Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis

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Abstract

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.

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Interoceptive inference, emotion, and the embodied self.

Anil K. Seth (2013)

The concept of the brain as a prediction machine has enjoyed a resurgence in the context of the Bayesian brain and predictive coding approaches within cognitive science. To date, this perspective has been applied primarily to exteroceptive perception (e.g., vision, audition), and action. Here, I describe a predictive, inferential perspective on interoception: 'interoceptive inference' conceives of subjective feeling states (emotions) as arising from actively-inferred generative (predictive) models of the causes of interoceptive afferents. The model generalizes 'appraisal' theories that view emotions as emerging from cognitive evaluations of physiological changes, and it sheds new light on the neurocognitive mechanisms that underlie the experience of body ownership and conscious selfhood in health and in neuropsychiatric illness. Copyright © 2013 Elsevier Ltd. All rights reserved.

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The relation between inflammation and neurodegeneration in multiple sclerosis brains

Josa M. Frischer, Stephan Bramow, Assunta Dal-Bianco … (2009)

Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

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Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy.

Benzi Kluger, Lauren Krupp, Roger Enoka (2013)

Fatigue is commonly reported in many neurologic illnesses, including multiple sclerosis, Parkinson disease, myasthenia gravis, traumatic brain injury, and stroke. Fatigue contributes substantially to decrements in quality of life and disability in these illnesses. Despite the clear impact of fatigue as a disabling symptom, our understanding of fatigue pathophysiology is limited and current treatment options rarely lead to meaningful improvements in fatigue. Progress continues to be hampered by issues related to terminology and assessment. In this article, we propose a unified taxonomy and a novel assessment approach to addressing distinct aspects of fatigue and fatigability in clinical and research settings. This taxonomy is based on our current knowledge of the pathophysiology and phenomenology of fatigue and fatigability. Application of our approach indicates that the assessment and reporting of fatigue can be clarified and improved by utilizing this taxonomy and creating measures to address distinct aspects of fatigue and fatigability. We review the strengths and weaknesses of several common measures of fatigue and suggest, based on our model, that many research questions may be better addressed by using multiple measures. We also provide examples of how to apply and validate the taxonomy and suggest directions for future research.

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Journal

Journal ID (nlm-ta): J Neurol Neurosurg Psychiatry

Journal ID (iso-abbrev): J. Neurol. Neurosurg. Psychiatry

Journal ID (hwp): jnnp

Journal ID (publisher-id): jnnp

Title: Journal of Neurology, Neurosurgery, and Psychiatry

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0022-3050

ISSN (Electronic): 1468-330X

Publication date (Print): June 2019

Publication date (Electronic): 25 January 2019

Volume: 90

Issue: 6

Pages: 642-651

Affiliations

[1 ] departmentDepartment of Neurology , Schulthess Clinic , Zürich, Switzerland

[2 ] departmentDepartment of Health Sciences and Technology , ETH Zurich , Zürich, Switzerland

[3 ] departmentDepartment of Neuroscience, Brighton and Sussex Medical School , University of Sussex , Brighton, UK

[4 ] Sussex Partnership NHS Foundation Trust , Brighton, UK

[5 ] departmentTranslational Neuromodeling Unit (TNU), Institute for Biomedical Engineering , University of Zurich and ETH Zurich , Zurich, Switzerland

[6 ] departmentLaboratory for Social and Neural Systems Research (SNS), Department of Economics , University of Zurich , Zurich, Switzerland

[7 ] departmentDepartment of Neurology , University Hospital Zurich , Zurich, Switzerland

[8 ] departmentWellcome Centre for Human Neuroimaging , University College London , London, UK

[9 ] Max Planck Institute for Metabolism Research , Cologne, Germany

Author notes

[Correspondence to ] Dr Zina-Mary Manjaly, Department of Neurology, Schulthess Clinic, Zürich 28008, Switzerland; zina-mary.manjaly@ 123456kws.ch

Author information

Zina-Mary Manjaly http://orcid.org/0000-0002-9217-1688

Article

Publisher ID: jnnp-2018-320050

DOI: 10.1136/jnnp-2018-320050

PMC ID: 6581095

PubMed ID: 30683707

SO-VID: b2e216c2-2ae8-40c5-9aed-1d45426765b0

License:

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: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 21 November 2018

Date revision received : 03 January 2019

Date accepted : 04 January 2019

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ScienceOpen disciplines: Surgery

Keywords: network,lesion,inflammation,dopamine,dyshomeostasis,interoception,metacognition

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ScienceOpen disciplines: Surgery

Keywords: network, lesion, inflammation, dopamine, dyshomeostasis, interoception, metacognition

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 114

Interoceptive inference, emotion, and the embodied self.

The relation between inflammation and neurodegeneration in multiple sclerosis brains

Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy.

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