You know the feeling. You’ve been cramming for a test or presentation all day when suddenly you can’t remember simple things like what you had for breakfast or where exactly Belize is. Now, a study hints at why we wind down so much after hours of hard mental work: a toxic build-up of glutamate, the brain’s most abundant chemical signal.

The study isn’t the first to try to explain cognitive fatigue — and it’s sure to spark controversy, says Jonathan Cohen, a neuroscientist at Princeton University who was not involved in the work. Many scientists once thought that performing difficult mental tasks consumed more energy than easy tasks, exhausting the brain as exercise can do to muscles. Some even suggested that drinking a sugary milkshake would make you mentally sharper than an artificially sweetened one, he says. But Cohen and many others in the field are skeptical of such simplistic explanations. “It’s all devalued,” he says.

In the new study, the researchers looked at whether glutamate levels are linked to the behavior that so often manifests itself when we are mentally exhausted. For example, seeking easy, immediate gratification, or acting impulsively. Glutamate normally excites neurons, playing key roles in learning and memory, but too much of it can wreak havoc on brain function, causing problems ranging from cell death to seizures.

The scientists used a non-invasive technique called magnetic resonance spectroscopy, which can detect glutamate through a combination of radio waves and powerful magnets. They chose to focus on a region of the brain called the lateral prefrontal cortex, which helps us stay focused and make plans. When a person is mentally tired, this region becomes less active.

The researchers divided 39 paid study participants into two groups, assigning one to a series of difficult cognitive tasks designed to induce mental exhaustion. In one, participants had to decide whether letters and numbers flashing on a computer screen in sequence were green or red, uppercase or lowercase, and other variations. In another, volunteers had to remember whether a number matched what three characters had seen before. The experiment lasted about 6 hours, with two 10-minute breaks and a simple lunch of a sandwich and a piece of fruit. In the second group, people did much easier versions of the same tasks.

Over the course of the day, the researchers repeatedly measured cognitive fatigue by asking participants to make choices that required self-control—deciding to give up money that was immediately available so that they could win a larger amount. later, for example. The group assigned to the more difficult tasks made about 10% more impulsive choices than the group with the easier tasks, the researchers observed. At the same time, their glutamate levels increased by about 8% in the lateral prefrontal cortexa pattern that did not appear in the other group, the scientists report today in Current Biology.

“We are still far from the point where we can say that mentally intense work causes a toxic build-up of glutamate in the brain,” says the study’s first author, Antonius Weihler, a computational psychiatrist at GHU Paris Psychiatry and Neurosciences. But if it does, it underscores the well-known restorative powers of sleep, which “cleanses” the brain by flushing out metabolic waste. It may be possible to use glutamate levels in the prefrontal cortex to detect severe fatigue and monitor recovery from conditions such as depression or cancer, the team suggests.

Abnormal glutamate signaling occurs in many brain disorders. There are already drugs that target neuronal receptors for glutamate, including esketamine, a form of the anesthetic ketamine used to treat depression, and memantine, which is used to treat symptoms of Alzheimer’s disease. Researchers are also exploring glutamate-based therapies for a variety of other disorders, such as schizophrenia and epilepsy.

An important limitation of the study is that the scanners used are not powerful enough to distinguish between glutamate and another closely related molecule, glutamine, notes Alexander Lin, a clinical spectroscopist at Brigham and Women’s Hospital. But the findings “provide the basis for examining how glutamate can potentially be modulated by drugs or devices such as neurostimulation,” he says.

Sebastian Musslick, a neuroscientist at Brown University, suspects that metabolic waste will turn out to be a major contributor to cognitive fatigue. Instead, he suspects that the increase in glutamate as the brain tires serves a purpose. The organs in our body are in constant communication with our brain, letting us know when we need to eat, sleep, drink water and go to the toilet. Perhaps the prefrontal cortex’s glutamate is sending a similar status update to the brain’s internal monitoring system, Musslick suggests.

For Cohen, the most compelling reason to be skeptical of the idea that waste products play an important role in cognitive fatigue is that it cannot explain the human ability to often postpone cognitive fatigue, or to effortlessly perform computationally demanding tasks such as cognition. of the face. that require megawatts of power for computers to run. To juggle these many demanding tasks, the brain must have a more sophisticated computational system for allocating effort than the simple accumulation or depletion of metabolic byproducts, he says. “It just can’t be that easy.”

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