“No one 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 Laboratory at Pitié Salpêtrière Hospital in Paris. “It has remained a mystery despite more than a century of scientific research. Machines can perform cognitive tasks continuously without fatigue, the brain is different, and we wanted to understand how and why. Mental fatigue has important consequences: for decisions economic, for labor management, for school education, for clinical care, etc.
The researchers were particularly interested in the role of glutamate, an excitatory neurotransmitter involved in various cognitive functions, including learning and memory. In addition, glutamate plays an important role in controlling the strength of synaptic connections. Too much or too little glutamate can cause neuronal dysfunction, so it is critical that this neurotransmitter is tightly regulated.
The new study looked at 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 more difficult versions of both 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 showed reduced pupil dilation during a subsequent economic choice task. They also showed a greater preference for immediate rewards, rather than waiting longer or striving for better rewards. Critically, they also had higher levels of glutamate at synapses in the brain’s prefrontal cortex.
“When intensive cognitive work is prolonged for several hours, some potentially toxic by-products of neural activity accumulate in the prefrontal cortex. This alters decision control, which shifts towards low-cost (effortless) actions , no wait), as cognitive fatigue sets in (note that we’re talking about mental exhaustion, not sleepiness),” Wiehler told PsyPost.
The findings provide evidence that glutamate accumulation makes additional activation of the prefrontal cortex more costly, making cognitive control more difficult after a mentally demanding workday.
To maintain regular cortical functioning, glutamate must remain in balance with inhibitory neurotransmitters. “Glutamate is present in cells in high concentrations as it is involved in ammonia detoxification and also serves as a precursor for protein synthesis,” the researchers explained. “Therefore, it is important to limit the release of glutamate, 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 suggest that fatigue is a kind of illusion set up by the brain to make us stop what we’re doing and switch to a more rewarding activity,” co-author Mathias Pessiglione said in a press release . “But our results show that cognitive work produces a real functional alteration -accumulation of harmful substances-, so fatigue would be a signal that would make us stop working but with a different purpose: to preserve the integrity of the functioning of the brain” .
Wiehler and 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 used 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).”
Although the findings provide unique insight into the basic mechanisms underlying mental fatigue, the researchers noted that much remains to be learned.
“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 such as the visual cortex? (After hours of spend watching TV, you can still see the world),” Wiehler commented. “Another would be: How does the brain detect glutamate accumulation and translate it into a fatigue signal that down-regulates the prefrontal cortex? At the clinical level: How could we prevent glutamate build-up and remove glutamate from synapses? Are our neurometabolic markers of fatigue predictive of clinical disease outcome (depression, cancer, etc.)?
Antonius Wiehler, Francesca Branzoli, Isaac Adanyeguh, Fanny Mochel and Mathias Pessiglione wrote the study, “A neurometabolic account of why one day’s cognitive work alters control over economic decisions.”