An fMRI study of cytokine-induced depressed mood and social pain: The role of sex differences
Open accessAbstract
Although research has demonstrated a relationship between proinflammatory cytokine activity and depressive symptoms, the neurocognitive processes underlying this relationship have remained largely unexplored. Here, we examined the effect of proinflammatory cytokine activation on the neural correlates of socially painful experience and associated depressed mood. Participants received either low-dose endotoxin or placebo through intravenous injection. Levels of the proinflammatory cytokine, IL-6, were repeatedly assessed through hourly blood draws; self-reported depressed mood was assessed hourly as well. Two hours post-injection, participants completed a neuroimaging session in which they were socially excluded during an online ball-tossing game. Replicating previous research, individuals exposed to endotoxin, compared to placebo, showed increases in IL-6 levels and depressed mood. Although there were no meaningful differences between the endotoxin and control groups in neural responses to social exclusion, there were sex differences in the relationships between IL-6 increases and neural responses to exclusion among subjects exposed to endotoxin. Among females, but not males, exposed to endotoxin, increases in IL-6 were associated with increases in social pain-related neural activity (dorsal anterior cingulate cortex, anterior insula) that mediated the relationship between IL-6 increases and depressed mood increases. Implications of these sex differences in the neural correlates of cytokine-associated depressed mood and social pain are discussed.
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Increases in IL-6 were associated with greater neural activity in the anterior insula and dACC.
“Increases in IL-6 were in turn associated with greater neural activity in the anterior insula and dACC”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Eisenberger et al., 2009
The Results (Neural Responses to Social Exclusion; page unavailable) associate IL-6 increases with greater anterior insula activity across the endotoxin group, but report the dACC association specifically for females in that group. The claim omits that sex-specific qualification and the finding’s social-exclusion-versus-inclusion condition. (LLM, conf=0.86)
Experimental — accuracy not yet measuredActivity in the anterior insula and dACC mediated the association between endotoxin-induced increases in IL-6 and depressive mood in female participants.
“activity in these brain regions mediated the association between endotoxin-induced increases in IL-6 and depressive mood in female participants”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Eisenberger et al., 2009
The Results section (Neural Responses to Social Exclusion) reports mediation in female participants exposed to endotoxin: the dACC result was significant, but the right anterior insula result was only marginally significant (p = .09, one-tailed). The claim presents both as unqualified mediation, omitting that uncertainty for the anterior insula. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAdministration of bacterial endotoxin elicits heightened anxiety and several symptoms of depression including sad mood, anhedonia, cognitive impairment, fatigue, reduced food intake, altered sleep, and social-behavioral withdrawal.
“administration of bacterial endotoxin, which is a relatively strong inflammatory challenge, elicits heightened anxiety, as well as several symptoms of depression including sad mood, anhedonia, cognitive impairment, fatigue, reduced food intake, altered sleep (e.g., disrupted sleep continuity, increased REM latency, and REM suppression), and social-behavioral withdrawal”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Eisenberger et al., 2009
The Results (Physiological and Behavioral Responses to Endotoxin; page unavailable) report increased depressed mood and physical sickness symptoms after endotoxin versus placebo. The Introduction describes anhedonia and reduced social activity as features of cytokine-associated sickness behavior, but the study does not establish that endotoxin elicited those particular effects. The copy does not support the claimed anxiety, cognitive impairment, reduced food intake, or sleep changes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLow-level inflammatory activity may feed back on the brain to alter sleep, promote hypervigilance, anxiety, and exaggerated perceptions of threat, and eventually lead to feelings of anhedonia and social disconnection.
“This low-level inflammatory activity prepares the developing body for possible threat, but it might also feed back on the brain to alter sleep; promote hypervigilance, anxiety, and exaggerated perceptions of threat; and eventually lead to feelings of anhedonia and social disconnection”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Eisenberger et al., 2009
The Introduction (page not provided) says cytokines may signal the brain and lists anhedonia and reduced social activity among sickness behaviors. The Discussion (page not provided) links experimentally increased inflammation to depressed mood and possible sensitivity to socially threatening situations. The paper does not establish that low-level inflammation alters sleep or promotes anxiety, hypervigilance, or exaggerated threat perceptions; its sleep discussion describes sleep loss increasing inflammation, not the reverse. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTyphoid vaccination and endotoxin administration both increase insula activity.
“Typhoid vaccination and endotoxin administration both increase insula activity (Eisenberger et al, 2009;Harrison et al, 2009b).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Eisenberger et al, 2009
In Results > Neural Responses to Social Exclusion (page unavailable), larger IL-6 increases within the endotoxin group were associated with greater anterior and posterior insula activity during social exclusion. The same section reports no significant difference in social-pain-related neural activity between the endotoxin and placebo groups. Thus, this paper supports an association with the inflammatory response, not a general claim that endotoxin administration increases insula activity; the typhoid-vaccination portion is associated with the other citation. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Endotoxin-induced increases in IL-6 were related to greater activity in several neural regions implicated in mentalizing, including the medial and dorsomedial prefrontal cortex, posterior cingulate cortex, and precuneus.
“Endotoxin-induced increases in IL-6 were also related to greater activity in several neural regions that have been implicated in mentalizing, or the process of thinking about the content of other people's minds, including the medial and dorso-medial prefrontal cortex, posterior cingulate cortex, and precuneus”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Eisenberger et al., 2009
Administration of bacterial endotoxin triggered increases in cortisol, IL-6, physical sickness symptoms, and depressive mood.
“administration of bacterial endotoxin triggered increases in cortisol, IL-6, physical sickness symptoms, and depressive mood”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Eisenberger, Inagaki, Rameson, Mashal, and Irwin (2009)
Typhoid vaccination is associated with greater activity in the subgenual ACC, which has been repeatedly implicated in depression.
“as well as with greater activity in the subgenual ACC, which has been repeatedly implicated in depression”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Eisenberger et al., 2009
The Introduction mentions typhoid vaccination in connection with negative mood, not subgenual ACC activity. The Methods and Results examine endotoxin administration and report activity in the dACC, a different ACC region. A search for subgenual ACC and typhoid vaccination found no passage in our copy linking them. (LLM, conf=0.77)
Experimental — accuracy not yet measuredIn females but not males, endotoxin-induced increases in IL-6 are associated with increased activation of threat-related neural regions (dACC, anterior insula), which mediate the relationship between IL-6 and depressed mood.
“Additionally, among females but not males, endotoxin-induced increases in IL-6 have been associated with increased activation of threat-related neural regions (dACC, anterior insula), which mediate the relationship between IL-6 levels and depressed mood (Eisenberger et al., 2009).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Eisenberger et al., 2009
A recent fMRI study also employing endotoxin application in humans did not report changes of neural activations in the amygdala.
“However, a recent fMRI study also employing endotoxin application in humans did not report changes of neural activations in the amygdala [61].”
From Dose-dependent effects of endotoxin on neurobehavioral functions in humans (2011) · cites this paper as [61]
Experimental activation of inflammation activates brain sites regulating positive and negative affect and is associated with increased depressed mood, especially in women.
“experimental activation of inflammation activates brain sites that regulate positive and negative effects (Eisenberger et al, 2009(Eisenberger et al, , 2010a(Eisenberger et al, , 2010b)), and is associated with increase in depressed mood, especially in women.”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Eisenberger et al, 2009
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References 68 · Cited by 313
- Authors
- Eisenberger, N. I., Inagaki, T. K., Rameson, L. T., Mashal, N. M., & Irwin, M. R.
- Affiliations
- University of California, Los Angeles (US)
- Northwestern University (US)
- Corresponding author
- Eisenberger, Naomi I.
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 47
- Issue
- 3
- Pages
- 881-890
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC2733873
- OpenAlex
- W2143741117
- Cited by
- 313
- References
- 68
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 11 · 2023: 21 · 2022: 19 · 2021: 23 · 2020: 17 · 2019: 20 · 2018: 32 · 2017: 21 · 2016: 23 · 2015: 16 · 2014: 12 · 2013: 16 · 2012: 21
- FWCI
- 5.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- National Institute on Aging (AG 026364, R01AG026364, P30AG028748)
- National Heart, Lung, and Blood Institute (HL 079955, R01HL079955)
- National Institute of Mental Health (T32MH019925, T32 MH 19925)
- National Cancer Institute (R01CA116778, CA-10014152, CA-116778)
- National Center for Research Resources ((M01 RR00865), M01RR000865)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Social Psychology › Death Anxiety and Social Exclusion
- Keywords
- inflammatory cytokines, interleukin-6, endotoxin, depressive mood, social pain, social exclusion, sex differences, dorsal anterior cingulate cortex, anterior insula, inflammation and depression
- MeSH terms
- Adolescent, Adult, Brain Mapping, Depression, Endotoxins, Estradiol, Female, Humans, Hydrocortisone, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Progesterone, Sex Characteristics, Social Isolation, Interleukin-6, Cytokines, Young Adult
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