Inflammation selectively enhances amygdala activity to socially threatening images
Open accessAbstract
Although social withdrawal is a prominent symptom of sickness, the mechanisms associated with this behavioral change remain unclear. In animals, the amygdala is a key neural region involved in sickness-induced social withdrawal. Consistent with this, in humans, heightened amygdala activity to negative social cues is associated with social avoidance tendencies. Based on these findings, we investigated whether an experimental inflammatory challenge selectively increased amygdala activity to socially threatening images as well as whether this activity related to feelings of social disconnection. Thirty-nine participants were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammatory activity. Pro-inflammatory cytokines were assessed at 7 hourly time points via blood draws; self-reported feelings of social disconnection and physical sickness symptoms were assessed hourly as well. Two hours post-injection, participants underwent an fMRI procedure to assess amygdala reactivity during the presentation of socially threatening images (fear faces) as well as non-socially threatening images (guns), socially non-threatening images (happy faces), and non-social, non-threatening images (household objects). Endotoxin led to greater amygdala activity in response to socially threatening vs. all other types of images. No such differences were found for placebo participants. Additionally, increased amygdala activity in endotoxin participants during the viewing of socially vs. non-socially threatening images was associated with increased feelings of social disconnection. These findings highlight the amygdala as a neural region that may be important for sickness-induced social withdrawal. The implications of amygdalar involvement in sickness-induced social withdrawal are discussed.
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Heightened amygdala response to stress is associated with increased IL-6 production.
“This heightened amygdala response to stress is associated with increased IL-6 production (Inagaki et al, 2012;Muscatell et al, 2015).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Inagaki et al, 2012
The Results (Behavioral Analyses; page unavailable) report increased IL-6 after endotoxin, and the Results (Effect of Condition and Stimulus Type on Amygdala Activity; page unavailable) report heightened amygdala responses to socially threatening images in the endotoxin group. The paper does not establish that individuals with greater amygdala responses produced more IL-6, or that a stress response increased IL-6; its reported amygdala correlation is with feelings of social disconnection. (LLM, conf=0.84)
Experimental — accuracy not yet measuredEndotoxin administration in healthy controls increases IL-6 and TNF-α levels and amygdala response to socially threatening stimuli.
“Specifically, endotoxin administration in healthy controls increases IL-6 and TNF-α levels (Eisenberger et al, 2010) and amygdala response to socially threatening stimuli (Harrison et al, 2009b;Inagaki et al, 2012).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Inagaki et al, 2012
LPS-induced inflammation increased amygdala activity while viewing negative facial expression images.
“LPS-induced inflammation was shown to increase amygdala activity while viewing negative facial expression images (Inagaki et al., 2012).”
From The interplay between stress, inflammation, and emotional attention: relevance for depression (2019) · cites this paper as Inagaki et al., 2012
The exaggerated amygdala response to socially threatening images was associated with increased feelings of social disconnection.
“Moreover, the exaggerated amygdala response to socially threatening images was associated with increased feelings of social disconnection (Inagaki et al., 2012); thus, inflammation may upregulate amygdala reactivity to social threats, resulting in the experience of social disconnection and withdrawal.”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Inagaki et al., 2012
Endotoxin led to exaggerated amygdala responses to threatening stimuli, particularly socially threatening stimuli.
“Another study similarly found that endotoxin led to exaggerated amygdala responses to threatening stimuli, particularly socially threatening stimuli (e.g., fear faces versus guns) (Inagaki et al., 2012).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Inagaki et al., 2012
Inflammation may upregulate amygdala reactivity to social threats, resulting in social disconnection and withdrawal.
“Moreover, the exaggerated amygdala response to socially threatening images was associated with increased feelings of social disconnection (Inagaki et al., 2012); thus, inflammation may upregulate amygdala reactivity to social threats, resulting in the experience of social disconnection and withdrawal.”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Inagaki et al., 2012
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References 32 · Cited by 264
- Authors
- Inagaki, T. K., Muscatell, K. A., Irwin, M. R., Cole, S. W., & Eisenberger, N. I.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Eisenberger, Naomi I.
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 59
- Issue
- 4
- Pages
- 3222-3226
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC3348143
- OpenAlex
- W2062145099
- Cited by
- 264
- References
- 32
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 17 · 2023: 19 · 2022: 33 · 2021: 25 · 2020: 21 · 2019: 24 · 2018: 20 · 2017: 17 · 2016: 16 · 2015: 14 · 2014: 8 · 2013: 7 · 2012: 7
- FWCI
- 2.04
- 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
- NARSAD Young Investigator Award
- Dana Foundation
- UCLA Faculty Senate Grant
- UCLA Cousins Center at the Semel Institute for Neurosciences
- UCLA Claude D. Pepper Older Americans Independence Center Inflammatory Biology Core
- General Clinical Research Centers Program (M01-RR00865)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Face Recognition and Perception
- Keywords
- amygdala, inflammation, endotoxin challenge, social danger, fearful faces, social disconnection, inflammatory cytokines, sickness behavior, social avoidance
- MeSH terms
- Adolescent, Adult, Amygdala, Double-Blind Method, Fear, Female, Humans, Inflammation, Magnetic Resonance Imaging, Male, Psychological Distance, Young Adult
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