Correlates of 1-Year Change in Quality of Life in Patients with Urologic Chronic Pelvic Pain Syndrome: Findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

PURPOSE: We evaluated and identified baseline factors associated with change in health related quality of life among patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: A total of 191 men and 233 women with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome (collectively referred to as urologic chronic pelvic pain syndrome) were followed for 12 months with bimonthly completion of the Short Form 12 to assess general mental and physical health related quality of life, and with biweekly assessment of condition specific health related quality of life using the Genitourinary Pain Index. A functional clustering algorithm was used to classify participants as improved, stable or worsened for each health related quality of life measure. Ordinal logistic regression was used to determine baseline factors associated with change. RESULTS: Physical health related quality of life improved in 22% of the participants, mental health related quality of life improved in 25% and condition specific health related quality of life improved in 47%. Better baseline physical health related quality of life, older age and the presence of nonurological symptoms were associated with lower likelihood of improvement in physical health related quality of life. Better baseline mental health related quality of life, female sex, and greater baseline depression and stress were associated with a lower likelihood of improvement in mental health related quality of life. Better baseline condition specific health related quality of life and more severe baseline urologic chronic pelvic pain syndrome pain symptoms were associated with a lower likelihood of improvement in condition specific health related quality of life. CONCLUSIONS: While several nonurologic chronic pelvic pain syndrome factors influenced the trajectory of general health related quality of life over time, only condition specific baseline health related quality of life and urologic chronic pelvic pain syndrome symptoms were associated with urologic chronic pelvic pain syndrome specific health related quality of life change. Significant differences in how urologic chronic pelvic pain syndrome impacts various aspects of health related quality of life suggest a multidisciplinary approach to assessment and treatment of these patients.

History of early life adversity is associated with increased food addiction and sex-specific alterations in reward network connectivity in obesity.

BACKGROUND: Neuroimaging studies have identified obesity-related differences in the brain's resting state activity. An imbalance between homeostatic and reward aspects of ingestive behaviour may contribute to obesity and food addiction. The interactions between early life adversity (ELA), the reward network and food addiction were investigated to identify obesity and sex-related differences, which may drive obesity and food addiction. METHODS: Functional resting state magnetic resonance imaging was acquired in 186 participants (high body mass index [BMI]: ≥25: 53 women and 54 men; normal BMI: 18.50-24.99: 49 women and 30 men). Participants completed questionnaires to assess ELA (Early Traumatic Inventory) and food addiction (Yale Food Addiction Scale). A tripartite network analysis based on graph theory was used to investigate the interaction between ELA, brain connectivity and food addiction. Interactions were determined by computing Spearman rank correlations, thresholded at q < 0.05 corrected for multiple comparisons. RESULTS: Participants with high BMI demonstrate an association between ELA and food addiction, with reward regions playing a role in this interaction. Among women with high BMI, increased ELA was associated with increased centrality of reward and emotion regulation regions. Men with high BMI showed associations between ELA and food addiction with somatosensory regions playing a role in this interaction. CONCLUSIONS: The findings suggest that ELA may alter brain networks, leading to increased vulnerability for food addiction and obesity later in life. These alterations are sex specific and involve brain regions influenced by dopaminergic or serotonergic signalling.

Asymmetries in reciprocal baroreflex mechanisms and chronic pain severity: Focusing on irritable bowel syndrome.

BACKGROUND: Objective measures of pain severity remain ill defined, although its accurate measurement is critical. Reciprocal baroreflex mechanisms of blood pressure (BP) control were found to impact differently on pain regulation, and thus their asymmetry was hypothesized to also connect to chronic pain duration and severity. METHODS: Seventy-eight female patients with irritable bowel syndrome (IBS) and 27 healthy women were assessed for IBS severity and chronicity, negative affect, and various measures of resting autonomic function including BP, heart rate and its variability (HRV), baroreceptor-sensitivity to activations and inhibitions, gains of brady- and tachy-cardiac baro-responses, gains of BP falls/rises, and BP start points for these spontaneous baroreflexes. KEY RESULTS: IBS directly and indirectly (through increased negative affect) was associated with asymmetry between baroreceptor activations/inhibitions compared to symmetrical baroreflex reciprocity in the healthy women. In the IBS group, independently of specific IBS symptoms, pain chronicity was associated with (i) decreased BP falls coupled with either (a) decreased tachycardia associated with lower disease severity (earlier "pain resilience" mechanism), or (b) decreased bradycardia associated with higher disease severity (later "pain decompensation" mechanism), or (ii) increased BP start point for baroreceptor activations coupled with either (a) BP increase (delayed "pain adaptation" mechanism) or (b) affect-related HRV decrease (delayed "pain aggravation" mechanism). CONCLUSION AND INFERENCES: We anticipate the findings to be a starting point for validating these autonomic metrics of pain suffering and pain coping mechanisms in other chronic pain syndromes to suggest them as biomarkers of its severity and duration for profiling and correct management of chronic pain patients.

Resilience is decreased in irritable bowel syndrome and associated with symptoms and cortisol response.

BACKGROUND: Irritable bowel syndrome (IBS) is a stress-sensitive disorder associated with early adverse life events (EALs) and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. Resilience is the ability to recover and adapt positively to stress but has not been well studied in IBS. The aims of this study are to compare resilience in IBS and healthy controls (HCs) and to assess its relationships with IBS symptom severity, quality of life (QOL), EALs, and HPA axis response. METHODS: Two hundred fifty-six subjects (154 IBS, 102 HCs) completed questionnaires for resilience (Connor-Davidson Resilience Scale [CD-RISC] and Brief Resilience Scale [BRS]), IBS symptoms, IBS-QOL, and EALs. Ninety-six of these subjects had serial serum adrenocorticotropic hormone (ACTH) and cortisol levels to exogenous corticotrophin-releasing hormone (CRH) and ACTH measured. The relationship between IBS status, resilience, and other variables of interest was assessed by regression analysis after adjusting for demographics and neuroticism, a predictor of resilience. KEY RESULTS: Resilience was significantly lower in IBS compared to HCs (CD-RISC: 72.16±14.97 vs 77.32±12.73, P=.003; BRS: 3.29±0.87 vs 3.93±0.69, P<.001); however, only BRS was significant after controlling for neuroticism (P=.001). Lower BRS scores were associated with greater IBS symptom severity (P=.002), poorer IBS-QOL (P<.001), and a higher number of EALs (P=.01). There was a significant interaction between BRS resilience and IBS status for ACTH-stimulated cortisol response (P=.031); more resilient IBS subjects had lower cortisol response, and more resilient HCs had higher cortisol response. CONCLUSIONS AND INFERENCES: Lower resilience is associated with IBS status, worse IBS symptom severity, lower IBS-QOL, greater EALs, and stress hyperresponsiveness.

Sex differences in the influence of body mass index on anatomical architecture of brain networks.

BACKGROUND/OBJECTIVES: The brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters. SUBJECTS/METHODS: Structural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age. RESULTS: In both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions. CONCLUSIONS: In individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology.

Gene expression profiles in peripheral blood mononuclear cells correlate with salience network activity in chronic visceral pain: A pilot study.

BACKGROUND: Distinct gene expression profiles in peripheral blood mononuclear cells (PBMCs) consistent with increased sympathetic nervous system activity have been described in different populations under chronic stress. Neuroinflammatory brain changes, possibly related to the migration of primed monocytes to the brain, have been implicated in the pathophysiology of chronic pain. Irritable bowel syndrome (IBS) is a stress-sensitive gastrointestinal disorder associated with altered brain-gut interactions and increased sympathetic/vagal tone and anxiety. Reports about immune alterations in IBS are conflicting. This pilot study aimed to test how PBMC gene expression inflammatory profiles are correlated with altered brain signatures in the salience system. METHODS: Sixteen IBS and 16 healthy controls (HCs) completed resting state MRI scans. Gene expression profiles in PBMCs were assessed using human transcriptome array-2. Bioinformatic analyses determined differential expression of PBMCs between IBS and HCs. Partial least squares, a multivariate analysis technique, was used to identify disease correlations between PBMC gene expression profiles and functional activity in the brain's salience network. KEY RESULTS: Regions of the salience network, including the mid cingulate cortex, and mid and superior temporal gyrus were positively correlated with several pro-inflammatory genes (interleukin 6, APOL2) in IBS, but negatively correlated with several anti-inflammatory genes (KRT8, APOA4) in HCs. CONCLUSIONS & INFERENCES: Based on rodent studies, one may speculate that chronically activated stress signaling pathways in IBS maintain a pro-inflammatory state in the periphery. Alternatively, primed monocytes may migrate to the brain during stress, inducing regional neuroinflammatory changes in salience regions involved in the modulation of visceral sensitivity.

Relationships of abdominal pain, reports to visceral and temperature pain sensitivity, conditioned pain modulation, and heart rate variability in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a heterogeneous condition with a number of pathophysiological mechanisms that appear to contribute to symptom chronicity. One of these is altered pain sensitivity. METHODS: Women between ages 18-45 were recruited the community. Of those enrolled, 56 had IBS and 36 were healthy control (HC) women. Participants completed questionnaires, kept a 4-week symptom diary and had a 12-h Holter placed to assess nighttime heart rate variability including high frequency power (HF), low frequency power (LF), and total power (TP). At mid-follicular phase approximately 80% of women completed a thermal pain sensitivity test with conditioned pain modulation and visceral pain sensitivity using a water load symptom provocation (WLSP) test. KEY RESULTS: As expected, daily abdominal pain was significantly higher in the IBS compared to HC group. There were no differences between the bowel pattern subgroups (IBS-diarrhea [IBS-D], IBS-constipation plus mixed [IBS-CM]). Thermal pain sensitivity did not differ between the IBS and the HC groups, but was significantly higher in the IBS-CM group than the IBS-D group. In the WLSP test, the IBS group experienced significantly more symptom distress than HCs and the IBS-CM group was higher than the IBS-D group. Heart rate variability indicators did not differ between the groups or IBS subgroups. Daily abdominal pain was positively correlated with LF and TP in the IBS group. CONCLUSIONS & INFERENCES: Despite similar levels of abdominal pain in IBS, the IBS-CM group demonstrated greater sensitivity to both thermal and visceral testing procedures.

Altered brain responses in subjects with irritable bowel syndrome during cued and uncued pain expectation.

BACKGROUND: A majority of the subjects with irritable bowel syndrome (IBS) show increased behavioral and brain responses to expected and delivered aversive visceral stimuli during controlled rectal balloon distension, and during palpation of the sigmoid colon. We aimed to determine if altered brain responses to cued and uncued pain expectation are also seen in the context of a noxious somatic pain stimulus applied to the same dermatome as the sigmoid colon. METHODS: A task-dependent functional magnetic resonance imaging technique was used to investigate the brain activity of 37 healthy controls (18 females) and 37 IBS subjects (21 females) during: (i) a cued expectation of an electric shock to the abdomen vs a cued safe condition; and (ii) an uncued cross-hair condition in which the threat is primarily based on context vs a cued safe condition. KEY RESULTS: Regions within the salience, attention, default mode, and emotional arousal networks were more activated by the cued abdominal threat condition and the uncued condition than in the cued safe condition. During the uncued condition contrasted to the cued safe condition, IBS subjects (compared to healthy control subjects) showed greater brain activations in the affective (amygdala, anterior insula) and attentional (middle frontal gyrus) regions, and in the thalamus and precuneus. These disease-related differences were primarily seen in female subjects. CONCLUSIONS & INFERENCES: The observed greater engagement of cognitive and emotional brain networks in IBS subjects during contextual threat may reflect the propensity of IBS subjects to overestimate the likelihood and severity of future abdominal pain.

Increased attentional network functioning related to symptom severity measures in females with irritable bowel syndrome.

BACKGROUND: Increased attention to gastrointestinal (GI) symptoms and disease-specific contexts may play an important role in the enhanced perception of visceral stimuli frequently reported in patients with irritable bowel syndrome (IBS). In this study, we test the hypothesis that altered attentional mechanisms underlie central pain amplification in IBS. METHODS: To evaluate brain networks that support alerting, orienting, and executive attention, we employed the attention network test (ANT), a modified flanker task which measures the efficiency of functioning of core attentional networks, during functional magnetic resonance imaging in 15 IBS patients (mean age = 31 [11.96]) and 14 healthy controls (HCs; mean age = 31 [10.91]). KEY RESULTS: Patients with IBS, compared to HCs, showed shorter reaction times during the alerting and orienting conditions which were associated with greater activation of anterior midcingulate and insular cortices, and decreased activity in the right inferior frontal junction and supplementary motor cortex. Patients also showed activation in the dorsal medial prefrontal cortex and concurrent thalamic deactivation during the executive control portion of the ANT relative to HCs, but no group difference in reaction times were found. The activity in brain regions showing group differences during the ANT were associated with measures of GI-specific anxiety, pain catastrophizing, and fear of uncertainty. In IBS, activity in the anterior midcingulate during alerting correlated with duration of GI-symptoms and overall symptom severity. CONCLUSIONS & INFERENCES: Together, these results suggest that IBS patients have specific abnormalities in attentional network functioning and these deficits may underlie symptom-related anxiety, hypervigilance, and visceral hypersensitivity.

Deficient habituation to repeated rectal distensions in irritable bowel syndrome patients with visceral hypersensitivity.

BACKGROUND: Irritable bowel syndrome (IBS) patients show evidence of altered central processing of visceral signals. One of the proposed alterations in sensory processing is an altered engagement of endogenous pain modulation mechanisms. The aim was to test the hypothesis that IBS patients with (IBS-S) and without visceral hypersensitivity (IBS-N) differ in their ability to engage endogenous pain modulation mechanism during habituation to repeated visceral stimuli. METHODS: Brain blood oxygen level dependent (BOLD) response was measured during repeated rectal distension and its anticipation in 33 IBS patients with and without visceral hypersensitivity and 18 healthy controls (HCs). BOLD response to early and late phase of the distension series was compared within and between groups. KEY RESULTS: While BOLD response was similar during the early phase of the experiment, IBS-S showed greater BOLD response than IBS-N and HCs during the late phase of the distension series. IBS-S showed increasing BOLD response both to the anticipation and delivery of low intensity rectal distensions in brain regions including insula, anterior and mid cingulate cortex. IBS-N showed decreasing BOLD response to repeated rectal distensions in brain regions including insula, prefrontal cortex and amygdala. CONCLUSIONS & INFERENCES: These findings are consistent with compromised ability of IBS-S to respond to repeated delivery of rectal stimuli, both in terms of sensitization of sensory pathways and habituation of emotional arousal. The fact that both IBS subgroups met Rome criteria, and did not differ in terms of reported symptom severity demonstrates that similar symptom patterns can result from different underlying neurobiological mechanisms.

Autonomic response to a visceral stressor is dysregulated in irritable bowel syndrome and correlates with duration of disease.

BACKGROUND: Previous studies reported altered autonomic nervous system (ANS) responses in irritable bowel syndrome (IBS) at baseline and to colonic balloon distension. This study examined heart rate variability (HRV) and plasma catecholamines as an index of ANS responsiveness in IBS during flexible sigmoidoscopy (FS) and explored associations of HRV with clinical measures. METHODS: Rome III-positive IBS patients and healthy controls completed questionnaires measuring gastrointestinal and psychological symptoms. Heart rate variability measures were calculated using electrocardiogram (ECG) data at rest and during FS. Plasma catecholamines were measured before and after the FS. Linear mixed effects models were used to compare HRV with IBS status and IBS duration across six time points. Significance was assessed at the 0.05 level. KEY RESULTS: Thirty-six IBS patients (53% F, mean age 37.89) and 31 controls (58% F, mean age 37.26) participated. After adjusting for age, sex, body mass index, and current anxiety symptoms, IBS patients had a non-significant lower cardiovagal tone (P = 0.436) and higher cardiosympathetic balance (P = 0.316) at rest. During FS, controls showed a transient increase in cardiosympathetic balance and decrease in cardiovagal tone. However, IBS patients had significantly less cardiosympathetic and cardiovagal responsiveness both leading up to (P = 0.003, P = 0.005) and following (P = 0.001) this stimulus. Those with longer duration of disease had less cardiosympathetic (P = 0.014) and cardiovagal (P = 0.009) responsiveness than those with shorter duration. No differences in catecholamines between IBS and controls were found. CONCLUSIONS & INFERENCES: Irritable bowel syndrome demonstrated dysregulated ANS responses to a visceral stressor which could be related to disease duration. Therefore, autonomic dysregulation is an objective physiologic correlate of IBS.

A combined nutrient and lactulose challenge test allows symptom-based clustering of patients with irritable bowel syndrome.

OBJECTIVES: The aim of the present pilot study was to evaluate the usefulness of a test meal containing lactulose in the non-invasive assessment of visceral sensitivity in irritable bowel syndrome (IBS), and to identify subsets of IBS patients based on gastrointestinal (GI) symptom generation. METHODS: We included 43 patients with IBS (Rome III) and 29 healthy controls. The fasted subjects were served three test meals consisting of a 400-ml liquid breakfast alone or containing lactulose (15 or 25 g) in a double-blind crossover design. Seven GI symptoms, overall digestive comfort, and exhaled H2/CH4 were assessed at baseline and every 15 min during 4 h after meal intake. Anxiety and depression were assessed only at baseline. A mapping of the seven GI symptoms was done using a Principal Component Analysis (4 h mean area under the curve, AUC). Independently, a hierarchical cluster analysis was performed on the same parameters to identify GI symptom-based IBS clusters. RESULTS: All three tests were well tolerated. The 25 g lactulose challenge enabled discrimination of IBS from healthy controls according to the symptom response. This challenge also enabled clustering of IBS subjects in two subgroups based mainly on bloating, distension, and discomfort symptoms (2,457 (2,043-2,872), 2,450 (1,910-2,990), 2,602 (2,126-3,079) vs. 537 (383-691), 619 (458-780), 643 (432-854); 4 h mean AUC; P<0.0001), overall digestive comfort (1807 (1318-2295) vs. 3350 (2942-3758); 4 h mean AUC; P<0.0001), and anxiety at baseline (9.2 (7.0-11.5) vs. 5.5 (4.2-6.9); Hospital Anxiety and Depression scale anxiety mean scores; P=0.003). This clustering was independent of the Rome III subtype and the amount of exhaled H2/CH4. CONCLUSIONS: The lactulose challenge test seems to be a promising tool to assess visceral sensitivity in IBS, and to subgroup IBS patients based on their symptom pattern.

Effect of hypnotherapy and educational intervention on brain response to visceral stimulus in the irritable bowel syndrome.

BACKGROUND: Gut-directed hypnotherapy can reduce IBS symptoms, but the mechanisms underlying this therapeutic effect remain unknown. AIM: To determine the effect of hypnotherapy and educational intervention on brain responses to cued rectal distensions in IBS patients. METHODS: Forty-four women with moderate-to-severe IBS and 20 healthy controls (HCs) were included. Blood oxygen level dependent (BOLD) signals were measured by functional Magnetic Resonance Imaging (fMRI) during expectation and delivery of high- (45 mmHg) and low-intensity (15 mmHg) rectal distensions. Twenty-five patients were assigned to hypnotherapy (HYP) and 16 to educational intervention (EDU). Thirty-one patients completed treatments and posttreatment fMRI. RESULTS: Similar symptom reduction was achieved in both groups. Clinically successful treatment (all responders) was associated with significant BOLD attenuation during high-intensity distension in the dorsal and ventral anterior insula (cluster size 142, P = 0.006, and cluster size 101, P = 0.005 respectively). Moreover HYP responders demonstrated a pre-post treatment BOLD attenuation in posterior insula (cluster sizes 59, P = 0.05) while EDU responders had a BOLD attenuation in prefrontal cortex (cluster size 60, P = 0.05). Pre-post differences for expectation conditions were almost exclusively seen in the HYP group. Following treatment, the brain response to distension was similar to that observed in HCs, suggesting that the treatment had a normalising effect on the central processing abnormality of visceral signals in IBS. CONCLUSIONS: The abnormal processing and enhanced perception of visceral stimuli in IBS can be normalised by psychological interventions. Symptom improvement in the treatment groups may be mediated by different brain mechanisms. CLINICAL TRIAL NUMBER: NCT01815164.

Randomised clinical trial: symptoms of the irritable bowel syndrome are improved by a psycho-education group intervention.

BACKGROUND: Evidence supports the effectiveness of cognitive behavioural approaches in improving the symptoms of the irritable bowel syndrome (IBS). Duration, cost and resistance of many patients towards a psychological therapy have limited their acceptance. AIM: To evaluate the effectiveness of a psycho-educational intervention on IBS symptoms. METHODS: Sixty-nine IBS patients (72% female) were randomised to an intervention or a wait-list control group. The IBS class consisted of education on a biological mind body disease model emphasising self-efficacy and practical relaxation techniques. RESULTS: Patients in the intervention showed significant improvement on GI symptom severity, visceral sensitivity, depression and QoL postintervention and most of these gains were maintained at 3-month follow-up (Hedge's g = -0.46-0.77). Moderated mediation analyses indicated change in anxiety, visceral sensitivity, QoL and catastrophising due to the intervention had moderate mediation effects (Hedge's g = -0.38 to -0.60) on improvements in GI symptom severity for patients entering the trial with low to average QoL. Also, change in GI symptom severity due to the intervention had moderate mediation effects on improvements in QoL especially in patients with low to average levels of QoL at baseline. Moderated mediation analyses indicated mediation was less effective for patients entering the intervention with high QoL. CONCLUSIONS: A brief psycho-educational group intervention is efficacious in changing cognitions and fears about the symptoms of the irritable bowel syndrome, and these changes are associated with clinically meaningful improvement in symptoms and quality of life. The intervention seems particularly tailored to patients with low to moderate quality of life baseline levels.

Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study.

BACKGROUND: Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P / neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS. AIM: To determine whether inhibition of the neurokinin-1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not. METHODS: Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross-over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed. RESULTS: Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus). CONCLUSIONS: Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.

Sex-related differences in prepulse inhibition of startle in irritable bowel syndrome (IBS).

Alterations in central networks involved in the regulation of arousal, attention, and cognition may be critical for irritable bowel syndrome (IBS) symptom maintenance and exacerbation. Differential sensitivities in these networks may underlie sex differences noted in IBS. The current study examined prepulse inhibition (PPI), a measure of sensorimotor gating, in male and female IBS patients. Relationships between PPI and symptom severity were examined, as well as potential menstrual status effects. Compared to healthy controls, male IBS patients had significantly reduced PPI; whereas female IBS patients (particularly naturally cycling women) had significantly enhanced PPI suggesting hypervigilance. Considering previously demonstrated sex-related differences in perceptual and brain imaging findings in IBS patients, the current findings suggest that different neurobiological mechanisms underlie symptom presentation in male and female IBS patients. Compromised filtering of information in male IBS patients may be due to compromised top down (prefrontal, midcingulate) control mechanisms while increased attention to threat due to increased limbic and paralimbic circuits may be characteristic of female IBS patients.

Measuring irritable bowel syndrome patient-reported outcomes with an abdominal pain numeric rating scale.

BACKGROUND: Controversy exists on how to measure patient-reported outcomes in irritable bowel syndrome (IBS) clinical trials effectively. Pain numeric rating scales (NRS) are widely used in the non-IBS pain literature. The Food and Drug Administration has proposed using the NRS in IBS. AIM: To test the psychometrics of an abdominal pain NRS in IBS. Methods We analysed data from a longitudinal cohort of Rome III IBS subjects. At entry, subjects completed a 10-point NRS, bowel symptoms, IBS severity measurements (IBS-SSS, FBDSI), health-related quality of life indices (IBS-QOL, EQ5D), and the Worker Productivity Activity Index (WPAI). We repeated assessments at 3 months along with a response scale to calculate the minimal clinically important difference. RESULTS: There were 277 subjects (82% women; age = 42 +/- 15) at baseline and 90 at 3 months. The NRS correlated cross-sectionally with IBS-SSS (r = 0.60; P < 0.0011), FBDSI (r = 0.49; P < 0.0001), IBS-QOL (r = 0.43; P < 0.0001), EQ5D (r = 0.48; P < 0.0001), presenteeism (r = 0.39; P < 0.0001), absenteeism (r = 0.17; P = 0.04) and distension (r = 0.46; P < 0.0001), but not stool frequency or form. The minimal clinically important difference was 2.2 points, correlating with a 29.5% reduction over time. CONCLUSIONS: An abdominal pain NRS exhibits excellent validity and can be readily interpreted with a minimal clinically important difference in patients with IBS. These data support the use of the NRS in IBS clinical trials.

Brain imaging approaches to the study of functional GI disorders: a Rome working team report.

Progresses in the understanding of human brain-gut interactions in health and disease have been limited by the lack of non-invasive techniques to study brain activity. The advent of neuroimaging techniques has made it possible not only to study the structure and function of the brain, but also to characterize signaling system underlying brain function. This article gives a brief overview of relevant functional neuroanatomy, and of the most commonly used brain imaging techniques. It summarizes published functional brain imaging studies using acute visceral stimulation of the oesophagus, stomach and colon in healthy control subjects and patients with functional GI disorders, and briefly discusses pertinent findings from these studies. The article concludes with a critical assessment of published studies, and with recommendations for improved study paradigms and analysis strategies.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.

Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study.

BACKGROUND: Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50-70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5-HT3R antagonist alosetron is correlated with reduced amygdala activity. AIM: To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with alosetron. METHODS: Basal psychological distress and neural activity (15O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of alosetron treatment. RESULTS: Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre-treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala. CONCLUSIONS: Irritable bowel disease symptom improvement with 5-HT3R antagonist alosetron is related to pre-treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome.