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.
Ouch!
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:
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.
Calcium Channel
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.
Spreading Depression
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.
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.
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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–
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GS, et al. Neurology
2005;
65:
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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:
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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;
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4):
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ML, Goldman
SA, Nedergaard M. Ann Neurol
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Other good reviews:
Recent advances in the diagnosis and management of migraine. Goadsby
PJ.
BMJ 2006;
332:
25–
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