IFN-Alpha-Induced Cortical and Subcortical Glutamate Changes Assessed by Magnetic Resonance Spectroscopy
Open accessAbstract
Cytokine effects on behavior may be related to alterations in glutamate metabolism. We therefore measured glutamate concentrations in brain regions shown to be affected by inflammatory stimuli including the cytokine interferon (IFN)-alpha. IFN-alpha is known to alter neural activity in the dorsal anterior cingulate cortex (dACC) and basal ganglia in association with symptoms of depression and increases in peripheral cytokines including the tumor necrosis factor (TNF) and its soluble receptor. Single-voxel magnetic resonance spectroscopy (MRS) was employed to measure glutamate concentrations normalized to creatine (Glu/Cr) in dACC and basal ganglia of 31 patients with hepatitis C before and after ∼ 1 month of either no treatment (n = 14) or treatment with IFN-alpha (n = 17). Depressive symptoms were measured at each visit using the Inventory of Depressive Symptoms-Clinician Rating (IDS-C) and the Multidimensional Fatigue Inventory. IFN-alpha was associated with a significant increase in Glu/Cr in dACC and left basal ganglia. Increases in dACC Glu/Cr were positively correlated with scores on the IDS-C in the group as a whole, but not in either group alone. Glu/Cr increases in left basal ganglia were correlated with decreased motivation in the group as a whole and in IFN-alpha-treated subjects alone. No Glu/Cr changes were found in the right basal ganglia, and no significant correlations were found between Glu/Cr and the inflammatory markers. IFN-alpha-induced increases in glutamate in dACC and basal ganglia are consistent with MRS findings in bipolar depression and suggest that inflammatory cytokines may contribute to glutamate alterations in patients with mood disorders and increased inflammation.
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Inflammatory stimuli are associated with reductions in reward responsiveness in the striatum across multiple neuroimaging platforms in otherwise non-depressed individuals given IFNα, endotoxin or typhoid vaccination.
“Inflammatory stimuli have been associated with reductions in reward responsiveness in the striatum across many neuroimaging platforms, demonstrating the validity and reproducibility of these cytokine-mediated effects on the brain in otherwise non-depressed individuals peripherally administered IFNα, endotoxin or typhoid vaccination and imaged by PET, functional magnetic resonance imaging (fMRI), M”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [83]
The Introduction (page unavailable) reports reduced ventral-striatal activation during reward tasks after IFNα and endotoxin. For typhoid vaccination, it instead reports altered substantia nigra activation associated with slower psychomotor speed, not reduced striatal reward responsiveness. The paper’s MRS findings concern increased glutamate and reduced motivation, so they do not establish the claimed reward finding across multiple imaging platforms. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAdministration of IFN-α for the treatment of hepatitis C increases glutamate to creatinine levels in the dACC that correlate with anhedonia and fatigue.
“For instance, administration of IFN-α for the treatment of hepatitis C increases glutamate to creatinine levels in the dACC that correlate with anhedonia and fatigue (Haroon et al, 2014).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Haroon et al, 2014
The Abstract reports that IFN-α treatment in patients with hepatitis C increased glutamate normalized to creatine (Glu/Cr) in the dACC. The Correlations section reports an association between dACC Glu/Cr changes and overall depression severity across treated patients and controls, but not within either group alone; it reports no significant association with fatigue subscales and does not establish a dACC association with anhedonia. (LLM, conf=0.92)
Experimental — accuracy not yet measuredThe observed NDI increase during interferon alpha therapy has been interpreted as representing the inflammatory process.
“the observed NDI increase has been interpreted as representing the inflammatory process.”
From NODDI in clinical research (2020) · cites this paper as Haroon et al., 2014
The Abstract and Discussion report increased glutamate measured as Glu/Cr during IFN-alpha treatment and discuss possible inflammatory mechanisms. Our copy does not report an NDI increase or interpret NDI as representing inflammation (searched: NDI, neurite density index). (LLM, conf=0.76)
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- Authors
- Haroon, E., Woolwine, B. J., Chen, X., Pace, T. W., Parekh, S., Spivey, J. R., Hu, X. P., & Miller, A. H.
- Affiliations
- Emory University (US)
- University of Arizona (US)
- Corresponding author
- Miller, Andrew H
- Venue
- Neuropsychopharmacology
- Published
- 2014-01-31
- Volume
- 39
- Issue
- 7
- Pages
- 1777-1785
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC4023151
- OpenAlex
- W2008760801
- Cited by
- 154
- References
- 46
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 9 · 2023: 12 · 2022: 13 · 2021: 15 · 2020: 20 · 2019: 14 · 2018: 15 · 2017: 9 · 2016: 13 · 2015: 16 · 2014: 6
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (K23MH091254)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- interferon-alpha, glutamate, dorsal anterior cingulate cortex, basal ganglia, hepatitis C, cytokines, depression, fatigue, motivation, neuroinflammation, mood disorders, TNF-α
- MeSH terms
- Adult, Aged, Antiviral Agents, Brain, Creatine, Depression, Female, Hepatitis C, Humans, Longitudinal Studies, Male, Middle Aged, Magnetic Resonance Spectroscopy, Statistics as Topic, Hepacivirus, Cytokines, Interferon-alpha, Glutamic Acid
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