Cortical spreading depression · Grey Matter

Cortical spreading depression is a slow wave of almost complete depolarisation that travels across the cortex at a few millimetres per minute, silencing the tissue it passes, and it is the event thought to cause the aura of migraine.

Cortical spreading depression. Cortical spreading depression is a slow wave of almost complete depolarisation that travels across the cortex at a few millimetres per minute, silencing the tissue it passes, and it is the event thought to cause the aura of migraine.

At the front of the wave, neurons and glia lose their ion gradients almost entirely: potassium and glutamate pour out into the extracellular space, sodium, calcium and water flow in, cells swell, and the membrane voltage collapses toward zero. The raised potassium and glutamate depolarise the neighbouring tissue, which is how the wave advances, at about 2 to 5 mm per minute (3 mm per minute is the figure most often quoted for the aura). Behind the front, the tissue cannot fire for several minutes while pumps and astrocytes restore the gradients; that silence is the depression the name refers to, and it is what an EEG over the area shows.

The front is depolarisation, the wake is silence. During the brief front neurons may fire a burst, which matches the bright, flickering part of a visual aura; the dark scotoma that follows matches the depressed tissue behind it.

It is expensive. Restoring the gradients is mostly sodium-potassium pump work, so the wave is followed by a large demand for oxygen and glucose and by changes in blood flow (a brief rise, then a longer reduction).

It was described in the rabbit cortex by Aristides Leão in 1944, and the link to the migraine aura rests on matching speeds and spread: imaging of the human visual cortex during an aura shows a disturbance moving at about 3.5 mm per minute in the retinotopic pattern of the percept.

In injured brain (stroke, trauma) the same kind of wave, called spreading depolarisation, recurs and can harm tissue that is short of energy; in a healthy cortex it is fully reversible.

Spreading depression is a failure of the gradients, and a seizure is a failure of control.

In spreading depression neurons stop firing because they have lost the charge to fire with, which is why it travels so slowly and leaves silence behind.

Questions: Can a spreading depression stop a seizure that set it off? In several animal models it can: a seizure raises extracellular potassium and glutamate until the tissue tips into spreading depression, and the depression immediately silences the seizure where it passes and keeps it from generalising. The two outcomes of the excitability map are therefore linked as well as opposed, since the collapse of the gradients removes the charge that the seizure needs. Whether the same sequence ends seizures in people, and whether it contributes to the confusion and weakness after some seizures, is still being studied. How can a wave in the cortex lead to a headache, if the brain itself feels no pain? The pain comes from the meninges and their blood vessels, which are innervated by sensory fibres of the trigeminal nerve, mostly its ophthalmic (V1) division. In animal models, the potassium, glutamate and other substances released by spreading depression reach these trigeminovascular fibres and activate them; the fibres release peptides such as CGRP, the meninges become sensitised, and the signal passes through the brainstem and thalamus to the cortex as throbbing pain. Spreading depression is therefore a plausible trigger for attacks with aura. Most attacks have no aura, however, and they share the same trigeminovascular pain pathway, so how those attacks begin is still studied. What does the potassium that astrocytes buffer have to do with spreading depression? Every spike leaves potassium in the narrow space between cells, and astrocytes normally take it up and spread it through their coupled network. If potassium and glutamate accumulate faster than astrocytes and pumps can clear them, the local neurons depolarise, release still more of both, and the tissue can cross into a self-sustaining collapse of the gradients. Spreading depression is that collapse travelling: the potassium and glutamate released at the front depolarise the next patch of cortex, and the wave advances at a few millimetres per minute. How easily a cortex supports such a wave depends in part on how well its astrocytes keep the extracellular space clean. What decides whether a perturbation in the cortex fades, becomes spreading depression or becomes a seizure? Most perturbations fade, because inhibition and ion clearance absorb them. In a seizure, neurons keep their gradients and fire too much and too synchronously, since inhibition no longer contains the excitation; in spreading depression the gradients themselves collapse and the tissue goes silent. The two are often described as different distances from a resting state, a seizure closer to normal physiology and spreading depression closer to a full loss of the gradients, and which one occurs depends on local conditions such as extracellular potassium, energy supply and the state of inhibition. They can also follow each other: seizures can trigger spreading depression, which in some models ends the seizure and stops it from spreading. Why does a migraine aura drift slowly across the visual field? The visual cortex is a map: neighbouring points of the visual field are handled by neighbouring patches of cortex. A wave of spreading depression crossing that map at about 3 mm per minute therefore produces a disturbance that crosses the visual field in the same order, a flickering edge (the wave front) followed by a blind patch (the depressed tissue behind it). Charting his own auras, Lashley estimated in 1941 that the underlying process moved at about 3 mm per minute, and functional MRI in 2001 showed a change in the occipital cortex advancing at about 3.5 mm per minute in step with a subject's aura.