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Mental Fatigue May Involve a Potentially Toxic Chemical Buildup in the Brain

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A workday doesn’t have to involve tiring manual labor to leave you feeling exhausted. A new study claims to have pinned down a functional reason why we feel fatigued after a day of mental effort.

Antonius Wiehler and Mathias Pessiglione, both researchers at Pitié-Salpêtrière University Hospital in Paris co-authored the study, which was published in Current Biology. First author Wiehler and colleagues asked 40 volunteers to undergo a “work-day” of 24 task trials, split over 5 sessions, that involved either easy or challenging levels of cognitive control.

What is cognitive control?

Cognitive control is the active and intentional choosing of appropriate feelings, behaviors and thoughts in response to a task and its context – and the suppression of inappropriate habits that don’t help. When you choose to, for example, continue reading a fascinating scientific news story to enhance your understanding of the brain, rather than clicking away to watch TikToks about frogs, you are flaunting your superior cognitive control.

The tasks were interspersed with choice trials, where the volunteers were asked to pick between monetary rewards – either small values given instantly, or larger values they would have to wait for. The team noted that the volunteers subjected to the cognitively demanding tasks were more likely to opt for low-effort rewards that require less waiting time to receive.

Taking the easy way

These decisions, the authors believe, could be a consequence of the brain trying to protect itself from potentially toxic products built up during intense cognitive effort. “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,” said Pessiglione in a press release. The new study, believes Pessiglione, implies that fatigue’s purpose is instead “to preserve the integrity of brain functioning.”

The team used a technique called magnetic resonance spectroscopy (MRS) to examine brain metabolites produced during the participants’ “workday”. Recording three of the five sessions from inside a scanner, the team measured from two areas – a region of the lateral prefrontal cortex (PFC) and a section of the visual cortex. The only metabolite that showed significant changes in time with participants doing harder tasks for longer was the brain’s primary excitatory neurotransmitter, glutamate.

While essential for much of the brain’s second-to-second functioning, glutamate must be tightly controlled in the brain. Present inside nerve cells in large quantities, the authors write that excessive release of glutamate into the spaces between cells can upset delicate balances of brain signals, impair information transmission or even cause toxicity in severe cases. Previous studies have noted that glutamate tends to accumulate in response to demanding or stressful work. The authors believe that, taken together, their findings suggest that excessive levels of glutamate could make future cognitive activation of the PFC more costly, so that the brain will opt for less-taxing decision making when it is tired out.

How can we beat fatigue?

However, this remains only a theory. Importantly, the study was not designed in a way that could tease out a cognitive role for excessive glutamate in fatigue – it merely co-occurred with longer, more stressful working conditions. But the authors hope that the metabolic changes could provide a more accurate measure of severe mental fatigue than subjective self-reports, which are notoriously unreliable. They also note the need to investigate metabolite levels in conditions that involve chronic mental fatigue, such as depression.

Can we use these new findings to create innovative ways to dodge fatigue and tiredness? Pessiglione’s suggestion is that the classic solutions work for a reason: “I would employ good old recipes: rest and sleep! There is good evidence that glutamate is eliminated from synapses during sleep.”


Reference: Wiehler A, Branzoli F, Adanyeguh I, Mochel F and Pessiglione M.  A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions. Curr. Bio. 2022;32:1-12. doi: 10.1016/j.cub.2022.07.010