[Psychobiological mechanisms in the pathophysiology of chronic visceral pain]. / Psychobiologische Mechanismen bei der Pathophysiologie chronischer viszeraler Schmerzen.

Although visceral pain is of high clinical relevance, it remains poorly understood especially when compared to somatic pain. Nevertheless, interdisciplinary research approaches bridging psychophysiology and neurogastroenterology have contributed to a more refined knowledge about the complex peripheral and central mechanisms of the bidirectional brain-gut axis in recent years. This review summarizes current knowledge regarding psychobiological mechanisms in the pathophysiology of chronic visceral pain in functional gastrointestinal disorders with a focus on irritable bowel syndrome (IBS). Special attention is paid to the role of affective disturbances and emotions, particularly psychological stress as well as to influences of cognition and learning on gastrointestinal motor and sensory functions in healthy individuals and patients with IBS. In this emerging field of research, new evidence from the fields of placebo research and pain-related fear conditioning provide new insights into the psychological and neurobiological mechanisms involved in the transition from acute to chronic pain and the maintenance of pain. This opens up new perspectives for innovative treatment approaches for IBS and other functional gastrointestinal disorders.

[Psychophysiology of visceral pain]. / Psychophysiologische Grundlagen viszeraler Schmerzen.

The psychophysiology of visceral pain is--different from cardiac psychophysiology--much less well investigated due to the invasiveness of its methods and problems associated with reliably and reproducibly stimulating as well as recording of the gastrointestinal tract. Despite these problems, the last 30 years have documented a number of psychophysiological phenomena such as the perception (interoception) of visceral stimuli, the effect of emotions and stress on visceral sensations, and the effect of visceral processes on cortical processing. This was mainly due to the application of neurophysiological techniques (cortical imaging and stimulation) in these investigations.

Post-infectious irritable bowel syndrome--a review of the literature.

INTRODUCTION: Despite considerable research efforts, the epidemiological characteristics of post-infectious symptoms of the irritable bowel syndrome-type (PI-IBS) are not yet well defined. Estimates of its incidence after gastrointestinal (GI) infection show considerable variation and the number of patients with a history of a GI infection among all patients with IBS is practically unknown. This review aims at summarizing published estimates (i) on the prevalence of PI-IBS among all IBS patients and (ii) on PI-IBS incidence after GI infection, critically discusses methodological differences that may explain the variation of the presented findings and gives an overview on currently identified risk factors for the development of PI-IBS. METHODS: A systematic literature review was perfomed of studies indexed in PUBMED that assessed the epidemiology and risk factors of PI-IBS. RESULTS: The reported incidence of PI-IBS ranges for epidemic infections between 7 and 36 %, for individual infections between 4 and 36 % and for traveller's diarrhea from 4 to 14 %. Estimates of the prevalence of PI-IBS range from as low as 7 % to more than ⅓ of all IBS patients, depending on the study design. The predictors and biomarkers are varying among the studies. CONCLUSION: PI-IBS appears to be common following infectious enteritis and among all IBS patients, but precise estimates are still lacking.

[Placebo response: in studies on pain and under other clinical conditions]. / Placeboresponse: In Studien zum Schmerz und anderen klinischen Bedingungen.

This contribution compares unexplained essential questions regarding the placebo response with current empirical evidence: (1) Are the placebo response rates equivalent in the groups treated with medication or placebo? Very little evidence has been gathered to support this generally accepted additivity while some findings negate its validity. (2) Is the placebo response a function of the probability of receiving medication or placebo? There are indications that the number of study groups included in a trial determines the level of placebo and medication response. (3) How great is the placebo response in trials that directly compare a (new) medication with one that for example is already on the market? There are indications that such comparative studies produce higher placebo response rates. (4) How high is the placebo response rate in everyday clinical practice--or does the response to a medication in trials substantiate the effect of the medication in everyday clinical practice?

Affective disturbances modulate the neural processing of visceral pain stimuli in irritable bowel syndrome: an fMRI study.

OBJECTIVE: To address the role of anxiety and depression symptoms in altered pain processing in irritable bowel syndrome (IBS). DESIGN: In this functional magnetic resonance imaging study, the blood oxygen level-dependent (BOLD) response to rectal distensions delivered at previously determined individual discomfort thresholds was assessed. PATIENTS: 15 female patients with irritable bowel syndrome (IBS) and with normal rectal pain thresholds, and 12 healthy women. MEASURES: The correlation of anxiety and depression symptoms, measured with the Hospital Anxiety and Depression Scale (HADS), with subjective pain ratings and the BOLD response during distension-induced brain activation were analysed within IBS. Group differences in pain-induced brain activation with and without controlling for HADS scores were evaluated. RESULTS: Patients with IBS experienced significantly more pain and discomfort upon rectal distensions in the scanner, despite unaltered rectal sensory thresholds. Anxiety and depression scores were associated with these subjective stimulus ratings, but not with rectal sensory thresholds. Anxiety symptoms in IBS were significantly associated with pain-induced activation of the anterior midcingulate cortex and pregenual anterior cingulate cortex. Depression scores correlated with activation of the prefrontal cortex (PFC) and cerebellar areas within IBS. Group comparisons with the two-sample t test revealed significant activation in the IBS versus controls contrast in the anterior insular cortex and PFC. Inclusion of anxiety and depression scores, respectively, as confounding variables led to a loss of significant group differences. CONCLUSIONS: Altered central processing of visceral stimuli in IBS is at least in part mediated by symptoms of anxiety and depression, which may modulate the affective-motivational aspects of the pain response.

Cortisol levels predict motion sickness tolerance in women but not in men.

A variety of intrinsic and extrinsic factors contribute to motion sickness severity in a stressful motion environment. The interplay of all these factors may partially explain the high inter-subject variability of motion sickness susceptibility found in many studies as well as some of the contradictory findings between studies regarding the modulating influence of single factors. We investigated the role of endogenous cortisol levels, gender and repetitive experience for motion sickness susceptibility. Motion sickness was induced in 32 healthy, but motion-sickness susceptible volunteers (16:16 males:females), by means of a vection drum. Subjects were investigated between 8:00 am (high cortisol) and 11:00 am (low cortisol), and on five consecutive days. Tolerance to rotation (RT) of the drum, motion sickness symptom ratings (SR) and salivary cortisol levels were assessed. Baseline cortisol levels correlated positively with RT in women, but not in men. RT showed a gender-specific time course across days, with higher values in males than in females on day 1, and sensitization on day 3 only in men. SR and cortisol levels following rotation did not differ between males and females, or between testing days. Gender differences in motion sickness susceptibility appear to be linked to a different role of basal cortisol levels for motion sickness tolerance. Results clearly indicate the need to control for gender, day time and cortisol levels in studies of motion sickness.

The effects of ageing on the colonic bacterial microflora in adults.

BACKGROUND: The composition of the fecal mircoflora and its changes on ageing have rarely been investigated in large samples of both patients and volunteers. METHODS: We analysed the fecal flora by conventional microbiological testing (Kyberstatus, Institute of Microecology, Herborn, Germany) of stool samples from 35 292 adults (age: 46.3 +/- 0.08 [18 to 96] years, 9564 males, 24 784 females; remaining = missing data) with different intestinal and non-intestinal diagnoses for total colony-forming units (CFU) (per g stool) as well as relative abundance of Bifidobacteria, Bacteroides spp., Escherichia coli, Enterococcus spp., and Lactobacillus spp. with respect to age, gender, and clinical data available (e. g., stool consistency and pH). RESULTS: The total CFU was stable and showed no age- or gender-related changes. Individual bacterial species constantly and significantly increased with age (E. coli, Enterococci spp.), or decreased at higher age (Bacteroides spp.), or were stable throughout the life span (Lactobacilli, Bifidobacteria). Gastrointestinal diagnoses (Crohn's disease, n = 198; ulcerative colitis, n = 515; irritable bowel syndrome, n = 7765; other GI diagnoses, n = 10 478) tended to exhibit some specificity of the bacterial profile, and when GI diagnoses were excluded, the age-related bacterial profile of the remaining group (n = 15 619, m:f = 4197:11 422) was not different. CONCLUSION: Conventional microbiological investigations of the fecal microbiota showed both bacteria-specific as well as a general pattern of ageing of the colonic microbiota, with the last decades (more than 60 years) demonstrating the most profound changes. It remains to be shown whether these changes reflect direct changes of the gut microbiota, the mucosal innate immunity, or indirect consequences of age-related altered nutrition.

[Hypnotherapy for irritable bowel syndrome--a systematic review]. / Hypnotherapeutische Interventionen beim Reizdarmsyndrom - eine systematische Ubersicht.

The Irritable bowel syndrome (IBS) is a highly prevalent functional disorder with a remarkable clinical and economic impact. Several pathogenetic factors of IBS are discussed and summarised within a bio-psycho-social model. Data from published hypnotherapeutic interventions with approximately 800 patients show long-lasting symptom relief. The underlying mechanisms of action are not well understood. Nine mechanism studies show influences of hypnosis on colorectal sensitivity, colorectal motility and mental strain (anxiety, depression, maladaptive cognitions). Results are often contradictory and effects of hypnosis on several of the proposed pathogenetic factors are not examined at all. This paper reviews previous studies on hypnotherapy in IBS patients with a focus on symptom relief and mechanisms of action.

[The placebo effect in medicine]. / Der Placeboeffekt in der Medizin.

Placebos are medication surrogates that are able to improve symptoms in patients when prescribed by a doctor and for a patient, and that cannot be explained by a drug. In clinical testing and presumably also in clinical routine, placebo effects contribute substantially to the efficacy of medicines, at least with every-day diseases and complaints. Placebos on the one hand, and the mechanisms the response on the other, have not interfered with the development on novel drugs in past years, but have also brought about research that investigates its mechanisms and public interest in its clinical use in everyday medicine. Current knowledge grows by about 10.000 publications per year on placebo-controlled studies, and by nearly 100 papers on the placebo effect itself. This review will focus on the history of placebo use in medicine, on ethical issues related to the use of placebos, on methodological problems in placebo-controlled trials and their alternatives, and on mechanisms of the placebo response in clinical and experimental research, e.g. on type, size, dynamics, determinants, and predictors of the placebo response in the literature.

The "Biology-First" Hypothesis: Functional disorders may begin and end with biology-A scoping review.

While it is generally accepted that gastrointestinal infections can cause functional disturbances in the upper and lower gastrointestinal tract-known as postinfectious irritable bowel syndrome (PI-IBS) and functional dyspepsia (PI-FD)-it has still not been widely recognized that such an infection can also initiate functional non-intestinal diseases, and that non-intestinal infections can provoke both intestinal and non-intestinal functional disturbances. We conducted a scoping review of the respective literature and-on the basis of these data-hypothesize that medically unexplained functional symptoms and syndromes following an infection may have a biological (genetic, endocrine, microbiological) origin, and that psychological and social factors, which may contribute to the disease "phenotype," are secondary to this biological cause. If this holds true, then the search for psychological and social theories and factors to explain why one patient develops a chronic functional disorder while another does not is-at least for postinfectious states-misleading and detracts from exploring and identifying the true origins of these essentially biological disorders. The biopsychosocial model may, as the term implies, always begin with biology, also for functional (somatoform) disorders.

Neuroendocrinological effects of acupuncture treatment in patients with irritable bowel syndrome.

OBJECTIVES: Quality of life (QoL) improvement in patients with irritable bowel syndrome (IBS) during acupuncture (AC) treatment seems to be due to a placebo effect. The aim was to explore if acupuncture has some specific influence on the neuroendocrinic and autonomic nervous system (ANS). DESIGN/SETTING: Patients with IBS were randomly assigned to receive either acupuncture (AC) or sham acupuncture (SAC) using the so-called "Streitberger needle". QoL was measured with the functional quality of life diseases quality of life questionnaire (FDDQL) and SF-36. The effect on ANS was evaluated by measuring salivary cortisol and by cardiovascular responses on a tilt table before and after 10 AC treatments. Complete data sets of tilt table and salivary morning cortisol were available for 9 patients in the AC and 12 in SAC group. RESULTS: QoL increased in both groups (p=0.001) with no group differences. Salivary cortisol decreased in all groups (F=10.55; p=0.006). However, the decrease was more pronounced in the AC group (F=4.07; p=0.033) (ANOVA repeated measures model). Heart rate response decreased during orthostatic stress in the AC group while it increased in the SAC group (F=9.234; p=0.005), indicating an increased parasympathetic tone in the AC group. Improvement of pain was positively associated with increased parasympathetic tone in the AC group (F=10.1; p=0.006), but not in the SAC group. CONCLUSIONS: The acupuncture specific physiological effects are in contrast to the unspecific improvement of QoL in both AC and SAC groups. Thus, different mechanisms seem to be involved in placebo and real-acupuncture driven improvements. The specific mechanism of action of acupuncture on the ANS remains unclear and deserves further evaluation.

Stress reactivity in childhood functional abdominal pain or irritable bowel syndrome.

BACKGROUND: Frequent abdominal pain (AP) in childhood has been shown to be associated with elevated experience of stress and with deficits in stress coping, but psychophysiological stress reactivity has been studied rarely. METHODS: We examined whether children with frequent AP show altered reactions of the parasympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis during and following an afternoon laboratory social stress task in comparison to healthy children and children with anxiety disorders. Twenty-four children with frequent AP (18 with functional AP and six with irritable bowel syndrome; M = 9.9 years), and 24 healthy controls underwent stressful free speech and arithmetic tasks. Twelve children with anxiety disorders served as second comparison sample. Groups were compared regarding parasympathetic reaction and saliva cortisol concentration. RESULTS: We found no differences in parasympathetic withdrawal between the groups. Concerning the HPA axis, we detected an attenuated cortisol reactivity in children with AP compared to both other groups. CONCLUSIONS: This study provides preliminary evidence that childhood AP is not associated with altered parasympathetic withdrawal during stress. It seems to be related to a down-regulated reactivity of the HPA axis. This pattern was ascertained in comparison to healthy children and also in comparison to children with anxiety disorders. SIGNIFICANCE: Childhood abdominal pain could be related to down-regulated HPA axis reactivity to stress but not to altered parasympathetic reaction. Children with abdominal pain and children with anxiety disorders exhibit a divergent stress-related HPA axis reaction.

A fresh look at IBS-opportunities for systems medicine approaches.

NeuroGUT is a EU-funded initial training network (ITN) of 14 research projects in neurogastroenterology that have employed an equal number of early-stage researchers. Neurogut trainees have-among other activities-attended an international conference on irritable bowel syndrome (IBS) in Bologna in 2016 and were asked to critically review and evaluate the current knowledge on IBS for their respective research activities, and to state what they were missing. Most appreciated were the topics brain imaging of gut activity, the role of the gut microbiota, the pharmacology of gut functions, the IBS-IBD interrelation, the new Rome IV criteria, the role of gas, and the placebo response in functional disorders. Missed were more detailed coverage of high-resolution manometry, functional brain imaging, advanced "systems medicine" approaches and bioinformatics technology, better sub-classification of IBS patients, and the development of disease biomarkers, extended at the molecular (genetic/epigenetic, proteonomic) level. They summarize that despite excellent specialized research, there is a gap open that should be filled with systems medicine. For this, it would be necessary that medical research learns even more from the data sciences and other basic disciplines, for example, information technology and system biology, and also welcomes a change in paradigm that enhances open sharing of data, information, and resources.

Passenger well-being in airplanes.

Passenger well-being is influenced by cabin environmental conditions which interact with individual passenger characteristics like age and health conditions. Cabin environment is composed of different aspects, some of which have a direct influence on gastrointestinal functions and may directly generate nausea, such as cabin pressure, oxygen saturation, and motion or vibration. For example, it has been shown that available cabin pressure during normal flight altitude can significantly inhibit gastric emptying and induce dyspepsia-like symptoms when associated with a fibre-rich meal. Other aspects of the cabin environment such as space and variability of seating, air quality, and noise, also have been shown to modulate (reduce or increase) discomfort and nausea during flights. Individual passenger characteristics and health status also have been demonstrated to increase vulnerability to adverse health outcomes and discomfort.

Functional neuroimaging studies in functional dyspepsia patients: a systematic review.

BACKGROUND: There is increasing evidence in support of the presence of abnormal central changes (compared to healthy controls) in functional dyspepsia (FD) in addition to the peripheral changes in gastrointestinal tract. PURPOSE: This systematic review aims to provide an integrative understanding of the abnormal functional brain activity, visceral sensation, dyspeptic symptoms, and psychological changes of FD. Electronic and hand searches were conducted to identify functional neuroimaging studies involving FD patients. Sixteen studies were selected and divided into three categories: 10 resting state studies, three visceral distention studies, and three acupuncture studies. Changes were reported in several brain areas in FD patients including the frontal cortex, somatosensory cortex, insula, anterior cingulate cortex, thalamus, hippocampus, and amygdala. These brain activity changes were associated with visceral hypersensitivity, dyspeptic symptoms, poorer quality of life, anxiety, and depression. The results show that FD is associated with functional abnormalities in sensory and pain modulation, emotion, saliency, and homeostatic processing regions. The diversity of conditions, heterogeneous results, poorly standardized diagnoses of FD, and various comorbidities may be responsible for the variability in the results.

Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity.

BACKGROUND: Gastrointestinal hormone release and the regulation of appetite and body weight are thought to be dysbalanced in obesity. However, human data investigating the expression of gastrointestinal hormones in the obese are rare. We studied the expression of ghrelin, leptin, and the serotonergic system in stomach tissue and serum of obese and non-obese individuals. METHODS: Gastric tissue and serum were collected from 29 adult obese (BMI 48.7 ± 10.6 kg/m(2) ; mean ± SD) who underwent laparoscopic sleeve gastrectomy. Gastric biopsies, surgery specimen or serum was obtained from 35 adult non-obese humans (BMI 22.7 ± 1.9 kg/m(2) ). Ghrelin, ghrelin O-acyl transferase (GOAT), leptin, leptin receptor, and tryptophan hydroxylase 1 (TPH1) mRNA expression were measured by qRT-PCR. Serotonin (5HT) and leptin protein concentration were quantified in tissue extracts and serum; GOAT and ghrelin-positive cells were immunohistologically quantified in tissue. Additionally, 21 blood immune markers were analyzed. KEY RESULTS: In gastric tissue, GOAT-positive cells were reduced (p < 0.01), but ghrelin-positive cells and mRNA were increased (both p < 0.05) in obese compared with non-obese individuals. Gastric leptin (p < 0.001) and leptin receptor (p < 0.001) mRNA expression, as well as leptin concentrations in serum (p < 0.001), were increased in obese compared with non-obese individuals. Serum 5HT was reduced (p < 0.05), while tissue 5HT and TPH1 mRNA were reduced only by trend. Interleukin 1 receptor a (IL1Ra), IL-8, IL-12, and monocyte chemoattractant protein 1 (IL1Ra) were increased and IL1Ra correlated negatively with serum leptin. CONCLUSIONS & INFERENCES: Our data indicate that obesity causes a dysregulation of gastrointestinal hormones at the tissue level and serum, including a negative correlation with an increased marker of subclinical inflammation.