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Laura C Seidman,1 Catherine R Temme,1 Lonnie K Zeltzer,2 Andrea J Rapkin,3 Bruce D Naliboff,4 Laura A Payne1,5 1Division of Women’s Mental Health, McLean Hospital, Belmont, MA, USA; 2Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 4Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 5Department of Psychiatry, Harvard Medical School, Boston, MA, USACorrespondence: Laura C SeidmanMcLean Hospital, Mail Stop 306, 115 Mill Street, Belmont, MA 02478, USATel +1 617 855 2746Email LCSeidman@mclean.harvard.eduPurpose: Primary dysmenorrhea (PD; menstrual pain without an identified organic cause) has been proposed as a possible risk factor for the development of chronic pelvic pain, but the mechanism through which this process occurs is unknown. One possible mechanism is central sensitization – alterations in the central nervous system that increase responsiveness to pain leading to hypersensitivity. Repeated episodes of pain, such as those experienced over time with PD, may alter how the brain processes pain. Ecological momentary assessment (EMA; collection of data in real time in participants’ natural environments) is a novel data collection method that may help elucidate pain occurring during non-menstrual cycle phases.Patients and Methods: The current observational study assessed the feasibility and acceptability of using EMA via text messages to collect pelvic pain data during menstrual and non-menstrual cycle phases in a community sample of adolescents and young adults (AYA) aged 16– 24 years with and without PD and explored occurrence rates and intensity of non-menstrual pelvic pain (NMPP) in each of these groups.Results: Thirty-nine AYA with PD and 53 healthy controls reported pelvic pain level via nightly text message. Global response rate was 98.5%, and all participants reported that the EMA protocol was acceptable. AYA with PD reported higher intensity (2.0 vs 1.6 on 0– 10 numeric rating scale; p=0.003) and frequency (8.7% vs 3.1% of days; p=0.004) of NMPP compared to healthy controls.Conclusion: The EMA protocol was feasible and acceptable. Though both the intensity and frequency of NMPP were low and at levels that would not typically warrant clinical assessment or intervention, these repeated nociceptive events may represent a potential mechanism contributing to the transition from cyclical to chronic pelvic pain in some individuals.Keywords: ecological momentary assessment, primary dysmenorrhea, menstrual pain, adolescents and young adults, central sensitization

Subhadra Evans,1 Laura C Seidman,1 Jennie CI Tsao,1 Kirsten C Lung,1 Lonnie K Zeltzer,1 Bruce D Naliboff21Pediatric Pain Program, University of California, Los Angeles, CA, USA; 2Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USAAbstract: Studies in adults have demonstrated a relationship between lowered heart rate variability (HRV) and poor health. However, less is known about the role of autonomic arousal in children's well-being. The aim of the current study was to examine resting HRV in children with chronic pain compared to healthy control children and, further, to examine children's HRV following a series of acute experimental pain tasks in both groups. Participants included 104 healthy control children and 48 children with chronic pain aged 8–17 years. The laboratory session involved a 5-minute baseline electrocardiogram followed by four pain induction tasks: evoked pressure, cold pressor, focal pressure, and a conditioned pain modulation task. After the tasks were complete, a 5-minute post-task electrocardiogram recording was taken. Spectral analysis was used to capture high-frequency normalized power and the ratio of low-to-high frequency band power, signifying cardiac vagal tone and sympathetic balance, respectively. Results revealed that children with chronic pain had significantly lower resting HRV (signified by low high-frequency normalized power and high ratio of low-to-high frequency band power) compared to healthy children; moreover, a significant interaction between groups and time revealed that children with chronic pain displayed a static HRV response to the pain session compared to healthy children, whose HRV was reduced concomitant with the pain session. These findings suggest that children with chronic pain may have a sustained stress response with minimal variability in response to new acute pain stressors.Keywords: laboratory pain, pediatric pain, cold pressor, experimental pain, childhood pain, stress task

The use of opioid medications for treating chronic noncancer pain is growing; however, there is a lack of good evidence regarding their long-term effectiveness, association with substance abuse, and proper prescribing guidelines. The current study directly compares for the first time in a randomized trial the effectiveness of a conservative, hold the line (Stable Dose) prescribing strategy for opioid medications with a more liberal dose escalation (Escalating Dose) approach. This 2-arm, parallel, randomized pragmatic clinical trial followed 135 patients referred to a specialty pain clinic at a Veterans Affairs Hospital for 12 months (94% male and 74% with musculoskeletal pain). Primary outcomes included monthly or quarterly evaluations of pain severity, pain relief from medications, pain-related functional disability, and opioid misuse behaviors. All subjects received identical pain treatment except for the application of treatment group specific strategies for opioid prescriptions. No group differences were found for primary outcomes of usual pain or functional disability although the Escalating Dose group did show a small but significantly larger increase in self-rated pain relief from medications. About 27% of patients were discharged over the course of the study due to opioid misuse/noncompliance, but there were no group differences in rate of opioid misuse. PERSPECTIVE: The results of this study demonstrate that even in carefully selected patients there is a significant risk of problematic opioid misuse. Although in general there were no statistically significant differences in the primary outcomes between groups, the escalating dose strategy did lead to small improvements in self-reported acute relief from medications without an increase in opioid misuse, compared to the stable dose strategy. [ABSTRACT FROM AUTHOR]

Investigates the cardiovascular and cellular immune system responses of healthy young men during brief mental arithmetic stress. Effects of the opiate antagonist naloxone on measures of cellular immune system responses during rest and brief psychological stress; Role of endogenous opioidsin mediating immunological change to stress; Increase in natural killer cell activity during mental arithmetic.

This study introduces the Addiction Behaviors Checklist (ABC), which is a brief (20-item) instrument designed to track behaviors characteristic of addiction related to prescription opioid medications in chronic pain populations. Items are focused on observable behaviors noted both during and between clinic visits. One hundred thirty-six consecutive veterans in a multidisciplinary Veterans Affairs Chronic Pain Clinic who were receiving long-term opioid medication treatment were included in this study. This study represents one of the first to follow a sample of chronic pain patients on opioid therapy over time, using a structured assessment tool to evaluate and track behaviors suggestive of addiction. Interrater reliability and concurrent validity data are presented, as well as a cut-off score for use in determining inappropriate medication use. The psychometric findings support the ABC as a viable assessment tool that can increase a provider's confidence in determinations of appropriate vs. inappropriate opioid use. © 2006 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]

Abstract: Pain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been tested in clinical trials for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). We explored this hypothesis using data from 3 previously published trials testing treatments for IC/BPS, which suggested modest benefits but did not meet a priori primary outcome statistical significance criteria. Importantly, these studies also collected symptom questionnaire data that allowed us to retrospectively identify participants with and without widespread pain. Analyzing the treatment by the degree of widespread pain revealed a difference in outcome and statistical significance level for each trial. Participants with predominately local pain (ie, limited widespread pain symptoms) responded to therapy targeting local symptoms, whereas those with widespread pain did not. Alternatively, participants with widespread pain beyond their local pelvic pain responded to more centrally acting treatments. Our results suggest that differentiating patients based on widespread vs more localized pain is a key consideration for designing future clinical trials for conditions with variable pain profiles, such as IC/BPS and potentially other pain-based syndromic disorders., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background Brainstem nuclei play a critical role in both ascending monoaminergic modulation of cortical function and arousal, and in descending bulbospinal pain modulation. Even though sex-related differences in the function of both systems have been reported in animal models, a complete understanding of sex differences, as well as menopausal effects, in brainstem connectivity in humans is lacking. This study evaluated resting-state connectivity of the dorsal raphe nucleus (DRN), right and left locus coeruleus complex (LCC), and periaqueductal gray (PAG) according to sex and menopausal status in healthy individuals. In addition, relationships between systemic estrogen levels and brainstem-network connectivity were examined in a subset of participants. Methods Resting-state fMRI was performed in 50 healthy men (age, 31.2 ± 8.0 years), 53 healthy premenopausal women (age, 24.7 ± 7.3 years; 22 in the follicular phase, 31 in the luteal phase), and 20 postmenopausal women (age, 54.6 ± 7.2 years). Permutation Analysis of Linear Models (5000 permutations) was used to evaluate differences in brainstem-network connectivity according to sex and menopausal status, controlling for age. In 10 men and 17 women (9 premenopausal; 8 postmenopausal), estrogen and estrogen metabolite levels in plasma and stool were determined by liquid chromatography-mass spectrometry/mass spectrometry. Relationships between estrogen levels and brainstem-network connectivity were evaluated by partial least squares analysis. Results Left LCC-executive control network (ECN) connectivity showed an overall sex difference (p = 0.02), with higher connectivity in women than in men; however, this was mainly due to differences between men and pre-menopausal women (p = 0.008). Additional sex differences were dependent on menopausal status: PAG-default mode network (DMN) connectivity was higher in postmenopausal women than in men (p = 0.04), and PAG-sensorimotor network (SMN) connectivity was higher in premenopausal women than in men (p = 0.03) and postmenopausal women (p = 0.007). Notably, higher free 2-hydroxyestrone levels in stool were associated with higher PAG-SMN and PAG-DMN connectivity in premenopausal women (p < 0.01). Conclusions Healthy women show higher brainstem-network connectivity involved in cognitive control, sensorimotor function, and self-relevant processes than men, dependent on their menopausal status. Further, 2-hydroxyestrone, implicated in pain, may modulate PAG connectivity in premenopausal women. These findings may relate to differential vulnerabilities to chronic stress-sensitive disorders at different life stages.

Purpose: This study tested the hypothesis that ecological momentary assessment (EMA) of pelvic pain (PP) and urinary urgency (UU) would reveal unique Urologic Chronic Pelvic Pain Syndrome (UCPPS) phenotypes that would be associated with disease specific quality of life (QOL) and illness impact metrics (IIM)., Materials and Methods: A previously validated smart phone app (M-app) was provided to willing Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) participants. M-app notifications were sent 4-times daily for 14 days inquiring about PP and UU severity. A clustering algorithm that accounted for variance placed participants into PP and UU variability? clusters. Associations between clusters and QOL and IIM were then determined., Results: A total of 204 participants enrolled in the M-app study (64% female). M-app compliance was high (median 63% of surveys). Cluster analysis revealed k = 3 (high, low, none) PP clusters and k = 2 (high, low) UU clusters. When adjusting for baseline pain severity, high PP variability, but not UU variability, was strongly associated with QOL and IIM; specifically worse mood, worse sleep and higher anxiety. UU and PP clusters were associated with each other (p < 0.0001), but a large percentage (33%) of patients with high PP variability had low UU variability., Conclusions: PP variability is an independent predictor of worse QOL and more severe IIM in UCPPS participants after controlling for baseline pain severity and UU. These findings suggest alternative pain indices, such as pain variability and unpredictability, may be useful adjuncts to traditional measures of worst and average pain when assessing UCPPS treatment responses., (© 2024 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Purpose: Urologic chronic pelvic pain syndrome (UCPPS), which encompasses interstitial cystitis/bladder pain syndrome in women and men and chronic prostatitis/chronic pelvic pain syndrome in men, is a common, often disabling urological disorder that is neither well understood nor satisfactorily treated with medical treatments. The past 25 years have seen the development and validation of a number of behavioral pain treatments, of which cognitive behavioral therapy (CBT) is arguably the most effective. CBT combines strategies of behavior therapy, which teaches patients more effective ways of behaving, and cognitive therapy, which focuses on correcting faulty thinking patterns. As a skills-based treatment, CBT emphasizes "unlearning" maladaptive behaviors and thoughts, and replacing them with more adaptive ones that support symptom self-management., Materials and Methods: This review describes the rationale, technical procedures, and empirical basis of CBT., Results: While evidence supports CBT for treatment-refractory chronic pain disorders, there is limited understanding of why or how CBT might work, for whom it is most beneficial, or the specific UCPPS symptoms (eg, pain, urinary symptoms) it effectively targets. This is the focus of EPPIC (Easing Pelvic Pain Interventions Clinical Research Program), a landmark NIH trial examining the efficacy of low-intensity, home-based CBT for UCPPS relative to a nonspecific comparator featuring self-care recommendations of AUA guidelines., Conclusions: Systematic efforts to increase both the efficiency of CBT and the way it is delivered (eg, home-based treatments) are critical to scaling up CBT, optimizing its therapeutic potential, and reducing the public health burden of UCPPS.

Purpose: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only., Materials and Methods: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site., Results: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations., Conclusions: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes., (© 2024 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: Stress reactivity (SR) is associated with increased risk of flares in ulcerative colitis (UC) patients. Because both preclinical and clinical data support that stress can influence gut microbiome composition and function, we investigated whether microbiome profiles of SR exist in UC., Methods: Ninety-one UC subjects in clinical and biochemical remission were classified into high and low SR groups by questionnaires. Baseline and longitudinal characterization of the intestinal microbiome was performed by 16S rRNA gene sequencing and fecal and plasma global untargeted metabolomics. Microbe, fecal metabolite, and plasma metabolite abundances were analyzed separately to create random forest classifiers for high SR and biomarker-derived SR scores., Results: High SR reactivity was characterized by altered abundance of fecal microbes, primarily in the Ruminococcaceae and Lachnospiraceae families; fecal metabolites including reduced levels of monoacylglycerols (endocannabinoid-related) and bile acids; and plasma metabolites including increased 4-ethyl phenyl sulfate, 1-arachidonoylglycerol (endocannabinoid), and sphingomyelin. Classifiers generated from baseline microbe, fecal metabolite, and plasma metabolite abundance distinguished high vs low SR with area under the receiver operating characteristic curve of 0.81, 0.83, and 0.91, respectively. Stress reactivity scores derived from these classifiers were significantly associated with flare risk during 6 to 24 months of follow-up, with odds ratios of 3.8, 4.1, and 4.9. Clinical flare and intestinal inflammation did not alter fecal microbial abundances but attenuated fecal and plasma metabolite differences between high and low SR., Conclusions: High SR in UC is characterized by microbial signatures that predict clinical flare risk, suggesting that the microbiome may contribute to stress-induced UC flares., (Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation 2023.)

Background: Patients with irritable bowel syndrome (IBS) show lower resilience than healthy controls (HCs), associated with greater symptom severity and worse quality of life. However, little is known about affected markers of resilience or the influence of sex. Furthermore, as resilience is complex, a comprehensive assessment, with multiple resilience measures, is needed. Therefore, we aimed to evaluate perceived and relative resilience and their neural correlates in men and women with IBS., Methods: In 402 individuals (232 IBS [73.3% women] and 170 HCs [61.2% women]), perceived resilience was assessed by the Connor-Davidson Resilience Scale (CDRISC) and Brief Resilience Scale (BRS); relative resilience was assessed by the standardized residual of the Short Form-12 mental component summary score predicted by the Adverse Childhood Experiences score. Non-rotated partial least squares analysis of region-to-region resting-state connectivity data was used to define resilience-related signatures in HCs. Disease and sex-related differences within these signatures were investigated., Key Results: Scores on all resilience measures were lower in IBS than in HCs (p's < 0.05). In all three resilience-related signatures, patients with IBS showed reduced connectivity largely involving the central autonomic network (p's < 0.001). Men with IBS showed lower CDRISC scores than women with IBS, and greater reductions in CDRISC-related connectivity, associated with worse symptom severity (p < 0.05)., Conclusions and Inferences: Individuals with IBS show reduced perceived and relative resilience, with reduced connectivity suggesting impaired homeostasis maintenance. Men with IBS may show additional impairment in specific aspects of resilience. Treatments aimed at improving resilience may benefit patients with IBS, especially men with IBS., (© 2023 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Abstract: Pain with bladder filling remains an unexplained clinical presentation with limited treatment options. Here, we aim to establish the clinical significance of bladder filling pain using a standardized test and the associated neural signature. We studied individuals diagnosed with urologic chronic pelvic pain syndrome (UCPPS) recruited as part of the multidisciplinary approach to the study of chronic pelvic pain (MAPP) study. Patients with urologic chronic pelvic pain syndrome (N = 429) and pain-free controls (N = 72) underwent a test in which they consumed 350 mL of water and then reported pain across an hour-long period at baseline and 6 months. We used latent class trajectory models of these pain ratings to define UCPPS subtypes at both baseline and 6 months. Magnetic resonance imaging of the brain postconsumption was used to examine neurobiologic differences between the subtypes. Healthcare utilization and symptom flare-ups were assessed over the following 18 months. Two distinct UCPPS subtypes were identified, one showing substantial pain related to bladder filling and another with little to no pain throughout the test. These distinct subtypes were seen at both baseline and 6 month timepoints. The UCPPS subtype with bladder-filling pain (BFP+) had altered morphology and increased functional activity in brain areas involved in sensory and pain processing. Bladder-filling pain positive status predicted increased symptom flare-ups and healthcare utilization over the subsequent 18 months when controlling for symptom severity and a self-reported history of bladder-filling pain. These results both highlight the importance of assessing bladder filling pain in heterogeneous populations and demonstrate that persistent bladder-filling pain profoundly affects the brain., (Copyright © 2023 International Association for the Study of Pain.)

Background: Living in a disadvantaged neighborhood is associated with worse health outcomes, including brain health, yet the underlying biological mechanisms are incompletely understood. We investigated the relationship between neighborhood disadvantage and cortical microstructure, assessed as the T1-weighted/T2-weighted ratio (T1w/T2w) on magnetic resonance imaging, and the potential mediating roles of body mass index (BMI) and stress, as well as the relationship between trans-fatty acid intake and cortical microstructure., Methods: Participants comprised 92 adults (27 men; 65 women) who underwent neuroimaging and provided residential address information. Neighborhood disadvantage was assessed as the 2020 California State area deprivation index (ADI). The T1w/T2w ratio was calculated at four cortical ribbon levels (deep, lower-middle, upper-middle, and superficial). Perceived stress and BMI were assessed as potential mediating factors. Dietary data was collected in 81 participants., Results: Here, we show that worse ADI is positively correlated with BMI (r = 0.27, p = .01) and perceived stress (r = 0.22, p = .04); decreased T1w/T2w ratio in middle/deep cortex in supramarginal, temporal, and primary motor regions (p < .001); and increased T1w/T2w ratio in superficial cortex in medial prefrontal and cingulate regions (p < .001). Increased BMI partially mediates the relationship between worse ADI and observed T1w/T2w ratio increases (p = .02). Further, trans-fatty acid intake (high in fried fast foods and obesogenic) is correlated with these T1w/T2w ratio increases (p = .03)., Conclusions: Obesogenic aspects of neighborhood disadvantage, including poor dietary quality, may disrupt information processing flexibility in regions involved in reward, emotion regulation, and cognition. These data further suggest ramifications of living in a disadvantaged neighborhood on brain health., (© 2023. Springer Nature Limited.)

Abstract: Urologic chronic pelvic pain syndrome (UCPPS) is a complex, debilitating condition in which patients often report nonpelvic pain in addition to localized pelvic pain. Understanding differential predictors of pelvic pain only vs widespread pain may provide novel pathways for intervention. This study leveraged baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network's Symptom Pattern Study to investigate the impact of childhood sexual and nonsexual violent trauma on pelvic and nonpelvic pain sensitivity among adult patients with UCPPS, as well as potential mediators of this association. Study participants who met inclusion criteria for UCPPS completed questionnaires assessing childhood and recent trauma, affective distress, cognitive dysfunction, and generalized sensory sensitivity. Experimental pain sensitivity was also evaluated using standardized pressure pain applied to the pubic region and the arm. Bivariate analyses showed that childhood violent trauma was associated with more nonviolent childhood trauma, more recent trauma, poorer adult functioning, and greater pain sensitivity at the pubic region, but not pain sensitivity at the arm. Path analysis suggested that childhood violent trauma was indirectly associated with pain sensitivity at both sites and that this indirect association was primarily mediated by generalized sensory sensitivity. More experiences of recent trauma also contributed to these indirect effects. The findings suggest that, among participants with UCPPS, childhood violent trauma may be associated with heightened pain sensitivity to the extent that trauma history is associated with a subsequent increase in generalized sensory sensitivity., (Copyright © 2023 International Association for the Study of Pain.)

The Specialized Center of Research Excellence (SCORE) on sex differences at University of California, Los Angeles (UCLA) has a long track record studying bidirectional interactions between different organs and the brain in health and disease with a strong focus on sex as a biological variable (SABV). While the initial focus was on brain-gut interactions in irritable bowel syndrome (IBS), one of the most common disorders of gut-brain interaction, the scope of our Center's research has expanded to a range of different diseases, including inflammatory bowel disease, alcohol use disorder, obesity, urological chronic pelvic pain syndrome, and vulvodynia. This expansion of research focused on the role of brain-body and brain-gut microbiome interactions in these various disorders, aligning well with the increasing importance of multidisciplinary and interdisciplinary team science. The SCORE's Career Enhancement Core (CEC) has modeled team science as applied to SABV research, with educational and training opportunities, a mentoring program, seed grant funding, and other career development experiences that enable mentees to work across the disciplines involved in brain body research. The CEC goals are: (1) To provide seed grant funds for innovative research relevant to the overall SCORE mission and research program; (2) to recruit and foster the career development of students, trainees, and junior investigators who conduct research focused on sex differences or women's health in IBS and chronic constipation and other brain-gut disorders; (3) to facilitate and promote collaboration between the UCLA SCORE and other academic programs involved in women's health education and research; and (4) to promote the importance of SABV through community outreach using collaborative and innovative approaches. These goals focus on establishing the leading research center in sex differences in basic, translational, and clinical aspects of brain-body interactions and on providing women and underrepresented individuals with research opportunities needed to become independent investigators.

Both early (ELA) and recent life adversity (RLA) have been linked with chronic pain conditions and persistent alterations of neuroendocrine and inflammatory responses. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic urologic disorder characterized by bladder and/or pelvic pain, and excessive urinary frequency and/or urgency. IC/BPS has been associated with high levels of ELA as well as a distinct inflammatory signature. However, associations between ELA and RLA with inflammatory mechanisms in IC/BPS that might underlie the link between adversity and symptoms have not been examined. Here we investigated ELA and RLA in women with IC/BPS as potential risk factors for inflammatory processes and hypothalamic-pituitaryadrenal (HPA) abnormalities using data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Women with IC/BPS and healthy controls (n = 154 and 32, respectively) completed surveys, collected salivary cortisol at awakening and bedtime for 3 days, and gave a blood sample which was analyzed for 7 LPS-stimulated cytokines and chemokines (IL-6, TNFα, IL-1β, MIP1α, MCP1, IL-8, and IL-10). Two cytokine/chemokine composites were identified using principal components analysis. Patients with greater exposure to RLA or cumulative ELA and RLA of at least moderate severity showed elevated levels of a composite of all cytokines, adjusting for age, body mass index, and study site. Furthermore, there was a trending relationship between ELA and the pro-inflammatory composite score. Nocturnal cortisol and cortisol slope were not associated with ELA, RLA, or inflammation. The present findings support the importance of adverse events in IC/BPS via a biological mechanism and suggest that ELA and RLA should be assessed as risk factors for inflammation as part of a clinical workup for IC/BPS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Symptom heterogeneity in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively termed urological chronic pelvic pain syndrome, has resulted in difficulty in defining appropriate clinical trial endpoints. We determine clinically important differences for 2 primary symptom measures, pelvic pain severity and urinary symptom severity, and evaluate subgroup differences., Materials and Methods: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study enrolled individuals with urological chronic pelvic pain syndrome. We defined clinically important differences by associating changes in pelvic pain severity and urinary symptom severity over 3 to 6 months with marked improvement on a global response assessment using regression and receiver operating characteristic curves. We evaluated clinically important differences for absolute and percent change and examined differences in clinically important differences by sex-diagnosis, presence of Hunner lesions, pain type, pain widespreadness, and baseline symptom severity., Results: An absolute change of -4 was clinically important in pelvic pain severity among all patients, but clinically important difference estimates differed by pain type, presence of Hunner lesions, and baseline severity. Pelvic pain severity clinically important difference estimates for percent change were more consistent across subgroups and ranged from 30% to 57%. The absolute change urinary symptom severity clinically important difference was -3 for female participants and -2 for male participants with chronic prostatitis/chronic pelvic pain syndrome only. Patients with greater baseline severity required larger decreases in symptoms to feel improved. Estimated clinically important differences had lower accuracy among participants with low baseline symptoms., Conclusions: A reduction of 30%-50% in pelvic pain severity is a clinically meaningful endpoint for future therapeutic trials in urological chronic pelvic pain syndrome. Urinary symptom severity clinically important differences are more appropriately defined separately for male and female participants.

Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is thought to involve alterations in the gut microbiome, but robust microbial signatures have been challenging to identify. As prior studies have primarily focused on composition, we hypothesized that multi-omics assessment of microbial function incorporating both metatranscriptomics and metabolomics would further delineate microbial profiles of IBS and its subtypes., Methods: Fecal samples were collected from a racially/ethnically diverse cohort of 495 subjects, including 318 IBS patients and 177 healthy controls, for analysis by 16S rRNA gene sequencing (n = 486), metatranscriptomics (n = 327), and untargeted metabolomics (n = 368). Differentially abundant microbes, predicted genes, transcripts, and metabolites in IBS were identified by multivariate models incorporating age, sex, race/ethnicity, BMI, diet, and HAD-Anxiety. Inter-omic functional relationships were assessed by transcript/gene ratios and microbial metabolic modeling. Differential features were used to construct random forests classifiers., Results: IBS was associated with global alterations in microbiome composition by 16S rRNA sequencing and metatranscriptomics, and in microbiome function by predicted metagenomics, metatranscriptomics, and metabolomics. After adjusting for age, sex, race/ethnicity, BMI, diet, and anxiety, IBS was associated with differential abundance of bacterial taxa such as Bacteroides dorei; metabolites including increased tyramine and decreased gentisate and hydrocinnamate; and transcripts related to fructooligosaccharide and polyol utilization. IBS further showed transcriptional upregulation of enzymes involved in fructose and glucan metabolism as well as the succinate pathway of carbohydrate fermentation. A multi-omics classifier for IBS had significantly higher accuracy (AUC 0.82) than classifiers using individual datasets. Diarrhea-predominant IBS (IBS-D) demonstrated shifts in the metatranscriptome and metabolome including increased bile acids, polyamines, succinate pathway intermediates (malate, fumarate), and transcripts involved in fructose, mannose, and polyol metabolism compared to constipation-predominant IBS (IBS-C). A classifier incorporating metabolites and gene-normalized transcripts differentiated IBS-D from IBS-C with high accuracy (AUC 0.86)., Conclusions: IBS is characterized by a multi-omics microbial signature indicating increased capacity to utilize fermentable carbohydrates-consistent with the clinical benefit of diets restricting this energy source-that also includes multiple previously unrecognized metabolites and metabolic pathways. These findings support the need for integrative assessment of microbial function to investigate the microbiome in IBS and identify novel microbiome-related therapeutic targets. Video Abstract., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To characterize Urologic Chronic Pelvic Pain Syndrome (UCPPS) pain and urinary symptom trajectories with up to 9 years of follow-up and evaluate whether initial 1-year trajectories are associated with longer-term changes., Materials and Methods: Data were analyzed from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Network's prospective observational protocols including the Epidemiology and Phenotyping Study (EPS; baseline to Year 1), EPS Extension (EXT; Years 1-5), and Symptom Patterns Study (SPS: 3-year study; Years 3-9). Adults with Interstitial Cystitis/Bladder Pain Syndrome or Chronic Prostatitis/Chronic Pelvic Pain Syndrome provided patient-reported assessments biweekly (EPS), every 4 months (EXT), or quarterly (SPS). Primary outcomes were composite pain (0-28) and urinary (0-25) severity scores. Multi-phase mixed effects models estimated outcomes over time, adjusted for baseline severity and stratified by EPS symptom trajectory., Results: 163 participants (52% women; mean ± SD age 46.4 ± 16.1 years) completed EPS and enrolled in EXT; 67 also enrolled in SPS. Median follow-up was 4.6 years (range 1.3-9.0). After 1 year: 27.6%, 44.8% and 27.6% and 27.0%, 38.0% and 35.0% were improved, stable or worse in pain and urinary symptom severity, respectively. On average, pain and urinary symptom scores did not change further during EXT and SPS periods., Conclusions: Women and men with UCPPS showed remarkable stability in pain and urinary symptom severity for up to 9 years, irrespective of their initial symptom trajectory, suggesting UCPPS is a chronic condition with stable symptoms over multiple years of follow-up., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Urologic chronic pelvic pain syndrome (UCPPS) encompasses several common, costly, diagnoses including interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome that are poorly understood and inadequately treated with conventional medical therapies. Behavioral strategies, recommended as a first-line treatment for managing symptoms, are largely inaccessible, time and labor intensive, and technically complex. The Easing Pelvic Pain Interventions Clinical Research Program (EPPIC) is a clinical trial examining the efficacy of low-intensity cognitive behavioral therapy (Minimal Contact CBT or MC-CBT) for UCPPS and its durability 3 and 6 months post treatment. Additional aims include characterizing the operative processes (e.g., cognitive distancing, context sensitivity, coping flexibility, repetitive negative thought) that drive MC-CBT-induced symptom relief and pre-treatment patient variables that moderate differential response., Methods: UCPPS patients (240) ages 18-70 years, any gender, ethnicity, and race, will be randomized to 4-session MC-CBT or a credible, non-specific education comparator (EDU) that controls for the generic effects from simply going to treatment. Efficacy assessments will be administered at pre-treatment, 2 weeks, and 3 and 6 months post treatment-week acute phase. A novel statistical approach applied to micro-analytic mediator assessment schedule will permit the specification of the most effective CBT component(s) that drive symptom relief., Discussion: Empirical validation of a low-intensity self-management therapy transdiagnostic in scope has the potential to improve the health of chronic pelvic pain patients refractory to medical therapies, reduce social and economic costs, conserve health care resources, as well as inform evidence-based practice guidelines. Identification of change mechanisms and moderators of treatment effects can provide proactive patient-treatment matching fundamental to goals of personalized medicine., Trial Registration: Clinicaltrials.gov NCT05127616. Registered on 9/19/21., (© 2022. The Author(s).)

Introduction: There has been a sparse exploration of the lived experience of men with urologic chronic pelvic pain syndrome (UCPPS), and none with the goal of Investigating the experience of "flares" as part of this chronic pain syndrome in men., Methods: We conducted three focus groups of male UCPPS patients at two sites of the MAPP Research Network (n = 16 total participants) to explore the full spectrum of flares and their impact on men's lives., Results: Flare experiences were common and specific symptom components varied widely. Men reported nonpelvic symptoms (e.g., diarrhea), and variability in symptom intensity (mild to severe), duration (minutes to days), and frequency of flares. Flares episodes, and the threat of flares, were disruptive to their lives, social roles, and relationships. Distinct long-term impacts were reported, such as decreased sexual activity, decreased travel, and potential loss of employment or career. The themes included social isolation and the need for a sense of control and understanding over their unpredictable symptoms., Conclusions: Given their negative impact, future research with men and UCPPS should focus on approaches to prevent flares, and should consider a multimodal approach to reducing the frequency, severity, and/or duration. Quality of life may be improved by providing men with a sense of control over their symptoms and offering them multimodal treatment options, consistent with the recommendations for further research for women with UCPPS., (© 2022 Wiley Periodicals LLC.)

This study tested the novel hypothesis that CBT-treated IBS patients who learn to self-manage painful GI symptoms by targeting rigid cognitive style show improvement in cognitive flexibility, GI symptoms (e.g., abdominal pain), and quality of life. Participants included 130 Rome-III diagnosed IBS patients (M age = 40.3, F = 83%) with moderate-to-severe symptoms randomly assigned to either cognitive behavioral therapy (CBT; N = 86) or a nonspecific education/support (EDU) comparator (N = 44). Participants completed an assessment battery at baseline and post-treatment 2 weeks after 10-week acute treatment phase. Measures included cognitive flexibility, psychological flexibility, emotion regulation strategies, IBS symptom severity, quality of life (QOL), and distress. CBT but not EDU patients showed significant GI sympton improvement from baseline to post-treatment in cognitive flexibility. For CBT patients, changes in cognitive flexibility were significantly associated with changes in IBS symptom severity, abdominal pain, and IBS QOL. Neither condition showed significant changes in psychological flexibility (Acceptance and Action Questionnaire-II) or use of emotion regulation strategies (Emotion Regulation Questionnaire). The ability to self-manage painful IBS symptoms refractory to conventional medical and dietary treatments is related to the ability to respond flexibly across shifting contexts using cognitive change procedures featured in CBT for IBS., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Materials and Methods: A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity., Results: PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Conclusions: Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.

Irritable bowel syndrome (IBS) is a common disorder of brain-gut interactions characterized by chronic abdominal pain, altered bowel movements, often accompanied by somatic and psychiatric comorbidities. We aimed to test the hypothesis that a baseline phenotype composed of multi-modal neuroimaging and clinical features predicts clinical improvement on the IBS Symptom Severity Scale (IBS-SSS) at 3 and 12 months without any targeted intervention. Female participants (N = 60) were identified as "improvers" (50-point decrease on IBS-SSS from baseline) or "non-improvers." Data integration analysis using latent components (DIABLO) was applied to a training and test dataset to determine whether a limited number of sets of multiple correlated baseline'omics data types, including brain morphometry, anatomical connectivity, resting-state functional connectivity, and clinical features could accurately predict improver status. The derived predictive models predicted improvement status at 3-months and 12-months with 91% and 83% accuracy, respectively. Across both time points, non-improvers were classified as having greater correlated morphometry, anatomical connectivity and resting-state functional connectivity characteristics within salience and sensorimotor networks associated with greater pain unpleasantness, but lower default mode network integrity and connectivity. This suggests that non-improvers have a greater engagement of attentional systems to perseverate on painful visceral stimuli, predicting IBS exacerbation. The ability of baseline multimodal brain-clinical signatures to predict symptom trajectories may have implications in guiding integrative treatment in the age of precision medicine, such as treatments targeted at changing attentional systems such as mindfulness or cognitive behavioral therapy., (© 2021. The Author(s).)

Objective: To examine how often urologic chronic pelvic pain syndrome (UCPPS) patients progressed from Pelvic Pain Only at baseline to Widespread Pain, or vice versa, during 1-year longitudinal follow-up., Methods: Men and women with UCPPS enrolled in the MAPP-I Epidemiology and Phenotyping Study completed a self-report body map to indicate their locations of pain every 2 months over 12 months. Patients were categorized at each assessment into one of three pain phenotypes: (1) Pelvic Pain Only, (2) an Intermediate group, (3) Widespread Pain. Only patients who completed 3 or more follow-ups were included in this longitudinal analysis. The primary outcome measure was pain classification at the majority (≥60%) of follow-up assessments. Longitudinal trends of somatic symptom burden were also assessed., Results: Among the 93 UCPPS participants with Pelvic Pain Only at baseline, only 2% (n = 2) showed a Widespread Pain phenotype for the majority of assessments over 12 months. Among the 121 participants who had Widespread Pain at baseline, 6% (n = 7) demonstrated Pelvic Pain Only for the majority of assessments over 12 months. Over half of participants (≥53%) stayed in their baseline phenotypic group. Somatic symptom burden remained stable over 12 months for each of the groups with high intra-class correlation coefficient (0.67 to 0.82)., Conclusion: It was uncommon for UCPPS patients to progress from Pelvic Pain Only to Widespread Pain, or vice versa, over 12 months. These data suggest that Pelvic Pain Only and Widespread Pain are distinct UCPPS phenotypes that are relatively stable over 12 months of follow up., (Copyright © 2021. Published by Elsevier Inc.)

Background & Aims: Resilience is the ability to adapt positively to stress and adversity. It is a potential therapeutic target as it is reduced in irritable bowel syndrome (IBS) compared to healthy controls and associated with worse symptom severity and poorer quality of life. The aim of this study was to examine if these findings are generalizable by comparing resilience between IBS versus the general population and other chronic gastrointestinal (GI) conditions., Methods: Participants in the general population completed an online survey containing questionnaires measuring demographics, diagnosis of IBS and other GI conditions, symptom severity, psychological symptoms, resilience, and early adverse life events (EALs). IBS was defined as having a physician diagnosis of IBS and/or meeting Rome criteria without co-morbid GI disease. All others were included in the general population group. The chronic GI conditions group included those with inflammatory bowel disease, celiac disease and/or microscopic colitis., Results: Resilience was lower in IBS (n = 820) than the general population (n = 1026; p < 0.001) and associated with worse IBS symptom severity (p < 0.05). Global mental health affected resilience differently in IBS compared to the general population (all p's < 0.05). EALs were associated with decreased ability to bounce back from adversity in both IBS and the general population (p < 0.001). Resilience scores were similar in IBS and other chronic GI conditions that present with similar symptoms., Conclusions: Resilience is lower compared to the general U.S. population but does not appear to be specific to IBS as it is comparable to other chronic GI conditions. Low resilience negatively affects symptom severity and mental health and thus, may serve as a novel therapeutic target., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: There is growing recognition that bidirectional signaling between the digestive tract and the brain contributes to irritable bowel syndrome (IBS). We recently showed in a large randomized controlled trial that cognitive behavioral therapy (CBT) reduces IBS symptom severity. This study investigated whether baseline brain and gut microbiome parameters predict CBT response and whether response is associated with changes in the brain-gut-microbiome (BGM) axis., Methods: Eighty-four Rome III-diagnosed IBS patients receiving CBT were drawn from the Irritable Bowel Syndrome Outcome Study (IBSOS; ClinicalTrials.gov NCT00738920) for multimodal brain imaging and psychological assessments at baseline and after study completion. Fecal samples were collected at baseline and post-treatment from 34 CBT recipients for 16S rRNA gene sequencing, untargeted metabolomics, and measurement of short-chain fatty acids. Clinical measures, brain functional connectivity and microstructure, and microbiome features associated with CBT response were identified by multivariate linear and negative binomial models., Results: At baseline, CBT responders had increased fecal serotonin levels, and increased Clostridiales and decreased Bacteroides compared to non-responders. A random forests classifier containing 11 microbial genera predicted CBT response with high accuracy (AUROC 0.96). Following treatment, CBT responders demonstrated reduced functional connectivity in regions of the sensorimotor, brainstem, salience, and default mode networks and changes in white matter in the basal ganglia and other structures. Brain changes correlated with microbiome shifts including Bacteroides expansion in responders., Conclusions: Pre-treatment intestinal microbiota and serotonin levels were associated with CBT response, suggesting that peripheral signals from the microbiota can modulate central processes affected by CBT that generate abdominal symptoms in IBS. CBT response is characterized by co-correlated shifts in brain networks and gut microbiome that may reflect top-down effects of the brain on the microbiome during CBT. Video abstract., (© 2021. The Author(s).)

Purpose: We sought to determine the time-lagged, bidirectional relationships among clinical variables of pelvic pain, urinary symptoms, negative mood, nonpelvic pain and quality of life in men and women with urological chronic pelvic pain syndrome, incorporating interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Materials and Methods: A total of 204 female and 166 male patients were assessed up to 24 times over a 48-week period on the 5 primary outcomes. A lagged autoregressive analysis was applied to determine the directional relationship of one variable to another 2 weeks later, beyond that of the concurrent relationships at each time point and autocorrelations and trends over time., Results: The results show clear evidence for a bidirectional positive relationship between changes in pelvic pain severity and urinary symptom severity. Increases in either variable predicted significant increases in the other 2 weeks later, beyond that explained by their concurrent relationship at each time point. Pelvic pain and to a lesser degree urinary frequency also showed similar bidirectional relationships with negative mood and decreased quality of life. Interestingly, neither pelvic pain or urinary symptom severity showed lagged relationships with nonpelvic pain severity., Conclusions: Results document for the first time specific short-term positive feedback between pelvic pain and urinary symptoms, and between symptoms of urological chronic pelvic pain syndrome, mood and quality of life. The feedforward aspects of these relationships can facilitate a downward spiral of increased symptoms and worsening psychosocial function, and suggest the need for multifaceted treatments and assessment to address this possibility in individual patients.

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.

Background: Irritable bowel syndrome (IBS) is a common and often debilitating chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Pharmacological treatments are often ineffective, leading to the development of a variety of behavioral interventions. Mindfulness-based stress reduction (MBSR) is one such program that has shown efficacy in reducing gastrointestinal (GI) symptoms and improving quality of life (QOL). This single-arm intervention study examines the association of clinical outcomes with changes in specific aspects of mindfulness., Methods: Adults with IBS (53 women, 15 men) participated in an 8-week MBSR class. Primary outcomes of GI symptom severity, quality of life, and GI-specific anxiety, as well as specific aspects of mindfulness using the Five Factor Mindfulness Questionnaire (FFMQ), were assessed at baseline, post-treatment, and 6-month follow-up., Key Results: Gastrointestinal symptom responder rate was 71%, and there was a significant pre-post treatment change for three of the five FFMQ scales. Regression analysis indicated that change in the Act with Awareness (P = .02) facet of mindfulness was the strongest predictor of GI symptom and QOL improvement., Conclusions & Inferences: Mindfulness-based stress reduction training was associated with robust improvements in GI symptoms and associated problems in participants with IBS. Although significant increases in 3 of the 5 measured facets of mindfulness were found, regression analyses suggest that increases in the ability to retain present moment focus and act with awareness may be particularly important for improving outcomes in individuals with IBS. These results may inform the refinement of mindfulness-based protocols specifically for treatment of IBS., (© 2020 John Wiley & Sons Ltd.)

Background: Bilateral cardiac sympathetic denervation (BCSD) is an effective therapy for ventricular arrhythmias (VAs) in cardiomyopathies (CMPs). After BCSD, residual autonomic nervous system (ANS) function is unknown., Objective: The purpose of this study was to assess ANS responses in patients with CMP before and after BCSD as compared with demographically matched healthy controls., Methods: Patients with CMP undergoing BCSD and matched healthy controls were recruited. Noninvasive measures-finger cuff beat-to-beat blood pressure (BP), electrocardiography, palmar electrodermal activity (EDA), and finger pulse volume (FPV)-were obtained at rest and during autonomic stressors-posture change, handgrip, and mental stress. Maximal as well as specific responses to stressors were compared., Results: Eighteen patients with CMP (mean age 54 ± 14 years; 16 men, 89%; left ventricular ejection fraction 36% ± 14%) with refractory VAs and 8 matched healthy controls were studied; 9 patients with CMP underwent testing before and after (median 28 days) BCSD, with comparable ongoing medication. Before BCSD, patients with CMP (n = 13) had lower resting systolic BP and FPV than did healthy controls (P < .01). Maximal FPV and systolic BP reflex responses, expressed as percent change were similar, while diastolic BP, mean BP, and EDA responses were blunted. After BCSD, resting measurements were unchanged relative to presurgical baseline (n = 9). EDA responses to stressors were abolished, confirming BCSD, while maximal FPV and BP responses were preserved. Diastolic BP, mean BP, and FPV responses to orthostatic challenge pointed toward a better tolerance of active standing after BCSD as compared with before. Responses to other stressors remained unchanged., Conclusion: Patients with CMP and refractory VAs on optimal medical therapy have detectable but blunted adrenergic responses, which are not disrupted by BCSD., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network initiated a second observational cohort study-the Symptom Patterns Study (SPS)-to further investigate the underlying pathophysiology of Urologic Chronic Pelvic Pain Syndrome (UCPPS) and to discover factors associated with longitudinal symptom changes and responses to treatments., Methods: This multisite cohort study of males and females with UCPPS features a run-in period of four weekly web-based symptom assessments before a baseline visit, followed by quarterly assessments up to 36 months. Controls were also recruited and assessed at baseline and 6 months. Extensive clinical data assessing urological symptoms, nonurological pain, chronic overlapping pain syndromes, and psychosocial factors were collected. Diverse biospecimens for biomarker and microbiome studies, quantitative sensory testing (QST) data under multiple stimuli, and structural and functional neuroimaging scans were obtained under a standardized protocol., Results: Recruitment was initiated (July 2015) and completed (February 2019) at six discovery sites. A total of 620 males and females with UCPPS and 73 Controls were enrolled, including 83 UCPPS participants who re-enrolled from the first MAPP Network cohort study (2009-2012). Baseline neuroimaging scans, QST measures, and biospecimens were obtained on 578 UCPPS participants. The longitudinal follow-up of the cohort is ongoing., Conclusions: This comprehensive characterization of a large UCPPS cohort with extended follow-up greatly expands upon earlier MAPP Network studies and provides unprecedented opportunities to increase our understanding of UCPPS pathophysiology, factors associated with symptom change, clinically relevant patient phenotypes, and novel targets for future interventions., (© 2020 Wiley Periodicals LLC.)

Background: Irritable bowel syndrome (IBS) is a stress-sensitive disorder of brain-gut interactions associated with a higher prevalence of early adverse life events (EALs). However, it is incompletely understood how trauma severity or disclosure influence the risk of developing IBS or symptom severity., Aims: To determine whether (1) IBS patients report a greater number of EALs compared with healthy controls; (2) trauma severity and first age of EAL increase the odds of IBS; (3) confiding in others reduces the odds of IBS; (4) the number, trauma severity, and first age of EAL are associated with symptom severity; (5) sex differences exist., Methods: In total, 197 IBS patients (72% women, mean age=30.28 y) and 165 healthy controls (59% women, mean age=30.77 y) completed the Childhood Traumatic Events Scale, measuring severity of EALs and degree of confiding in others. Regression analyses were used to predict IBS status from EALs and association between gastrointestinal symptoms and EALs., Results: A greater number of EALs [odds ratio (OR)=1.36, 95% confidence interval (CI), 1.14-1.62; P<0.001] and higher perceived trauma severity (OR=1.13, 95% CI, 1.08-1.19; P<0.001) were associated with increased odds of IBS. Confiding in others decreased the odds of having IBS (OR=0.83, 95% CI, 0.72-0.96; P=0.012). The first age of EAL was not predictive of IBS. No sex differences were found., Conclusions: Assessing the traumatic severity of EALs and amount of confiding in others is important as they can affect the risk of having IBS. Our findings emphasize early intervention to improve health outcomes in individuals with EALs.

Objective: To investigate changes in whole body pain during urologic chronic pelvic pain syndrome (UCPPS) flares., Materials and Methods: UCPPS participants at one site of the multidisciplinary approach to the study of chronic pelvic pain research network reported their daily flare status and pain levels in 7 pelvic/genital and 42 extrapelvic body areas (scale = 0-10) for 10 days at baseline and during their first flare. Linear mixed models and conditional logistic regression were used to investigate symptom changes during flares. Analyses were stratified by chronic overlapping pain condition (COPC) status., Results: Fifty-five out of 60 participants completed the study, 27 of whom provided information on both nonflare (n = 281) and flare (n = 208) days. Pelvic/genital pain intensity (mean change = 3.20 of 10) and widespreadness (mean = 1.48) increased significantly during flares for all participants (all P interaction > .1), whereas extrapelvic pain intensity increased significantly only among participants with COPCs (mean = 2.09; P interaction < .0001). Pelvic/genital and extrapelvic pain also varied on nonflare days but symptom fluctuations were generally ≤1 point (80.0%-100% of participants). Increases of ≥2 points in pelvic/genital pain intensity (odds ratio (OR) = 22.0, 95% confidence interval (CI) = 4.0-118.6) and ≥1 point in urination-related pain (OR = 9.10, 95% CI = 1.74-47.7) were independently associated with flare onset for all participants., Conclusion: Our observations of extrapelvic pain increases during flares for patients with COPCs and our independent associations between pelvic/genital/urination-related pain intensity and flare onset may provide insight into mechanisms underlying flare development (eg, common biologic pathways between UCPPS phenotypes and flares), flare management (eg, local vs systemic therapies by COPC status), and patient flare definitions., (© 2019 Wiley Periodicals, Inc.)

Background & Aims: Irritable bowel syndrome (IBS) is a stress-sensitive disorder associated with dysregulation of the hypothalamic-pituitary-adrenal axis. We studied the cumulative effect of events during adulthood on this pathway in patients with IBS., Methods: We studied 129 patients with IBS, based on Rome III criteria (mean age 28.1 years, 66% women), and 108 healthy individuals (controls; mean age 29.8 years, 60% women) who completed the Life Experiences Survey from August 2013 to September 2017. Data were collected on the presence and effects of events since age 18, IBS severity scores, and IBS-related quality of life. For a subset of subjects, we measured serum cortisol and adrenocorticotropic hormone (ACTH) production in response to administration of corticotropin-releasing factor and ACTH., Results: Compared with controls, patients with IBS perceived more adulthood life events as negative and had a significantly higher negative life event impact score (14.17 ± 12.04 vs 10.83 ± 9.98; P=.022). In patients with IBS, the presence of more-negatively perceived adulthood life events was associated with worse IBS symptom severity (β = 1.53, 95% CI, 0.21-2.84; P = .025) and IBS-related quality of life (β = -0.70; 95% CI, -1.02 to -0.38; P < .001). Negatively perceived adulthood life events were associated with reduced production of ACTH in response to corticotropin-releasing factor in patients with IBS compared with controls (P < .05)., Conclusion: In a study of more than 200 subjects, we associated more-negatively perceived events during adulthood with an increased risk for IBS, worse symptom severity and quality of life, and a dysregulated stress response. Understanding the effects of events that cause stress in adults and their perceived effects on IBS may help guide disease management., (Copyright © 2019. Published by Elsevier Inc.)

Objective: To describe the frequency, intensity and duration of urological chronic pelvic pain syndrome symptom exacerbations ('flares'), as well as risk factors for these features, in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Epidemiology and Phenotyping longitudinal study., Participants and Methods: Current flare status ('urological or pelvic pain symptoms that are much worse than usual') was ascertained at each bi-weekly assessment. Flare characteristics, including start date, and current intensity of pelvic pain, urgency and frequency (scales of 0-10), were assessed for participants' first three flares and at three randomly selected times when they did not report a flare. Generalized linear and mixed effects models were used to investigate flare risk factors., Results: Of the 385 eligible participants, 24.2% reported no flares, 22.9% reported one flare, 28.3% reported 2-3 flares, and 24.6% reported ≥4 flares, up to a maximum of 18 during the 11-month follow-up (median incidence rate = 0.13/bi-weekly assessment, range = 0.00-1.00). Pelvic pain (mean = 2.63-point increase) and urological symptoms (mean = 1.72) were both significantly worse during most flares (60.6%), with considerable within-participant variability (26.2-37.8%). Flare duration varied from 1 to 150 days (94.3% within-participant variability). In adjusted analyses, flares were more common, symptomatic, and/or longer-lasting in women and in those with worse non-flare symptoms, bladder hypersensitivity, and chronic overlapping pain conditions., Conclusion: In this foundational flare study, we found that pelvic pain and urological symptom flares were common, but variable in frequency and manifestation. We also identified subgroups of participants with more frequent, symptomatic, and/or longer-lasting flares for targeted flare management/prevention and further study., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Pain is a highly complex and individualized experience with biopsychosocial components. Neuroimaging research has shown evidence of the involvement of the central nervous system in the development and maintenance of chronic pain conditions, including urological chronic pelvic pain syndrome (UCPPS). Furthermore, a history of early adverse life events (EALs) has been shown to adversely impact symptoms throughout childhood and into adulthood. However, to date, the role of EAL's in the central processes of chronic pain have not been adequately investigated. We studied 85 patients (56 females) with UCPPS along with 86 healthy controls (HCs) who had resting-state magnetic resonance imaging scans (59 females), and data on EALs as a part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Study. We used graph theory methods in order to investigate the impact of EALs on measures of centrality, which characterize information flow, communication, influence, and integration in a priori selected regions of interest. Patients with UCPPS exhibited lower centrality in the right anterior insula compared to HCs, a key node in the salience network. Males with UCPPS exhibited lower centrality in the right anterior insula compared the HC males. Females with UCPPS exhibited greater centrality in the right caudate nucleus and left angular gyrus compared to HC females. Males with UCPPS exhibited lower centrality in the left posterior cingulate, angular gyrus, middle temporal gyrus, and superior temporal sulcus, but greater centrality in the precuneus and anterior mid-cingulate cortex (aMCC) compared to females with UCPPS. Higher reports of EALs was associated with greater centrality in the left precuneus and left aMCC in females with UCPPS. This study provides evidence for disease and sex-related alterations in the default mode, salience, and basal ganglia networks in patients with UCPPS, which are moderated by EALs, and associated with clinical symptoms and quality of life (QoL)., Competing Interests: The authors have declared that no competing interests exist.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

Primary dysmenorrhea (PD; menstrual pain without an underlying medical condition) is associated with enhanced pain sensitivity and temporal summation (TS) in adult women, which may reflect the presence of central pain processes. Research in this area has been limited by focusing on only adult populations and incomplete assessments of central sensitization. The current study explored both excitatory and inhibitory measures of pain processing in girls and young adult women with and without PD. Thirty-two young women with PD and 34 healthy controls underwent laboratory pain testing during each of 3 menstrual cycle phases (menstrual, ovulatory, and midluteal), which included measures of pain tolerance and threshold, TS, and conditioned pain modulation. Results indicated enhanced pain sensitivity in young women with PD as measured by heat pain tolerance and Average Pain50 (P50), compared with healthy controls. These group differences were evident at all phases of the menstrual cycle. No group differences in cold pain tolerance, TS, or conditioned pain modulation were evident at any phase of the menstrual cycle. These data suggest some evidence of central sensitization in young women with PD, although no evidence of enhanced excitatory or deficient inhibitory mechanisms were observed. Future research should focus on identifying other potential phenotypes for PD to determine those at risk of developing other pain problems.

Urologic chronic pelvic pain syndrome (UCPPS), which encompasses interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, is characterized by chronic pain in the pelvic region or genitalia that is often accompanied by urinary frequency and urgency. Despite considerable research, no definite aetiological risk factors or effective treatments have been identified. The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network uses a novel integrated strategy to characterize UCPPS as a systemic disorder that potentially involves multiple aetiologies. The first phase, MAPP I, included >1,000 participants who completed an intensive baseline assessment followed by a 12-month observational follow-up period. MAPP I studies showed that UCPPS pain and urinary symptoms co-vary, with only moderate correlation, and should be evaluated separately and that symptom flares are common and can differ considerably in intensity, duration and influence on quality of life. Longitudinal clinical changes in UCPPS correlated with structural and functional brain changes, and many patients experienced global multisensory hypersensitivity. Additionally, UCPPS symptom profiles were distinguishable by biological correlates, such as immune factors. These findings indicate that patients with UCPPS have objective phenotypic abnormalities and distinct biological characteristics, providing a new foundation for the study and clinical management of UCPPS.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates. Results identified a brainstem region that showed a strong correlation between both ADC (R2 = 0.49, P<0.0001) and FA (R2 = 0.39, P = 0.0002) with urinary MMP9 levels as well as a correlation between both ADC (R2 = 0.42, P = 0.0001) and FA (R2 = 0.29, P = 0.0020) and urinary MMP9/NGAL complex. Results also identified significant correlations between FA and urinary MMP9 in white matter adjacent to sensorimotor regions (R2 = 0.30, P = 0.002; R2 = 0.36, P = 0.0005, respectively), as well as a correlation in similar sensorimotor regions when examining ADC and urinary MMP2 levels (R2 = 0.42, P<0.0001) as well as FA and urinary MMP9/NGAL complex (R2 = 0.33, P = 0.0008). A large, diffuse cluster of white matter was identified as having a strong correlation between both ADC (R2 = 0.35, P = 0.0006) and FA (R2 = 0.43, P<0.0001) with urinary NGAL levels. In contrast, no significant association between DTI measurements and VEGF was observed. Results suggest that elevated MMP9 or MMP9/NGAL in UCPPS may be related to degenerative neuronal changes in brainstem nuclei through excitotoxicity, while also facilitating synaptic plasticity in sensorimotor regions., Competing Interests: The authors have declared that no competing interests exist.

Chronic overlapping pain conditions (COPCs) are characterized by aberrant central nervous system processing of pain. This "centralized pain" phenotype has been described using a large and diverse set of symptom domains, including the spatial distribution of pain, pain intensity, fatigue, mood imbalances, cognitive dysfunction, altered somatic sensations, and hypersensitivity to external stimuli. Here, we used 3 cohorts, including patients with urologic chronic pelvic pain syndrome, a mixed pain cohort with other COPCs, and healthy individuals (total n = 1039) from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to explore the factor structure of symptoms of centralized pain. Using exploratory and confirmatory factor analysis, we identified 2 general factors in all 3 cohorts, one characterized by a broad increased sensitivity to internal somatic sensations,environmental stimuli, and diffuse pain, termed Generalized Sensory Sensitivity, and one characterized by constitutional symptoms-Sleep, Pain, Affect, Cognition, Energy (SPACE). Longitudinal analyses in the urologic chronic pelvic pain syndrome cohort found the same 2-factor structure at month 6 and 1 year, suggesting that the 2-factor structure is reproducible over time. In secondary analyses, we found that Generalized Sensory Sensitivity particularly is associated with the presence of comorbid COPCs, whereas SPACE shows modest associations with measures of disability and urinary symptoms. These factors may represent an important and distinct continuum of symptoms that are indicative of the centralized pain phenotype at high levels. Future research of COPCs should accommodate the measurement of each factor.