Neurostructural and neurophysiological correlates of multiple sclerosis physical fatigue: systematic review and meta-analysis of cross-sectional studies

Paula Ellison, Stuart Goodall, Niamh Kennedy, Helen Dawes, Allan Clark, Valerie Pomeroy, Martin Duddy, Mark R Baker, John Saxton

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7 Citations (Scopus)
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Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (­22.74 ml; 95% CI: -37.72 to -7.76 ml; p=0.003), grey matter (­18.81 ml; 95% CI: ­29.60 to ­8.03 ml; p<0.001), putamen (­0.40 ml; 95% CI: ­0.69 to ­0.10 ml; p=0.008) and acumbens (­0.09 ml; 95% CI: ­0.15 to ­0.03 ml; p=0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p<0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (­19.23 N; 95% CI: ­35.93 to ­2.53 N; p=0.02) and an attenuation of upper-limb (­5.77 %; 95% CI:­8.61 to ­2.93%; p<0.0001) and lower-limb (­2.16%; 95% CI:­4.24 to ­0.07%; p=0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (­5.61%; 95% CI: -9.57 to -1.65%; p=0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation.
Original languageEnglish
Number of pages14
JournalNeuropsychology Review
Early online date7 May 2021
Publication statusPublished online - 7 May 2021

Bibliographical note

Funding Information:
Our thanks to Dr Moussa Chalah, Dr Samar Ayache, Professor Inge Zijdewind; Dr Clelia Pellicano, Dr Jorge Sepulcre, Dr Anton Steens, Dr Ria Wolkorte, Dr Alexander Ng, Dr Oliver Schiegegger, Dr Fuchun Lin, Dr Ekaterina Dobryakova, Professor Peter Feys, Dr Chris Hanstock and Dr Michael Dwyer, for providing additional original data partitioned by perceived fatigue status of participants for inclusion in meta-analyses where it was not presented, as such, in the published article. JS, PE, NK, VP, AC and HD (supported by Elizabeth Casson Trust and Oxford BRC) acknowledge the support of the UK Multiple Sclerosis Society, which provided funding to support this research (Grant Ref. 987).

Funding Information:
This research was supported by a project grant from the UK Multiple Sclerosis Society (Grant Ref. 987).

Publisher Copyright:
© 2021, The Author(s).


  • Multiple sclerosis
  • Neuroimaging
  • Neurostructural
  • Fatigue
  • Neurophysiology


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