Could Stress Contribute to Pain-Related Fear in Chronic Pain?

Learning to predict pain based on internal or external cues constitutes a fundamental and highly adaptive process aimed at self-protection. Pain-related fear is an essential component of this response, which is formed by associative and instrumental learning processes. In chronic pain, pain-related fear may become maladaptive, drive avoidance behaviors and contribute to symptom chronicity. Pavlovian fear conditioning has proven fruitful to elucidate associative learning and extinction involving aversive stimuli, including pain, but studies in chronic pain remain scarce. Stress demonstrably exerts differential effects on emotional learning and memory processes, but this has not been transferred to pain-related fear. Within this perspective, we propose that stress could contribute to impaired pain-related associative learning and extinction processes and call for interdisciplinary research. Specifically, we suggest to test the hypotheses that (1) extinction-related phenomena inducing a re-activation of maladaptive pain-related fear (e.g., reinstatement, renewal) likely occur in everyday life of chronic pain patients and may alter pain processing, impair perceptual discrimination and favour overgeneralization; (2) acute stress prior to or during acquisition of pain-related fear may facilitate the formation and/or consolidation of pain-related fear memories, (3) stress during or after extinction may impair extinction efficacy resulting in greater reinstatement or context-dependent renewal of pain-related fear; and (4) these effects could be amplified by chronic stress due to early adversity and/or psychiatric comorbidity such as depression or anxiety in patients with chronic pain

Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required

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

Modulation of Sleep Quality and Autonomic Functioning by Symptoms of Depression in Women with Irritable Bowel Syndrome

The objective of this study was to determine how depressive symptoms affect autonomic activity during sleep, objective and subjective sleep, and gastrointestinal symptom severity in women with irritable bowel syndrome (IBS). Seventy women who met the Rome II criteria for IBS and 21 healthy volunteers participated. All participants were recruited from the surrounding community. IBS patients were stratified into two groups based on their Beck Depression Inventory II score and 44 IBS patients with depressive symptoms (IBS+DS) were compared to 26 IBS patients without depressive symptoms (IBS−DS). Autonomic activity was measured by heart rate variability (HRV) analysis. Fifteen-minute segments were selected from a baseline presleep period, stage 2, slow-wave sleep, and rapid-eye movement sleep for heart rate variability spectral analysis. Subjective sleep quality was assessed by the Pittsburg Sleep Quality Index (PSQI) and gastrointestinal symptom severity was assessed by an 18-item questionnaire. The IBS+DS group reported significantly ( P <0.01) more sleep complaints, measured by the PSQI, than the IBS−DS group and healthy controls. The IBS+DS group took significantly ( P <0.05) longer to enter their first rapid-eye movement period than healthy controls. The IBS+DS group reported significantly ( P =0.01) increased gastrointestinal symptom severity compared to the IBS−DS group. There were no significant group differences in autonomic activity during the baseline presleep period or sleep stages. The results demonstrated that IBS patients with significant depressive symptoms had increased gastrointestinal symptom severity, increased sleep complaints, and alterations in sleep architecture compared to healthy controls and IBS patients without significant depressive symptoms.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44433/1/10620_2004_Article_494230.pd

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

Meta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data

The brain systems underlying placebo analgesia are insufficiently understood. Here we performed a systematic, participant-level meta-analysis of experimental functional neuroimaging studies of evoked pain under stimulus-intensity-matched placebo and control conditions, encompassing 603 healthy participants from 20 (out of 28 eligible) studies. We find that placebo vs. control treatments induce small, widespread reductions in pain-related activity, particularly in regions belonging to ventral attention (including mid-insula) and somatomotor networks (including posterior insula). Behavioral placebo analgesia correlates with reduced pain-related activity in these networks and the thalamus, habenula, mid-cingulate, and supplementary motor area. Placebo-associated activity increases occur mainly in frontoparietal regions, with high between-study heterogeneity. We conclude that placebo treatments affect pain-related activity in multiple brain areas, which may reflect changes in nociception and/or other affective and decision-making processes surrounding pain. Between-study heterogeneity suggests that placebo analgesia is a multi-faceted phenomenon involving multiple cerebral mechanisms that differ across studies

The stress concept in gastroenterology: from Selye to today [version 1; referees: 2 approved]

More than eighty years after Hans Selye (1907–1982) first developed a concept describing how different types of environmental stressors affect physiological functions and promote disease development (called the “general adaptation syndrome”) in 1936, we herein review advances in theoretical, mechanistic, and clinical knowledge in stress research, especially in the area of gastroenterology, and summarize progress and future perspectives arising from an interdisciplinary psychoneurobiological framework in which genetics, epigenetics, and other advanced (omics) technologies in the last decade continue to refine knowledge about how stress affects the brain-gut axis in health and gastrointestinal disease. We demonstrate that neurobiological stress research continues to be a driving force for scientific progress in gastroenterology and related clinical areas, inspiring translational research from animal models to clinical applications, while highlighting some areas that remain incompletely understood, such as the roles of sex/gender and gut microbiota in health and disease. Future directions of research should include not only the genetics of the stress response and resilience but also epigenetic contributions

Vom Bauchgefühl zum viszeralen Schmerz

Disturbances of the gut-brain axis are characterized by complex dysfunctions on peripheral and central nervous system levels, which can contribute to visceral hypervigilance and hyperalgesia and imprint visceral pain. Numerous cognitive, emotional and psychoneurobiological factors are involved in visceral pain modulation, which in the psychosocial treatment concept can have a positive as well as a negative impact on the experience of visceral pain. Nocebo effects induced by negative expectations are of high clinical relevance in acute and especially in chronic visceral pain but the underlying mechanisms remain insufficiently understood. Verbal instructions, previous experiences and learning processes as well as emotional factors, such as fear and stress contribute to the development and maintenance of negative expectation effects. Targeted communication strategies, a sensitive use of information in the clarification and positive environmental context conditions can contribute to establishing an adequate expectation management and minimize negative expectation effects in the clinical practice. At the same time, translational research approaches are required to gain further insights into the mediators and moderators of negative expectation effects and to transfer these into clinical practice. In this way the treatment of patients with disorders of the gut-brain communication can be improved