You know the feeling. You’ve been preparing 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’re so drained 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 bound to spark controversy, says Jonathan Cohen, a Princeton University neuroscientist who wasn’t involved in the work. Many scientists once thought that doing difficult mental tasks consumed more energy than easy tasks, exhausting the brain like exercise can do to muscles. Some even suggested that drinking a sugary shake 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. “Everything has been debunked,” he says.
In the new study, the researchers looked at whether glutamate levels are linked to the behavior that often manifests itself when we are mentally exhausted. Seeking easy and immediate gratification, for example, or acting impulsively. Glutamate normally excites neurons, playing a key role in learning and memory, but too much 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 using 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 exhausted, this region becomes less active.
The researchers divided 39 paid study participants into two groups, assigning one to a series of challenging cognitive tasks designed to induce mental exhaustion. In one, participants had to decide whether letters and numbers flashing on a computer screen in rapid succession were green or red, uppercase or lowercase, and other variations. In another, volunteers had to remember whether a number matched one they had seen three characters before. The experiment lasted about 6 hours, with two 10-minute breaks and a simple lunch of sandwich and piece of fruit. In the second group, people did much easier versions of the same tasks.
As the day progressed, the researchers repeatedly measured cognitive fatigue by asking participants to make decisions that required self-control; for example, they decided to forgo cash that was immediately available in order to earn a larger amount later. The researchers observed that the group that had been assigned to more difficult tasks made about 10% more impulsive choices than the group with easier tasks. At the same time, their glutamate levels increased by about 8% in the lateral prefrontal cortex—a pattern that was not shown in the other group, the scientists report today in current biology.
“We are still far from the point where we can say that working hard mentally 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 removing metabolic waste. The team suggests that 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.
Abnormal glutamate signaling occurs in many brain disorders. There are already drugs that target neuronal glutamate receptors, such as 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. ‘Alzheimer’s. Researchers are also exploring glutamate-based therapies for a number of other disorders, including schizophrenia and epilepsy.
A major 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 might be modulated by drugs or devices such as neurostimulation,” he says.
Sebastian Musslick, a neuroscientist at Brown University, doubts that metabolic waste turns out to be a key factor in cognitive fatigue. Instead, he suspects that the increase in glutamate as the brain gets tired serves a purpose. The organs of our body are in constant communication with our brain, and they let us know when we should 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 control 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 overcome cognitive fatigue or effortlessly perform demanding computational tasks, such as now facial recognition. which require megawatts of power for computers to operate. 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 can’t be that easy.”