Elsevier

NeuroImage

Volume 59, Issue 4, 15 February 2012, Pages 3222-3226
NeuroImage

Inflammation selectively enhances amygdala activity to socially threatening images

https://doi.org/10.1016/j.neuroimage.2011.10.090Get rights and content

Abstract

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.

Highlights

► We investigated neural responses to social stimuli after an inflammatory challenge. ► Inflammation led to greater amygdala to socially threatening vs. other images. ► Amygdala activity was positively correlated with feelings of social disconnection. ► Amygdala activity may be important for sickness-induced social withdrawal.

Introduction

In response to illness or infection, organisms display a coordinated motivational response, termed “sickness behavior,” which includes symptoms such as fatigue, loss of appetite, hyperalgesia, and social withdrawal (Dantzer et al., 2008, Hart, 1988). Sickness behavior occurs in response to the release of proinflammatory cytokines, such as interleukin-6 (IL-6), which act directly on the brain to change behavior (Dantzer et al., 2008). These behavioral changes are considered to be a survival adaptation that motivates rest and recovery in order to cope with infectious pathogens (Dantzer et al., 2008, Hart, 1988). In addition, evolutionary analyses suggest that social withdrawal might play a role in limiting the spread of infectious diseases (Cole, 2006).

Although social withdrawal is commonly observed in response to inflammation, little is known about the neural mechanisms that lead people to withdraw socially when ill. Based on previous research, the amygdala is one neural region that may relate to sickness-induced sensitivity to social cues and social withdrawal. In animals, lipopolysaccharide (LPS)-induced inflammation increases activity in the amygdala (Frenois et al., 2007), which is associated with a reduction of certain social behaviors, such as grooming, sniffing, and close following with an interaction partner (Marvel et al., 2004). Furthermore, blocking activity in the amygdala by using a reversible lesion eliminates this inflammation-induced social withdrawal behavior (Marvel et al., 2004). In humans, the contribution of amygdala activity to sickness-induced social withdrawal has not been investigated, but substantial work has shown that social withdrawal tendencies, such as those observed in social phobia and inhibited temperament, are linked with heightened amygdala activity to negative and/or novel social cues (Blackford et al., 2010, Blair et al., 2008, Phan et al., 2006, Schwartz et al., 2003). Taken together, these findings suggest that the amygdala contributes to sickness-induced social withdrawal in humans.

The current study examined the role of the amygdala in inflammatory-induced sensitivity to socially threatening cues and social withdrawal in humans. Specifically, this study examined the effect of endotoxin, an inflammatory challenge safe for use in humans (Andreasen et al., 2008, Suffredini and O'Grady, 1999), vs. placebo on amygdala activity to socially threatening images (e.g., fearful facial expressions), which are known to elicit amygdala activity (Morris et al., 1996, Whalen et al., 2001). Amygdala activity to socially threatening images was compared with amygdala activity to: non-socially threatening images (e.g., spiders, weapons), socially non-threatening images (e.g. happy facial expressions), and non-social, non-threatening images (e.g., household objects). To the extent that inflammatory activity increases social withdrawal by heightening amygdala activity to socially threatening images, we hypothesized that endotoxin vs. placebo would lead to greater amygdala activity in response to the socially threatening images vs. all the other image types. Finally, amygdala activity to socially vs. non-socially threatening images and their relation to feelings of social disconnection was also examined. We hypothesized that greater amygdala activity in response to socially vs. non-socially threatening images would be associated with greater feelings of social disconnection.

Section snippets

Participants

Thirty-nine participants (mean age = 21.8 ± 3.4 years; range: 18–36 years) were randomly assigned to receive either endotoxin (n = 23, 12 females) or placebo (n = 16, 8 females). All participants were confirmed to be in good health and scanner ready (metal-free, right-handed, not claustrophobic) during an initial telephone interview. The procedures outlined below have been described previously (Eisenberger et al., 2009, Eisenberger et al., 2010a, Eisenberger et al., 2010b), but are summarized below.

Behavioral analyses

As reported previously (Eisenberger et al., 2009, Eisenberger et al., 2010a, Eisenberger et al., 2010b), endotoxin (vs. placebo) led to significant increases over time in proinflammatory cytokines (IL-6, TNF-α), vital signs (body temperature, pulse), physical sickness symptoms, and feelings of social disconnection.

Effect of condition and stimulus type on amygdala activity

To test whether inflammation selectively increased amygdala activity (in anatomically defined ROIs) to socially threatening images, a 2 (condition: endotoxin vs. placebo) × 2 (social:

Discussion

In line with our hypothesis, subjects exposed to an inflammatory challenge, compared to placebo participants, showed a selective increase in amygdala activity to socially threatening images (relative to all other image types). Moreover, among endotoxin-exposed participants, greater amygdala activity in response to socially vs. non-socially threatening images was associated with greater increases in self-reported feelings of social disconnection. Together, these results highlight a possible role

Acknowledgments

Research was funded by a NARSAD Young Investigator Award, a Dana Foundation grant, a UCLA Faculty Senate Grant, and a postdoctoral research fellowship (T32-MH19925) to N.I.E. The authors wish to thank the staff and support of the UCLA General Clinical Research Center, Anthony Suffredini, M. D. and George Grimes, R. P. at the National Institute of Health, Warren Grant Magnuson Clinical Center, for providing standard reference endotoxin and Thanh Luu and Elizabeth Breen for completing the

References (30)

  • K.L. Phan et al.

    Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia

    Biol. Psychiatry

    (2006)
  • N. Tottenham et al.

    The NimStim set of facial expressions: judgments from untrained research participants

    Psychiatry Res.

    (2009)
  • N. Tzourio-Mazoyer et al.

    Automated anatomical labeling of the MNI MRI single-subject brain

    NeuroImage

    (2002)
  • C.E. Wright et al.

    Acute inflammation and negative mood: mediation by cytokine activation

    Brain Behav. Immunol.

    (2005)
  • R. Adolphs et al.

    A role for the human amygdala in recognizing emotional arousal from unpleasant stimuli

    Psychol. Sci.

    (1999)
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