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: 10.26). 05/2009; 66(5):415-22. DOI: 10.1016/j.biopsych.2009.03.007
Source: PubMed


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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    • "Essentially, inflammatory mediators activate neuronal pathways, including vagal afferents, spinal afferents and humoral pathways including sensory circumventricular organs. These interoceptive signals are integrated in the 'viscerosensory hubs' within the brainstem including the raphe nuclei, with further relay to higher subcortical and cortical centres, evoking sickness behaviour including fatigue, malaise etc (Brydon et al., 2008; Critchley and Harrison, 2013; Harrison et al., 2009b; Strike et al., 2004). Brainstem raphe nuclei are highly connected with circumventricular organs and their proximity to the cerebral aqueduct make them vulnerable to inflammatory cytokines in the CSF (Hornung, 2003; Howerton et al., 2014). "
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    • "Systemic inflammation promotes the activation of brain immune cells in humans as well as in non - human primates ( Brydon et al . , 2008 ; Harrison et al . , 2009 ; Hannestad et al . , 2012 ) and can prime neurons and immune cells in the brain increasing the risk of developing neurological disorders ( Deleidi and Isacson , 2012 ; Perry and Holmes , 2014 ) . The molecular pathways that link low - grade systemic inflammation to brain aging and neuroinflammation remain unclear ."
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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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