Neural origins of human sickness in interoceptive responses to inflammation.
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.
Harrison
Neil A
NA
Wellcome Trust, Centre for Neuroimaging, Institute of Cognitive Neuroscience, UCL, 17 Queen Square, London WC1N 3AR, UK. n.harrison@fil.ion.ucl.ac.uk
Brydon
Lena
L
Walker
Cicely
C
Gray
Marcus A
MA
Steptoe
Andrew
A
Dolan
Raymond J
RJ
Critchley
Hugo D
HD
D000328:Adult; D000339:Affect / Q000502:physiology*; D001921:Brain / Q000503:physiopathology; D006801:Humans; D055809:Illness Behavior / Q000502:physiology*; D007249:Inflammation / Q000097:blood / Q000503:physiopathology / Q000523:psychology*; D015850:Interleukin-6 / Q000097:blood; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology*; D011597:Psychomotor Performance / Q000502:physiology; D014436:Typhoid-Paratyphoid Vaccines
D015850:Interleukin-6; D014436:Typhoid-Paratyphoid Vaccines