The Wandering Cells of Migraine Aura

microglia-levy-cropMany people who suffer from regular migraines experience a kind of prelude to their attack, known as a migraine aura. Less than an hour before the headache begins, the person experiences a sensory or motor disturbance, such as flickering shapes and a blind spot, or disturbances of a motor or language nature. In 1941, a psychologist named Karl Lashley took the very scientific step of measuring how fast his own migraine aura moved across his visual field, indirectly calculating the speed of the unknown brain process causing his symptoms. In an organ where normal communication is as fast as flicking on a light switch, the aura moved at a relative crawl – only 3 millimeters/minute.

Seventy years later, University of Chicago scientists have discovered a highly unusual consequence of that slow brain phenomenon. Brains are dynamic structures, with neurons constantly changing the strength of their connections and extending and retracting their branches. But cells in the brain don’t normally pick up and travel. So when Yelena Grinberg, a graduate student in the laboratory of neurologist Richard Kraig, simulated the electrical changes thought to underlie migraine aura in a slice of brain, the response of a type of cell called microglia was quite amazing.

“We have found cells doing something different than they’ve ever been known to do,” said Kraig, a professor of neurology and expert on migraines. “They’re moving the same way an organism would…that’s never been seen before in cells from a tissue.”

Microglia are the resident immune cells of the central nervous system, attacking infection and repairing damage in the brain. To get to the brain in the first place, microglia must travel from the bone marrow (where they are born as monocytes) across the blood-brain barrier into the brain, so their wanderlust is well known. But once they set up shop in a neighborhood of neurons, their subsequent movement was largely thought to be restricted to the motion of their branches.

In an article for the journal PLoS ONE, Grinberg roused microglia from their new homes by triggering an effect called “spreading depression” in her cultured rat brain slices. In the 1950’s, the slow speed of Lashley’s aura was matched to this electrical phenomenon, which travels at an equally methodical crawl through the brain tissue, inhibiting neurons as it passes. From its origin point, the spreading depression spirals out through susceptible gray matter areas of the brain, “like a ripple on a pond,” Grinberg said. When it crosses the cells of the occipital lobe responsible for visual perception, it corresponds to the flickering dots and blind spots of a migraine aura.

After triggering the synaptic depression, Grinberg tracked the movement of microglia for 6 hours, and observed another interesting pattern. To the naked eye, the microglia might look as though they are moving at random with no discernible purpose. But a mathematical analysis suggested by co-author John Milton revealed that the microglia wanderings actually conformed to a well-known natural pattern known as a Lévy flight. Described as an optimal search pattern, Lévy flights are marked by a flurry of small movements interrupted by large steps – behavior often observed in animals scavenging or hunting in the wild (or as Grinberg said, someone looking for their lost keys).

“Scientists have observed the same pattern in the swimming or flight of sharks and seagulls,” Grinberg said. “The idea is that within these stops along the journey they are searching the nearby environment, and once they do or don’t find something there they move to a different spot.”

[Video: Microglia move in response to a spreading depression. The video is sped up to show the distance traveled in the hours following the stimulus. From Grinberg et al., PLoS ONE, 2011]

Why would microglia take Lévy flight after a spreading depression?

Kraig thinks that the microglia are locked in place by synaptic activity, but when the spreading depression passes by and temporarily dampens that activity, they are freed to wander once more. In cases of brain injury, scientists have observed microglial branches moving toward the site of injury to block off the damage. But in the case of spreading depression, the motion is more dramatic and the microglia may be attempting a more subtle alteration in brain function.

“When the brain is working they sit still. They are interacting with neurons, while neurons interact with them, and everyone’s happy,” Grinberg said. “But when brain activity is reduced, they move in an attempt to bring it back to normal. It’s probably a scaling response to try to get the brain back to where it was.”

But does spreading depression have anything to do with the actual migraine? This is a subject of some debate in neurology, Kraig said, but the curious motion of microglia may offer some new evidence of a link between the two. A spreading depression only lasts 60 to 90 seconds in a given area of the brain, but the pain of a migraine can last anywhere from 3 to 72 hours. If activated microglia are moving through the brain for hours, releasing powerful immune factors and cytokines that stimulate the brain’s pain center in the trigeminal nucleus, it could explain the prolonged pain associated with migraine.

“The pain that lingers, the reason why the pain lasts for 3 to 72 hours, is a post-event inflammatory reaction,” Kraig said. “We and many others believe that episodic migraines, the transformation to chronic migraines, is simply firing spreading depression frequently enough that a person never recovers from it.”

Witnessing the strange path of microglia movement after spreading depression has given Kraig’s laboratory clues as to how they might prevent migraines before they start – ideas that are patent-pending and not quite ready for public discussion, he said. But in general, keeping the brain active is a promising strategy for warding off synaptic depression, the flight of the microglia, and migraines.

“If you look at a migraineur’s brain like a dry tinderbox forest out on the west coast, and a non-migraineur’s brain as a Minnesota damp forest, the migraine triggers are all the same, but which one is going to take afire?” Kraig said. “Enriching or altering brain activity is a means to take the dry forest and transform it into the damp forest. If you increase social, physical, and intellectual activity, it will alter brain function and, we believe, prevent migraine by altering neural immune signaling – including that from microglia.”

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Grinberg YY, Milton JG, & Kraig RP (2011). Spreading depression sends microglia on lévy flights. PloS one, 6 (4) PMID: 21541289

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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