The Causes of Migraines


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Main Causes of Migraines and Headaches

In a sentence, in my opinion, the main reason people get migraines or frequent headaches is because of vascular instability.  This instablity is brought on by inflammation and a dysregulated hypothalamus-thyroid-pituitary-adrenal axis.

Migraines vs Headaches

Migraines and headaches are not one and the same.  Migraines is a disease which has headaches as the main symptom.  Isolated headaches are usually not caused by the same processes as migraines.  Chronic migraines are usually caused by too much vasodilation.  Headaches are caused by either too much vasodilation or vasoconstriction.  If someone has a tendency for either states, certain triggers can be tipping points which leads to a headache.  Sensitive people may think that they have migraines, but instead they have frequent headaches that can be triggered by environmental circumstances.  These may be referred to as migraines, but for the purpose of this blog post I will not refer to them as migraines.  Migraines are more consistent and chronic, while vasoconstriction headaches are more sporadic and much more likely to be induced by environmental triggers such as stress or tyramines (both of which cause vasoconstriction).

Migraines, cluster headaches and exercise headaches are generally caused by vasodilation. Tension headaches  are caused by vasoconstriction.

So what causes vasodilation/vasoconstriction in migraine or headache sufferers?

1)Endocrine dysfunction/dysregulation/insufficiency.

This is a dysfunction in the endocrine/hormonal system – specificially of the HPA axis leading to cortisol, angiotensinII, vasopressin, neuropeptide Y, substance P, epinpehrine and norepinephrine dysregulation, but can also be related to other hormones such as testosterone, estrogen and melatonin.

This hormonal list is not comprehensive, but these are large players and the idea is that every one of these hormones play a role in vasodilation/vasoconstriction and it seems apparent to me that dysregulation of the endocrine system will result in uncontrolled vasodilation and/or vasoconstriction.

Cortisol, angiotensinII, vasopressin, epinephrine, norepinephrine, neuropeptide Y, testosterone and melatonin are all hormones that cause vasoconstriction.  Estrogen and substance P are hormones that cause vasodilation and low levels can cause vasoconstriction.  When hormonal signaling is out of whack and too little or too much of one or more hormones is excreted at the wrong time you get excess vasodilation or vasoconstriction.

2)Neurotransmitter dysregulation.

Glutamate(and aspartate), serotonin, acetylcholine and gaba, listed in the order of relative importance (IMO), play a role in vasodilation and vasoconstriction.  Glutamate excess, serotonin deficiency and to a lesser extent acetylcholine and gaba deficiency causes vasodilation.

Glutamate and vasodilation:  “Glutamate-induced cerebral vasodilation is mediated by nitric oxide through N-methyl-D-aspartate receptors…It was found that glutamate, a major neurotransmitter, is vasoactive in the cerebral circulation. However, the mechanism is unclear. This study was designed to investigate the role of nitric oxide (NO) and N-methyl-D-aspartate (NMDA) receptors in cerebral arteriolar dilation to glutamate.” (ref)

Serotonin causes vasoconstriction: “Migraine treatment has evolved into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine; 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an i.v. infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation. ” (ref)

Excess acetylcholine causes vasoconstriction: “Acetylcholine-mediated increase in vascular tone may play a role in aggravating cerebral perfusion when endothelial cell damage occurs during brain ischemia.” (ref).  GABA is vasodilatory (could be indirect): “Administration of GABA (1-100 micrograms) directly into the cerebral circulation produced dose-dependent increases in cerebral blood flow.” (ref)

There also may be a role played by substance P and pain perception.  But substance P is released along with glutamate, so if there’s too much glutamate release then there may be an increase in pain perception.  Substance P also causes neurogenic inflammation, which ties into the third cause.

3)Inflammation.

Inflammation is a natural and healthy response to injury.  People with acute bouts of inflammation from injuries can get headaches, but for people with migraines this inflammation is chronic.  Inflammation is actually quite complex even though it’s become a nice buzzword these days by quacks and clueless bloggers.

In any case, inflammation causes vasodilation: “Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators.” (ref)

There seems to be some role played by mitochondrial dysfunction in headaches, but I think what’s happening is that mitochondiral dysfunction is causing or amplifying inflammation through ROS production and NF-κB activation, so it can be put under the umbrella of inflammation. (ref).  Inflammation can then damage mitochondria even more, leading to downward spiral.

Alternatively, mitochondrial dysfunction can be put under the umbrella of glutamate excitotoxicity  because the reason why mitochondrial dysfunction happens in the first place (besides inflammation) is because glutamate excitotoxicity causes a cascade of events such as an increase in free radicals, ROS and phospholipases, which break down the neuronal membrane, allowing harmful chemicals and ions to enter and ultimately degrading the cell’s mitochondria.

Mitochondrial dysfunction may also play a role in vasoconstrictive headaches because it can lead to an increase in trace amines(which are vasoconstrictive).  Some researches believe migraines arise from functional changes in the trigeminal nerve, one of the main facial nerves that also houses a major pain pathway.  But it seems like this may be a result of inflammation. (ref)

Migraine sufferers are more likely than other people to have an incomplete network of arteries that supply blood to the brain.  This structural difference may be caused by frequent headaches instead of it being the cause of the headaches.  But even if this structural difference contributed to headaches, it likely only potentiates or necessitates frequent headaches, but wouldn’t be sufficient by itself without one of the three causes above.  I would be willing to bet money that scientists will continue to discover necessitating factors, but my guess is that these factors likewise wouldn’t be sufficient to cause migraines/headaches.

I’d also like to point out that there are many interactions taking place.  Any hormone could lead to an increase or decrease of another hormone and this can influence inflammation and neurotransmitter levels as well.  The interactions are complex, but aren’t necessary in figuring out a treatment strategy.  These three causes are highly connected to one another and one cause can contribute to another.

Which Category Are You In?

Vasodilatory headaches

People with vasodilatory migraines will experience a worsening in their condition in heat, during or post exercise, during an infection or sickness, during injury or if they ingest any food or chemical that they are sensitive to (gluten, casein, etc..).   These latter states contribute to inflammation, which leads to vasodilation and worsens symptoms or causes a flair up.   These people will usually have lower blood pressure(diastolic under 70) because low levels of vasoconstrictive hormones(Cortisol, angiotensinII, epinpehrine, norepinephrine, testosterone and melatonin) and higher levels of vasodilatory hormones(estrogen), which in turn leads to lower blood pressure.

Different foods which cause increases in vasodilatory neurotransmitters can also aggravate symptoms or cause a flair up.  These vasodilatory headaches are least responsive to NSAIDs like aspirin because while aspirin will block the pain to a certain extent and bring down inflammation, it is a vasodilator.  So in one way it makes it better (by decreasing inflammation) and in another it exacerbates the problem (by increasing vasodilation). NSAIDs have been shown not to work for vasodilatory headaches like cluster or exercise headaches because NSAIDs vasodilatory actions will only help for vasoconstrictive headaches. Allergies and allergic reactions cause an inflammatory response which will trigger or make this headache worse. In addition, vasodilatory foods or herbs such as cocoa or chocolate can worsen symptoms.  Sex and masturbation are also potent vasodilators.

Vasoconstriction headaches

For people with vasoconstriction headaches (tension headaches for example) they will usually have higher blood pressure and experience episodes in times when they have higher levels of vasoconstrictive hormones and lower levels of vasodilative hormone.  Stress and tyramines, for example, can trigger vasoconstriction.  Stress triggers vasoconstriction through cortisol, epinephrine and norepineprhine.  Tyramines displace norepinephrine from neuronal storage vesicles, which leads to vasoconstriction.  These headaches can come often but they aren’t as consistent as vasodilatory headaches.

These headaches are most responsive to NSAIDs like aspirin because aspirin is both a pain killer and vasodilator. And indeed, the research demonstrates its effectiveness for tension headaches.  Menstrual cycles, pregnancy and  menarche can cause fluctuations in estrogen and lead to vasoconstriction when estrogen levels fall or availability is reduced and vasodilation when its levels increase.  Also, hot flushes by perimenopausal women increases vasodilation, which can exacerbate symptoms.  Any stimulus that causes the body to release stress hormones such as low carb diets, fasting or skipping meals, emotional stress, cold, alcohol, bright lights and loud noise can aggravate these headaches.

Glutamate

MSG or excess glutamine/glutamic acid consumption can worsen vasodilatory migraines because glutamate excess causes vasodilation.  The degree of harm caused by MSG is probably minimal.  Instead, glutamate excess is more likely caused by a host of other factors not related to dietary consumption of glutamate such as hypoglycemia caused by eating high glycemic index foods, hyperinsulinema, fasting/skipping meals or low carb dieting.   Also, hypoxia can cause glutamate excitotoxicity, such as when we are so stressed we forget to breath.

Serotonin

Serotonergics like SSRI’s and tryptophan or foods which contain high levels of tryptophan may increase serotonin levels and possibly exacerbate vasoconstriction headaches but be of benefit to vasodilatory headaches.

Acetylcholine

Too much cholinergic transmission can trigger headaches in people with vasoconstriction and too little can possibly trigger vasodilatory headaches.  Too much or too little inhibition of the enzyme acetylcholinesterase will influence acetylcholine levels(inhibition will cause a rise in acetylcholine and vice versa).

GABA

GABA seems to play a more minor role but can also influence vascular tone.  These neurotransmitters interact with each other in complex ways and an increase in one may cause an increase or decrease in another.

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