Specific Definition of Fatigue in MS Proposed as Way to Advance Research into Symptom

Researchers from Colorado State University propose a new model of fatigue in multiple sclerosis (MS), designed to overcome the lack of a unified definition of fatigue that can be objectively tested using experimental approaches.

With this model, the authors behind the article, “Fatigue in Multiple Sclerosis: Misconceptions and Future Research Directions,” published in the journal Frontiers in Neurology, believe that research into the mechanisms of fatigue can be advanced, as well as treatments that might better address this symptom and possibly conquer it.

Fatigue affects up to 92% of people with MS and is often perceived as one of the disease’s most burdensome symptoms. But researchers know little about why and how it arises, and none of the current MS therapies treat it in a satisfying way.

The authors of this “perspective article” believe that the lack of effective research is caused by an inadequate definition of fatigue, and propose the following model and definition: “Fatigue is the decrease in physical and/or mental performance that results from changes in central, psychological, and/or peripheral factors.”

Although everyone intuitively knows what fatigue is, the lack of rigid descriptions make it difficult for scientists studying it. One study exploring a particular drug’s effects might describe fatigue in one way and relate those effects to the description given, while other studies use different descriptions and measures of outcomes — making it impossible to compare results across studies.

“When compared to advances made in other domains of disease status and disability in [people with] MS, fatigue continues to lag behind. The lack of progress is largely due to the varying subjectivity in the definition and assessment of fatigue between research groups,” the authors said. “Our proposed theoretical model provides specific areas of objective fatigue assessment that can be applied in research and intervention settings.”

The new definition differs from how fatigue is commonly viewed in that it assumes that it cannot be tied to a particular bodily process, but rather is always influenced by many ‘factors.’ Central factors may be differences in brain neurotransmitters, inflammatory molecules, or brain metabolism; peripheral factors include muscle changes, such as the ability to contract or generate enough energy. Psychological factors can also impact fatigue, like perceived effort, a subjective sense of worsening performance over time, motivation, and cognitive impairment, the authors state.

The definition also takes into account that fatigue is likely dependent on the surrounding conditions, such as the environment and the task being performed.

A definition of fatigue on which researchers agree, however, is only the first necessary step toward a real understanding of the problem, the researchers said. Better experimental set-ups are also needed, as current measurements often miss the target. Questionnaires, often used to measure fatigue, are not specific enough and often include measures of tiredness and other MS symptoms that are not always linked to fatigue. These questionnaires are also entirely subjective.

Objective measures of fatigue can be obtained by measuring performance before, during, and after a task. Such measurements could assess what researchers call performance fatigability, which can be measured separately for movement and cognitive performance. If such tests take into account factors such as depression, anxiety, and reduced cognitive processing speed, all known to impact results on such tests, investigators will get closer to the core of the problem itself. Such measurements, the authors pointed out, need to make use of multiple tools, including various forms of brain scans and neuropsychological tests.

These researchers, however, acknowledge that this proposed model is purely theoretical, and conclude that future research needs to provide proof that it is a valid way of studying fatigue.