Neuroimaging study suggests mental fatigue helps preserve the chemical integrity of the brain

Strenuous cognitive work leads to an accumulation of glutamate in the prefrontal cortex, according to new research published in the journal Current Biology. The new findings suggest that mental fatigue is a neuropsychological mechanism that helps to avert the build up of potentially toxic byproducts of prolonged cognitive activity.

“Nobody knows what mental fatigue is, how it is generated and why we feel it,” said study author Antonius Wiehler, a member of the Motivation, Brain and Behavior Lab at Pitié Salpêtrière Hospital in Paris. “It has remained a mystery despite more than a century of scientific research. Machines can do cognitive tasks continuously without fatigue, the brain is different and we wanted to understand how and why. Mental fatigue has important consequences: for economic decisions, for management at work, for education at school, for clinical cure, etc.”

The researchers were particularly interested in the role of glutamate, an excitatory neurotransmitter that is involved in a variety of cognitive functions, including learning and memory. In addition, glutamate plays a role in controlling the strength of synaptic connections. Too much or too little glutamate can lead to neuronal dysfunction, so it is critical that this neurotransmitter is tightly regulated.

The new study examined brain imaging data from 40 participants. The researchers induced mental fatigue using two cognitive control tasks. One group of participants completed an easy version of the tasks, while a second group completed substantially harder versions of the two tasks. Both groups, however, completed the tasks for the same duration. Participants alternated between performing the tasks inside and outside a brain scanner.

Both groups reported similar levels of subjective fatigue after completing the tasks. But participants who completed the difficult cognitive tasks exhibited a reduction of pupil dilation during an subsequent economic choice task. They also displayed a greater preference for immediate rewards, rather than waiting longer or exerting more effort to obtain better rewards. Critically, they also had higher levels of glutamate in synapses of the brain’s prefrontal cortex.

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“When intense cognitive work is prolonged for several hours, some potentially toxic byproducts of neural activity accumulate in the prefrontal cortex. This alters the control over decisions, which are shifted towards low-cost actions (no effort, no wait), as cognitive fatigue emerges (note that we are talking mental exhaustion here, not drowsiness),” Wiehler told PsyPost.

The findings provide evidence that glutamate accumulation makes further activation of the prefrontal cortex more costly, such that cognitive control is more difficult after a mentally tough workday.

To maintain regular cortical functioning, glutamate needs to be held in balance with inhibitory neurotransmitters. “Glutamate is present in the cells at high concentrations, as it is involved in the detoxification of ammonia and also serves as a precursor for the synthesis of proteins,” the researchers explained. “It is therefore important to limit glutamate release, both because it is a useful resource in the intracellular compartment and because it is a potentially toxic byproduct in the extracellular compartment.”

“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 co-author Mathias Pessiglione in a news release. “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.”

Wiehler and his colleagues used magnetic resonance spectroscopy to monitor the diffusion of glutamate-related substances in the brain. Magnetic resonance spectroscopy is a technique that uses magnetic fields and radio waves to study the structure and function of molecules. It can be used to detect changes in the chemical composition of tissues.

“We employed a new technique to measure the diffusion of brain substances with magnetic resonance spectroscopy and — it worked!” Wiehler told PsyPost. “It was particularly useful in our case, to show that glutamate accumulates in synapses (outside neurons), where diffusion is faster than in cellular compartments (inside neurons).”

While the findings provide unique insight into the basic mechanisms underlying mental fatigue, the researchers noted that there is still much to learn.

“On the basic science side: a follow-up question would be why is the prefrontal cortex susceptible to fatigue and glutamate accumulation, and not other brain regions like the visual cortex?(After hours spend watching TV, you can still see the world),” Wiehler remarked. “Another one would be: how does the brain detect glutamate accumulation and translate it into a fatigue signal that down-regulates the prefrontal cortex? On the clinical side: how could we prevent glutamate accumulation and clear glutamate out of the synapses? Are our neuro-metabolic markers of fatigue predictive of clinical outcome across diseases (depression, cancer, etc.)?

The study, “A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions“, was authored by Antonius Wiehler, Francesca Branzoli, Isaac Adanyeguh, Fanny Mochel, and Mathias Pessiglione.