It’s not just hard physical labor that can wear us out, challenging mental labor – say, having to concentrate on something difficult for hours – makes us feel worn out, too. Researchers at Pitié-Salpêtrière University and colleagues have now uncovered evidence to explain why this is. Based on their findings, they also suggest that the reason we feel mentally exhausted (as opposed to drowsy) from intense thinking isn’t all in the head.

The team’s studies in human volunteers showed that when intense cognitive work is prolonged for several hours, it causes potentially toxic by-products to build up in the prefrontal cortex region of the brain. This in turn alters control over decisions, so there is a shift toward low-cost actions requiring no effort or waiting as cognitive fatigue sets in.

There may be other practical implications to the findings. For example, the researchers say, monitoring of prefrontal metabolites could help to detect severe mental fatigue. Such an ability may help adjust work agendas to avoid burnout. Research lead Mathias Pessiglione PhD, advises people to avoid making important decisions when they’re tired.

“Influential theories suggested that fatigue is a sort of illusion cooked up by the brain to make us stop whatever we are doing and turn to a more gratifying activity,” He noted, “But our findings show that cognitive work results in a true functional alteration—accumulation of noxious substances—so fatigue would indeed be a signal that makes us stop working but for a different purpose: to preserve the integrity of brain functioning.” The team is also curious to learn whether the same markers of fatigue in the brain may predict recovery from health conditions, such as depression or cancer.

The researchers reported their findings in Current Biology, in a paper titled, “A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions.”

While machines can compute continuously, the brain can’t. Chess players, for example, need be able to carry cognitive or executive control over their decisions, as they plan which of a huge number of possible moves they should make when, in order to eventually win the game. It’s not just a case of repeatedly following previously learned routine. “Winning the game, therefore, requires the capacity to monitor new context-action mappings, a capacity that is known as cognitive or executive control,” the authors wrote. However, as they further pointed out, “Even professional chess players start making mistakes, typically after 4–5 h in the game that they would not make when well rested.” It’s a form of fatigue, the team explained. “Behavioral activities that require control over automatic routines typically feel effortful and result in cognitive fatigue.”

Pessiglione, together with first author Antonius Wiehler, PhD, and colleagues, wanted to understand what mental fatigue really is. “… the reason why exerting cognitive control is exhausting remains unclear,” the investigators noted. According to previous theories, “Beyond subjective report, cognitive fatigue has been conceived as an inflated cost of cognitive control, objectified by more impulsive decisions.”

In contrast, Pessiglione and colleagues suspected that cognitive fatigue had more to do with the need to recycle potentially toxic substances that arise from neural activity. “…we suggest a neuro-metabolic account: the cost would relate to the necessity of recycling potentially toxic substances accumulated during cognitive control exertion,” they commented.

To look for evidence of this, they used magnetic resonance spectroscopy (MRS) to monitor brain chemistry over the course of a workday. They quantified metabolites in neural tissues in two groups of participants. One group was given tasks that required the participants to think hard, while individuals in other group had relatively easier cognitive tasks.

The investigators saw signs of fatigue, including reduced pupil dilation, only in the group doing the hard cognitive work. Participants in that group also showed in their choices a shift toward options proposing rewards at short delay with little effort. “Choice-related fatigue markers were only present in the high-demand group, with a reduction of pupil dilation during decision-making and a preference shift toward short-delay and little-effort options …” the scientists pointed out.

Critically, they also had higher levels of glutamate in synapses of the brain’s prefrontal cortex. “At the end of the day, high-demand cognitive work resulted in higher glutamate concentration and glutamate/glutamine diffusion in a cognitive control brain region (lateral prefrontal cortex [lPFC]), relative to low-demand cognitive work and to a reference brain region …” they pointed out.

Together with earlier evidence, the authors say the study findings support the notion that glutamate accumulation makes further activation of the prefrontal cortex more costly, such that cognitive control is more difficult after a mentally tough workday. “This pattern of results is compatible with the assumption of an increase in the cost of cognitive control, related to the necessity of maintaining glutamate levels within acceptable boundaries,” the investigators wrote. “The elevated cost would both limit the recruitment of cognitive control during choice and bias decisions away from costly options.”

So, is there some way around this limitation of our brain’s ability to think hard? “Not really, I’m afraid,” Pessiglione said. “I would employ good old recipes: rest and sleep! There is good evidence that glutamate is eliminated from synapses during sleep.”

The authors acknowledged that their reported findings are “ … only correlational and cannot be taken as proof that what limits cognitive control exertion is the need to prevent glutamate accumulation. Causal manipulations would be required to validate this assumption,” they stated.

Nevertheless, as they pointed out, “Taken together with previous fMRI data, these results support a neuro-metabolic model in which glutamate accumulation triggers a regulation mechanism that makes lPFC activation more costly, explaining why cognitive control is harder to mobilize after a strenuous workday. … it has been shown that glutamate concentrations decrease during sleep, in relation to EEG slow-wave activity. Glutamate could therefore belong to the potentially toxic substances that are eliminated during sleep, which could mediate recovery from cognitive fatigue.”

In future studies, the investigators hope to learn why the prefrontal cortex seems especially susceptible to glutamate accumulation and fatigue.