Can Neuroscience Explain What Makes Fatigue Chronic?

If you are living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or long COVID, you’ve likely learned to be very careful about not overdoing it. After meticulous efforts not to exceed your "energy envelope", you may have achieved some hard-won, yet tentative stability. At this point, it might not seem too much to try and do a little more activity.

However, within a few days of attempting the activity, you find yourself hit by a fresh wave of symptoms. It feels like you are being punished by your body for having the temerity to try and do something that most people take utterly for granted. This, of course, is known as post-exertional malaise (PEM), a hallmark symptom of ME/CFS and long COVID. Based on my own experience, "brutal" might be the best word to describe it.

I am grateful to say that I have fully recovered from ME/CFS and long COVID, and looking back, that time in my life has come to feel like a bad dream. It was so horrendous that I now spend much of my time thinking about how to help others escape the quagmire. On my journey reading through the emerging research and doing clinical work with people living with ME/CFS and long COVID, I have become convinced that findings from neuroscience offer a powerful and compelling explanation for how fatigue becomes chronic.

The Brain Is a Predictive Machine

Our understanding of how the brain works has been turned upside down in the last 15 years or so. We used to assume that the brain was “a kind of passive window onto the world,” in the words of philosopher Andy Clark. In other words, we presumed that what we see, hear, touch, taste, and feel was a straightforward result of information travelling from our eyes, ears, skin, taste buds, and the inside of our body up to the brain, where it would be faithfully transmitted into our direct experience.

As it happens, neuroscientists now believe that what we experience as reality is actually the result of an ongoing conversation between our brain’s expectations of a given situation and the raw data travelling to the brain through our sensory apparatus. This might sound odd at first, or quite possibly, like something out of "The Matrix."

But it starts to make sense when we consider that the brain's main job is to keep our body in balance. In order to do this job, the brain makes endless predictions. Predictions about the world around us: Is it safe out there, or dangerous? Predictions about the world inside of us: Are we resilient enough to handle potential dangers out there?

Rather than having to scan the endless stream of data being received from our outer and inner worlds, it is far more efficient for the brain to build templates of how it expects things to be. Through the course of our life, our brain's templates get increasingly sophisticated. These predictions shape our experience directly. (To understand how this works, check out this video. The words you hear in the looping football chant actually seem to change, based on predictions fed to your brain by the text shown on the screen.)

This newer model of how the brain works, known as predictive processing, is thought to apply not only to our experience of the world around us, but also the one inside of us: our body and its fluctuating states. Think about how the sight, smell, or even thought of a food that once gave you violent food poisoning may be sufficient to induce a feeling of nausea in your body. This is the result of your brain coding, or learning to associate, that food with illness. One research study was able to induce fatigue in its participants purely by playing a sound that had become associated with a mentally draining task.

As a result of this new science of predictive processing, we are now coming to understand body sensations, like fatigue and hunger, in a new way. Rather than being real-time representations of the body’s current state, feelings of hunger and tiredness might be better understood as messages from the brain about its anticipation of the challenges that lie ahead. By sending messages of fatigue or hunger, it’s as if the brain is saying to us: “This situation is likely to be incredibly demanding, we should rest, or eat, or both!”

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Of course, it wouldn't be useful for the brain to rely solely on its templates of the world, since sometimes the world surprises us. As a result, when there is a significant gap between what the brain expects us to experience and the information being received, the brain receives a message that it needs to update its model of the world. This is called a prediction error.

Learning to Predict the Worst

So, how can the emerging neuroscience of predictive processing help explain ME/CFS and long COVID? Well, as I discussed in a previous post, these conditions may be precipitated by a sort of confidence crisis in the brain, which has been described by researchers as a loss of allostatic self-efficacy. On the back of cumulative stressors, which may be psychological, biological or environmental, the brain comes to doubt its ability to perform its main role: to maintain balance in the entire organism. Commonly, a final insult, such as a viral infection, triggers a "state of emergency" in the brain, also known as central sensitisation.

In this hyper-vigilant state, the brain’s predictive baseline becomes dislocated. It defaults to assuming that the world is unsafe, that there are simply too many stresses facing us, and that the body is not resilient enough to handle them. Monty Lyman summarises this state of emergency in The Immune Mind:

Persistent fatigue can be viewed as the brain’s recognition of its futile battle to restore balance. …And as the predicting brain is dealing with persistent, unresolved uncertainty, not even rest relieves this fatigue. An uncertain brain predicts that it needs more fuel, taking energy from the rest of the body.

Source: Brandon Morgan / Unsplash.

If all of this sounds a bit confusing, think of the brain as a weather forecaster with god-like powers to create the weather. On the back of an overwhelmingly stormy period of life, the brain comes to assume that the world has become an interminably tempestuous place. Until further notice, the brain defaults to forecasting — and therefore creating — terrible weather, i.e., disabling physical symptoms.

“But didn't you talk about prediction errors?” I hear you ask. After the real-life storms have died down — the pandemic ends, we make significant lifestyle changes, we learn to rest and pace — shouldn't the brain ultimately get the message that things are different now? That a more accurate forecast may even include some sunshine?

Well, emerging evidence suggests that the brains of people with chronic fatigue or pain may be both more prone to prediction errors around receiving signals from the body and less receptive to updating their templates of the world. In other words, the brain becomes a cynic, convinced of the dangers of the world, and the vulnerability of the body.

The bottom line is inherently hopeful. If the brain has learned to predict storms which show up in the form of deeply unpleasant and debilitating symptoms, we can gradually help the brain to update its forecasts. We can harness its inherent malleability — its neuroplasticity — to nudge it to gradually become more flexible in its outlook. I look forward to exploring with you what this process may look like in future posts.