Feb 11 2020

Hyperexcitability in Migraines

Migraines are a complex neurological phenomenon that offer a window into some general principles of brain function. A new study confirms previous findings and adds more details to the observation that the visual cortex in those who suffer from migraines is hyperexcitable – it has increased activity in response to stimuli. But this is also clearly only part of the picture.

Let’s start with some background on what migraines are. They are a clinical syndrome, which means they are defined entirely by how people present, not by any diagnostic tests. There is no imaging study, blood test, biopsy, or anything else helpful or used to make the diagnosis. Here are the specific criteria doctors use to make the diagnosis:

(1) At least five attacks fulfilling criteria (2)–(4)
(2) Headache attacks lasting 4–72 h (untreated or unsuccessfully treated)
(3) Headache has at least two of the following four characteristics:
(a) unilateral location
(b) pulsating quality
(c) moderate or severe pain intensity
(d) aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
(4) During headache at least one of the following:
(a) nausea and/or vomiting
(b) photophobia and phonophobia
(5) Not better accounted for by another ICHD-3 diagnosis.

This does not mean that migraines are not “real”, it just means we don’t understand their causes well enough to design an objective test that is accurate enough to be clinically useful. Many medical diagnoses begin their life as a recognized pattern of signs and symptoms, until we figure out what the cause is. Also, a clinical syndrome like migraine may have many causes, and that is certainly the case here. About 60% of migraine sufferers have a family history, and there is at least one known strictly genetic form of migraine (familial hemiplegic migraine). Likely migraine is a threshold phenomenon, meaning that may possible factors can make it more likely for someone to have migraines, and if a person has enough of any combination of these factors, they get migraines. This makes the disorder challenging to study and to treat.

While we don’t fully understand what causes migraines, we have accumulated quite a bit of knowledge about what is happening during a migraine. We know that parts of the brain become hyperexcitable, meaning they overreact to stimuli. This fits with the symptoms, which dominantly involve being very sensitive to various stimuli – smells, sounds, light, and even touch. We also know that the trigeminal system is heavily involved. The trigeminal nerve is one of the cranial nerves (it comes off the brain rather than going through the spinal cord), and provides sensation to the head. There is also something called the trigeminovascular reflex, which involves trigeminal nerve activity and causes blood vessels in the brain to dilate (open up). Further, researchers have found that after about 40 minutes or so into a migraine attack patient’s develop something called “central sensitization” – the central trigeminal pathways become overstimulated by peripheral input. Once this happens the migraine can no longer be stopped, although the severity of the symptoms can be reduced.

Unsurprisingly the drugs we use as preventive treatment for migraines, to prevent and reduce attacks, all inhibit brain function. There are GABA agonists (GABA is an inhibitory neurotransmitter), glutamate inhibitors (glutamate is an excitatory neurotransmitter), sodium channel blockers, beta blockers, and calcium channel blockers. Many of these drugs are also used to treat seizures, and many researchers liken a migraine attack physiologically to a seizure. There is also an inflammatory component to a migraine attack, which is why anti-inflammatories (like aspirin) are helpful. Serotonin is involved, which lead to the triptan class of drugs. Migraines often activate nausea, and so anti-nausea medication can be critical. And the latest class of drugs, the CGRP inhibitors, block receptors in the trigeminal nerve system to reduce migraine activity.

But there are other clues to migraines as well. Migraines are associated in some patients with low magnesium, low vitamin B2, and low coenzyme Q10 (a cofactor needed for mitochondria to make energy). Supplementing these nutrients helps some migraine patients a little. Many patients also have triggers, such as lack of sleep, dehydration, bright lights, strong odors, alcohol, possibly caffeine or caffeine withdrawal, and some foods. So avoiding known triggers is important. An in about 60% of women the fluctuation in their monthly hormone cycle can be a trigger. Again, all this complexity leads to the notion that migraines are complex multifactorial threshold phenomena.

But definitely one common theme in much of what is known about migraines is hyperexcitability, which brings us back to the current study. They looked at migraineurs vs non-migraineur controls, and also compared migraineurs to non-migraineurs who have visual sensitivity. They exposed them to striped visual patterns known to cause discomfort, and asked subjects to report their discomfort, while also looking at brain activity with EEGs. They found that migraineurs had a greater activation to the striped pattern, and also a decreased late inhibitory response – so their brains overreacted to the stimuli, and then did not quiet themselves down as much or as quickly. The non-migraineurs with visual sensitivity had the same pattern, but to a lesser degree. This adds some details to what we already suspected.

I want to back up a bit and also put all this into a broader perspective. First, our brains largely work by exquisitely balancing activation and inhibition. The electrical signals of the brain are carefully controlled, and there is baseline inhibition to constantly keep these signals from getting out of control. Seizures are one manifestation of this inhibitory control breaking down, and migraines are another. Evolution has fine-tuned this balance for optimal functioning, but it shows how so many things in biology are a trade-off. Also, almost everything in biology occurs along a spectrum of variation. In migraineurs part of this balance is shifted a bit, from a large number of possible sources, and the result is migraines.

But his variation is also a source for possible evolutionary change. Different individual organisms strike a different balance of various trade-offs, and some of those variations may work better in certain niches. The pre-Darwinian way to look at life is that there is a perfect type of each creature. This thinking has invaded medical thinking, where we assume there is one optimal healthy type. However, we know understand that a great deal of variation is both normal and healthy. One manifestation of this different way of thinking is the notion of “neurotypical” and “neurodiversity”. Not every recognized syndrome is necessarily a disorder. It could just be a different balance of trade-offs. Although I would not take this notion to far, to deny that any neurological disorders even exist. Sometimes the variation simply results in a significant loss of function. There is no law of biology or neurology that says that the ledger of positive and negative effects always has to balance.

Also, the two notions are not mutually exclusive. A person can have neurological function that in some aspects represents neurodiversity – not objectively better or worse, just different. But at the same time may include one or more traits that can reasonably be considered a disorder, because they lack an ability that causes them demonstrable harm. Migraines, for example, are clearly a disorder. No one benefits from having migraines or wants to have them. But at the same time, it is not inconceivable that some pathways to migraine may include changes to neurological function that have benefits elsewhere. (This is just a hypothetical.) If that were true, it would not stop migraines from being a disorder.

In any case, our understanding of this complex condition grinds slowly forward. Despite how much we still don’t understand, it is clear that migraines are largely a disorder of hyperexcitability in the nervous system.

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