Article Text

Download PDFPDF

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis
  1. Zina-Mary Manjaly1,2,
  2. Neil A Harrison3,4,
  3. Hugo D Critchley3,4,
  4. Cao Tri Do5,
  5. Gabor Stefanics5,6,
  6. Nicole Wenderoth2,
  7. Andreas Lutterotti7,
  8. Alfred Müller1,
  9. Klaas Enno Stephan5,8,9
  1. 1 Department of Neurology, Schulthess Clinic, Zürich, Switzerland
  2. 2 Department of Health Sciences and Technology, ETH Zurich, Zürich, Switzerland
  3. 3 Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
  4. 4 Sussex Partnership NHS Foundation Trust, Brighton, UK
  5. 5 Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland
  6. 6 Laboratory for Social and Neural Systems Research (SNS), Department of Economics, University of Zurich, Zurich, Switzerland
  7. 7 Department of Neurology, University Hospital Zurich, Zurich, Switzerland
  8. 8 Wellcome Centre for Human Neuroimaging, University College London, London, UK
  9. 9 Max Planck Institute for Metabolism Research, Cologne, Germany
  1. Correspondence to Dr Zina-Mary Manjaly, Department of Neurology, Schulthess Clinic, Zürich 28008, Switzerland; zina-mary.manjaly{at}


Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients’ quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.

  • network
  • lesion
  • inflammation
  • dopamine
  • dyshomeostasis
  • interoception
  • metacognition

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Contributors Z-MM and KES performed the literature search, selected the relevant articles, wrote the paper and led the discussion. NAH, HDC, CTD, GS, NW, AL and AM added further references, contributed to the discussion and edited the paper.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.