The Representation of Inflammatory Signals in the Brain – A Model for Subjective Fatigue in Multiple Sclerosis
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In multiple sclerosis (MS) patients, fatigue is rated as one of the most common and disabling symptoms. However, the pathophysiology underlying this fatigue is not yet clear. Several lines of evidence suggest that immunological factors, such as elevated levels of pro-inflammatory cytokines, may contribute to subjective fatigue in MS patients. Pro-inflammatory cytokines represent primary mediators of immune-to-brain-communication, modulating changes in the neurophysiology of the central nervous system. Recently, we proposed a model arguing that fatigue in MS patients is a subjective feeling, which is related to inflammation. Moreover, it implies that fatigue can be measured behaviorally only by applying specific cognitive tasks related to alertness and vigilance. In the present review, we focus on the subjective feeling of MS-related fatigue. We examine the hypothesis that the subjective feeling of MS-related fatigue may be a variant of inflammation-induced sickness behavior, resulting from cytokine-mediated activity changes within brain areas involved in interoception and homeostasis including the insula, the anterior cingulate, and the hypothalamus. We first present studies demonstrating a relationship between pro-inflammatory cytokines and subjective fatigue in healthy individuals, in people with inflammatory disorders, and particularly in MS patients. Subsequently, we discuss studies analyzing the impact of anti-inflammatory treatment on fatigue. In the next part of this review, we present studies on the transmission and neural representation of inflammatory signals, with a special focus on possible neural concomitants of inflammation-induced fatigue. We also present two of our studies on the relationship between local gray and white matter atrophy and fatigue in MS patients. Finally, we discuss some implications of our findings and future perspectives.
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In multiple sclerosis, neuroimaging studies relate fatigue to structural and functional properties of insula, ACC, and hypothalamus.
“For multiple sclerosis, (Hanken et al., 2014) reviewed neuroimaging studies relating fatigue to structural and functional properties of insula, ACC, and hypothalamus6.”
From Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression (2016) · cites this paper as Hanken et al., 2014
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Flagged first, then by citations
Research works printed but not linked: 1
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Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression
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“For multiple sclerosis, (Hanken et al., 2014) reviewed neuroimaging studies relating fatigue to structural and functional properties of insula, ACC, and hypothalamus6.”
BackgroundInsular cortex neurons encode and retrieve specific immune responses
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Fatigue in multiple sclerosis is associated with multimodal interoceptive abnormalities
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- Authors
- Hanken, K., Eling, P., & Hildebrandt, H.
- Affiliations
- Radboud University Nijmegen (NL)
- Corresponding author
- Hildebrandt, Helmut
- Venue
- Frontiers in Neurology
- Publisher
- Frontiers Media SA
- Published
- 2014-12-11
- Volume
- 5
- Pages
- 264-264
- ISSN
- 1664-2295 (ISSN-L)
- PMC
- PMC4263099
- OpenAlex
- W2154065686
- Cited by
- 92
- References
- 118
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 8 · 2022: 5 · 2021: 8 · 2020: 11 · 2019: 10 · 2018: 8 · 2017: 10 · 2016: 10 · 2015: 5
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neurology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Fibromyalgia and Chronic Fatigue Syndrome Research
- Keywords
- multiple sclerosis, subjective fatigue, inflammatory cytokines, sickness behavior, neuroinflammation, interoception, insula, anterior cingulate cortex, hypothalamus, anti-inflammatory therapy
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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