The Role of Chronic Stress in Normal Visceroception: Insights From an Experimental Visceral Pain Study in Healthy Volunteers.

Visceroception is a complex phenomenon comprising the sensation, interpretation, and integration of sensations along the gut-brain axis, including pain or defecatory urgency. Stress is considered a crucial risk factor for the development and maintenance of disorders of gut-brain signaling, which are characterized by altered visceroception. Although the broad role of stress and stress mediators in disturbed visceroception is widely acknowledged, the putative contribution of chronic stress to variations in normal visceroception remains incompletely understood. We aimed to elucidate the role of chronic stress in shaping different facets of visceroception. From a well-characterized, large sample of healthy men and women (N = 180, 50% female), volunteers presenting with low (n = 57) and elevated (n = 61) perceived chronic stress were identified based on the validated Trier Inventory for Chronic Stress (TICS). Visceral sensitivity together with perceived and recalled intensity and defecatory urgency induced by repeated rectal distensions was experimentally assessed, and compared between low and elevated stress groups. Subgroups were compared regarding state anxiety and salivary cortisol concentrations across experimental phases and with respect to psychological measures. Finally, in the full sample and in chronic stress subgroups, a recall bias in terms of a discrepancy between the perception of experimentally-induced symptoms and their recall was tested. Participants with elevated chronic stress presented with increased state anxiety and higher cortisol concentrations throughout the experimental phases compared to the group with low chronic stress. Group differences in visceral sensitivity were not evident. The elevated stress group perceived significantly higher urgency during the stimulation phase, and recalled substantially higher feelings of urgency induced by rectal distensions, while perceived and recalled intensity were comparable between groups. Volunteers with elevated stress exhibited a recall bias in terms of a higher recall relative to mean perception of urgency, whereas no such bias was observed for the intensity of experimental visceral stimulation. Our findings in healthy men and women provide first evidence that the troublesome symptom of urgency might be particularly modifiable by chronic stress and support the relevance of memory biases in visceroception. These results may help to disentangle the impact of chronic stress on altered visceroception in disturbances of gut-brain communication.

Are there sex differences in visceral sensitivity in young healthy men and women?

BACKGROUND: Visceral hypersensitivity plays a key role in the pathophysiology of chronic visceral pain like irritable bowel syndrome (IBS), which is significantly more prevalent in women. Possible sex differences in visceral sensitivity remain poorly studied. We assessed sex differences in visceral sensitivity and their association with subclinical symptoms, trait anxiety, and chronic stress in a large sample of healthy men and women. METHODS: In 280 young healthy volunteers (50% female), visceral sensory and pain thresholds were determined using rectal balloon distensions. Gastrointestinal (GI) symptoms, chronic stress, and trait anxiety as IBS-related risk factors were assessed with questionnaires. Men and women were compared regarding visceral sensitivity and multiple regression analyses were conducted to evaluate the predictive value of sex and risk factors for visceral sensitivity. Subgroups with high, intermediate, and low sensitivity were compared regarding psychological and biological characteristics. KEY RESULTS: Men and women did not differ in sensory or pain thresholds or in IBS-related risk factors. In multiple regression analyses, no predictor of visceral sensitivity could be identified. While sensitivity subgroups differed in sensory and pain thresholds, the proportions of men and women were comparable, and groups did not differ in IBS-related risk factors. CONCLUSIONS AND INFERENCES: Despite the large sample size, we found no evidence supporting sex differences in visceral sensitivity. At least in healthy young volunteers, our findings suggest that sex, GI symptoms, anxiety, or chronic stress do not contribute to altered visceral sensitivity.

Can a Brief Relaxation Exercise Modulate Placebo or Nocebo Effects in a Visceral Pain Model?

Translational research aiming to elucidate mediators and moderators of placebo and nocebo effects is highly relevant. This experimental study tested effects of a brief progressive muscle relaxation (PMR) exercise, designed to alter psychobiological stress parameters, on the magnitude of placebo and nocebo effects in a standardized psychosocial treatment context. In 120 healthy volunteers (60 men, 60 women), pain expectation, pain intensity, and pain unpleasantness in response to individually-calibrated rectal distensions were measured with visual analog scales during a baseline. Participants were then randomized to exercise PMR (relaxation group: N = 60) or a simple task (control group: N = 60), prior to receiving positive (placebo), negative (nocebo) or neutral suggestions regarding an intravenous administration that was in reality saline in all groups. Identical distensions were repeated (test). State anxiety, salivary cortisol, heart rate, and blood pressure were assessed repeatedly. Data were analyzed using analysis of covariance, planned Bonferroni-corrected group comparisons, as well as exploratory correlational and mediation analyses. Treatment suggestions induced group-specific changes in pain expectation, with significantly reduced expectation in placebo and increased expectation in nocebo groups. PMR had no discernable effect on pain expectation, state anxiety or cortisol, but led to significantly lower heart rate and systolic blood pressure. Relaxation significantly interacted with positive treatment suggestions, which only induced placebo analgesia in relaxed participants. No effects of negative suggestions were found in planned group comparisons, irrespective of relaxation. Exploratory correlation and mediation analyses revealed that pain expectation was a mediator to explain the association between treatment suggestions and pain-related outcomes. Clearly, visceral pain modulation is complex and involves many cognitive, emotional, and possibly neurobiological factors that remain to be fully understood. Our findings suggest that a brief relaxation exercise may facilitate the induction of placebo analgesia by positive when compared to neutral treatment suggestions. They underscore the contribution of relaxation and stress as psychobiological states within the psychosocial treatment context-factors which clearly deserve more attention in translational studies aiming to maximize positive expectancy effects in clinical settings.

Does Human Experimental Endotoxemia Impact Negative Cognitions Related to the Self?

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences.

Effects of acute systemic inflammation on the interplay between sad mood and affective cognition.

Experimental endotoxemia is a translational model to study inflammatory mechanisms involved in the pathophysiology of mood disorders including depression. Disturbed affective cognition constitutes a core aspect in depression, but has never been studied in the context of inflammation. We combined experimental endotoxemia with an established experimental mood induction procedure to assess the interaction between acute inflammation and sad mood and their effects on affective cognition. In this randomized cross-over study, N = 15 healthy males received endotoxin (0.8 ng/kg lipopolysaccharide iv) on one study day and placebo an otherwise identical study day. The affective Go/Nogo task was conducted after experimental induction of neutral and sad mood. Inflammatory markers were assessed hourly. Endotoxin application induced a transient systemic inflammation, characterized by increased leukocyte counts, TNF-alpha and interleukin-6 plasma concentrations (all p < 0.01, interaction effects). Mood induction led to greater sadness ratings, with highest ratings when sad mood was induced during inflammation (p < 0.05, interaction effect). Based on a 2 (endotoxin vs. placebo) × 2 (sad vs. neutral mood) × 2 (sad vs. happy Go/Nogo target words) factorial design, we observed a significant target × endotoxin condition interaction (p < 0.01) reflecting slower responses to sad targets during endotoxemia. Additionally, we found a valence × mood interaction (p < 0.05), reflecting slower reaction times to sad targets in sad mood. In summary, acute inflammation and sad mood are risk factors for disturbed affective cognition. The results may reflect a mood-congruency effect, with prolonged and sustained processing of mood-congruent information during acute inflammation, which may contribute to depression risk.

Effects of acute psychological stress on placebo and nocebo responses in a clinically relevant model of visceroception.

There is evidence to suggest a role of emotions in placebo and nocebo effects, but whether acute psychological stress changes the magnitude of placebo or nocebo responses has not been tested. In a clinically relevant model of visceroception, we assessed effects of acute psychological stress on changes in urgency and pain in response to positive or negative treatment suggestions. In 120 healthy volunteers, perceived urge-to-defecate and pain in response to individually calibrated rectal distensions were measured with visual analogue scales during a BASELINE. Participants then underwent the Trier Social Stress Test (N = 60) or a simple cognitive task (control, N = 60) and were randomized to positive (placebo), negative (nocebo), or neutral treatment information regarding intravenous administration of saline. The series of distensions was repeated, and changes in visual analogue scales from BASELINE to TEST were compared between groups using analysis of covariance and planned post hoc tests. Treatment information emerged as a main factor (P <0.001), supporting treatment information effects for both urgency and pain. Effects for urgency were modulated by stress (interaction effect: P <0.05): Positive information reduced urgency (P = 0.025), while negative information increased urgency (P = 0.026) only in stressed groups. For pain, effects of stress emerged for nocebo responses, which were only evident in stressed groups (P = 0.009). This is the first experimental study supporting effects of acute psychological stress on placebo and nocebo responses in visceroception. Results call for mechanistic as well as patient studies to assess how psychological stress shapes patients' treatment expectations and thereby affects health outcomes.

Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia?

A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation-induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-α and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P < 0.001, condition effects), with more pronounced LPS-induced cytokine increases in women (P < 0.05, interaction effects). Although both rectal and pressure pain thresholds were significantly decreased in the LPS condition (all P < 0.05, condition effect), no sex differences in endotoxin-induced sensitization were observed. In summary, LPS-induced systemic immune activation leads to visceral and musculoskeletal hyperalgesia, irrespective of biological sex. These findings support the broad applicability of experimental endotoxin administration as a translational preclinical model of inflammation-induced pain sensitization in both sexes.