headache that are not migraines.

Eight Ways to Tell if a Headache is a Migraine

  • If your headache is one-sided, it is more likely to be a migraine.
  • Migraine pain is generally moderate or severe.
  • Most migraine pain is pounding or a throbbing sensation in head.
  • Migraine pain is often made worse by routine physical activity.
  • If you have nausea or vomiting with your headache, it is more likely to be a migraine.
  • If bright light or noises bother you during a headache or make your pain worse, it is likely that your headache is a migraine.
  • If your headache is preceded by an aura—a warning phase with flashing lights, colored shapes, lines, blind spots or any other kind of neurologic symptom like numbness, your headache is a migraine.
  • If you have headache at the back of the neck, it can still be a migraine, as long as you have other migraine symptoms. Neck pain associated with migraine is actually more common than nausea in migraine attacks.

What is harder for people is how to tell headache types apart when you happen to suffer from more than one kind of headache. It’s important to know which one is a migraine so you can take the right medication. If you only get so many migraine medications a month, you don’t want to “waste” one on a headache that isn’t a migraine. Plus, taking these too often can lead to more headaches.

It’s not always easy to tell various headaches apart, as they may start out the same.  Remember, too, that not every migraine attack is going to be exactly the same. But keeping a headache diary can help you begin to sort your own headaches out, and this can help you and your physician figure out what is going on.

Migraine Art Video

Please view this excellent Migraine Art Video, which was put together by James at Headache and Migraine News and Relieve-Migraine-Headache.com. I was struck by the statistic that over a billion people alive today will have a migraine attack in their lifetime. I am also impressed—as I have always been by exhibits of migraine art—by the creativity of migraineurs.

Excellent work, James.

Migraine Quiz

Migraine Quiz

If you think you may be experiencing migraines, it will help a lot to understand precisely what a migraine is. You know it’s an intense headache. But what else is involved?  Find out more about migraine as well as what’s going on inside your brain during a migraine, also known as pathophysiology.

Excerpted from The Woman’s Migraine Survival Guide

However, all answers are equally true for men or women.

Answer ” true” or “false” to the following questions:

1. My headaches are severe and pounding.

True

 

False

 

2. I often feel nauseous during a headache attack.

True

 

False

 

3. The headaches come before or during my period.

True

 

False

 

4. My mother or my sister (or daughter or father) has the same kind of headaches.

True

 

False

 

5. I have missed work or important events because of my headaches,

True

 

False

 

6. I can’t stand any light or noise when I have a bad headache.

True

 

False

 

7. Moving around too much or bending over can make the pain worse.

True

 

False

 

8. The pain is often on one side of my head.

True

 

False

 

9. Tylenol or aspirin doesn’t help much (or not at all).

True

 

False

 

10. My headache can last from about five hours to several days.

True

 

False

 

If you answered “true” to more than three of these questions, you may indeed be suffering from migraines. If you answered “true” to six or more, then you probably do have migraines. Have your doctor make the final analysis.

 

If you think you may be experiencing migraines, it will help a lot to understand precisely what a migraine is.
You know it’s an intense headache. But what else is involved? Find out more about migraine as well as what’s going on inside your brain during a migraine, also known as pathophysiology.