Combining clinical, Behavioural and Neuroimaging Methods to Understand Multiple Sclerosis Fatigue

  • Iulia Danciut

    Student thesis: Doctoral Thesis



    Fatigue has high prevalence and impact on quality of life and employment in multiple sclerosis (MS), but the mechanisms are yet to be elucidated. New evidence points towards the role of interoception and metacognition. Interoception is the general sensitivity to internal bodily signals, entailing three dimensions: accuracy, awareness and sensibility. Metacognition refers to the brain’s assessment of its own performance.

    MS causes brain tissue damage, which might cause disruptions in structures supporting interoceptive and metacognitive function. Considering this rationale, this Doctoral Thesis reports the findings of Multiple Sclerosis Fatigue and Interoception Study (MS-FIN), looking at the relationship between interoception, metacognition, brain tissue damage and fatigue.


    Seventy-one relapsing-remitting MS patients participated in MS-FIN cross-sectional study. Patient outcomes relevant for fatigue were measured, including disability, disease duration, depression, anxiety, sleepiness, cognitive function, MS disease modifying treatment and quality of life. Interoceptive and metacognitive parameters were measured using behavioural tasks.

    Non-invasive magnetic resonance imaging (MRI) was performed in 69 participants, including Diffusion Tensor Imaging, Neurite Orientation Dispersion and Density Imaging and quantitative Magnetization Transfer. Analyses were performed looking at white matter, using Tract-Based Spatial Statistics for the first time using these three combined MRI modalities to study MS fatigue, alongside behavioural model testing.

    Three alternative hypotheses to explain fatigue as a consequence of, respectively, reduced interoceptive accuracy, reduced interoceptive awareness, or reduced global metacognition are explored.


    The top-down interoceptive brain processing hypothesis was confirmed. The odds of cognitive fatigue were higher in the low interoceptive awareness tracking group. No significant relationships were found between MS fatigue and other interoceptive or metacognitive parameters.

    Diffusion parameters fractional anisotropy and neurite density index showed significant negative associations with cognitive fatigue in a widespread bilateral white matter network. Moreover, there was significant interaction between cognitive fatigue and interoceptive tracking awareness, with effects on diffusion parameters fractional anisotropy and neurite density index and the quantitative magnetization parameters. When accounting for disability, depression and disease duration, the significant interaction results were maintained only for the diffusion parameters.


    MS-FIN is the first hypothesis-driven study to combine behavioural and advanced MRI techniques to understand the mechanisms of MS fatigue. The results point towards metacognitive impairment confined to the interoceptive domain, in relapsing-remitting patients with cognitive fatigue. The neural basis of this impairment is supported by a widespread white matter network in which loss of neurite density plays a role. However, as shown by the magnetization transfer results, myelin integrity may also play a part.
    Date of AwardJan 2021
    Original languageEnglish
    Awarding Institution
    • University of Brighton

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