Inflammation shapes neural processing of interoceptive fear predictors during extinction learning in healthy humans.

Inflammation could impact on the formation and persistence of interoceptive fear and hypervigilance, with relevance to psychiatric disorders and chronic pain. To systematically analyze effects of inflammation on fear learning and extinction, we performed two complementary randomized, double-blind, placebo-controlled functional magnetic resonance imaging (fMRI) studies combining experimental endotoxemia as a translational model of acute systemic inflammation with a two-day multiple-threat fear conditioning paradigm involving interoceptive and exteroceptive unconditioned stimuli (US). Healthy volunteers (N = 95) were randomized to receive intravenous injections of either endotoxin (lipopolysaccharide, LPS; 0.4 ng/kg) or placebo prior to fear acquisition (study 1) or extinction training (study2). Treatment effects on behavioral and neural responses to conditioned stimuli (CS) predicting interoceptive or exteroceptive threat were assessed during fear learning and extinction phases, along with US valence ratings. Despite robust inflammatory and emotional responses triggered by LPS, no direct effects of inflammation on US ratings or on the formation or extinction of conditioned fear, as assessed with CS valence ratings, were observed. However, in the group treated with LPS prior to acquisition (i.e., study 1), we found enhanced neural responses to the interoceptive but not the exteroceptive CS in key regions of the central fear circuitry during extinction learning. After extinction, this group further showed enhanced negative valence ratings selectively for the interoceptive US during unexpected US re-exposure when compared to the placebo group. Together, inflammation during fear acquisition may promote the establishment of a more robust neural signature of the interoceptive fear memory trace, which may contribute to altered interoceptive pain perception. The fear extinction circuitry engaged during interoceptive fear memory processing may be particularly vulnerable to inflammation, with transdiagnostic implications for gut-brain mechanisms underlying disturbed interoception in psychiatric conditions and chronic visceral pain.

Circulating Pro-inflammatory Cytokines Do Not Explain Interindividual Variability in Visceral Sensitivity in Healthy Individuals.

A role of the immune system in the pathophysiology of pain and hyperalgesia has received growing attention, especially in the context of visceral pain and the gut-brain axis. While acute experimental inflammation can induce visceral hyperalgesia as part of sickness behavior in healthy individuals, it remains unclear if normal plasma levels of circulating pro-inflammatory cytokines contribute to interindividual variability in visceral sensitivity. We herein compiled data from a tightly screened and well-characterized sample of healthy volunteers (N = 98) allowing us to assess associations between visceral sensitivity and gastrointestinal symptoms, and plasma concentrations of three selected pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-8), along with cortisol and stress-related psychological variables. For analyses, we compared subgroups created to have distinct pro-inflammatory cytokine profiles, modelling healthy individuals at putative risk or resilience, respectively, for symptoms of the gut-brain axis, and compared them with respect to rectal sensory and pain thresholds and subclinical GI symptoms. Secondly, we computed multiple regression analyses to test if circulating pro-inflammatory markers predict visceral sensitivity in the whole sample. Despite pronounced subgroup differences in pro-inflammatory cytokine and cortisol concentrations, we observed no differences in measures of visceroception. In regression analyses, cytokines did not emerge as predictors. The pain threshold was predicted by emotional state and trait variables, especially state anxiety, together explaining 10.9% of the variance. These negative results do not support the hypothesis that systemic cytokine levels contribute to normal interindividual variability in visceroception in healthy individuals. Trajectories to visceral hyperalgesia as key marker in disorders of gut-brain interactions likely involve complex interactions of biological and psychological factors in keeping with a psychosocial model. Normal variations in systemic cytokines do not appear to constitute a vulnerability factor in otherwise healthy individuals, calling for prospective studies in at risk populations.

Associative learning and extinction of conditioned threat predictors across sensory modalities.

The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood. We elucidated behavioural and neural correlates involved in the acquisition and extinction of negative expectations towards different threats across sensory modalities. In two complementary functional magnetic resonance imaging studies in healthy humans, differential conditioning paradigms combined interoceptive visceral pain with somatic pain (study 1) and aversive tone (study 2) as exteroceptive threats. Conditioned responses to interoceptive threat predictors were enhanced in both studies, consistently involving the insula and cingulate cortex. Interoceptive threats had a greater impact on extinction efficacy, resulting in disruption of ongoing extinction (study 1), and selective resurgence of interoceptive CS-US associations after complete extinction (study 2). In the face of multiple threats, we preferentially learn, store, and remember interoceptive danger signals. As key mediators of nocebo effects, conditioned responses may be particularly relevant to clinical conditions involving disturbed interoception and chronic visceral pain.