Migraines: A Neurobiological Adaptive Alarm System

ABSTRACT

Most people will experience at least one migraine in their lifetime. For chronic sufferers, migraine is a complex and confusing disease that afflicts and disables. Various treatments for migraines exist and ranges from home remedies to prescription medication. These treatments may or may not work, leaving the patient to try various medications throughout their lifetime and creating a stressful experience. Migraines have strong associations with psychiatric disorders, cardiovascular diseases, and other illnesses. This strong association has not been discussed in depth, but it is here that a larger question arises: what if migraines are a sort of alarm for the body, alerting us to our own illnesses, like depression and anxiety?

KEY WORDS AND ABBREVIATIONS 

aura: some migraine sufferers experience visual or sensory symptoms before the pain of a migraine sets in. It can also be experienced on its own, without the pain afterwards. Auras can act as a warning to the sufferer of an incoming migraine.

chronic migraineurs: sufferers with more than 15 headache days per month.

episodic migraineurs: sufferers with less than 15 headache days per month.

MA: migraines with aura.

MO: migraines without aura.


INTRODUCTION

Migraines are a debilitating illness, recognized as a disability under the Americans with Disabilities Act. A migraine and its symptoms disrupts life, daily function, and even the ability to communicate and take care of oneself by affecting neurological functions. Migraines are often left untreated by patients who either do not know that they are suffering from migraines and that treatment is available, or by patients or have tried multiple forms of treatment to no avail. Only by looking at the epidemiology, pathophysiology, symptoms, and treatments for migraines can we begin to understand migraines from an evolutionary medicine perspective.

SYMPTOMS AND TRIGGERS

Migraines are common in the human population, but what exactly happens when getting a migraine? Migraines are characterized as a severe and intense headache usually unilateral in location, with pulsating pain, autonomic nervous system dysfunction, and occasionally the sufferer will have an aura (visual disturbances: flashes, zig zags, colored lights surrounding a blind spot) before the pain. (Goadsby et al 2002, Sole-Smith 2012). Other well-known symptoms include: sensory sensitivity (light, sound, smell, movement), nausea, and vomiting.  These debilitating incidents can be chronic in some patients, leading to a lower quality of life and for the illness to be recognized under the ADA.

Scientists and their research often look at the lifestyles of those afflicted with chronic migraines to find potential triggers. It is important to note that not all sufferers have triggers for their migraines. Triggers can be anything from fluorescent lights, a specific scent (vanilla is a common trigger), or even certain foods (caffeine, alcohol, chocolate, aged cheeses, and avocados have been suggested). Stress is a prevalent trigger for all migraineurs, regardless of gender. For women specifically, who are more prone to migraines than men, stress – including anxiety related stress and depression related stress – is a more powerful trigger for migraines than the withdrawal of estrogen during menstruation. (Parashar et al., 2014) This may mean that women are under more stress than men, or at the very least were under more stress as migraines developed in the human species.

A study on chronic and episodic migraines concluded that “52% [of chronic sufferers are] more likely to be female, 41% more likely to be white… 34% more likely to be obese, 205% more likely to have depression, and 140% more likely to have anxiety than episodic migraineurs.” (Adams et al., 2015) This study and others suggest strong ties between mental health illnesses and migraines, as well as significant ties to neurological diseases. 

MECHANISMS

Initially thought of as a solely neurovascular disease, new research suggests that while blood vessels in the brain are associated with migraines and play a role in it, they are not the sole originator of a migraine. Rather, blood flow increases to the brain immediately before the migraine pain (upwards of 300 percent), and is normal or reduced during migraine pain. Scientists now believe that the root of migraines comes from the brain stem1 as a malfunction or abnormality. (Dodick & Gargus, 2008) Brain stem activation in specific areas has been found during spontaneous and induced migraine attacks, and it should be noted that activation extends into and outside of the headache phase of the migraine attacks. (Rothrock, 2008) Consensus suggests that migraines are a neurobiological illness, that originate from both the brain stem and with neurovascular changes. It has also been theorized that there are multiple different causes in the brain for migraines, and these causes could exist in multiples for genetically predisposed patients. (Rothrock, 2008) Migraineurs with “genetic predisposition have a reduced threshold for the activation of the brain’s ‘pain centers’ and become hypersensitive to stimuli that cause pain.” (Sole-Smith, 2012) 

There is a wave of nerve activity that passes through the brain and correlates with the pain of a migraine, and this wave can be set off by various triggers as mentioned above. This wave, a “brainstorm” of sorts, is known as cortical spreading depression. Cortical spreading depression is an intense wave of neuron activity through a large portion of the cortex. It is this wave of activity and the subsequent “neurotransmitter release that activates blood vessel inflammation, feeding pain structures deep in the brain.” (Sole-Smith, 2012) After the wave of intense neuron activity, the neurons are, in a sense, exhausted and experience a prolonged state of neural inhibition. It is in this inhibitory phase that neurons cannot be excited or stimulated. (Dodick & Gargus, 2008)

Migraines are a heterogeneous disorder. (Buzzi et al, 2005) This implies an association between other neurological, psychiatric, and cardiovascular diseases such as epilepsy, cerebrovascular disorders, anxiety, depression, arterial hypertension, mitral valve prolapses, and patent foramen ovale. This may be due to a common genetic substrate and various mutations in the same gene. (Buzzi et al, 2005; Nappi et al., 2000) There is a high risk of familial recurrence and risk of up to 1.9 times for MO and 1.4 time for MA. (Montagna, 2008) Migraine is likely a polygenetic disease, but it is unknown exactly how many genes it stems from. Some rejected theories suggest Migraine as transmitted via “autosomal dominant with female preponderance and possibly sex determined, autosomal recessive with 70% penetrance… maternal and X-linked.” (Montagna, 2008) Migraine without aura (MO) is likely to first occur during puberty, triggered by declining oestrogens. Migraine with aura (MA), on the other hand, is likely to begin “with sustained high sex hormone levels, during pregnancy, or with oestrogen replacement.” (Buzzi et al., 2005)

Familial hemiplegic migraines (FHM), a subtype of MA, is autosomal dominant in its hereditary transmission. This is also called a mendelian migraine (following a mendelian type of genetic transmission). This is the only subtype whose transmission is known, and for our purposes is not the focus of this paper. 

TREATMENTS

Migraineurs utilize a myriad of treatments, ranging from in-home remedies to doctor prescribed medications. Some treatments simply lessen the pain to a tolerable level, others work to completely eradicate the migraine upon onset, and still others work as a preventative measure to hopefully end a migraineurs disease or turn attacks into a rare event.

Home remedies often work to lessen the severity of an attack. The most basic treatment is prevalent in migraineurs: an ice pack. Some sufferers will opt for a freezable face mask, but the results are the same. Ice is anti-inflammatory – the cold relieves the pulsating feeling that can become overwhelming during attacks and lessens it for a time. Relaxation techniques are also fairly popular, such as massages for the neck and shoulder and hatha and restorative yoga. (Sole-Smith, 2012) Herbal medicine is also a popular avenue, especially for migraineurs who have tried prescription medication but to no avail. Butterbur has been confirmed by the American Academy of Neurology to prevent migraines (studies suggest this may be because it supports healthy blood flow to the brain). Feverfew is also a well known remedy, but clinical evidence is still inconclusive. (Sole-Smith, 2012)

Vitamin supplements are touted by both sufferers and some doctors and the cure-all for migraineurs (usually not chronic migraineurs). Fixing vitamin D and melanin deficiencies have been known to drastically reduce occurrence of migraines, but this does not work for every patient. More recent studies have shown that participants who took 400 mg of riboflavin (vitamin B2) daily had drastically reduced migraines. (Sole-Smith 2012)

For some migraineurs, relief only comes from seeing a neurologist. Most prescription medications used for migraines were not originally formulated for that purpose. Botox is a newly approved treatment for chronic migraines, consisting of 31 shots given every 12 weeks, and have been clinically proven to be preventative with minimal side effects. (Sole-Smith, 2012) Beta-blockers and anti-hypertensives were originally intended to treat high blood pressure, angina, and rapid heart rate. Used because they are believed to affect relevant blood vessels, these medications have few side effects but can result in dangerous heart-rate drops. (Sole-Smith, 2012) Anti-seizure medication like topiramate act as a preventative drug, and when taken every day can reduce or even eliminate migraines all together by inhibiting some neurotransmitters. These do have adverse side effects, though, including irritability, confusion, drowsiness, and depression. (Sole-Smith, 2012) Anti-depressants have been used by balancing abnormal levels of serotonin, but are not advised for migraineurs who do not have or are not in need of treatment for depression.

Triptans are the most prevalent prescription medication for migraineurs. Consisting of medications such as Imitrex, Maxolt, Axert, and Relpax, these medications are formulated specifically to stop migraines. (Sole-Smith, 2012) Triptans are not a preventative treatment, though, and are used at the onset of a migraine (either onset of aura or pain). Triptans work by affecting several different migraine-causing mechanisms in the brain and as a result can cause mild to severe side effects (ranging from a tingling sensation all over the body to a change in the perception of taste) and will occasionally cause rebound headaches or migraines.

PHYLOGENY

The phylogenetic origins of migraines is somewhat of a mystery. Migraines cannot be seen or biologically tested for (such as a blood test), but instead symptoms are often described to medical professionals for diagnosis. Fulfilling a certain number of these symptoms will result in a diagnosis – i.e., nausea, light sensitivity, and severe pain in the temples. Currently, there is no animal model for migraines. Primates and other animals cannot speak to the pain, so diagnosing migraines is very difficult, if not impossible. In testing treatments for migraines scientists have induced migraine symptoms in rodents, cats, macaques, and other mammals. To induce the symptoms scientists have used medication, surgery, and electricity to activate various areas of the brain.

A case study on a 5 year old female Cocker Spaniel takes steps towards discovering if animals outside of humans can be afflicted by migraines. She is described as presenting with “paroxysmal episodes of vocalization and apparent fear since [she] was 6 months old.” (Plessas et al., 2013) The dog would vocalize as if in pain, have low head carriage, remain conscious and responsive, but also would refuse to eat or drink. Occasionally the dog would show signs suggestive of nausea, such as hypersalivation, frequent swallowing, lip smacking, and vomiting.  (Plessas et al., 2013) There is no known disease or condition with similar expression in veterinary literature; the case study suggests the dog is experiencing migraines as a result. To further this theory, the dog was prescribed several different types of treatments including opioids like morphine and methadone, diazepam, non steroidal anti-inflammatory drugs, phenobarbital, and a combination of acetaminophen and codeine. All treatments did not reduce the severity of the episodes. After these trials they dog was prescribed topiramate, a seizure medication that is known and used to treat migraines. The topiramate was successful: “[she] continued to experience these episodes, but the duration would last only 1–3 hours and the intensity was dramatically reduced to the point that the dog would only seem quiet, no longer vocalize, and be keen to go for walks, eat, and drink as normal. The dog no longer appeared to be photophobic and phonophobic. Interestingly, the owners reported that if they failed to give topiramate quickly enough and they administered it when she had already started vocalizing, it took longer to recover (6–7 hours); however, the intensity improved within 30 minutes of administration, she would appear more quiet, stop vocalizing and hyperventilating, and would eventually go to sleep.” (Plessas et al., 2013). Upon applying the dogs symptoms to diagnostic criteria for migraines in humans, the dog fulfilled all of them.

“THE ALARM SYSTEM” – MIGRAINES AS ADAPTATION

Migraine tends to disappear after traumatic  and severe brain injury, but recur after a degree of cognitive functioning has been regained. This suggests a degree of high level pain processing is needed in order to perceive migrainous pain and the potential aura. (Buzzi et al., 2005) Neurodegenerative diseases with focal brain damage in dopaminergic areas, like Parkinson’s, may shorten migraines’ clinical life span. This may suggest that the migraines are a potential “alarm system” for the brain; this alarm system may be an effort to protect the brain from inner injury.

Migraines have been found to be comorbid with mood and anxiety disorders. (Hung et al., 2013; Adams et al., 2015) Studies following the comorbidity with depression find a poorer quality of life, and increase in suicide risk, and predicts a poorer outcome for these patients with both. Another study found that psychiatric patients with migraine experienced a significantly greater severity of depression, anxiety, somatic symptoms, and a poorer health-related quality of life. (Hung et al., 2013) This also suggests an imbalance of neurotransmitters (like serotonin, noradrenalin, and dopamine) could partly be a cause for both the depression and the migraine. (Hung et al., 2013) The study also found that pain intensity in the migraine was significantly correlated to the severity of depression, anxiety, somatic symptoms, and health-related quality of life. As a result, the migraine severity could be used to predict the mental health illnesses and possibly their severity. Hung’s study did not include patients with manic episodes of psychotic features, and thus no patients had bipolar I disorder. Bipolar II was included, but had a small sample size (and also the highest percentage of migraine). This strengthens the suggestion of a specific relationship between migraines and depression and anxiety. 

In another study focusing on the migraine-obesity relationship, higher migraine frequency and migraine-related disability are strongest in migraineurs with both depression and anxiety. It also found that frequency and disability were increasing with and increasing BMI. (Tietjen et al., 2008) There is evidence suggesting common genetic substrates, notably monoamines and peptides in the brain (serotonin, dopamine, norepinephrine, neuropeptide Y, and corticotrophin releasing hormone) that influence depression, anxiety, migraine, and body weight regulation. This could be a neurobiological link between these illnesses. (Tietjen et al., 2008)

CONCLUSIONS

More research needs to be done on migraines and the exact origins in the brain. The exact neurobiological processes that lead to a migrainous attack need to be understood to make concrete connections between MA and MO and other diseases.

That being said, current research strongly correlates migraines with a variety of illnesses, the strongest being depression and anxiety and other psychiatric disorders. The link between severity of migraines and severity of depression and anxiety can serve as the base for further research. If other organs have ways of warning us to disease, or some illnesses serve as precursors for others, then it’s not a far stretch to suggest that migraines act as the brain’s alarm system. Migraines could very well be a way for the brain to tell us that our own mental health is unstable, that something has gone wrong in our hearts, or that our nervous systems are failing. 


FOOTNOTES

1 More research needs to be done on this theory – some current papers are published under the assumption of a neurovascular origin and others are using the brain stem theory as the origin. Dodick and Gargus acknowledge this in their paper.


REFERENCES

Adams, A. M., Serrano, D., Buse, D. C., Reed, M. L., Marske, V., Fanning, K. M., & Lipton, R. B. (May 13, 2015). The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia, 35, 7, 563-578.

Buzzi, M. G., Cologno, D., & Formisano, R. (September 01, 2005). Migraine disease: evolution and progression. The Journal of Headache and Pain : Official Journal of the Italian Society for the Study of Headaches, 6, 4, 304-306.

Dodick, D. W., & Gargus, J. J. (August 01, 2008). Why Migraines Strike. Scientific American, 299, 2, 56.

Gil-Gouveia, R., Oliveira, A. G., & Martins, I. P. (June 09, 2015). Cognitive dysfunction during migraine attacks: A study on migraine without aura. Cephalalgia, 35, 8, 662-674.

Goadsby, P. J., Lipton, R. B., & Ferrari, M. D. (January 01, 2002). Migraine–current understanding and treatment. The New England Journal of Medicine, 346, 4, 257-70.

Hung, C.-I., Liu, C.-Y., & Wang, S.-J. (December 01, 2013). Migraine predicts physical and pain symptoms among psychiatric outpatients. The Journal of Headache and Pain : Official Journal of the “european Headache Federation” and of “lifting the Burden – the Global Campaign against Headache”, 14, 1, 1-8.

Montagna, P. (January 01, 2008). The primary headaches: genetics, epigenetics and a behavioural genetic model. The Journal of Headache and Pain, 9, 2, 57-69.

Nappi, G., Costa, A., Fortini, D., Damiano, M. G., Casali, C., Pierelli, F., & Santorelli, F. M. (December 01, 2000). Migraine comorbidity: from genotype to phenotype. The Journal of Headache and Pain : Official Journal of the Italian Society for the Study of Headaches, 1, 2.)

Parashar, R., Bhalla, P., Rai, N. K., Pakhare, A., & Babbar, R. (January 01, 2014). Migraine: is it related to hormonal disturbances or stress?. International Journal of Women’s Health, 6, 921-5.

Plessas, I.N., Volk, H.A., Kenny, P.J. (2013) Migraine-like episodic pain behavior in a dog: can dogs suffer from migraines?. J Vet Intern Med., 27:1034–1040.

Rothrock, J. F. (October 03, 2008), “Outside-In” vs “Inside-Out”: Revisiting Migraine’s Vascular Hypothesis. Headache: The Journal of Head and Face Pain, 48: 1409–1410. 

Rothrock J. (2009) Migraine aura. Headache.;49:1123–1124.

Sole-Smith, V. (2012). Migraines. Prevention, 64(12), 51-55.

Tietjen, G. E., Peterlin, B. L., Brandes, J. L., Hafeez, F., Hutchinson, S., Martin, V. T., Dafer, R. M., … Khuder, S. A. (June 01, 2007). Depression and Anxiety: Effect on the Migraine–Obesity Relationship. Headache: the Journal of Head & Face Pain, 47, 6.)

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