Neural origins of human sickness in interoceptive responses to inflammation

Neil A Harrison, Lena Brydon, Cicely Walker, Marcus A Gray, Andrew Steptoe, Raymond J Dolan, Hugo D Critchley, Neil A Harrison, Lena Brydon, Cicely Walker, Marcus A Gray, Andrew Steptoe, Raymond J Dolan, Hugo D Critchley

Abstract

Background: Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking.

Methods: In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning.

Results: Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions.

Conclusions: These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states.

Figures

Figure 1
Figure 1
Response to inflammatory challenge. Typhoid vaccination induced a robust inflammatory cytokine response and symptoms of sickness behavior. (A) Plasma inflammatory cytokine level (± SEM) at baseline and 3 hours after typhoid and placebo (sodium chloride [NaCl]) injection. Interleukin-6 (IL-6) showed a significant response to typhoid but not NaCl (*p < .001; n = 16). There is a nonsignificant increase in IL-1Ra to typhoid and no change in tumor necrosis factor α (not shown). (B) Symptoms of sickness at baseline and 3 hours after typhoid and placebo. Confusion and fatigue were significantly greater after vaccine (**p < .01; n = 16) but not placebo. (C) Additional indexes of an inflammatory response. There was no significant potentially confounding increase in temperature or salivary cortisol after either vaccine or placebo (p > .05). (D) Color word Stroop task. Incongruent and congruent conditions, subjects selected the response word that correctly identified the color of the target word above. (E) Response time (RT) and total errors for incongruent and congruent trials in both the inflammation and placebo conditions. Response times and errors were significantly greater for incongruent trials in both vaccine and placebo conditions. §Mean RT difference (± SEM) = 377.6 msec (± 21.6) [t(23) = 17.46, p < .001]. §§Mean difference errors (± SEM) = 4.21 (± .66) [t(23) = 6.38, p < .001]. There was no significant main effect of inflammatory state on either RT (p = .31, n = 24) or errors (p = .79, n = 24).
Figure 2
Figure 2
Functional magnetic resonance imaging analysis of the color word Stroop task. (A) Incongruent trials enhanced activity within bilateral inferior temporal junction regions, bilateral intraparietal sulci, and right V4 (plotted for illustrative purposes at false detection rate [FDR] p < .05 corrected). (B) Performance of the Stroop task (congruent and incongruent conditions combined vs. implicit baseline) under inflammation-activated projection areas of the vagus nerve and spinal lamina I afferent pathways together with the periaqueductal gray, the central autonomic efferent region (plotted at FDR p < .05 corrected). (C) Illustration of primary and secondary projection areas of the afferent vagus nerve and spinal lamina I afferents adapted by permission from MacMillan Publishers Ltd: Nature Reviews Neuroscience (17) copyright 2002. (D) Interaction of task and inflammatory state. Performance of cognitively demanding incongruent events under inflammation-recruited right dorsolateral prefrontal (DLPFC) and bilateral anterior cingulate cortices (ACC) (plotted for illustrative purposes at p < .005 uncorrected).
Figure 3
Figure 3
Neural regions correlating with vaccine-associated fatigue (A) and confusion (B). Values shown are for the first eigenvariate for 8-mm diameter regions of interest centered on the coordinates shown in Table 3 in Supplement 1. Lt, left; Rt, right; BOLD, blood-oxygen-level-dependent.

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