What is a Migraine?
[posting to my journal for posterity xposted: migraines tag: what is migraine]
Chapter 1: What Is A Migraine
What Is A Migraine?
More than just a headache, migraine is a chronic illness that affects over 30 million Americans annually; roughly 10% of the population. There have been great advancements in migraine management in the last 20 years, and an ever increasing awareness about migraines in general. But there is still an alarming amount of misinformation, myth, and misunderstanding out there, even among medical professionals.
Migraine sufferers, or migraineurs, often find themselves at the mercy of people who don’t understand (or worse, don’t believe in) their condition or its seriousness. It is the goal of this article, therefore, to provide an in-depth view of the disease of migraine, perhaps expanding your knowledge of what you the migraineur can do to get the best possible management of your symptoms, and what the friends, family, and caretakers of the migraineur can do to support that management.
Not caused by blood flow changes
In this article we’re going to look at what happens when a migraine occurs. We’re going to focus our observations based on how the migraine affects the neurological and chemical systems of the body. Neurologically, we’re going to look at the brain and nervous system. Chemically we’re going to look at neurotransmitters (the chemicals that carry messages through the brain), hormones, and the chemicals that make up the nerves themselves. Together, the changes in these systems combine to make up the event that is experienced as a migraine.
New studies [1] show that neurological changes are responsible for the generation of migraines and that these changes are also behind the mechanisms of migraine, including vasodilatation [a]. This is a huge breakthrough, because as far back as the 17th century it was believed that changes is blood flow were responsible for generation of migraine and the resulting neurological effects, not the other way around. This outdated theory is known as the vascular [b] theory of migraine generation. Most doctors and nurses currently practicing were taught the vascular theory of migraines.
Much of the documentation made available to the public still explains migraines using the vascular theory, and much of the documentation on the neurological basis of migraines is restricted to scientific articles and medical journals. They are not written for the general public and can be very difficult to understand without advanced education in the field. Though authors of books and articles written in the last twenty years should know about the neurological theory of migraines, the theory was widely debated until discoveries made in the last few years. We now know that neurological changes are behind all the mechanisms of migraine, from aura to vasodilatation to pain. Though there are still many discoveries to be made, we are now pointed in the right direction to make these discoveries.
To start, there are many mechanisms to migraine and not all of them are fully understood. In this article, I will give you a comprehensive view of exactly what is thought to be going on in the body of a migraineur, for indeed, it’s not just the head of a migraineur that is affected, and indeed it is not just during the headache that migraine mechanisms are active. I’ll be taking you deep into the brain to the trigeminal nerve: the nerve that processes all sensory input and connects the brain stem to the nerves of the head and face. I’ll be discussing many brain chemicals-neurochemicals-used by the brain and nervous system. We’ll look at the strange phenomenon of Cortical Spreading Depression (CSD), once though to be the key behind visual auras, and now known to be part of migraine pain as well.
The brain of a migraineur is different than that of other people. Even when not in the headache phase, there are chemical imbalances in neurotransmitters such as Substance P, dopamine, serotonin, and magnesium, to name a few. The average concentration of Substance P in migraineurs is nearly double [c] that of controls. [2] The average concentration of serotonin, which is depleted during a migraine attack, was about 25% lower [d] than controls during non-migraine phases. [3] And when given nitroglycerine, a vasodilator used by some heart patients, “a delayed migraine-like headache [resulted] in migraine patients but not in control patients.” [4]
I’ll talk about some of the symptoms that go along with the different phases of migraine, although the list I provide will be no where near complete. Just as each migraine may manifest in different ways, so is each migraineur and their experience of symptoms different. Hopefully the information I provide will give to you what it has given to me: insight into my own condition and several realizations as to, ‘Oh! That’s why that happens!’ And while it may not take the pain away, knowing that I’m not alone in my symptoms and that I’m not imagining things has been a great comfort.
Neurological: Inflammation of the Meninges
Migraine starts with a trigger-either internal or external-that starts a cascade of events leading to headache. Before the headache starts, either hours or days prior, is the prodrome. Up to 40% of migraineurs [e] experience prodrome [5]. Prodrome symptoms include mood change, loss of concentration, loss of the ability to verbalize, muddled thinking, irritability, confusion, lack of coordination, social withdrawal, loss of balance, stiff neck, cold hands and feet (peripheral vasoconstriction), loss of appetite, constipation or diarrhea, fluid retention (swelling, edema), fatigue, yawning, increased urination, nausea and vomiting, and food cravings to name a few. That may seem like an excessive list of symptoms, but remember we’re dealing with a condition that is a malfunction in brain activity-the primary control for most bodily functions. Specifically, prodrome symptoms have been associated with increased dopamine activity [6].
Moreover, “exposed to repeated sounds or images, the neuron responses in the cortex of the brain usually decline over time, but in migraineurs, such cortical activity fails to decline. In fact, in some, the electrical activity even increased [7]. The sensitivity that migraineurs experience to normal sights, sounds, smells, and other stimuli is as if their brains have turned up the volume on the world. Instead of tuning out, as most people’s brains normally do, migraineurs’ brains can’t help but stay tuned in.
Additionally, Marina de Tommaso from the University of Bari, Italy found that even between attacks, migraineurs experience pain differently. Using a laser to heat a patch of skin to produce mild pain, she had the migraineur perform distracting tasks such as word games. Distracting the mind while it experiences pain normally causes the pain threshold in a person to rise. Literally thinking about something else should take your mind off the pain and give attention to the task at hand. But in migraineurs, their pain threshold didn’t change. It wasn’t that they couldn’t take their mind off the pain-their brains couldn’t be distracted from the pain as a normal person’s would. “Possibly there is some problem with their attention to a stimulus.” [8]
Not only to migraineurs have hyperexcitable brains, but they have hypersensitive brains as well. When exposed to a magnetic pulse, migraineurs see a flash of light “at a significantly lower power pulse than do nonmigraineurs.” [9] The brains of migraineurs have a lowered threshold and sensitivity to their environment. So not only will the brain overreact to the stimulus, but it will notice the stimulus a lot sooner in the first place. It’s a double-whammy that makes the world that migraineurs deal with a lot more difficult.
The ability to regulate environmental and/or internal input is made even more problematic as a result of changes in the brain during a migraine attack. Migraine changes start with a malfunction in the brainstem. This is the part of nervous system that connects the brain to the spinal cord. Within the brainstem is an area called the pons, and it is in this area specifically that the migraine generates [10]. “The pons is an ‘attention center,’ controlling how much notice the brain pays to sensory information.” [11] The trigeminal nerve, which innervates [f] the head, scalp, face, and meninges [g], enters the brainstem at an area called the pons, where some of the neurons [h] travel up past a region called the periaqueductal gray matter (PAG), into the rest of the brain. There are neurons that return from the PAG to the pons in a negative feedback loop to damp down trigeminal signaling. The PAG is a relay station between cortical and brainstem structures and plays a major role in the modulation of pain. It provides an antinociceptive [i] effect to the primary afferent system-the nerves that conduct impulses from the periphery of the body back to the brain-as well as influencing autonomic [j] and defensive behavioral responses.
Input into the pons stimulates the trigeminal nerve. The fine branches of the trigeminal nerve supplies nerves to blood vessels around the meninges. This membrane becomes inflamed in response to neuropeptides such as Substance P and Calcitonin Gene-Related Peptide (CGRP) leaked from the blood into the meninges based on responses from the trigeminal nerve. But this inflammation isn’t widespread. Most migraineurs have a specific ‘spot’ that they can point to on their head where they feel migraine pain. Some people have more than one spot where migraine pain occurs, but typically only one is active during a single migraine attack. That spot is where the meninges is inflamed, as discovered by Dr. Marco Pappagallo of Hopkins Medical Research, using Single Photon Emission Computed Tomography (SPECT). “The images showed bright, diffuse patches-a sign of inflammation-at areas in the meninges that precisely matches where patients said they felt their headaches.” [12] The inflammation in migraine causes the sensation of throbbing and the symptoms of nausea, sensitivity to light, sound, smells and movement; the same symptoms that occur as a result of bacterial or viral meningitis, which also has inflammation as one of its mechanisms.
Leakage of neuropeptides into the meninges sensitizes nearby pain receptors and sends the message of pain back to the pons, PAG, and trigeminal nerve. This creates a sort of neurological merry-go-round as actions in the brainstem cause a reaction in the meninges, which causes a reaction in the brainstem, which causes… et cetera. And since the brains of migraineurs don’t tune out over time and can’t be distracted from the pain, the neurological merry-go-round spins out of control. The result is one of the mechanisms of migraine. Next, we’ll be looking at other migraine mechanisms, namely the chemical changes that occur with migraine.
Chemical: Neurochemical Changes and Cortical
Spreading Depression
The chemical mechanisms of migraine happen simultaneous to the neurological changes discussed before. Let’s go back to the trigger stage of migraine, and the prodrome. External changes, such as change in pressure due to weather or altitude, increase or decrease in stress (both positive and negative), exercise or exertion, too much or too little sleep, bright or flashing lights (especially fluorescent lights and computer monitors), loud or high-pitched noises, strong smells (especially perfume), or medications, internal triggers, such as hormonal changes, a drop in blood sugar levels, reactions to food, craving for nicotine, illness, allergies, or changes in metabolism all can trigger the chemical changes that lead to migraine. There are also pre-existing chemical states, such as decreased serotonin and/or magnesium levels that can make it easier for migraine to occur. Moreover, there are genetic factors such as the mutation in the calcium channel genes that have been found to be responsible for familial hemiplegic migraine.
Inflammation of the meninges, as mentioned earlier, isn’t the immediate cause of migraine pain. It’s more of a response to migraine pain. Much of what happens in migraine is actually as a result of chemical changes in the brainstem and along the nerves connected to the brainstem. Chemicals tell the brain and nerves how to function, and the brain and nerves in turn tell the meninges and the rest of the body how to function (or malfunction, as the case may be). One such set of chemical are the ions of calcium (Ca++), magnesium (Mg++), sodium (Na+), and potassium (K+) and their interactions with ion channels. Another set of chemicals is serotonin, norepinephrine, and dopamine-three powerful neurotransmitters that act as messengers throughout the brain and nervous system.
Abnormalities of the channels [k] within cells that transport the ions Ca++, Mg++, Na+, and K+ are one cause of migraines. “While voltage-gated ion channel mutants have been recognized for some time in organisms such as Drosophila [l], the first channelopathy [m] in humans was reported within the last decade [13],” notes Louis Ptacek of the Howard Hughes Medical Institute Department of Neurology and Human Genetics at the University of Utah School of Medicine.
To understand how channels malfunction, we need to understand first how they operate normally. The plasma membrane of nerve cells, like all other cells, has an unequal distribution of ions and electrical charges between the two sides of its membrane. The outside of the membrane has a positive charge, the inside has a negative charge. This charge difference is a resting potential and is measured in millivolts (mV - one thousandth (0.001) of a volt). If there is no active change in the membrane-no stimulation-it stays at its resting potential. In most cells the resting potential has a negative value. The resting potential is mostly determined by the concentrations of the ions in the fluids surrounding the cell membrane and the ion transport proteins that are in the cell membrane.
One important type of membrane ion transport proteins are ion channels. Ion channel proteins create paths through which ions can pass across cell membranes. They have selectivity for certain ions. That is, there are ion channels that only respond to a certain ion such as selectivity for Ca++ or Mg++. Different cells will have different amounts of each ion channel. Even different parts of a cell can have varying amounts of each ion channel. The amount of particular ion channels in their selective locations is what controls the resting potential of the nerve cell.
The action potential is a temporary reversal (a few milliseconds) of the electrical potential in the plasma membrane that occurs when a nerve cell is stimulated. Ion channels open to allow their selective ions to pass to the outside of the membrane. Ion pumps are then activated to restore the membrane charges to the original resting potential, moving the ions back to their original sides of the membrane.
Channelopathy is when ion channels are defective. These defects cause a disruption in normal ion activity. Examples of channelopathy in migraine include alterations in the number of ion channels, changes in the rate at which ion channels open and close, or causing ion channels to open at inappropriate times. Calcium channels, for example, allow an influx of calcium ions that help regulate neuronal impulses, such as the transmission of painful stimuli. Magnesium interacts with calcium channels, playing a role in overall nerve cell function: “Low magnesium can result in opening of calcium channels, increased intracellular calcium, glutamate release, and increased extracellular potassium, which may in turn trigger cortical spreading depression.” [14]
A second cause of migraines deals with serotonin. Dr. Joel R. Saper of the Michigan Headache and Neurological Institute in Ann Arbor, Michigan holds the theory that, “people [with migraine] are born with or acquire a disturbance in serotonin function,” involving an insufficiency or abnormality in serotonin itself, a defect in the receptors that permit nerve cells to take up and release serotonin, or an abnormality in the enzymes that destroy serotonin, breaking it down too quickly-one way of starting the chain of events that lead to migraine [15].
Abnormalities in the processing of dopamine may also have similar migraine-triggering effects. There is evidence that suggests certain people are overly sensitive to the effects of dopamine [16], which includes nerve cell excitation (read: neurological merry-go-round), and that this sensitivity could trigger events leading to migraine. Suffice to say, there are many chemical interactions that are a part the susceptibility and triggering of migraine. Now let’s look at its manifestation and process.
Prior to the headache phase and at the very beginnings of the migraine attack, there is a drop in magnesium levels, which is believed to be a destabilizing factor causing the nerves in the brain to misfire [17] (one theory behind types of visual aura). At the same time, increased dopamine activity is observed, which has been connected with such prodromal symptoms as mood change, yawning and drowsiness. Stimulation of the trigeminal nerve leads to the release of serotonin (5-HT) from the dorsal raphe nucleus, which suppresses pain initially: “Serotonin appears to block the peptides involved in over-stimulating nerves and producing inflammation.” [18] but then depletion over the course of the migraine attack results in pain [19]. (Serotonin depletion also causes depression and anxiety, two common prodromal symptoms.)
Along with norepinephrine (also known as noradrenaline), serotonin release causes a decline in nerve cell function, and along with dopamine, decreased blood flow in the brain. This decline in nerve cell function begins a process known as cortical spreading depression (CSD), which is characterized by a transient, reversible depression of electroencephalogram [n] (EEG) activity that advances across the cortical surface at a velocity of 2-5mm per minute from the back of the brain to the front. This is the start of the aura phase of the migraine attack.
Cortical spreading depression was once sited as just the mechanism behind visual auras (such as floaters or zigzag lines appearing in some migraineur’s vision up to an hour prior to the headache), but it’s now linked to migraine pain as well. CSD activates a set of enzymes that allow the blood-brain barrier, the protective membrane that separates local blood vessels and most parts of the central nervous system (CNS), to become leaky. Remember our pain spot mentioned in the first section?
The blood-brain barrier usually has more control over which substances pass from the blood to the CNS. But after CSD activates these enzymes (known as metalloproteinases), potassium, nitric oxide (NO), adenosine, and other products are allowed to pass through. These products then reach and sensitize the nerves around the blood vessels in the meninges that carry impulses back to the trigeminal nerve [20]. These impulses are enhanced due to serotonin depletion, which increases cortical excitability and sensitivity of the trigeminal pain transmission system [21]. Remember our neurological merry-go-round?
Based on responses from the trigeminal nerve, neuropeptides such as Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP) are leaked from the blood into the meninges causing further inflammation. Substance P, besides causing inflammation of blood vessels, releases serotonin (5-HT) from platelets and increases the permeability of capillaries so that other substances, such as bradykinin, are released into the meninges. Bradykinin, like SP and CGRP, is yet another irritating and inflammatory chemical that stimulates pain-conducting nerves as well.
Substance P is also a potent vasodilator, causing the release of nitric oxide (NO) from the endothelium [o]. Nitric oxide, too, causes vasodilatation. Note that in the sequence of things, vasodilatation happens as a response to pain, not as the cause of pain.
All this neurochemical activity begs the question, why would the body react in such a way that only seems to enhance the problem rather than control it? Why would the body want to increase its pain sensitivity and irritated state? One answer may lie in observing the body’s response to damage: inflammation and tissue repair.
When the body is damaged, such as when you skin your knee, the nervous system responds initially with vasoconstriction [p]. You may have noticed that the area around the scrape goes white at first (more noticeable with thermal burns-that is burns from hot or cold; not sun burns, which are caused by UV radiation). Then the area around the most damaged tissue then becomes inflamed, turning bright red as a result of localized vasodilatation. Increased blood flow to the area also causes the area to heat up, and forces fluid out of surrounding tissues resulting in swelling (edema). Mediators of inflammation are released to drive and control the healing process. Some of these inflammation-mediation chemicals may sound familiar: histamine, serotonin, bradykinin, and nitric oxide. Nitric oxide, besides mediating inflammation, is a free radical that is toxic to microbes and helps prevent infection. In this way, the injury is neutralized and tissue repair begins.
When headache pain starts and the brain reacts, it is responding with the same healing process used for a scrape, burn or infection. But since there is actually no damaged tissue to which to respond, the substances released that would otherwise be helpful instead aggravate the pain process already begun.
How the headache stops is not clearly understood, and very little is written on the matter. It may be that the headache ends once the brain has finished cycling through its “healing” (tissue damage reaction) process. It may be that some mechanism deeper in the brain resolves and ends the headache. No matter what the case, what is known is that even after the headache phase is over, there is still the postdrome phase of migraine wherein abnormal cerebral blood flow and EEG readings can be detected up to 24 hours after the pain stops. More research in this area is necessary. Hopefully someday we will be able to stop migraines as easily as they seem to start.
[a]
Vasodilatation - the expansion and widening of blood vessels due to relaxation
of the smooth muscle in the vessel wall, causing a drop in blood pressure
[b]
Vascular - related to the blood vessels
[c]
Nearly double - the actual number was 1.97
[d]
About 25% lower - actual percentage was 23.7
[e]
I suspect this number is actually a lot higher because I didn’t recognize my
own prodrome symptoms until I’d been suffering from migraines for over a
decade.
[f]
Innervate - to supply an organ or body part with nerves
[g]
Meninges - a membrane that encloses the brain and is an very important to
migraine mechanisms
[h]
Neurons - any of the impulse-conducting cells
that constitute the brain, spinal column, and nerves, consisting of a nucleated
cell body with one or more dendrites and a single axon; also called nerve cell,
neurocyte
[i]
Antinociceptive - increased pain tolerance
[j]
Autonomic - involuntary
[k]
Channels - the proteins that span the cell membranes of neurons
[l]
Drosophila - fruit flies
[m]
Channelopathy - dysfunctions caused by ion channel mutations
[n]
Electroencephalogram - a graphic record of brain waves as recorded by an
electroencephalograph, an instrument that measures electrical potentials on the
scalp and generates a record of the electrical activity of the brain
[o]
Endothelium - a thin layer of cells that lines blood vessels
[p]
Vasoconstriction - the shrinking and narrowing of blood vessels due to flexing
of the smooth muscle in the vessel wall, causing a rise in blood pressure
[1]
Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA, “Intrinsic brain
activity triggers trigeminal meningeal afferents in a migraine model,” Natural
Medicine 2002 Feb; 8(2): 136-42.
[2]
Nakano T, Shimomura T, Takahashi K, Ikawa S, “Platelet Substance P and
5-hydroxytryptamine in migraine and tension-type headache,” Headache, 1993
Nov-Dec; 33(10): 528-32
[3]
Nakano T, Shimomura T, Takahashi K, Ikawa S, “Platelet Substance P and
5-hydroxytryptamine in migraine and tension-type headache,” Headache, 1993
Nov-Dec; 33(10): 528-32
[4]
Tepper, Stewart J. MD, Rapport, Alan MD, Sheeftell, Fred MD, “The
Pathophysiology of Migraine,” Neurologist, 2001 Sep, 7(5): 279-286.
[5]
“Migraines and Migraine Management,” MEDCEU, MFI Group Inc., http://www.medceu.com/index/index.php?page=get_course&courseID=1445&nocheck,
2006
[6]
“Causes of Migraine,” Nidus Information Services, Inc., http://www.nym.org/healthinfo/docs/097/doc97causes.html,
2001.
[7]
Phillips H, “All in the Mind,” New Scientist, 21 June 2003: 36-39.
[8]
Pain, vol 101: 25.
[9]
Young W, MD and S Silberstein, “Migraine and Other Headaches,” AAN Press, American Academy of Neurology, 2004, p 67
[10]
Goadsby PJ, “Neuroimaging in headache,” Microscopy Research and Technique 2001;
53(3): 179-187.
[11]
Phillips H, “All in the Mind,” New Scientist, 21 June 2003: 36-39.
[12]
Centofanti M, "Migraine Pain Not Mainly in the Brain," The Gazette
Online, The Newspaper of the Johns Hopkins University, May 3, 1999; 28(33).
[13]
Ptacek L, "Channelopathies: Episodic Disorders of the Nervous
System," Sodium Channels and Neuronal Hyperexcitability, Eds: Gregory
Bock, Jamie A. Goode, Novartis Foundation, 2002
[14]
Tepper, Stewart J. MD, Rapport, Alan MD, Sheeftell, Fred MD, “The
Pathophysiology of Migraine,” Neurologist, 2001 Sep, 7(5):279-286.
[15]
Brody J, “Studies Unmask Origins of Brutal Migraines,” The New York Times,
October 11, 1988.
[16]
“Causes of Migraine,” Nidus Information Services, Inc., http://www.nym.org/healthinfo/docs/097/doc97causes.html,
2001.
[17]
“Causes of Migraine,” Nidus Information Services, Inc., http://www.nym.org/healthinfo/docs/097/doc97causes.html,
2001.
[18]
“Causes of Migraine,” Nidus Information Services, Inc., http://www.nym.org/healthinfo/docs/097/doc97causes.html,
2001.
[19]
Brody J, “Studies Unmask Origins of Brutal Migraines,” The New York Times,
October 11, 1988.
[20]
Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA, “Intrinsic brain
activity triggers trigeminal meningeal afferents in a migraine model,” Natural
Medicine 2002 Feb; 8(2):136-42.
[21]
Supornsilpchai W, Sanguanrangsirikul S, Maneesri S, Srikiatkhachorn A,
“Seratonin depletion, cortical spreading depression, and trigeminal
nociception,” Headache, 2006 Jan;46(1):34-39.
Chapter 1: What Is A Migraine
What Is A Migraine?
More than just a headache, migraine is a chronic illness that affects over 30 million Americans annually; roughly 10% of the population. There have been great advancements in migraine management in the last 20 years, and an ever increasing awareness about migraines in general. But there is still an alarming amount of misinformation, myth, and misunderstanding out there, even among medical professionals.
Migraine sufferers, or migraineurs, often find themselves at the mercy of people who don’t understand (or worse, don’t believe in) their condition or its seriousness. It is the goal of this article, therefore, to provide an in-depth view of the disease of migraine, perhaps expanding your knowledge of what you the migraineur can do to get the best possible management of your symptoms, and what the friends, family, and caretakers of the migraineur can do to support that management.
Not caused by blood flow changes
In this article we’re going to look at what happens when a migraine occurs. We’re going to focus our observations based on how the migraine affects the neurological and chemical systems of the body. Neurologically, we’re going to look at the brain and nervous system. Chemically we’re going to look at neurotransmitters (the chemicals that carry messages through the brain), hormones, and the chemicals that make up the nerves themselves. Together, the changes in these systems combine to make up the event that is experienced as a migraine.
New studies [1] show that neurological changes are responsible for the generation of migraines and that these changes are also behind the mechanisms of migraine, including vasodilatation [a]. This is a huge breakthrough, because as far back as the 17th century it was believed that changes is blood flow were responsible for generation of migraine and the resulting neurological effects, not the other way around. This outdated theory is known as the vascular [b] theory of migraine generation. Most doctors and nurses currently practicing were taught the vascular theory of migraines.
Much of the documentation made available to the public still explains migraines using the vascular theory, and much of the documentation on the neurological basis of migraines is restricted to scientific articles and medical journals. They are not written for the general public and can be very difficult to understand without advanced education in the field. Though authors of books and articles written in the last twenty years should know about the neurological theory of migraines, the theory was widely debated until discoveries made in the last few years. We now know that neurological changes are behind all the mechanisms of migraine, from aura to vasodilatation to pain. Though there are still many discoveries to be made, we are now pointed in the right direction to make these discoveries.
To start, there are many mechanisms to migraine and not all of them are fully understood. In this article, I will give you a comprehensive view of exactly what is thought to be going on in the body of a migraineur, for indeed, it’s not just the head of a migraineur that is affected, and indeed it is not just during the headache that migraine mechanisms are active. I’ll be taking you deep into the brain to the trigeminal nerve: the nerve that processes all sensory input and connects the brain stem to the nerves of the head and face. I’ll be discussing many brain chemicals-neurochemicals-used by the brain and nervous system. We’ll look at the strange phenomenon of Cortical Spreading Depression (CSD), once though to be the key behind visual auras, and now known to be part of migraine pain as well.
The brain of a migraineur is different than that of other people. Even when not in the headache phase, there are chemical imbalances in neurotransmitters such as Substance P, dopamine, serotonin, and magnesium, to name a few. The average concentration of Substance P in migraineurs is nearly double [c] that of controls. [2] The average concentration of serotonin, which is depleted during a migraine attack, was about 25% lower [d] than controls during non-migraine phases. [3] And when given nitroglycerine, a vasodilator used by some heart patients, “a delayed migraine-like headache [resulted] in migraine patients but not in control patients.” [4]
I’ll talk about some of the symptoms that go along with the different phases of migraine, although the list I provide will be no where near complete. Just as each migraine may manifest in different ways, so is each migraineur and their experience of symptoms different. Hopefully the information I provide will give to you what it has given to me: insight into my own condition and several realizations as to, ‘Oh! That’s why that happens!’ And while it may not take the pain away, knowing that I’m not alone in my symptoms and that I’m not imagining things has been a great comfort.
Neurological: Inflammation of the Meninges
Migraine starts with a trigger-either internal or external-that starts a cascade of events leading to headache. Before the headache starts, either hours or days prior, is the prodrome. Up to 40% of migraineurs [e] experience prodrome [5]. Prodrome symptoms include mood change, loss of concentration, loss of the ability to verbalize, muddled thinking, irritability, confusion, lack of coordination, social withdrawal, loss of balance, stiff neck, cold hands and feet (peripheral vasoconstriction), loss of appetite, constipation or diarrhea, fluid retention (swelling, edema), fatigue, yawning, increased urination, nausea and vomiting, and food cravings to name a few. That may seem like an excessive list of symptoms, but remember we’re dealing with a condition that is a malfunction in brain activity-the primary control for most bodily functions. Specifically, prodrome symptoms have been associated with increased dopamine activity [6].
Moreover, “exposed to repeated sounds or images, the neuron responses in the cortex of the brain usually decline over time, but in migraineurs, such cortical activity fails to decline. In fact, in some, the electrical activity even increased [7]. The sensitivity that migraineurs experience to normal sights, sounds, smells, and other stimuli is as if their brains have turned up the volume on the world. Instead of tuning out, as most people’s brains normally do, migraineurs’ brains can’t help but stay tuned in.
Additionally, Marina de Tommaso from the University of Bari, Italy found that even between attacks, migraineurs experience pain differently. Using a laser to heat a patch of skin to produce mild pain, she had the migraineur perform distracting tasks such as word games. Distracting the mind while it experiences pain normally causes the pain threshold in a person to rise. Literally thinking about something else should take your mind off the pain and give attention to the task at hand. But in migraineurs, their pain threshold didn’t change. It wasn’t that they couldn’t take their mind off the pain-their brains couldn’t be distracted from the pain as a normal person’s would. “Possibly there is some problem with their attention to a stimulus.” [8]
Not only to migraineurs have hyperexcitable brains, but they have hypersensitive brains as well. When exposed to a magnetic pulse, migraineurs see a flash of light “at a significantly lower power pulse than do nonmigraineurs.” [9] The brains of migraineurs have a lowered threshold and sensitivity to their environment. So not only will the brain overreact to the stimulus, but it will notice the stimulus a lot sooner in the first place. It’s a double-whammy that makes the world that migraineurs deal with a lot more difficult.
The ability to regulate environmental and/or internal input is made even more problematic as a result of changes in the brain during a migraine attack. Migraine changes start with a malfunction in the brainstem. This is the part of nervous system that connects the brain to the spinal cord. Within the brainstem is an area called the pons, and it is in this area specifically that the migraine generates [10]. “The pons is an ‘attention center,’ controlling how much notice the brain pays to sensory information.” [11] The trigeminal nerve, which innervates [f] the head, scalp, face, and meninges [g], enters the brainstem at an area called the pons, where some of the neurons [h] travel up past a region called the periaqueductal gray matter (PAG), into the rest of the brain. There are neurons that return from the PAG to the pons in a negative feedback loop to damp down trigeminal signaling. The PAG is a relay station between cortical and brainstem structures and plays a major role in the modulation of pain. It provides an antinociceptive [i] effect to the primary afferent system-the nerves that conduct impulses from the periphery of the body back to the brain-as well as influencing autonomic [j] and defensive behavioral responses.
Input into the pons stimulates the trigeminal nerve. The fine branches of the trigeminal nerve supplies nerves to blood vessels around the meninges. This membrane becomes inflamed in response to neuropeptides such as Substance P and Calcitonin Gene-Related Peptide (CGRP) leaked from the blood into the meninges based on responses from the trigeminal nerve. But this inflammation isn’t widespread. Most migraineurs have a specific ‘spot’ that they can point to on their head where they feel migraine pain. Some people have more than one spot where migraine pain occurs, but typically only one is active during a single migraine attack. That spot is where the meninges is inflamed, as discovered by Dr. Marco Pappagallo of Hopkins Medical Research, using Single Photon Emission Computed Tomography (SPECT). “The images showed bright, diffuse patches-a sign of inflammation-at areas in the meninges that precisely matches where patients said they felt their headaches.” [12] The inflammation in migraine causes the sensation of throbbing and the symptoms of nausea, sensitivity to light, sound, smells and movement; the same symptoms that occur as a result of bacterial or viral meningitis, which also has inflammation as one of its mechanisms.
Leakage of neuropeptides into the meninges sensitizes nearby pain receptors and sends the message of pain back to the pons, PAG, and trigeminal nerve. This creates a sort of neurological merry-go-round as actions in the brainstem cause a reaction in the meninges, which causes a reaction in the brainstem, which causes… et cetera. And since the brains of migraineurs don’t tune out over time and can’t be distracted from the pain, the neurological merry-go-round spins out of control. The result is one of the mechanisms of migraine. Next, we’ll be looking at other migraine mechanisms, namely the chemical changes that occur with migraine.
Chemical: Neurochemical Changes and Cortical
Spreading Depression
The chemical mechanisms of migraine happen simultaneous to the neurological changes discussed before. Let’s go back to the trigger stage of migraine, and the prodrome. External changes, such as change in pressure due to weather or altitude, increase or decrease in stress (both positive and negative), exercise or exertion, too much or too little sleep, bright or flashing lights (especially fluorescent lights and computer monitors), loud or high-pitched noises, strong smells (especially perfume), or medications, internal triggers, such as hormonal changes, a drop in blood sugar levels, reactions to food, craving for nicotine, illness, allergies, or changes in metabolism all can trigger the chemical changes that lead to migraine. There are also pre-existing chemical states, such as decreased serotonin and/or magnesium levels that can make it easier for migraine to occur. Moreover, there are genetic factors such as the mutation in the calcium channel genes that have been found to be responsible for familial hemiplegic migraine.
Inflammation of the meninges, as mentioned earlier, isn’t the immediate cause of migraine pain. It’s more of a response to migraine pain. Much of what happens in migraine is actually as a result of chemical changes in the brainstem and along the nerves connected to the brainstem. Chemicals tell the brain and nerves how to function, and the brain and nerves in turn tell the meninges and the rest of the body how to function (or malfunction, as the case may be). One such set of chemical are the ions of calcium (Ca++), magnesium (Mg++), sodium (Na+), and potassium (K+) and their interactions with ion channels. Another set of chemicals is serotonin, norepinephrine, and dopamine-three powerful neurotransmitters that act as messengers throughout the brain and nervous system.
Abnormalities of the channels [k] within cells that transport the ions Ca++, Mg++, Na+, and K+ are one cause of migraines. “While voltage-gated ion channel mutants have been recognized for some time in organisms such as Drosophila [l], the first channelopathy [m] in humans was reported within the last decade [13],” notes Louis Ptacek of the Howard Hughes Medical Institute Department of Neurology and Human Genetics at the University of Utah School of Medicine.
To understand how channels malfunction, we need to understand first how they operate normally. The plasma membrane of nerve cells, like all other cells, has an unequal distribution of ions and electrical charges between the two sides of its membrane. The outside of the membrane has a positive charge, the inside has a negative charge. This charge difference is a resting potential and is measured in millivolts (mV - one thousandth (0.001) of a volt). If there is no active change in the membrane-no stimulation-it stays at its resting potential. In most cells the resting potential has a negative value. The resting potential is mostly determined by the concentrations of the ions in the fluids surrounding the cell membrane and the ion transport proteins that are in the cell membrane.
One important type of membrane ion transport proteins are ion channels. Ion channel proteins create paths through which ions can pass across cell membranes. They have selectivity for certain ions. That is, there are ion channels that only respond to a certain ion such as selectivity for Ca++ or Mg++. Different cells will have different amounts of each ion channel. Even different parts of a cell can have varying amounts of each ion channel. The amount of particular ion channels in their selective locations is what controls the resting potential of the nerve cell.
The action potential is a temporary reversal (a few milliseconds) of the electrical potential in the plasma membrane that occurs when a nerve cell is stimulated. Ion channels open to allow their selective ions to pass to the outside of the membrane. Ion pumps are then activated to restore the membrane charges to the original resting potential, moving the ions back to their original sides of the membrane.
Channelopathy is when ion channels are defective. These defects cause a disruption in normal ion activity. Examples of channelopathy in migraine include alterations in the number of ion channels, changes in the rate at which ion channels open and close, or causing ion channels to open at inappropriate times. Calcium channels, for example, allow an influx of calcium ions that help regulate neuronal impulses, such as the transmission of painful stimuli. Magnesium interacts with calcium channels, playing a role in overall nerve cell function: “Low magnesium can result in opening of calcium channels, increased intracellular calcium, glutamate release, and increased extracellular potassium, which may in turn trigger cortical spreading depression.” [14]
A second cause of migraines deals with serotonin. Dr. Joel R. Saper of the Michigan Headache and Neurological Institute in Ann Arbor, Michigan holds the theory that, “people [with migraine] are born with or acquire a disturbance in serotonin function,” involving an insufficiency or abnormality in serotonin itself, a defect in the receptors that permit nerve cells to take up and release serotonin, or an abnormality in the enzymes that destroy serotonin, breaking it down too quickly-one way of starting the chain of events that lead to migraine [15].
Abnormalities in the processing of dopamine may also have similar migraine-triggering effects. There is evidence that suggests certain people are overly sensitive to the effects of dopamine [16], which includes nerve cell excitation (read: neurological merry-go-round), and that this sensitivity could trigger events leading to migraine. Suffice to say, there are many chemical interactions that are a part the susceptibility and triggering of migraine. Now let’s look at its manifestation and process.
Prior to the headache phase and at the very beginnings of the migraine attack, there is a drop in magnesium levels, which is believed to be a destabilizing factor causing the nerves in the brain to misfire [17] (one theory behind types of visual aura). At the same time, increased dopamine activity is observed, which has been connected with such prodromal symptoms as mood change, yawning and drowsiness. Stimulation of the trigeminal nerve leads to the release of serotonin (5-HT) from the dorsal raphe nucleus, which suppresses pain initially: “Serotonin appears to block the peptides involved in over-stimulating nerves and producing inflammation.” [18] but then depletion over the course of the migraine attack results in pain [19]. (Serotonin depletion also causes depression and anxiety, two common prodromal symptoms.)
Along with norepinephrine (also known as noradrenaline), serotonin release causes a decline in nerve cell function, and along with dopamine, decreased blood flow in the brain. This decline in nerve cell function begins a process known as cortical spreading depression (CSD), which is characterized by a transient, reversible depression of electroencephalogram [n] (EEG) activity that advances across the cortical surface at a velocity of 2-5mm per minute from the back of the brain to the front. This is the start of the aura phase of the migraine attack.
Cortical spreading depression was once sited as just the mechanism behind visual auras (such as floaters or zigzag lines appearing in some migraineur’s vision up to an hour prior to the headache), but it’s now linked to migraine pain as well. CSD activates a set of enzymes that allow the blood-brain barrier, the protective membrane that separates local blood vessels and most parts of the central nervous system (CNS), to become leaky. Remember our pain spot mentioned in the first section?
The blood-brain barrier usually has more control over which substances pass from the blood to the CNS. But after CSD activates these enzymes (known as metalloproteinases), potassium, nitric oxide (NO), adenosine, and other products are allowed to pass through. These products then reach and sensitize the nerves around the blood vessels in the meninges that carry impulses back to the trigeminal nerve [20]. These impulses are enhanced due to serotonin depletion, which increases cortical excitability and sensitivity of the trigeminal pain transmission system [21]. Remember our neurological merry-go-round?
Based on responses from the trigeminal nerve, neuropeptides such as Substance P (SP) and Calcitonin Gene-Related Peptide (CGRP) are leaked from the blood into the meninges causing further inflammation. Substance P, besides causing inflammation of blood vessels, releases serotonin (5-HT) from platelets and increases the permeability of capillaries so that other substances, such as bradykinin, are released into the meninges. Bradykinin, like SP and CGRP, is yet another irritating and inflammatory chemical that stimulates pain-conducting nerves as well.
Substance P is also a potent vasodilator, causing the release of nitric oxide (NO) from the endothelium [o]. Nitric oxide, too, causes vasodilatation. Note that in the sequence of things, vasodilatation happens as a response to pain, not as the cause of pain.
All this neurochemical activity begs the question, why would the body react in such a way that only seems to enhance the problem rather than control it? Why would the body want to increase its pain sensitivity and irritated state? One answer may lie in observing the body’s response to damage: inflammation and tissue repair.
When the body is damaged, such as when you skin your knee, the nervous system responds initially with vasoconstriction [p]. You may have noticed that the area around the scrape goes white at first (more noticeable with thermal burns-that is burns from hot or cold; not sun burns, which are caused by UV radiation). Then the area around the most damaged tissue then becomes inflamed, turning bright red as a result of localized vasodilatation. Increased blood flow to the area also causes the area to heat up, and forces fluid out of surrounding tissues resulting in swelling (edema). Mediators of inflammation are released to drive and control the healing process. Some of these inflammation-mediation chemicals may sound familiar: histamine, serotonin, bradykinin, and nitric oxide. Nitric oxide, besides mediating inflammation, is a free radical that is toxic to microbes and helps prevent infection. In this way, the injury is neutralized and tissue repair begins.
When headache pain starts and the brain reacts, it is responding with the same healing process used for a scrape, burn or infection. But since there is actually no damaged tissue to which to respond, the substances released that would otherwise be helpful instead aggravate the pain process already begun.
How the headache stops is not clearly understood, and very little is written on the matter. It may be that the headache ends once the brain has finished cycling through its “healing” (tissue damage reaction) process. It may be that some mechanism deeper in the brain resolves and ends the headache. No matter what the case, what is known is that even after the headache phase is over, there is still the postdrome phase of migraine wherein abnormal cerebral blood flow and EEG readings can be detected up to 24 hours after the pain stops. More research in this area is necessary. Hopefully someday we will be able to stop migraines as easily as they seem to start.
[a]
Vasodilatation - the expansion and widening of blood vessels due to relaxation
of the smooth muscle in the vessel wall, causing a drop in blood pressure
[b]
Vascular - related to the blood vessels
[c]
Nearly double - the actual number was 1.97
[d]
About 25% lower - actual percentage was 23.7
[e]
I suspect this number is actually a lot higher because I didn’t recognize my
own prodrome symptoms until I’d been suffering from migraines for over a
decade.
[f]
Innervate - to supply an organ or body part with nerves
[g]
Meninges - a membrane that encloses the brain and is an very important to
migraine mechanisms
[h]
Neurons - any of the impulse-conducting cells
that constitute the brain, spinal column, and nerves, consisting of a nucleated
cell body with one or more dendrites and a single axon; also called nerve cell,
neurocyte
[i]
Antinociceptive - increased pain tolerance
[j]
Autonomic - involuntary
[k]
Channels - the proteins that span the cell membranes of neurons
[l]
Drosophila - fruit flies
[m]
Channelopathy - dysfunctions caused by ion channel mutations
[n]
Electroencephalogram - a graphic record of brain waves as recorded by an
electroencephalograph, an instrument that measures electrical potentials on the
scalp and generates a record of the electrical activity of the brain
[o]
Endothelium - a thin layer of cells that lines blood vessels
[p]
Vasoconstriction - the shrinking and narrowing of blood vessels due to flexing
of the smooth muscle in the vessel wall, causing a rise in blood pressure
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