Answering a Century-Old Question: How do Brain Oscillations Emerge?

Waves of synchronized, coordinated neuronal activity have been observed and studied in the brain for over a century. But for the first time, Yale researchers have identified where a certain type—known as gamma activity—emerges and they have connected it to behavior.

By developing a new, much more precise approach for measuring this activity, the researchers have overcome the major challenges that have limited scientists’ understanding of what role these waves play in processing information and initiating behavior.

The findings were published Oct. 8 in Nature.

But Jessica Cardin, PhD, Gordon M. Shepherd Professor of Neuroscience at Yale School of Medicine and senior author of the study, had no intention of studying this type of brain activity. She worked on gamma waves as a postdoc, and through that work showed for the first time that you can artificially initiate these waves in the brain. But the problem was that what she refers to as “the perfect experiment” isn’t really possible with these rhythms of activity.

The way to determine what something like gamma waves or, say, a gene or a particular protein, is doing in the brain, is to break it and see what happens. You silence that one gene and see how that affects behavior, for example.

“The problem is, and always has been, that for something like an oscillation or a pattern of activity, you really can’t turn it off without affecting everything in the surrounding brain circuit,” says Cardin, who is also a member of Yale’s Wu Tsai Institute. “So when I started my own lab, I thought we’d never work in this area.”

But then one of her postdocs—Quentin Perrenoud, PhD, first author of the study—showed her some intriguing data he had collected while trying to track the flow of information through the brain while a task was undertaken. It looked a lot like gamma waves might predict behavior. So they followed the science, and their findings upend the way scientists have thought about how these waves emerge in the brain.

“It’s not quite a perfect experiment, but it’s a lot closer to a perfect experiment than we’ve ever been able to get,” says Cardin.

For the study, the researchers developed a new approach for measuring gamma waves. While it was once thought that these oscillations were continuous, looking much like a sound wave with an unbroken pattern of peaks and troughs, more recent research has found evidence that the oscillation isn’t quite continuous but can come in small bursts.

Pursuing this idea, the researchers recorded brain activity in 16 different sites in the visual cortex—the part of the brain that processes sight—in order to get a much more detailed look at the spatial and timing aspects of gamma activity. Then they broke down that data into individual events, much like one peak-trough-peak cycle of a wave.

If the gamma activity really was an oscillation, then putting each of these individual events together should look like a continuous wave that’s rolling through each of the spots where the researchers recorded.

“But it turned out that these events can happen together, or in little bursts, or all by themselves,” says Cardin. “They’re not happening in a long sequence.”

This approach, which the researchers have named CBASS (Clustering Band-limited Activity by State and Spectrotemporal feature), offers a much greater level of sensitivity than other techniques for studying gamma activity.

“It allows us to get very fine timing and to clearly identify these short events, which means we can map them with great precision during interesting moments, like when an animal is making a decision,” says Cardin. “That means we can map the events in the brain to the behavior of the animal with more precision than we’ve ever had before.”

When it comes to where gamma activity arises, there have been two schools of thought. A lot of the available evidence has supported the idea that gamma activity is generated in the cortex. But some research has suggested the cortex inherits the activity from elsewhere in the brain—for example, from the thalamus, which sends a lot of sensory and motor information to the cortex.

“With this new method, our data suggest both are wrong, and that this activity arises due to an interaction between the thalamus and the cortex. Gamma arises dynamically as the thalamus sends input to the cortex, where it’s then amplified,” says Cardin.

The precision of CBASS also gives the researchers that much-sought-after ability to break the system, to disrupt these patterns of activity in a way that doesn’t affect the entire brain.

To do that, the researchers first trained mice on a visual task wherein the mice received a reward if they licked a waterspout only when a certain visual stimulus was shown. Then, the researchers disrupted the signals that the thalamus sent to the cortex, which, in turn, disrupted the gamma activity in the cortex.

This gamma disruption caused the mice to perform much worse on the visual task. So then the researchers took the opposite approach and artificially initiated gamma activity.

“We recorded gamma activity from mice who were detecting the visual stimulus and then played it back into the brain of other mice. And when we did that, it tricked the mice into thinking they had detected a stimulus,” says Cardin.

Together, the findings indicate that gamma activity in the cortex supports the integration of visual information and is involved in the behavioral responses that emerge from that integration. And this is important information to have, as studies have shown that this type of activity is altered in people with neurodevelopmental disorders, schizophrenia and bipolar disorder, as well as neurodegenerative diseases.

Cardin’s lab is now looking into whether gamma activity in the cortex could be used as an early biomarker for conditions like Alzheimer’s disease. Acetylcholine and norepinephrine, key signaling molecules in the thalamus and cortex, are tightly linked to cognition and lost in neurodegenerative diseases. These neuromodulatory signals are known to regulate the pattern of brain activity.

“We’re starting to look at how neuromodulatory signals are associated with these gamma events and we’ll apply our tools to better understand the sequence of things that go wrong in neurodegeneration,” says Cardin. “This could lead to an interpretable early biomarker for Alzheimer’s disease that is easily accessible in humans.”