Mentally exhausted? The study blames the build-up of key chemicals in the 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 had for breakfast, or where Belize is. Now, a study points to why we get so groggy after hours of intense 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 bound to spark controversy, says Princeton University neuroscientist Jonathan Cohen, who wasn’t involved in the work. Many scientists once thought that because difficult mental tasks require more energy than easy tasks, exercise can affect muscles such as brain fatigue. Some even suggest that drinking sugary milkshakes makes you mentally sharper than artificial sweeteners, he says. But Cohen and many others in the field are skeptical of such simplistic explanations. “It’s all been debunked,” he says.

In a new study, researchers looked at whether glutamate levels are associated with behaviors that often manifest when we’re mentally fatigued. Seeking easy, immediate gratification, for example, or acting impulsively. Glutamate normally stimulates neurons, playing a key role 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 detects 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 is mentally tired, this area becomes less active.

Researchers divided 39 paid study participants into two groups, assigning one to a series of difficult cognitive tasks designed to induce mental fatigue. In one, participants had to decide whether letters and numbers flashed in rapid succession on a computer screen were green or red, uppercase or lowercase, and other differences. In another, volunteers had to remember which number matched the three letters they had seen before. The experiment lasted about 6 hours, with two 10-minute breaks and a simple snack of a sandwich and piece of fruit. In the second group, people performed much easier versions of the same tasks.

As the day wore on, the researchers measured cognitive fatigue by repeatedly asking participants to make choices that required self-control—deciding to give up immediately available cash, for example, because they might earn a larger sum later. The group that was assigned the more difficult tasks made about 10% more impulsive choices than the group that had the easier task, the researchers observed. At the same time, their glutamate levels in the lateral prefrontal cortex increased by about 8%.A pattern that didn’t appear in the other group, the scientists report today Current Biology.

“We are still far from the point where we can say that mentally hard work leads to a toxic build-up of glutamate in the brain,” says the study’s first author Antonius Weiler, computational psychiatrist at GHU Paris Psychiatry and Neurosciences. But if it does, it undermines sleep’s well-known restorative powers, which “cleanse” 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 that is used to treat depression, and memantine, which is used to treat symptoms of Alzheimer’s disease. Researchers are also exploring glutamate-based treatments for 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, said Alexander Lin, a clinical spectroscopist at Brigham and Women’s Hospital. But the findings “provide a basis for examining how glutamate can potentially be modulated by drugs or tools such as neurostimulation,” he says.

Sebastian Muslik, a neuroscientist at Brown University, suspects that metabolic waste may be a major contributor to cognitive fatigue. It is suspected that the increase in glutamate as a brain tire serves a purpose. Our body parts are in constant communication with our brain, letting us know our needs to eat, sleep, drink water, and go to the bathroom. Perhaps glutamate in the prefrontal cortex is sending a similar status update to the brain’s internal monitoring system, Muslik suggests.

For Cohen, the most compelling reason to doubt the idea that waste products play an important role in cognitive fatigue is that it often cannot explain the human ability to push through cognitive fatigue, or to smoothly perform demanding computational tasks such as face recognition. It requires megawatts of energy to run a computer. To juggle these more demanding tasks, the brain must have a more sophisticated computational system for allocating effort than the simple manufacture or degradation of metabolic byproducts, he says. “It can’t be that easy.”

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