Headaches are one of the most common and debilitating conditions humans experience.  Fortunately, they leave few obvious lasting physical consequences, but this means that, for those who don’t experience them, it can be difficult to sympathize with the person who is experiencing the agony of a migraine, or the desperation of a cluster headache.  For people who are fortunate enough to have never had a headache, here are a few statistics and facts to help put what could be called “the headache of headache” in perspective:

  1. The World Health Organization considers a person suffering with a migraine to be as debilitated as a quadriplegic!
  2. Estimates reported by Lars Stovner and colleagues in a 2022 paper published in The Journal of Headache and Pain, suggest that 15.8% of the world’s population experiences headaches every day.  That’s 1.2 Billion headaches per day!
  3. Headaches are the 4th leading reason why people go to the emergency department, and data from a decade ago showed that costs for those visits averaged between $1,000 and $2,000!
  4. Migraine diagnoses, when they show up in patients who have other diagnoses ranging from depression and anxiety to asthma and GI problems, raises the healthcare costs of managing these people by as much as 300%!

If those statistics don’t sway you, then how about the fact that cluster headache is also called “the suicide headache” because their suicide rate is 20 times higher than the general population.  Other headache types include the Primary Thunderclap Headache (the name alone tells you it’s probably not a walk in the park), Primary Stabbing Headache that sufferers describe as “taking an icepick to the skull multiple times per day” (sometimes as often as 100 times or more), and Hypnic headaches that wake you up in the middle of the night and last for hours at least 10 times per month (Freddy Kruger couldn’t make people more scared to go to sleep).

If the headache problem is going to be solved, then we have to understand them, which means more than just categorizing them, it means asking what causes them?  If you are one of the 70 percent of Americans who have had tension headaches, that question has probably crossed your mind.  If you’re one of the 12 percent who get migraines, and as many as 3 in 10 women get them during their periods, then the chances are pretty good that during the hours you’ve spent in pain in a cold dark room, you’ve pondered that question. And if you’ve writhed in pain with a cluster headache, then you’ve most certainly prayed to God for an answer to the question.

At its most basic, a headache has two types of treatments.  The first is quickly and effectively stopping a headache that has started (or the signs of one coming have started).  The second is preventing them from even occurring.  The latter is obviously a more comprehensive solution, but both treatment strategies have a place in the world.  We’re going to tackle both today, starting with the acute treatment of a headache attack.

In the late 1800s, the prevailing medical dogma concerning the brain was still largely dominated by the writings of the Roman physician, Galen, from the first century AD.  In the intervening millennia, many extracts and potions had been concocted to treat migraines.  One such brew contained an extract from a poisonous fungus, called ergot, that infected rye plants.  Ergot derivatives have been used since the 16th century to prevent hemorrhage during childbirth because they caused strong vasoconstriction, which is shrinking of blood vessels.  Keen observers had made the link that the throbbing of migraines was synchronized with heartbeat, so it made sense how a vasoconstrictor might stop the pain.  In a sense, the understanding of headaches inched forward by retrospectively connecting the mechanism of the treatments to a possible mechanism generating headaches. A few decades later, Arthur Stoll isolates the specific ergotamine, and a company called Sandoz (now part of Pfizer) marketed the product as Gynergen.

You may be thinking, that’s really simple!  Is that all there is to medical science?!?  The answer is, of course, no.  However, simple observations like these lead to deeper understandings of how things like the blood brain barrier work.  The blood brain barrier, or the BBB, is formed by several different cells working in concert, including astrocytes (think neuron helper cells) that wrap parts of themselves around the blood vessels in the brain to prevent anything leaking in or out that they don’t agree should.  How these astrocytes are controlled plays an important role in migraine, but it is only part of the story.

Fast forward half a century, and the understanding of how the brain functions had expanded.  Biochemists and medical researchers had discovered a lot more about how neurons communicate with one another, i.e., using chemicals called neurotransmitters.  While the theory of migraine being related to blood vessel dilation and constriction was relatively widely held, among the new breed of neuroscientists, there was a sense that imbalances in neurotransmitters might also play a role (and maybe even influence the BBB).  Within a few decades, a whole class of receptors for a neurotransmitter called serotonin were identified, and chemicals were developed to turn them on (agonists), turn them off (antagonists), and even block other chemicals from doing either (interfering antagonists).  A group of these chemicals that turn on the serotonin 1B and 1D variants of these receptors, called triptans, have turned out to be more effective and somewhat safer than ergotamine.

Interestingly, these triptans, which were introduced in the early 1990s, have side effects that suggest they are acting on blood vessels and the blood itself, including a rare side effect of overdose in which the blood of the patient actually turns green. (Worry not, Mr. Spock, it reverts back to red in a few weeks!).  Chest pain, vasospasm of the coronary arteries, heart attacks, and tachycardia have also all been listed as possible complications of triptans.

More recently, the focus of migraine research has shifted to a 37-amino acid molecule called calcitonin gene-related peptide. 

CGRP, as it is abbreviated, is generated and released by motor neurons in the lower brainstem and the very top of the spinal cord, in areas associated with pain processing.  CGRP is an extremely potent vasodilator, and one of the key triggers for its release is pro-inflammatory signaling.  Consistent with the concept of vasoconstriction being good to treat headaches and vasodilation being associated with headaches, pharmaceuticals were developed to prevent the CGRP vasodilation effect.  The small molecules associated with CGRP blockage have been approved for the treatment of migraine.

CGRP modulation is the first molecule that can be used to treat headaches acutely as well as preventatively.  In order to have the preventative benefits for long periods (weeks or months) the CGRP modulators were developed using antibodies versus small molecules.  These “biologics” were designed either to bind to CGRP (sequestering the molecule itself) or to block the receptors that CGRP binds to (blocking CGRP from exerting its effect).  These antibodies were developed and launched with much fanfare, but the data are only moderately better than drugs that were developed decades ago and are used to reduce the frequency of migraine occurrence.  To better understand these older drugs, we need to do a brief dive into epilepsy.

Seizures are typically caused by a sudden hyperexcitation phenomenon within a small region the brain that spreads across larger regions.  When it effects motor control regions, the typical convulsions of a grand mal seizure are evident.  When the seizure affects only non-motor areas, petit mal or absence seizures occur, in which consciousness is lost.  Medications, including drugs like topiramate, were developed that inhibited the excitation of the brain.  Their effects on migraine as well as were quickly appreciated.  As was the case previously, the observation that a medication having a known (or widely appreciated) mechanism was having benefits for migraine suggested that the cause of migraine was related.

The truth is, the idea that migraine was related to hyperexcitation in the brain was not an entirely new concept.  Migraineurs had long reported interesting phenomena occurring prior to the onset of the pain phase of the headache, including a visual disturbance known as “aura.”  Aura is a form of hyperexcitation phenomenon called cortical spreading depression, or CSD, that disrupts normal neuronal function (along with the local support cells as well).  CSDs have been found to occurs in both migraine and ischemic stroke patients, and it has recently been suggested that one of the purposes of CSDs is to prepare the brain for periods of hypoxia (lack of normal oxygen levels).  Studies with drugs like topiramate showed a reduction in the susceptibility of brain tissue to CSDs, which matched the clinical experiences of reduced migraine attacks.

So, let’s take inventory of what we’ve covered.  Acute migraine attacks appear to be related to either vasodilation or neurotransmitters imbalances around serotonin, and thus can be treated by drugs that cause vasoconstriction (ergotamines or CGRP modulators), or serotonin receptor agonists (triptans).  Prevention of migraines seems like it can be accomplished either by preventing the vasodilation from CGRP over longer periods (like chronically being on acute therapy) or by using anti-seizure drugs that impact the excitability of the neurons to prevent the CSDs.  Readers might wonder if the recent theory that CSDs relate to hypoxia and that involves blood flow and oxygenation could link the two prevention strategies, and that may be the case.

On this blog, I’ve talked a lot about the autonomic nervous system (ANS) , the innate immune system (IIS), and the relationship between them.  I’ve also mentioned vagus nerve stimulation (VNS) as a great way to modulate both the ANS and the IIS, and it tuns out that headache treatment and prevention is a great convergence of all that I’ve mentioned in this blog today.

Let’s start with the effects of VNS on the blood brain barrier.  In a published study in Brain Stimulation, back in 2018, Yi Yang and colleagues showed that VNS has the ability to prevent the leakiness of the BBB that occurs after an ischemic stroke.  More specifically, the VNS (which was achieved non-invasively) reduced the damage that the brain sustained as a result of the ischemia-induced vasodilation and leakiness.

To discuss the effects of VNS on serotonin, it is helpful to understand what it is, what it is used for, and what the effects of inflammatory cytokines (like TNF-  ) are on this neurotransmitter.  It turns out that serotonin is made in a two-step process that starts with tryptophan.  It is made for multiple reasons, the first of which is to serve as the precursor for making melatonin which is critically important for cell function (it’s not just to help you sleep).  Use of serotonin as a neurotransmitter is actually the second use (third use if you consider its importance in intestinal motility).

It turns out that an alternative process that starts with tryptophan makes an entirely separate series of products that are toxic (they are made in order to be antimicrobial to defend the cell against a bacterial invasion).  When inflammation is present, cells opt for the latter process, and serotonin production drops.  This is bad for the cell because the more important use for serotonin is making melatonin, not being used as a neurotransmitter.  In fact, this use of serotonin for melatonin production is so important that inflammation actually causes neurons and their support cells (called astrocytes) to increase their production of serotonin reuptake mechanisms.  Antidepressant drugs called SSRIs, or selective serotonin reuptake inhibitors, are designed to slow serotonin reuptake mechanisms in order to keep what little serotonin is available as a neurotransmitter around longer outside the cell.  If they are fighting inflammatory signaling, they are fighting an uphill battle, and more importantly, they may actually be damaging cells as they are trying to pull that serotonin back in to reuse it so they can still make some melatonin.

All of this is background to the fact that VNS has been shown to block inflammation through the cholinergic anti-inflammatory pathway.  This is a mechanism that I cover in many other blogs, so I won’t go into detail about it here other than to say that VNS stimulates the release of acetylcholine throughout the brain from the nucleus basalis of Maynert (NBM).  This acetylcholine binds to receptors called  7nAChRs (alpha 7 nicotinic acetylcholine receptors) that are on many immune cells and on the membranes of all mitochondria.  Activating these receptors blocks the inflammatory processes along no fewer than 5 separate cellular and mitochondrial pathways.  The practical upshot of all of this is that VNS works in large part because it enhances the brain’s ability to produce serotonin.

The group that demonstrated that first demonstrated the importance of serotonin in the mechanisms that VNS has in treatment of migraine is led by Cenk Ayata at Harvard MGH.  They have published a number of papers, going back to 2016.  In their first report, in the journal called Pain, they showed how VNS could reduce the susceptibility of the brain to hyperexcitation phenomena like CSDs.  In the series of papers that Cenk and team have published, they have shown that CSDs induced by physical, chemical, electrical, and even optogenetic triggers can be inhibited by brief doses of VNS (again, delivered non-invasively).  Cenk’s team went even further and showed that the inflammatory cytokine (like TNF- ) expression was increased by CSDs, and VNS inhibited that expression even when CSDs were forced through the brain with much higher voltages than would have been required without VNS.  The final piece of Cenk’s team’s efforts were to show that the release of CGRP dropped dramatically as a result of VNS.

If VNS can prevent leakiness of the BBB, enhance the production of serotonin, reduce inflammation, and block the release of CGRP, then VNS has checked a lot of the boxes that drugs check in terms of how it works to treat headaches.  I hope this blog explains a little more why this safe and effective therapy has been FDA cleared for both acute migraine treatment as well as prevention.  Beyond that, I hope it makes you think about where else it could be used.  For example, you might think about depression, and you’d be right that (implanted) VNS has been approved for that as well.  Keep reading this blog, and you’ll hear about dozens more applications for VNS.

 *A peptide is a small sequence of amino acids, i.e., less than 50 amino acids, that really are like small proteins.

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