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Mentally exhausted? Study blames buildup of key chemical in brain | Science

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 ate for breakfast, or where exactly Belize is. Now, a study hints at why we get so unraveled after hours of hard mental labor: a toxic buildup of glutamate, the brain’s most abundant chemical signal.

The study isn’t the first to try to explain cognitive fatigue—and it is bound to stir up controversy, says Jonathan Cohen, a neuroscientist at Princeton University who wasn’t involved with the work. Many scientists once thought that doing difficult mental tasks used up more energy than easy tasks, exhausting the brain like exercise can do to muscles. Some even suggested 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 been debunked,” he says.

In the new study, researchers looked at whether levels of glutamate are related to behavior that so often manifests when we’re mentally exhausted. Seeking easy, immediate gratification, for example, or acting impulsively. Glutamate typically 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 noninvasive technique called magnetic resonance spectroscopy, which can detect glutamate through a combination of radio waves and powerful magnets. They chose to focus on a brain region called the lateral prefrontal cortex, which helps us stay focused and make plans. When a person becomes mentally exhausted, this region becomes less active.

The researchers divided 39 paid study participants into two groups, assigning one to a series of difficult cognitive tasks that were designed to induce mental exhaustion. In one, participants had to decide whether letters and numbers flashing on a computer screen in quick succession were green or red, uppercase or lowercase, and other variations. In another, volunteers had to remember whether a number matched one they’d seen three characters earlier. The experiment lasted for 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.

As the day dragged on, the researchers repeatedly measured cognitive fatigue by asking participants to make choices that required self-control—deciding to forgo cash that was immediately available so they could earn a larger amount later, for example. The group that had been assigned to more difficult tasks made about 10% more impulsive choices than the group with easier tasks, the researchers observed. At the same time, their glutamate levels rose by about 8% in the lateral prefrontal cortexa pattern that did not show up in the other group, the scientists report today Current Biology.

“We’re still far from the point where we can say that working hard mentally causes a toxic buildup of glutamate in the brain,” says the study’s first author, Antonius Weihler, a computational psychiatrist at the 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 might 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 the neuronal receptors for glutamate, including esketamine, a form of the anesthetic ketamine which is used to treat depression, and memantine, which is used to treat the symptoms of Alzheimer’s disease. Researchers are also exploring glutamate-based therapies for a number of other disorders, such as schizophrenia and epilepsy.

One important limitation of the study is that the scanners used aren’t 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 could potentially be modulated by medications or devices such as neurostimulation,” he says.

Sebastian Musslick, a neuroscientist at Brown University, doubts metabolic waste will turn out to be a key contributor to cognitive fatigue. He suspects instead that the uptick in glutamate as the brain tires serves a purpose. The organs in our bodies are in constant communication with our brains, letting us know when we need to eat, sleep, drink water, and go to the bathroom. Maybe 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 can’t explain the human ability to often push through cognitive fatigue, or effortlessly perform demanding computational tasks such as face recognition that require megawatts of energy for computers to perform. To juggle these many demanding tasks, the brain has to have a more sophisticated computational system for allocating effort than the simple buildup or depletion of metabolic byproducts, he says. “It just can’t be that easy.”

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