April 30, 2019
Written by: Sarah Reitz
While a majority of people experience headaches at some point in their life, many are fortunate enough to never suffer through a migraine. Roughly 12% of the world’s population suffers from migraines each year, with many experiencing their first migraine during puberty1. A smaller subset of people (still 146 million people!) experience chronic migraines, defined as 15 or more migraines a month2. As anyone who has ever had a migraine will tell you, these attacks are debilitating and oftentimes prevent them from working, socializing, and going about their normal lives. Even with over 800 million people experiencing migraines each year, there are currently no treatments available that are universally effective in preventing or stopping migraines. In order to develop successful treatments, it is critical to thoroughly understand the underlying neuroscience behind migraine attacks. While we still don’t fully understand what goes on in the brain both before and during a migraine, neuroscience research has uncovered some of the key contributors, which has already led to the development of new migraine medications.
What exactly is a migraine?
Though migraines are classified as a type of headache, the pain is much more intense than other types, and many symptoms other than pain also occur. Additionally, unlike other types of headache, migraines can be broken down into distinct phases that occur hours or even days before and after the migraine itself. During the premonition phase, which can occur up to 3 days before the headache, migraine sufferers may experience prodomes, or symptoms that signal a migraine is near. These include feelings of fatigue, depression, irritability, increased hunger or thirst, increased yawning, or even euphoria. Only some people experience the next phase of a migraine: the aura phase. During this phase, which occurs immediately before the headache, people may experience visual hallucinations, numbness, or changes in speech. The actual headache phase of the migraine typically lasts between a few hours to 2-3 days and includes throbbing pain in the head, nausea or vomiting, anxiety, fatigue, and sensitivity to light, sound, smell, or touch. The final phase, the resolution phase, during which the migraine pain and symptoms eventually fade, can last anywhere from a few hours to a few days.
The fact that such a diverse range of symptoms occurs during a migraine makes the neurological basis of these headaches so hard to understand. However, in searching for the root cause of a migraine, neuroscientists know that it must affect many diverse areas of the brain in order to produce the wide range of symptoms experienced during an attack. But before we can understand what happens in the migraine brain, we first have to understand how the brain senses and processes pain.
How does the brain sense pain?
We perceive pain through specialized nerve fibers that express special sensors called nociceptors. These nociceptor-expressing neurons are found in our skin, muscles, joints, and even some organs, and send signals to the brain, which then tells us that we are in pain. Ok great, so a headache is probably just nociceptors in the brain becoming activated, right? Actually, the brain doesn’t contain any nociceptors, so it cannot feel pain itself!
While neurons in the brain don’t contain any nociceptors, the neurons that innervate the protective layers of membranes between the brain and the skull – known as the meninges – do (Figure 1)3. Scientists now think that the headache portion of a migraine is caused by activation of these nociceptor-expressing neurons in the meninges. But what activates these neurons in the first place?
The hyperexcitable migraine brain
One prevalent theory that might explain why nociceptor-expressing neurons in the meninges become activated more frequently in people with migraines is that the migraine brain is generally hyperexcitable. This means that neurons are more likely to be activated by a certain stimulus than in a non-migraine brain. We see evidence to support this theory in brain imaging studies as well as genetic studies of families who experience severe migraines. Brain imaging studies show that many areas across the brain are more active in people who experience migraines compared to people who do not4. Additionally, genetic studies show that families who experience severe migraines have mutations in genes that regulate glutamate transmission at the synapse (the communication point between two neurons)4. Glutamate is the brain’s primary excitatory neurotransmitter, so mutations that increase the amount of glutamate available at the synapse lead to increased excitability and firing of neurons throughout the brain, including the neurons that express nociceptors in the meninges.
Hyperexcitability caused by enhanced glutamate transmission is not the only way that nociceptors in the meninges can become overly activated. Research shows that the brains of people who experience migraines are also more susceptible to a phenomenon called cortical spreading depression (CSD)1-4. While its name may make you think CSD only causes inhibition across the cortex, the first phase of CSD is actually a wave of activation that spreads across the cortex, which is then followed by inhibition. While we still don’t understand exactly what causes CSD to occur in the first place, we do know that for over an hour after CSD, the brain becomes less able to adapt to sensory stimuli and responses to these stimuli are enhanced1. This may explain some of the non-pain symptoms of a migraine, such as the increased sensitivity to light, sound, touch, and even smell reported by migraine sufferers.
The increased neuronal activity resulting from CSD and enhanced glutamate transmission also results in the release of a molecule called calcitonin gene-related peptide (CGRP)1. CGRP is thought to trigger an inflammatory response in the brain. This inflammatory response causes blood vessels in the meninges to narrow, and also releases many different proinflammatory molecules into the environment surrounding the meningeal nociceptors. This double whammy of the narrowing blood vessels and altered cellular environment sensitizes the nociceptors, causing them to fire and tell the brain that something painful is happening in the head. Interestingly, a recent study showed that application of CGRP in the meninges of rodents produced migraine-like behaviors (light sensitivity, grimacing, and enhanced pain response) only in the females5! This may explain why women are 3 times more likely than men to experience a migraine.
Ultimately, the hyperexcitability of neurons in the brain caused by enhanced glutamate signaling and CSD causes nociceptors in the meninges to respond to stimuli that did not trigger a response previously. In other words, things that were previously not painful – like a soft touch or the light in the room – the brain now perceives as unbearably painful.
A better understanding of migraine
Given how many people are affected by migraines each year, and the devastating psychological, social, and economic impacts they have on migraine sufferers, it is crucial that we fully understand the migraine brain in order to develop therapies that reliably stop these headaches before they begin. The research mentioned earlier has already led to the development of an exciting new migraine treatment: an antibody against CGRP. An injection of this antibody effectively neutralizes CGRP, reducing the inflammatory response and subsequent activation of meningeal nociceptors. Clinical trials show that this medication reduces the number of migraine days per year by an entire month and a half on average!
While research has discovered a few likely contributors to the many symptoms of a migraine, there is still so much we don’t understand about these debilitating headaches. For instance, what actually causes a migraine to start? Migraines are triggered by a huge variety of stimuli: everything from sleep deprivation to stress to certain foods or drinks, among others. Further complicating the study of migraines is the fact that these triggers all vary between people, and don’t always trigger a migraine in the same person. Why does a trigger lead to a migraine at some times, but not others? As research continues, we will hopefully be able to answer these questions and more.
Cover Image by VSRao via Pixabay, https://pixabay.com/illustrations/brain-inflammation-stroke-medical-3168269/
Figure 1 Image by Mysid via Wikimedia Commons, CC BY-SA 3.0. https://en.wikipedia.org/wiki/Meninges#/media/File:Meninges-en.svg
- Brennan KC & Pietrobon D (2018) A systems neuroscience approach to migraine. Neuron Perspective 97:1004-1021. https://doi.org/10.1016/j.neuron.2018.01.029
- Burstein R, Noseda R, Borsook D. (2015) Migraine: multiple processes, complex pathophysiology. J Neurosci 35(17):6619-6629 DOI: https://doi.org/10.1523/JNEUROSCI.0373-15.2015
- Charles A & Brennan KC (2010) The neurobiology of migraine. Handn Clin Neurol 97:99-108. doi: 10.1016/S0072-9752(10)97007-3
- Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR (2009) Neurobiology of migraine. Neuroscience 161(2)327-341. doi: 10.1016/j.neuroscience.2009.03.019
- Avona A et al. (2019) Dural calcitonin gene-related peptide produces female-specific responses in rodent migraine models. J Neurosci DOI: https://doi.org/10.1523/JNEUROSCI.0364-19.2019