Hiding in Plain Sight: The Fatigue Mystery

What is the most tired you have ever been? So tired that all you wanted to do was crawl up into a little ball, take refuge in bed, and never do anything ever again? Tired enough to fall asleep immediately as your head hits the pillow, sleep like the dead, and reawaken feeling energized and just fine, like you had the best night of sleep anyone has ever had? Now imagine that you are as tired today as you were then. However, after your nap, you do not feel fine. You are every bit as tired as when you first closed your eyes. And that no matter what you do, you are shadowed by an ever-present feeling of exhaustion.

Welcome to the world of pathological fatigue, a mind-boggling and vastly underappreciated health condition within the greater landscape of neurological disease treatment and research. Fatigue is a lack of energy or motivation that interferes with the ability to sustain effortful activity. It can arise from many different sources and has a pervasive influence on the human body, shaping everything from molecular interactions to the decision-making process.¹ I was surprised to learn that fatigue is such an active field of study, as it is not usually the first idea that comes to mind when thinking about cutting-edge biomedical research. Deceptively mundane, fatigue is nonetheless a critically necessary part of our lives. It is intimately connected with the well-being of our bodies, warning us when bodily resources are low and signaling the severity of disease.² Indeed, pathological fatigue is implicated in virtually every neurological disorder you can name. Furthermore, it is described as the most bothersome symptom by the majority of patients with cancer as well as being the primary or secondary reason for 10%–20% of patient consultations in primary care.³ Despite this, our understanding of fatigue and how to treat it is superficial at best.

If fatigue is so central to the experience and treatment of disease, then why do we not know more about it? There are several factors that make fatigue difficult to study. First, we lack the proper language to describe fatigue. The definition offered above does not adequately encapsulate the fatigue experience and its myriad components. Fatigue researchers have concocted terms such as central fatigue and peripheral fatigue to focus the conversation, but these labels have only served to muddy the waters. To experts, central fatigue could mean anything from how fatigue impacts mental performance to the microscopic, yet significant, effects that fatigue has on brain chemistry.⁴ Yet, researchers consistently employ the same terms to characterize profoundly different phenomena, making the comparison of results across studies difficult to interpret and generally slowing the progress of the field.

Recently, there have been attempts to solve this problem by introducing new terms to distinguish a person’s perspective of their fatigue — known as subjective fatigue — from performance fatigability, or the measurable effect of fatigue on physical or mental performance.⁵ When you cannot finish that last rep at the gym or have difficulty collecting your thoughts toward the end of an exam, you are experiencing fatigability. It may seem like an arbitrary distinction, yet subjective fatigue and performance fatigability are different sensations associated with separate mechanisms. Objectively measurable, fatigability can be linked to physiological processes, such as the lactic acid buildup in muscles that cuts your lift short, and thus targets for study and treatment can be feasibly identified.

In contrast, subjective fatigue is, by nature, subjective — it cannot be measured by an external observer. This is the second reason why fatigue is difficult to study. For all our medical and technological advances, the best we can do currently when it comes to measuring subjective fatigue is rely on self-report questionnaires. While these are invaluable for research, they are biased by the patient’s unique circumstances and their experience of fatigue. Typically, biomedical researchers prefer to use bodily substances like blood as biomarkers to reliably measure the severity and timecourse of a disease. However, we do not have a reliable biomarker for subjective fatigue; we do not have a biomarker at all!

These and other reasons are what make fatigue such a difficult and heartbreaking topic of study. It severely limits the patient’s quality of life while remaining elusive to investigation in the laboratory. But this is also what makes fatigue such a high-value target of research investment. If we can crack the code of fatigue, we may just find the key to understanding and treating every health condition in which it appears. Beyond that, as fatigue acts as a thermometer for the body’s energy stores, better understanding the mechanisms of this phenomenon could provide a way to identify a problem before symptoms become too severe. If we can learn to understand fatigue, we can revolutionize our understanding of the body and disease.

References:

1. Manjaly ZM, Harrison NA, Critchley HD, Do CT, Stefanics G, Wenderoth N, Lutterotti A, Müller A, Stephan KE (2019) Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis. J Neurol Neurosurg Psychiatry 90:642–651.
2. Stephan KE, Manjaly ZM, Mathys CD, Weber LAE, Paliwal S, Gard T, Tittgemeyer M, Fleming SM, Haker H, Seth AK, Petzschner FH (2016) Allostatic self-efficacy: A metacognitive theory of dyshomeostasis-induced fatigue and depression. Front Hum Neurosci 10:550.
3. Maisel P, Baum E, Donner-Banzhoff N (2021) Fatigue as the chief complaint—epidemiology, causes, diagnosis, and treatment. Dtsch Arztebl Int 118:566–576.
4. Kluger BM, Krupp LB, Enoka RM (2013) Fatigue and fatigability in neurologic illnesses: Proposal for a unified taxonomy. Neurol 80:409–416.
5. Kuppuswamy A (2022) The neurobiology of pathological fatigue: New models, new questions. The Neuroscientist 28:238–253.4

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