Exposure to an inflammatory challenge enhances neural sensitivity to negative and positive social feedback.
Open accessAbstract
Inflammation, part of the body's innate immune response, can lead to "sickness behaviors," as well as alterations in social and affective experiences. Elevated levels of pro-inflammatory cytokines have been associated with increased neural sensitivity to social rejection and social threat, but also decreased neural sensitivity to rewards. However, recent evidence suggests that inflammation may actually enhance sensitivity to certain social rewards, such as those that signal support and care. Despite a growing interest in how inflammation influences neural reactivity to positive and negative social experiences, no known studies have investigated these processes in the same participants, using a similar task. To examine this issue, 107 participants were randomly assigned to receive either placebo or low-dose endotoxin, which safely triggers an inflammatory response. When levels of pro-inflammatory cytokines were at their peak, participants were scanned using fMRI while they received positive, negative, and neutral feedback from an "evaluator" (actually a confederate) about how they came across in an audio-recorded interview. In response to negative feedback (vs. neutral), participants in the endotoxin condition showed heightened neural activity in a number of threat-related neural regions (i.e., bilateral amygdala, dorsal anterior cingulate cortex) and a key mentalizing-related region (i.e., dorsomedial PFC), compared to placebo participants. Interestingly, when receiving positive feedback (vs. neutral), endotoxin (vs. placebo) led to greater neural activity in the ventral striatum and ventromedial PFC, regions often implicated in processing reward, as well as greater activity in dorsomedial PFC. Together, these results reveal that individuals exposed to an inflammatory challenge are more "neurally sensitive" to both negative and positive social feedback, suggesting that inflammation may lead to a greater vigilance for both social threats and social rewards.
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Laboratory stressor-evoked increases in soluble TNF-α receptor were positively correlated with increased activation in dorsal anterior cingulate cortex and anterior insula in response to social rejection.
“Laboratory stressor-evoked increases in the soluble TNF-α receptor (sTNFαRII) have been shown to be positively correlated with increased activation in dorsal anterior cingulate cortex (dACC) and anterior insula (AI) in response to social rejection (Slavich et al., 2010; Muscatell et al., 2016).”
From The interplay between stress, inflammation, and emotional attention: relevance for depression (2019) · cites this paper as Muscatell et al., 2016
LPS-stimulated increase in IL-6 was positively associated with increased activation of the bilateral amygdala, dorsal anterior cingulate cortex, and dorsal prefrontal cortex in response to negative feedback.
“the LPS-stimulated increase in IL-6 was positively associated with increased activation of the bilateral amygdala, dACC, and dorsal prefrontal cortex (dPFC) in response to negative feedback from the confederate”
From The interplay between stress, inflammation, and emotional attention: relevance for depression (2019) · cites this paper as Muscatell et al., 2016
Endotoxin did not increase self-reported affective reactivity to social stress but led to exaggerated activation of threat-related neural circuits, including greater amygdala and dACC activation.
“For example, although endotoxin did not increase self-reported affective reactivity to social stress, endotoxin did lead to exaggerated activation of threat-related neural circuits, including greater activation of the amygdala and dACC (Muscatell et al., 2016).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Muscatell et al., 2016
Inflammation can increase ventral striatal reactivity to social rewards, specifically positive social feedback and images of close others.
“inflammation can lead to heightened ventral striatal reactivity to social rewards, specifically positive social feedback (Muscatell et al., 2016) and viewing images of close others (Inagaki et al., 2015)”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Muscatell et al., 2016
Recent findings indicate inflammation can lead to heightened ventral striatum reactivity specifically to social rewards.
“and the recent findings indicating that inflammation can lead to heightened VS reactivity specifically to social rewards (Inagaki et al., 2015; Muscatell et al., 2016)”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Muscatell et al., 2016
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References 35 · Cited by 146
- Authors
- Muscatell, K. A., Moieni, M., Inagaki, T. K., Dutcher, J. M., Jevtic, I., Breen, E. C., Irwin, M. R., & Eisenberger, N. I.
- Affiliations
- University of California, Berkeley (US)
- University of California, Los Angeles (US)
- University of Pittsburgh (US)
- Corresponding author
- Muscatell, Keely A.
- Eisenberger, Naomi I.
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 57
- Pages
- 21-29
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5011017
- OpenAlex
- W2312308020
- Cited by
- 146
- References
- 35
- Citations by year
- 2026: 15 · 2025: 7 · 2024: 16 · 2023: 16 · 2022: 19 · 2021: 20 · 2020: 14 · 2019: 13 · 2018: 16 · 2017: 6 · 2016: 4
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIMH (5R01MH091352)
- National Center for Advancing Translational Sciences UCLA CTSI (UL1TR000124)
- Cousins Center for Psychoneuroimmunology
- 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
- inflammation, endotoxin challenge, inflammatory cytokines, social feedback, social rejection, social danger, social reward, neuronal sensitivity, amygdala, dorsal anterior cingulate cortex, dorsomedial prefrontal cortex, ventral striatum, ventromedial prefrontal cortex, mentalization, sickness behavior
- MeSH terms
- Adult, Amygdala, Endotoxins, Female, Gyrus Cinguli, Humans, Inflammation, Interpersonal Relations, Magnetic Resonance Imaging, Male, Reward, Cytokines, Prefrontal Cortex, Feedback, Psychological, Young Adult
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