More On Migraines

The Trigeminovascular Theory:

Most of what is written about why we have headaches is based on a theory of head pain that was generated in the 1960’s called the “trigeminovascular theory”. This theory, of how and why headache or migraine occurs, is based on where the pain nerves are located in the head. That’s not such a bad place to start but it turns out it doesn’t have anything to do with spontaneous head pain, better known as “headache”.

Surprisingly the pinkish grey “stuff” of the brain does not “feel” pain when touched. The only parts of the brain that feel pain when touched are the blood vessels and the linings that cover the brain, called “meninges”. Because the patient only feels pain when those parts are touched the doctors trying to understand headache incorrectly concluded that spontaneous head pain was also “generated” there.

It is important to realize that the pain system in our body exists to tell us about the mechanical limitations of our body. The brain is vulnerably soft, and although the skull is well designed to protect from penetrating injury, the hard skull is quite unforgiving when the brain smashes against it. Both the brain and the spinal cord rely on the boney skull and spinal column to prevent injury, but as the brain is floating in fluid it can still be injured by banging against the inside of the skull. Thus, we need the head pain system to tell us not to bang our heads.

The pain endings on the surface of the brain and on the blood vessels, that are tethered into the neck, send pain messages when the brain is shaken or smacked against the skull. The muscles and skin of our body do not have a protective layer like the skull so they need pain fibers inside them to tell us not to hurt them. That explains why there are no pain fibers in the brain itself but it does not explain why we have headaches.

The trigeminovascular theory is named for the trigeminal nerve, which is one of the nerves that transmits head pain. It is responsible for the front 2/3rd’s of the head and the face, transmitting a pain message to the brain stem trigeminal nucleus caudalis.

The trigeminal nerve supplies the face and front of scalp.

When we get hit on the head we do actually perceive the pain through the trigeminal nerves and upper cervical roots. They transmit a message to the brain where we think “ouch”. But normal people, who have not been hit on the head, do not have headaches generated in this way.

Where is spontaneous head pain generated?

If the trigeminovascular theory isn’t the answer how do headaches occur?Over the last 15 years there have been amazing advances in the genetics of migraine as well as some very novel ideas about a brainstem “migraine generator” that provide a very sensible explanation of migraine and headache in general. This new view is quite different than the “trigeminovascular” theory, and has not yet been widely embraced by the headache establishment who write the books on migraine.

To understand the newer genetic literature and our own experiences with our headaches we must direct our attention to this brainstem “headache generator”, a concept proposed by Dr. KMA Welch and Dr. Peter Goadsby (1,2) based on PET scan literature showing that headache sufferers have a stripe of abnormally increased signal in the posterior brain stem, suggesting that this segment of the brainstem is “hyper metabolic”, or too “turned on”. (3, 4)

The posterior brain stem “lights up”on PET scans of migraine patients.

The anatomy of the head pain system:

The head pain system is in two parts. The front two thirds of the head and the face send pain signals to the brain through the trigeminal nerves to the trigeminal caudal nucleus, a long, thin stripe of cells in the posterior brain stem. The back one third of the head and the neck send pain signals through cervical roots 1–4 into a similar nucleus in the posterior cervical cord. These two nuclei are supposed to sit quietly until a pain message is received, then transmit that message to the brain areas where the pain is perceived. Unfortunately the headache sufferer inherits a gene that makes these brain stem nuclei “hyper excitable”, i.e. they turn on without a blow to the head.

Genetic channel mutations causing migraine:

Calcium Channel

The most important advance in the understanding of migraine has come with the genetic mutations that cause migraine. The first reported gene mutation linked to migraine was in a protein called a Calcium Channel.(5) Over the last 15 years there have been several other calcium channel gene mutations and sodium channel gene mutations linked to migraine.(5,6,7) The difficulty with linking these genetic discoveries to the traditional explanation of migraine has been that most of the migraine literature is still looking at the nerve endings on the blood vessels and it’s hard to put together the channel mutations with the older theories on migraine physiology. However, if one is looking at migraine as an inherited disorder of brainstem “hyper excitability” the channel mutations make sense.

What are Channels and why are they important?

All of the cells in our body turn on and off using “electricity”. The electricity that we use is not like the wires in the walls, but more like a car battery. The car battery is a box containing liquid that has positive and negative charges floating on either side of a partition. The charges want to be together so wires connecting one side to the other let the negative charges flow over to join the positive. We use positive and negative charges in our body too. The positive and negative charges that we use, floating in the liquid that makes up our body, are calcium; Ca++, sodium Na+, potassium; K+, chloride Cl-. Each of our cells is “off” when it has many negative charges inside, and “on” when it has many positive charges inside. The trick is, how to get the “+”s and “-“s to go where we want, when we want. The way we control the charges entering is by using “channels”. Channels are proteins that are tubular, shaped like a hotdog bun. The channels are incorporated into the membrane of the cell. When they open they create a hole in the membrane. If it’s a calcium channel it only lets calcium in, a potassium channel only lets potassium in.

How do channels help turn our cells on and off?

A cell receives a neurotransmitter message to turn on, that receptor is linked to a calcium channel. The channel opens, calcium enters the cell. As more positive charges enter the cell the cell is “on”, it sends its message and then it must turn “off” again. It turns off by pumping the calcium out with specialized calcium pumps. The first mutation linked to migraine created a calcium channel that gets stuck in the “open” position. Thus, as the cell is pumping out the calcium, trying to turn “off”, the calcium is leaking back in through the channel that is stuck open and the cell is unable to turn completely “off”. (8) The migraine sufferer inherits a gene that makes the brainstem cells stay a little more “on” all of the time.

Why do doctors use epilepsy and “blood pressure” medications to prevent headaches?

With the channel mutation discoveries we have finally been provided an explanation for the success of both the seizure medications and the “blood pressure” medications in preventing migraine. The calcium channel blockers such as verapamil, the “beta blockers” such as propranolol and atenolol (which are also calcium channel active), and the seizure medications, such as valproic acid and topiramate,(sodium channel stabilizers) are all medicines that act on channels.

Are headaches and “migraine” different?

The next important concept in understanding headache is that almost all the headaches that we experience are “migraine” in mechanism. We’ve learned this from our patients as they have used the triptan medications (sumatriptan. naratriptan, eletriptan, zolmatriptan, etc.) for their migraines. The triptans act on serotonin 1B and 1D receptors, which are feedback inhibitors of the release of serotonin. The triptans are specific for the chemistry of migraine, they are not general pain relievers. We originally told our patients “save this medicine for your migraine headaches” but our patients were smarter than we were and found that they were more successful when they took the medications earlier. When they used the triptans successfully for their milder headaches we learned that their milder headaches (that we had told them were “stress” or “muscle contraction” or “sinus” headaches) were also “migraine” in mechanism.

The majority of patients with “migraine” have milder headaches as well as what they call “migraines”. It is my belief that most of the headaches we all have are “migraine” in mechanism, and that there is a continuum of headache from milder headaches to very severe headaches. Patients with the migraine gene not only turn on their headache center without a blow to the head but they are also unable to turn off the headache center and are more likely to get a headache that won’t go away after minor head injury.

Why do migraine suffers go to bed when they get a headache?

Any of you who have had a migraine know it is not just head pain. There is an accompanying feeling of “my brain is not right” that makes it difficult or impossible to function, so the migraine sufferer goes to bed. Most people with milder migraine can “break” the headache if they can get to sleep and sleep long enough. The migraine generator that I explained above does not do “thinking” it just does pain, so how does this global malfunction of the brain occur?

The first observations on the electrical events of “migraine” were performed, in the late 1960’s, by putting patients in a magnetic field and observing the electrical changes in the whole brain during a migraine.

In order to know when the headache would start, and then record what happened in the brain, they had to use patients who experienced a visual “aura” or warning, preceding the headache. This allowed them to put the patient into the machine as the headache was starting. What they observed was a wave of electrical activity that started at the back of the brain (the visual cortex), during the visual aura, and spread slowly forward, from back to front, taking about 15 minutes to cross the brain.


At the same time Dr. Leao, in experiments on rabbit brain slices, showed that electrical stimulation of the brain produced a spreading wave of electrical depression, moving across the brain in three dimensions at about the same rate, 3mm/minute. This phenomenon was then called: spreading depression of Leao. The next section explains this spreading wave of activity.

Spreading Depression

Why the astrocyte is important in understanding migraine:

The next big breakthrough in understanding migraine came with a better understanding of the brain cell that makes up the background, pinkish-grey substance of the brain, called the astrocyte. Astrocytes are called that because they look like a star, they have many little “finger-like” processes called dendrites, spreading out in all directions.

Astrocytes and Neurons

Because of these spreading fingers we thought that the astrocytes were a sort of “skeletal” system of the brain. Recently, with microscopes that can see the brain cells in three dimensions, we can see that the dendrites are not a supporting network, they are much more important than that. Each dendrite ends on the surface of neurons. Each small astrocyte is assigned 20–40 neurons and their finger-like processes end on the surface of those neurons to talk to them.

 

 

 

The Astrocyte Neurovascular Unit

The astrocyte also has a process that wraps around the surface of a nearby blood vessel. This collection of 20–40 neurons, their astrocyte, and its blood vessel connection has been called an “astrocyte neuro-vascular unit”. (10) The astrocyte talks to its neurons, and can have “inhibitory” or “excitatory” input on the neurons it contacts, i.e. it can make the neuron more “on” or more “off”. The astrocyte also has a very special adaptation that other brain cells do not have, namely the ability to open pores between adjoining astrocytes, called “gap junctions”. When a gap junction opens between two brother or sister astrocytes, the ionic environment of the two astrocytes is directly shared.

With these discoveries concerning the anatomy and function of the astrocyte, it was time to repeat the original Dr. Leao experiments, and it was shown that the wave measured moving slowly through the brain, is actually a calcium wave spreading through the astrocyte population. (11)

Spreading depression is a calcium wave spreading through the astrocytes of the brain.

The misbehaving calcium channels that cause migraine are probably in the cell membrane of the astrocyte, not the neuron. Thus the migraine usually starts in the brainstem but can quickly spread through the astrocyte population into the whole brain causing our inability to think, and our need to go to bed. The astrocytes are inhibiting or turning “off” the function of large areas of neurons in our brain. All of our neurons are thinking “I just don’t feel right”.

The astrocyte neuro-vascular unit also explains another observation made during experiments carried out in the late 1960’s. Experiments performed to show changes in blood flow of the brain during a migraine showed a spreading wave of decreased blood flow that was seen to parallel the change in neuronal excitability. The misbehaving astrocytes are affecting the diameter of the blood vessel that they envelope. But, when our migraine sufferers tell us that they “can’t think right” during their migraine it is not the change in blood flow, but a change in the neurons’ functioning that is affecting their thinking. Their neurons are being inhibited, turned down or “off” by the astrocytes.

If I’ve had this migraine gene all my life why are my headaches so bad now? And why do I have a headache every day?

The level of excitability of the brain stem “migraine generator” (as well as the rest of the brain), is affected by many other chemicals that affect the brain. The major factors that worsen migraine, in my view, are sleep disorders, gonadotropin releasing hormone (GnRH), and monosodium glutamate.

Why do we humans have so many genes that cause headaches?

It’s interesting to note that the trigeminal caudal nucleus and its analogous nucleus of the upper cervical roots that transmit pain signals continue down the entire spinal cord performing the same function for the body below the neck, yet it’s not common for that portion of the spinal cord to turn on spontaneously. If the genes that cause this hyper excitability were manifested in the pain stripe itself the entire stripe should turn on spontaneously. For instance why don’t I have the other half of my Neurology practice filled with patients in whom pain occurs spontaneously in the body below the neck just like headache? There certainly are people who have pain below the neck but humans do not think it’s “normal” for that lower 2/3 of their body to just start hurting the way they do the head. My explanation is that the trigeminal caudal nucleus and the cervical pain nucleus that turn on spontaneously do so because they’re next to another set of nuclei, that do not continue into the spinal cord, called the periaquiductal grey, where the timing mechanism for sleep resides. It is my belief that the entire posterior brainstem and upper spinal cord becomes hyper excitable in migraine sufferers because the genes that cause migraine are actually intended to make the sleep mechanism work properly.

There are several other nuclei in the brainstem that turn on spontaneously in migraine but have nothing to do with head pain. The chemotrigger zone, that is just behind the trigeminal caudal nucleus, is really there in order to protect us from eating dangerous chemicals, it causes nausea and vomiting when we eat something dangerous. There’s a nucleus just anterior to the trigeminal caudal nucleus, the superior salvatory nucleus, that causes nasal congestion. It also tends to turn on spontaneously, thus the migraine sufferer who thinks they have “sinus headache” really does have a stuffy nose but it’s really a part of this spontaneous “turning on” of several parts of the posterior brain stem.

Migraine and sleep are intertwined:

It is my belief that the multiple genes for migraine that have been carried on for generations in humans are not there to cause headache. They’re probably conserved within the population because they improve sleep. Sleep is always designed to turn on and off spontaneously. That is absolutely by design, and it trumps all other functions of human life. Therefore any gene that makes sleep happen more perfectly, but “oops” causes an occasional headache in the process will probably be passed on because sleeping well is one of the things that improves survival and successful reproduction. It is actually the most important thing we do every day. Unfortunately, you and I are living in a time when much or most of the population of the developed world does not sleep well, this means that the genes that were meant to improve things leave us with pain syndromes that are more noticeable, frequent and severe than they were really “intended” to be.

Sleep and migraine have always been intertwined. Most of the teenagers I see with daily headache have trouble falling asleep. Most of the women in menopause who now have daily headache can’t stay asleep. Most migraine sufferers have already realized that if they have one or two nights of bad sleep they’re more likely to get a headache the following day. It turns out that the women who wake with a headache in the middle of the night usually do so at a time when they stop breathing in REM sleep, and sleep disorders turn out to be the major cause of daily headache in my practice. (Please see the section on Sleep).

Gonadotropin releasing hormone and migraine:

My explanation for the menstrual fluctuation of migraine relates not to estrogen and progesterone, but to the boss hormone that comes from the brain to tell the ovary when to make estrogen. This hormone is called Gonadotropin Releasing Hormone (GnRH). We know that migraines usually begin at puberty. They are worse in the females in the family. They get worse during menopause and usually go away after menopause. We know from our experience with replacement hormones that estrogen and progesterone don’t take the headaches away. But Lupron, which acts as a GnRH blocker, is very effective for severe, menstrual related migraine. (13)

GnRH is released from the brain during puberty in both boys and girls. In boys, through leutinizing hormone (LH) it causes testosterone to be formed by the testes. Then testosterone feeds back to the brain to inhibit GnRH. In girls, also through LH, GNRH causes the ovaries to make estrogen, which also feeds back to the brain to inhibit GnRH. The boys, at about 18, begin to make the same amount of testosterone every day, so their GnRH does not fluctuate like the girls’, which spikes twice a month; at ovulation and menstruation. Around menopause, when the ovaries run low on eggs, the estrogen levels fall and GnRH goes up to try to tell the ovaries to make more estrogen. GnRH is a hormone, meaning it is made in one part of the body to tell another part what to do, but it is also a “neurotransmitter” which means it has receptors in the brainstem, perhaps adding to the brainstem hyper excitability, leading to increase in migraine, and interrupted sleep.

What should I do about my headaches?

If the over the counter pain relievers don’t completely take the headache away and your headaches are once a week or less, your doctor will usually start with one of the “triptans”. The triptans work on serotonin receptors in the brainstem. When you get the right dose early enough, they turn all the receptors to “off” and the head pain, nausea, light and sound sensitivity, and the “I can’t think right” feeling all go completely away together. All of the medications in this category: sumatriptan, naratriptan, eletriptan etc, have scary side effects of chest pressure, body stiffness, and a feeling of throat closure that will freak you out if you aren’t warned about them. You are not having a heart attack or an allergic reaction, but if you feel bad you’re not likely to want to take that medication as early as you need to. Most people can find one of the triptans that takes the headache completely away without significant side effects. It’s well worth finding that medication and using it as early as possible. In my view there is no one triptan that is “the best”. Find one that has no side effects and use it early. Use whatever dose is successful at the beginning. Once the headache is severe and has lasted more than one day, the medications, even strong narcotic medications, are not usually very successful, and the only thing that really “breaks” the headache is sleep.

If the triptans fail it’s often because you’re not taking them at the beginning. Usually because you have frequent or daily headaches that the doctors have told you are some other type of headache. You wait to take the triptan until “it’s a migraine” and by then it’s too late. In my view all the headaches we all have are migraine in mechanism, some are baby migraine, some are big migraine but they all happen in the same way. Many of the daily headache sufferers find that the triptans don’t work for them. Once your sleep has improved or you find the right daily headache preventative the triptans will work for you again, so once the headaches are once a week or less try them again.

When should I take a daily, preventative medication?

Migraine sufferers with daily, or almost daily, milder headache, (or daily neck pain) usually will see a Neurologist and be started on a “preventative medicine”. This is a medication that changes the excitability of the brain stem and will hopefully prevent the headaches; verapamil (180-240mg), propranolol (120-180mg), or atenolol (50-100mg). Topiramate (50−100 mg hs, higher doses in some patients cause the headaches to return), zonisimide (200-500mg start <100mg), valproic acid (250-1000mg). Success is one mild headache a week that goes away immediately with a triptan medication. If the first medicine fails, your doctor will usually stop it and try another. If the medication ‘wears off” after it worked it usually means you have a sleep disorder, you’re sleeping but not getting into the deeper “work” phases of sleep.

Rebound headaches:

I disagree with the authors who think that most daily headache sufferers have caused their own headaches by taking medications daily. I see no reason to blame the patient for their own disease. Most of my patients stop their daily medicine and still have a headache daily or almost daily. I believe it’s the doctor’s job to treat the headaches by finding a medication that prevents the headache.

What about MSG?

Watch for monosodium glutamate (MSG). Glutamine is the main excitatory neurotransmitter in the brain. It is used to excite the taste buds but in the patient with migraine it also turns on their hyper excitable brainstem. Anything flavored with “smoky” “hickory” “Cajun” etc, is likely to have added MSG. Most canned soups and bouillon cubes have MSG, as do many diet foods.

How does sleep affect my headaches?

Sleep disorders are much more common than we realized. Many of my young, female patients with severe daily headache have turned out to have abnormal sleep on a sleep study. Usually it is the main reason for their lack of success with the preventative medicines. Sleep apnea is not a disorder of obese, older men. It is a disorder that can come at any age, and it is only one of the sleep disorders that are seen in daily headache sufferers. (See sleep disorders section for more detailed discussion of sleep disorders.)

Vitamin D deficiency, with or without accompanying B12 deficiency appears to be the most common cause of these sleep disorders in my patients. It may be the most common cause of sleep apnea and non restful sleep in the US and the world. (Please see Sleep section and Vitamin D for a more in depth discussion of these topics.)

Channel disorders and vertigo and epilepsy.

There are several other disorders of brain cell hyper excitability that are also channel disorders. Familial Episodic Ataxia (FEA) is an inherited disorder that causes abrupt onset of severe vertigo and staggering. It is a mutation of the same calcium channel that can cause migraine, but the mutation affects another part of the protein (5) FEA and migraine have several similarities. Both occur spontaneously, in normal people, without any clear triggering event. The patient’s brain malfunctions for hours to days, then is able to correct the malfunction and return to normal. The MRI of the brain is normal, i.e., there is no permanent injury. The anatomy is normal, but the physiology is not. Some families have mutations that can manifest sometimes as vertigo, sometimes as migraine. The most common presentation is migraine before menopause, vertigo after menopause. Most family members have been told they have “benign positional vertigo” which is probably a disorder of the gyroscope apparatus in the external ear and is a different problem. Most patients with this benign positional vertigo will have one or two attacks and they will resolve and not recur. Patients with repeated attacks should be treated like migraine: after the normal MRI of the head, fix the sleep disorder (check the vitamin D and B12 levels) or use a calcium or sodium channel blocker.

Similar calcium channel mutations occur spontaneously in mice. (9) The mice could never tell the investigators whether they had a headache, but they did have staggering episodes and seizures. Not surprisingly most of the inherited epilepsy disorders in humans have also been found to be channel disorders, usually chloride or sodium channel mutations, more rarely calcium channel mutations. Obviously epilepsy is also a disorder of hyper excitable brain cells, which is treated with seizure medications that are generally sodium or calcium channel stabilizers. In my experience seizure disorders can also get worse when the sleep is worse. ( See sleep section and vitamin D section.)

References:

1) Imaging the brain of m igraine sufferers. Flippen C, Welch KMA. Current Opin Neurol 1997;10:226–230.

2) The periaqueductal grey matter modulates trigeminovascular input: A role in migraine? Knight YE, Goadsby PJ. Neuroscience 2001;106(4):793–800.

3) Brain stem activation in spontaneous human migraine attacks. Weiller C, May A Limmroth V, et al. Nature Med 1995 Jul;1(7):658–660.

4) A positron emission tomographic study in spontaneous migraine. Afridi SK, Giffin NJ, Kaube H, Fiston KJ, Ward NS, Frackowiak RS, Goadsby PJ. Arch Neurol 2005; 62(8): 1270–5.

5) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca++ channel gene CACNL1A4. Cell 1996;87:543–552.

6) Mutations in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine type 3. van den Maagdenberg A, Vanmolkot KRJ, Welch KMA, et al. Cephalalgia 2005;25:1189–1205.

7) Familial basilar migraine associated with a new mutation in the ATP1A2 gene. Ambrosini A, D’Onofrio M, Grieco GS, et al. Neurology 2005;65:1826–1828

8) Three new familial hemiplegic migraine mutants affect P/Q type Ca++ channel kinetics. Kraus RL, Sinnegger MJ, Koschak A, et al. Jour Biol Chem 2000;275:9239–9243.

9) Migraine, ataxia and epilepsy: a challenging spectrum of genetically determined calcium channelopathies. Terwindt GM, Ophoff RA, Joost Haan, Sandkuijl LA, Frants RR, Ferrari MD. Eur Jour Hum Gen 1998; 6(4): 297–307

10) Glial cells under physiologic and pathologic conditions. Kurosinski P, Gotz J. Arch Neurol 2002;59:1524–1528.

11) Meningeal cells can communicate with astrocytes by calcium signaling. Grafstein B, Liu S, Cotrina ML, Goldman SA, Nedergaard M. Ann Neurol 2000;47:18–25.

12) Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Bowyer SM, Aurora SK, Moran JE, Tepley N, Welch KMA. Ann Neurol 2001;50:582–587.

13) Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and “add-back” therapy. Murry SA, Muse KN. Fertility and Sterility 1997;67(2)390–393.

14) Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Hall GC, Brown MM, Mo J, MacRae KD. Neurology 2004;62(4):563–8.

Other good reviews:

Recent advances in the diagnosis and management of migraine. Goadsby PJ. BMJ 2006;332:25–28.

Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Welch KMA, Nagesh V, Aurora SK, Gelman N. Headache 2001;41:629–637.