Cortical Spreading Depression: What Actually Happens in the Brain During a Migraine Attack

Among the neurological phenomena involved in migraine, cortical spreading depression occupies a central position. It is the mechanism that produces migraine aura, the perceptual disturbances that precede the headache phase in approximately one third of people with migraine. It is also believed to play a role in initiating the trigeminovascular activation that produces migraine pain, even in people who do not experience aura. Understanding cortical spreading depression provides a window into the neuroscience of migraine that goes beyond the surface description of symptoms and into the actual electrical and chemical events occurring in the brain during an attack.

What Cortical Spreading Depression Is

Cortical spreading depression was first described by the Brazilian neurophysiologist Aristides Leao in 1944. Working with animal models, Leao observed a wave of intense electrical activity in the cortex, the outer layer of the brain, followed by a prolonged period of suppressed electrical activity. This wave spread slowly across the cortical surface at a rate of approximately three to five millimeters per minute, moving outward from its point of origin in all directions like a ripple across water.

Leao called this phenomenon spreading depression because the initial wave of excitation was followed by a depression of normal electrical activity that persisted for minutes before gradually recovering. The combination of intense excitation followed by suppression distinguishes cortical spreading depression from other forms of brain electrical activity.

The connection between Leao's animal observation and human migraine aura was established over subsequent decades through a combination of neuroimaging studies, electrophysiological recordings, and the observation that the speed and direction of cortical spreading depression closely match the progression of visual aura symptoms in people with migraine.

How Cortical Spreading Depression Produces Aura

Visual aura, the most common form, typically begins as a small area of visual disturbance near the center of the visual field and expands over fifteen to thirty minutes, often taking the form of a scintillating scotoma, a crescent-shaped region of flickering or shimmering light that gradually moves toward the periphery of vision and leaves a blind spot in its wake.

This progression maps precisely onto the movement of cortical spreading depression across the visual cortex, the region of the occipital lobe that processes visual information. As the wave of cortical spreading depression moves across the visual cortex, it first activates and then suppresses the neurons responsible for processing different regions of the visual field. The expanding arc of the scintillating scotoma reflects the expanding arc of cortical activation, while the blind spot reflects the zone of neuronal suppression that follows.

Sensory aura, which typically produces numbness or tingling that moves from the hand up the arm to the face, follows the same pattern across the somatosensory cortex. Motor and speech auras, which are less common, reflect cortical spreading depression moving into the motor cortex and speech areas respectively.

The Chemical Events of Cortical Spreading Depression

Cortical spreading depression is not purely an electrical phenomenon. It involves dramatic shifts in the ionic environment of the cortex that both drive the spreading wave and produce the conditions for subsequent migraine pain.

At the cellular level, cortical spreading depression involves a massive influx of sodium and calcium ions into neurons and a corresponding efflux of potassium ions into the extracellular space. This ionic redistribution depolarizes neurons across a large region of cortex simultaneously, producing the intense excitatory phase. The subsequent suppression reflects the exhaustion of the ionic gradients that normally maintain neuronal function.

The potassium efflux and the release of other signaling molecules during cortical spreading depression activate the trigeminal nerve fibers that surround the cortical blood vessels and penetrate the meninges. This activation initiates the trigeminovascular cascade that produces migraine pain. In this way, cortical spreading depression connects the aura phase directly to the headache phase through a defined neurochemical pathway.

Cortical Spreading Depression in Migraine Without Aura

The role of cortical spreading depression in migraine without aura is less certain but increasingly supported by evidence. Neuroimaging studies have detected changes in cortical blood flow consistent with cortical spreading depression during migraine attacks in some people who do not experience aura. The current understanding is that cortical spreading depression may occur in a silent zone of the brain, or at a subcortical level, in people without aura, producing trigeminovascular activation without perceptible aura symptoms.

This hypothesis, if confirmed, would mean that cortical spreading depression is not specific to migraine with aura but is a more general feature of the migraine attack, with aura representing the perceptible manifestation when spreading depression reaches the visual, sensory, or motor cortex.

Implications for Treatment

Understanding cortical spreading depression has several implications for migraine treatment. Medications that suppress cortical spreading depression, including valproate and topiramate, are effective migraine preventives. The suppression of cortical spreading depression is believed to be a contributing mechanism to their effectiveness.

CGRP monoclonal antibodies, while developed primarily for their effects on the trigeminovascular system, may also influence cortical spreading depression through their effects on meningeal trigeminal signaling. Research into this relationship is ongoing.

Understanding that aura reflects cortical spreading depression also informs the clinical approach to migraine with aura. People with migraine with aura have a modestly elevated risk of ischemic stroke compared to people without migraine, particularly women who use combined oral contraceptives. This risk relationship is believed to reflect the vascular effects of cortical spreading depression on the cerebral vasculature.