The fatigue that comes from performing demanding mental tasks may stem from a buildup of the neurotransmitter glutamate, according to research published today (August 11) in Current Biology.

Mental fatigue also appears to shift decision-making toward a kind of easy-button mode where the brain favors low-cost, immediate-reward options, says Antonius Wiehler, a study coauthor and cognitive neuroscientist at the Paris Brain Institute’s Motivation, Brain, and Behavior Lab. “So after a day of work, you [make] different choices compared to when you’re fresh in the morning,” he says. “We believe that this is [due to] glutamate accumulation.”

Matthew Apps, a cognitive neuroscientist at the University of Birmingham in the UK who was not involved in the research but who peer-reviewed the paper for the journal, says the research has identified a potential marker of fatigue to study more widely in athletes or in people with disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). “I think it’s a really nice first step, and I think it’s going to open up a lot of new avenues of work.”

I think it’s a really nice first step, and I think it’s going to open up a lot of new avenues of work.

—Matthew Apps, University of Birmingham

Previous theories posited that the tiredness people experience from mental exertion stemmed from the depletion of energy reserves. But research hasn’t borne that out, the study authors write. Wiehler and his colleagues instead hypothesized that something was accumulating in the brain, so they looked for evidence of this in a region that helps orchestrate cognitive control: the left lateral prefrontal cortex.  

Apps explains that in addition to helping us undertake complex tasks like solving a Sudoku puzzle, playing chess, or designing an experiment, the left lateral cortex helps control the processes required to remember and manipulate information to solve those problems. “It’s also part of the system that says, ‘Well, actually, maybe I don’t want to play chess. I want to watch Netflix and do something simpler,’” he says.

In their analysis, the researchers behind the new study evaluated two groups of people over six and a half hours: One group of 24 people performed difficult cognitive tasks that frequently changed, while the other group of 16 people performed easy tasks that rarely changed. At several points during the cognitive exercises, the researchers scanned participants’ left lateral prefrontal cortices using magnetic resonance spectroscopy, which detects biochemical changes in the brain and is commonly used to diagnose tumors. The scans revealed that the difficult-task group had higher levels of the neurotransmitter glutamate in that area of the brain at the end of the day when compared to the easy-task group.

That result suggested to the researchers that mental fatigue could be the result of the glutamate diffusing out of neurons and building up this area of the brain, perhaps causing it to work less efficiently. “The most surprising thing for us was that we see [a] glutamate concentration . . . reduction in the easy-group,” says Wiehler, indicating that the brain may be clearing the molecule away to refresh the mind when it’s less taxed, almost as if the neurotransmitter acts as a waste product.

The study also evaluated how the participants’ decision-making changed throughout the day by asking people in both groups to periodically make economic choices. For example, participants had to choose between scenarios such as riding a bike at high intensity for a decent chunk of change or at low intensity for much less money. Or, they had to choose to receive a large sum in a year’s time or a smaller amount immediately. “The theory we have behind our study is that the brain is doing some form of cost-benefit trade off when it comes to resources and, therefore, when it comes to fatigue,” says Wiehler. The results support this notion, with people in the difficult-group choosing the lower-cost, lower-effort options toward the end of the day.

Glenn Wylie, a neuroscientist with the nonprofit Kessler Foundation in New Jersey who was not involved with the research, describes the experiment as elegant. “They tired these people out by having them perform tasks for six and a half hours. That’s monumental,” he says, adding that a particularly interesting part of the research was evaluating changes in participants’ economic decision-making.

However, he points out that when participants assessed their own levels of fatigue, both groups reported similar levels that increased throughout the day. “That’s kind of problematic, because you would expect the hard tasks to fatigue people more and the easy tasks to fatigue people less,” he says. While self-reporting can be unreliable, he says that it was a mistake for the researchers to discount how participants felt: “Maybe they both really are getting fatigued, but for different reasons.”

The easy group may have been mentally fatigued from boredom, Wylie surmises. “If you were to spend all day formatting documents [for example], at the end, you’re drained, but not because you’ve been expending creative energy. It’s because you’ve been doing this repetitive, boring task.”

Apps agrees that boredom or frustration could have influenced how participants assessed their own fatigue levels. “I think it probably would have slightly strengthened the paper if they’d have found that these feelings of fatigue are actually really strongly linked,” he says, adding it’s not surprising the researchers didn’t because those self-measurements can be noisy. Future experiments with a lot more subjects could compensate for that, he says.

Wylie also points out that if glutamate significantly impeded cognitive control, then you’d expect the performance of those participants with higher concentrations of it to drop off, which it didn’t. “I don’t know if glutamate is related to fatigue generally, or if it has to do with these particular tasks,” he says, and suggests that there may be other areas of the brain or metabolites that play a role in fatigue.

Regardless of his view of the research’s limitations, Wylie says that studies like this have important implications for people with traumatic brain injuries, ME/CFS, multiple sclerosis, and other conditions that cause the brain to have to work harder. He says that this research “does definitely move the conversation along.”

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