Migraines are one of the most prevalent neurological disorders and are ranked the seventh most disabling disease globally . They are estimated to affect 12–20% of the adult population and are more prevalent than diabetes, epilepsy and asthma combined [1–2]. Despite previous misconceptions, the most common being that migraines are a “bad headache”, a migraine is a sensory processing defect within the brain. This affects how the brain deals with incoming information, causing normally harmless inputs to be painful [3–4]. Over the past decade, the understanding of migraine pathophysiology has significantly advanced. Improved characterization and diagnosis of the symptoms have revealed migraines to be a complex disorder. Thus, the aim of this editorial is to shed light on the key advances in migraine genetics, their neurobiology and future outlook.
Headache vs migraine
Migraines are often mistaken for headaches; however, the latter is often a symptom of an attack. Difficulty to diagnose and characterize the wide range of migraine triggers and symptoms has been a long-standing issue, which has resulted in few effective treatments. The characterization of a migraine includes a severe re-occurring headache that can lead to other symptoms such as nausea, phonophobia and photophobia, where the most severe can lead to transient focal neurological symptoms termed auras . Clinically there are several different types and stages of migraines and they were previously believed to be a vascular disorder. However, some essential elements that need to be considered are the genetics, physiological mechanisms and the anatomy of the migraine pain . In recent years, a strong genetic basis for the neurobiology of migraines has been determined.
Advances in migraine genetics
Genome-wide studies have contributed significantly to identifying the genetic components involved in migraines, although the neuropathophysiological mechanisms remain a complex puzzle to solve. For centuries researchers have been working to prove or disprove four possible theories that could be the cause of migraines (see Table 1).
|Table 1. The neuropathophysiological theories for migraines.|
|Vascular||Increased dilation of cerebral blood vessels results in migraines.|
|Depolarization||Disruption to the structure and function of ion channels affects the depolarization and repolarization of sensory neurons.|
|Serotonin||A sudden increase in serotonin release causes the attack.|
|Hyperthyroidism||Low thyroid hormones increase migraine susceptibility.|
|Data taken from .|
To this day, it is still unknown as to what specifically causes a migraine, however, researchers anticipate that it is a combination of all the theories listed.
“This could suggest that migraine symptoms arise from abnormal ionic transport, neuronal excitability and/or neurotransmission…”
One of the most important aspects of the pathophysiology of migraines is the inherited nature and genetic factors. Genetic studies have identified over 40 different loci associated with migraines . Over 70% of individuals who have reported having migraines have a family history of occurrence. In addition to this, many of the identified genetic mutations affect proteins essential for regulating neuronal membrane potential . This could suggest that migraine symptoms arise from abnormal ionic transport, neuronal excitability and/or neurotransmission . Therefore, studies focusing on the functional consequences of these mutations is a thriving area of migraine research.
The discovery of a mutation in TRESK in 2010, which is a frame shift mutation in the KCNK18 gene, is a prime example for this . TRESK is a calcium-activated two-pore domain potassium channel that is responsible for setting and maintaining the membrane resting potential of the trigeminal ganglia and dorsal root ganglia. Trigeminal fibers surround multiple brain structures and are key neuronal circuits in detecting pain. It is anticipated that migraine pain involves the activation and sensitization of trigeminovascular pathways and an altered state of excitability. This combined with primary dysregulation of sensory processing could lead to the wide range of neurological symptoms observed in migraines . This explanation for migraine neurobiology backs the depolarization theory, and several more recent studies have also added to this growing body of evidence [6–10].
The neurobiology of migraines and CGRP
“Therefore, CGRP is important in modulating nociceptive input and disruption to this system can cause normally harmless inputs to become painful.”
The discovery of TRESK was not the only finding that suggested a disruption to the trigeminal system and pain processing of the brain. In one study that utilized neuroimaging, a difference in the resting state of various pain processing areas (e.g., frontal cortex and temporal cortex) was noted in people with migraines compared with control participants . A role for the trigeminovascular system was also supported by the observation that CGRP – a multifunctional neuropeptide – is released during a migraine attack . It has also been suggested that CGRP plays an important role in the cardiovascular, integrative and gastrointestinal systems . When the trigeminal ganglion is stimulated, CGRP is locally released and results in vasodilation and pain. Therefore, CGRP is important in modulating nociceptive input  and disruption to this system can cause normally harmless inputs to become painful.
CGRP is known to have diverse activities within the body and CGRP-containing nerve fibers innervate every major organ system of the body . This could be a potential reason for the wide range of migraine symptoms observed. Considerable evidence points towards CGRP as a key player in the pathogenesis of migraines and it has been a key in determining more effective treatments (e.g., erenumab).
Treatment strategies and future outlook
While the complex mechanisms involved in migraine pathophysiology are starting to be uncovered, there remains an unmet need for treatments to prevent migraine attacks and the development of chronic migraines . Erenumab (Aimovig®) is a monoclonal antibody that blocks the CGRP receptor and was approved in 2018 by the US FDA for migraine prevention. This was a huge milestone in paving the way for the use of antibody therapeutics for migraine treatment. Since then, three additional CGRP monoclonal antibody drugs – fremanezumab (Ajovy®), galcanezumab (Emgality®) and eptinezumab – have been developed, as well as CGRP receptor antagonists .
“…while there are lots of different drugs for the treatment of migraines, it is unknown as to which one will be the first or best to use.”
Stephen Silberstein (Jefferson University Hospital; PA, USA) explained in a recent interview that while there are lots of different drugs for the treatment of migraines, it is unknown as to which one will be the first or best to use. Silberstein’s current research consequently focuses on 1) migraine drug markers, as there are little comparative trials available that compare older drugs to new drugs; and 2) combination therapies to investigate which drugs work better in combination .
There is great difficulty with treating migraines due to their heterogeneity. Richard Lipton (Albert Einstein College of Medicine; NY, USA) described that not only do the genetic and symptomatic profiles differ in migraine but also the prognosis and occurrence. This combined with the differences in treatment responses during clinical trials makes it challenging to treat. Therefore, a key goal is to identify homogenous groups that have similar symptoms, genetics and responses to treatment. Sub-group analysis could then make it easier to identify more effective treatment options to match different disease profiles .
Additionally, the future for migraine therapies may include personalized treatment, whether this be CGRP antagonists, TRESK-targeted drugs or combination therapy. As more is discovered about the neurobiology of migraines, this could guide the development of more effective treatments. There is a long way to go but the future for effective migraine treatment is hopeful.
“…what is exciting about migraine research at present is that there is an incredible collective of different approaches being investigated…”
In a recent video, Peter Goadbsy (Kings College London, UK) discussed the current state and future of migraine research. To conclude, he stated that what is exciting about migraine research at present is that there is an incredible collective of different approaches being investigated, including neuromodulation, noninvasive vagal nerve stimulation and transcranial magnetic stimulation. Goadsby also explained that while he was unsure of what we would have at our fingertips in 5–7 years, he was sure that there will be more effective and more tolerated treatments. This would result in patients and physicians being more satisfied with regards to treatment options for migraines .
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 Lafrenière RG, Cader MZ, Poulin JF et al. A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat. Med. 16(10), 1157–1160 (2010).
 Royal P, Andres-Bilbe, Prado P et al. Migraine-associated TRESK mutations increase neuronal excitability through alternative translation initiation and inhibition of TREK. Cell Press 101(2), 232–245 (2019).
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 Neurology Live. Positive outlook on the future of migraine treatment.
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The opinions expressed in this editorial are those of the author and do not necessarily reflect the views of Neuro Central or Future Science Group.
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