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It\u2019s been a grueling year for Hongmei Xia. A Ph.D. student in cognitive neuroscience at Ludwig Maximilian University of Munich in Germany, she\u2019s spent long days wrestling with an enduring scientific mystery: What happens in the brain to cause mental fatigue<\/a>?<\/p>\n The problem was personal for Xia\u2014she often felt drained after hours of research. But for decades, scientists didn\u2019t understand the neural underpinnings of cognitive exhaustion<\/a>. Now she and her colleagues have discovered a likely molecular culprit: glutamate, a common neurotransmitter.<\/p>\n 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\u2014even when we stand to gain big by persevering.<\/p>\n If you’re enjoying this article, consider supporting our award-winning journalism by subscribing<\/a>. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.<\/p>\n The work builds on past research that had hinted at glutamate\u2019s 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<\/a> in the lateral prefrontal cortex, a brain region responsible for cognitive control. But experts say Xia and her colleagues\u2019 work provides the strongest evidence yet of a link between glutamate and mental fatigue. \u201cThis is a causal study,\u201d says Clay Holroyd, a cognitive neuroscientist at Ghent University in Belgium, who was not involved in the new study. \u201cIt\u2019s a very nice piece to this overall puzzle.\u201d<\/p>\n To test their theory, the researchers used electrodes to stimulate the dorsolateral prefrontal cortex in participants\u2019 brains as they tried to remember letters they\u2019d 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\u2019t stimulated, suggesting higher mental fatigue. A statistical analysis revealed that increasing levels of glutamate could account for the fatigue. The team\u2019s results were published on Monday<\/a> in the Proceedings of the National Academy of Sciences<\/i>.<\/p>\n 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 \u201ca safety signal to tell you, \u2018Okay, you should take a break.\u2019\u201d If our minds are constantly running at full throttle, potentially harmful molecules might keep piling up faster than the brain can dispose of them.<\/p>\n 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\u2019re doing and redirect our cognitive resources toward something more worthwhile.<\/p>\n 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. \u201cA comprehensive account should articulate the two levels,\u201d he says.<\/p>\n Glutamate may not be the only molecule involved in mental fatigue. Holroyd\u2019s 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.<\/p>\n 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, \u201cGive some time to your brain.\u201d<\/p>\n<\/div>\n Great science journalism requires human expertise, time, effort and creativity. And it costs money. That\u2019s why I and the journalists here at Scientific American<\/i> hope you\u2019ll join our community.<\/p>\n When you subscribe, you are supporting staff and freelance journalists who are passionate about telling science stories that are true, important and compelling. Our editors and reporters are often experts in their fields, which means they understand the nuances of big discoveries and can untangle the breakthroughs from the hype. With a subscription, you are also supporting rigorous fact-checking to ensure the words we publish are precise and accurate. And you\u2019re supporting original illustrations, graphics and photos that bring you closer to an advanced laboratory, an ice sheet in Antarctica or a space mission in orbit. You\u2019re helping us craft other types of high-quality journalism as well: Our newsletters are carefully written, edited and curated by staffers you have or will come to know and love. Our Science Quickly<\/i> podcast is based on original reporting, collaboration with editors and scientists and exacting production.<\/p>\n Subscriptions keep this engine running so we can continue to deliver thoughtful, rigorous and independent science journalism to you. In an era of viral misinformation, this work is crucial. 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