The Brain Tsunami: Implications and Mechanisms of Migraine Aura

Eli Kanetsky

Illustrations by Alexandra Adsit

Everyone is bound to experience a headache at some point, whether it be from poor sleep the night before or from seasonal allergies. However, only about 10% of people experience migraines, a subset of headaches characterized by a unique set of intense symptoms [1]. Imagine you have a friend named Maya, who has been plagued by migraines her entire life. When she experiences a migraine attack, Maya feels a strong, pulsating pain on one side of her face that lasts for several hours [2]. Her throbbing headache is often combined with nausea, dizziness, and a sensitivity to light, differentiating it from what is considered a typical headache [2]. Interestingly, Maya can occasionally predict that a migraine attack will occur when she notices peculiar changes in her vision, like a blurry patch or floating bright dots. These bizarre visual manifestations that Maya experiences are part of a collection of symptoms referred to as migraine aura [1]. Unfortunately, the discomfort caused by migraine aura symptoms may not be easily relieved as there are no current treatments that specifically target aura. Nevertheless, numerous aura-specific treatments are undergoing testing and show promise in reducing migraine aura symptoms [1].

What is Migraine Aura?

Migraine aura is defined as a collection of temporary, neurological symptoms that can precede migraine headaches, affecting approximately a third of those who experience migraines [1, 3]. These symptoms can manifest in various ways, affecting linguistic, motor, or sensory functions, including difficulty speaking, motor fatigue, numbness of the limbs, or visual disturbances [4]. Our friend Maya experiences visual disturbances, which are the most common group of symptoms associated with migraine aura [2, 5]. Visual symptoms can be defined as positive or negative, depending on whether the visual aura ‘adds’ a hallucination or ‘takes away’ part of one’s vision, respectively [2, 3, 5, 6]. One instance of a positive symptom that Maya experienced was the appearance of colorful zigzags in her left visual field one morning. The zigzag pattern Maya saw is one of the most common forms of positive aura symptoms [5]. During another time, Maya stopped playing basketball with her friends after she noticed a blind spot that began interfering with her vision. The temporary blindness Maya experienced within a concentrated area of her vision is called scotoma, a common negative aura symptom [5]. In addition to zigzags and scotomas, other geometric shapes or light disturbances — including foggy vision, flashing lights, and black or white spots — are commonly experienced by individuals with migraine aura [5, 6]. Still, some individuals may hallucinate ‘complex aura,’ which means they picture entire people or objects, although this phenomenon is far less researched and understood [6].

The assortment of symptoms a person may experience is not the only unpredictable aspect of migraine aura [6, 7]. Aura symptoms can also vary from episode to episode in terms of their onset and duration [7]. Aura typically begins ten minutes before a migraine headache sets in, and lasts between five minutes and an hour, meaning that aura can occur before the start of a headache as well as continue during the headache [6]. The severity of each experience with aura may also differ — for instance, when Maya saw zigzags, they vanished shortly afterward and were not accompanied by a migraine headache, allowing her to go about the rest of her day as usual. Contrarily, during her less fortunate experience playing basketball, the blind spot continued for an hour and overlapped with a painful headache, forcing Maya to recuperate at home for the rest of the day. Evidently, experiencing aura can be stressful and disorienting, potentially interfering with one’s daily activities [6, 8]. As distressing as aura symptoms may be, the causes of migraine headaches and aura are not fully understood [1, 2]. Thus, working to understand the mechanisms underlying aura may help narrow this gap in knowledge and reveal more about migraines as a whole [1, 2].

CSD: The Wave Underlying Migraine Aura

While there are multiple theories surrounding the processes that generate migraine aura, the leading explanation is that cortical spreading depression (CSD) may be the underlying mechanism [3, 4, 6]. CSD can be understood when broken down into a few different stages. The first stage of CSD involves a wave of activity in the outermost layer of the brain, called the cerebral cortex [6, 9]. Brain cells that specialize in receiving and transmitting information, called neurons, are found throughout the brain, including within the cerebral cortex [10]. At rest, neurons have a more negative charge inside compared to their more positive surroundings [11]. This resting state can be changed through a process called depolarization, which alters the distribution of electrical charges and makes the inside of the cell more positive. Typically, when depolarization occurs and the neuron reaches a certain threshold of positivity, the neuron will ‘turn on’ to communicate with other cells, which is referred to as an action potential. The relationship between depolarization and an action potential is analogous to flushing a toilet: to flush a toilet, the handle must first be pushed down enough. Similarly, to cause an action potential, a neuron’s voltage must be made positive enough. Then, once the toilet is flushed, it cannot un-flush. Action potentials work the same way — they either happen fully or do not happen at all [11].

While depolarization and action potentials are important functional mechanisms in the brain, these processes occur at an abnormally large scale in CSD [6]. Once one neuron is depolarized during CSD, the change in the distribution of charges also affects neighboring neurons, inducing depolarization in those neurons as well [6]. The activation of surrounding neurons then leads to more depolarization, causing a self-sustaining wave of spreading neuron activation [12]. This wave of activity that passes through the cerebral cortex constitutes the first stage, or the spreading stage, of ‘cortical spreading depression’ [6]. Therefore, CSD can be thought of as a ‘brain tsunami;’ each activated neuron acts like a droplet of water, accumulating to form a massive tsunami of neural activation. After the ‘brain tsunami’ occurs, however, it takes a prolonged amount of time for the affected area of the brain to return to baseline neural activity [6].

The disruption following the ‘brain tsunami’ constitutes the second stage of CSD — a period of suppressed neural activity across the cerebral cortex caused by the massive redistribution of charges in the first stage of CSD [6, 12]. Typically, depolarization and action potentials are followed by repolarization, during which the inside of a neuron returns to its resting, negative state before another action potential can occur [11]. The restoration of a negative charge via repolarization is similar to what happens after a toilet is flushed. Once water is drained from the toilet bowl, the water has to return before the toilet can be flushed again. If the water does not return properly, the toilet is ‘stuck.’ The toilet getting stuck is symbolic of what goes wrong during CSD: neurons do not undergo repolarization and thus cannot return to their normal functions, inducing a period of inactivity during which they are unable to fire [12]. As hinted at through the name ‘cortical spreading depression,’ the period of activity suppression constitutes the stage of CSD that is an inhibition, or depression, in neural activity [6, 12]. Fortunately, due to the temporary nature of CSD, inhibited neurons eventually repolarize and return to normal function [12]. All in all, CSD can be conceptualized as a wave of depolarization across the cerebral cortex, followed by a period of neural inhibition in the same region [1, 6]. 

BOLD Connections Between CSD and Migraine Aura

So, what’s the connection between CSD and migraine aura? Establishing a relationship between the two is done primarily by observing blood flow changes in the brain during migraine attacks with aura [3, 13]. Tracking the movement of blood flow can be used to visualize neural activity, elucidating similarities between neural activity seen in migraine aura and in CSD [13]. In CSD, cerebral blood flow initially increases before subsequently decreasing below its baseline level [3, 14]. The ‘rise and fall’ pattern of blood flow observed in CSD meets our brains’ demand for oxygen and nutrients — a wave of depolarization calls for more blood flow to sustain neural activity, whereas a period of inactivity that follows depolarization requires fewer resources [3]. Functional MRI (fMRI) is used to observe the relationship between the characteristic blood flow pattern in CSD and the blood flow pattern seen during instances of migraine aura. fMRI often uses Blood Oxygen Level Dependent (BOLD) signals to map brain activity by measuring changes in blood flow that reflect neuronal activity [13]. When a person experiences an instance of visual migraine aura and simultaneously receives an fMRI scan, an initial increase and subsequent decrease in BOLD signals is observed, indicating a rise and successive decline of cerebral blood flow [7, 14]. Therefore, cerebral blood flow increases and decreases during aura in a way that parallels neuronal activity and blood flow in CSD [7]. Additionally, the BOLD signal spreads at the same rate as the spread of CSD, which supports parallels observed between migraine aura and CSD [3]. 

Another similarity between blood flow in CSD and instances of migraine aura is the distinction between positive and negative aura symptoms [2, 6, 15]. The specific phases of activity in CSD are related to the occurrence of positive and negative symptoms — positive symptoms correspond with the wave of depolarization, and negative symptoms with the period of inactivity — and the blood flow patterns of each phase reflect this connection [2, 6, 15]. Accordingly, BOLD signals of individuals experiencing positive aura symptoms increase, but decrease while they experience negative aura symptoms [15]. An association can therefore be drawn between specific types of aura symptoms and different neural responses during CSD [15]. Beyond the correlation between CSD and migraine aura, a connection between CSD and the type of pain experienced during migraine headaches may also exist [3, 16]. Migraine headaches can be triggered by the activation of a group of neurons that form the trigeminal nerve, a cranial nerve involved in pain transmission and blood flow regulation [3, 16, 17]. CSD can trigger the activation of the trigeminal nerve, which could result in the pain associated with migraine headaches [3, 16]. If CSD is involved in both migraine headaches and aura, CSD may be a crucial connection for clarifying the physiological processes of both these aspects of migraine attacks. 

Complex Currents: Migraine and Other Health Concerns

In addition to CSD’s implications for migraine with and without aura, CSD may serve as an overall connection between other conditions that are comorbid with, or that typically coexist with, migraine [3, 18, 19, 20]. Individuals who experience migraine with aura are at a higher risk of experiencing ischemic stroke, a type of stroke characterized by reduced cerebral blood due to blockage of blood flow to the brain [3, 21]. People who experience migraine with aura are at double the risk of developing ischemic stroke in their lifetime compared to people who do not have migraines at all. In rare circumstances, an episode of aura may be severe enough to cause an ischemic stroke [12, 22]. In contrast, there is no established connection between experiencing migraine without aura and the occurrence of ischemic stroke [3, 22]. However, the exact nature of the relationship between ischemic stroke and migraine with aura is also difficult to interpret due to confusion as to whether stroke or aura occurs first [22, 23]. Furthermore, complications in distinguishing ischemic stroke from migraine with aura arise from the misdiagnosis of migraine aura with a transient ischemic attack — a separate brain dysfunction caused by reduced blood flow that can be a sign of an oncoming ischemic stroke [22, 23]. Nevertheless, migraine with aura and ischemic stroke may be connected through the decrease of blood flow during the period of inactivity in CSD [24]. The decrease in blood flow may not only lead to ischemic stroke but can also increase the intensity of the stroke experienced [12, 22, 24].

A comorbidity between migraine both with and without aura and epilepsy is also observed [24]. Epilepsy, a disorder characterized by recurring seizures, is considered related to migraine disorders because the two share many similarities, which may cause difficulty in distinguishing them from one another [19, 20]. Both epilepsy and migraine with aura seem to share underlying pathophysiological mechanisms that can lead to hyperexcitability, a state in which neurons are more likely to activate than usual [18, 19, 20, 25]. In epilepsy, hyperexcitability leads to unrestricted depolarization and may cause groups of neurons in the cortex to fire action potentials simultaneously, which is a crucial part of the development of seizures in epilepsy [24]. In migraines, the depolarizing effects of hyperexcitability may progress into CSD [19, 24]. Hyperexcitability’s possible role in migraines is supported by the fact that individuals who experience both migraines with or without aura demonstrate increased hyperexcitability in the visual processing area of their cerebral cortex compared to individuals without migraine at all [26]. In addition to similarities in epilepsy and migraine aura initiation, the two phenomena are also connected through migraine aura-triggered seizures, which are characterized by an epileptic attack during or within an hour after the occurrence of migraine with aura [2, 19, 24]. Due to similarities in epilepsy and migraine aura — including resemblances in visual aura and possible sensory disturbances in epilepsy — misdiagnosis may occur when identifying migraine aura-triggered seizures since it is difficult to differentiate which characteristics may be attributed to epilepsy and which to migraine aura [19, 20]. 

Glutamate: A Potential Therapeutic Target

While it becomes apparent that CSD may underlie migraine with aura and other related disorders, there is no current treatment that targets aura [1]. A potential aura-specific treatment may aim to suppress CSD by targeting its mechanism of initiation [1]. The initiation of CSD involves the release of glutamate, an excitatory neurotransmitter that is often released by neurons after firing an action potential [1, 4, 27, 28]. After being released, glutamate binds to receptors on neurons that stimulate depolarization and trigger action potentials [28]. If an action potential is like a toilet flushing, excitatory neurotransmitters are like your hand — the force that increases the pressure put on the toilet handle. When pressure pushes the handle down enough, the toilet flushes. Glutamate’s excitatory role may be a significant aspect of the initiation and spreading of CSD [4, 27].

Glutamate can notably ‘turn on’ certain receptors that play a crucial role in the generation of CSD [4, 27]. The specific type of glutamate receptors involved in the stimulation of CSD are called NMDA receptors [29, 30]. When NMDA receptors are activated, they provide a channel for positive charges to travel into the cell, making the cell more likely to depolarize [31]. So, when a stimulus triggers the release of glutamate, glutamate binds to and activates NMDA receptors, and this contributes to depolarization [27]. NMDA receptor activity likely plays a role in the prolongation and spreading of depolarization in CSD, as well [27, 30]. By creating a way for positive charges to flow into neurons continuously, active NMDA receptors initiate the self-propagating nature of depolarization in CSD [30]. Furthermore, NMDA receptors are necessary for CSD to occur because CSD can be completely inhibited when NMDA receptors are blocked [1, 30]. 

Due to the role of NMDA receptors in CSD, NMDA receptors may be a useful target for managing migraine aura symptoms [1, 4]. Ketamine, a quick-acting general anesthetic, has been explored as a potential treatment for migraine aura because of its ability to block the action of NMDA receptors [1, 4, 32]. Ketamine can reduce the severity of aura symptoms, but does not always impact the duration of aura [1, 29]. In a small subset of people, the use of ketamine has even stopped aura symptoms altogether [29]. Ketamine is an effective NMDA receptor blocker, but it has potential adverse side effects including nausea, high blood pressure, abnormally high heart rate, and dissociation [1, 29, 33]. However, ketamine’s ability to reduce aura symptoms illuminates the utility of targeting NMDA receptors as a method of regulating migraine aura. 

Gaining a greater understanding of migraine aura and its mechanisms may elucidate the functions of a myriad of neural systems. Currently, however, most studies regarding migraine treatments include a variety of people both with and without aura, making it difficult to develop a treatment based on one subtype of migraine [1]. Differentiating experiments to focus on either people experiencing migraine with aura or people experiencing migraine without aura may be a promising direction for managing specific aspects of migraine attacks [1]. Using such an approach to develop an aura-specific treatment may help in alleviating harrowing aura symptoms, and reveal how migraine with aura relates to debilitating phenomena such as ischemic stroke and epilepsy [3, 18, 19]. Fortunately, applying the knowledge that blocking NMDA receptors can inhibit CSD means that continuing research on the effects of drugs on NMDA receptors may eventually illuminate a successful way to suppress CSD and manage migraine aura symptoms [1, 29]. Future research should build off of current knowledge and pursue separate studies between migraine with and without aura to solidify our understanding of migraine aura and lead to the development of aura-specific treatments [1].

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