Sickness behaviors
The response that makes interoception a two-way street with the immune system. Quadt et al. (2018) use sickness behaviours (SBs) to make a point the wiki’s mostly-neural, mostly-cardiac interoception material underweights: a large part of the body-to-brain traffic is humoral (blood-borne cytokines, hormones) and immune, not electrical, and it drives a specific, evolutionarily conserved behavioural syndrome.
The syndrome and its channels
Peripheral infection/inflammation is signalled to the brain through three routes: vagal afferents, humoral cytokines reaching the brain via the circumventricular organs (area postrema, OVLT, subfornical organ) and the NTS, and microglial transduction (inflammatory mediators propagating waves of microglial activation across the brain). The output is a narrow, stereotyped repertoire — fatigue, reduced calorie/fluid intake, social isolation, anhedonia, fever — evoked by a wide range of insults. That mismatch (many causes, one behavioural pattern) is the argument that SBs are a coordinated physiological/motivational reaction to a class of interoceptive challenge, not an incidental byproduct: fatigue motivates rest, social withdrawal reduces onward infection, fever fights pathogens.
Experimentally the syndrome is induced with typhoid vaccine, endotoxin infusion, or inhaled antigens, which let the interoceptive pathway be imaged: typhoid vaccination recruits basal/posterior ventromedial thalamus and dorsal mid/posterior insula, and specific SB components map to specific regions — mid-insula (fatigue), subgenual cingulate (mood change), substantia nigra (psychomotor slowing).
The insula mediates the experience
The load-bearing claim for the wiki is that the insula carries the experiential side of being sick: right anterior insula metabolism tracks loss of interest in social interaction, and AI–middle-cingulate connectivity predicts subjective malaise and discomfort after an inflammatory challenge. So the same interoceptive cortex that re-represents cardiac and homeostatic state also renders “I feel ill, I want to withdraw” — inflammation entering conscious feeling through the interoceptive hierarchy, exactly as the IPP account of feeling would predict.
The bridge to depression
Because SBs and major depression share their hallmark — changed motivation, anhedonia, social withdrawal, fatigue — and the same regions (insula, ventral striatum, subgenual cingulate) carry both, SBs are Quadt et al.’s proposed mechanistic bridge from inflammation to mood disorder. Endotoxin reduces ventral-striatum reward reactivity and raises anhedonia (Eisenberger et al. 2010); prolonged or severe inflammation can convert adaptive energy-conserving withdrawal into a depressive episode. Depression’s raised inflammatory markers (IL-6, CRP) sit on the same axis. See interoceptive-psychopathology for the transdiagnostic frame and computational-psychiatry for the “locked-in” EPIC reading in which downweighted, chronically unresolved interoceptive error enlists SBs to conserve energy.
Fatigue as the paradigmatic SB
Fatigue is both a component of SBs and a chronic condition in its own right (chronic fatigue syndrome; a symptom in ~50% of immune-compromised conditions — cancer, MS, fibromyalgia — and a core DSM-5/ICD-10 depression criterion). Its neurobiology is the frontostriatal reward network (ventral striatum) plus insula, reached by immune-to-brain microglial signalling. The newer, top-down reading (Stephan et al. 2016) casts fatigue not only as a bottom-up inflammatory effect but as a metacognitive verdict — aberrant beliefs about the brain’s capacity to predictively control the body (low allostatic self-efficacy), possibly sustained by chronic stress, cortisol, and HPA-axis disturbance feeding back into belief-updating. This is the computational-psychiatry account; the shared point is that fatigue is an interoceptive-regulatory failure, not merely peripheral tiredness.
The therapeutic corollary: treat the signal, not the reading of it
Bonaz et al. (2021) draw the intervention consequence Quadt et al. leave implicit. If inflammation reaches mood through a specific interoceptive channel, that channel is a drug target — and the review reports that growing understanding of interoceptive immune pathways “has already opened up therapeutic applications” for psychiatric disorders: anticytokine therapy, NSAIDs, and minocycline suppression of microglial activation for depression (Wittenberg et al. 2020, a mega-analysis of immunomodulatory drugs on depressive symptoms in inflammatory disorders).
The bioelectronic version of the same logic runs through the vagus. Bonaz’s own line is the cholinergic anti-inflammatory pathway: efferent vagal activity suppresses peripheral inflammation, so vagus nerve stimulation is an anti-inflammatory intervention and not merely a neuromodulatory one. That makes the immune-to-brain arm of this page bidirectional in a clinically usable way — see bioelectronic-medicine, bruno-bonaz.
Also worth adding here: the same vagal afferents carry signals from the gut microbiome, directly (bacterial lipopolysaccharide onto TLR4 receptors) and via enteroendocrine relay. So the humoral/immune channel this page introduced is shared with a signalling source that is not the organism’s own tissue. See microbiota-gut-brain-axis.
The efferent limb, and sensory traffic as an immune variable (Berntson & Khalsa 2021)
This page has been about immune signals reaching the brain. Berntson & Khalsa (2021) complete the loop with the descending arm and add one finding that runs in an unexpected direction.
The reflex, both limbs. Peripheral inflammation → vagal afferents → NTS → ascending to hypothalamus, amygdala, striatum, cingulate and insula; and laterally, through intermediaries, to the dorsal vagal motor nucleus, nucleus ambiguus and RVLM, which are the efferent limb. Stimulating mouse RVLM (Abe et al. 2017, C1 neurons mediating a stress-induced anti-inflammatory reflex) or mouse vagal efferents (Wang et al. 2003, α7 nicotinic receptor) suppresses innate immune responses and downregulates splenic proinflammatory cytokines cholinergically. This is Tracey’s reflex control of immunity, and it is the mechanism bioelectronic-medicine exploits.
The authors are careful where the wiki should be too: the precise role of those ascending targets in regulating immune function, and their relationship to interoceptive signalling, “is unclear.” The efferent arc is well evidenced; what the cortical and limbic recipients do with the afferent copy is not.
Microglia are gated by sensory activity. The result worth keeping. Reducing sensory neuronal activity in mice — globally by general anaesthesia, or locally by whisker trimming — increased microglial process surveillance in the brain, under direct noradrenergic control via microglial β-adrenergic receptors, and only in awake animals (Liu et al. 2019). Neuronal activity related to both exteroceptive and interoceptive input regulates microglial dynamics.
That inverts this page’s usual direction. Elsewhere microglia are the transducer carrying inflammation into mood and behaviour; here the brain’s sensory traffic sets the immune surveillance state. If arousal and sensory load modulate microglial behaviour, then the inflammation→depression bridge above has a second, less-discussed lane running the other way — and conditions of sensory deprivation (see floatation-rest) or chronic hypoarousal acquire an immune dimension the wiki has not considered. Recorded as a single mouse study with a clean manipulation, not as an established human mechanism.
Where it touches the debates
SBs are a clean case for is-more-interoceptive-awareness-better in reverse: here the adaptive response is to feel the body’s inflammatory state and act on it (rest, withdraw), so blunted interoception of sickness would be maladaptive — but the same machinery, over-run in chronic inflammation, produces the depressive lock-in. More contact is protective acutely and pathological chronically, which is the debate’s recurring shape.