Hidden Part of the Brain Controls How We Prepare for Uncertainties

The claustrum is a thin sheet of neurons buried deep within the cerebral cortex. The structure is so small and hidden that neuroscientists once found it very difficult to access, let alone investigate. Now, researchers at Yale School of Medicine have not only found a way to peer into this enigmatic structure but have also discovered its surprising role in how humans learn and adapt to uncertainties.

In a study published Oct. 6 in Nature Neuroscience, researchers recorded the activity of the claustrum for the first time in seven patients undergoing epilepsy surgery.

For their epilepsy treatment, the patients had electrodes implanted on various parts of their brains to identify the precise regions that trigger their seizures. Because typical electrodes are too big for the claustrum, the scientists deployed tiny, 40-micrometer wires at the tip of the electrodes that are small enough to target a single neuron.

Claustrum neurons have been shown to wrap around the entire brain of a mouse, but data in humans are incomplete. “It is the most connected region of the entire brain, yet it is also extremely easy to miss,” says Eyiyemisi "Yemi" Damisah, MD, assistant professor of neurosurgery at Yale School of Medicine and senior author of the study.

She first encountered the human claustrum while implanting an electrode on her patient’s brain, which made her wonder what the claustrum does. Damisah later found that there were very few studies on the human claustrum. While the structure had been described for centuries, it only gained renewed interest after Francis Crick, PhD—the Nobel Laureate known for his work on the DNA double helix—and neuroscientist Christof Koch, PhD, wrote a paper proposing the claustrum’s role in conscious experience.

Despite the widespread interest, studies that test Crick and Koch’s hypothesis on the claustrum remain limited. Research done with animals such as reptiles, monkeys, and mice has yielded conflicting results. For example, the claustrum was shown to operate as a filter for sensory inputs in monkeys and a regulator of slow waves during sleep in reptiles—both regarded as low-level cognitive functions. But in mice, the structure was shown to influence behavioral choice, something that is considered a higher-order function.

To settle the matter, researchers needed a reliable method to track the claustrum’s activity in humans, Damisah thought. In 2024, she and her team developed a way to sample the claustrum during slow wave sleep using electrodes equipped with microwires. These microwires allowed her team to track single claustrum neurons, which became highly active as a person fell into non-REM, slow-wave sleep. The measurement confirmed what others had observed earlier in reptiles.

In the new study, Damisah used the same microwire electrode technique to assess whether the claustrum also plays a part in high-order cognitive function.

To answer this question, seven patients with epilepsy who had electrode implants played a computer game. Each player controlled a spaceship and avoided crashing into asteroids. Because the asteroids approached in unpredictable ways, the players were typically unable to react quickly enough and would need to learn the safest paths to navigate the spaceship. The task was adapted from the aversive-learning paradigm—an experimental model commonly used to study how humans learn, predict, and avoid negative stimuli under uncertainty.

As the participants played the game, the researchers recorded the activity of the claustrum neurons with other parts of the brain, such as the amygdala, which is involved in low-level cognitive tasks like processing emotions, and the anterior cingulate cortex, which is involved in high-level tasks such as logical thinking.

Damisah and her team found that the claustrum neurons behaved in a mixed manner. Some claustrum neurons would fire when the asteroids appeared and the spaceship was about to crash—a high uncertainty event. But the same set of neurons would return to baseline before any outcome. “As if it does not care about the outcome,” Damisah says. This suggested that the neuron was behaving like a sensory neuron, a low-level function.

Other claustrum neurons fired when participants were unsure of where to place their spaceship—a sign of high uncertainty. The latter pattern was associated with an eventual crash.

Overall, the claustrum showed activities more similar to the anterior cingulate cortex than the amygdala. But unlike the anterior cingulate cortex, whose activity was evenly distributed between crashes and successful asteroid avoidances, the claustrum seemed to be more active when crashes took place than when avoidance was successful.

“The result shows that not only do the claustrum neurons track the simple things, but they also track higher-order cognitive things like uncertainty and prediction error that are driving behavior,” Damisah says.

The findings also help clarify what was previously shown in the animal studies, she adds. “Investigating the claustrum can be really meaningful to our understanding of human arousal, attention, and conscious perception, which are the foundations of all kinds of neuropsychiatric disorders,” Damisah says.