• Similar to physical work, mental work over a long duration can produce a feeling of tiredness, also referred to as cognitive fatigue.
• Previous studies have shown that the prefrontal cortex plays a critical role in cognitive processes that underlie mental effort.
• A new study suggests that intense mental work may result in the accumulation of potentially toxic metabolites in the prefrontal cortex, subsequently leading to cognitive fatigue.
• The increase in the levels of metabolites could trigger mechanisms necessary to regulate its levels and make the mental effort more difficult.

A recent study published in Current Biology shows that mental fatigue is associated with the accumulation of the neurotransmitter glutamate in the prefrontal cortex.

The necessity to remove excess glutamate levels due to its potentially toxic effect could increase the effort required for mental work, resulting in fatigue. This is a significant step toward understanding the mechanisms underlying the experience of mental tiredness.

Dr. Antonius Wiehler, the study’s author and psychologist at the Paris Brain Institute, Pitié-Salpêtrière University Hospital, elaborated to Medical News Today on why they chose to research this particular topic:

“Nobody knows what mental fatigue is, how it is generated and why we feel it. 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.”

“Besides, mental fatigue has important consequences: for economic decisions, for management at work, for education at school, for clinical cure, etc.,” he added.

“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.”
— Dr. Antonius Wiehler

Potential reasons

The feeling of fatigue after a day of engaging in challenging tasks that require mental effort or cognitive control is a commonly experienced phenomenon.

Cognitive control refers to cognitive or mental processes that allow an individual to adapt their thoughts and behaviors according to their goals while inhibiting automatic or impulsive behaviors. For instance, controlling the impulse to eat junk food to pursue the long-term goal of maintaining a healthy weight requires cognitive control.

During cognitive fatigue, individuals may experience a decrease in their ability to maintain cognitive control, increasing their tendency to engage in impulsive behaviors that provide immediate gratification.

Scientists previously uncovered the brain regions involved in cognitive control and fatigue, and one is the lateral prefrontal cortex (LPFC). The LPC is one of the brain regions that shows increased activation while performing tasks requiring cognitive control. Moreover, previous studies have shown a decrease in the activity of LPFC with increasing mental or cognitive fatigue.

But the reason underlying this experience of fatigue after engaging in tasks requiring prolonged cognitive effort remains unknown.

Researchers have proposed that depletion of overall energy reserves, such as blood glucose levels, after a day of mental work may deprive the brain of the necessary energy resources to exert cognitive control. However, studies show that overall energy supplies are not affected by cognitive tasks.

Dr. Clay Holroyd, a neuroscientist at Ghent University, who was not involved in the study, said this is referred to as the glucose hypothesis or biophysical theory.

Instead, the authors of the present study have suggested that depletion or accumulation of certain metabolites in the brain could be responsible for mental fatigue.

The metabolic changes in the brain due to cognitive fatigue could make it more costly or difficult to exert cognitive control and increase preference for behaviors requiring less cognitive effort. Moreover, according to this model, when an individual is sufficiently motivated, they may still be able to maintain high levels of cognitive control despite experiencing mental fatigue.

In the present study, the researchers conducted a daylong experiment involving participants engaged in cognitive activities requiring different levels of mental effort to test this model.

How the experiment went

The present study involved 40 participants who performed cognitive tasks during 5 sessions, lasting a total of 6.25 hours. The 40 participants were split into two groups: the test group composed of 24 participants that performed the harder or more demanding version of the task, and the control group, with the remaining 16 participants, that performed the simpler or less demanding version of the same task.

Dr. Holroyd pointed out that the time frame chosen by researchers was “far longer (and far more fatiguing) than is typical of most such studies,” which made the researchers’ novel combination of techniques stand out.

In previous studies, researchers have measured mental fatigue based on a decline in cognitive performance with the passage of time, but such a decline can occur due to other reasons, such as boredom or lack of motivation. Moreover, participants in such studies may adjust their cognitive effort upon observing a decline in their performance.

Hence, the authors of the present study made the participants choose a monetary reward associated with either more or less cognitive effort for the task. The authors chose this protocol because the economic decision was subjective, making it difficult for the participants to observe changes in their behavior as they experienced mental fatigue and compensate for these changes.

After they completed their cognitive tasks, the participants had to choose between a small and a large monetary reward for providing the correct response. To acquire the small reward, the participants needed to expend less cognitive effort, whereas they needed a greater amount of cognitive effort to obtain the larger reward.

Specifically, in comparison with the smaller reward, the larger monetary reward required participants to either wait for a longer duration to receive the reward or to engage in a task requiring greater cognitive or physical effort (such as a difficult cognitive test or riding an exercise bike at a higher resistance level) after they completed the experiment.

Accepting a delay in payment requires an individual to exert cognitive effort to curb their impulsiveness. Similarly, an individual agreeing to perform activities that are not automatic or habitual, such as taking a harder cognitive test or engaging in intense physical activity, requires more cognitive effort.

Cognitive fatigue affects decisions

The researchers hypothesized that cognitive fatigue would deter participants from opting for these high cost options and cause them to choose rewards that need less cognitive effort and provide immediate gratification.

Although the participants in the easy cognitive task group had a higher rate of accuracy than the hard task group, the performance of the participants in the hard task group did not show greater deterioration with the passage of time. In other words, the participants in the high-demand group did not show increased mental fatigue while performing the cognitive tests than the low-demand group.

However, as the experiment progressed, the participants performing the high-demand tasks were more likely to opt for a smaller economic reward requiring lower cognitive effort than those assigned to the low-demand group.

The researchers also measured pupil dilation while the participants made their decision about the economic reward. An individual’s pupils may dilate accordingly with the amount of effort they expend during a task requiring cognitive control or deliberation.

As the number of sessions increased, the participants in the high cognitive demand group showed a decline in their pupil dilation while making the decision about the reward. This further suggests a decline in cognitive effort in the high-demand group due to mental fatigue.

In sum, these data suggest that the participants in the high-demand group were able to maintain high levels of performance in the cognitive test but showed signs of fatigue while making the economic decision.

The certainty of obtaining a monetary reward upon providing accurate responses in the cognitive test may have motivated the participants in the high-demand group to maintain high levels of cognitive control despite experiencing fatigue.

In contrast, there was a lack of objectively correct answers when choosing between monetary rewards. This may have resulted in lower levels of deliberation or cognitive effort due to fatigue while making economic decisions in the high-demand group.

Changes in brain metabolites 

The researchers then assessed metabolic changes in the brains of the participants using a noninvasive technique called magnetic resonance spectroscopy (MRS). Specifically, they measured levels of metabolites in the LPFC, a region implicated in cognitive control, while participants were performing their tasks during the first, third, and the last (fifth) session of the experiment.

The participants who performed the more demanding cognitive tasks showed higher levels of the neurotransmitter glutamate in the lateral prefrontal cortex of their brains by the end of the experiment compared to their counterparts in the low-demand group. Additional analysis suggested that there was a greater accumulation of glutamate and its byproduct outside brain cells in the lateral prefrontal cortex in the high-demand group.

Furthermore, these changes were specific to the lateral prefrontal cortex and were not observed in the visual cortex, which processes all visual information.

Glutamate is the major excitatory neurotransmitter, and previous studies have shown increased release of glutamate by neurons during tasks requiring cognitive control. However, excess glutamate outside neurons can disrupt communication between neurons and have toxic effects.

Thus, the accumulation of glutamate during the performance of demanding cognitive tasks could make it necessary to regulate its levels. The regulation of glutamate levels could make cognitive effort more costly and result in individuals opting for less cognitively demanding options.

Interestingly, previous studies have shown that the levels of glutamate in the brain decrease after sleeping and this could potentially explain the decrease in cognitive fatigue after sleeping.

“This is an impressive, groundbreaking study. The reason why some cognitive tasks feel effortful and others don’t has been debated ad nauseam by researchers for more than a decade,” said Dr. Holroyd.

The researchers note that their study only shows a correlation between an increase in glutamate levels and mental fatigue, and changes in glutamate levels could be a byproduct of other metabolic processes.

What this means for future treatment

Dr. Wiehler commented on the implications of the study’s findings and said it may be particularly useful in several areas.

“Prefrontal metabolites could be monitored (using MRS) to detect cases of severe fatigue/burnout in many different situations: employees after work (say nurses at hospital), athletes during heavy training programs or before competitions, students during their revisions before their exams, etc. This may help [adjust the] work agenda to avoid exhaustion,” he told MNT.

Further research will be needed to determine the molecule monitored by the brain to track levels of mental fatigue and the brain region/s that detect these changes.

Dr. Holroyd said he was sure that the findings “will generate a great deal of discussion and interest in the field.” However, he said that there are still several important questions that remain to be addressed.

“Wiehler et al. have demonstrated that levels of glutamate in the [LPFC] and feelings of cognitive effort are associated with each other, but they haven’t shown a causal connection between the two,” he told MNT.

“Experiments will need to be conducted that show that increases in glutamate concentrations drive the feelings of cognitive effort in a causal way. This seems challenging and possibly not even possible given existing methods.”
— Dr. Clay Holroyd

“[O]ne would also like to know why LPFC activity, in particular, results in excessive glutamate concentrations; much of the rest of the brain seems to work equally hard even during easy tasks, so why doesn’t activity in those brain areas also result in excess glutamate? In other words, what is the neural process associated with cognitive effort that uniquely produces glutamate in LPFC?” he added.

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