• Two areas of the brain may work in combination to tell the brain when it's "feeling" tired.
• People with depression and post-traumatic stress disorder (PTSD) often experience cognitive fatigue.
• Results of the study may provide a way for physicians to better evaluate and treat people who experience such fatigue.

In experiments with healthy volunteers undergoing functional MRI imaging, scientists have found increased activity in two areas of the brain that work together to react to, and possibly regulate, the brain when it's "feeling" tired and either quits or continues exerting mental effort.

The experiments, designed to help detect various aspects of brain fatigue, may provide a way for physicians to better evaluate and treat people who experience overwhelming mental exhaustion, including those with depression and post-traumatic stress disorder (PTSD), the scientists say.

A report on the NIH-funded study was published online June 11 in the Journal of Neuroscience, detailing results on 18 female and 10 male healthy adult volunteers given tasks to exercise their memory.

"Our lab focuses on how [our minds] generate value for effort," says Vikram Chib, Ph.D., associate professor of biomedical engineering at the Johns Hopkins University School of Medicine and a research scientist at Kennedy Krieger Institute. "We understand less about the biology of cognitive tasks, including memory and recall, than we do about physical tasks, even though both involve a lot of effort." Anecdotally, Chib says, scientists know cognitive tasks are tiring, and relatively less about why and how such fatigue develops and plays out in the brain.

The 28 study participants, who ranged in age from 21 to 29, were paid $50 to participate in the study, and were told they could receive additional payments based on their performance and choices. All participants received a baseline MRI scan before the experiments began.

The tests of their working memory, which took place while undergoing subsequent MRI scans of their brains, included looking at a series of letters, in sequence, on a screen and recalling the position of certain letters. The farther back a letter was in the series of letters, the harder it was to recall its position, increasing the cognitive effort expended. The participants were given feedback on their performance after each test and opportunities to receive increasing payments ($1-$8) with more difficult recall exercises. The participants also were asked before and after each test to self-rate their level of cognitive fatigue.

Overall, the test results found increased activity and connectivity in two brain areas when participants reported cognitive fatigue: the right insula, an area deep in the brain that has been associated with feelings of fatigue, and the dorsal lateral prefrontal cortex, areas on both sides of the brain that control working memory. For each participant, activity in both brain locations during cognitive fatigue increased by more than twice the level of baseline measurements taken before starting the tests.

"Our study was designed to induce cognitive fatigue and see how people's choices to exert effort change when they feel fatigue, as well as identify locations in the brain where these decisions are made," says Chib.

Notably, Chib and his research team members Grace Steward and Vivian Looi found that the financial incentives need to be high in order for participants to exert increased cognitive effort, suggesting that external incentives prompt such effort.

"That outcome wasn't entirely surprising, given our previous work finding the same need for incentives in spurring physical effort," says Chib.

"The two areas of the brain may be working together to decide to avoid more cognitive effort unless there are more incentives offered. However, there may be a discrepancy between perceptions in cognitive fatigue and what the human brain is actually capable of doing," says Chib.

Fatigue is linked with many neurological conditions, including PTSD and depression, says Chib. "Now that we've likely identified some of the neural circuits for cognitive effort in healthy people, we need to look at how fatigue manifests in the brains of people with these conditions," he adds.

Chib says it may be possible to use medication or cognitive behavior therapy to combat cognitive fatigue, and the current study using decision tasks and functional MRI could be a framework for objectively classifying cognitive fatigue.

Functional MRI uses blood flow to measure broad areas of activity in the brain; however, it does not directly measure neuron activation, nor more subtle nuances in brain activity.

"This study was performed in an MRI scanner and with very specific cognitive tasks. It will be important to see how these results generalize to other cognitive effort and real-world tasks," says Chib.

Funding for the research was provided by the National Institutes of Health (R01HD097619, R01MH119086).

The research has identified a striking biological phenomenon: older adults who feel anxious on Mondays exhibit significantly higher long-term stress hormone levels, up to two months later. This "Anxious Monday" effect, observed in both working and retirees, points to a deep-rooted link between the start of the week and dysregulation of the body's stress response system, a known driver of cardiovascular disease (CVD). Published in the Journal of Affective Disorders, the study analyzed data from over 3,500 older adults participating in the English Longitudinal Study of Ageing (ELSA).

Key Findings

• 23% Higher Cortisol Levels: Older adults reporting Monday anxiety had 23% elevated cortisol levels in hair samples (reflecting cumulative exposure over two months) compared to peers anxious on other days.
• Non-Workers Not Spared: The effect persisted among retirees, challenging assumptions that workplace stress alone explains Monday's toll.
• CVD Connection: Mondays are linked to a 19% spike in heart attacks -- this study identifies HPA-axis dysregulation as a potential biological bridge.
• Not just higher levels of Monday anxiety: Only 25% of the Monday effect was due to greater feelings of anxiety on Mondays. The rest was because of the greater effect of feeling anxious on Mondays compared to other days.

The hypothalamic-pituitary-adrenal (HPA) axis regulates stress hormones like cortisol, which, when chronically elevated, contribute to hypertension, insulin resistance, and immune dysfunction. While prior research noted higher cortisol on weekdays versus weekends, this is the first study to pinpoint Mondays as uniquely disruptive. The findings suggest societal rhythms -- not just job demands -- embed themselves in human physiology, with lasting health risks.

"Mondays act as a cultural 'stress amplifier,'" said Professor Chandola. "For some older adults, the week's transition triggers a biological cascade that lingers for months. This isn't about work -- it's about how deeply ingrained Mondays are in our stress physiology, even after careers end.

The study underscores how the "Monday blues" can become biologically embedded, with chronic stress hormone dysregulation posing long-term cardiovascular risks. Addressing Monday-specific stress could unlock new strategies to combat heart disease in aging populations.

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