Quantitative magnetization transfer imaging as a biomarker for effects of systemic inflammation on the brain
Open accessAbstract
BACKGROUND: Systemic inflammation impairs brain function and is increasingly implicated in the etiology of common mental illnesses, particularly depression and Alzheimer's disease. Immunotherapies selectively targeting proinflammatory cytokines demonstrate efficacy in a subset of patients with depression. However, efforts to identify patients most vulnerable to the central effects of inflammation are hindered by insensitivity of conventional structural magnetic resonance imaging. METHODS: We used quantitative magnetization transfer (qMT) imaging, a magnetic resonance imaging technique that enables quantification of changes in brain macromolecular density, together with experimentally induced inflammation to investigate effects of systemic inflammatory challenge on human brain microstructure. Imaging with qMT was performed in 20 healthy participants after typhoid vaccination and saline control injection. An additional 20 participants underwent fluorodeoxyglucose positron emission tomography following the same inflammatory challenge. RESULTS: The qMT data demonstrated that inflammation induced a rapid change in brain microstructure, reflected in increased magnetization exchange from free (water) to macromolecular-bound protons, within a discrete region of insular cortex implicated in representing internal physiologic states including inflammation. The functional significance of this change in insular microstructure was demonstrated by correlation with inflammation-induced fatigue and fluorodeoxyglucose positron emission tomography imaging, which revealed increased resting glucose metabolism within this region following the same inflammatory challenge. CONCLUSIONS: Together these observations highlight a novel structural biomarker of the central physiologic and behavioral effects of mild systemic inflammation. The widespread clinical availability of magnetic resonance imaging supports the viability of qMT imaging as a clinical biomarker in trials of immunotherapeutics, both to identify patients vulnerable to the effects of systemic inflammation and to monitor neurobiological responses.
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Inflammation-induced activity changes in posterior insula and ACC are associated with subjectively perceived fatigue.
“Importantly, they showed that inflammation-induced activity changes in posterior insula and ACC were associated with subjectively perceived fatigue,”
From Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression (2016) · cites this paper as Harrison et al., 2015
The Results (Effects of Acute Inflammation on qMT; page unavailable) report that inflammation-induced changes in the left posterior insula predicted changes in fatigue. The paper does not report an association between ACC changes and fatigue, and its measured changes were in magnetization transfer rather than neural activity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInflammation-induced activity changes in SGC predict mood changes.
“while activity changes in SGC predicted mood changes.”
From Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression (2016) · cites this paper as Harrison et al., 2015
The Discussion (page unavailable) says previously reported inflammation-related functional changes in the subgenual cingulate correspond to effects on mood. It does not say that SGC activity changes predicted mood changes; the paper’s own Results instead report that insular changes predicted fatigue. (LLM, conf=0.82)
Experimental — accuracy not yet measuredTyphoid vaccination to induce peripheral immunological response and inflammation causes structural and functional changes in posterior insula, anterior insula, and ACC.
“in several elegant studies using MRI and PET in conjunction with typhoid vaccination to induce a peripheral immunological response and inflammation, Harrison and colleagues provided compelling evidence for structural and functional changes in posterior insula, anterior insula, and ACC (Harrison et al., 2009a,b, 2015).”
From Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression (2016) · cites this paper as Harrison et al., 2015
The Results (Effects of Acute Inflammation on qMT; page not provided) report changes in both posterior and anterior insula after the inflammatory challenge. The Results (Effects of Inflammation on Resting Glucose Metabolism; page not provided) report a PET change in left posterior insula, but not a significant change in left anterior insula. This paper does not establish the claimed ACC change; its Discussion mentions cingulate findings from previous studies. (LLM, conf=0.88)
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Inflammation, Sickness Behaviour and Depression
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Joint analysis of area and thickness as a replacement for the analysis of cortical volumePreprint
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- Authors
- Harrison, N. A., Cooper, E., Dowell, N. G., Keramida, G., Voon, V., Critchley, H. D., & Cercignani, M.
- Affiliations
- Brighton and Sussex Medical School (GB)
- Fondazione Santa Lucia (IT)
- University of Cambridge (GB)
- Corresponding author
- Harrison, Neil A.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 78
- Issue
- 1
- Pages
- 49-57
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4503794
- OpenAlex
- W1968629304
- Cited by
- 129
- References
- 55
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 19 · 2021: 9 · 2020: 14 · 2019: 11 · 2018: 12 · 2017: 14 · 2016: 10 · 2015: 8
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biological Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
- Figshare (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- systemic inflammation, brain microstructure, insula, typhoid vaccination, fatigue, neuroinflammation, biomarkers, immunotherapy response, depression, Alzheimer's disease
- MeSH terms
- Adult, Brain, Encephalitis, Fatigue, Female, Humans, Magnetic Resonance Imaging, Male, Typhoid-Paratyphoid Vaccines, Biomarkers, Fluorodeoxyglucose F18, Receptors, Interleukin-6, Positron-Emission Tomography
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