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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Available from: Neil A Harrison, Oct 04, 2015
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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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    ABSTRACT: Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 08/2015; DOI:10.1016/j.bbi.2015.08.005 · 5.89 Impact Factor
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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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    ABSTRACT: Fatigue is related to a number of serious diseases, as well as to general well-being. It is also a major cause of sickness absence and use of health facilities. Still, the determinants of variations in fatigue are little investigated. The purpose of present study was to investigate the relationships between the daily variations of fatigue with sleep during the previous night, stress or disease symptoms during the same day - across 42 consecutive days of normal life. 50 individuals participated and gave diary reports and used an actigraph across the 42days. The data was analyzed using a multilevel approach with mixed model regression. The analyses showed that the day-to-day variation in fatigue was related to (poor) sleep quality (p<.001) and (reduced) sleep duration (p<.01) the previous night, as well as to higher stress (p<.05), and to the occurrence of a cold or fever (p<.001) during the same day as the fatigue rating. Fatigue was also strongly related to poorer subjective health (p<.001) and sleepiness (p<.001) during the same day. The results indicate that prior sleep (and sleepiness) as well as stress and illness are consistently connected to how fatigue is experienced during normal living conditions.
    Journal of psychosomatic research 04/2014; 76(4):280-5. DOI:10.1016/j.jpsychores.2014.01.005 · 2.74 Impact Factor
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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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    ABSTRACT: Cytokine effects on behavior may be related to alterations in glutamate metabolism. We therefore measured glutamate concentrations in brain regions shown to be affected by inflammatory stimuli including the cytokine interferon (IFN)-alpha. IFN-alpha is known to alter neural activity in the dorsal anterior cingulate cortex (dACC) and basal ganglia in association with symptoms of depression and increases in peripheral cytokines including tumor necrosis factor (TNF) and its soluble receptor. Single voxel magnetic resonance spectroscopy (MRS) was employed to measure glutamate concentrations normalized to creatine (Glu/Cr) in dACC and basal ganglia of 31 patients with hepatitis C before and after approximately 1 month of either no treatment (n=14) or treatment with IFN-alpha (n=17). Depressive symptoms were measured at each visit using the Inventory of Depressive Symptoms-Clinician Rating (IDS-C) and the Multidimensional Fatigue Inventory. IFN-alpha was associated with a significant increase in Glu/Cr in dACC and left basal ganglia. Increases in dACC Glu/Cr were positively correlated with scores on the IDS-C in the group as a whole, but not in either group alone. Glu/Cr increases in left basal ganglia were correlated with decreased motivation in the group as a whole and in IFN-alpha-treated subjects alone. No Glu/Cr changes were found in the right basal ganglia, and no significant correlations were found between Glu/Cr and the inflammatory markers. IFN-alpha-induced increases in glutamate in dACC and basal ganglia are consistent with MRS findings in bipolar depression and suggest that inflammatory cytokines may contribute to glutamate alterations in patients with mood disorders and increased inflammation.Neuropsychopharmacology accepted article preview online, 31 January 2014. doi:10.1038/npp.2014.25.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2014; 39(7). DOI:10.1038/npp.2014.25 · 7.05 Impact Factor
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