Evolution and migraine are discussed in the outstanding article “Did Going North Give Us Migraine”.1 The accompanying editorial, “Toward a Philosophy of Migraine” is remarkably thought provoking.2 Analyzing evolutionary processes with regards to disease is more than an academic exercise. Taking evolution into account is vital for a complete understanding of the disease. Interpreting the evolutionary underpinnings of illness may help us in developing safe and effective treatments.
Illness may be viewed through two lenses:
- A proximate view.
- An evolutionary lens.
The proximate view involves the nuts and bolts of a disease: biochemistry, pathophysiology, treatment, etc. It is equally important to view the disease process through an evolutionary lens.3 One primary question is: why have migraines persisted, and why is our species still so vulnerable to migraine? The proximate explanation is that migraine is a physical trait, involving multiple physiologic processes. The evolutionary question asks: “why does our DNA code for migraine?”
Much of evolution involves various trade-offs. The sickle cell gene protects against malaria, but actual sickle cell disease is devastating. Cystic fibrosis is similar to the sickle cell story. Heterozygotes for cystic fibrosis were less likely to suffer dehydration from illnesses such as cholera. Genes exist in order to propagate themselves (the “selfish gene”), sometimes to the detriment of the organism.4 This is the case with migraine. There are possible evolutionary benefits to having migraine.5 It is also conceivable that the benefits are few, and our species simply remains remarkably vulnerable to migraine. Evolution tinkers; it does not invent. There are a number of genes involved in migraine, and evolution does not possess mechanisms to easily eliminate “bad genes”.5
Humans probably suffered an increase in migraines as a result of our northern migration.1 Low vitamin D levels may help to explain the increased migraine prevalence at northern latitudes.6 The TRPM8 gene involves a receptor that plays a role in thermoregulation and cold sensation. TRPM8 (the “T” variation) is also associated with increased migraine risk.7 Those who carry this “T” variant of TRPM8 are better adapted to cold environments. This probably resulted in enhanced survival and reproductive success. Migraine may have been the negative trade?off for this cold adaptation. The TRPM8 and latitudinal studies were the first to link evolution, geography, natural selection, and migraine.1
The reasons for the persistence of migraine are varied. The prevalence of migraine may be increasing, although we do not have epidemiologic data from past millennia. A heightened sensitivity to sound, smells, and light could be advantageous under certain conditions. Migraine may provide some benefit in fighting certain infections.5 This may occur via an enhanced immune response, or by an increase in blood flow. Only 1% of women and 7% of men never suffer from headaches, indicating that there may be some evolutionary benefit derived from headache.
Some genes are harmless “quirks” in one environment, but deadly in another. Our modern environment certainly contributes to migraine frequency. After millions of years of evolution, our environment has radically changed.8 For almost all of human history, we were primarily hunting and gathering. The Southwest Asia “fertile crescent” societies only began to domesticate animals and cultivate plants 10?12 thousand years ago. The many factors that may contribute to an increase in migraine frequency include changes in culture, living circumstances, agriculture and diet, environmental toxins, densely packed populations, infections (particularly viral), harsh indoor lighting, excessively loud sounds, poor sleep, and increased stress.5 When modern hunter?gatherer societies begin to consume our “western diet,” they suffered from an increase in cancer and heart disease.9 One example (of many) demonstrating the effect of a changing environment on disease involves the genes for heart disease. These genes may not have been particularly deleterious for Stone Age humans, due to short lifespans. Now that we are living significantly longer, these genes have become dangerous. Phenotypic and adaptive plasticity may have played a key role in our adaptation to the changing environment.3
Migraine is more common in women than in men. The evolutionary reasons for this are unclear. Men generally did most of the hunting and gathering for which migraine may present impediments. For child-rearing, preparing food, and taking care of the home, migraine may possibly provide small evolutionary advantages. Migraine often lessens during pregnancy, offering an evolutionary incentive for more pregnancies.
It is likely that humans are the only species susceptible to migraine. Our ancient brainstem has challenges in coping with the recently enlarged cortex. Our brainstem may become overwhelmed with excessive afferent input. Higher cortical functions that are not found in other primates may render us susceptible to migraine.
Migraine may act as a defense mechanism against excessive noise, light, or stress.5 The heightened sensitivity to smells may protect from viruses or toxins entering the CNS. Vomiting may help to expel toxins. As compared to those without migraine, women migraineurs probably have a lower prevalence of type 2 diabetes.10 An activation of the trigeminal nuclear complex could be protective.5 If migraine is protective for an individual, that person’s genes may be propagated more readily. If an ancestral human suffered from 100 migraines over a year, but just one of those migraines protected the person from harm, the trade?off would have been worthwhile. The evolutionary cost of migraine may be inexpensive.
We must distinguish between a defense and a defect. Cough is a defense, but becoming blue from hypoxia is not. We do not want to eliminate our natural defenses. The calcitonin gene?related peptide (CGRP) that is associated with migraine may be beneficial under stress.11 CGRP has existed in various species for the past 180 million years. CGRP serves a number of roles in the body, some positive, some harmful.11 Under stress, CGRP is beneficial for our cardiovascular and cerebrovascular systems. Blocking this natural defense, as happens with our CGRP monoclonal antibodies, may lead to harm.
Natural selection depends upon reproductive success. After the reproductive years, a particular trait may have deleterious consequences, but that does not affect propagation of the gene. For understanding a trait (or disease) such as migraine, we must consider all of the various evolutionary processes. These include mutations, migration, natural selection, genetic drift, and non?random mating.3 Natural selection sometimes produces opposing effects, and the result is increased vulnerability to disease.
It is important not only to view individuals through an evolutionary lens but to examine the phylogeny of the species.3 Relationships among humans have changed in the past 12,000 years.8 One of the primary factors driving these phylogenetic changes is the increased population density, with most humans living within significantly smaller spaces. Culture, which influences our state of disease or health, may also have contributed to an increase in headache.
Pain and headache are adaptive responses. Being still, or in bed, may help in the repair of damaged tissues. Inadequate or incomplete natural selection is often blamed for our diseases or flaws, but it is more likely that many illnesses are the result of compromises and design flaws.12 For instance, our esophagus crosses the trachea. As a result, our airway must be closed every time that we swallow, lest we choke. Nearsightedness, atherosclerosis, allergies, and nausea in pregnancy are similar conditions, resulting from evolutionary compromises, along with design flaws.12, 13
Intrinsic vulnerability is an important evolutionary concept.14 It helps in determining whether a species is vulnerable to a disease or is somewhat resilient. Our species matures slowly, with infrequent reproduction. This is one factor in our enhanced vulnerability to certain diseases. It is difficult for our species to eliminate genes that cause harm. Migraine involves a number of factors and genes, and it is unlikely that natural selection would be able to eliminate migraine.
To understand migraine, we should venture beyond the proximate and physiologic processes. The evolutionary underpinnings of migraine are vitally important to study. The evolutionary history may help us in evaluating the safety of new treatments, such as the CGRP monoclonal antibodies. We ignore evolution at our peril.
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