How are brain oscillations born?

Waves of synchronized and 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 of activity, called gamma activity, appears and linked it to behavior.

By developing a new, much more precise approach to measuring this activity, researchers overcame major challenges that limited scientists’ understanding of the role these waves play in information processing and behavior initiation. The results are published in Nature.

But Jessica Cardin, Ph.D., Gordon M. Shepherd Professor of Neuroscience at the Yale School of Medicine and lead author of the study, didn’t intend to study this type of brain activity. She worked on gamma waves as a postdoctoral fellow and, through this work, showed for the first time that it was possible to artificially initiate these waves in the brain. But the problem was that what she calls “the perfect experience” isn’t really possible with these activity rhythms.

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

“The problem is, and always has been, that for something like an oscillation or pattern of activity, you really can’t turn it off without affecting the entire 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 would never work in this field.”

But then one of his postdocs, Quentin Perrenoud, Ph.D., first author of the study, showed him some intriguing data he had collected while trying to track the flow of information in the brain while a task was undertaken. It seemed that gamma waves could predict behavior. So they followed the science, and their findings changed the way scientists thought about how these waves emerge in the brain.

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

Gamma activity emerges from interactions between the thalamus and cortex

For this study, the researchers developed a new approach to measuring gamma waves. While these oscillations were once thought to be continuous, closely resembling a sound wave with an uninterrupted pattern of peaks and troughs, more recent research has shown that the oscillation is not quite continuous but can occur in small bursts.

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

If the gamma activity was truly an oscillation, then the combination of each of these individual events should look like a continuous wave that passes through each of the locations where the researchers recorded.

“But it turned out that these events can happen together, or in small bursts, or on their own,” says Cardin. “They don’t occur in a long sequence.”

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

“This allows us to get very precise timing and clearly identify these short events, which means we can map them with great precision at interesting moments, like when an animal makes a decision,” Cardin explains. “This means we can map brain events to animal behavior more precisely than ever before.”

When it comes to where gamma activity occurs, there are two schools of thought. Much available evidence supports the idea that gamma activity is generated in the cortex.

But some research suggests that the cortex inherits activity 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 suggests that both are false and that this activity is due to an interaction ‘between’ the thalamus and the cortex. Gamma appears dynamically when the thalamus sends input to the cortex, where it is then amplified,” says Cardin.

Disruption of signals from the thalamus affects behavior

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

To do this, the researchers first trained mice in a visual task in which they received a reward if they licked a waterspout only when a certain visual stimulus was displayed. Next, the researchers disrupted the signals sent from the thalamus to the cortex, which, in turn, disrupted gamma activity in the cortex.

This gamma disruption made the mice perform much worse in the visual task. The researchers then took the opposite approach and artificially triggered gamma activity.

“We recorded the gamma activity of mice that detected the visual stimulus and then transmitted it back into the brains of other mice. And when we did that, it made the mice think they had detected a stimulus,” Cardin explains.

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

Cardin’s lab is currently studying whether gamma activity in the cortex could be used as an early biomarker for diseases like Alzheimer’s.

Acetylcholine and norepinephrine, key signaling molecules in the thalamus and cortex, are closely linked to cognition and lost in neurodegenerative diseases. These neuromodulatory signals are known to regulate the pattern of brain activity.

“We are beginning to examine how neuromodulatory signals are associated with these gamma events and will apply our tools to better understand the sequence of problems related to neurodegeneration,” says Cardin.

“This could lead to an interpretable early biomarker of Alzheimer’s disease that is easily accessible in humans.”