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

doi:10.1016/j.biopsych.2009.03.007

Abstract

BackgroundInflammation 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.MethodsIn 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.ResultsTyphoid 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.ConclusionsThese findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states.

Highlights

Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior
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
These behaviors might be induced iatrogenically by the therapeutic administration of interferon-␣ (IFN-␣) for the treatment of chronic viral infections and cancer [7,8]. The latter observation provides direct evidence that cytokines are central to the etiology of human sickness behaviors and represents a clinical impetus for determining their underlying neurobiological basis

Summary

Methods

In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Subjects and Study Design The study design was a randomized, double-blind crossover trial. Mean age (Ϯ SD) 24.9 years (Ϯ 4.8), were tested twice a mean of 7 days apart. Procedures were approved by the joint University College London (UCL)/University College London Hospitals (UCLH) Ethics Committee. Of note, these are the same group of subjects that were reported on in our previous study [26] and in [23]

Results

Discussion

Conclusion