Migraine is an extremely common and surprisingly debilitating neurological disorder, estimated to affect 10-20% of all people. Yet the origins of migraine attacks remain obscure. For about one-third of migraineurs, a telltale feature called the migraine aura can precede an attack. Typically a change in vision or sensation, it is the first measurable element of a migraine attack—measurable because it results from massive waves of electricity in the brain called spreading depolarizations. These waves sweep across the surface of the brain, leading to intense headaches.
“Everyone knows about epilepsy and seizures, but not everyone knows about spreading depolarizations,” says clinician-scientist KC Brennan, M.D., Vice Chair for Research in the Department of Neurology at the University of Utah. “[They] occur in the brains of nearly all creatures that have been studied… They are also involved in nearly every form of brain injury: stroke, traumatic brain injury, subarachnoid hemorrhage, subdural hematoma, you name it. Nearly every state in which the brain is injured can have these spreading depolarizations occur. But migraine is not brain injury, and it is still a complete mystery why these waves should appear in the brains of people with migraine.”
Recently, Brennan received a $5.4 million Javits Neuroscience Investigator Award from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS). The reason? His group discovered brain events that happen right before spreading depolarizations—meaning they could help us understand how migraine develops in an uninjured brain.
The Javits Award, created in honor of the late Senator Jacob K. Javits of New York, supports researchers who have a distinguished record of substantial contributions in a field of neurological science. It is granted to scientists with the expectation that they be highly productive over the next seven years.
“It’s a genuine privilege,” Brennan says of receiving the award. “It was completely unexpected.” This is by design; Javits awardees cannot apply for the grants. Instead, they are nominated by NINDS Program Officers from among the highest-scored grants of the year and voted by the National Advisory Neurological Disorders and Stroke Council.
Brennan recalled when he received a text from Michael Oshinsky, Ph.D., director at the NINDS Office of Preclinical Pain Research, asking for a phone call.
“I said, ‘I’m sorry; I’m in the middle of clinic,’ and he said, ‘Well, here. You have seven years of funding. Congrats,’” Brennan laughs. “I texted him back the instant I could, like, ‘Holy cow!’”
The award funds Brennan’s investigations into the origins of spreading depolarizations and migraine. Brennan and his team at the Headache Physiology Lab discovered unusual patterns of release of the neurotransmitter glutamate in the lead-up to spreading depolarizations. Glutamate is typically released in small, precise increments in the brain; however, the lab observed large “plumes” of the chemical appearing right before the start of a spreading depolarization. The focus of Brennan’s current research centers on deepening our understanding of these plumes. Where do they come from? What causes them? Can they be stopped?
With the funding from the Javits award, Brennan and his team plan to explore these questions by using advanced microscopy to record from the brains of awake mice, closely studying brain processes as they’re happening. They also plan to evaluate new treatments that may be effective against migraine and spreading depolarizations.
Brennan says, “The better we understand the mechanisms of the initiation of spreading depolarizations, and thus the migraine attack, the closer we are to therapies that interrupt that process.”