How does mental fatigue begin in the brain?

It’s been a grueling year for Hongmei Xia. A Ph.D. student in cognitive neuroscience at Ludwig Maximilian University of Munich in Germany, she’s spent long days wrestling with an enduring scientific mystery: What happens in the brain to cause mental fatigue?

The problem was personal for Xia—she often felt drained after hours of research. But for decades, scientists didn’t understand the neural underpinnings of cognitive exhaustion. Now she and her colleagues have discovered a likely molecular culprit: glutamate, a common neurotransmitter.

They found that glutamate builds up in parts of the brain when we perform challenging mental tasks. As the molecules accumulate, they seem to tank our motivation—even when we stand to gain big by persevering.

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The work builds on past research that had hinted at glutamate’s role in mental fatigue. In 2022, for example, a team of researchers in Paris reported that sustained mental effort led to the accumulation of glutamate in the lateral prefrontal cortex, a brain region responsible for cognitive control. But experts say Xia and her colleagues’ work provides the strongest evidence yet of a link between glutamate and mental fatigue. “This is a causal study,” says Clay Holroyd, a cognitive neuroscientist at Ghent University in Belgium, who was not involved in the new study. “It’s a very nice piece to this overall puzzle.”

To test their theory, the researchers used electrodes to stimulate the dorsolateral prefrontal cortex in participants’ brains as they tried to remember letters they’d seen flashed on a screen. The zaps boosted their performance on the task, but afterward the participants were less willing to engage in other cognitively demanding tasks than those whose brains weren’t stimulated, suggesting higher mental fatigue. A statistical analysis revealed that increasing levels of glutamate could account for the fatigue. The team’s results were published on Monday in the Proceedings of the National Academy of Sciences.

The findings could help explain why mental fatigue feels unpleasant. In large enough concentrations, glutamate can damage brain cells, Xia says, so perhaps the sense of fighting to stay focused is actually “a safety signal to tell you, ‘Okay, you should take a break.’” If our minds are constantly running at full throttle, potentially harmful molecules might keep piling up faster than the brain can dispose of them.

Scientists have long debated whether mental fatigue is a neurobiological or psychological process. Some in the psychology camp argue that fatigue creeps up when we fixate on a relatively unimportant task at the expense of more rewarding activities; the exhaustion alerts us that we should abandon what we’re doing and redirect our cognitive resources toward something more worthwhile.

According to Mathias Pessiglione, a cognitive neuroscientist at the Paris Brain Institute and senior author of the 2022 glutamate paper, the new study rules out a purely psychological explanation by showing that neurobiological changes alone can induce fatigue. But Pessiglione suspects that psychological factors, such as motivations and beliefs, also play a key role. “A comprehensive account should articulate the two levels,” he says.

Glutamate may not be the only molecule involved in mental fatigue. Holroyd’s lab is investigating both glutamate and lactate, an important energy source for the brain, as well as the contribution of the anterior cingulate cortex, a region of the brain involved in attention and decision-making.

Xia hopes the findings will one day lead to treatments for people who are especially prone to mental fatigue, such as those with depression and schizophrenia. For now, however, her prescription for an overworked mind is simple: switch to easier tasks and let your gray matter recover. As she puts it, “Give some time to your brain.”

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