Neural response to emotional stimuli during experimental human endotoxemia

Abstract

Increases in peripheral cytokines during acute inflammation may affect various neuropsychological functions. The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the effects of acute endotoxemia on mood and the neural response to emotionally aversive visual stimuli in healthy human subjects. In a double-blind, randomized crossover study, 18 healthy males received a bolus injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline. Plasma levels of pro- and anti-inflammatory cytokines and cortisol as well as mood ratings were analyzed together with the blood-oxygen-level dependent (BOLD) response during the presentation of aversive versus neutral pictures. Endotoxin administration induced pronounced transient increases in plasma levels of TNF-α, IL-1ra, IL-6, IL-10, and cortisol. Positive mood was decreased and state anxiety increased. In addition, activation of right inferior orbitofrontal cortex (OFC) in response to emotional visual stimuli was significantly increased in the LPS condition. Increased prefrontal activation during the presentation of emotional material may reflect enhanced cognitive regulation of emotions as an adaptive response during an acute inflammation. These findings may have implications for the putative role of inflammatory processes in the pathophysiology of depression.

Keywords: cytokines; emotional processing; endotoxin; fMRI; peripheral inflammation; sickness behavior.

Figure 1

Time schedule of the experimental sessions. Subjects received either endotoxin or placebo on the first study session. B = blood samples for analysis of cortisol and cytokine (IL‐6, IL‐1ra, IL‐10, and TNF‐α) plasma concentrations and record of vital signs and M = mood questionnaires. During fMRI scanning, subjects underwent a visual stimulation task and were asked to look at alternating emotional and neutral visual stimuli.

Figure 2

A–D: Temporal changes of plasma cytokine levels in healthy male subjects (n = 18) following bolus administration of 0.4 ng/kg endotoxin (LPS) or placebo (saline). Data are shown as mean ± SEM. Significant differences between treatments: *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 3

A–C: Numbers of circulating neutrophils, body temperature, and plasma cortisol levels in healthy male subjects (n = 18) following bolus administration of 0.4 ng/kg endotoxin (LPS) or placebo (saline). Data are shown as mean ± SEM. Significant differences between treatments: *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4

A–D: Results of the modified German version of the Profile of Mood States (MDBF) (A–C) and the State Anxiety (STAI‐S) questionnaires (D) in healthy male subjects (n = 18) following bolus administration of 0.4 ng/kg endotoxin (LPS) or placebo (saline). Data are shown as mean ± SEM. Significant differences between treatments: *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 5

Cortical activation during the presentation of emotional vs. neutral visual stimuli. Paired t‐test computed for the LPS_{emotional>neutral} > placebo_{emotional>neutral} condition. LPS‐treated subjects displayed a stronger activation in (A) right inferior orbitofrontal gyrus ([26, 24, −20], t = 4.39, P < 0.05 based on ROI analysis using SVC with FWE correction), (B) left inferior orbitofrontal gyrus ([−46, 38, −14], t = 3.68, P < 0.001, uncorr.), (C) left medial frontal gyrus ([−8, 16, 50], t = 3.91, P < 0.001, uncorr.), and (D) right superior frontal gyrus ([14, 24, 62], t = 4.16, P < 0.001, uncorr.) after administration of 0.4 ng/kg E. coli endotoxin (n = 18).