Neural Origins of Human Sickness in Interoceptive Responses to Inflammation

Wellcome Trust, Centre for Neuroimaging, Institute of Cognitive Neuroscience, UCL, 17 Queen Square, London WC1N 3AR, UK.
Biological psychiatry (Impact Factor: 9.47). 05/2009; 66(5):415-22. DOI: 10.1016/j.biopsych.2009.03.007
Source: PubMed

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

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Available from: Neil A Harrison, Aug 26, 2015
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    • "Fatigue is also an integral part of sickness behavior in relation to a number of inflammatory states [7]. For example, administration of a (typhoid) vaccine that causes an increase in interleukin (IL-6) levels is paralleled by increased fatigue [8]. Along the same line, observational studies show that poor subjective health, which is closely associated with fatigue, is related to both lowgrade inflammation [9] [10] and short sleep [11] [12] [13]. "
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    • "In addition, administration of typhoid vaccination was associated with increased dACC activation compared with placebo using a Stroop task in healthy volunteers (Harrison et al, 2009). Increased secretion of soluble tumor necrosis factor receptor 2 (sTNFR2) during psychosocial stress has also been found to correlate with greater dACC activation in response to social isolation using a cyberball-exclusion paradigm during fMRI (Slavich et al, 2010). "
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    • "Group neuroimaging results are shown from fMRI experiments in which participants were scanned during states of (typhoid vaccine) induced peripheral inflammation or after placebo injection. (A) Reactivity of right insula cortex to (Stroop task) stimuli; predicted inflammation (not placebo) induced fatigue over the course of the experiment (Harrison et al., 2009a). (B) Following induced inflammation, brain regions showing greater reactivity map onto known central visceral afferent pathways: dorsal pons and periaqueductal gray matter (PAG); ventromedial pallidum (vmp), amygdala (AMY), and insula (Harrison et al., 2009b). "
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