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We’ve all experienced that thick mental fog after an intense day of cognitively demanding work, be it studying, coding, or planning. As if, no matter how hard you try, your brain cannot conceive of anything other than lying on your couch and staring into the void. Thoughts simply don’t come into focus anymore. Any kind of decision-making, particularly that which requires even the smallest amount of self-control, is doomed to fail. But why is that? And is there anything you can do to get rid of it?

PSA: It has recently come to my attention that a significant number of people have had troubles in finding citations for the sources we use. We are currently working on a better solution for including citations, but until then, I would like to point out the fact that at the end of every article published on our blog you will find a list of peer-reviewed scientific articles based on which the article has been written. Additionally, if you click on the journal name of each cited peer-reviewed article, it will take you to that specific article.

Cognitive fatigue, as that pesky brain fog is known in research, has been the subject of intense study over the years. But despite decades of work and many formulated theories, a well-substantiated explanation of cognitive fatigue has been eluding us. Fortunately, if there’s one thing scientists have plenty of, it’s interesting new directions of research. Before we can talk about what’s new though, we need to do some good old-fashioned myth busting.

Myth #1: cognitive fatigue is caused by resource depletion

For quite some time, scientists believed that your brain became tired because it ran out of resources. Intuitively, it makes sense. When you do some type of physical effort, you also get tired. But throw in a healthy meal and you’ll feel better in no time. Plus, we know the brain is quite resource-hungry: it uses up ~20% of your body’s glucose. So probably when you think extra hard, the brain eats up more glucose, no?

Well, no. When put to the test, this idea simply doesn’t stand up. Researchers have monitored blood glucose levels during cognitively demanding tasks and found no significant decrease in glucose amounts. They’ve also tried feeding people sugar to “replenish” the glucose used up by the brain and still, these people did not perform better on difficult tasks.

Finally, scientists went on to measure energy consumption directly in the brain both during demanding tasks and effortless rest. What they found was that global energy consumption remains relatively constant in both cases. In other words, thinking doesn’t really use up more energy (i.e. more glucose). So no energetic resources are actually being depleted.

Myth #2: through cognitive fatigue, your brain is asking for fun

The resource depletion hypothesis proven wrong left a vacuum for new explanations. So another interesting idea was born: what if your brain basically pretended to be tired so that you’d give it a fun break?

In more scientific terms, it was hypothesized that the brain is constantly performing a cost-benefit analysis between enjoying short-term pleasurable activities and delaying that fun for a bigger future reward. In this framework, the distant reward seems more appealing in the beginning of the strenuous activity, thus motivating us to work hard. But as time goes on, the cost-benefit analysis of the brain reveals that it’s no longer so rewarding to work for the future. Instead, it’s time to engage in pleasant exploration of the present environment. So the brain hits you with fatigue to get you to switch away from the cognitively demanding task.

If this idea seems wishy-washy and a bit full of plotholes, it’s because, well, it kind of is. The one piece of evidence in support of it is that increasing future rewards gets people to keep working on difficult tasks even after they’ve become cognitively fatigued. But even that doesn’t hold much water when you take into account pathological conditions such as burnout and depression where, regardless of magnitude, rewards cannot get rid of fatigue.

What’s more, creating such an illusion seems like an overly complicated way of balancing distant and immediate rewards. Plus, it doesn’t actually explain anything in terms of neural substrates. What is the neurobiological mechanism through which the brain creates this illusion? Just like this hypothesis, unclear.

New & improved theory: “toxic brain waste” causes cognitive fatigue

With the previous two myths unceremoniously collapsing due to lack of supporting evidence, scientists kept looking for new hypotheses that could explain what causes cognitive fatigue. Of course, they didn’t start from scratch. Instead, they managed to salvage bits and pieces from previous work. They started from knowing that:

1. cognitive fatigue makes it more difficult to focus the more time is spent doing difficult mental work;
2. the new hypothesis needs to include a plausible neurobiological mechanism;
3. previous literature strongly supports that cognitive fatigue is associated with decreased activity in the executive center of the brain, i.e. the lateral prefrontal cortex. That means neurons in this region become less and less capable of firing action potentials over time;
4. it’s definitely not due to glucose depletion.

With this in mind, they settled on a promising candidate: glutamate. You see, glutamate is a neurotransmitter that, when released from a neuron, makes another neuron fire. Afterwards, enzymes in the synaptic space clean up and recycle glutamate. But, like all neurotransmitters, both glutamate deposits and the rate of recycling are finite. Normally this isn’t too much of a problem.

However, during intense cognitive effort, neurons fire more than usual. That means more glutamate is released from inside neurons and the clean-up enzymes have a harder job keeping the synapses tidy. Consequently, if glutamate is related to cognitive fatigue, it has two plausible neurobiological mechanisms: either deposits inside neurons become depleted, making it increasingly more difficult for neurons to send out communications, or there is too much glutamate floating around the synapse, making it difficult for the receiving neurons to understand the message.

To examine that, researchers used a method called magnetic resonance spectroscopy or MRS. Similar to MRI, another famous neuroscientific method, MRS uses big magnets, complicated physics, and hydrogen atoms to produce fancy brain images. Unlike MRI, however, which focuses on hydrogen in water and fat, MRS looks at other molecules. In this study, for example, the authors used it to investigate glutamate, but also other control metabolites, such as creatine or myo-inositol.

Researchers used two groups of participants: one performing high-intensity and another low-intensity cognitive tasks. Out of all tested metabolites, as expected, glutamate was the only one which showed differences in concentration between the two groups. More specifically, the high-intensity group had more glutamate accumulating outside the neurons compared to the low-intensity one. This basically confirmed the second potential neurobiological mechanism from above: that cognitive effort leads to too much glutamate floating around synapses and impairing neuronal communication.

Finally, to make sure that this is a mechanism specific to cognitive fatigue and not just something that happens all around the brain during stimulation, the authors performed the same analysis in a control region, namely the primary visual cortex. As the cognitive tasks involved perceiving some visual information, this was also a highly active area throughout the task. However, the researchers found no glutamate accumulation here, suggesting this is something that happens only in the executive part of the brain.

The good, the bad, and the ugly

Ok, now we have one study which shows that accumulation of a neurotransmitter called glutamate in the space between neurons in the executive center of the brain seems to be related to cognitive fatigue. But what does it really mean? And what can we do with this information other than store it away?

First, the good part: from a scientific perspective, new research like this is important. It bring us closer to understanding the brain and one day this study in particular could turn out to be what laid the foundation of a new anti-fatigue pill, for example. This information also ties in nicely with theories we had about sleep. We have plenty of evidence showing that glutamate is cleared away during sleep and we know that sleep makes the brain fog go away. In this context, the current study could help explain why that is.

Now for the bad part: it doesn’t help us, as non-researchers, with much. Maybe it makes us feel less bad about getting tired after intense work. After all, that’s how the brain works. But the only way to get rid of cognitive fatigue is still the classic one: take breaks and sleep. As I’ve already said before, maybe in the future we will devise ways to clear glutamate out without needing sleep, but at this point, that’s just sci-fi and wishful thinking (if someone tries to sell you supplements that “clear your glutamate” or something along those lines, you’ve heard it here first, it’s definitely a scam!).

And the ugly part: this is a correlational study, meaning we don’t actually know if glutamate accumulation causes fatigue. We have a hypothesis that it impairs neuronal communication, but we still need interventional studies and we need to make sure that it’s not actually other substances which have as a side effect glutamate accumulation. Also, we are talking about one single study that has looked at this. In science, results need to be replicated across studies. In other words, we need a body of evidence. Plus, we’re still left with more questions than answers. For example, to list just a few: what’s so special about the lateral prefrontal cortex? If you remember, visual cortex stimulation didn’t have the same effect. Was it not intense enough? Or is there something else going on? How does this relate to disorders in which fatigue is a common symptom? What about other higher-order areas? And what about other neurotransmitters? We simply need more studies to thoroughly address the implications of this new research.

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Further reading

Miller, E. K., & Cohen, J. D. (2001). An integrative theory of prefrontal cortex function. Annual review of neuroscience, 24(1), 167-202.

Molden, D. C., Hui, C. M., Scholer, A. A., Meier, B. P., Noreen, E. E., D’Agostino, P. R., & Martin, V. (2012). Motivational versus metabolic effects of carbohydrates on self-control. Psychological science, 23(10), 1137-1144.

Raichle, M. E. (2015). The brain’s default mode network. Annual review of neuroscience, 38, 433-447.

Wiehler, A., Branzoli, F., Adanyeguh, I., Mochel, F., & Pessiglione, M. (2022). A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions. Current Biology, 32(16), 3564-3575.