Nature reports on new findings about the roots of mental fatigue — which has implications not just for generally feeling worn out, but also for conditions like chronic fatigue, surgical recovery, and long covid:
Researchers and clinicians have long struggled to define, measure and treat cognitive fatigue — relying mostly on self-reports of how tired someone says they feel. Now, however, scientists from across disciplines are enlisting innovative experimental approaches and biological markers to probe the metabolic roots and consequences of cognitive fatigue.
The efforts are getting a boost in attention and funding in large part because of long COVID, which afflicts roughly 6 in every 100 people after infection with the coronavirus SARS-CoV-2, says Vikram Chib, a biomedical engineer at Johns Hopkins University in Baltimore, Maryland. “The primary symptom of long COVID is fatigue,” says Chib. “I think that has opened a lot of people’s eyes.”
Chib and others hope that a fundamental understanding of cognitive fatigue will help the billions of people who face it from time to time, as well as the tens of millions who carry it as a more extreme and chronic companion. As well as being common in long COVID, debilitating fatigue is a symptom of chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CFS), post-traumatic stress disorder, multiple sclerosis, depression and Parkinson’s disease. Extreme mental exhaustion can also follow cancer treatment, head injury, stroke or exposure to certain toxins.
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Cognitive control is the term that scientists give to this effortful directing and regulating of thought. Over time, as a leading theory goes, maintaining control becomes costly for the brain, and fatigue emerges. Scientists aren’t entirely sure why. Some think it is related to how cells cope when their energy supply is strained; others point to a build-up of toxins from neural activity1. But researchers tend to agree that the sensation of fatigue is protective — a warning that the brain is nearing a physiological boundary and it’s time to rest.
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Researchers have found potential links between cognitive fatigue and changing levels of metabolites such as glucose and lactate, neurochemical messengers such as glutamate and adenosine, and a protein involved in learning and memory called brain-derived neurotrophic factor2. Even amyloid-β, a protein fragment associated with Alzheimer’s disease, might contribute by disrupting synapses, interfering with the clearance of glutamate or increasing neuroinflammation3. But it is uncertain what is a marker and what is a cause.
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To better understand fatigue, [Paris Brain Institute researcher Mathias] Pessiglione, Chib and other researchers are trying to bridge an understanding of its biochemical workings with how it affects motivation4. The current hypothesis: cognitive fatigue arises from metabolic changes in parts of the brain that are responsible for cognitive control. And those changes, whether resulting from depleted energy stores or amassed waste, alter how brain circuits weigh the costs and benefits of exerting mental effort — nudging decisions towards easier options that are more immediately rewarding1.
In a 2022 study5, Pessiglione and his team simulated a workday by asking otherwise healthy participants to spend several hours on either easy or hard versions of the same cognitive tasks. In one task, participants viewed letters appear
ing one after another on a screen and had to decide whether each new letter matched one a certain number of letters earlier. Recalling whether the letter on screen matched the third letter back, for example, would be much more difficult than recalling whether it matched the first letter back.
After this simulated workday, participants made choices between smaller immediate rewards and larger delayed ones. Those who had completed the harder tasks were more likely to opt for instant gratification. That preference was also consistent with greater accumulation of glutamate — one of the metabolites suspected to build up with cognitive exertion — in the lateral prefrontal cortex. This brain region is involved in executive functions, such as working memory and decision-making, and has been found to have lower activity after a hard day of simulated work6.
Matthew Apps, a cognitive neuroscientist at the University of Birmingham, UK, says that the dynamics of dopamine — which interacts closely with adenosine, glutamate and other metabolic players in the brain — might help to explain the connection between neurometabolic strain and the experience of fatigue. Because dopamine enhances the perceived value of rewards, it typically boosts motivation to invest effort. He proposes that sustained effort might cause dopamine levels to drop, leaving people less willing to work for the same pay-off.