Dépression corticale envahissante dans l'aura migraineuse

Invasive cortical depression: origin of migraine aura

Nov 10, 2020

Pervasive cortical depression: the origin of migraine aura?

Pervasive cortical depression is probably the cause of the migraine aura. The more research advances, the more it is believed that this phenomenon may even be present in migraines without aura. We advise you to read our simplified article on the mechanisms of migraine before reading this article.

In a few simple words:

The link between the triggers of a migraine attack and the onset of pain has always been the most obscure subject in the understanding of migraine. We know that the multitude of triggering factors identified by migraine patients are likely to over-activate a deep area of ​​the brain called the hypothalamus. For some unknown reason, there follows a sudden activation of certain neurons in different areas of the brain, followed by a period of silence. This sudden activation is not yet fully explained. However, we know that a multitude of neurons will very quickly become excited, we speak of depolarization, then enter a phase of silence. This massive depolarization will gradually spread from the back of the brain to the front. This is called cortical pervasive depression; a depression of neurons at the level of the cortex and which gradually invades the front. This pervasive cortical depression essentially occurs in an area where neurons are sensitive to variations. This area is the visual area, which is located at the back of the brain. Perhaps that is why the majority of migraine auras are visual disturbances. If progressively the evolution of the invasive cortical depression reaches other areas, the symptoms experienced may be different. If the pervasive cortical depression involves the motor area, the patient may experience difficulty in movement. If it affects the language area, it may be a speech disorder. What is certain is that this invading cortical depression will massively release protons. The protons will diffuse and stimulate pain receptors located in the meninges, the envelope that surrounds the brain. This is the beginning of the headache phase where pain is felt by the patient. One theory is that cortical pervasive depression exists even in patients who do not suffer from migraine aura. It's just that it would develop in areas of the brain that would not cause the symptoms experienced by the patient. It would therefore be present, but would go unnoticed.

Pervasive cortical depression, a history of migraine

In 1941, Professor Lashley studied his own migraine visual scotoma and related it to the architectural organization of the visual cortex (Lashley 1941). He then estimates that it corresponds to a cortical excitation moving progressively along the striated area at a speed of 3 mm/min, followed by a period of inhibition. Three years later, the neurophysiologist Leao reproduced experimentally on the cortex of rats and cats a similar phenomenon, which he called invasive cortical depression (Leao 1944). Pervasive cortical depression (CED) can be induced in animals by multiple physico-chemical stimuli, such as direct trauma to the cortex, magnesium ion depletion, stimulation of glutamate receptors or excess potassium ions and hydrogen in the extracellular environment (Ayata et al. 2015).

The experimental DCE corresponds to a wave of depolarization which extends by continuity in the cerebral gray matter at a speed of 3 to 6 mm/min (Somjen et al. 2001). It is accompanied by a transient interruption of neuronal activity for 5 to 20 minutes. It is exclusively of neuronal origin since it can appear in the absence of any vascular structure, but is however accompanied by a change in blood flow (Smith et al. 2007). It begins with brief and intense neuronal hyperactivity, responsible for an increase in local blood flow (Ayata et al. 2015). It corresponds to a massive release of potassium ions and glutamate in the extracellular environment, as well as an entry of water, sodium and calcium into neurons and astrocytes (Costa et al. 2013).

The DCE: A transient neuronal metabolic dysfunction

The neurons then become inactive and inactivable and the blood flow decreases by 20 to 30%. It is therefore a fleeting initial hyperperfusion of a few minutes, followed by a hypo-flow of 60 to 90 minutes (Ayata et al. 2015). This hypoperfusion is the consequence of a transient neuronal metabolic dysfunction responsible for the aura symptoms. The greatest frequency of auras is visual, which means that the DCE would start preferentially at the occipital level, where the visual areas are. This would be due to the particularity of glial cells in the occipital cortex, which are more sensitive to variations in the extracellular environment (Shibata et al. 2017).

Cortical hypoperfusion

Cerebral hypoperfusion remains within oligemic limits, there is no evidence for tissue ischemia, and oxygen level remains normal. However, it should be noted that hypoperfusion can start before the aura, and that it can persist after it during the headache phase (Unekawa et al. 2015). In addition, it can appear in migraine attacks without aura. This is exactly what was shown by the observation of a patient who had a migraine attack without aura, while she was being observed for a cognitive activation test.

From the onset of the migraine headache, large amplitude posterior cerebral hypoperfusion appeared, which then extended forward during successive measurements (Géraud et al. 2015). This observation of hypoperfusion progressing from the occipital regions to the temporal and parietal regions has been repeatedly demonstrated in patients (Ayata et al. 2015). Thus, the migraine attack without aura may be accompanied by cortical hypoperfusion, similar to that observed during a DCE in patients with aura. The question then arises of the role of this hypoperfusion in triggering the DCE and the migraine attack. If hypoperfusion is the consequence of a DCE, it is because it goes unnoticed in patients with migraines without aura.

However, this hypothesis seems unlikely, due to the very high neuronal density in the occipital cortex. A second possible theory would be that the hypoperfusion is the consequence of a primitive vascular phenomenon, which would occur at the start of the migraine attack, with or without aura and could, depending on its intensity and the level of cortical excitability, cause or not a DCE then responsible for a clinical aura. This arteriolar vasoconstriction could be caused by the activation of brainstem vasoconstrictor nuclei, such as the LC and the NRM (Géraud et al. 2015).

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