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

Pawlik, Robert Jan; Petrakova, Liubov; Cueillette, Alexandra; Krawczyk, Katharina; Theysohn, Nina; Elsenbruch, Sigrid; Engler, Harald

doi:10.1016/j.bbi.2022.12.010

Cited by 11 publications

(16 citation statements)

References 74 publications

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“…However, this needs to be confirmed in future studies by determining other important anti-inflammatory cytokines such as IL-4 and IL-10. At the symptom level, the acute cytokine response was accompanied by an increase in physical and psychological sickness symptoms, including a worsening of mood and an increase in anxiety, again confirming previous findings from the human LPS model [17][18][19]23].…”

Section: Discussionsupporting

confidence: 87%

“…The LPS-induced inflammatory response is accompanied by behavioral and negative affective changes (e.g., decrease in positive mood, increase in negative mood and anxiety) that resemble core symptoms of depression [17][18][19]. The depression-like symptoms typically emerge within 2 h after LPS administration, persist during the acute phase of inflammation for about 4 h, and correlate with cytokine levels in the blood and cerebrospinal fluid [18][19][20][21][22][23]. In inflammation-associated depression, mood symptoms are present for longer periods of time and correlate with elevated serum levels of C-reactive protein (CRP), a clinical marker of inflammation [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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Endotoxin-Induced Physiological and Psychological Sickness Responses in Healthy Humans: Insights into the Post-Acute Phase

Engler,

Brinkhoff,

Wilde

et al. 2023

Neuroimmunomodulation

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Introduction: Experimental endotoxemia is a translational model of systemic inflammation that has contributed significantly to our current understanding of sickness behavior and inflammation-associated depression. Previous studies using this model revealed a strong association between cytokine levels, endocrine changes, and psychological sickness symptoms during the acute phase of inflammation. The objective of this randomized, double-blind, placebo-controlled crossover study was to gain insight into potential post-acute physiological and psychological consequences of endotoxin administration that may either persist or newly emerge between 24 to 72 h after injection. The main focus was on associations between serum levels of C-reactive protein (CRP) and affective symptoms as well as alterations in diurnal cortisol profile, two key features of inflammation-associated depression. Methods: Healthy male volunteers (N=18) received an injection of either endotoxin (0.8 ng/kg) or placebo on two separate but otherwise identical study days, 7 days apart. Blood and saliva samples were collected during acute and post-acute phases after injection to measure blood inflammatory markers (interleukin [IL]-6, IL-1 receptor antagonist [ra], CRP) and salivary cortisol levels. In addition, participants completed a comprehensive battery of questionnaires to assess physical and psychological sickness symptoms. Results: Endotoxin treatment induced a short-time rise in plasma IL-6 and a longer increase in IL-1ra. The increase in serum CRP was delayed compared to cytokines, peaking at 24 h and gradually decreasing until 72 h after injection. The inflammatory response was accompanied by bodily and psychological sickness symptoms which occurred only in the acute phase, whereas none of the symptoms persisted or recurred in the post-acute phase. Salivary cortisol levels were significantly increased during acute phase and exhibited pronounced circadian changes. However, no significant differences in diurnal cortisol profiles were observed between placebo and endotoxin conditions on the days after treatment. Conclusion: Our findings suggest that CRP, which is elevated in patients with inflammation-associated depression, does not appear to be responsible for depressive symptomatology. Moreover, a single inflammatory episode is not sufficient to alter diurnal cortisol profiles, as observed in inflammation-associated depression. In addition, the absence of persistent LPS-induced psychological and physiological changes beyond the acute phase further supports the safety of endotoxin administration in humans.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Endotoxin-Induced Physiological and Psychological Sickness Responses in Healthy Humans: Insights into the Post-Acute Phase

Engler,

Brinkhoff,

Wilde

et al. 2023

Neuroimmunomodulation

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“…Such long-term effects may persist beyond—or even emerge after—the resolution of acute inflammation, as suggested by our recent work supporting effects on visceral pain-related fear memory processing induced by pain-related conditioning during endotoxaemia [an experimentally-induced inflammatory state]. 23 In animal models of colitis, behavioural responses associated with abdominal discomfort and anxiety-related behaviours have been documented in rats 50 days after repeated inflammatory challenges. 55 Changes in afferent sensory pathways and the central nervous system [CNS] have also been documented after the resolution of intestinal inflammation, including persistent central inflammation, 56 and widespread changes in the neural response to acute experimental visceral pain including thalamocortical sensitisation.…”

Section: Discussionmentioning

confidence: 84%

“… 18 , 22 Distinct differences are also observable at the level of neural representations of visceral versus somatic pain, 13 , 17 , 18 , 21 in line with a proposed greater biological salience of visceral signals 20 which appears to shape perception and pain-related cognitive and emotional responses such as learning and memory processes. 19 , 23 …”

Section: Introductionmentioning

confidence: 99%

Distinct Alterations in Central Pain Processing of Visceral and Somatic Pain in Quiescent Ulcerative Colitis Compared to Irritable Bowel Syndrome and Health

Öhlmann,

Lanters,

Theysohn

et al. 2023

Journal of Crohn's and Colitis

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Background and Aims Despite relevance to pain chronicity, disease burden, and treatment, mechanisms of pain perception for different types of acute pain remain incompletely understood in patients with inflammatory bowel disease (IBD). Building on experimental research across pain modalities, we herein addressed behavioral and neural correlates of visceral versus somatic pain processing in women with quiescent ulcerative colitis (UC) compared to irritable bowel syndrome (IBS) as a patient control group, and healthy women (HC). Methods Thresholds for visceral and somatic pain were assessed with rectal distensions and cutaneous thermal pain, respectively. Using functional magnetic resonance imaging, neural and behavioral responses to individually calibrated and intensity-matched painful stimuli from both modalities were compared. Results Pain thresholds were comparable across groups, but visceral thresholds correlated with gastrointestinal symptom severity and chronic stress burden exclusively within UC. Upon experience of visceral and somatic pain, both control groups demonstrated enhanced visceral pain-induced neural activation and greater perceived pain intensity, whereas UC patients failed to differentiate between pain modalities at both behavioral and neural levels. Conclusions When confronted with acute pain from multiple bodily sites, UC patients’ responses are distinctly altered. Their failure to prioritize pain arising from the viscera may reflect a lack of adaptive behavioral flexibility possibly resulting from long-lasting central effects of repeated intestinal inflammatory insults persisting during remission. The role of psychological factors, particularly chronic stress, in visceral sensitivity and disease-specific alterations in the response to acute pain call for dedicated mechanistic research as a basis for tailoring interventions for intestinal and extraintestinal pain symptoms in IBD.

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“…However, maladaptive pain-related learning and memory processes may also contribute to the chronification of pain [ 75 ]. Against the background that inflammation can interfere with learning and memory processes, two studies have addressed LPS effects on pain-related learning and memory in the visceral pain model [ 22 , 109 ]. Implementing a classical fear-conditioning paradigm with painful rectal distensions as unconditioned stimuli and visual cues as conditioned stimuli, the impact of endotoxemia on the acquisition and extinction of pain-related fear was assessed in a series of complementary experiments.…”

Section: Mood and Cognition Interact With Inflammation And Painmentioning

confidence: 99%

How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review

Benson,

Karshikoff

2023

Neuroimmunomodulation

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Background: The immune system and the central nervous system exchange information continuously. This communication is a prerequisite for adaptive responses to physiological and psychological stressors. While the implicate relationship between inflammation and pain is increasingly recognized in clinical cohorts, the underlying mechanisms and the possibilities for pharmacological and psychological approaches aimed at neuro-immune communication in pain are not fully understood yet. This calls for preclinical models which build a bridge from clinical research to laboratory research. Summary: Experimental models of systemic inflammation (experimental endotoxemia) in humans have been increasingly recognized as an approach to study the direct and causal effects of inflammation on pain perception. This narrative review provides an overview of what experimental endotoxemia studies on pain have been able to clarify so far. We report that experimental endotoxemia results in a reproducible increase in pain sensitivity, particularly for pressure and visceral pain (deep pain), which is reflected in responses of brain areas involved in pain processing. Increased levels of blood inflammatory cytokines are required for this effect, but cytokine levels do not always predict pain intensity. We address sex-dependent differences in immunological responses to endotoxin, and discuss why these differences do not necessarily translate to differences in behavioral measures. We summarize psychological and cognitive factors that may moderate pain sensitization driven by immune activation. Key messages: Together, studying the immune-driven changes in pain during endotoxemia offers a deeper mechanistic understanding of the role of inflammation in chronic pain. Experimental endotoxemia models can specifically help to tease out inflammatory mechanisms underlying individual differences, vulnerabilities, and comorbid psychological problems in pain syndromes. The model offers the opportunity to test the efficacy of interventions, increasing their translational applicability for personalized medical approaches.

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

Cited by 11 publications

References 74 publications

Endotoxin-Induced Physiological and Psychological Sickness Responses in Healthy Humans: Insights into the Post-Acute Phase

Endotoxin-Induced Physiological and Psychological Sickness Responses in Healthy Humans: Insights into the Post-Acute Phase

Distinct Alterations in Central Pain Processing of Visceral and Somatic Pain in Quiescent Ulcerative Colitis Compared to Irritable Bowel Syndrome and Health

How Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review

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