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In this paper, we provide a general framework for understanding the functional gastrointestinal disorders (FGID) from a biopsychosocial perspective. More specifically, we provide an overview of the recent research on how the complex interactions of environmental, psychological, and biological factors contribute to the development and maintenance of the FGID. We emphasize that considering and addressing all these factors is a conditio sine qua non for appropriate treatment of these conditions. First, we provide an overview of what is currently known about how each of these factors - the environment, including the influence of those in an individual's family, the individual's own psychological states and traits, and the individual's (neuro)physiological make-up - interact to ultimately result in the generation of FGID symptoms. Second, we provide an overview of commonly used assessment tools which can assist clinicians in obtaining a more comprehensive assessment of these factors in their patients. Finally, the broader perspective outlined earlier is applied to provide an overview of centrally acting treatment strategies, both psychological and pharmacological, which have been shown to be efficacious to treat FGID., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls)., Methods: We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting., Results: Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula., Conclusions: Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Several studies have examined structural brain changes associated with chronic pain syndromes, including irritable bowel syndrome (IBS), but study sample sizes have been small and heterogeneous., Methods: We used magnetic resonance imaging-based techniques, voxel-based morphometry, and cortical thickness analysis to examine brain anatomical differences in a relatively large, tightly screened sample of IBS patients (n = 55); we compared data with that from healthy persons (controls; n = 48)., Results: IBS was associated with decreased gray matter density (GMD) in widespread areas of the brain, including medial prefrontal and ventrolateral prefrontal cortex, posterior parietal cortex, ventral striatum, and thalamus. Compared with controls, we observed increased GMD in patients with IBS in the pregenual anterior cingulate cortex and the orbitofrontal cortex, as well as trends in the posterior insula/secondary somatosensory cortex, (para)hippocampus, and left dorsolateral prefrontal cortex. In accounting for anxiety and depression, we found that several of the regions involved in affective processing no longer differed between patients with IBS and controls, whereas the differences in prefrontal and posterior parietal cortices remained. The areas of decreased GMD associated with IBS were largely consistent across clinical subgroups, based on predominant bowel habit and pain predominance of symptoms. No overall or regional differences were observed in cortical thickness between patients with IBS and controls., Conclusions: Changes in density of gray matter among regions involved in cognitive/evaluative functions are specifically observed in patients with IBS, whereas changes in other areas of the brain can be explained by levels of anxiety and depression., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Most patients with gastroesophageal reflux disease (GERD) report that stress exacerbates their symptoms, yet mechanisms underlying this association remain unknown. We sought to determine the effect of an acute laboratory stressor on perceptual and emotional responses to intraesophageal acid perfusion in healthy controls and patients with GERD., Methods: Forty-six patients with heartburn and 10 healthy controls underwent upper endoscopy and, if negative, pH monitoring. Assessment of psychologic factors and health-related quality of life was done by a questionnaire. Perceptual and emotional responses to intraesophageal acid at baseline, during auditory stress, and during an auditory control condition were determined using a randomized crossover design. Plasma levels of norepinephrine, adrenocorticotropic hormone, and cortisol were assessed., Results: Twenty-nine subjects were identified as nonerosive reflux disease and 17 as erosive esophagitis. Quality of life, psychologic profile, and personality assessment variables were similar among the 2 patient groups and the controls. There was a significant reduction in mean lag time to initial symptom perception and an increase in mean intensity rating and mean acid perfusion sensitivity score in the 2 patient groups during the stress period, which was not seen during the control condition. Healthy controls demonstrated lack of a significant change in all parameters of stimulus response functions to acid, regardless of condition., Conclusions: Acute auditory stress can exacerbate heartburn symptoms in GERD patients by enhancing perceptual response to intraesophageal acid exposure. This greater perceptual response is associated with greater emotional responses to the stressor.

Background & Aims: Abuse history is common in irritable bowel syndrome (IBS) and is associated with greater pain reporting, psychologic distress, and poorer health outcome. These effects may be mediated by enhanced responses to aversive visceral stimuli. We investigated the effects of IBS and abuse history on pain reporting and brain activation in response to rectal distentions., Methods: Ten female patients with IBS and 10 controls were included. Half of patients in each group reported a history of abuse. Brain functional magnetic resonance imaging (fMRI) images and pain ratings were obtained during rectal distentions. Statistical parametric mapping identified activation in subregions of the dorsal cingulate cortex and covariation with rated pain., Results: (1) Distention-elicited pain correlated with anxiety and activation of the posterior (PCC) and middle (MCC) dorsal cingulate subregions. (2) Subjects with a history of abuse showed greater activation in the left MCC (P = .022; t = 5.61) and PCC (P = .033; t = 5.00) than subjects without abuse. (3) Those with IBS and abuse reported greater pain than all others (P = .004), had more activity in the left MCC (P = .021; t = 5.29) and PCC (P = .049; t = 4.81), and had less activity in the left supragenual anterior cingulate (sACC) (P = .01; t = 4.86)., Conclusions: Pain ratings during rectal distention are associated with activation of dorsal cingulate regions implicated in homeostatic afferent processing, and prior abuse enhances this activation. Patients with IBS and abuse report more pain, greater MCC/PCC activation, and reduced activity of a region implicated in pain inhibition and arousal (sACC). These findings suggest a possible explanation for the clinical observation of greater pain reporting and poorer outcome in IBS patients with a history of abuse.

Background & Aims: Symptom-related fears and associated hypervigilance toward visceral stimuli may play a role in central pain amplification and irritable bowel syndrome (IBS) pathophysiology. Repeated stimulus exposure leads to decreased salience of threat and reduction of hypervigilance. We sought to evaluate hypervigilance in IBS visceral hypersensitivity and associated brain activity., Methods: Twenty IBS patients (14 female; moderate to severe symptoms) and 14 healthy controls participated in symptom and rectal distention assessments 6 times over 12 months. In a subset of 12 IBS patients, H2 15O-positron emission tomography images were obtained during baseline, rectal distentions, and anticipation of an aversive distention during the first and last session. Statistical parametric mapping (SPM99) was used to identify areas and networks activated during each session as well as those with differential activation across the 2 sessions., Results: Perceptual ratings of the rectal inflations normalized over 12 months, whereas IBS symptom severity did not. There were no sex-related differences in these response patterns. Stable activation of the central pain matrix was observed over 12 months, and activity in limbic, paralimbic, and pontine regions decreased. During the anticipation condition, there were significant decreases in amygdala, dorsal anterior cingulate cortex, and dorsal brainstem activation at 12 months. Covariance analysis supported the hypothesis of changes in an arousal network including limbic, pontine, and cortical areas underlying the decreased perception seen over the multiple stimulations., Conclusions: In IBS patients, repeated exposure to experimental aversive visceral stimuli results in the habituation of visceral perception and central arousal, despite stable activation of networks processing visceral pain and its anticipation.

This report reviews recent research on the psychosocial aspects of the functional gastrointestinal disorders (FGIDs). A review and evaluation of existing literature was conducted by a multidisciplinary committee of experts in this field. This report is a synopsis of a chapter published in the Rome III book. The committee reached consensus in finding considerable evidence supporting the association between psychological distress, childhood trauma and recent environmental stress, and several of the FGIDs but noted that this association is not specific to FGIDs. There is also considerable evidence that psychosocial variables are important determinants of the outcomes of global well-being, health-related quality of life, and health care seeking. In line with these descriptive findings, there is now increasing evidence that a number of psychological treatments and antidepressants are helpful in reducing symptoms and other consequences of the FGIDs in children and adults. The FGIDs are a result of complex interactions between biological, psychological, and social factors, and they can only be treated satisfactorily when all these factors are considered and addressed. Therefore, knowledge about the psychosocial aspects of FGIDs is fundamental and critical to the understanding, assessment, and treatment of these disorders. More extensive physician training is needed if these aspects of treatment are to be used effectively and widely in clinical practice.

Functional abdominal pain syndrome (FAPS) differs from the other functional bowel disorders; it is less common, symptoms largely are unrelated to food intake and defecation, and it has higher comorbidity with psychiatric disorders. The etiology and pathophysiology are incompletely understood. Because FAPS likely represents a heterogeneous group of disorders, peripheral neuropathic pain mechanisms, alterations in endogenous pain modulation systems, or both may be involved in any one patient. The diagnosis of FAPS is made on the basis of positive symptom criteria and a longstanding history of symptoms; in the absence of alarm symptoms, an extensive diagnostic evaluation is not required. Management is based on a therapeutic physician-patient relationship and empirical treatment algorithms using various classes of centrally acting drugs, including antidepressants and anticonvulsants. The choice, dose, and combination of drugs are influenced by psychiatric comorbidities. Psychological treatment options include psychotherapy, relaxation techniques, and hypnosis. Refractory FAPS patients may benefit from a multidisciplinary pain clinic approach.

This report reviews the advantages and disadvantages of 2 types of outcome assessment regularly used in the literature on incontinence: (1) global assessments of symptoms or relief and (2) ratings of specific symptoms of incontinence. Global assessments are usually used when the target condition involves multiple and variable symptoms. They are easy for patients to understand and yield data that seem to correspond closely to the target of the treatment (e.g., symptom severity). The 2 major scaling approaches used in clinical symptom assessment, categorical scaling and cross-modality matching of symptom intensity to line length (visual analogue scales), are reviewed for their reliability and validity. Numerical scales provide the advantage of a large number of possible ratings (usually 9-100) and are intuitively easy to use. All methods of symptom assessment using patient recall are subject to potential reporting bias. Measures of current symptoms, although less biased, may not reflect ongoing symptom levels, and current symptom levels tend to influence patients' recall of both symptom severity and medication counts. However, patient-initiated ratings are relevant to assessing "real-time" symptoms in incontinence trials, and even single retrospective ratings of "usual" symptom intensity may actually be an adequate reflection of the average symptom severity (at least for chronic pain). Applying subjective, predetermined criteria for success, such as the provision of "adequate relief," allows researchers to closely mimic clinical situations and use a cutoff point ("threshold") specifically associated with the condition and treatment being investigated. Devices such as personal digital assistants that can cue subjects for information at set or random intervals, record multiple types of responses, and accurately assess compliance with data recording should help facilitate future research.

Design: Randomized prospective cohort study., Setting: Long-term care facilities., Participants: Two hundred seven subjects with stage III or IV pressure ulcers., Intervention: Two separate randomized control studies of advanced pressure ulcers that compared wound healing on 3 different support surfaces. Subjects were allocated to low air loss bed, upgraded bed overlay (only in study 1), or 4h/d sitting on an experimental generic total contact seat. The seat was designed using prosthetics principles aimed at distributing pressure off bony prominences onto less pressure-sensitive areas. Subjects were followed for 6 months or until they were totally healed., Main Outcome Measures: Number of subjects who totally healed, time to total healing, and pressure ulcer status score after 4 weeks of treatment. Interface pressures and functional capacity were also measured at 4 weeks., Results: In study 1, 3 subjects worsened on the bed overlay condition and were withdrawn from the study. None worsened on low air loss or generic total contact seat. At 4 weeks in both studies, pressure ulcer status score was lowest for the generic total contact seat (P<.0001), compared with the other surfaces. Subject populations were similar, so to analyze total healing, results from both studies were combined. Total healing of pressure ulcers occurred as early as 4 weeks in some subjects using the generic total contact seat. Even at 8 weeks, total healing was primarily seen with use of that seat, on which interface pressures, function, and seating tolerance were best., Conclusions: Faster healing and better function indicate that treatment using the generic total contact seat is superior to low air loss bed therapy, which is standard care for advanced pressure ulcers.

Background & Aims: Women have a higher prevalence of irritable bowel syndrome (IBS) and possible differences in response to treatment, suggesting sex-related differences in underlying pathophysiology. The aim of this study was to determine possible sex-related differences in brain responses to a visceral and a psychological stressor in IBS., Methods: Regional cerebral blood flow measurements using H(2)(15)O positron emission tomography were compared across 23 female and 19 male nonconstipated patients with IBS during a visceral stimulus (moderate rectal inflation) and a psychological stimulus (anticipation of a visceral stimulus)., Results: In response to the visceral stimulus, women showed greater activation in the ventromedial prefrontal cortex, right anterior cingulate cortex, and left amygdala, whereas men showed greater activation of the right dorsolateral prefrontal cortex, insula, and dorsal pons/periaqueductal gray. Similar differences were observed during the anticipation condition. Men also reported higher arousal and lower fatigue., Conclusions: Male and female patients with IBS differ in activation of brain networks concerned with cognitive, autonomic, and antinociceptive responses to delivered and anticipated aversive visceral stimuli.

Background & Aims: The 5-HT3 receptor (5-HT3R) antagonist Alosetron (Alos) reduces the symptoms of female patients with diarrhea-predominant irritable bowel syndrome (IBS); yet, the mechanism(s) underlying this effect remains incompletely understood. We determined the effect of Alos on regional cerebral blood flow (rCBF) in the absence and presence of rectal or sigmoid stimulation to evaluate 2 hypothesized mechanisms of therapeutic action: peripheral antinociception and inhibition of emotional motor system (EMS) regions in the brain., Methods: Forty-nine nonconstipated irritable bowel syndrome (IBS) patients (26 female) received H(2)(15)O positron emission tomography (PET) brain scans before a randomized, placebo-controlled, 3-week trial with Alos (1-4 mg twice daily). PET scans were repeated after treatment in 37 completers. We assessed rCBF during baseline, rectal distention, and anticipation of undelivered rectal distention. The 3 conditions were repeated after a series of noxious sigmoid distentions. Rectal (45 mm Hg) and sigmoid (60 mm Hg) distentions were performed with a computer-controlled barostat device., Results: Alos treatment, as compared with placebo, improved IBS symptoms and reduced rCBF in 5-HT3R containing regions of the EMS, but not in areas activated by pain. Reduction of rCBF appeared greatest in the absence of visceral stimulation, and was partially reversed by rectal or sigmoid distention. Symptom improvement across sessions was significantly correlated with rCBF decreases in the 5-HT3R-rich amygdala, ventral striatum, and dorsal pons., Conclusions: Reduction in IBS symptoms correlated with a drug-induced reduction in the activity of central autonomic networks mediating emotional expression that was maximal in the absence of nociceptive input.

Since rabbit prostate extract strongly stimulated intestinal zinc absorption and improved the diabetic condition of streptozotocin-induced diabetic rats, we examined the effects of 200 mg bovine prostate powder supplemented with 20 mg zinc (Pro-Z) on the clinical manifestations of older male patients with type II diabetes. Twenty-two male patients who received Pro-Z capsules two to four times per day for 3 months showed reduced mean fasting blood glucose levels from 202 to 169 mg/dL, hemoglobin A1C-(HbA1C) concentrations from 12.2% to 9.5%, and mean values for the 3-hour area response above the fasting glucose concentration (TAFGC) from 141 to 102 mg glucose/dL/h. In eighteen patients who received placebo, mean values for fasting blood glucose decreased from 167 to 165 mg/dL and HbA1C from 10.4% to 10.2%, and for TAFGC increased from 121 to 126 mg glucose/dL/h. No detrimental changes occurred in the liver and kidney function of patients receiving either Pro-Z or placebo. However, blood cholesterol and low-density lipoprotein in patients receiving Pro-Z decreased slightly, whereas values in the placebo group tended to increase. The mean fasting plasma insulin decreased 15.5 to 13.8 microU/mL in subjects given Pro-Z, while the zinc concentration increased from 1.21 to 1.39 microg/mL. In contrast, the mean value for plasma insulin in the placebo group changed from 14.4 to 15.4 microU/mL (worsened), and for zinc, from 1.24 to 1.30 microg/ml. Interestingly, fasting urinary glucose concentrations in subjects given Pro-Z decreased from 1,249 to 378 mg/dL, whereas in those given placebo the values changed from 877 to 778 mg/dL. Since plasma zinc concentrations in both the placebo and the Pro-Z group were normal, these results suggest that biochemical constituents in the prostate including zinc may be involved in controlling glucose metabolism in patients with non-insulin-dependent diabetes mellitus.