Cognitive and Physical Fatigue in Multiple Sclerosis

Fatigue is one of the most pervasive and disabling symptoms experienced by people with multiple sclerosis (MS). It manifests in two closely interrelated domains: cognitive fatigue, characterised by a progressive decline in mental stamina and concentration during sustained cognitive effort; and physical fatigue, noted as reduced muscle endurance and a heightened perception of exertion during motor tasks. Both forms of fatigue substantially impair daily functioning, quality of life and vocational participation. The underlying mechanisms are multifactorial, involving immune-mediated inflammation, demyelination, axonal loss and compensatory neural reorganisation. Disruption within cortico‐subcortical circuits—particularly those encompassing the thalamus and basal ganglia—appears central to fatigue generation. Altered brain activation patterns and network connectivity, combined with peripheral and central inflammatory mediators, contribute to the subjective sensation of exhaustion and the objective decline in performance. The complexity of fatigue in MS has spurred development of specialised assessment scales, quantitative neuroimaging techniques and experimental paradigms to disentangle its cognitive and physical components and to evaluate the efficacy of pharmacological, rehabilitative and neuromodulatory interventions.

Research from Nature Portfolio

Recent studies have adopted a cross-condition design to examine cognitive fatigue in individuals with MS alongside other neurological populations. By inducing fatigue through sustained cognitive tasks while acquiring functional imaging data, researchers have demonstrated that increases in subjective fatigue correlate with slower response times across groups. Neuroimaging findings have highlighted the caudate nucleus and thalamus as common nodes whose activation parallels the accrual of fatigue, suggesting these structures act as central hubs for fatigue perception. Moreover, more dorsal regions of the caudate exhibit group-specific variations in activation, indicating that structural or pathological differences in MS may modulate the engagement of these subregions during task performance. Such insights underscore the value of combining behavioural measures with task-based imaging to delineate the neural signatures of cognitive fatigue in MS and to identify targets for potential therapeutic modulation.

Cognitive and Physical Fatigue in Multiple Sclerosis publication trend

The graph below shows the total number of articles in cognitive and physical fatigue in multiple sclerosis across all publications each year (not limited to Nature Index journals).

Technical terms

Cognitive fatigue: A decline in mental energy and performance efficiency during prolonged cognitive activity.

Physical fatigue: Reduced muscle force and endurance accompanied by an increased subjective sense of exertion.

Interoception: The brain’s ability to perceive and interpret signals from within the body, such as heart rate or respiratory effort.

Metacognition: The capacity to monitor and evaluate one’s own cognitive processes and performance.

Microstate: A transient, quasi-stable scalp potential configuration reflecting coordinated activity of large-scale brain networks.

Fractional anisotropy: A diffusion MRI metric indicating the directional coherence of white matter fibre tracts.

Salience network: A set of brain regions, including the anterior insula and dorsal anterior cingulate cortex, involved in detecting and filtering behaviourally relevant stimuli.

Connectome fingerprinting: A method for identifying individual-specific patterns of functional or structural brain connectivity.

References

1. Fatigue in multiple sclerosis: can we measure it and can we treat it?. Journal of Neurology (2024).
2. Understanding the mechanisms of fatigue in multiple sclerosis: linking interoception, metacognition and white matter dysconnectivity. Brain Communications (2024).
3. Reduced clinical connectome fingerprinting in multiple sclerosis predicts fatigue severity. NeuroImage Clinical (2023).
4. Evaluating the effects of brain injury, disease and tasks on cognitive fatigue. Scientific Reports (2023).
5. Fatigue in Multiple Sclerosis: A Resting-State EEG Microstate Study. Brain Topography (2024).
6. Thalamo‐striato‐cortical determinants to fatigue in multiple sclerosis. Brain and Behavior (2013).
7. The Representation of Inflammatory Signals in the Brain – A Model for Subjective Fatigue in Multiple Sclerosis. Frontiers in Neurology (2014).
8. Subjective Cognitive Fatigue in Multiple Sclerosis Depends on Task Length. Frontiers in Neurology (2014).