Throwback Thursday: Neuroanatomy and Pathophysiology of a Migraine

Abstract

Migraines are a common but disabling form of severe headache. Patients with more than fifteen migraines per month are considered to have chronic migraines. Alongside severe headache, migraines are associated with allodynia, fatigue, nausea, vomiting, and light and sound sensitivity. About one-third of migraine sufferers will experience “aura” which often presents as colorful or blacked out spots in the visual field, about ten to thirty minutes before the onset of a migraine. Patients with migraines with aura have increased cardiovascular health and stroke risks compared to those with migraines without aura. The prevailing theory of migraine pain links migraine headaches to the trigeminal system and cortical spreading depression. Other theories involve various genes and mutations, including calcitonin gene-related peptide (CGRP), as well as neurotransmitters such as serotonin and glutamate. 

Neuroanatomy and Pathophysiology of a Migraine

Migraines are a “common, recurrent, hereditary neurovascular headache disorder” (Burstein et al., 2015). Patients often begin experiencing migraines in childhood, usually a couple every year, which can progress to multiple migraines per month or week in adulthood. Migraines are differentiated from typical headaches by the presence of aura, a warning sign which takes the form of colors or spots in the visual field which may be accompanied by nausea, vomiting, head pain largely restricted to the periorbital area, and sensitivity to light, smell and noise (Burstein et al., 2015). Though, some people experience migraines without auras. 

Migraines are the second most prevalent type of primary headache, and are considered the “most disabling form of primary headache” (Pradeep et al., 2020). Chronic migraines, defined as severe headaches more than fifteen days per month, affect about 1% of the population (Becker, 2017). A majority of migraine sufferers are women, mostly between the ages of 18-44 (Burch et al., 2015).  Most patients with migraines report that they significantly decrease their quality of life, with anxiety and depression having high comorbidity with migraines (Pradeep et al., 2020).

There are several current theories as to why migraines happen. The current prevailing theory says that migraines are a result of cortical hyperexcitability, and that the pain of a migraine is linked to the trigeminovascular pathway. Other theories involve mutations of genes regulating serotonin, glutamate, or synaptic plasticity. 

This review will examine: the clinical definition and diagnosis of migraines, the various theories for the neuroanatomical basis and pathophysiology of migraines, and briefly overview the current treatments for migraines.

Clinical Definition of a Migraine

Migraines are distinguished from typical headaches, such as tension headaches, by their intensity of pain and the association of concurrent symptoms such as nausea, vomiting, temporary vision loss, seeing spots or colors, or sensitivity to light and sound. The pain of a migraine is also typically localized to one side of the head, usually behind the eye or ear (Burstein et al., 2015). Migraines are subdivided into “migraines with aura” and “migraines without aura” – where aura is a warning sign, typically ten to thirty minutes before a migraine attack, which can include seeing flashing lights or colors, or tingling and numbness in the hands or face (Viana et al., 2019). Migraines with auras are associated with increased risk of cardiovascular disease, ischemic attacks and epilepsy. 

Depending on the frequency, a patient can be diagnosed with episodic (or occasional) migraines, or chronic migraines (defined as fifteen or more migraine attacks per month). An overuse of abortive migraine medication is thought to contribute to the progression from episodic to chronic migraines (Deneris et al., 2017; Mathew, 2011).  Those who suffer from chronic migraines typically also have a secondary diagnosis of medication overuse headaches (Becker, 2017). One study found that patients with more than ten migraines per month used more NSAIDS to medicate their migraines, which correlated to increased risk of developing chronic migraines. However, the use of NSAIDS decreased the risk of developing chronic migraines in patients with less than ten headache days per month (Lipton et al., 2013).

There are structural changes associated with chronic migraines of reduced cortical gray matter as well as iron accumulation, which correlate to the duration of migraines and are more pronounced in patients with chronic migraines as opposed to episodic migraines (Mathew, 2011). Instances of cortical excitability as well as migraine symptoms such as allodynia (the experience of pain from a stimulus which is not typically painful) are also increased with chronic migraines, which is linked to the chronic sensitization of nociceptive neurons (Mathew, 2011). This chronic sensitization is thought to contribute to the resistance to treatment often seen in chronic migraines.  

Phases of a Migraine

Migraines can be divided into phases: premonitory, aura, headache, postdrome and interictal (Dodick, 2018). The premonitory, or predrome, phase begins up to three days before the onset of the headache, and is linked to nociceptive signaling from the nuclei in the hypothalamus and brainstem. About one-third of patients experience aura. The visual symptoms of aura indicate the involvement of the visual pathways in some capacity. The prevalent theory for the cause of migraine aura is cortical spreading depression (CSD) which is a slowly propagating wave of neuronal and glial cell depolarization and hyperpolarization, beginning in the occipital lobe (Shibata, 2007). 

The headache of a migraine is linked to the trigeminovascular system. Many headache and facial pain disorders, migraines included, fifth cranial nerve, or trigeminal nerve, involvement. “Nociceptive activation of C- and Aδ-fibres” which are innervated by the trigeminal nerve are thought to play a role in the headache phase of a migraine (Edvinnson et al., 2020). The postdrome phase is the period between the end of the headache and being fully recovered, and is often accompanied by fatigue and a stiff neck. The interictal phase is the period between migraines attacks, which can be anywhere from months to hours (Dodick, 2018). 

Pathophysiology of a Migraine

There is some evidence that patients with migraines with aura have structural differences of the brain compared to those without migraines and those with migraines without aura. One study which looked at white matter alterations found that patients with migraine with aura have “decreased radial diffusivity bilaterally in the white matter of the parieto-occipital region and corpus callosum” (Szabó et al., 2018).  Another study found reduced cortical gray matter as well as iron accumulation, correlated to the duration of migraines and which are more pronounced in patients with chronic migraines as opposed to episodic migraines (Mathew, 2011). Migraine patients also show a thickening in parts of the subcortical white matter, particularly in areas involved in sensory processing, which is linked to hypersensitivity to visual, olfactory and auditory stimuli (Noseda & Burstein, 2013). 

Migraine Aura

As mentioned previously, about one-third of migraine sufferers experience aura. The prevailing theory explaining visual aura preceding migraines is cortical spreading depression, beginning in the occipital cortex, and is linked to the photophobia, or light sensitivity, which commonly accompanies migraines (Shibata, 2007). Cortical spreading depression is also indicated as an explanation for the allodynia experienced before and during a migraine, through the sensitization of brainstem trigeminal neurons (Mathew, 2011). 

Cortical spreading depression is defined as “a slowly propagated wave of depolarization followed by suppression of brain activity, [which] is a remarkably complex event that involves dramatic changes in neural, glial and vascular function” (Charles & Baca, 2013). The mechanism of cortical spreading depression in migraine aura is not completely understood, but is thought to involve molecular changes in cortical upregulation of genes involved in inflammatory processing such “cyclooxygenase-2, tumor necrosis factor-α, interleukin-1β, galanin, or metalloproteinases” (Borsook et al., 2015). Cortical spreading depression leads to activation and sensitization of dural nociceptors and dural perivascular trigeminal afferents, which is linked to the headache pain of a migraine which follows the aura. 

There is experimental evidence in animal studies done in rats which indicated that cortical spreading depression can activate the “ipsilateral trigeminal nucleus caudalis neurons, resulting in a long-lasting blood flow increase in the rat middle meningeal artery, and leakage of dural plasma protein, that can be inhibited by section of the ipsilateral trigeminal nerve” (Bolay et al., 2002). However, current research is divided over whether cortical spreading depression plays a significant role in the cause of migraines because only some patients experience aura before the headache. 

Trigeminovascular Pathway and Hyperexcitability 

As mentioned above, headache pains are associated with the trigeminovascular system. During the premonitory phase of a migraine, dysfunction occurs in the brain stem and diencephalic systems which leads to sound and light sensitivity which eventually progresses to headache pain through the trigeminal neurovascular afferent pathway (Goadsby et al., 2017). 

The trigeminocervical nucleus receives stimulus from nociceptors as well as from afferent fibers from the spinal tract of the trigeminal nerve and the C1 through C3 spinal nerves, and terminates in the trigeminocervical nucleus (Saito, 1996). Upper cervical nerves and the glossopharyngeal and vagal nerve afferents also terminate in the trigeminocervical nucleus, and the convergence of these stimuli can  conduct impulses which is perceived as a headache. The headache pain of a migraine is often localized around the periorbital area and behind the eye, as well as sometimes behind the ear, which follows the innervation of the trigeminal nerve in the face (Burstein et al., 2015). 

Migraine pain can present as either intra- or extracranial pain and sensitivity. Intracranial pain is described as a throbbing headache, and patients often report that even mundane activities worsen the pain. Extracranial pain is accompanied by allodynia, and patients often report their skin, particularly of their face, hurting, with the pressure from wearing glasses or tight clothing aggravating the face. Sensitization of neurons which innervate the meninges as part of the trigeminovascular is linked to intracranial pains, while sensitization of third-order trigeminovascular neurons in the posterior thalamic nuclei are linked to extracranial pains (Bernstein & Burstein, 2012). Migraine related pains of tenderness and nausea are linked to the spinal trigeminal nucleus, and “stems from noxious signals from sensate intracranial and extracranial structures, including cerebral vasculature, scalp muscles, and neck muscles” (Yanes, 2019). Patients who suffer from migraine with aura have abnormal visual and trigeminal hyperexcitability which persists during and between migraine attacks (Shibata, 2007).

Activation of the trigeminal system induces a vascular response, which is thought to play a role in triggering a migraine in susceptible individuals. Specifically implicated are calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide which play a role in the nociceptive activity in the trigeminovascular system (Hoffman et al., 2017). 

The sensory fibers which inverate the intracranial blood vessel originate in the trigeminal pathway, and neurotransmitters such as glutamate, neuropeptides and dynorphins such as “Calcitonin Gene-Related Peptide (CGRP), serotonin, amylin, substance P, neurokinin A/B, Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)” are stored in those neurons (Edvinsson et al., 2020). Reception of these neurotransmitters are critical for pain processes and headache perception. Migraine pain seems to rely on the CGRP pathway in the trigeminovascular system. Satellite glial cells cover the sensory neurons in the trigeminovascular system, and are critical for glutamate regulation.  Satellite glial cells are involved in the perception of neuropathic pain, and are involved in the “sensorial malfunctioning leading to maladaptive plasticity that are responsible for chronification process widely described in common forms of headache (e.g. migraine)” (Edvinsson et al., 2020). 

Some therapeutic methods have been studied to alleviate pain originating from the trigeminal pathway include “triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators” (Goadsby et al., 2017). The exact mechanism of the role of peptides and neurotransmitters is not completely understood however.

Other Theories of Migraine Causes

As migraines are largely attributed to genetic predisposition, some theories for the causes of migraines are centered on gene mutations and neurotransmitter metabolism. One major area of research is “serotonin metabolism after an increase of 5-hydroxyindoleacetic acid (5-HIAA)” which is elevated in migraine patients (Gasparini et al., 2017). Migraine patients both with and without aura tend to have insufficient serotonergic input, which is thought to be genetically linked, and is believed to contribute to vulnerability to migraines. One specific gene which is implicated is the serotonin transporter gene SERT. However, the possible effect of differing neurotransmitter metabolism in migraine patients is not well understood. 

Another theory behind the genetic evolution of migraines suggests that migraines are a response to “cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity and that the attack itself helps to restore brain energy homeostasis and reduces harmful oxidative stress levels” and thus a result of abnormalities in energy metabolism and mitochondrial function in patients with migraines (Gross et al., 2019). 

There is one rare subtype of migraine with aura, called hemiplegic migraine where patients experience weakness in one side of the body concurrent with migraine attack. Studies have linked hemiplegic migraines specifically to mutations in the CACNA1A, ATP1A2 and SCN1A genes, which encode the α1 subunit of a calcium channel called CaV2.1, α2 subunit of the Na⁺/K⁺ ATPase and α1 subunit of the neuronal voltage-gated sodium channel Na_v1.1 specifically (Sutherland et al., 2019). These mutations result in impaired glutaminergic transmission and cortical hyperexcitability. Because of this, other gene mutations which affect the function and regulation of ion channels, neurotransmitters and vascular function are suspected to play a role in migraine susceptibility. 

Migraines have been identified to have comorbidity with epilepsy and major depressive disorder, which leads many to believe that there is a shared underlying pathophysiology between these disorders involving serotonergic dysfunction in the brain (Deneris et al., 2017). Because of this, medications for epilepsy and depression are sometimes used to treat migraines. 

Migraine Treatments

Because migraines are both common and potentially disabling, treatment is a major area of research. Only about two-thirds of patients with migraines who seek medical treatment are prescribed medication. 

Treatment of migraine headaches has three major components: “1) treatment of acute attacks (abortive therapy), 2) prevention of subsequent episodic attacks, and 3) mitigating the potential for episodic migraines to progress to chronic migraines” (Deneris et al., 2017). Managing episodic migraines focuses on abortive treatment, which seeks to lessen the duration and intensity of a migraine after the onset of aura or pain symptoms. Treatment of chronic migraines most often focuses on preventive therapies to reduce the number of, frequency and severity of migraine attacks. 

Besides medications, another goal of treatment is identifying and avoiding patient-specific migraine triggers. Lifestyle modification and trigger reduction is a major focus of migraine treatment. Triggers often become easier to recognize as chronic migraines start to improve with medication. Reduction of stress, as well as eating, sleeping and hydrating properly are shown to reduce the frequency and intensity of migraines (Weatherall, 2015). 

Nonsteroidal anti‐inflammatory drugs (NSAIDs) or acetaminophen are often used as a first‐line abortive therapy for those with acute and episodic migraines. 

Many patients self-medicate with over-the-counter medications such as NSAIDS, and an abuse of this medication can contribute to the increase in frequency of migraines and the progression from episodic to chronic migraines in patients with more than ten headache days per month (Deneris et al., 2017; Lipton et al., 2013; Mathew, 2011). This overuse can also contribute to a secondary diagnosis of medication overuse headaches (Becker, 2017). 

Those with chronic migraines often do not respond to these over-the-counter medications. Currently, the most common treatment for chronic migraines are prophylactic medications for prevention and reduction of monthly migraines days. There are two prophylactic drugs with high efficacy in preventing chronic migraines: topiramate and onabotulinumtoxinA (Becker, 2017). Serotonin receptor agonists (5‐HT1B/1D), known as triptans are the most commonly prescribed abortive medication for chronic migraines. 

Sleep is also an effective disrupter of migraine activity, and many patients “sleep off” their migraines even after taking abortive medication. In extreme cases where the migraine attacks are severely disabling and no other treatment seems effective, techniques such as electroconvulsive therapy, peripheral nerve stimulation, and transcranial nerve stimulation may be prescribed (Brennan & Pietrobon, 2018).

Conclusion

Migraines are a common and disabling form of primary headache, which can be categorized as episodic (occasional) or chronic (occurring fifteen or more days per month). About one-third of patients with migraines present with aura, which involves seeing spots and colors in the visual field and occurs about thirty minutes before the onset of head pain. Aura is associated with cortical spreading depression, hyperexcitability, photophobia and increased allodynia compared to migraine without aura. Migraines are considered to be genetic, and the head pain is largely attributed to the trigeminovascular pathway. Genes involving the metabolism of the neurotransmitters serotonin and glutamate are also implicated in migraines, as well as calcitonin gene-related peptide (CGRP). Treatments for migraines include lifestyle changes, abortive medications such as NSAIDS and triptans, and prophylactic and preventive medications such as topiramate and onabotulinumtoxinA. An overuse of abortive medication, particularly NSAIDS, is known to contribute to a progression from episodic to chronic migraines. While migraines can be reduced in frequency and intensity with treatment, someone who is susceptible to migraines will likely always experience migraines and never be completely cured.       

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