Publications

137 Publications from 2009 – 2024:

2024

Widespread Pain Phenotypes Impact Treatment Efficacy Results in Randomized Clinical Trials for Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Network Study.

Farrar JT, Locke KT Jr., Clemens JQ, Griffith JW, Harte SE, Kirkali Z, Kreder KJ, Krieger JN, Lai HH, Moldwin RM, Mullins C, Naliboff BD, Pontari MA, Rodriguez LV, Schaeffer AJ, Schrepf A, Stephens-Shields A, Sutcliffe S, Taple BJ, Williams DA, Landis JR.  Pain. 2024 Nov 5. doi: 10.1097/j.pain.0000000000003455. Online ahead of print. [PMID: 39499552] [PMC – ePub]

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.

Keywords: Pelvic pain; Widespread pain; Reanalysis of clinical trial results; Pain measurement; Interstitial cystitis

Brain predicted age in chronic pelvic pain: a study by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network.

Leech KA, Kettlety SA, Mack WJ, Kreder KJ, Schrepf A, Kutch JJ. Pain. 2024 Oct 16. doi: 10.1097/j.pain.0000000000003424. Online ahead of print. Epub 2024 Jan 22. [PMID: 39432808] [ePub]

Abstract

The effect of chronic pain on brain-predicted age is unclear. We performed secondary analyses of a large cross-sectional and 3-year longitudinal data set from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network to test the hypothesis that chronic pelvic pain accelerates brain aging and brain aging rate. Brain-predicted ages of 492 chronic pelvic pain patients and 72 controls were determined from T1-weighted MRI scans and used to calculate the brain-predicted age gap estimation (brainAGE; brain-predicted - chronological age). Separate regression models determined whether the presence of chronic pelvic pain could explain brainAGE and brain aging rate when accounting for covariates. We performed secondary analyses to understand whether brainAGE was associated with factors that subtype chronic pelvic pain patients (inflammation, widespread pain, and psychological comorbidities). We found a significant association between chronic pelvic pain and brainAGE that differed by sex. Women with chronic pelvic pain had higher brainAGE than female controls, whereas men with chronic pelvic pain exhibited lower brainAGE than male controls on average-however, the effect was not statistically significant in men or women when considered independently. Secondary analyses demonstrated preliminary evidence of an association between inflammatory load and brainAGE. Further studies of brainAGE and inflammatory load are warranted.

Keywords: Chronic pain; Pelvic pain; Brain age; Structural MRI; Inflammation

Trial registration: ClinicalTrials.gov NCT02514265.

Ecological Momentary Assessment of Pelvic Pain and Urinary Urgency Variability in Urologic Chronic Pelvic Pain Syndrome and Their Association with Illness Impact and Quality of Life: Findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study.

Erickson BA, Griffith JW, Wensheng G, Mengying Y, Herman T, Bradley CS, Quentin Clemens J, Farrar JT, Gupta P, Kreder KJ, Henry Lai H, Naliboff BD, Newman DK, Rodriguez LV, Spitznagle T, Sutcliffe S, Sutherland SE, Taple BJ, Richard Landis J.  Neurourol Urodyn. 2024 Apr;43(4):893-901. doi: 10.1002/nau.25363. Epub 2024 Jan 22. [PMID: 38247366] [PMC11031348]

Abstract

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.

Keywords: ecological momentary assessment; illness impact; phone application; quality of life; urologic chronic pelvic pain syndrome; variability.

Urologic Chronic Pelvic Pain Syndrome Flares: A Comprehensive, Systematic Review and Meta-Analysis of the Peer-Reviewed Flare Literature.

Barker ES, Chiu K, Brown VL, Morsy H, Yaeger LH, Catna A, Pakpahan R, Moldwin R, Shorter B, Lowder JL, Lai HH, Sutcliffe S.  J Urol. 2024 Mar;211(3):341-353. doi: 10.1097/JU.0000000000003820. Epub 2023 Dec 18. [PMID: 38109700 Review] [PMC11037930]

Abstract

Purpose: We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research.

Materials and methods: We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals.

Results: Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. "Flare" was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants' nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms.

Conclusions: Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.

Keywords: bladder pain syndrome; chronic pelvic pain syndrome; chronic prostatitis; interstitial cystitis; symptom exacerbation.

Validation of a simple body map to measure widespread pain in urologic chronic pelvic pain syndrome: A MAPP research network study.

Clemens JQ, Locke K Jr, Landis JR, Kreder K, Rodriguez LV, Yang CC, Tu FF, Harte SE, Schrepf A, Farrar JT, Sutcliffe S, Naliboff BD, Williams DA, Afari N, Spitznagle T, Taple BJ, Lai HH; Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.  Neurourol Urodyn. 2024 Mar;43(3):727-737. doi: 10.1002/nau.25400. Epub 2024 Jan 25. [PMID: 38270336] [PMC10981467]

Abstract

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.

Keywords: chronic prostatitis/chronic pelvic pain syndrome; interstitial cystitis/bladder pain syndrome; pelvic pain; prostate; urinary bladder.

Mapping Brain Structure Variability in Chronic Pain: The Role of Widespreadness and Pain Type and Its Mediating Relationship With Suicide Attempt.

Bhatt RR, Haddad E, Zhu AH, Thompson PM, Gupta A, Mayer EA, Jahanshad N.  Biol Psychiatry. 2024 Mar 1;95(5):473-481. doi: 10.1016/j.biopsych.2023.07.016. Epub 2023 Aug 4. [PMID: 37543299] [PMC10838358]; Supported by: DK082370 (MAYER, E; RODRIGUEZ L)

Abstract

Background: Chronic pain affects nearly 20% of the U.S.

Population: It is a leading cause of disability globally and is associated with a heightened risk for suicide. The role of the central nervous system in the perception and maintenance of chronic pain has recently been accepted, but specific brain circuitries involved have yet to be mapped across pain types in a large-scale study.

Methods: We used data from the UK Biobank (N = 21,968) to investigate brain structural alterations in individuals reporting chronic pain compared with pain-free control participants and their mediating effect on history of suicide attempt.

Results: Chronic pain and, more notably, chronic multisite pain was associated with, on average, lower surface area throughout the cortex after adjusting for demographic, clinical, and neuropsychiatric confounds. Only participants with abdominal pain showed lower subcortical volumes, including the amygdala and brainstem, and lower cerebellum volumes. Participants with chronic headaches showed a widespread thicker cortex compared with control participants. Mediation analyses revealed that precuneus thickness mediated the relationship of chronic multisite pain and history of suicide attempt. Mediating effects were also identified specific to localized pain, with the strongest effect being amygdala volume in individuals with chronic abdominal pain.

Conclusions: Results support a widespread effect of chronic pain on brain structure and distinct brain structures underlying chronic musculoskeletal pain, visceral pain, and headaches. Mediation effects of regions in the extended ventromedial prefrontal cortex subsystem suggest that exacerbated negative internal states, negative self-referencing, and impairments in future planning may underlie suicidal behaviors in individuals with chronic pain.

Keywords: Big data; Biobank; Chronic pain; MRI; Neuroimaging; Suicide.

Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Neural correlates of perceived and relative resilience in male and female patients with irritable bowel syndrome.

Kilpatrick LA, Gupta A, Tillisch K, Labus JS, Naliboff BD, Mayer EA, Chang L.  Neurogastroenterol Motil. 2024 Feb;36(2):e14710. doi: 10.1111/nmo.14710. Epub 2023 Nov 29. [PMID: 38031358] [PMC11014739]; Supported by: DK082370 (MAYER, E; RODRIGUEZ L)

Abstract

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.

Keywords: functional magnetic resonance imaging; irritable bowel syndrome; psychological resilience; sex differences.

© 2023 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.

Believing Women: A Qualitative Exploration of Provider Disbelief and Pain Dismissal among Women with Interstitial Cystitis/Bladder Pain Syndrome from the MAPP Research Network

Brown VL, James A, Hunleth J, Bradley CS, Farrar JT, Gupta P, Lai HH, Lowder JL, Moldwin R, Rodriguez LV, Yang CC, Sutcliffe S.  Int Urogynecol J. 2024 Jan;35(1):139-148. doi: 10.1007/s00192-023-05677-0. Epub 2023 Nov 22. [PMID: 37991567] [PMC11019919]

Abstract

Introduction and hypothesis: Although allusions to the importance of a good physician-patient relationship are present throughout the interstitial cystitis/bladder pain syndrome (IC/BPS) literature, qualitative analysis of patients' perspectives on the clinical encounter is lacking, particularly among women who are most commonly affected by IC/BPS. Therefore, we adopted a patient-centered experiential approach to understanding female patients' perception of clinical encounters.

Methods: We re-analyzed previously collected data from a qualitative study on patient flare experiences including eight focus groups of female IC/BPS patients (n = 57, mean = 7/group). Qualitative analysis applied grounded theory to index all physician-patient interactions, then thematically coded these interactions to elucidate common experiences of clinical encounters.

Results: Women with IC/BPS shared common experiences of provider disbelief and pain dismissal. Discussions with participants demonstrated the extent to which these negative encounters shape patients' health care-seeking behavior, outlook, and psychosocial well-being. Appearing in more than one guise, provider disbelief and dismissal occurred as tacit insinuations, explicit statements, silence, oversimplification, and an unwillingness to listen and discuss alternative treatment. As a result, women adopted several strategies including: rotating specialists; "testing" physicians; self-advocacy; self-management; avoiding the stigma of chronic pain; crying; and opting for alternative medicine over biomedicine.

Conclusions: The prevalence of provider disbelief and pain dismissal among women with IC/BPS indicates a need to improve physician-patient communication, informed by the struggles, anxieties, and gendered inequities that female patients with chronic pain experience in their diagnostic journey. Results suggest that further investigation into the power dynamics of clinical encounters might be required.

Keywords: Chronic pain; Delayed diagnosis; Interstitial cystitis; Patient–provider encounter; Qualitative; Women.

© 2023. The International Urogynecological Association.

Links between brain neuroimaging and blood inflammatory markers in urological chronic pelvic pain syndrome.

Martucci KT, Karshikoff B, Mackey SC. Physiol Behav. 2023 Nov 1;271:114358. doi: 10.1016/j.physbeh.2023.114358. Epub 2023 Sep 26. [PMID: 37769862] [PMC10599305]

Abstract

Urological chronic pelvic pain syndrome (UCPPS) is a debilitating painful condition with unclear etiology. Prior researchers have indicated that compared to healthy controls, patients with UCPPS demonstrated altered brain activity. Researchers have also shown that in UCPPS, several blood inflammatory markers relate to clinical variables of pain, fatigue, and pain widespreadness. However, how altered brain function in patients with UCPPS relates to blood inflammation remains unknown. To extend and connect prior findings of altered brain function and inflammatory factors in UCPPS, we conducted a secondary analysis of data from a cohort of UCPPS patients (N = 29) and healthy controls (N = 31) who provided both neuroimaging and blood data (National Institute of Health MAPP Research Network publicly available dataset). In our present study, we aimed to evaluate relationships between a priori-defined brain neuroimaging markers and inflammatory factors of interest and their relationships to pain-psychological variables. We hypothesized that two brain alterations of interest (i.e., PCC - left hippocampus functional connectivity and PCC - bilateral amygdala functional connectivity) would be correlated with four cytokine markers of interest: interleukin (IL) - 6, tumor necrosis factor-alpha (TNF-a), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the UCPPS cohort, we identified a significant PCC - left hippocampus functional connectivity relationship with IL-6 (p = 0.0044). Additionally, in the UCPPS cohort, we identified a PCC - amygdala functional connectivity relationship with GM-CSF which did not meet our model's threshold for statistical significance (p = 0.0665). While these data are preliminary and cross-sectional, our findings suggest connections between brain function and levels of low-grade systemic inflammation in UCPPS. Thus, while further study is needed, our data indicate the potential for advancing the understanding of how brain functional circuits may relate to clinical symptoms and systemic inflammation.

Keywords: Amygdala; Cytokine; Hippocampus; IL-6; Inflammation; fMRI.

Neurobiology and long-term impact of bladder-filling pain in humans: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network study.

Schrepf AD, Mawla I, Naliboff BD, Gallop B, Moldwin RM, Tu F, Gupta P, Harte S, Krieger JN, Yang C, Bradley C, Rodriguez L, Williams D, Magnotta V, Ichesco E, Harris RE, Clemens Q, Mullins C, Kutch JJ. Pain. 2023 Oct 1;164(10):2343-2351. doi: 10.1097/j.pain.0000000000002944. Epub 2023 Jun 6.  [PMID: 37278657] [PMC10524087]

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.

Keywords: Chronic pain, Bladder, Urology, Resting-state, fMRI, Flare-up, Healthcare utilization.

Trial registration: ClinicalTrials.gov NCT02514265.

Mediators of the association between childhood trauma and pain sensitivity in adulthood: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network analysis.

Pierce J, Harte SE, Afari N, Bradley CS, Griffith JW, Kim J, Lutgendorf S, Naliboff BD, Rodriguez LV, Taple BJ, Williams D, Harris RE, Schrepf A; MAPP Research Network. Pain. 2023 Sep 1;164(9):1995-2008. doi: 10.1097/j.pain.0000000000002895. Epub 2023 May 5. [PMID: 37144687] [PMC10440258]

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.

Keywords: Trauma, Childhood abuse, Pain sensitivity, Quantitative sensory testing.

Copyright © 2023 International Association for the Study of Pain.

Functional Magnetic Resonance Imaging Signal Variability Is Associated With Neuromodulation in Fibromyalgia.

Lim M, Kim DJ, Nascimento TD, Ichesco E, Kaplan C, Harris RE, DaSilva AF.  Neuromodulation. 2023 Jul;26(5):999-1008. doi: 10.1111/ner.13512. Epub 2022 Jun 14. [PMID: 34309138] [PMC8789944]

Abstract

Objectives: Although primary motor cortex (M1) transcranial direct current stimulation (tDCS) has an analgesic effect in fibromyalgia (FM), its neural mechanism remains elusive. We investigated whether M1-tDCS modulates a regional temporal variability of blood-oxygenation-level-dependent (BOLD) signals, an indicator of the brain's flexibility and efficiency and if this change is associated with pain improvement.

Materials and methods: In a within-subjects cross-over design, 12 female FM patients underwent sham and active tDCS on five consecutive days, respectively. Each session was performed with an anode placed on the left M1 and a cathode on the contralateral supraorbital region. The subjects also participated in resting-state functional magnetic resonance imaging (fMRI) at baseline and after sham and active tDCS. We compared the BOLD signal variability (SDBOLD), defined as the standard deviation of the BOLD time-series, between the tDCS conditions. Baseline SDBOLD was compared to 15 healthy female controls.

Results: At baseline, FM patients showed reduced SDBOLD in the ventromedial prefrontal cortex (vmPFC), lateral PFC, and anterior insula and increased SDBOLD in the posterior insula compared to healthy controls. After active tDCS, compared to sham, we found an increased SDBOLD in the left rostral anterior cingulate cortex (rACC), lateral PFC, and thalamus. After sham tDCS, compared to baseline, we found a decreased SDBOLD in the dorsomedial PFC and posterior cingulate cortex/precuneus. Interestingly, after active tDCS compared to sham, pain reduction was correlated with an increased SDBOLD in the rACC/vmPFC but with a decreased SDBOLD in the posterior insula.

Conclusion: Our findings suggest that M1-tDCS might revert temporal variability of fMRI signals in the rACC/vmPFC and posterior insula linked to FM pain. Changes in neural variability would be part of the mechanisms underlying repetitive M1-tDCS analgesia in FM.

Keywords: Brain signal variability; brain stimulation; fibromyalgia; resting-state fMRI; tDCS

Copyright © 2022. Published by Elsevier Inc.

Early and Recent Exposure to Adversity, TLR-4 Stimulated Inflammation, and Diurnal Cortisol in Women with Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Research Network Study.

Lutgendorf SK, Zia S, Luo Y, O’Donnell M, van Bokhoven A, Bradley CS, Gallup R, Pierce J, Taple BJ, Naliboff BD, Quentin Clemens J, Kreder KJ, Schrepf A.  Brain Behav Immun. 2023 Jul;111:116-123. doi: 10.1016/j.bbi.2023.03.024. Epub 2023 Mar 29. [PMID: 37001828] [PMC10474614]

Abstract

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

Keywords: Chronic stress; Cortisol; Early life adversity; HPA axis; IC/BPS; Inflammation; Interstitial cystitis; Pain; Recent life adversity.

Copyright © 2023 Elsevier Inc. All rights reserved.

Clinically Important Differences for Pain and Urinary Symptoms in Urological Chronic Pelvic Pain Syndrome: A MAPP Network Study.

Stephens-Shields AJ, Lai HH, Landis JR, Kreder K, Rodriguez LV, Naliboff BD, Afari N, Sutcliffe S, Moldwin R, Griffith JW, Clemens JQ, Bradley CS, Quallich S, Gupta P, Harte SE, Farrar JT.  J Urol. 2023 Jun;209(6):1132-1140. doi: 10.1097/JU.0000000000003394. Epub 2023 Feb 27. [PMID: 36848118] [PMC11062515]

Abstract

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.

Keywords: cystitis, interstitial; minimal clinically important difference; pelvic pain; research design; treatment outcome.

Associations Between Urological Chronic Pelvic Pain Syndrome Symptom Flares, Illness Impact, and Health Care Seeking Activity: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study.

Sutcliffe S, Newcomb C, Bradley CS, Clemens JQ, Erickson B, Gupta P, Lai HH, Naliboff B, Strachan E, Stephens-Shields A.  J Urol. 2023 Apr 1;209(4):719-725. doi: 10.1097/JU.0000000000003155. Epub 2023 Jan 11. [PMID: 36630590] [PMC10333444]

Abstract

Purpose: Most studies on interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome use typical or average levels of pelvic pain or urological symptom intensity as their outcome, as both are associated with reduced quality of life. Symptom exacerbations or "flares" have also been found to be associated with reduced quality of life, but no studies, to our knowledge, have investigated whether these associations are independent of typical pelvic pain levels and thus might be useful additional outcome measures (or stated differently, whether reducing flare frequency even without reducing mean pain intensity may be important to patients).

Materials and methods: We used screening visit and weekly run-in period data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study to investigate associations between flare frequency and multiple measures of illness impact and health care seeking activity, independent of typical nonflare and overall pelvic pain levels.

Results: Among the 613 eligible participants, greater flare frequency was associated with worse condition-specific illness impact (standardized β coefficients=0.11-0.68, P trends < .0001) and health care seeking activity (odds ratios=1.52-3.94, P trends .0039 to < .0001) in analyses adjusted for typical nonflare and overall pelvic pain levels. Experiencing ≥1/d was also independently associated with worse general illness impact (standardized β coefficients=0.11-0.25).

Conclusions: Our findings suggest that flare frequency and possibly other flare characteristics may be worth considering as additional outcome measures in urological chronic pelvic pain syndrome research to support the development of new preventive and therapeutic flare strategies.

Keywords: cystitis, interstitial; prostatitis; symptom flare up.

Reproducible Microstructural Changes in the Brain Associated With the Presence and Severity of Urologic Chronic Pelvic Pain Syndrome (UCPPS): A 3-Year Longitudinal Diffusion Tensor Imaging Study From the MAPP Network.

Wang C, Kutch JJ, Labus JS, Yang CC, Harris RE, Mayer EA, Ellingson BM.  J Pain. 2023 Apr;24(4):627-642. doi: 10.1016/j.jpain.2022.11.008. Epub 2022 Nov 23. [PMID: 36435486] [PMC10676766]

Abstract

Microstructural alterations have been reported in patients with urologic chronic pelvic pain syndrome (UCPPS). However, it isn't clear whether these alterations are reproducible within 6 months or whether long-term symptom improvement is associated with specific microstructural changes. Using data from the MAPP-II Research Network, the current study performed population-based voxel-wise DTI and probabilistic tractography in a large sample of participants from the multicenter cohort with UCPPS (N = 364) and healthy controls (HCs, N = 61) over 36 months. While fractional anisotropy (FA) differences between UCPPS patients and HCs were observed to be unique at baseline and 6-month follow-up visits, consistent aberrations in mean diffusivity (MD) were observed between UCPPS and HCs at baseline and repeated at 6 months. Additionally, compared to HCs, UCPPS patients showed stronger structural connectivity (SC) between the left postcentral gyrus and the left precuneus, and weaker SC from the left cuneus to the left lateral occipital cortex and the isthmus of the left cingulate cortex at baseline and 6-month. By 36 months, reduced FA and MD aberrations in these same regions were associated with symptom improvement in UCPPS. Together, results suggest changes in white matter microstructure may play a role in the persistent pain symptoms in UCPPS. PERSPECTIVE: This longitudinal study identified reproducible, "disease-associated" patterns in altered mean diffusivity and abnormal microstructural connectivity in UCPPS comparing to HCs over 6 months. These differences were found in regions involved in sensory processing and integration and pain modulation, making it potentially amenable for clinical interventions that target synaptic and/or neuronal reorganization.

Keywords: Urological chronic pelvic pain; UCPPS; Longitudinal observation; Diffusion tensor imaging; Probabilistic tractography.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Widespread Pain Phenotypes Impact Treatment Efficacy Results in Randomized Clinical Trials for Interstitial Cystitis/ Bladder Pain Syndrome: A MAPP Network Study.

Farrar JT, Locke KT Jr., Clemens JQ, Griffith JW, Harte SE, Kirkali Z, Kreder KJ, Krieger JN, Lai HH, Moldwin RM, Mullins C, Naliboff BD, Pontari MA, Rodriguez LV, Schaeffer AJ, Schrepf A, Stephens-Shields A, Sutcliffe S, Taple BJ, Williams DA, Landis JR.   Res Sq. 2023 Feb 23;rs.3.rs-2441086. doi: 10.21203/rs.3.rs-2441086/v1. Preprint [PMID: 36865104] [PMC9980200]

Abstract

Clinical trials of pain are notoriously difficult and inefficient in demonstrating efficacy even for known efficacious treatments. Determining the appropriate pain phenotype to study can be problematic. Recent work has identified the extend of widespread pain as an important factor in the likelihood of response to therapy, but has not been tested in clinical trials. Using data from three previously published negative studies of the treatment of interstitial cystitis/ bladder pain with data on the extent of widespread pain, we examined the response of patients to different therapies base on the amount of pain beyond the pelvis. Participants with predominately local but not widespread pain responded to therapy targeting local symptoms. Participants with widespread and local pain responded to therapy targeting widespread pain. Differentiating patients with and without widespread pain phenotypes may be a key feature of designing future pain clinical trials to demonstrate treatments that are effective versus not.

Keywords: Randomized controlled trials; Chronic pain; Epidemiology; Functional clustering.

This is a preprint. It has not yet been peer reviewed by a journal. The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

2022

Predictors of Male Sexual Dysfunction in Urologic Chronic Pelvic Pain Syndrome (UCPPS), Other Chronic Pain Syndromes, and Healthy Controls in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network

Loh-Doyle JC, Stephens-Shields AJ, Rolston R, Newcomb C, Taple B, Sutcliffe S, Yang CC, Lai H, Rodriguez LV.   J Sex Med. 2022 Dec;19(12):1804-1812. doi: 10.1016/j.jsxm.2022.08.196. Epub 2022 Sep 28. [PMID: 36180370] [PMC10916540]

Abstract

Background: Sexual dysfunction (SD), including erectile (ED) and ejaculatory dysfunction, is associated with diminished quality of life (QoL) in men with UCPPS (chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and/or interstitial cystitis/bladder pain syndrome (IC/BPS)).

Aim: We sought to compare SD among male patients with UCPPS, other chronic pain conditions (positive controls, PC), and healthy controls (HC) without chronic pain, and to evaluate the association of comorbidities, psychosocial factors, and urologic factors of SD in all 3 groups.

Methods: Baseline data from male UCPPS participants, PC (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) and HC enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Epidemiology and Phenotyping Study were included in the analysis. Sexual function was assessed using the International Index of Erectile Function-Erectile Function Domain (IIEFEF) and Ejaculatory Function Scale (EFS). Male ED was defined as a composite IIEF-EF score <21. Higher EFS score indicated worse sexual dysfunction; no threshold to define SD was identified for the EFS. Multivariable logistic and linear regression was used to investigate associations of comorbidities, psychosocial factors, and urologic factors with ED and ejaculatory, respectively.

Outcomes: Comorbidities, genital pain, and psychosocial factors are associated with SD across the study population and male patients with UCPPS had a high prevalence of ED and greater ejaculatory dysfunction.

Results: There were 191 males with UCPPS; 44 PC; and 182 HC. Males with UCPPS had worse SD compared to PC and HC including lower mean IIEF-EF scores, greater degree of ejaculatory dysfunction, and lower quality of sexual relationships. Among all 3 cohorts, depression, stress, and pain were associated with ED in univariable and multivariable analysis, as was diabetes mellitus. Pain in the genitalia, severity of urinary symptoms, depression, stress, and history of childhood sexual trauma were associated with ejaculatory dysfunction in univariable and multivariable analysis.

Clinical implications: A multidisciplinary approach that addresses the identified risk factors for SD may improve overall QoL in males with UCPPS.

Strengths and limitations: Our study is strengthened by its use of validated, patient-reported questionnaires and inclusion of healthy and positive controls. Our understanding of the role of IC in this study is limited because only 1 patient in the study had IC/BPS as a sole diagnosis.

Conclusions: When compared to healthy controls and patients with other chronic pain conditions, males with UCPPS experience higher degrees of SD, including erectile and ejaculatory dysfunction. Loh-Doyle JC, Stephens-Shields AJ, Rolston R, et al. Predictors of Male Sexual Dysfunction in Urologic Chronic Pelvic Pain Syndrome (UCPPS), Other Chronic Pain Syndromes, and Healthy Controls in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. J Sex Med 2022;19:1804-1812.

Keywords: Chronic Pelvic Pain; Chronic Prostatitis; Ejaculatory Dysfunction; Erectile Dysfunction; Sexual Dysfunction.

Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Long-term Symptom Trajectories in Urologic Chronic Pelvic Pain Syndrome: A MAPP Research Network Study.

Bradley CS , Gallop R , Sutcliffe S, Kreder KJ, Lai HH, Clemens JQ, Naliboff BD, for the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.   Urology. 2022 Nov;169:58-64. doi: 10.1016/j.urology.2022.07.045. Epub 2022 Aug 9. [PMID: 35961564] [PMC10590538]

Abstract

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.

Keywords: Chronic prostatitis; extended follow-up; interstitial cystitis; MAPP network cohort study; urologic chronic pelvic pain syndrome; bladder pain syndrome.

Clinical Phenotyping for Pain Mechanisms in Urologic Chronic Pelvic Pain Syndromes: A Mapp Research Network Study.

Schrepf A, Gallop R, Naliboff B, Harte SE, Afari N, Lai HH, Pontari M, McKernan LC, Strachan E, Kreder KJ, As-Sanie SA, Rodriguez LV, Griffith JW, Williams DA; Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. J Pain. 2022 Sep;23(9):1594-1603. doi: 10.1016/j.jpain.2022.03.240. Epub 2022 Apr 25. [PMID: 35472518] [PMC10547025]

Abstract

Three categories of pain mechanisms are recognized as contributing to pain perception: nociceptive, neuropathic, and nociplastic (ie, central nervous system augmented pain processing). We use validated questionnaires to identify pain mechanisms in Urologic Chronic Pelvic Pain Syndrome (UCCPS) patients (n = 568, female = 378, male = 190) taking part in the Symptom Patterns Study of the Multidisciplinary Approach to the study of chronic Pelvic Pain Research Network. A cutoff score of 12 on the painDETECT questionnaire (-1 to 38) was used to classify patients into the neuropathic category while the median score of 7 on the fibromyalgia survey criteria (0-31) was used to classify patients into the nociplastic category. Categories were compared on demographic, clinical, psychosocial, psychophysical and medication variables. At baseline, 43% of UCPPS patients were classified as nociceptive-only, 8% as neuropathic only, 27% as nociceptive+nociplastic, and 22% as neuropathic+nociplastic. Across outcomes nociceptive-only patients had the least severe symptoms and neuropathic+nociplastic patients the most severe. Neuropathic pain was associated with genital pain and/or sensitivity on pelvic exam, while nociplastic pain was associated with comorbid pain conditions, psychosocial difficulties, and increased pressure pain sensitivity outside the pelvis. A self-report method classifying individuals on pain mechanisms reveals clinical differences that could inform clinical trials and novel targets for treatment. PERSPECTIVE: This article presents differences in clinical characteristics based on a simple self-report method of classifying pain mechanisms for Urologic Chronic Pelvic Pain Syndrome patients. This method can be easily applied to other chronic pain conditions and may be useful for exploring pathophysiology in pain subtypes.

Keywords: Nociceptive pain; central nervous system sensitization; chronic pain; cystitis; neuropathic pain.

The healthy urinary microbiome in asymptomatic participants in the MAPP Network Study: Relation to gender, age, and menopausal status.

Nickel JC, Stephens A, Ackerman AL, Anger JT, Lai HH, Ehrlich GD. Can Urol Assoc J. 2022 Sep;16(9):E448-E454. doi: 10.5489/cuaj.7775. [PMID: 35426787] [PMC9484748]

Abstract

Introduction: To understand the role of the urinary microbiome in disease states and interpret non-culture-based diagnostic urine testing of midstream urine specimens, we must have a better understanding of the urinary microbiome in asymptomatic, healthy individuals. We examined the impact of gender, age, and menopausal status on the healthy human urinary microbiome in asymptomatic control subjects enrolled in the multi-institution National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Multidisciplinary Approach to the Study of Chronic Pelvic Pain Network (MAPP) study.

Methods: Asymptomatic, healthy controls, recruited to be ageand sex-matched to patients in the Trans-MAPP Epidemiology and Phenotyping Study, provided midstream urine collection for polymerase chain reaction (PCR)-electrospray ionization mass spectrometry identification of urinary microbiota. The microbiomes of male and female participants were described and analyzed for differences in composition and diversity at the species and genus level by sex, age, and, in females, by menopausal status.

Results: Sixty-six total species were detected with a mean of 1.2 species (standard deviation [SD] 1.1) per male (n=97; mean age=43) and 2.3 (SD 1.3) per female (n=110, mean age=38) in asymptomatic, healthy controls. Species and genera diversity analyses showed significantly greater richness and diversity in females. With regard to species, Bifidobacterium subtile, Lactobacillus crispatus, and Lactobacillus johnsonii were more predominant in females. The genera Bifidobacterium, Staphylococcus, Lactobacillus, and Corynebacterium were more predominant in females, while for males the most prevalent organisms included Staphylococcus and Propionibacterium; only Propionibacterium approached a significant difference between genders. No significant difference in the presence and/or diversity of micro-organisms with menopausal status could be observed. Sex-specific age trends, particularly diversity, were larger for females than males.

Conclusions: These results suggest the urinary microbiome of healthy, asymptomatic subjects differed between genders and age in females, but not menopausal status. Gender differences may be attributable to the detection of urethral/vaginal organisms in females and prostate organisms in males. These findings will better allow us to interpret the results of microbiome reports in the midstream urine specimens of patients with urinary symptoms.

Keywords: Microbiome; Urinary; Urinary Tract Infection; Age; Gender.

Is Pelvic Floor Muscle Tenderness a Distinct Urologic Chronic Pelvic Pain Syndrome Phenotype? Findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Symptom Pattern Study.

Gupta P, Gallop R, Spitznagle T, Lai H, Tu F, Krieger JN, Clemens JQ, Bradley CS, Yang C, Sutcliffe S, Moldwin R, Kreder K, Kutch J, Rodriguez LV.   J Urol. 2022 Aug;208(2):341-349. doi: 10.1097/JU.0000000000002679. Epub 2022 Mar 28. [PMID: 35344391] [PMC10123541]

Abstract

Purpose: Of women with interstitial cystitis/bladder pain syndrome and men with chronic prostatitis/chronic pelvic pain syndrome 85% have concomitant pelvic floor muscle tenderness (PFT). The significance of this finding is incompletely understood. This study examines PFT among participants in the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network and its relationship with urologic chronic pelvic pain syndrome (UCPPS) symptom severity in order to determine whether this is a phenotypic predictor in UCPPS.

Materials and methods: Participants in the MAPP Network Symptom Patterns Study underwent a standardized pelvic examination (PEX). Trained examiners palpated 6 locations evaluating the pelvic musculature for PFT. Participants were assigned a 0 to 6 PEX score based on the number of areas with tenderness on PEX. Using regression tree models, PEX scores were divided into low (0, 1), mid (2, 3, 4, 5) and high (6). The relationship between PFT and UCPPS symptoms was examined using several validated questionnaires.

Results: The study cohort consisted of 562 UCCPS participants (375 females and 187 males) and 69 controls. Diagnoses included interstitial cystitis/bladder pain syndrome (397), chronic prostatitis/chronic pelvic pain syndrome (122), both (34) or no diagnosis (9). Of UCPPS participants 81% had PFT on PEX compared to 9% of controls: 107 (19%) low, 312 (56%) mid and 143 (25%) high. Participants with higher PFT scores had more severe disease burden (worse pelvic pain and urinary symptoms), worse quality of life and more widespread distribution of nonpelvic pain.

Conclusions: UCPPS patients with more widespread PFT have severe pain and urinary symptoms, worse quality of life and a more centralized pain phenotype.

Keywords: chronic prostatitis with chronic pelvic pain syndrome; cystitis; interstitial; pelvic pain.

Flares and their impact among male urologic chronic pelvic pain syndrome patients: An in-depth qualitative analysis in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

Quallich SA, Quentin Clemens J, Ronstrom C, James AS, Kreder KJ, Henry Lai H, Naliboff BD, Rodriguez LV, Berry SH, Sutcliffe S.   Neurourol Urodyn. 2022 Aug;41(6):1468-1481. doi: 10.1002/nau.24983. Epub 2022 Jun 10. [PMID: 35686553] [PMC11033701]

Abstract

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.

Keywords: chronic prostatitis; diet; focus group; pelvic pain; prostatitis; quality of life; symptom exacerbation; urinary bladder.

Reliability and validity of pain and urinary symptom severity assessment in urologic chronic pelvic pain; A MAPP Network Analysis.

Naliboff BD, Locke K Jr, Schrepf D, Griffith JW, Moldwin R, Krieger JN, Rodriguez LV, Stephens-Shields AJ, Clemens JQ, Lai HH, Sutcliffe S, Taple BJ, Williams D, Pontari MA, Mullins C, Landis JR; MAPP Research Network.   J Urol. 2022 Jun;207(6):1246-1255. doi: 10.1097/JU.0000000000002438. Epub 2022 Jan 21. [PMID: 35060778] [PMC10494963]

Abstract

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.

Keywords: cystitis, interstitial; lower urinary tract symptoms; pelvic pain; prostatitis.

Functional Mixed Effects Clustering with Application to Longitudinal Urologic Chronic Pelvic Pain Syndrome Symptom Data.

Guo, WS; You, MY; Yi, JL; Pontari, MA; Landis, JR. J Am Stat Assoc. 2022;117(540):1631-1641. doi: 10.1080/01621459.2022.2066536. Epub 2022 May 13. [PMID: 36845296] [PMC9949755]

Abstract

By clustering patients with the urologic chronic pelvic pain syndromes (UCPPS) into homogeneous subgroups and associating these subgroups with baseline covariates and other clinical outcomes, we provide opportunities to investigate different potential elements of pathogenesis, which may also guide us in selection of appropriate therapeutic targets. Motivated by the longitudinal urologic symptom data with extensive subject heterogeneity and differential variability of trajectories, we propose a functional clustering procedure where each subgroup is modeled by a functional mixed effects model, and the posterior probability is used to iteratively classify each subject into different subgroups. The classification takes into account both group-average trajectories and between-subject variabilities. We develop an equivalent state-space model for efficient computation. We also propose a cross-validation based Kullback-Leibler information criterion to choose the optimal number of subgroups. The performance of the proposed method is assessed through a simulation study. We apply our methods to longitudinal bi-weekly measures of a primary urological urinary symptoms score from a UCPPS longitudinal cohort study, and identify four subgroups ranging from moderate decline, mild decline, stable and mild increasing. The resulting clusters are also associated with the one-year changes in several clinically important outcomes, and are also related to several clinically relevant baseline predictors, such as sleep disturbance score, physical quality of life and painful urgency.

Keywords: Functional clustering; Kullback-Leibler information criterion; Smoothing Spline; State Space model.

Longitudinal Changes in the Pelvic Pain Only and Widespread Pain Phenotypes Over One Year in the MAPP-I Urologic Chronic Pelvic Pain Syndrome (UCPPS) Cohort.

Lai H, Bayman EO, Bishop MO, Landis R, Harte SE, Clemens Q, Rodriguez LV, Sutcliffe S, Taple BJ, Naliboff BD; MAPP Research Network.  Urology. 2022 Mar;161:31-35. doi: 10.1016/j.urology.2021.12.016. Epub 2022 Jan 10. [PMID: 35021046] [PMC9502024]

Abstract

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.

Keywords: Complex Multiple Symptoms Inventory; chronic prostatitis/chronic pelvic pain syndrome; interstitial cystitis/bladder pain syndrome; Intra-class coefficient; intermediate pain; pelvic pain only; urologic chronic pelvic pain syndrome; widespread pain.

The urinary proteomic profile implicates key regulators for urologic chronic pelvic pain syndrome (UCPPS): A MAPP Research Network Study.

Froehlich JW, Scott Wang HH, Logvinenko T, Kostel S, DiMartino S, van Bokhoven A, Moses MA, Lee RS; MAPP Research Network.  Mol Cell Proteomics. 2022 Jan;21(1):100176. doi: 10.1016/j.mcpro.2021.100176. Epub 2021 Nov 11. [PMID: 34774759] [PMC8733275]

Abstract

Urologic chronic pelvic pain syndrome (UCPPS) is a condition of unknown etiology characterized by pelvic pain and urinary frequency and/or urgency. As the proximal fluid of this syndrome, urine is an ideal candidate sample matrix for an unbiased study of UCPPS. In this study, a large, discovery-phase, TMT-based quantitative urinary proteomics analysis of 244 participants was performed. The participants included patients with UCPPS (n = 82), healthy controls (HC) (n = 94), and disparate chronic pain diseases, termed positive controls (PC) (n = 68). Using training and testing cohorts, we identified and validated a small and distinct set of proteins that distinguished UCPPS from HC (n = 9) and UCPPS from PC (n = 3). The validated UCPPS: HC proteins were predominantly extracellular matrix/extracellular matrix modifying or immunomodulatory/host defense in nature. Significantly varying proteins in the UCPPS: HC comparison were overrepresented by the members of several dysregulated biological processes including decreased immune cell migration, decreased development of epithelial tissue, and increased bleeding. Comparison with the PC cohort enabled the evaluation of UCPPS-specific upstream regulators, contrasting UCPPS with other conditions that cause chronic pain. Specific to UCPPS were alterations in the predicted signaling of several upstream regulators, including alpha-catenin, interleukin-6, epidermal growth factor, and transforming growth factor beta 1, among others. These findings advance our knowledge of the etiology of UCPPS and inform potential future clinical translation into a diagnostic panel for UCPPS.

Keywords: TMT; UCPPS; bladder; inflammation; urine.

2021

Cerebral Perfusion and Sensory Testing Results Differ in Interstitial Cystitis/Bladder Pain Syndrome Patients with and without Fibromyalgia: A Site-Specific MAPP Network Study.

Deutsch G, Deshpande H, Lai HH, Kutch JJ, Ness TJ.   J Pain Res. 2021 Dec 23;14:3887-3895. doi: 10.2147/JPR.S343695. eCollection 2021.  [PMID: 34992450] [PMC8711634]

Abstract

Purpose: Fibromyalgia is a common co-morbidity in patients with interstitial cystitis/bladder pain syndrome. Quantitative sensory testing measures and regional cerebral blood flow measures have been noted to differ from healthy controls in both subjects with fibromyalgia and those with interstitial cystitis when studied independently. The present study examined such measures in subjects with the diagnosis of interstitial cystitis both with and without the co-diagnosis of fibromyalgia to determine whether differences in these measures may be associated with co-morbidity.

Patients and methods: Female subjects with the diagnosis of interstitial cystitis with (n = 15) and without (n = 19) the co-diagnosis of fibromyalgia as well as healthy control subjects (n = 41) underwent quantitative sensory testing. A subset of these patients (9 with and 9 without fibromyalgia) underwent brain perfusion studies using arterial spin labeled functional magnetic resonance imaging. An analysis was performed of absolute regional cerebral blood flow of regions-of-interest when experiencing a full bladder compared with an empty bladder.

Results: Subjects with both interstitial cystitis and fibromyalgia were more hypersensitive than those without fibromyalgia as well as healthy controls in most sensory measures except heat. Subjects with interstitial cystitis, but no fibromyalgia, differed from healthy controls only in toleration of the ischemic forearm task. Other co-morbidities were more common in those subjects with both interstitial cystitis and fibromyalgia. Bladder fullness was associated with significantly greater whole brain gray matter blood flow in subjects with interstitial cystitis and fibromyalgia when compared with that of subjects with interstitial cystitis without fibromyalgia. Examination of regional cerebral blood flow in individual regions-of-interest demonstrated statistically significant differences between the subjects with interstitial cystitis with and those without fibromyalgia bilaterally in the thalamus, amygdala and hippocampus, as well as the right prefrontal cortex and greater responsiveness to changes in bladder fullness in the insula.

Conclusion: Quantitative sensory testing and brain perfusion data support that there are two phenotypes of interstitial cystitis patients, which can be differentiated by a co-diagnosis of fibromyalgia. This may affect responsiveness to treatment and suggest the utility of stratifying interstitial cystitis patients according to their co-morbidities.

Keywords: QST; arterial spin labelling; fMRI; interstitial cystitis.

Anesthetic Bladder Capacity is a Clinical Biomarker for Interstitial Cystitis/Bladder Pain Syndrome Subtypes.

Plair A, Evans RJ, Langefeld CD, Matthews CA, Badlani G, Walker SJ.   Urology. 2021 Dec;158:74-80. doi: 10.1016/j.urology.2021.07.009. Epub 2021 Jul 22. [PMID: 34303757] [PMC8671173]

Abstract

Objective: To further examine anesthetic bladder capacity as a biomarker for interstitial cystitis/bladder pain syndrome (IC/BPS) patient subtypes, we evaluated demographic and clinical characteristics in a large and heterogeneous female patient cohort.

Material and methods: This is a retrospective review of data from women (n = 257) diagnosed with IC/BPS who were undergoing therapeutic bladder hydrodistention (HOD). Assessments included medical history and physical examination, validated questionnaire scores, and anesthetic BC. Linear regression analyses were computed to model the relationship between anesthetic BC and patient demographic data, symptoms, and diagnoses. Variables exhibiting suggestive correlations (P ≤ .1) were candidates for a multiple linear regression analysis and were retained if significant (P ≤ .05).

Results: Multiple regression analysis identified a positive correlation between BC and endometriosis (P = .028) as well as negative correlations between BC and both ICSI score (P < .001) and the presence of Hunner's lesions (P < .001). There were higher average numbers of pelvic pain syndrome (PPS) diagnoses (P = .006) and neurologic, autoimmune, or systemic pain (NASP) diagnoses (P = .003) in IC/BPS patients with a non-low BC, but no statistical difference in the duration of diagnosis between patients with low and non-low BC (P = .118).

Conclusion: These data, generated from a large IC/BPS patient cohort, provide additional evidence that higher BC correlates with higher numbers of non-bladder-centric syndromes while lower BC correlates more closely with bladder-specific pathology. Taken together, the results support the concept of clinical subgroups in IC/BPS.

Keywords: interstitial cystitis/bladder pain syndrome, hydrodistention, anesthetic bladder capacity, biomarker; DK082316 (Stephens-Shields AJ; Landis JR)

Cognitive behavioral therapy for irritable bowel syndrome induces bidirectional alterations in the brain-gut-microbiome axis associated with gastrointestinal symptom improvement.

Jacobs JP, Gupta A, Bhatt RR, Brawer J, Gao K, Tillisch K, Lagishetty V, Firth R, Gudleski GD, Ellingson BM, Labus JS, Naliboff BD, Lackner JM, Mayer EA.   Microbiome. 2021 Nov 30;9(1):236. doi: 10.1186/s40168-021-01188-6. [PMID: 34847963] [PMC8630837]

Abstract

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.

Keywords: Biomarkers; Brain-gut-microbiome axis; Cognitive behavioral therapy; Irritable bowel syndrome; Neuroimaging; Outcome prediction.

Urobiome: An outlook on the metagenome of urological diseases.

Shoemaker R, Kim J.  Investig Clin Urol. 2021 Nov;62(6):611-622. doi: 10.4111/icu.20210312. [PMID: 34729961] [PMC8566783]

Abstract

Abstract

The urinary tract likely plays a role in the development of various urinary diseases due to the recently recognized notion that urine is not sterile. In this mini review, we summarize the current literature regarding the urinary microbiome and mycobiome and its relationship to various urinary diseases. It has been recently discovered that the healthy urinary tract contains a host of microorganisms, creating a urinary microbiome. The relative abundance and type of bacteria varies, but generally, deviations in the standard microbiome are observed in individuals with urologic diseases, such as bladder cancer, benign prostatic hyperplasia, urgency urinary incontinence, overactive bladder syndrome, interstitial cystitis, bladder pain syndrome, and urinary tract infections. However, whether this change is causative, or correlative has yet to be determined. In summary, the urinary tract hosts a complex microbiome. Changes in this microbiome may be indicative of urologic diseases and can be tracked to predict, prevent, and treat them in individuals. However, current analytical and sampling collection methods may present limitations to the development in the understanding of the urinary microbiome and its relationship with various urinary diseases. Further research on the differences between healthy and diseased microbiomes, the long-term effects of antibiotic treatments on the urobiome, and the effect of the urinary mycobiome on general health will be important in developing a comprehensive understanding of the urinary microbiome and its relationship to the human body.

Keywords: Microbiome; Mycobiome; Urology; DK103260 (ANGER, J; FREEMAN, M)

Stress-Induced Accumulation of HnRNP K into Stress Granules.

Kim J, Yeon A, Kim WK, Kim KH, Ohn T.   J Cancer Sci Clin Ther. 2021;5(4):434-447. doi: 10.26502/jcsct.5079129. Epub 2021 Oct 15. [PMID: 35340804] [PMC8955021]

Abstract

Abstract

Stress granules (SGs) are cytoplasmic aggregates to reprogram gene expression in response to cellular stimulus. Here, we show that while SGs are being assembled in response to clotrimazole, an antifungal medication heterogeneous nuclear ribonucleoprotein (hnRNP) K, an RNA-binding protein that mediates translational silencing of mRNAs, is rapidly accumulated in SGs in U-2OS osteosarcoma cells. Forced expression of hnRNP K induces resistance to clotrimazole-induced apoptosis. Erk/MAPK is transiently activated in response to clotrimazole, and pharmacological suppression of the Erk/MAPK pathway sensitizes the cells to apoptosis. Inhibition of the Erk/MAPK pathway promotes the assembly of SGs. These results suggest that dynamic cytoplasmic formation of SGs and hnRNP K relocation to SGs may be defensive mechanisms against clotrimazole-induced apoptosis in U-2OS osteosarcoma cells.

Keywords: Apoptosis; Erk/MAPK; Stress granules; hnRNPK; DK103260 (ANGER, J; FREEMAN, M)

Relationship Between Blood Cytokine Levels, Psychological Comorbidity, and Widespreadness of Pain in Chronic Pelvic Pain.

Karshikoff B, Martucci KT, Mackey S.   Front Psychiatry. 2021 Jun 25;12:651083. doi: 10.3389/fpsyt.2021.651083. eCollection 2021. [PMID: 34248700] [PMC8267576]

Abstract

Abstract

Background: Low-grade inflammation has been implicated in the etiology of depression, long-term fatigue and chronic pain. TNFα and IL-6 are perhaps the most studied pro-inflammatory cytokines in the field of psychoneuroimmunology. The purpose of our study was to further investigate these relationships in patients with chronic pelvic pain specifically. Using plasma samples from a large, well-described cohort of patients with pelvic pain and healthy controls via the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network, we examined the relationship between TNFα and IL-6 and comorbid psychological symptoms. We also investigated the relationship between IL-8 and GM-CSF, and widespreadness of pain. 

Methods: We included baseline blood samples in the analyses, 261 patients (148 women) and 110 healthy controls (74 women). Fourteen pro- and anti-inflammatory or regulatory cytokines were analyzed in a Luminex® xMAP® high-sensitivity assay. We used regression models that accounted for known factors associated with the outcome variables to determine the relationship between cytokine levels and clinical measures. 

Results: There were no statistical differences in cytokine levels between patients and healthy controls when controlling for age. In patients, TNFα was significantly associated with levels of fatigue (p = 0.026), but not with pain intensity or depression. IL-6 was not significantly related to any of the outcome variables. Women with pelvic pain showed a negative relationship between IL-8 and widespreadness of pain, while men did not (p = 0.003). For both sexes, GM-CSF was positively related to widespreadness of pain (p = 0.039). 

Conclusion: Our results do not suggest low-grade systemic inflammation in chronic pelvic pain. Higher TNFα blood levels were related to higher fatigue ratings, while higher systemic GM-CSF levels predicted more widespread pain. Our study further suggests a potentially protective role of IL-8 with regard to with regard to the widepreadness of pain in the body, at least for women.

Keywords: chronic pain; comorbidity; cytokine-immunological terms; inflammation; pelvic pain; DK082316 (Stephens-Shields AJ; Landis JR).

Temporal relationships between pain, mood and urinary symptoms in urological chronic pelvic pain syndrome: A MAPP Network Study.

Naliboff BD, Schrepf AD, Stephens-Shields AJ, Clemens JQ, Pontari MA, Labus J, Taple BJ, Rodriguez LV, Strachan E, Griffith JW.   J Urol. 2021 Jun;205(6):1698-1703. doi: 10.1097/JU.0000000000001595. Epub 2021 Feb 4. [PMID: 33535797] [PMC9179931]

Abstract

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02514265.

Keywords: cystitis, interstitial; lower urinary tract symptoms; pain; pelvic pain; prostatitis.

Does pollen trigger urological chronic pelvic pain syndrome flares? a case-crossover analysis in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network.

Javed I, Yu T, Li J, Pakpahan R, Milbrandt M, Andriole GL, Lowder JL, Lai HH, Colditz GA, Sutcliffe S.   J Urol. 2021 Apr;205(4):1133-1138. doi: 10.1097/JU.0000000000001482. Epub 2020 Dec 21. [PMID: 33347771] [PMC9075343]

Abstract

Abstract

Purpose: We sought to determine whether pollen triggers urological chronic pelvic pain syndrome flares.

Materials and methods: We assessed flare status every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain case-crossover analysis of flare triggers (NCT01098279). Flare symptoms, flare start date and exposures in the 3 days before a flare were queried for the first 3 flares and at 3 randomly selected nonflare times. These data were linked to daily pollen count by date and the first 3 digits of participants' zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to nonflare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the 3 weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders.

Results: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (OR 1.31, 95% CI 1.04-1.66) and full longitudinal (RR 1.23, 95% CI 1.03-1.46) samples.

Conclusions: We found some evidence to suggest that rising pollen count may trigger flares of urological chronic pelvic pain syndrome. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention and treatment, and control over the unpredictability of flares.

Keywords: cystitis, interstitial; pelvic pain; pollen; prostatitis; symptom flare up.

Comparison of deep phenotyping features of UCPPS with and without Hunner lesion: A MAPP-II Research Network Study.

Lai HH, Newcomb C, Harte S, Appleby D, Ackerman AL, Anger JT, Nickel JC, Gupta P, Rodriguez LV, Landis JR, Clemens JQ; MAPP Research Network.   Neurourol Urodyn. 2021 Mar;40(3):810-818. doi: 10.1002/nau.24623. Epub 2021 Feb 19. [PMID: 33604963] [PMC8159180]

Abstract

Abstract

Objective: To use the phenotyping data from the MAPP-II Symptom Patterns Study (SPS) to compare the systemic features between urologic chronic pelvic pain syndrome (UCPPS) with Hunner lesion (HL) versus those without HL.

Methods: We performed chart review on 385 women and 193 men with UCPPS who enrolled in the MAPP-II SPS. 223 had cystoscopy and documentation of HL status. Among them, 12.5% had HL and 87.5% did not.

Results: UCPPS participants with HL were older, had increased nocturia, higher Interstitial Cystitis Symptom and Problem Indexes, and were more likely to report "painful urgency" compared with those without HL. On the other hand, UCPPS without HL reported more intense nonurologic pain, greater distribution of pain outside the pelvis, greater numbers of comorbid chronic overlapping pain conditions, higher fibromyalgia-like symptoms, and greater pain centralization, and were more likely to have migraine headache than those with HL. UCPPS without HL also had higher anxiety, perceived stress, and pain catastrophizing than those with HL. There were no differences in sex distribution, UCPPS symptom duration, intensity of urologic pain, distribution of genital pain, pelvic floor tenderness on pelvic examination, quality of life, depression, pain characteristics (nociceptive pain vs. neuropathic pain), mechanical hypersensitivity in the suprapubic area during quantitative sensory testing, and 3-year longitudinal pain outcome and urinary outcome between the two groups.

Conclusions: UCPPS with HL displayed more bladder-centric symptom profiles, while UCPPS without HL displayed symptoms suggesting a more systemic pain syndrome. The MAPP-II SPS phenotyping data showed that Hunner lesion is a distinct phenotype from non-Hunner lesion.

Keywords: Hunner lesion; chronic prostatitis; clinical phenotyping; interstitial cystitis; personalized medicine; ulcerative interstitial cystitis.

© 2021 Wiley Periodicals LLC.

A Mobile Phone Application for Assessing Daily Variation in Pain Location and Pain Intensity in Patients with Urologic Chronic Pelvic Pain Syndrome: A MAPP Network Study.

Erickson BA, Herman T, Hahn AE, Taple BJ, Bass M, Lloyd RB, Sutcliffe S, Griffith JW.   Urol Pract. 2021 Mar;8(2):189-195. doi: 10.1097/UPJ.0000000000000203. Epub 2020 Oct 14. [PMID: 36419906] [PMC9662822]

Abstract

Abstract

Introduction: We created and tested a mobile app that facilitates the ecological momentary assessment of pain intensity and pain location and identifies heterogeneous patient pain phenotypes.

Methods: A mobile app was created with patient, clinician and researcher input. A sample of 20 participants with urologic chronic pelvic pain syndrome were then asked to complete a 14-day pain assessment using the app. Data were analyzed to assess compliance, usability and the ability for the app to capture variation in pain intensity and pain location. Ecological momentary assessment pain data were then compared to end-of-week pain summary questions to determine construct validity.

Results: Mean compliance was 70±8%, higher earlier in the study period (p <0.0005) and better in older individuals (p <0.0001). During the 14-day assessment, 90% of participants reported daily variation in pelvic pain intensity (SD 0.64-3.02; out of 10), 95% reported variation in their nonpelvic pain (SD 0.17-3.63; out of 10) and 100% reported variations in number of sites with pain (SD 0.22-1.44; out of 7). Pelvic pain and nonpelvic pain intensity, as determined by cumulative app scores, were associated with patient reported end-of-week scores; worst pain (r pelvic =0.67; r nonpelvic =0.53) and average pain (r pelvic =0.78; r nonpelvic =0.73).

Conclusions: The easy-to-use app captured unique patterns of pain not fully captured by traditional end-of-day/week summary questions or by traditional in-office assessments. Mobile apps for assessing chronic conditions will become increasingly important as telehealth becomes more commonplace.

Keywords: data collection; ecological momentary assessment; mobile applications; prostatitis.

Association of longitudinal changes in symptoms and urinary biomarkers in patients with urological chronic pelvic pain syndrome: A MAPP Research Network Study.

Roy R, Stephens AJ, Daisy C, Merritt L, Newcomb CW, Yang J, Dagher A, Curatolo A, Sachdev M, McNeish B, Landis R, van Bokhoven A, El-Hayek A, Froehlich J, Pontari MA, Zurakowski D, Lee RS, Moses MA.   J Urol. 2021 Feb;205(2):514-523. doi: 10.1097/JU.0000000000001391. Epub 2020 Oct 7. [PMID: 33026902] [PMC8139408]

Abstract

Abstract

Purpose: We analyzed a series of novel noninvasive urinary biomarkers for their ability to objectively monitor the longitudinal clinical status of patients with urological chronic pelvic pain syndrome.

Materials and methods: Baseline, 6 and 12-month urine samples were collected (216) and used to quantify vascular endothelial growth factor, vascular endothelial growth factor (VEGF) receptor 1 (R1), neutrophil gelatinase associated lipocalin (NGAL), matrix metalloproteinase-2, matrix metalloproteinase (MMP)-9, and MMP-9/NGAL complex by enzyme-linked immunosorbent assays. Patient symptom changes were classified as improved, stable or worse using a functional clustering algorithm. Proportional odds models were used to evaluate the association between symptom change and urinary biomarkers.

Results: Across all sampled participants, longitudinal decreases in normalized VEGF concentration (pg/μg) were associated with pain severity improvement, and decreases in MMP-9, NGAL and VEGF-R1 concentration (pg/ml) as well as NGAL normalized concentration were associated with improved urinary symptoms. Longitudinal decreases in normalized VEGF-R1 were associated with pain improvement in patients with moderate widespreadness, no bladder symptoms and no painful filling. Lower baseline normalized VEGF-R1 concentration was associated with pain improvement in patients with pelvic pain only. Higher baseline MMP-9/NGAL levels were associated with pain and urinary improvement across all participants. Moreover, longitudinal increases in MMP-2 concentration was associated with improved pain in men and patients with painful filling.

Conclusions: Our results suggest these urinary biomarkers may be useful in monitoring urological chronic pelvic pain syndrome symptom changes with respect to both urinary severity and pain severity. With further testing, they may represent objective biological measures of urological chronic pelvic pain syndrome progression and/or resolution while also providing insight into the pathophysiology of urological chronic pelvic pain syndrome.

Keywords: lipocalin-2; matrix metalloproteinases; pelvic pain; vascular endothelial growth factor; vascular endothelial growth factor receptor.

2020

Natural bladder filling alters resting brain function at multiple spatial scales: a proof-of-concept MAPP Network Neuroimaging Study.

Mawla I, Schrepf A, Ichesco E, Harte SE, Klumpp DJ, Griffith JW, Strachan E, Yang CC, Lai H, Andriole G, Magnotta VA, Kreder K, Clauw DJ, Harris RE, Clemens JQ, Landis JR, Mullins C, Rodriguez LV, Mayer EA, Kutch JJ. Sci Rep. 2020 Nov 16;10(1):19901. doi: 10.1038/s41598-020-76857-x. [PMID: 33199816] [PMC7669903]

Abstract

Abstract

Neural circuitry regulating urine storage in humans has been largely inferred from fMRI during urodynamic studies driven by catheter infusion of fluid into the bladder. However, urodynamic testing may be confounded by artificially filling the bladder repeatedly at a high rate and examining associated time-locked changes in fMRI signals. Here we describe and test a more ecologically-valid paradigm to study the brain response to bladder filling by (1) filling the bladder naturally with oral water ingestion, (2) examining resting state fMRI (rs-fMRI) which is more natural since it is not linked with a specific stimulus, and (3) relating rs-fMRI measures to self-report (urinary urge) and physiologic measures (voided volume). To establish appropriate controls and analyses for future clinical studies, here we analyze data collected from healthy individuals (N = 62) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Participants orally ingested approximately 350 mL of water, and had a 10 min "fuller bladder" rs-fMRI scan approximately 1 h later. A second 10 min "empty bladder" rs-fMRI scan was conducted immediately following micturition. We examined multiple spatial scales of brain function, including local activity, circuits, and networks. We found changes in brain function distributed across micturition loci (e.g., subregions of the salience, sensorimotor, and default networks) that were significantly related to the stimulus (volume) and response (urinary urge). Based on our results, this paradigm can be applied in the future to study the neurobiological underpinnings of urologic conditions.

Keywords: bladder; functional magnetic resonance imaging.

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.

Clemens JQ, Stephens-Shields AJ, Newcomb C, Rodriguez LV, Lai HH, Bradley CS, Naliboff BD, Griffith JW, Taple BJ, Gupta P, Afari N, Harte SE, Strachan E, Guo W, Landis JR.  J Urol. 2020 Oct;204(4):754-759. doi: 10.1097/JU.0000000000001080. Epub 2020 Apr 15. [PMID: 32294397] [PMC7483873]

Abstract

Abstract

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.

Keywords: cystitis; interstitial; prostatitis.

AOAH remodels arachidonic acid-containing phospholipid pools in a model of interstitial cystitis pain: A MAPP Network study.

Yang W, Yaggie RE, Schaeffer AJ, Klumpp DJ.  PLoS One. 2020 Sep 14;15(9):e0235384. doi: 10.1371/journal.pone.0235384. eCollection 2020. [PMID: 32925915] [PMC7489500]

Abstract

Abstract

Interstitial cystitis/bladder pain syndrome (IC) is a debilitating condition of chronic pelvic pain with unknown etiology. Recently, we used a genetic approach in a murine model of IC to identify the lipase acyloxyacyl hydrolase (AOAH) as a modulator of pelvic pain. We found that AOAH-deficient mice have elevated pelvic pain responses, and AOAH immunoreactivity was detected along the bladder-brain axis. Lipidomic analyses identified arachidonic acid (AA) and its metabolite PGE2 as significantly elevated in the sacral spinal cord of AOAH-deficient mice, suggesting AA is a substrate for AOAH. Here, we quantified the effects of AOAH on phospholipids containing AA. Spinal cord lipidomics revealed increased AA-containing phosphatidylcholine in AOAH-deficient mice and concomitantly decreased AA-phosphatidylethanolamine, consistent with decreased CoA-independent transferase activity (CoIT). Overexpression of AOAH in cell cultures similarly altered distribution of AA in phospholipid pools, promoted AA incorporation, and resulted in decreased membrane fluidity. Finally, administration of a PGE2 receptor antagonist reduced pelvic pain in AOAH-deficient mice. Together, these findings suggest that AOAH represents a potential CoA-independent AA transferase that modulates CNS pain pathways at the level of phospholipid metabolism.

Keywords: pain; phospholipids; spinal cord; allodynia; transferases; lipids; homeostasis; cell membranes.

The Multidisciplinary Approach to The Study of Chronic Pelvic Pain (MAPP) Research Network*: Design and implementation of the Symptom Patterns Study (SPS).

Clemens JQ, Kutch JJ, Mayer EA, Naliboff BD, Rodriguez LV, Klumpp DJ, Schaeffer AJ, Kreder KJ, Clauw DJ, Harte SE, Schrepf AD, Williams DA, Andriole GL, Lai HH, Buchwald D, Lucia MS, van Bokhoven A, Mackey S, Moldwin RM, Pontari MA, Stephens-Shields AJ, Mullins C, Landis JR.   Neurourol Urodyn. 2020 Aug;39(6):1803-1814. doi: 10.1002/nau.24423. Epub 2020 Jun 23. [PMID: 32578257] [PMC8025696]

Abstract

Abstract

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.

Keywords: chronic; interstitial cystitis; plasma biomarkers; prostatitis; urine biomarkers; urological chronic pelvic pain syndromes.

Ceftriaxone inhibits stress-induced bladder hyperalgesia and alters cerebral micturition and nociceptive circuits in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study.

Holschneider DP, Wang Z, Chang H, Zhang R, Gao Y, Guo Y, Mao J, Rodriguez LV. Neurourol Urodyn. 2020 Aug;39(6):1628-1643. doi: 10.1002/nau.24424. Epub 2020 Jun 23. [PMID: 32578247] [PMC7642011]

Abstract

Abstract

Aims: Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress-induced bladder hyperalgesia, a core feature of IC/BPS.

Methods: Wistar-Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [14 C]-iodoantipyrine during passive bladder distension. Regional CBF was quantified in autoradiographs of brain slices and analyzed in three dimensional reconstructed brains with statistical parametric mapping.

Results: WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress-related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus.

Conclusions: CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress-related bladder dysfunction may be a novel approach to the treatment of IC/BPS.

Keywords: animal model; brain mapping; glutamate; micturition; painful bladder syndrome/interstitial cystitis; water avoidance stress.

Analysis of viruses present in urine from patients with interstitial cystitis.

Robles MTS, Cantalupo PG, Duray AM, Freeland M, Murkowski M, van Bokhoven A, Stephens-Shields AJ, Pipas JM, Imperiale MJ. Virus Genes. 2020 Aug;56(4):430-438. doi: 10.1007/s11262-020-01767-z. Epub 2020 May 23. [PMID: 32447589] [PMC7339973]

Abstract

Abstract

The question of whether some cases of interstitial cystitis may have an infectious etiology has been debated for some time. Previous studies have looked for the presence of certain specific viruses, but generally did not use the types of sensitive and unbiased approaches that are currently available. As part of the MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Research Network, we examined urine specimens from interstitial cystitis patients who provided specimens over time and also reported various symptoms at the time of urine collection. We first performed next-generation sequencing to look for the presence of viruses in urines, and detected two human polyomaviruses that are known to be excreted into urine, BKPyV and JCPyV. We were especially interested in BKPyV because it is a known cause of another bladder disease, hemorrhagic cystitis, in bone marrow transplant recipients. Further analysis of individual samples indicates a trend toward higher excretion of polyomaviruses in patients experiencing increased symptoms.

Keywords: Interstitial cystitis; NGS; PCR; Polyomavirus; Virus discovery.

Does weather trigger urologic chronic pelvic pain syndrome flares? A case-crossover analysis in the multidisciplinary approach to the study of the chronic pelvic pain research network.

Li J, Yu T, Javed I, Siddagunta C, Pakpahan R, Langston ME, Dennis LK, Kingfield DM, Moore DJ, Andriole GL, Lai HH, Colditz GA, Sutcliffe S; MAPP Research Network. Neurourol Urodyn. 2020 Jun;39(5):1494-1504. doi: 10.1002/nau.24381. Epub 2020 May 4. [PMID: 32893408] [PMC7479643]

Abstract

Abstract

Background: To investigate whether meteorological factors (temperature, barometric pressure, relative humidity, ultraviolet index [UVI], and seasons) trigger flares in male and female urologic chronic pelvic pain patients.

Methods: We assessed flare status every 2 weeks in our case-crossover study of flare triggers in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain 1-year longitudinal study. Flare symptoms, flare start date, and exposures in the 3 days preceding a flare or the date of questionnaire completion were assessed for the first three flares and at three randomly selected nonflare times. We linked these data to daily temperature, barometric pressure, relative humidity, and UVI values by participants' first 3 zip code digits. Values in the 3 days before and the day of a flare, as well as changes in these values, were compared to nonflare values by conditional logistic regression. Differences in flare rates by astronomical and growing seasons were investigated by Poisson regression in the full study population.

Results: A total of 574 flare and 792 nonflare assessments (290 participants) were included in the case-crossover analysis, and 966 flare and 5389 nonflare (409 participants) were included in the full study analysis. Overall, no statistically significant associations were observed for daily weather, no patterns of associations were observed for weather changes, and no differences in flare rates were observed by season.

Conclusions: We found minimal evidence to suggest that weather triggers flares, although we cannot rule out the possibility that a small subset of patients is susceptible.

Keywords: bladder pain syndrome; chronic pelvic pain syndrome; chronic prostatitis; flare; interstitial cystitis; trigger.

Sensitivity of functional connectivity to periaqueductal gray localization, with implications for identifying disease-related changes in chronic visceral pain: A MAPP Research Network neuroimaging study.

Fenske SJ, Bierer D, Chelimsky G, Conant L, Ustine C, Yan K, Chelimsky T, Kutch JJ. Neuroimage Clin. 2020;28:102443. doi: 10.1016/j.nicl.2020.102443. Epub 2020 Sep 20. [PMID: 33027702] [PMC7548991]

Abstract

Abstract

Previous studies examining the resting-state functional connectivity of the periaqueductal gray (PAG) in chronic visceral pain have localized PAG coordinates derived from BOLD responses to provoked acute pain. These coordinates appear to be several millimeters anterior of the anatomical location of the PAG. Therefore, we aimed to determine whether measures of PAG functional connectivity are sensitive to the localization technique, and if the localization approach has an impact on detecting disease-related differences in chronic visceral pain patients. We examined structural and resting-state functional MRI (rs-fMRI) images from 209 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We applied three different localization techniques to define a region-of-interest (ROI) for the PAG: 1) a ROI previously-published as a Montreal Neurological Institute (MNI) coordinate surrounded by a 3 mm radius sphere (MNI-sphere), 2) a ROI that was hand-traced over the PAG in a MNI template brain (MNI-trace), and 3) a ROI that was hand-drawn over the PAG in structural images from 30 individual participants (participant-trace). We compared the correlation among the rs-fMRI signals from these PAG ROIs, as well as the functional connectivity of these ROIs with the whole brain. First, we found important non-uniformities in brainstem rs-fMRI signals, as rs-fMRI signals from the MNI-trace ROI were significantly more similar to the participant-trace ROI than to the MNI-sphere ROI. We then found that choice of ROI also impacts whole-brain functional connectivity, as measures of PAG functional connectivity throughout the brain were more similar between MNI-trace and participant-trace compared to MNI-sphere and participant-trace. Finally, we found that ROI choice impacts detection of disease-related differences, as functional connectivity differences between pelvic pain patients and healthy controls were much more apparent using the MNI-trace ROI compared to the MNI-sphere ROI. These results indicate that the ROI used to localize the PAG is critical, especially when examining brain functional connectivity changes in chronic visceral pain patients.

Keywords: Brain parcellation; Brainstem; PAG; Resting-state; UCPPS; fMRI.

Exercise modulates neuronal activation in the micturition circuit of chronically stressed rats: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

Holschneider DP, Wang Z, Guo Y, Sanford MT, Yeh J, Mao JJ, Zhang R, Rodriguez LV. Physiol Behav. 2020 Mar 1;215:112796. doi: 10.1016/j.physbeh.2019.112796. Epub 2019 Dec 27. [PMID: 31884113] [PMC7269603]

Abstract

Abstract

Background: Rats exposed to water avoidance stress (WAS) show increased urinary frequency, increased somatosensory nociceptive reflex responses, as well as altered brain responses to bladder distension, analogous to similar observations made in patients with urologic chronic pelvic pain syndrome (UCPPS). Exercise has been proposed as a potential treatment option for patients with chronic urinary frequency and urgency. We examined the effects of exercise on urinary voiding parameters and functional brain activation during bladder distension in rats exposed to WAS.

Methods: Adult, female Wistar Kyoto rats were exposed to 10 days of WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Thereafter, cerebral blood flow (CBF) mapping was performed during isotonic bladder distension (20 cm H2O) after intravenous bolus injection of [14C]-iodoantipyrine. Regional CBF was quantified in autoradiographs of brain slices and analyzed in 3-D reconstructed brains by statistical parametric mapping. Functional connectivity was examined between regions of the micturition circuit through interregional correlation analysis.

Results: WAS exposure in sedentary animals (WAS/no-EX) increased voiding frequency and decreased urinary volumes per void. Exercise exposure in WAS animals (WAS/EX) resulted in a progressive decline in voiding frequency back to the baseline, as well as increased urinary volumes per void. Within the micturition circuit, WAS/EX compared to WAS/no-EX demonstrated a significantly lower rCBF response to passive bladder distension in Barrington's nucleus that is part of the spinobulbospinal voiding reflex, as well as in the periaqueductal gray (PAG) which modulates this reflex. Greater rCBF was noted in WAS/EX animals broadly across corticolimbic structures, including the cingulate, medial prefrontal cortex (prelimbic, infralimbic areas), insula, amygdala, and hypothalamus, which provide a 'top-down' decision point where micturition could be inhibited or triggered. WAS/EX showed a significantly greater positive brain functional connectivities compared to WAS/no-EX animals within regions of the extended reflex loop (PAG, Barrington's nucleus, intermediodorsal thalamic nucleus, pons), as well as within regions of the corticolimbic decision-making loop of the micturition circuit, with a strikingly negative correlation between these pathways. Urinary frequency was positively correlated with rCBF in the pons, and negatively correlated with rCBF in the cingulate cortex.

Conclusion: Our results suggest that chronic voluntary exercise may decrease urinary frequency at two points of control in the micturition circuit. During the urine storage phase, it may diminish the influence of the reflex micturition circuit itself, and/or it may increase corticolimbic control of voiding. Exercise may be an effective adjunct therapeutic intervention for modifying the urinary symptoms in patients with UCPPS.

Keywords: Bladder pain syndrome; Exercise; Functional brain mapping; Interstitial cystitis; Micturition circuit; Psychological stress.

Voluntary exercise improves voiding function and bladder hyperalgesia in an animal model of stress-induced visceral hypersensitivity: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study.

Sanford MT, Yeh JC, Mao JJ, Guo Y, Wang Z, Zhang R, Holschneider DP, Rodriguez LV. Neurourol Urodyn. 2020 Feb;39(2):603-612. doi: 10.1002/nau.24270. Epub 2020 Jan 13. [PMID: 31944369] [PMC7043234]

Abstract

Abstract

Objective: The underlying mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS) is not well understood and evaluation of current therapeutic interventions has not identified any generally effective treatments. Physical activity has shown beneficial effects on individuals suffering from chronic pain. Anxiety-prone rats exposed to water avoidance stress (WAS) develop urinary frequency and lower bladder sensory thresholds with high face and construct validity for the study of IC/BPS. The aim of this study was to evaluate the role of chronic voluntary exercise on urinary frequency, voiding function, and hyperalgesia in animals exposed to WAS.

Materials and methods: Twenty-six female Wistar-Kyoto rats were exposed to WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Before euthanasia, the animals underwent cystometrogram (CMG), external urinary sphincter electromyography, and assessment of visceromotor response (VMR) to isotonic bladder distension (IBD).

Results: WAS exposure resulted in adverse changes in voiding parameters. Compared with sedentary animals, animals in the voluntary exercise group had improved voiding parameters during metabolic cage and CMG testing, as well as improved bladder sensory thresholds as determined by VMR during IBD.

Conclusion: Voluntary exercise in an animal model of chronic stress leads to improvement in voiding function and visceral bladder hyperalgesia.

Keywords: animal model; exercise; interstitial cystitis/bladder pain syndrome; psychological stress.

Urinary fungi associated with urinary symptom severity among women with interstitial cystitis/bladder pain syndrome (IC/BPS).

Nickel JC, Stephens A, Landis JR, Mullins C, van Bokhoven A, Anger JT, Ackerman AL, Kim J, Sutcliffe S, Krol JE, Sen B, Hammond J, Ehrlich GD; Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. World J Urol. 2020 Feb;38(2):433-446. doi: 10.1007/s00345-019-02764-0. Epub 2019 Apr 26. [PMID: 31028455] [PMC6815247]

Abstract

Abstract

Purpose: To correlate the presence of fungi with symptom flares, pain and urinary severity in a prospective, longitudinal study of women with IC/BPS enrolled in the MAPP Research Network.

Methods: Flare status, pelvic pain, urinary severity, and midstream urine were collected at baseline, 6 and 12 months from female IC/BPS participants with at least one flare and age-matched participants with no reported flares. Multilocus PCR coupled with electrospray ionization/mass spectrometry was used for identification of fungal species and genus. Associations between "mycobiome" (species/genus presence, relative abundance, Shannon's/Chao1 diversity indices) and current flare status, pain, urinary severity were evaluated using generalized linear mixed models, permutational multivariate analysis of variance, Wilcoxon's rank-sum test.

Results: The most specific analysis detected 13 fungal species from 8 genera in 504 urine samples from 202 females. A more sensitive analysis detected 43 genera. No overall differences were observed in fungal species/genus composition or diversity by flare status or pain severity. Longitudinal analyses suggested greater fungal diversity (Chao1 Mean Ratio 3.8, 95% CI 1.3-11.2, p = 0.02) and a significantly greater likelihood of detecting any fungal species (OR = 5.26, 95% CI 1.1-25.8, p = 0.04) in high vs low urinary severity participants. Individual taxa analysis showed a trend toward increased presence and relative abundance of Candida (OR = 6.63, 95% CI 0.8-58.5, p = 0.088) and Malassezia (only identified in 'high' urinary severity phenotype) for high vs low urinary symptoms.

Conclusion: This analysis suggests the possibility that greater urinary symptom severity is associated with the urinary mycobiome urine in some females with IC/BPS.

Keywords: Bladder pain syndrome; Flares; Fungal; Interstitial cystitis; Mycobiome.

A MAPP network case-control study of urological chronic pelvic pain compared with nonurological pain conditions.

Afari N, Buchwald D, Clauw D, Hong B, Hou X, Krieger JN, Mullins C, Stephens-Shields AJ, Gasperi M, Williams DA; MAPP Research Network.  Clin J Pain. 2020 Jan;36(1):8-15. doi: 10.1097/AJP.0000000000000769. Epub 2019 Sep 26. [PMID: 31794439] [PMC7055954]

Abstract

Abstract

Objectives: Limited research suggests commonalities between urological chronic pelvic pain syndromes (UCPPS) and other nonurological chronic overlapping pain conditions (COPCs) including fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome. The goal of this case-control study was to examine similarities and differences between UCPPS and these other COPCs.

Materials and methods: As part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research (MAPP) Network, we examined 1039 individuals with UCPPS (n=424), nonurological COPCs (n=200), and healthy controls (HCs; n=415). Validated standardized measures were used to assess urological symptoms, nonurological pain symptoms, and psychosocial symptoms and traits.

Results: Participants with UCPPS had more urological symptoms than nonurological COPCs or HCs (P<0.001); nonurological COPC group also had significantly worse urological symptoms than HCs (P<0.001). Participants with nonurological COPCs reported more widespread pain than those with UCPPS (P<0.001), yet both groups had similarly increased symptoms of anxiety, depression, negative affect, perceived stress, neuroticism, and lower levels of extraversion than HCs (P<0.001). Participants with UCPPS with and without COPCs reported more catastrophizing than those with nonurological COPCs (P<0.001).

Discussion: Findings are consistent with the hypothesis of common underlying biopsychosocial mechanisms and can guide the comprehensive assessment and treatment of these conditions regardless of the primary site of pain or diagnosis. Heightened catastrophizing in UCPPS should be examined to inform psychosocial interventions and improve patient care.

Keywords: catastrophizing, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, pelvic pain.

Assessing somatization in urologic chronic pelvic pain syndrome.

North CS, Hong BA, Lai HH, Alpers DH. BMC Urol. 2019 Dec 10;19(1):130. doi: 10.1186/s12894-019-0556-3. [PMID: 31823813] [PMC6902613]

Abstract

Abstract

Background: This study examined the prevalence of somatization disorder in Urological Chronic Pelvic Pain Syndrome (UCPPS) and the utility of two self-report symptom screening tools for assessment of somatization in patients with UCPPS.

Methods: The study sample included 65 patients with UCPPS who enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Study at Washington University. Patients completed the PolySymptomatic PolySyndromic Questionnaire (PSPS-Q) (n = 64) and the Patient Health Questionnaire-15 Somatic Symptom Severity Scale (PHQ-15) (n = 50). Review of patient medical records found that only 47% (n = 30) contained sufficient documentation to assess Perley-Guze criteria for somatization disorder.

Results: Few (only 6.5%) of the UCPPS sample met Perley-Guze criteria for definite somatization disorder. Perley-Guze somatization disorder was predicted by definite PSPS-Q somatization with at least 75% sensitivity and specificity. Perley-Guze somatization disorder was predicted by severe (> 15) PHQ-15 threshold that had > 90% sensitivity and specificity but was met by only 16% of patients. The moderate (> 10) PHQ-15 threshold had higher sensitivity (100%) but lower specificity (52%) and was met by 52% of the sample.

Conclusions: The PHQ-15 is brief, but it measures symptoms constituting only one dimension of somatization. The PSPS-Q uniquely captures two conceptual dimensions inherent in the definition of somatization disorder, both number of symptoms and symptom distribution across multiple organ systems, with relevance for UCPPS as a syndrome that is not just a collection of urological symptoms but a broader syndrome with symptoms extending beyond the urological system.

Keywords: Chronic prostatitis; Interstitial cystitis; Polysymptomatic; Polysyndromic; Psychiatric diagnosis; Psychoform; Somatization disorder; Somatoform; Symptom screening; Urological chronic pelvic pain syndrome.

Changes in whole body pain intensity and widespreadness during urologic chronic pelvic pain syndrome flares-Findings from one site of the MAPP study.

Xu T, Lai HH, Pakpahan R, Vetter J, Andriole GL, Bradley C, Naliboff BD, Colditz GA, Sutcliffe S.  Neurourol Urodyn. 2019 Nov;38(8):2333-2350. doi: 10.1002/nau.24150. Epub 2019 Sep 4. [PMID: 31483064] [PMC9188843]

Abstract

Abstract

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.

Keywords: chronic prostatitis; flares; interstitial cystitis; longitudinal study; symptom exacerbations.

Flares of chronic pelvic pain syndrome: lessons learned from the MAPP Research Network.

Kessler TM.  BJU Int. 2019 Sep;124(3):360-361. doi: 10.1111/bju.14843. [PMID: 31436041] [ZORA 174299]

Abstract

No abstract available

Comment on

A longitudinal analysis of urological chronic pelvic pain syndrome flares in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Sutcliffe S, Gallop R, Henry Lai HH, Andriole GL, Bradley CS, Chelimsky G, Chelimsky T, Quentin Clemens J, Colditz GA, Erickson B, Griffith JW, Kim J, Krieger JN, Labus J, Naliboff BD, Rodriguez LV, Sutherland SE, Taple BJ, Landis JR. BJU Int. 2019 Sep;124(3):522-531. doi: 10.1111/bju.14783. Epub 2019 May 29. PMID: 31012513 Keywords: chronic disease; chronic pain; pelvic pain.

A longitudinal analysis of urological chronic pelvic pain syndrome flares in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

Sutcliffe S, Gallop R, Henry Lai HH, Andriole GL, Bradley CS, Chelimsky G, Chelimsky T, Quentin Clemens J, Colditz GA, Erickson B, Griffith JW, Kim J, Krieger JN, Labus J, Naliboff BD, Rodriguez LV, Sutherland SE, Taple BJ, Landis JR.  BJU Int. 2019 Sep;124(3):522-531. doi: 10.1111/bju.14783. Epub 2019 May 29. [PMID: 31012513] [PMC6706296]

Abstract

Abstract

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.

Keywords: epidemiology; interstitial cystitis; prostatitis; symptom flare-up.

Acyloxyacyl hydrolase modulates depressive-like behaviors through aryl hydrocarbon receptor.

Aguiniga LM, Yang W, Yaggie RE, Schaeffer AJ, Klumpp DJ; MAPP Research Network Study Group.  Am J Physiol Regul Integr Comp Physiol. 2019 Aug 1;317(2):R289-R300. doi: 10.1152/ajpregu.00029.2019. Epub 2019 Apr 24. [PMID: 31017816] [PMC6732428]

Abstract

Abstract

Corticotropin-releasing factor (CRF) regulates stress responses, and aberrant CRF signals are associated with depressive disorders. Crf expression is responsive to arachidonic acid (AA), where CRF is released from the hypothalamic paraventricular nucleus (PVN) to initiate the hypothalamic-pituitary-adrenal axis, culminating in glucocorticoid stress hormone release. Despite this biological and clinical significance, Crf regulation is unclear. Here, we report that acyloxyacyl hydrolase, encoded by Aoah, is expressed in the PVN, and Aoah regulates Crf through the aryl hydrocarbon receptor (AhR). We previously showed that AOAH-deficient mice mimicked interstitial cystitis/bladder pain syndrome, a condition frequently associated with comorbid anxiety and depression. With the use of novelty-suppressed feeding and sucrose preference assays to quantify rodent correlates of anxiety/depression, AOAH-deficient mice exhibited depressive behaviors. AOAH-deficient mice also had increased CNS AA, increased Crf expression in the PVN, and elevated serum corticosterone, consistent with dysfunction of the hypothalamic-pituitary-adrenal axis. The human Crf promoter has putative binding sites for AhR and peroxisome proliferator-activated receptor (PPARγ). PPARγ did not affect AA-dependent Crf expression in vitro, and conditional Pparγ knockout did not alter the AOAH-deficient depressive phenotype, despite previous studies implicating PPARγ as a therapeutic target for depression. In contrast, Crf induction was mediated by AhR binding sites in vitro and increased by AhR overexpression. Furthermore, conditional Ahr knockout rescued the depressive phenotype of AOAH-deficient mice. Finally, an AhR antagonist rescued the AOAH-deficient depressive phenotype. Together, our results demonstrate that Aoah is a novel genetic regulator of Crf mediated through AhR, and AhR is a therapeutic target for depression.

Keywords: AOAH; AhR; CRF; arachidonic acid; interstitial cystitis; stress.

Impact of early adverse life events and sex on functional brain networks in patients with urological chronic pelvic pain syndrome (UCPPS): A MAPP Research Network study.

Gupta A, Bhatt RR, Naliboff BD, Kutch JJ, Labus JS, Vora PP, Alaverdyan M, Schrepf A, Lutgendorf S, Mayer EA; MAPP Research Network. PLoS One. 2019 Jun 20;14(6):e0217610. doi: 10.1371/journal.pone.0217610. eCollection 2019. [PMID: 31220089] [PMC6586272]

Abstract

Abstract

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).

Keywords: centrality; pain; eigenvectors; neural networks; neuroimaging; caudate nucleus; urology; basal ganglia.

Quantitative assessment of nonpelvic pressure pain sensitivity in urologic chronic pelvic pain syndrome: a MAPP Research Network study.

Harte SE, Schrepf A, Gallop R, Kruger GH, Lai HHH, Sutcliffe S, Halvorson M, Ichesco E, Naliboff BD, Afari N, Harris RE, Farrar JT, Tu F, Landis JR, Clauw DJ; MAPP Research Network. Pain. 2019 Jun;160(6):1270-1280. doi: 10.1097/j.pain.0000000000001505. [PMID: 31050659] [PMC6527452]

Abstract

Abstract

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.

Keywords: Quantitative sensory testing; Pressure pain threshold; Interstitial cystitis; Bladder pain syndrome; Chronic prostatitis; Chronic pelvic pain syndrome; Central sensitization.

Trial registration: ClinicalTrials.gov NCT01098279.

Optimization of DNA extraction from human urinary samples for mycobiome community profiling.

Ackerman AL, Anger JT, Khalique MU, Ackerman JE, Tang J, Kim J, Underhill DM, Freeman MR; NIH Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP). PLoS One. 2019 Apr 25;14(4):e0210306. doi: 10.1371/journal.pone.0210306. eCollection 2019. [PMID: 31022216] [PMC6483181]

Abstract

Abstract

Introduction: Recent data suggest the urinary tract hosts a microbial community of varying composition, even in the absence of infection. Culture-independent methodologies, such as next-generation sequencing of conserved ribosomal DNA sequences, provide an expansive look at these communities, identifying both common commensals and fastidious organisms. A fundamental challenge has been the isolation of DNA representative of the entire resident microbial community, including fungi.

Materials and methods: We evaluated multiple modifications of commonly-used DNA extraction procedures using standardized male and female urine samples, comparing resulting overall, fungal and bacterial DNA yields by quantitative PCR. After identifying protocol modifications that increased DNA yields (lyticase/lysozyme digestion, bead beating, boil/freeze cycles, proteinase K treatment, and carrier DNA use), all modifications were combined for systematic confirmation of optimal protocol conditions. This optimized protocol was tested against commercially available methodologies to compare overall and microbial DNA yields, community representation and diversity by next-generation sequencing (NGS).

Results: Overall and fungal-specific DNA yields from standardized urine samples demonstrated that microbial abundances differed significantly among the eight methods used. Methodologies that included multiple disruption steps, including enzymatic, mechanical, and thermal disruption and proteinase digestion, particularly in combination with small volume processing and pooling steps, provided more comprehensive representation of the range of bacterial and fungal species. Concentration of larger volume urine specimens at low speed centrifugation proved highly effective, increasing resulting DNA levels and providing greater microbial representation and diversity.

Conclusions: Alterations in the methodology of urine storage, preparation, and DNA processing improve microbial community profiling using culture-independent sequencing methods. Our optimized protocol for DNA extraction from urine samples provided improved fungal community representation. Use of this technique resulted in equivalent representation of the bacterial populations as well, making this a useful technique for the concurrent evaluation of bacterial and fungal populations by NGS.

Keywords: urine; DNA isolation; centrifugation; DNA extraction; bacteria; fungi; cell disruption; specimen disruption.

Management of symptom flares and patient-reported flare triggers in interstitial cystitis/bladder pain syndrome (ic/bps)-findings from one site of the MAPP Research Network.

Lai HH, Vetter J, Song J, Andriole GL, Colditz GA, Sutcliffe S.  Urology. 2019 Apr;126:24-33. doi: 10.1016/j.urology.2019.01.012. Epub 2019 Jan 22. [PMID: 30682464] [PMC6874838]

Abstract

Abstract

Objective: To document patient-reported interstitial cystitis/bladder pain syndrome (IC/BPS) flare management strategies and triggers.

Materials and methods: Twenty-four male and 29 female participants enrolled at the Washington University site of the MAPP Research Network completed a questionnaire on strategies they utilized to manage flares and factors they believed triggered their flares (eg, specific food items, physical activities, sexual activities, infections, and stress). Participants were also asked about the diurnal timing of their flares.

Results: A total of 96.2% of participants reported having ever experienced a symptom flare. Participants treated or managed their flares using a wide variety of strategies, ranging from common strategies, such as drinking additional water or fluid (74.5%), to less common strategies, such as acupuncture/acupressure (5.9% of participants). Participants also reported a wide range of perceived flare triggers, including previously reported factors (citrus fruits, tomatoes, spicy food, alcoholic and caffeinated beverages, driving/sitting in forms of transportation, urinary tract infections, stress, and tight clothing), as well as some less common, previously undocumented factors (eg, certain foods, nongenitourinary infections, wearing high-heeled shoes/boots or perfume, hair dye, and toothpaste). In general, female participants and those with somatic sensory hypersensitivity reported greater numbers of therapies and triggers. Finally, flares were reported most commonly in the afternoon or evening.

Conclusion: IC/BPS participants reported diverse flare management strategies and numerous perceived triggers. These findings, together with those from the small body of literature to date, provide a wide array of candidates and hypotheses for future global and tailored flare management and prevention interventions.

Keywords: cystitis; interstitial; self management; self report; symptom flare up.

Urologic chronic pelvic pain syndrome: insights from the MAPP Research Network.

Clemens JQ, Mullins C, Ackerman AL, Bavendam T, van Bokhoven A, Ellingson BM, Harte SE, Kutch JJ, Lai HH, Martucci KT, Moldwin R, Naliboff BD, Pontari MA, Sutcliffe S, Landis JR; MAPP Research Network Study Group. Nat Rev Urol. 2019 Mar;16(3):187-200. doi: 10.1038/s41585-018-0135-5. [PMID: 30560936] [PMC6800057]

Abstract

Abstract

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.

Keywords: bladder/bladder disease; Urologic chronic pelvic pain syndromes; chronic pain; prostatitis.

A culture-independent analysis of the microbiota of female interstitial cystitis/bladder pain syndrome participants in the MAPP Research Network.

Nickel JC, Stephens-Shields AJ, Landis JR, Mullins C, van Bokhoven A, Lucia MS, Henderson JP, Sen B, Krol JE, Ehrlich GD; MAPP Research Network.  J Clin Med. 2019 Mar 26;8(3):415. doi: 10.3390/jcm8030415. [PMID: 30917614] [PMC6462969]

Abstract

Abstract

We surveyed urine microbiota of females diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) and matched control participants enrolled in the National Institutes of Health (NIH) Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network using the culture-independent methodology. Midstream urine specimens were analyzed with the Plex-ID molecular diagnostic platform that utilizes polymerase chain reaction⁻electrospray ionization⁻time-of-flight⁻mass spectrometry (PCR-ESI-TOF MS) to provide a comprehensive identification of bacterial and select fungal species. IC/BPS and control participants were evaluated for differences (presence, diversity, and abundance) in species and genus. Urine specimens obtained from 181 female IC/BPS and 182 female control participants detected a total of 92 species (41 genera). Mean (SD) species count was 2.49 (1.48) and 2.30 (1.28) among IC/BPS and control participants, respectively. Overall species composition did not significantly differ between IC/BPS and control participants at any level (p = 0.726 species level, p = 0.222 genus level). IC/BPS participants urine trended to an overabundance of Lactobacillus gasseri (p = 0.09) detected but had a lower prevalence of Corynebacterium compared with control participants (p = 0.002). The relative abundance data analysis mirrored the prevalence data differences with no significant differences in most species or genus abundance other than Lactobacillus gasseri and Corynebacterium (p = 0.08 and p = 0.001, respectively). No cause and/or effect conclusion can be drawn from this observation, but it suggests that a more comprehensive evaluation (vaginal, bowel, catheterized bladder and/or tissue-based specimens) of the lower urinary tract microbiota in IC/BPS patients is warranted.

Keywords: bladder pain syndrome; infection; interstitial cystitis; microbiome; microbiota.

Symptom duration in patients with urologic chronic pelvic pain syndrome is not associated with pain severity, nonurologic syndromes and mental health symptoms: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Network Study.

Rodríguez LV, Stephens AJ, Clemens JQ, Buchwald D, Yang C, Lai HH, Krieger JN, Newcomb C, Bradley CS, Naliboff B; MAPP Research Network. Urology. 2019 Feb;124:14-22. doi: 10.1016/j.urology.2018.11.015. Epub 2018 Nov 16. [PMID: 30452963] [PMC7037673]

Abstract

Abstract

Objective: To evaluate if patients with urologic chronic pelvic pain syndromes (UCPPS) with longer duration of symptoms experience more severe pain and urologic symptoms, higher rates of chronic overlapping pain conditions (COPC) and psychosocial comorbidities than those with a more recent onset of the condition. We evaluated cross-sectional associations between UCPPS symptom duration and (1) symptom severity, (2) presence of COPC, and (3) mental health comorbidities.

Methods: We analyzed baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain. Symptom severity, COPC, and mental health comorbidities were compared between patients with symptom duration of < 2 vs ≥ 2 years. Symptom severity was assessed by the Genitourinary Pain Index, the Interstitial Cystitis Symptom and Problem Index, and Likert scales for pelvic pain, urgency, and frequency. Depression and anxiety were evaluated with the Hospital Anxiety and Depression Scale and stress with the Perceived Stress Scale.

Results: Males (but not females) with UCPPS symptom duration ≥2 years had more severe symptoms than those with <2 years. Participants with short (<2 years) and longer (≥2 years) symptom duration were as likely to experience COPC.

Conclusion: Longer UCPPS symptom duration was associated with more severe symptoms only in limited patient subpopulations. Symptom duration was not associated with risk for COPC or mental health comorbidities. Females with longer UCPPS duration had decreased distress, but the association was largely attributable to age.

Keywords: chronic pain; mental disorders; pain measurement; pelvic pain; severity of illness index; symptom assessment.

Trial registration: ClinicalTrials.gov NCT01098279.

2018

Changes in brain white matter structure are associated with urine proteins in urologic chronic pelvic pain syndrome (UCPPS): A MAPP Network study.

Woodworth DC, Dagher A, Curatolo A, Sachdev M, Ashe-McNalley C, Naliboff BD, Labus JS, Landis JR, Kutch JJ, Mayer EA, Lee RS, Moses MA, Ellingson BM; MAPP Research Network. PLoS One. 2018 Dec 5;13(12):e0206807. doi: 10.1371/journal.pone.0206807. eCollection 2018. [PMID: 30517112] [PMC6281196]

Abstract

Abstract

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.

Keywords: Urinary biomarkers; Diffusion tensor imaging; Brainstem; Pain; Urine; Biomarkers; Brain; Neuroimaging.

Sensory sensitivity and symptom severity represent unique dimensions of chronic pain: a MAPP Research Network study.

Schrepf A, Williams DA, Gallop R, Naliboff BD, Basu N, Kaplan C, Harper DE, Landis JR, Clemens JQ, Strachan E, Griffith JW, Afari N, Hassett A, Pontari MA, Clauw DJ, Harte SE; MAPP Research Network. Pain. 2018 Oct;159(10):2002-2011. doi: 10.1097/j.pain.0000000000001299.
[PMID: 29863527] [PMC6705610]

Abstract

Abstract

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.

Keywords: Interstitial cystitis/painful bladder syndrome; Factor analysis; statistical; Fibromyalgia; Central nervous system sensitization; Interoception.

Adverse childhood experiences and symptoms of urologic chronic pelvic pain syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study.

Schrepf A, Naliboff B, Williams DA, Stephens-Shields AJ, Landis JR, Gupta A, Mayer E, Rodriguez LV, Lai H, Luo Y, Bradley C, Kreder K, Lutgendorf SK; MAPP Research Network. Ann Behav Med. 2018 Sep 13;52(10):865-877. doi: 10.1093/abm/kax060. [PMID: 30212850] [PMC6135957]

Abstract

Abstract

Background: Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illness, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS).

Purpose: We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the association of ACE severity with psychological factors known to impact pain and to determine whether ACEs are associated with patterns of improvement or worsening of symptom over a year of naturalistic observation.

Methods: For longitudinal analyses we used functional clusters identifying broad classes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being.

Results: ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly associated with factors associated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and less likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year.

Conclusions: These results confirm the association between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS.

Keywords: Interstitial Cystitis/Painful Bladder Syndrome; Chronic Prostatitis with Chronic Pelvic Pain Syndrome; Psychological Trauma; Sexual Abuse.

Clinical trial registration: NCT01098279.

A MAPP Network study: overexpression of tumor necrosis factor-? in mouse urothelium mimics interstitial cystitis.

Yang W, Searl TJ, Yaggie R, Schaeffer AJ, Klumpp DJ. Am J Physiol Renal Physiol. 2018 Jul 1;315(1):F36-F44. doi: 10.1152/ajprenal.00075.2017. Epub 2018 Feb 21. [PMID: 29465304] [PMC6087793]

Abstract

Abstract

Interstitial cystitis/bladder pain syndrome is a chronic bladder condition associated with pain and voiding dysfunction that is often regarded as a neurogenic cystitis. Patient symptoms are correlated with the presence of urothelial lesions. We previously characterized a murine neurogenic cystitis model that recapitulates mast cell accumulation and urothelial lesions, and these events were dependent on TNF. To further explore the role of TNF in bladder inflammation and function, we generated a transgenic mouse model with chronic TNF overexpression in urothelium under the control of the uroplakin II (UPII) promoter. Transgenic mouse lines were maintained by backcross onto wild-type C57BL/6J mice and evaluated for pelvic tactile allodynia as a measure of visceral pain, urinary function, and urothelial lesions. TNF mRNA and protein were expressed at greater levels in bladders of UPII-TNF mice than in those of wild-type mice. UPII-TNF mice showed significantly increased urinary frequency and decreased void volume. UPII-TNF mice had increased urothelial apoptosis and loss of urothelial integrity consistent with urothelial lesions. Overexpression of TNF was also associated with pelvic tactile allodynia. Consistent with these findings, UPII-TNF mice exhibited increased bladder afferent activity in response to stretch ex vivo. In summary, UPII-TNF mice display significant pelvic pain, voiding dysfunction, urothelial lesions, and sensory input. Thus UPII-TNF mice are a model for characterizing mechanisms of interstitial cystitis symptoms and evaluating therapies.

Keywords: TNF; interstitial cystitis; pelvic pain; transgenic mouse model.

Correlates of health care seeking activities in patients with urological chronic pelvic pain syndromes: findings from the MAPP Cohort.

Clemens JQ, Stephens-Shields A, Naliboff BD, Lai HH, Rodriguez L, Krieger JN, Williams DA, Kusek JW, Landis JR; MAPP Research Network. J Urol. 2018 Jul;200(1):136-140. doi: 10.1016/j.juro.2017.12.055. Epub 2018 Jan 4. [PMID: 29307682] [PMC6002941]

Abstract

Purpose: We examined health care seeking activities during a 12-month period in a cohort of men and women with urological chronic pelvic pain syndromes.

Materials and methods: A total of 191 men and 233 women with urological chronic pelvic pain syndrome were followed with biweekly, Internet based questionnaires about symptoms and health care seeking activities, including 1) health care provider contacts, 2) office visits, 3) emergency room/urgent care visits, 4) medication changes and 5) medical procedures. Multivariable modeling was used to determine the association of demographic and clinical variables with health care seeking. Super users were defined as individuals who reported health care seeking activity at least 11 times during the 23 biweekly assessments.

Results: Health care seeking activities included a mean of 2.4 office contacts, 2.5 office visits, 1.9 medication changes, 0.9 medical procedures and 0.3 emergency room/urgent care visits. A total of 31 health care seeking super users accounted for 26% of health care seeking activities. Worse baseline pain severity and female gender were associated with a higher rate of all health care seeking activities except emergency room/urgent care visits. A nonurological chronic pain condition was associated with more provider contacts, office visits and medical procedures. Greater baseline depression symptoms were associated with more provider contacts, office visits and medication changes. Other examined variables, including patient age, symptom duration, catastrophizing, anxiety, urinary symptom severity and symptom variability, had a minimal association with health care seeking.

Conclusions: Health care seeking activities were strongly influenced by the severity of pain in patients with urological chronic pelvic pain syndromes but not by urinary symptom severity. Women and patients with nonurological overlapping pain conditions were more likely to be seen and treated for symptoms.

Keywords: cystitis; interstitial; patient acceptance of health care; pelvic pain; prostate; urinary bladder.

Physical examination for men and women with urologic chronic pelvic pain syndrome: A MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Network Study.

Yang CC, Miller JL, Omidpanah A, Krieger JN. Urology. 2018 Jun;116:23-29. doi: 10.1016/j.urology.2018.03.021. Epub 2018 Mar 28. [PMID: 29604315] [PMC6237096]

Abstract

Objective: To examine the feasibility of implementing a standardized, clinically relevant genitourinary examination for both men and women, and to identify physical examination findings characteristic of urologic chronic pelvic pain syndrome (UCPPS).

Materials and methods: This study analyzed 2 samples: men and women with UCPPS who participated in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Epidemiology and Phenotyping (EP) Study, and age-matched controls who were either positive for chronic fatigue syndrome or healthy (pain-free). We compared physical examination findings in both positive and healthy controls with UCPPS cases: findings from both the EP examinations and from an extended genitourinary examination.

Results: EP and extended examinations were performed on 143 participants: 62 UCPPS cases (30 women, 32 men), 42 positive controls (15 women, 27 men), and 39 healthy controls (22 women, 17 men). EP examinations showed that pelvic floor tenderness was more prevalent in cases (55.0%) than in positive (14.6%) or healthy controls (10.5%). Extended examinations revealed specific areas of tenderness in the pelvic floor musculature. Cases were also more likely than healthy controls to report tenderness in multiple areas, including suprapubic, symphysis pubis, and posterior superior iliac spine, and on bimanual examination. No comparative findings were specific to biological sex, and no evidence of pudendal neuropathy was observed on extended examination of cases or controls.

Conclusion: The extended genitourinary examination is an easily administered addition to the assessment of men and women during evaluation for UCPPS. Physical findings may help to better categorize patients with UCPPS into clinically relevant subgroups for optimal treatment.

Keywords: algorithms; anthropometry; chronic fatigue syndrome; chronic pain; cross-sectional studies; cystitis; feasibility studies; palpation; pelvic floor disorders; pelvic pain; prostatitis; pudendal nerve.

A case-crossover study of urological chronic pelvic pain syndrome flare triggers in the MAPP Research Network.

Sutcliffe S, Jemielita T, Lai HH, Andriole GL, Bradley CS, Clemens JQ, Gallop R, Hooton TM, Kreder KJ, Krieger JN, Kusek JW, Labus J, Lucia MS, Mackey S, Naliboff BD, Robinson NA, Rodriguez LV, Stephens-Shields A, van Bokhoven A, Wolin KY, Yan Y, Yang CC, Landis JR, Colditz GA; MAPP Research Network. J Urol. 2018 May;199(5):1245-1251. doi: 10.1016/j.juro.2017.12.050. Epub 2017 Dec 27. [PMID: 29288643] [PMC5911194]

Abstract

Purpose: Although many factors have been proposed to trigger symptom exacerbations (flares) in patients with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, few studies have investigated these factors empirically. Therefore, we embedded a case-crossover study in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain longitudinal study to evaluate a range of patient reported triggers.

Materials and methods: We assessed exposure to proposed triggers, including diet, physical activities, sedentary behaviors, stress, sexual activities, infection-like symptoms and allergies, by questionnaire a maximum of 3 times when participants reported flares and at 3 randomly selected times. We compared participant preflare to nonflare exposures by conditional logistic regression.

Results: In our full analytical sample of 292 participants only 2 factors, including recent sexual activity (OR 1.44, 95% CI 1.06-1.96) and urinary tract infection symptoms (OR 3.39, 95% CI 2.02-5.68), which may overlap with those of flares, were associated with flare onset. On subanalyses restricted to flares with specific suspected triggers additional positive associations were observed for some factors such as certain dietary factors, abdominal muscle exercises, and vaginal infection-like symptoms and fever, but not for other factors (eg stress).

Conclusions: Except for sexual activity our findings suggest that patient reported triggers may be individual or group specific, or they may not contribute to flares. These findings suggest caution in following rigid, global flare prevention strategies and support additional research to develop evidence-based strategies.

Keywords: cystitis; interstitial; prostatitis; surveys and questionnaires; symptom flare up; urinary bladder.

Sub-noxious Intravesical lipopolysaccharide triggers bladder inflammation and symptom onset in a transgenic autoimmune cystitis model: A MAPP Network Animal Study.

Kogan P, Xu S, Wang Y, O’Donnell MA, Lutgendorf SK, Bradley CS, Schrepf A, Kreder KJ, Luo Y. Sci Rep. 2018 Apr 26;8(1):6573. doi: 10.1038/s41598-018-24833-x.
[PMID: 29700406] [PMC5919907]

Abstract

Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) can potentially develop symptom flares after exposure to minor bladder irritants such as subclinical bacterial infection. To reproduce this symptom onset, we intravesically instilled a sub-noxious dose of uropathogenic E. coli component lipopolysaccharide (LPS) in young URO-OVA/OT-I mice, a transgenic autoimmune cystitis model that spontaneously develops bladder inflammation at ≥10 weeks of age. Female URO-OVA/OT-I mice (6-weeks old) were treated intravesically with phosphate-buffered saline (PBS) or PBS containing a sub-noxious dose (1 μg) of LPS. Mice were evaluated for bladder inflammation, pelvic pain, and voiding dysfunction at days 1, 7, and 14 post-treatment. Mice treated with LPS but not PBS developed early bladder inflammation with increased macrophage infiltration. Accordingly, the inflamed bladders expressed increased levels of mRNA for proinflammatory cytokines (IL-1β and IL-6) and pain mediator (substance P precursor). In addition, LPS-treated mice exhibited pelvic pain and voiding dysfunction such as increased urinary frequency and reduced bladder capacity. These functional changes sustained up to day 14 tested. Our results indicate that a single sub-noxious dose of intravesical LPS triggers early bladder inflammation and symptom onset in URO-OVA/OT-I mice, providing a useful model for IC/BPS symptom flare study.

Keywords: autoimmunity; experimental models of disease.

Acyloxyacyl hydrolase modulates pelvic pain severity.

Yang W, Yaggie RE, Jiang MC, Rudick CN, Done J, Heckman CJ, Rosen JM, Schaeffer AJ, Klumpp DJ. Am J Physiol Regul Integr Comp Physiol. 2018 Mar 1;314(3):R353-R365. doi: 10.1152/ajpregu.00239.2017. Epub 2017 Nov 8. [PMID: 29118019] [PMC5899250]

Abstract

Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2CxB progeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.

Keywords: AOAH; QTL; allodynia; pelvic pain; pseudorabies virus.

The role of C-fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

Gao Y, Zhang R, Chang HH, Rodríguez LV. Neurourol Urodyn. 2018 Feb;37(2):673-680. doi: 10.1002/nau.23374. Epub 2017 Aug 9. [PMID: 28792095] [PMC5988434]

Abstract

Aims: To evaluate C fiber-mediated changes in bladder sensation and nociception in an animal model of stress induced bladder hyperalgesia and urinary frequency.

Methods: Female Wistar-Kyoto (WKY) rats were exposed to a chronic (10 days) water avoidance stress (WAS) and compared to controls. Rats were evaluated by cystometrogram (CMG) and visceromotor reflex (VMR) to bladder infusion with room temperature (RT) or cold saline. Cold saline activates afferent C-fibers via cold bladder receptors. To further evaluate bladder hyperalgesia, CMG and VMR were also obtained during RT isometric bladder distention (RT-iBD) at variable pressures.

Results: During RT infusion, WAS rats had significant decreases in pressure threshold (PT) and in the ratio of VMR threshold/maximum intravesical pressure (IVPmax), and a significant increase in VMR duration. Cold infusion also induced significant decreases in PT and in the ratio of VMR threshold/IVPmax in WAS rats. During RT-iBD, rats exposed to WAS showed a significant decrease in VMR latency and a significant increase in VMR area under the curve (AUC) compared to controls.

Conclusion: Chronic WAS induced bladder hypersensitivity manifested by earlier voiding with earlier VMR appearance. Chronic stress also enhanced bladder nociceptive responses. WAS leads to increase responses to ice cold water infusion, implying a role of sensitized C-fibers and mechanoreceptors in WAS-induced bladder dysfunction and hypersensitivity.

Keywords: bladder hypersensitivity; cystometrogram; hyperalgesia; interstitial cystitis; visceromeotor reflex; water avoidance stress.

2017

Relationships between brain metabolite levels, functional connectivity, and negative mood in urologic chronic pelvic pain syndrome patients compared to controls: A MAPP research network study.

Harper DE, Ichesco E, Schrepf A, Halvorson M, Puiu T, Clauw DJ, Harris RE, Harte SE; MAPP Research Network. Neuroimage Clin. 2017 Nov 15;17:570-578. doi: 10.1016/j.nicl.2017.11.014. eCollection 2018. [PMID: 29201643] [PMC5702874]

Abstract

Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy (1H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p = 0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p = 0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome.

Keywords: Centralized pain; Choline; Gamma aminobutyric acid (GABA); Interstitial cystitis; MAPP; Proton magnetic resonance spectroscopy.

Anti-vascular endothelial growth factor treatment decreases bladder pain in cyclophosphamide cystitis: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network animal model study.

Lai HH, Shen B, Vijairania P, Zhang X, Vogt SK, Gereau RW 4th. BJU Int. 2017 Oct;120(4):576-583. doi: 10.1111/bju.13924. Epub 2017 Jun 29. [PMID: 28581681] [PMC5716917]

Abstract

Objective: To investigate whether treatment with anti-vascular endothelial growth factor (VEGF)-neutralizing antibodies can reduce pain and voiding dysfunction in the cyclophosphamide (CYP) cystitis model of bladder pain in mice.

Materials and methods: Adult female mice received anti-VEGF-neutralizing antibodies (10 mg/kg i.p. B20-4.1.1 VEGF mAb) or saline (control) pre-treatment, followed by CYP (150 mg/kg i.p.) to induce acute cystitis. Pelvic nociceptive responses were assessed by applying von Frey filaments to the pelvic area. Spontaneous micturition was assessed using the void spot assay.

Results: Systemic anti-VEGF-neutralizing antibody treatment significantly reduced the pelvic nociceptive response to CYP cystitis compared with control (saline). In the anti-VEGF pre-treatment group, there was a significant increase in pelvic hypersensitivity, measured by the area under the curve (AUC) using von Frey filaments at 5 h post-CYP administration (P = 0.004); however, by 48 h and 96 h post-CYP administration, pelvic hypersensitivity had reduced by 54% and 47%, respectively, compared with the 5 h post-CYP administration time point, and were no longer significantly different from baseline (P = 0.22 and 0.17, respectively). There was no difference in urinary frequency and mean voided volume between the two pre-treatment groups.

Conclusion: Systemic blockade of VEGF signalling with anti-VEGF-neutralizing antibodies was effective in reducing pelvic/bladder pain in the CYP cystitis model of bladder pain. Our data support the further investigation of the use of anti-VEGF antibodies to manage bladder pain or visceral pain.

Keywords: bladder pain; cyclophosphamide cystitis; interstitial cystitis; vascular endothelial growth factor anti-VEGF.

Brain signature and functional impact of centralized pain: a multidisciplinary approach to the study of chronic pelvic pain (MAPP) network study.

Kutch JJ, Ichesco E, Hampson JP, Labus JS, Farmer MA, Martucci KT, Ness TJ, Deutsch G, Apkarian AV, Mackey SC, Klumpp DJ, Schaeffer AJ, Rodriguez LV, Kreder KJ, Buchwald D, Andriole GL, Lai HH, Mullins C, Kusek JW, Landis JR, Mayer EA, Clemens JQ, Clauw DJ, Harris RE; MAPP Research Network. Pain. 2017 Oct;158(10):1979-1991. doi: 10.1097/j.pain.0000000000001001. [PMID: 28692006] [PMC5964335]

Abstract

Chronic pain is often measured with a severity score that overlooks its spatial distribution across the body. This widespread pain is believed to be a marker of centralization, a central nervous system process that decouples pain perception from nociceptive input. Here, we investigated whether centralization is manifested at the level of the brain using data from 1079 participants in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network (MAPP) study. Participants with a clinical diagnosis of urological chronic pelvic pain syndrome (UCPPS) were compared to pain-free controls and patients with fibromyalgia, the prototypical centralized pain disorder. Participants completed questionnaires capturing pain severity, function, and a body map of pain. A subset (UCPPS N = 110; fibromyalgia N = 23; healthy control N = 49) underwent functional and structural magnetic resonance imaging. Patients with UCPPS reported pain ranging from localized (pelvic) to widespread (throughout the body). Patients with widespread UCPPS displayed increased brain gray matter volume and functional connectivity involving sensorimotor and insular cortices (P < 0.05 corrected). These changes translated across disease diagnoses as identical outcomes were present in patients with fibromyalgia but not pain-free controls. Widespread pain was also associated with reduced physical and mental function independent of pain severity. Brain pathology in patients with centralized pain is related to pain distribution throughout the body. These patients may benefit from interventions targeting the central nervous system.

Keywords: Centralized; Chronic; Pain; fMRI; Widespread; Fibromyalgia; Pelvic; VBM; Connectivity.

Clinical and psychosocial predictors of urological chronic pelvic pain symptom change in 1 year: a prospective study from the MAPP Research Network.

Naliboff BD, Stephens AJ, Lai HH, Griffith JW, Clemens JQ, Lutgendorf S, Rodriguez LV, Newcomb C, Sutcliffe S, Guo W, Kusek JW, Landis JR; MAPP Research Network. J Urol. 2017 Oct;198(4):848-857. doi: 10.1016/j.juro.2017.05.065. Epub 2017 May 18. [PMID: 28528930] [PMC5720154]

Abstract

Purpose: We examined baseline clinical and psychosocial characteristics that predict 12-month symptom change in men and women with urological chronic pelvic pain syndromes.

Materials and methods: A total of 221 female and 176 male patients with urological chronic pelvic pain syndromes were recruited from 6 academic medical centers in the United States and evaluated at baseline with a comprehensive battery of symptom, psychosocial and illness-impact measures. Based on biweekly symptom reports, a functional clustering procedure classified participant outcome as worse, stable or improved on pain and urinary symptom severity. Cumulative logistic modeling was used to examine individual predictors associated with symptom change as well as multiple predictor combinations and interactions.

Results: About 60% of participants had stable symptoms with smaller numbers (13% to 22%) showing clear symptom worsening or improvement. For pain and urinary outcomes the extent of widespread pain, amount of nonurological symptoms and poorer overall health were predictive of worsening outcomes. Anxiety, depression and general mental health were not significant predictors of outcomes but pain catastrophizing and self-reported stress were associated with pain outcome. Prediction models did not differ between men and women and for the most part they were independent of symptom duration and age.

Conclusions: These results demonstrate for the first time in a large multisite prospective study that presence of widespread pain, nonurological symptoms and poorer general health are risk factors for poorer pain and urinary outcomes in men and women. The results point to the importance of broad based assessment for urological chronic pelvic pain syndromes and future studies of the mechanisms that underlie these findings.

Keywords: cystitis; interstitial; pelvic pain; prostate; prostatitis; urinary bladder.

Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

Wang Z, Chang HH, Gao Y, Zhang R, Guo Y, Holschneider DP, Rodriguez LV. PLoS One. 2017 Sep 8;12(9):e0182976. doi: 10.1371/journal.pone.0182976. eCollection 2017. [PMID: 28886046] [PMC5590813]

Abstract

Stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitive syndromes, such as interstitial cystitis/bladder pain syndrome (IC/BPS), characterized by urinary frequency and bladder hyperalgesia and heightened stress responsiveness. Given the overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function, as well as its effects on regional brain activation during bladder filling. Female Wistar-Kyoto rats were exposed to WAS (10 days) or sham paradigms. One day thereafter, cystometrograms were obtained during titrated bladder dilation, with visceromotor responses (VMR) recorded simultaneously. Cerebral perfusion was assessed during passive bladder distension (20-cmH2O) following intravenous administration of [14C]-iodoantipyrine. Regional cerebral blood flow was quantified by autoradiography and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. WAS animals compared to controls demonstrated a decreased pressure threshold and visceromotor threshold triggering the voiding phase. At 20-cmH2O, VMR was significantly greater in WAS animals compared to controls. WAS animals showed greater activation in cortical regions of the central micturition circuit, including the posterior cingulate, anterior retrosplenial, somatosensory, posterior insula, orbital, and anterior secondary ("supplementary") motor cortices, as well as in the thalamus, anterior hypothalamus, parabrachial and Barrington nuclei, and striatum. Seed analysis showed increased functional connectivity of WAS compared to control animals of the posterior cingulate cortex to the pontine parabrachial nucleus; of the Barrington nucleus to the anterior dorsal midline and ventrobasilar thalamus and somatosensory and retrosplenial cortices; and of the posterior insula to anterior secondary motor cortex. Our findings show a visceral hypersensitivity during bladder filling in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency, viscerosensory perception and its relay to motor regions coordinating imminent bladder contraction. Results are consistent with recent findings in patients with interstitial cystitis, suggesting that WAS may serve as an animal model to elucidate the mechanisms leading to viscerosensitive brain phenotypes in humans with IC/BPS.

Keywords: Bladder; Urination; Psychological stress; Sensory perception; Pain; Motor cortex; Pain sensation; Thalamus.

Characterization of whole-body pain in urological chronic pelvic pain syndrome at baseline: A MAPP Research Network Study.

Lai HH, Jemielita T, Sutcliffe S, Bradley CS, Naliboff B, Williams DA, Gereau RW 4th, Kreder K, Clemens JQ, Rodriguez LV, Krieger JN, Farrar JT, Robinson N, Landis JR; MAPP Research Network. J Urol. 2017 Sep;198(3):622-631. doi: 10.1016/j.juro.2017.03.132. Epub 2017 Mar 31. [PMID: 28373134] [PMC5562525]

Abstract

Purpose: We characterized the location and spatial distribution of whole body pain in patients with urological chronic pelvic pain syndrome using a body map. We also compared the severity of urinary symptoms, pelvic pain, nonpelvic pain and psychosocial health among patients with different pain patterns.

Materials and methods: A total of 233 women and 191 men with urological chronic pelvic pain syndrome enrolled in a multicenter, 1-year observational study completed a battery of baseline measures, including a body map describing the location of pain during the last week. Participants were categorized with pelvic pain if they reported pain in the abdomen and pelvis only. Participants who reported pain beyond the pelvis were further divided into 2 subgroups based on the number of broader body regions affected by pain, including an intermediate group with 1 or 2 additional regions outside the pelvis and a widespread pain group with 3 to 7 additional regions.

Results: Of the 424 enrolled patients 25% reported pelvic pain only and 75% reported pain beyond the pelvis, of whom 38% reported widespread pain. Participants with a greater number of pain locations had greater nonpelvic pain severity (p <0.0001), sleep disturbance (p = 0.035), depression (p = 0.005), anxiety (p = 0.011), psychological stress (p = 0.005) and negative affect scores (p = 0.0004), and worse quality of life (p ≤0.021). No difference in pelvic pain and urinary symptom severity was observed according to increasing pain distribution.

Conclusions: Three-quarters of the men and women with urological chronic pelvic pain syndrome reported pain outside the pelvis. Widespread pain was associated with greater severity of nonpelvic pain symptoms, poorer psychosocial health and worse quality of life but not with worse pelvic pain or urinary symptoms.

Keywords: cystitis; interstitial; pelvic pain; prostate; prostatitis; urinary bladder.

Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

Dagher A, Curatolo A, Sachdev M, Stephens AJ, Mullins C, Landis JR, van Bokhoven A, El-Hayek A, Froehlich JW, Briscoe AC, Roy R, Yang J, Pontari MA, Zurakowski D, Lee RS, Moses MA; MAPP Research Network. BJU Int. 2017 Jul;120(1):130-142. doi: 10.1111/bju.13832. Epub 2017 Apr 11. [PMID: 28263447] [PMC5951631]

Abstract

Objective: To examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies.

Methods: Baseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n = 259), positive controls (PCs; chronic pain without pelvic pain, n = 107) and healthy controls (HCs, n = 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF-R1) and NGAL were assayed and quantitated using mono-specific enzyme-linked immunosorbent assays for each protein. Log-transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student's t-test, with P values adjusted for multiple comparisons. Multivariable logistic regression and receiver-operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression.

Results: Significantly higher normalized concentrations (pg/μg) of VEGF, VEGF-R1 and MMP-9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP-9 and MMP-9/NGAL complex, and urinary severity was significantly positively associated with MMP-9, MMP-9/NGAL complex and VEGF-R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP-9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP-2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF-R1.

Conclusion: Altered levels of MMP-9, MMP-9/NGAL complex and VEGF-R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP-9 and VEGF-R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.

Keywords: Lipocalin 2 (also known as NGAL); Multidisciplinary Approach to the Study of Chronic Pelvic Pain; matrix metalloproteinase; neutrophil gelatinase associated lipocalin; vascular endothelial growth factor; vascular endothelial growth factor receptor 1.

Resting-state functional connectivity predicts longitudinal pain symptom change in urologic chronic pelvic pain syndrome: a MAPP network study.

Kutch JJ, Labus JS, Harris RE, Martucci KT, Farmer MA, Fenske S, Fling C, Ichesco E, Peltier S, Petre B, Guo W, Hou X, Stephens AJ, Mullins C, Clauw DJ, Mackey SC, Apkarian AV, Landis JR, Mayer EA; MAPP Research Network. Pain. 2017 Jun;158(6):1069-1082. doi: 10.1097/j.pain.0000000000000886. [PMID: 28328579] [PMC5435510]

Abstract

Chronic pain symptoms often change over time, even in individuals who have had symptoms for years. Studying biological factors that predict trends in symptom change in chronic pain may uncover novel pathophysiological mechanisms and potential therapeutic targets. In this study, we investigated whether brain functional connectivity measures obtained from resting-state functional magnetic resonance imaging at baseline can predict longitudinal symptom change (3, 6, and 12 months after scan) in urologic chronic pelvic pain syndrome. We studied 52 individuals with urologic chronic pelvic pain syndrome (34 women, 18 men) who had baseline neuroimaging followed by symptom tracking every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. We found that brain functional connectivity can make a significant prediction of short-term (3 month) pain reduction with 73.1% accuracy (69.2% sensitivity and 75.0% precision). In addition, we found that the brain regions with greatest contribution to the classification were preferentially aligned with the left frontoparietal network. Resting-state functional magnetic resonance imaging measures seemed to be less informative about 6- or 12-month symptom change. Our study provides the first evidence that future trends in symptom change in patients in a state of chronic pain may be linked to functional connectivity within specific brain networks.

Keywords: Neuroimaging; Prediction; Chronic pain; Urologic pain.

Evidence for the role of mast cells in cystitis-associated lower urinary tract dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study.

Wang X, Liu W, O’Donnell M, Lutgendorf S, Bradley C, Schrepf A, Liu L, Kreder K, Luo Y. PLoS One. 2016 Dec 21;11(12):e0168772. doi: 10.1371/journal.pone.0168772. eCollection 2016. [PMID: 28002455] [PMC5176179]

Abstract

Bladder inflammation frequently causes cystitis pain and lower urinary tract dysfunction (LUTD) such as urinary frequency and urgency. Although mast cells have been identified to play a critical role in bladder inflammation and pain, the role of mast cells in cystitis-associated LUTD has not been demonstrated. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and LUTD. In this study we investigated the role of mast cells in LUTD using a transgenic autoimmune cystitis model (URO-OVA) that reproduces many clinical correlates of IC/BPS. URO-OVA mice express the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develop bladder inflammation upon introduction of OVA-specific T cells. To investigate the role of mast cells, we crossed URO-OVA mice with mast cell-deficient KitW-sh mice to generate URO-OVA/KitW-sh mice that retained urothelial OVA expression but lacked endogenous mast cells. We compared URO-OVA mice with URO-OVA/KitW-sh mice with and without mast cell reconstitution in response to cystitis induction. URO-OVA mice developed profound bladder inflammation with increased mast cell counts and LUTD, including increased total number of voids, decreased mean volume voided per micturition, and decreased maximum volume voided per micturition, after cystitis induction. In contrast, similarly cystitis-induced URO-OVA/KitW-sh mice developed reduced bladder inflammation with no mast cells and LUTD detected. However, after mast cell reconstitution URO-OVA/KitW-sh mice restored the ability to develop bladder inflammation and LUTD following cystitis induction. We further treated URO-OVA mice with cromolyn, a mast cell membrane stabilizer, and found that cromolyn treatment reversed bladder inflammation and LUTD in the animal model. Our results provide direct evidence for the role of mast cells in cystitis-associated LUTD, supporting the use of mast cell inhibitors for treatment of certain forms of IC/BPS.

Keywords: Mast cells; Bladder; Cystitis; Mouse models; Inflammation; Urination; Habits; Pain.

Brain white matter changes associated with urological chronic pelvic pain syndrome: multisite neuroimaging from a MAPP case-control study.

Huang L, Kutch JJ, Ellingson BM, Martucci KT, Harris RE, Clauw DJ, Mackey S, Mayer EA, Schaeffer AJ, Apkarian AV, Farmer MA; MAPP Research Network. Pain. 2016 Dec;157(12):2782-2791. doi: 10.1097/j.pain.0000000000000703. [PMID: 27842046] [PMC5117992]

Abstract

Clinical phenotyping of urological chronic pelvic pain syndromes (UCPPSs) in men and women have focused on end organ abnormalities to identify putative clinical subtypes. Initial evidence of abnormal brain function and structure in male pelvic pain has necessitated large-scale, multisite investigations into potential UCPPS brain biomarkers. We present the first evidence of regional white matter (axonal) abnormalities in men and women with UCPPS, compared with positive (irritable bowel syndrome, IBS) and healthy controls. Epidemiological and neuroimaging data were collected from participants with UCPPS (n = 52), IBS (n = 39), and healthy sex- and age-matched controls (n = 61). White matter microstructure, measured as fractional anisotropy (FA), was examined by diffusion tensor imaging. Group differences in regional FA positively correlated with pain severity, including segments of the right corticospinal tract and right anterior thalamic radiation. Increased corticospinal FA was specific and sensitive to UCPPS, positively correlated with pain severity, and reflected sensory (not affective) features of pain. Reduced anterior thalamic radiation FA distinguished patients with IBS from those with UCPPS and controls, suggesting greater microstructural divergence from normal tract organization. Findings confirm that regional white matter abnormalities characterize UCPPS and can distinguish between visceral diagnoses, suggesting that regional axonal microstructure is either altered with ongoing pain or predisposes its development.

Keywords: Pain; Urological; Pelvic; Irritable bowel syndrome; Diffusion tensor imaging.

Symptom variability and early symptom regression in the MAPP study: a prospective study of urological chronic pelvic pain syndrome.

Stephens-Shields AJ, Clemens JQ, Jemielita T, Farrar J, Sutcliffe S, Hou X, Landis JR; MAPP Research Network. J Urol. 2016 Nov;196(5):1450-1455. doi: 10.1016/j.juro.2016.04.070. Epub 2016 Apr 27. [PMID: 27131464] [PMC5069105]

Abstract

Purpose: We examined symptom variability in men and women with urological chronic pelvic pain syndrome. We describe symptom fluctuations as related to early symptom regression and its effect on estimated 1-year symptom change. We also describe a method to quantify patient specific symptom variability.

Materials and methods: Symptoms were assessed biweekly in 424 subjects with urological chronic pelvic pain syndrome during 1 year. To evaluate the impact of early symptom regression subjects were classified as improved, no change or worse according to the rate of change using 1) all data, 2) excluding week 0 and 3) excluding weeks 0 and 2. Patient specific, time varying variability was calculated at each interval using a sliding window approach. Patients were classified as high, medium or low variability at each time and ultimately as high or low variability overall based on the variability for the majority of contacts.

Results: Prior to excluding early weeks to adjust for early symptom regression 25% to 38% and 5% to 6% of patients were classified as improved and worse, respectively. After adjustment the percent of patients who were improved or worse ranged from 15% to 25% and 6% to 9%, respectively. High and low variability phenotypes were each identified in 25% to 30% of participants.

Conclusions: Patients with urological chronic pelvic pain syndrome show symptom variability. At study enrollment patients had worse symptoms on average, resulting in a regression effect that influenced the estimated proportion of those who were improved or worse. Prospective studies should include a run-in period to account for regression to the mean and other causes of early symptom regression. Further, symptom variability may be quantified and used to characterize longitudinal symptom profiles of urological chronic pelvic pain syndrome.

Keywords: cystitis; epidemiologic research design; interstitial; pain; prostate; symptom assessment.

Transgenic mice expressing mcp-1 by the urothelium demonstrate bladder hypersensitivity, pelvic pain and voiding dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study.

Xu S, Wang X, Wang Y, Lutgendorf S, Bradley C, Schrepf A, Kreder K, O’Donnell M, Luo Y. PLoS One. 2016 Sep 29;11(9):e0163829. doi: 10.1371/journal.pone.0163829. eCollection 2016. [PMID: 27684718] [PMC5042429]

Abstract

Monocyte chemoattractant protein-1 (MCP-1) is one of the key chemokines that play important roles in diverse inflammatory and chronic pain conditions. Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating inflammatory condition of the urinary bladder characterized by the hallmark symptoms of pelvic pain and voiding dysfunction. To facilitate IC/BPS research, we used transgenic technology to develop a novel urothelial MCP-1 secretion mouse model (URO-MCP-1). A transgene consisting of the uroplakin II gene promoter and the mouse MCP-1 coding sequence with a secretory element was constructed and microinjected. URO-MCP-1 mice were found to express MCP-1 mRNA in the bladder epithelium and MCP-1 protein in the urine, and developed bladder inflammation 24 hours after intravesical administration of a single sub-noxious dose of lipopolysaccharide (LPS). The inflamed bladders of URO-MCP-1 mice exhibited elevated mRNAs for interleukin (IL)-1ß, IL-6, substance P precursor, and nerve growth factor as well as increased macrophage infiltration. In parallel with these phenotypic changes, URO-MCP-1 mice manifested significant functional changes at days 1 and 3 after cystitis induction. These functional changes included pelvic pain as measured by von Frey filament stimulation and voiding dysfunction (increased urinary frequency, reduced average volume voided per micturition, and reduced maximum volume voided per micturition) as measured by micturition cages. Micturition changes remained evident at day 7 after cystitis induction, although these changes were not statistically significant. Control wild-type C57BL/6 mice manifested no clear changes in histological, biochemical and behavioral features after similar cystitis induction with LPS. Taken together, our results indicate that URO-MCP-1 mice are hypersensitive to bladder irritants such as LPS and develop pelvic pain and voiding dysfunction upon cystitis induction, providing a novel model for IC/BPS research.

Keywords: Bladder; Mouse models; Inflammation; Pain; Genetically modified animals; Cystitis; Habits; Urination.

Bladder distension increases blood flow in pain related brain structures in subjects with interstitial cystitis.

Deutsch G, Deshpande H, Frölich MA, Lai HH, Ness TJ. J Urol. 2016 Sep;196(3):902-10. doi: 10.1016/j.juro.2016.03.135. Epub 2016 Mar 24. [PMID: 27018508] [PMC5014638]

Abstract

Purpose: In healthy control subjects certain brain regions of interest demonstrate increased regional cerebral blood flow in response to painful stimuli. We examined the effect of bladder distension on arterial spin label functional magnetic resonance imaging measures of regional cerebral blood flow in regions of interest in subjects with interstitial cystitis.

Materials and methods: A total of 11 female subjects with interstitial cystitis and 11 healthy controls underwent 3 brain perfusion scan studies using arterial spin label functional magnetic resonance imaging, including 1) with a full bladder, 2) with an empty bladder and 3) while experiencing heat pain. Regional cerebral blood flow was calculated using custom software and individual scans were spatially normalized to the MNI (Montreal Neurological Institute) template. Region of interest based, absolute regional cerebral blood flow was determined for each condition and for the within group/within subject regional cerebral blood flow distribution changes induced by each condition.

Results: Bladder distension was associated with robust increases in regional cerebral blood flow in subjects with interstitial cystitis. The increases were greater than those in healthy controls in multiple regions of interest, including the supplemental motor area (mainly Brodmann area 6), the motor and sensory cortex, the insula bilaterally, the hippocampal structures bilaterally, and the middle and posterior cingulate areas bilaterally. During heat pain healthy controls had more robust regional cerebral blood flow increases in the amygdala bilaterally. At baseline with an empty bladder there was lower regional cerebral blood flow in the insula, and the mid and posterior cingulate cortex bilaterally in subjects with interstitial cystitis.

Conclusions: Compared to healthy controls, subjects with interstitial cystitis have limited differences in regional cerebral blood flow in baseline (empty bladder) conditions as well as during heat pain. However, they had robust regional cerebral blood flow increases in the full bladder state in regions of interest typically associated with pain, emotion and/or motor control, indicating altered processing of bladder related sensations.

Keywords: brain; cerebrovascular circulation; cystitis, interstitial; pain; urinary bladder.

Urinary metabolomics identifies a molecular correlate of interstitial cystitis/bladder pain syndrome in a multidisciplinary approach to the study of chronic pelvic pain (MAPP) research network cohort.

Parker KS, Crowley JR, Stephens-Shields AJ, van Bokhoven A, Lucia MS, Lai HH, Andriole GL, Hooton TM, Mullins C, Henderson JP. EBioMedicine. 2016 May;7:167-74. doi: 10.1016/j.ebiom.2016.03.040. Epub 2016 Mar 31. [PMID: 27322470] [PMC4909380]

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood syndrome affecting up to 6.5% of adult women in the U.S. The lack of broadly accepted objective laboratory markers for this condition hampers efforts to diagnose and treat this condition. To identify biochemical markers for IC/BPS, we applied mass spectrometry-based global metabolite profiling to urine specimens from a cohort of female IC/BPS subjects from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. These analyses identified multiple metabolites capable of discriminating IC/BPS and control subjects. Of these candidate markers, etiocholan-3α-ol-17-one sulfate (Etio-S), a sulfoconjugated 5-β reduced isomer of testosterone, distinguished female IC/BPS and control subjects with a sensitivity and specificity >90%. Among IC/BPS subjects, urinary Etio-S levels are correlated with elevated symptom scores (symptoms, pelvic pain, and number of painful body sites) and could resolve high- from low-symptom IC/BPS subgroups. Etio-S-associated biochemical changes persisted through 3-6months of longitudinal follow up. These results raise the possibility that an underlying biochemical abnormality contributes to symptoms in patients with severe IC/BPS.

Keywords: biomarkers; cystitis; interstitial; mass spectrometry; pain measurement; steroids; steroids/urine; sulfates; sulfates/urine.

Cognitive - behavioral therapy in central sensitivity syndromes.

Williams DA. Curr Rheumatol Rev. 2016;12(1):2-12. doi: 10.2174/157339711201160303103241. [PMID: 26717953] [2016]

Abstract

Cognitive-Behavioral Therapy (CBT) is a formal therapeutic approach that encourages selfmanagement of illnesses in accordance with the BioPsychoSocial model. CBT is composed of numerous skills grounded in known principles of behavioral and cognitive change. Each skill is designed to influence one of the facets associated with the perception of pain (i.e., sensory factors, emotional factors, or cognitive factors). Across the various Central Sensitivity Syndromes (CSS), CBT is thought to be beneficial to at least a portion of individuals afflicted. This paper provides a description of CBT, some recommendations for integrating CBT into clinical practice, and a brief review of the evidence supporting the use of CBT with various forms of CSS.

Keywords: BioPsychoSocial; central sensitivity syndromes; chronic overlapping pain conditions; cognitive behavioral therapy.

Pain and urinary symptoms should not be combined into a single score: psychometric findings from the MAPP Research Network.

Griffith JW, Stephens-Shields AJ, Hou X, Naliboff BD, Pontari M, Edwards TC, Williams DA, Clemens JQ, Afari N, Tu F, Lloyd RB, Patrick DL, Mullins C, Kusek JW, Sutcliffe S, Hong BA, Lai HH, Krieger JN, Bradley CS, Kim J, Landis JR. J Urol. 2016 Apr;195(4 Pt 1):949-54. doi: 10.1016/j.juro.2015.11.012. Epub 2015 Nov 14. [PMID: 26585679] [PMC4867140]

Abstract

Purpose: The purpose of this study was to create symptom indexes, that is scores derived from questionnaires to accurately and efficiently measure symptoms of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively referred to as urological chronic pelvic pain syndromes. We created these indexes empirically by investigating the structure of symptoms using exploratory factor analysis.

Materials and methods: As part of the MAPP (Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain) Research Network 424 participants completed questionnaires, including GUPI (Genitourinary Pain Index), ICSI (Interstitial Cystitis Symptom Index) and ICPI (Interstitial Cystitis Problem Index). Individual items from questionnaires about bladder and pain symptoms were evaluated by principal component and exploratory factor analyses to identify indexes with fewer questions to comprehensively quantify symptom severity. Additional analyses included correlating symptom indexes with symptoms of depression, which is a known comorbidity of patients with pelvic pain.

Results and conclusions: Exploratory factor analyses suggested that the 2 factors pain severity and urinary severity provided the best psychometric description of items in GUPI, ICSI and ICPI. These factors were used to create 2 symptom indexes for pain and urinary symptoms. Pain, but not urinary symptoms, was associated with symptoms of depression on multiple regression analysis, suggesting that these symptoms may impact patients with urological chronic pelvic pain syndromes differently (B ± SE for pain severity = 0.24 ± 0.04, 95% CI 0.16-0.32, β = 0.32, p <0.001). Our results suggest that pain and urinary symptoms should be assessed separately rather than combined into 1 total score. Total scores that combine the separate factors of pain and urinary symptoms into 1 score may be limited for clinical and research purposes.

Keywords: chronic pain; cystitis, interstitial; factor analysis, statistical; prostatitis; urinary bladder.

Alterations in connectivity on functional magnetic resonance imaging with provocation of lower urinary tract symptoms: A MAPP Research Network Feasibility Study of Urological Chronic Pelvic Pain Syndromes.

Kleinhans NM, Yang CC, Strachan ED, Buchwald DS, Maravilla KR. J Urol. 2016 Mar;195(3):639-45. doi: 10.1016/j.juro.2015.09.092. Epub 2015 Oct 22. [PMID: 26497778] [PMC5035686]

Abstract

Purpose: Urological chronic pelvic pain syndromes have refractory bladder or pelvic pain as the dominant symptom. This has been attributed to changes in the central nervous system caused by a chronic barrage of noxious stimuli. We developed what is to our knowledge a novel challenge protocol that induced bladder distention in study participants to reproduce pain and urinary symptoms. We tested to see whether it could discriminate between persons with urological chronic pelvic pain syndrome-like symptoms and asymptomatic controls.

Materials and methods: We recruited 10 female twin pairs who were discordant for urological chronic pelvic pain syndrome-like symptoms. Before scanning each twin urinated to completion and then consumed 500 cc water. Each twin was scanned with our resting state functional magnetic resonance imaging protocol immediately and approximately 50 minutes after consumption. Time series were extracted from the right and left periaqueductal gray, and the right and left amygdala subregions. We performed the repeated measures 2-sample t-test to assess differences in connectivity between symptomatic and asymptomatic twins before and after bladder distention.

Results: Group by condition interaction effects were found from the periaqueductal gray to the right cerebellum VIIIa, the amygdala, the right premotor cortex/supplementary motor area and the insular cortex, and between the amygdala and the frontal pole/medial orbital frontal cortex, the hypothalamus, the insular cortex, the thalamus and the anterior cingulate cortex.

Conclusions: These findings demonstrate that our noninvasive bladder distention protocol can detect differences in the processing of urinary sensation between twins discordant for lower urinary tract pain.

Keywords: brain; cystitis; interstitial; magnetic resonance imaging; pain; urinary bladder.

Assessment of the lower urinary tract microbiota during symptom flare in women with urologic chronic pelvic pain syndrome: A MAPP Network Study.

Nickel JC, Stephens A, Landis JR, Mullins C, van Bokhoven A, Lucia MS, Ehrlich GD; MAPP Research Network. J Urol. 2016 Feb;195(2):356-62. doi: 10.1016/j.juro.2015.09.075. Epub 2015 Sep 26. [PMID: 26410734] [PMC4770794]

Abstract

Purpose: We compared culture independent assessment of microbiota of the lower urinary tract in standard culture negative female patients with urological chronic pelvic pain syndrome who reported symptom flare vs those who did not report a flare.

Materials and methods: Initial stream (VB1) and midstream (VB2) urine specimens (233 patients with urological chronic pelvic pain syndrome) were analyzed with Ibis T-5000 Universal Biosensor system technology for comprehensive identification of microorganism species. Differences between flare and nonflare groups for presence or number of different species within a higher level group (richness) were examined by permutational multivariate analysis of variance and logistic regression.

Results: Overall 81 species (35 genera) were detected in VB1 and 73 (33) in VB2. Mean (SD) VB1 and VB2 species count per person was 2.6 (1.5) and 2.4 (1.5) for 86 flare cases and 2.8 (1.3) and 2.5 (1.5) for 127 nonflare cases, respectively. Overall the species composition did not significantly differ between flare and nonflare cases at any level (p=0.14 species, p=0.95 genus in VB1 and VB2, respectively) in multivariate analysis for richness. Univariate analysis, unadjusted as well as adjusted, confirmed a significantly greater prevalence of fungi (Candida and Saccharomyces) in the flare group (15.7%) compared to the nonflare group in VB2 (3.9%) (p=0.01). When adjusted for antibiotic use and menstrual phase, women who reported a flare remained more likely to have fungi present in VB2 specimens (OR 8.3, CI 1.7-39.4).

Conclusions: Among women with urological chronic pelvic pain syndrome the prevalence of fungi (Candida and Saccharomyces sp.) was significantly greater in those who reported a flare compared to those who did not.

Keywords: cystitis; infection; interstitial; microbiota; symptom assessment.

Multisite, multimodal neuroimaging of chronic urological pelvic pain: Methodology of the MAPP Research Network.

Alger JR, Ellingson BM, Ashe-McNalley C, Woodworth DC, Labus JS, Farmer M, Huang L, Apkarian AV, Johnson KA, Mackey SC, Ness TJ, Deutsch G, Harris RE, Clauw DJ, Glover GH, Parrish TB, Hollander Jd, Kusek JW, Mullins C, Mayer EA; MAPP Research Network Investigators. Neuroimage Clin. 2016 Jan 6;12:65-77. doi: 10.1016/j.nicl.2015.12.009. eCollection 2016. [PMID: 27408791] [PMC4925887]

Abstract

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.

Keywords: Brain; DTI; Diffusion tensor imaging; Functional magnetic resonance imaging; Magnetic resonance imaging; TransMAPP; Urologic chronic pelvic pain syndromes.

Altered brain connectivity in dysmenorrhea: pain modulation and the motor cortex.

Kutch JJ, Tu FF. Pain. 2016 Jan;157(1):5-6. doi: 10.1097/j.pain.0000000000000364. [PMID: 26683107] [PMC4941100]

Abstract

Primary dysmenorrhea, menstrual pain without an identified cause, is a common and often debilitating problem. Fifteen to twenty percentage of women fail to respond to conservative treatment and experience significant reduction in quality of life.5 An important consideration, that we and others have proposed, is that these treatment failures may reflect a completely different phenotype, where the primary disorder is aberrant central processing of pain rather than solely peripherally based uterine inflammation.4 Consistent with this idea, high rates of comorbidity have been identified between dysmenorrhea and other idiopathic pain disorders, notably irritable bowel syndrome and painful bladder syndrome.18 The epidemiological overlap with these visceral pain conditions suggests that sensitization in the central nervous system may also play a role in menstrual uterine pain. Correspondingly, there is a growing body of evidence showing that some dysmenorrhea sufferers exhibit widespread reductions in both somatic2,6 and visceral16 hyperalgesia, suggesting fundamental changes in central pain modulatory systems.

Keywords: brain; brain mapping; dysmenorrhea; magnetic resonance imaging; motor cortex; Nerve Net; neural pathways.

Painful bladder filling and painful urgency are distinct characteristics in men and women with urological chronic pelvic pain syndromes: A MAPP Research Network Study.

Lai HH, Krieger JN, Pontari MA, Buchwald D, Hou X, Landis JR; MAPP Research Network.  J Urol. 2015 Dec;194(6):1634-41. doi: 10.1016/j.juro.2015.05.105.  Epub 2015 Jul 17. [PMID: 26192257] [PMC4669971]

Abstract

urpose: We describe bladder associated symptoms in patients with urological chronic pelvic pain syndromes. We correlated these symptoms with urological, nonurological, psychosocial and quality of life measures.

Materials and methods: Study participants included 233 women and 191 men with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome in a multicenter study. They completed a battery of measures, including items asking whether pain worsened with bladder filling (painful filling) or whether the urge to urinate was due to pain, pressure or discomfort (painful urgency). Participants were categorized into 3 groups, including group 1-painful filling and painful urgency (both), 2-painful filling or painful urgency (either) and 3-no painful filling or painful urgency (neither).

Results: Of the men 75% and of the women 88% were categorized as both or either. These bladder characteristics were associated with more severe urological symptoms (increased pain, frequency and urgency), a higher somatic symptom burden, depression and worse quality of life (3-group trend test each p<0.01). A gradient effect was observed across the groups (both>either>neither). Compared to those in the neither group men categorized as both or either reported more frequent urological chronic pelvic pain syndrome symptom flares, catastrophizing and irritable bowel syndrome, and women categorized as both or either were more likely to have a negative affect and chronic fatigue syndrome.

Conclusions: Men and women with bladder symptoms characterized as painful filling or painful urgency had more severe urological symptoms, more generalized symptoms and worse quality of life than participants who reported neither characteristic, suggesting that these symptom characteristics might represent important subsets of patients with urological chronic pelvic pain syndromes.

Keywords: cystitis; interstitial; pain; prostatitis; questionnaires; urinary bladder.

Unique microstructural changes in the brain associated with urological chronic pelvic pain syndrome (UCPPS) revealed by diffusion tensor MRI, super-resolution track density imaging, and statistical parameter mapping: A MAPP Network Neuroimaging Study.

Woodworth D, Mayer E, Leu K, Ashe-McNalley C, Naliboff BD, Labus JS, Tillisch K, Kutch JJ, Farmer MA, Apkarian AV, Johnson KA, Mackey SC, Ness TJ, Landis JR, Deutsch G, Harris RE, Clauw DJ, Mullins C, Ellingson BM; MAPP Research Network. PLoS One. 2015 Oct 13;10(10):e0140250. doi: 10.1371/journal.pone.0140250. eCollection 2015.  [PMID: 26460744] [PMC4604194]

Abstract

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.

Keywords: Pain; Central nervous system; Corpus callosum; Diffusion tensor imaging; Basal ganglia; Microstructure; Anisotropy; Pain sensation.

The posterior medial cortex in urologic chronic pelvic pain syndrome: detachment from default mode network-a resting-state study from the MAPP Research Network.

Martucci KT, Shirer WR, Bagarinao E, Johnson KA, Farmer MA, Labus JS, Apkarian AV, Deutsch G, Harris RE, Mayer EA, Clauw DJ, Greicius MD, Mackey SC. Pain. 2015 Sep;156(9):1755-1764. doi: 10.1097/j.pain.0000000000000238. [PMID: 26010458] [PMC4545714]

Abstract

Altered resting-state (RS) brain activity, as a measure of functional connectivity (FC), is commonly observed in chronic pain. Identifying a reliable signature pattern of altered RS activity for chronic pain could provide strong mechanistic insights and serve as a highly beneficial neuroimaging-based diagnostic tool. We collected and analyzed RS functional magnetic resonance imaging data from female patients with urologic chronic pelvic pain syndrome (N = 45) and matched healthy participants (N = 45) as part of an NIDDK-funded multicenter project (www.mappnetwork.org). Using dual regression and seed-based analyses, we observed significantly decreased FC of the default mode network to 2 regions in the posterior medial cortex (PMC): the posterior cingulate cortex (PCC) and the left precuneus (threshold-free cluster enhancement, family-wise error corrected P < 0.05). Further investigation revealed that patients demonstrated increased FC between the PCC and several brain regions implicated in pain, sensory, motor, and emotion regulation processes (eg, insular cortex, dorsolateral prefrontal cortex, thalamus, globus pallidus, putamen, amygdala, hippocampus). The left precuneus demonstrated decreased FC to several regions of pain processing, reward, and higher executive functioning within the prefrontal (orbitofrontal, anterior cingulate, ventromedial prefrontal) and parietal cortices (angular gyrus, superior and inferior parietal lobules). The altered PMC connectivity was associated with several phenotype measures, including pain and urologic symptom intensity, depression, anxiety, quality of relationships, and self-esteem levels in patients. Collectively, these findings indicate that in patients with urologic chronic pelvic pain syndrome, regions of the PMC are detached from the default mode network, whereas neurological processes of self-referential thought and introspection may be joined to pain and emotion regulatory processes.

Keywords: UCPPS; Interstitial cystitis; Bladder pain syndrome; Posterior cingulate cortex; Default mode network [DMN]; Precuneus; Dual regression; Resting state; fMRI.

Search for microorganisms in men with urologic chronic pelvic pain syndrome: a culture-independent analysis in the MAPP Research Network.

Nickel JC, Stephens A, Landis JR, Chen J, Mullins C, van Bokhoven A, Lucia MS, Melton-Kreft R, Ehrlich GD; MAPP Research Network.  J Urol. 2015 Jul;194(1):127-35. doi: 10.1016/j.juro.2015.01.037.  Epub 2015 Jan 14. [PMID: 25596358] [PMC4475477]

Abstract

Purpose: We used next-generation, state-of-the-art, culture independent methodology to survey urine microbiota of males with urologic chronic pelvic pain syndrome and control participants enrolled in the MAPP Network to investigate a possible microbial etiology.

Materials and methods: Male patients with urologic chronic pelvic pain syndrome and matched controls were asked to provide initial, midstream and post-prostatic massage urine specimens. Specimens were analyzed with Ibis T-5000 Universal Biosensor technology to provide comprehensive identification of bacterial and select fungal species. Differences between urologic chronic pelvic pain syndrome and control study participants for the presence of species or species variation in a higher taxonomic grouping (genus) were evaluated using permutational multivariate analysis of variance and logistic regression.

Results: Initial and midstream urine specimens were obtained from 110 (post-prostatic massage urine in 67) participants with urologic chronic pelvic pain syndrome and 115 (post-prostatic massage urine in 62) controls. Overall 78, 73 and 54 species (42, 39 and 27 genera) were detected in initial, midstream and post-prostatic massage urine specimens, respectively. Mean (SD) initial, midstream and post-prostatic massage urine species count per person was 1.62 (1.28), 1.38 (1.36) and 1.33 (1.24) for cases, and 1.75 (1.32), 1.23 (1.15) and 1.56 (0.97) for controls, respectively. Overall species and genus composition differed significantly between participants with urologic chronic pelvic pain syndrome and controls in initial stream urine (p=0.002 species level, p=0.004 genus level), with Burkholderia cenocepacia overrepresented in urologic chronic pelvic pain syndrome. No significant differences were observed at any level in midstream or post-prostatic massage urine samples.

Conclusions: Assessment of baseline culture-independent microbiological data from male subjects enrolled in the MAPP Network has identified overrepresentation of B. cenocepacia in urologic chronic pelvic pain syndrome. Future studies are planned to further evaluate microbiota associations with variable and changing urologic chronic pelvic pain syndrome symptom patterns.

Keywords: chronic pain; infection; microbiota; pelvic pain; prostatitis.

Urological chronic pelvic pain syndrome flares and their impact: qualitative analysis in the MAPP network.

Sutcliffe S, Bradley CS, Clemens JQ, James AS, Konkle KS, Kreder KJ, Lai HH, Mackey SC, Ashe-McNalley CP, Rodriguez LV, Barrell E, Hou X, Robinson NA, Mullins C, Berry SH. Int Urogynecol J. 2015 Jul;26(7):1047-60. doi: 10.1007/s00192-015-2652-6. Epub 2015 Mar 20. [PMID: 25792349] [PMC4489981]

Abstract

Introduction and hypothesis: Although in-depth qualitative information is critical to understanding patients' symptom experiences and to developing patient-centered outcome measures, only one previous qualitative study has assessed urological chronic pelvic pain syndrome (UCPPS) symptom exacerbations ("flares").

Methods: We conducted eight focus groups of female UCPPS (interstitial cystitis/bladder pain syndrome) patients at four sites from the MAPP Research Network (n = 57, mean = 7/group) to explore the full spectrum of flares and their impact on patients' lives.

Results: Flare experiences were common and varied widely in terms of UCPPS symptoms involved, concurrent nonpelvic symptoms (e.g., diarrhea), symptom intensity (mild to severe), duration (minutes to years), and frequency (daily to < once/year), although the most commonly described flares were painful flares lasting days. These latter flares were also most disruptive to participants' lives, causing some to cancel social events, miss work or school, and in the worst cases, go to the emergency room or on disability leave. Participants also reported a longer-term impact of flares, including negative effects on their sexual functioning and marital, family, and social relationships; and the loss of employment or limited career or educational advancement. Emerging themes included the need for a sense of control over unpredictable symptoms and reduced social engagement.

Conclusions: Given their negative impact, future research should focus on approaches to prevent flares, and to reduce their frequency, severity, and/or duration. Patients' quality of life may also be improved by providing them with a sense of control over their symptoms through ready access to flare medications/therapy, and by engaging them socially.

Keywords: Urological chronic pelvic pain syndrome; Interstitial cystitis; Bladder pain syndrome; Symptom exacerbation; Flare; Focus group.

Brain white matter abnormalities in female interstitial cystitis/bladder pain syndrome: A MAPP Network Neuroimaging Study.

Farmer MA, Huang L, Martucci K, Yang CC, Maravilla KR, Harris RE, Clauw DJ, Mackey S, Ellingson BM, Mayer EA, Schaeffer AJ, Apkarian AV; MAPP Research Network. J Urol. 2015 Jul;194(1):118-26. doi: 10.1016/j.juro.2015.02.082. Epub 2015 Feb 21. [PMID: 25711200] [PMC4475466]

Abstract

Purpose: Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network.

Materials and methods: We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence.

Results: Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi.

Conclusions: To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.

Keywords: cystitis; diffusion tensor imaging; interstitial; pain; urinary bladder; white matter.

Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study.

Kutch JJ, Yani MS, Asavasopon S, Kirages DJ, Rana M, Cosand L, Labus JS, Kilpatrick LA, Ashe-McNalley C, Farmer MA, Johnson KA, Ness TJ, Deutsch G, Harris RE, Apkarian AV, Clauw DJ, Mackey SC, Mullins C, Mayer EA. Neuroimage Clin. 2015 Jun 5;8:493-502. doi: 10.1016/j.nicl.2015.05.013. eCollection 2015. [PMID: 26106574] [PMC4474411]

Abstract

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing.

Keywords: brain mapping; Brief Pain Inventory; chronic prostatitis; functional magnetic resonance imaging; Functional Neuroimaging; image processing; magnetic resonance imaging; motoneuron; motor control; motor cortex; muscle contraction; nerve cell network; Nerve Net; neuroimaging; nuclear magnetic resonance imaging; pathophysiology; pelvis pain syndrome; posterior insula; prostatitis; resting state network.

Animal models of urologic chronic pelvic pain syndromes: findings from the multidisciplinary approach to the study of chronic pelvic pain research network.

Lai H, Gereau RW 4th, Luo Y, O’Donnell M, Rudick CN, Pontari M, Mullins C, Klumpp DJ. Urology. 2015 Jun;85(6):1454-65. doi: 10.1016/j.urology.2015.03.007. [PMID: 26099889] [PMC4479414]

Abstract

Objective: To describe the approach taken by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network investigators to advance the utility of urologic chronic pelvic pain syndromes (UCPPS) animal models.

Methods: A multidisciplinary team of investigators representing basic science and clinical expertise defined key phenotypic criteria for rodent models of UCPPS. UCPPS symptoms were prioritized based on their clinical significance. Methods for quantifying animal correlates to patient symptoms were developed. The methods were implemented across proposed rodent models for evaluation and comparison of animals for phenotypic characteristics relevant to human symptomatology.

Results: Pelvic pain and urinary frequency were deemed primary features of human UCPPS and were prioritized for assessment in animals. Nociception was quantified using visceromotor response to bladder distention and by applying von Frey filaments to the lower abdomen (referred tactile allodynia). Micturition activity was assessed as free voiding using micturition cages or blotting pad assays and in response to bladder filling by cystometry. Models varied in both depth of characterization and degree of recapitulating pelvic pain and urinary frequency characteristics of UCPPS.

Conclusion: Rodent models that reflect multiple key characteristics of human UCPPS may be identified and provide enhanced clinical significance to mechanistic studies. We have developed a strategy for evaluating current and future animal models of UCPPS based on human symptomatology. This approach provides a foundation for improved translation between mechanistic studies in animals and clinical research and serves as a validation strategy for assessing validity of models for symptom-driven disorders of unknown etiology.

Keywords: interstitial cystitis; chronic prostatitis; animal models; pain models; translational research; pelvic pain.

Widespread psychosocial difficulties in men and women with urologic chronic pelvic pain syndromes: case-control findings from the multidisciplinary approach to the study of chronic pelvic pain research network.

Naliboff BD, Stephens AJ, Afari N, Lai H, Krieger JN, Hong B, Lutgendorf S, Strachan E, Williams D; MAPP Research Network. Urology. 2015 Jun;85(6):1319-27. doi: 10.1016/j.urology.2015.02.047. [PMID: 26099876] [PMC4479402]

Abstract

Objective: To determine the extent, severity, and sex differences of psychosocial deficits in men and women with urologic chronic pelvic pain syndromes (UCPPS), which in the past have been considered separate bladder (interstitial cystitis-painful bladder syndrome) and prostate (chronic prostatitis-chronic pelvic pain syndrome) disorders. Evaluations of men and women separately suggest UCPPS is associated with increased anxiety and depression. However, studies directly testing deficits in broader psychosocial domains such as cognitive processes, intimate relationships, and trauma history, or tests of sex differences in the pattern of difficulties associated with UCPPS have not been performed.

Methods: A total of 233 female and 191 male UCPPS patients and 235 female and 182 male healthy controls (HCs) were recruited from 6 academic medical centers in the United States and evaluated with a comprehensive battery of symptom, psychosocial, and illness impact measures. Primary comparisons of interest were between UCPPS patients and HCs and between men and women with UCPPS.

Results: In addition to greater negative effect, male and female UCPPS patients show higher levels of current and lifetime stress, poorer illness coping, increased self-report of cognitive deficits, and more widespread pain symptoms compared with sex- and education-matched HCs. Similar problems were found in male and female UCPPS patients although female UCPPS patients showed increased self-report of childhood adversity and more widespread symptoms of pain and discomfort.

Conclusion: Given the significance of psychosocial variables in prognosis and treatment of chronic pain conditions, the results add substantially to our understanding of the breath of difficulties associated with UCPPS and point to important areas for clinical assessment. Copyright © 2015 Elsevier Inc. All rights reserved.

Keywords: chronic pain; pelvic pain; severity of illness index; urologic diseases.

Comparison of baseline urological symptoms in men and women in the MAPP research cohort.

Clemens JQ, Clauw DJ, Kreder K, Krieger JN, Kusek JW, Lai HH, Rodriguez L, Williams DA, Hou X, Stephens A, Landis JR; MAPP Research Network. J Urol. 2015 May;193(5):1554-8. doi: 10.1016/j.juro.2014.11.016. Epub 2014 Nov 13. [PMID: 25463989] [PMC4454891]

Abstract

Purpose: The clinical features of the interstitial cystitis/bladder pain syndrome are similar to those of the chronic prostatitis/chronic pelvic pain syndrome. However, to our knowledge no studies have directly compared the characteristics of these syndromes in men and women.

Materials and methods: The MAPP Research Network recruited 191 men and 233 women with IC/BPS or CP/CPPS. Baseline data included demographics, Interstitial Cystitis Symptom Index and Problem Index scores; Genitourinary Pain Index score; American Urological Association Symptom Index score; Likert scales to assess urinary urgency, frequency, pain and overall symptom severity; and a single question about the most bothersome pelvic symptom.

Results: After adjustment for age, income and symptom duration, measures of pain severity were similar across genders. Mean scores for the ICSI, ICPI and AUASI were significantly higher in women than in men, reflecting more bladder focused symptoms in women. The most bothersome single symptom in men as well as in women was pain in the pubic/bladder area (men 34%, women 58%). The characteristics of the men and women in the MAPP cohort were similar to those reported in other research cohorts for IC/BPS and CP/CPPS.

Conclusions: Our findings indicate that pain severity is similar for both genders and that bladder focused symptoms (urgency, suprapubic pain, frequency) are more common in women. However, a substantial proportion of men also reported these types of bladder symptoms.

Keywords: chronic pain; cystitis; interstitial; pelvic pain; prostatitis.

Relationship between chronic nonurological associated somatic syndromes and symptom severity in urological chronic pelvic pain syndromes: baseline evaluation of the MAPP study.

Krieger JN, Stephens AJ, Landis JR, Clemens JQ, Kreder K, Lai HH, Afari N, Rodríguez L, Schaeffer A, Mackey S, Andriole GL, Williams DA; MAPP Research Network. J Urol. 2015 Apr;193(4):1254-62. doi: 10.1016/j.juro.2014.10.086. Epub 2014 Oct 22. [PMID: 25444992] [PMC4497586]

Abstract

Purpose: We used MAPP data to identify participants with urological chronic pelvic pain syndromes only or a chronic functional nonurological associated somatic syndrome in addition to urological chronic pelvic pain syndromes. We characterized these 2 subgroups and explored them using 3 criteria, including 1) MAPP eligibility criteria, 2) self-reported medical history or 3) RICE criteria.

Materials and methods: Self-reported cross-sectional data were collected on men and women with urological chronic pelvic pain syndromes, including predominant symptoms, symptom duration and severity, nonurological associated somatic syndrome symptoms and psychosocial factors.

Results: Of 424 participants with urological chronic pelvic pain syndromes 162 (38%) had a nonurological associated somatic syndrome, including irritable bowel syndrome in 93 (22%), fibromyalgia in 15 (4%), chronic fatigue syndrome in 13 (3%) and multiple syndromes in 41 (10%). Of 233 females 103 (44%) had a nonurological associated somatic syndrome compared to 59 of 191 males (31%) (p = 0.006). Participants with a nonurological associated somatic syndrome had more severe urological symptoms and more frequent depression and anxiety. Of 424 participants 228 (54%) met RICE criteria. Of 228 RICE positive participants 108 (47%) had a nonurological associated somatic syndrome compared to 54 of 203 RICE negative patients (28%) with a nonurological associated somatic syndrome (p < 0.001).

Conclusions: Nonurological associated somatic syndromes represent important clinical characteristics of urological chronic pelvic pain syndromes. Participants with a nonurological associated somatic syndrome have more severe symptoms, longer duration and higher rates of depression and anxiety. RICE positive patients are more likely to have a nonurological associated somatic syndrome and more severe symptoms. Because nonurological associated somatic syndromes are more common in women, future studies must account for this potential confounding factor in urological chronic pelvic pain syndromes.

Keywords: cystitis; female; interstitial; male; questionnaires; urinary bladder.

Changes in symptoms during urologic chronic pelvic pain syndrome symptom flares: findings from one site of the MAPP Research Network.

Sutcliffe S, Colditz GA, Pakpahan R, Bradley CS, Goodman MS, Andriole GL, Lai HH. Neurourol Urodyn. 2015 Feb;34(2):188-95. doi: 10.1002/nau.22534. Epub 2013 Nov 23. [PMID: 24273163] [PMC4032370]

Abstract

Aims: To provide the first description and quantification of symptom changes during interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome symptom exacerbations ("flares").

Methods: Participants at one site of the Trans-Multidisciplinary Approaches to the study of chronic Pelvic Pain Epidemiology and Phenotyping Study completed two 10-day diaries over the 1-year study follow-up period, one at baseline and one during their first flare (if not at baseline). On each day of the diary, participants reported whether they were currently experiencing a flare, defined as "symptoms that are much worse than usual" for at least 1 day, and their levels of urination-related pain, pelvic pain, urgency, and frequency on a scale of 0-10. Linear mixed models were used to calculate mean changes in symptoms between non-flare and flare days from the same participant.

Results: Eighteen of 27 women and 9 of 29 men reported at least one flare during follow-up, for a total of 281 non-flare and 210 flare days. Of these participants, 44.4% reported one flare, 29.6% reported two flares, and 25.9% reported ≥ 3 flares over the combined 20-day diary observation period, with reported flares ranging in duration from 1 day to >2 weeks. During these flares, each of the main symptoms worsened significantly by a mean of at least two points and total symptoms worsened by a mean of 11 points for both sexes (all P ≤ 0.01).

Conclusions: Flares are common and correspond to a global worsening of urologic and pelvic pain symptoms.

Keywords: bladder pain syndrome; chronic pelvic pain syndrome; chronic prostatitis; flare; interstitial cystitis; symptom exacerbation.

Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome.

Kairys AE, Schmidt-Wilcke T, Puiu T, Ichesco E, Labus JS, Martucci K, Farmer MA, Ness TJ, Deutsch G, Mayer EA, Mackey S, Apkarian AV, Maravilla K, Clauw DJ, Harris RE.  J Urol. 2015 Jan;193(1):131-7. doi: 10.1016/j.juro.2014.08.042. Epub 2014 Aug 14. [PMID: 25132239] [PMC4435781]

Abstract

Purpose: Interstitial cystitis is a highly prevalent pain condition estimated to affect 3% to 6% of women in the United States. Emerging data suggest there are central neurobiological components to the etiology of this disease. We report the first brain structural imaging findings from the MAPP network with data on more than 300 participants.

Materials and methods: We used voxel based morphometry to determine whether human patients with chronic interstitial cystitis display changes in brain morphology compared to healthy controls. A total of 33 female patients with interstitial cystitis without comorbidities and 33 age and gender matched controls taken from the larger sample underwent structural magnetic resonance imaging at 5 MAPP sites across the United States.

Results: Compared to controls, females with interstitial cystitis displayed significant increased gray matter volume in several regions of the brain including the right primary somatosensory cortex, the superior parietal lobule bilaterally and the right supplementary motor area. Gray matter volume in the right primary somatosensory cortex was associated with greater pain, mood (anxiety) and urological symptoms. We explored these correlations in a linear regression model, and found independent effects of these 3 measures on primary somatosensory cortex gray matter volume, namely clinical pain (McGill pain sensory total), a measure of urgency and anxiety (HADS).

Conclusions: These data support the notion that changes in somatosensory gray matter may have an important role in pain sensitivity as well as affective and sensory aspects of interstitial cystitis. Further studies are needed to confirm the generalizability of these findings to other pain conditions.

Keywords: cystitis; interstitial; pain; somatosensory cortex.

Urological chronic pelvic pain syndrome symptom flares: characterisation of the full range of flares at two sites in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.

Sutcliffe S, Colditz GA, Goodman MS, Pakpahan R, Vetter J, Ness TJ, Andriole GL, Lai HH. BJU Int. 2014 Dec;114(6):916-25. doi: 10.1111/bju.12778. Epub 2014 Aug 11. [PMID: 24730356] [PMC4198521]

Abstract

Objectives: To describe the full range of symptom exacerbations defined by people with interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome as 'flares', and to investigate their associated healthcare utilization and bother at two sites of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Epidemiology and Phenotyping study.

Subjects and methods: Participants completed a flare survey that asked them: 1) whether they had ever had flares ('symptoms that are much worse than usual') that lasted <1 h, >1 h and <1 day, and >1 day; and 2) for each duration of flare, to report: their average length and frequency; their typical levels of urological and pelvic pain symptoms; and their levels of healthcare utilization and bother. We compared participants' responses to their non-flare MAPP values and by duration of flare using generalized linear mixed models.

Results: Of 85 participants, 76 (89.4%) completed the flare survey, 72 (94.7%) of whom reported experiencing flares. Flares varied widely in terms of their duration (seconds to months), frequency (several times per day to once per year or less), and intensity and type of symptoms (e.g. pelvic pain vs urological symptoms). Flares of all durations were associated with greater pelvic pain, urological symptoms, disruption to participants' activities and bother, with increasing severity of each of these factors as the duration of flares increased. Days-long flares were also associated with greater healthcare utilization. In addition to duration, symptoms (pelvic pain, in particular) were also significant determinants of flare-related bother.

Conclusions: Our findings suggest that flares are common and associated with greater symptoms, healthcare utilization, disruption and bother. Our findings also show the characteristics of flares most bothersome to patients (i.e. increased pelvic pain and duration), and thus of greatest importance to consider in future research on flare prevention and treatment.

Keywords: bladder pain syndrome; chronic pelvic pain syndrome; chronic prostatitis; flare; interstitial cystitis; symptom exacerbation.

Evaluation of urinary protein precipitation protocols for the multidisciplinary approach to the study of chronic pelvic pain research network.

Jonscher KR, Osypuk AA, van Bokhoven A, Lucia MS. J Biomol Tech. 2014 Dec;25(4):118-26. doi: 10.7171/jbt.14-2504-004. [PMID: 25365794] [PMC4211279]

Abstract

Standardization of sample collection, shipping, and storage has been a major focus of biorepositories servicing large, multi-institute studies. The standardization of total protein concentration measurements may also provide an important metric for characterizing biospecimens. The measurement of total protein concentration in urine is challenging because of widely variable sample dilutions obtained in the clinic and the lack of a reference matrix for use with a standard curve and blank subtraction. Urinary proteins are therefore typically precipitated and reconstituted in a reference solution before quantitation. We have tested three different methods for protein precipitation and evaluated them using variability in total protein concentration measurement as a metric. The methods were tested on four urine samples ranging from very concentrated to very dilute. A method using a commercially available kit provided the most reproducible results, with average coefficients of variation <10%. Addition of a freeze/thaw did not lead to significant protein loss or additional variability. Samples were titrated and the measurements obtained appeared to be linearly correlated with sample starting volume. This method was applied to analysis of 77 urine biorepository samples and provided reproducible results when the same sample was assayed on different microwell plates.

Keywords: chemical precipitation; proteomics; quantitation; urine.

Preliminary structural MRI based brain classification of chronic pelvic pain: A MAPP network study.

Bagarinao E, Johnson KA, Martucci KT, Ichesco E, Farmer MA, Labus J, Ness TJ, Harris R, Deutsch G, Apkarian VA, Mayer EA, Clauw DJ, Mackey S. Pain. 2014 Dec;155(12):2502-2509. doi: 10.1016/j.pain.2014.09.002. Epub 2014 Sep 19. [PMID: 25242566] [PMC4504202]

Abstract

Neuroimaging studies have shown that changes in brain morphology often accompany chronic pain conditions. However, brain biomarkers that are sensitive and specific to chronic pelvic pain (CPP) have not yet been adequately identified. Using data from the Trans-MAPP Research Network, we examined the changes in brain morphology associated with CPP. We used a multivariate pattern classification approach to detect these changes and to identify patterns that could be used to distinguish participants with CPP from age-matched healthy controls. In particular, we used a linear support vector machine (SVM) algorithm to differentiate gray matter images from the 2 groups. Regions of positive SVM weight included several regions within the primary somatosensory cortex, pre-supplementary motor area, hippocampus, and amygdala were identified as important drivers of the classification with 73% overall accuracy. Thus, we have identified a preliminary classifier based on brain structure that is able to predict the presence of CPP with a good degree of predictive power. Our regional findings suggest that in individuals with CPP, greater gray matter density may be found in the identified distributed brain regions, which are consistent with some previous investigations in visceral pain syndromes. Future studies are needed to improve upon our identified preliminary classifier with integration of additional variables and to assess whether the observed differences in brain structure are unique to CPP or generalizable to other chronic pain conditions.

Keywords: Gray matter density; Machine learning; SVM; Support vector machine; UCPPS.

Asymptomatic bacteriuria Escherichia coli are live biotherapeutics for UTI.

Rudick CN, Taylor AK, Yaggie RE, Schaeffer AJ, Klumpp DJ. PLoS One. 2014 Nov 18;9(11):e109321. doi: 10.1371/journal.pone.0109321. eCollection 2014. [PMID: 25405579] [PMC4236008]

Abstract

Urinary tract infections (UTI) account for approximately 8 million clinic visits annually with symptoms that include acute pelvic pain, dysuria, and irritative voiding. Empiric UTI management with antimicrobials is complicated by increasing antimicrobial resistance among uropathogens, but live biotherapeutics products (LBPs), such as asymptomatic bacteriuria (ASB) strains of E. coli, offer the potential to circumvent antimicrobial resistance. Here we evaluated ASB E. coli as LBPs, relative to ciprofloxacin, for efficacy against infection and visceral pain in a murine UTI model. Visceral pain was quantified as tactile allodynia of the pelvic region in response to mechanical stimulation with von Frey filaments. Whereas ciprofloxacin promoted clearance of uropathogenic E. coli (UPEC), it did not reduce pelvic tactile allodynia, a measure of visceral pain. In contrast, ASB E. coli administered intravesically or intravaginally provided comparable reduction of allodynia similar to intravesical lidocaine. Moreover, ASB E. coli were similarly effective against UTI allodynia induced by Proteus mirabilis, Enterococccus faecalis and Klebsiella pneumoniae. Therefore, ASB E. coli have anti-infective activity comparable to the current standard of care yet also provide superior analgesia. These studies suggest that ASB E. coli represent novel LBPs for UTI symptoms.

Keywords: Allodynia; Analgesics; Pain; Bladder; Bacterial pathogens; Urinary tract infections; Antimicrobial resistance; Escherichia coli infections.

Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome.

Kilpatrick LA, Kutch JJ, Tillisch K, Naliboff BD, Labus JS, Jiang Z, Farmer MA, Apkarian AV, Mackey S, Martucci KT, Clauw DJ, Harris RE, Deutsch G, Ness TJ, Yang CC, Maravilla K, Mullins C, Mayer EA. J Urol. 2014 Sep;192(3):947-55. doi: 10.1016/j.juro.2014.03.093. Epub 2014 Mar 26. [PMID: 24681331] [PMC4432915]

Abstract

Purpose: The pathophysiology of interstitial cystitis/painful bladder syndrome remains incompletely understood but is thought to involve central disturbance in the processing of pain and viscerosensory signals. We identified differences in brain activity and connectivity between female patients with interstitial cystitis/painful bladder syndrome and healthy controls to advance clinical phenotyping and treatment efforts for interstitial cystitis/painful bladder syndrome.

Materials and methods: We examined oscillation dynamics of intrinsic brain activity in a large sample of well phenotyped female patients with interstitial cystitis/painful bladder syndrome and female healthy controls. Data were collected during 10-minute resting functional magnetic resonance imaging as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network project. The blood oxygen level dependent signal was transformed to the frequency domain. Relative power was calculated for multiple frequency bands.

Results: Results demonstrated altered frequency distributions in viscerosensory (post insula), somatosensory (postcentral gyrus) and motor regions (anterior paracentral lobule, and medial and ventral supplementary motor areas) in patients with interstitial cystitis/painful bladder syndrome. Also, the anterior paracentral lobule, and medial and ventral supplementary motor areas showed increased functional connectivity to the midbrain (red nucleus) and cerebellum. This increased functional connectivity was greatest in patients who reported pain during bladder filling.

Conclusions: Findings suggest that women with interstitial cystitis/painful bladder syndrome have a sensorimotor component to the pathological condition involving an alteration in intrinsic oscillations and connectivity in a cortico-cerebellar network previously associated with bladder function.

Keywords: brain mapping; cystitis; interstitial; magnetic resonance imaging; pain; urinary bladder.

The MAPP research network: design, patient characterization and operations.

Landis JR, Williams DA, Lucia MS, Clauw DJ, Naliboff BD, Robinson NA, van Bokhoven A, Sutcliffe S, Schaeffer AJ, Rodriguez LV, Mayer EA, Lai HH, Krieger JN, Kreder KJ, Afari N, Andriole GL, Bradley CS, Griffith JW, Klumpp DJ, Hong BA, Lutgendorf SK, Buchwald D, Yang CC, Mackey S, Pontari MA, Hanno P, Kusek JW, Mullins C, Clemens JQ; MAPP Research Network Study Group. BMC Urol. 2014 Aug 1;14:58. doi: 10.1186/1471-2490-14-58. [PMID: 25085119] [PMC4126395]

Abstract

Background: The "Multidisciplinary Approach to the Study of Chronic Pelvic Pain" (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network's central study and common data elements are described.

Methods: The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as "positive" controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.

Discussion: The MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.

Keywords: Urologic chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Urine biomarkers; Plasma biomarkers; Non-urologic associated syndromes; Quantitative sensory testing (QST); Neuroimaging.

Trial registration: ClinicalTrials.gov identifier: NCT01098279 "Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)". http://clinicaltrials.gov/show/NCT01098279.

The MAPP research network: a novel study of urologic chronic pelvic pain syndromes.

Clemens JQ, Mullins C, Kusek JW, Kirkali Z, Mayer EA, Rodríguez LV, Klumpp DJ, Schaeffer AJ, Kreder KJ, Buchwald D, Andriole GL, Lucia MS, Landis JR, Clauw DJ; MAPP Research Network Study Group. BMC Urol. 2014 Aug 1;14:57. doi: 10.1186/1471-2490-14-57. [PMID: 25085007] [PMC4134515]

Abstract

Urologic chronic pelvic pain syndrome (UCPPS) may be defined to include interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The hallmark symptom of UCPPS is chronic pain in the pelvis, urogenital floor, or external genitalia often accompanied by lower urinary tract symptoms. Despite numerous past basic and clinical research studies there is no broadly identifiable organ-specific pathology or understanding of etiology or risk factors for UCPPS, and diagnosis relies primarily on patient reported symptoms. In addition, there are no generally effective therapies. Recent findings have, however, revealed associations between UCPPS and "centralized" chronic pain disorders, suggesting UCPPS may represent a local manifestation of more widespread pathology in some patients. Here, we describe a new and novel effort initiated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U.S. National Institutes of Health (NIH) to address the many long standing questions regarding UCPPS, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. The MAPP Network approaches UCPPS in a systemic manner, in which the interplay between the genitourinary system and other physiological systems is emphasized. The network's study design expands beyond previous research, which has primarily focused on urologic organs and tissues, to utilize integrated approaches to define patient phenotypes, identify clinically-relevant subgroups, and better understand treated natural history and pathophysiology. Thus, the MAPP Network provides an unprecedented, multi-layered characterization of UCPPS. Knowledge gained is expected to provide important insights into underlying pathophysiology, a foundation for better segmenting patients for future clinical trials, and ultimately translation into improved clinical management. In addition, the MAPP Network's integrated multi-disciplinary research approach may serve as a model for studies of urologic and non-urologic disorders that have proven refractory to past basic and clinical study.

Keywords: Urological chronic pelvic pain syndromes; Interstitial cystitis; Chronic prostatitis; Translational research; Multi-disciplinary.

Trial registration: ClinicalTrials.gov identifier: NCT01098279 "Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)".

Urological symptoms in a subset of patients with urological chronic pelvic pain syndrome and a polysymptomatic, polysyndromic pattern of presentation.

Lai HH, North CS, Andriole GL, Cupps L, Song D, Ness TJ, Hong BA. J Urol. 2014 Jun;191(6):1802-7. doi: 10.1016/j.juro.2013.12.031. Epub 2013 Dec 19. [PMID: 24361369] [PMC4411959]

Abstract

Purpose: We characterized urological symptoms in a subset of patients with urological chronic pelvic pain syndrome who have a high somatic symptom burden and a wide symptom distribution fitting a polysymptomatic, polysyndromic presentation pattern.

Materials and methods: A total of 81 patients with urological chronic pelvic pain syndrome enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases MAPP Research Network Study at Washington University in St. Louis and University of Alabama at Birmingham sites. They completed a symptom questionnaire to assess the somatic symptom burden and its distribution, and GUPI (Genitourinary Pain Index) to assess urological chronic pelvic pain syndrome symptoms, impact on quality of life and self-reported treatment seeking behaviors for urological chronic pelvic pain symptoms. The polysymptomatic, polysyndromic symptom pattern was defined by self-report of numerous painful and nonpainful somatic symptoms across many organ systems and by symptom categories on the polysymptomatic, polysyndromic questionnaire.

Results: Patients with urological chronic pelvic pain syndrome and the symptom pattern reported more severe genitourinary pain on a Likert scale, more frequent pain in the last week and more widespread pain distribution in the genital and pelvic areas than patients with urological chronic pelvic pain syndrome without the pattern. Patients with the symptom pattern also had significantly higher scores on the GUPI pain subscale, quality of life subscale (worse) and total questionnaire scores than patients without the pattern. Patients with the pattern reported significantly more treatment seeking behavior than others.

Conclusions: The polysymptomatic, polysyndromic pattern might be an important phenotypic factor to assess in the evaluation of urological chronic pelvic pain syndrome with clinical and research implications. This may be a distinct clinical subgroup among patients with urological chronic pelvic pain syndrome.

Keywords: chronic pain; cystitis; interstitial; prostatitis; somatosensory disorders; urinary bladder.

2013

The importance of psychological assessment in chronic pain.

Williams DA. Curr Opin Urol. 2013 Nov;23(6):554-9. doi: 10.1097/MOU.0b013e3283652af1. [PMID: 24080806] [PMC4295636]

Abstract

Purpose of review: Much confusion has surrounded the purpose of the psychological assessment in the context of chronic pain. For many clinicians, the psychological assessment is used to rule out psychiatric illness and to identify the nonmedical causes for pain and disability. In essence, it is used to identify the causes of pain that fall outside of the biomedical model. Supported by over 30 years of evidence, the bio-psycho-social model acknowledges that psychosocial factors are inherent in chronic pain and require assessment if meaningful diagnostics and treatments are to occur.

Recent findings: Five broad categories of psychosocial assessment are relevant to chronic pain. These categories have been shown to enhance the diagnosis of the underlying forms of pain, predict the transition from acute to chronic status, and help to phenotype individuals for the discovery of the underlying mechanisms responsible for pain.

Summary: Informed assessment of chronic pain needs to include relevant biological, psychological, and social domains. This article describes those domains and offers suggestions of specific instruments to use in clinical or research settings.

Keywords: Affect; Cognition; pain perception; modulation.

Development and validation of a pressure-type automated quantitative sensory testing system for point-of-care pain assessment.

Harte SE, Mitra M, Ichesco EA, Halvorson ME, Clauw DJ, Shih AJ, Kruger GH. Med Biol Eng Comput. 2013 Jun;51(6):633-44. doi: 10.1007/s11517-013-1033-x. Epub 2013 Feb 5. [PMID: 23381890]

Abstract

Quantitative sensory testing (QST) can provide useful information about the underlying mechanisms involved in chronic pain. However, currently available devices typically employed suffer from operator-dependent effects, or are too cumbersome for routine clinical care. This paper presents the design and initial validation of a novel automated pressure-pain type QST platform, termed the multi-modal automated sensory testing (MAST) system. The MAST configuration presented consists of wireless, hand-held thumbnail pressure stimulators (with circular 10 mm² rubber tips) and graphical touch screen interface devices to manage the QST process and obtain patient feedback. Validation testing of the custom-designed force sensor showed a 1 % error for low forces increasing to 2 % error for larger loads up to 100 N (full-scale). Validation of the controller using three ramp rates (64, 248, and 496 kPa/s) and six pressures (32, 62, 124, 273, 620, and 1116 kPa) showed an overall mean error of 1.7 % for applied stimuli. Clinical evaluation revealed decreased pressure pain thresholds in chronic pain patients (98.07 ± SE 16.34 kPa) compared to pain free, healthy control subjects (259.88 ± SE 33.54 kPa, p = 0.001). The MAST system is portable and produces accurate, repeatable stimulation profiles indicating potential for point-of-care applications.

Keywords: Chronic pain; Fibromyalgia; MAST; Pressure pain threshold.

Evidence for overlap between urological and nonurological unexplained clinical conditions.

Bullones Rodríguez MÁ, Afari N, Buchwald DS; National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Urological Chronic Pelvic Pain. J Urol. 2013 Jan;189(1 Suppl):S66-74. doi: 10.1016/j.juro.2012.11.019. [PMID: 23234637] [PMC9159381]

Abstract

Purpose: Unexplained clinical conditions share common features such as pain, fatigue, disability out of proportion to physical examination findings, inconsistent laboratory abnormalities, and an association with stress and psychosocial factors. We examined the extent of the overlap among urological and nonurological unexplained clinical conditions characterized by pain. We describe the limitations of previous research and suggest several possible explanatory models.

Materials and methods: Using hallmark symptoms and syndromes as search terms a search of 12 databases identified a total of 1,037 full-length published articles in 8 languages from 1966 to April 2008. The search focused on the overlap of chronic pelvic pain, interstitial cystitis, painful bladder syndrome, chronic prostatitis/chronic pelvic pain syndrome or vulvodynia with fibromyalgia, chronic fatigue syndrome, temporomandibular joint and muscle disorders or irritable bowel syndrome. We abstracted information on authorship, type of case and control groups, eligibility criteria, case definitions, study methods and major findings.

Results: The literature suggests considerable comorbidity between urological and nonurological unexplained clinical conditions. The most robust evidence for overlap was for irritable bowel syndrome and urological unexplained syndromes with some estimates of up to 79% comorbidity between chronic pelvic pain and symptoms of irritable bowel syndrome. However, most studies were limited by methodological problems, such as varying case definitions and selection of controls.

Conclusions: The overlap between urological and selected nonurological unexplained clinical conditions is substantial. Future research should focus on using standardized definitions, and rigorously designed, well controlled studies to further assess comorbidity, clarify the magnitude of the association and examine common pathophysiological mechanisms.

Keywords: urogenital system; fatigue syndrome; chronic; fibromyalgia; irritable bowel syndrome; temporomandibular joint disorders.

Protamine sulfate-induced bladder injury protects from distention induced bladder pain.

Stemler KM, Crock LW, Lai HH, Mills JC, Gereau RW 4th and Mysorekar IU. J Urol. 2013 Jan;189(1): 343-51. doi: 10.1016/j.juro.2012.08.189. Epub 2012 Nov 20. [PMID: 23174261] [PMC3662487]

Abstract

Purpose: Bladder pain is a debilitating symptom of many urological conditions. There is no generally effective treatment. Abnormal urothelial turnover is common to multiple disease states but the specific components of urothelial injury and the resulting molecular signals that lead to bladder pain are unknown. We examined mouse models of bladder injury induced by uropathogenic Escherichia coli, protamine sulfate (Sigma®) and bacterial lipopolysaccharide to identify cellular and molecular correlates underlying pain sensitization in response to the stimuli.

Materials and methods: C57BL/6 female mice (Jackson Laboratory, Bar Harbor, Maine) were given intravesicular protamine sulfate, lipopolysaccharide or uropathogenic E. coli. The impact of each on nociception was determined by measuring the evoked visceromotor response to bladder distention 24 hours after inoculation. Levels of pyuria and tissue inflammation were examined by urinary cytology and tissue histology. Quantitative polymerase chain reaction and gene expression analysis were used to identify injury profiles associated with nociception.

Results: Protamine sulfate treatment was significantly analgesic upon bladder distention. Protamine treated bladders did not show pyuria or extensive tissue damage. Protamine injury was associated with a global decrease in the expression of inflammation associated genes. In contrast, uropathogenic E. coli injury significantly increased the nociceptive response to bladder distention. Lipopolysaccharide treatment did not affect nociception. Finally, injury induced expression of inflammation associated genes correlated with nociceptive responses.

Conclusions: Protamine treatment of the bladder is analgesic and tissue protective, and it suppresses the inflammatory cytokine expression normally associated with nociception. Also, the injury modalities that result in differential tissue response patterns provide an innovative method for identifying mediators of visceral pain.

Keywords: urinary bladder; pain; protamines; nociception; inflammation.

2012

Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain.

Crock LW, Kolber BJ, Morgan CD, Sadler KE, Vogt SK, Bruchas MR, Gereau RW 4th. J Neurosci. 2012 Oct 10;32(41):14217-26. doi: 10.1523/JNEUROSCI.1473-12.2012. [PMID: 23055491] [PMC3494864]

Abstract

Painful bladder syndrome is a debilitating condition that affects 3-6% of women in the United States. Multiple lines of evidence suggest that changes in CNS processing are key to the development of chronic bladder pain conditions but little is known regarding the underlying cellular, molecular, and neuronal mechanisms. Using a mouse model of distention-induced bladder pain, we found that the central nucleus of the amygdala (CeA) is a critical site of neuromodulation for processing of bladder nociception. Furthermore, we demonstrate that metabotropic glutamate receptor 5 (mGluR5) activation in the CeA induces bladder pain sensitization by increasing CeA output. Thus, pharmacological activation of mGluR5 in the CeA is sufficient to increase the response to bladder distention. Additionally, pharmacological blockade or virally mediated conditional deletion of mGluR5 in the CeA reduced responses to bladder distention suggesting that mGluR5 in the CeA is also necessary for these responses. Finally, we used optogenetic activation of the CeA and demonstrated that this caused a robust increase in the visceral pain response. The CeA-localized effects on responses to bladder distention are associated with changes in extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation in the spinal cord. Overall, these data demonstrate that mGluR5 activation leads to increased CeA output that drives bladder pain sensitization.

Keywords: amygdala/physiology; Grm5 protein; metabotropic glutamate 5; NAP kinase signaling system; pain measurement; visceral pain.

The siderophore yersiniabactin binds copper to protect pathogens during infection.

Chaturvedi KS, Hung CS, Crowley JR, Stapleton AE, Henderson JP. Nat Chem Biol. 2012 Aug;8(8):731-6. doi: 10.1038/nchembio.1020. Epub 2012 Jul 8. [PMID: 22772152] [PMC3600419]

Abstract

Bacterial pathogens secrete chemically diverse iron chelators called siderophores, which may exert additional distinctive functions in vivo. Among these, uropathogenic Escherichia coli often coexpress the virulence-associated siderophore yersiniabactin (Ybt) with catecholate siderophores. Here we used a new MS screening approach to reveal that Ybt is also a physiologically favorable Cu(II) ligand. Direct MS detection of the resulting Cu(II)-Ybt complex in mice and humans with E. coli urinary tract infections demonstrates copper binding to be a physiologically relevant in vivo interaction during infection. Ybt expression corresponded to higher copper resistance among human urinary tract isolates, suggesting a protective role for this interaction. Chemical and genetic characterization showed that Ybt helps bacteria resist copper toxicity by sequestering host-derived Cu(II) and preventing its catechol-mediated reduction to Cu(I). Together, these studies reveal a new virulence-associated function for Ybt that is distinct from iron binding.

Keywords: Bacterial pathogenesis; Chemical genetics; Iron.

Polysymptomatic, polysyndromic presentation of patients with urological chronic pelvic pain syndrome.

Lai HH, North CS, Andriole GL, Sayuk GS, Hong BA. J Urol. 2012 Jun;187(6):2106-12. doi: 10.1016/j.juro.2012.01.081. Epub 2012 Apr 12. [PMID: 22503014] [PMC3957225]

Abstract

Purpose: Somatization disorder has been described in several comorbid functional syndromes of urological chronic pelvic pain syndrome, such as irritable bowel syndrome. We investigated whether a subset of patients with urological chronic pelvic pain syndrome may have the polysymptomatic, polysyndromic presentation pattern that is common in somatization disorder.

Materials and methods: A total of 70 male and female patients with urological chronic pelvic pain syndrome and 35 age matched controls without the syndrome completed a 59-item symptom checklist to assess the classic polysymptomatic, polysyndromic symptom pattern. The 2 operational tools used were the Perley-Guze derived symptom checklist and the somatic symptom algorithm used for Diagnostic and Statistical Manual, 4th Edition, Text Revision somatization disorder criteria.

Results: Female patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome) reported significantly more nonpain symptoms and pain symptoms outside the pelvis than control female urology patients (p=0.0016 and 0.0018, respectively). Female patients with urological chronic pelvic pain syndrome were more likely to endorse a polysymptomatic, polysyndromic symptom pattern than female controls (27% vs 0%, p=0.0071). In contrast, male patients with urological chronic pelvic pain syndrome (interstitial cystitis/bladder pain syndrome and/or chronic prostatitis/chronic pelvic pain syndrome) did not report more extrapelvic pain than male controls (p=0.89). Male patients with urological chronic pelvic pain syndrome were not more likely than male controls to have a polysymptomatic, polysyndromic symptom pattern.

Conclusions: A subset of female patients with urological chronic pelvic pain syndrome endorses numerous extrapelvic symptoms across multiple organ systems. The checklist may be valuable to assess patients for this polysymptomatic, polysyndromic symptom pattern, which is common in somatization disorder. Recognizing this polysymptomatic, polysyndromic presentation will prompt clinicians to investigate further to determine whether somatization disorder may be an underlying diagnosis in a small subset of patients with urological chronic pelvic pain syndrome who complain of numerous extrapelvic symptoms.

Keywords: urinary bladder; prostate; cystitis, interstitial; prostatitis; somatization disorders.

O-antigen modulates infection-induced pain states.

Rudick CN, Jiang M, Yaggie RE, Pavlov VI, Done J, Heckman CJ, Whitfield C, Schaeffer AJ, Klumpp DJ. PLoS One. 2012;7(8):e41273. doi: 10.1371/journal.pone.0041273. Epub 2012 Aug 10. [PMID: 22899994] [PMC3416823]

Abstract

The molecular initiators of infection-associated pain are not understood. We recently found that uropathogenic E. coli (UPEC) elicited acute pelvic pain in murine urinary tract infection (UTI). UTI pain was due to E. coli lipopolysaccharide (LPS) and its receptor, TLR4, but pain was not correlated with inflammation. LPS is known to drive inflammation by interactions between the acylated lipid A component and TLR4, but the function of the O-antigen polysaccharide in host responses is unknown. Here, we examined the role of O-antigen in pain using cutaneous hypersensitivity (allodynia) to quantify pelvic pain behavior and using sacral spinal cord excitability to quantify central nervous system manifestations in murine UTI. A UPEC mutant defective for O-antigen biosynthesis induced chronic allodynia that persisted long after clearance of transient infections, but wild type UPEC evoked only acute pain. E. coli strains lacking O-antigen gene clusters had a chronic pain phenotype, and expressing cloned O-antigen gene clusters altered the pain phenotype in a predictable manner. Chronic allodynia was abrogated in TLR4-deficient mice, but inflammatory responses in wild type mice were similar among E. coli strains spanning a wide range of pain phenotypes, suggesting that O-antigen modulates pain independent of inflammation. Spinal cords of mice with chronic allodynia exhibited increased spontaneous firing and compromised short-term depression, consistent with centralized pain. Taken together, these findings suggest that O-antigen functions as a rheostat to modulate LPS-associated pain. These observations have implications for an infectious etiology of chronic pain and evolutionary modification of pathogens to alter host behaviors.

Keywords: Pain; Allodynia; Bladder; Inflammation; Spinal cord; Neutrophils; Bacterial pathogens; Hypersensitivity.

2011

Yersinia high pathogenicity island genes modify the Escherichia coli primary metabolome independently of siderophore production.

Lv H, Henderson JP. J Proteome Res. 2011 Dec 2;10(12):5547-54. doi: 10.1021/pr200756n. Epub 2011 Nov 15. [PMID: 22035238] [PMC3626101]

Abstract

Bacterial siderophores may enhance pathogenicity by scavenging iron, but their expression has been proposed to exert a substantial metabolic cost. Here we describe a combined metabolomic-genetic approach to determine how mutations affecting the virulence-associated siderophore yersiniabactin affect the Escherichia coli primary metabolome. Contrary to expectations, we did not find yersiniabactin biosynthesis to correspond to consistent metabolomic shifts. Instead, we found that targeted deletion of ybtU or ybtA, dissimilar genes with similar roles in regulating yersiniabactin expression, were associated with a specific shift in arginine pathway metabolites during growth in minimal media. This interaction was associated with high arginine levels in the model uropathogen Escherichia coli UTI89 compared to its ybtU and ybtA mutants and the K12 strain MG1655, which lacks yersiniabactin-associated genes. Because arginine is not a direct yersiniabactin biosynthetic substrate, these findings show that virulence-associated secondary metabolite systems may shape bacterial primary metabolism independently of substrate consumption.

Keywords: metabolomics; siderophore; yersiniabactin; Escherichia coli; primary metabolism; ybtU; ybtA; arginine biosynthesis.

Development of an integrated metabolomic profiling approach for infectious diseases research.

Lv H, Hung CS, Chaturvedi KS, Hooton TM, Henderson JP. Analyst. 2011 Nov 21;136(22):4752-63. doi: 10.1039/c1an15590c. Epub 2011 Sep 16. [PMID: 21922104] [PMC3746514]

Abstract

Metabolomic profiling offers direct insights into the chemical environment and metabolic pathway activities at sites of human disease. During infection, this environment may receive important contributions from both host and pathogen. Here we apply an untargeted metabolomics approach to identify compounds associated with an E. coli urinary tract infection population. Correlative and structural data from minimally processed samples were obtained using an optimized LC-MS platform capable of resolving ~2300 molecular features. Principal component analysis readily distinguished patient groups and multiple supervised chemometric analyses resolved robust metabolomic shifts between groups. These analyses revealed nine compounds whose provisional structures suggest candidate infection-associated endocrine, catabolic, and lipid pathways. Several of these metabolite signatures may derive from microbial processing of host metabolites. Overall, this study highlights the ability of metabolomic approaches to directly identify compounds encountered by, and produced from, bacterial pathogens within human hosts.

Keywords: integrated approach; LC-MS; untargeted urine metabolomics; urinary tract infection; Escherichia coli; infectious diseases.

Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder.

Lai HH, Qiu CS, Crock LW, Morales MEP, Ness TJ, Gereau RW 4th. Pain. 2011 Sep;152(9):2117-2124. doi: 10.1016/j.pain.2011.05.017. Epub 2011 Jun 25. [PMID: 21705143] [PMC3157542]

Abstract

Activation of extracellular signal-regulated kinases (ERK) 1/2 in dorsal horn neurons is important for the development of somatic hypersensitivity and spinal central sensitization after peripheral inflammation. However, data regarding the roles of spinal ERK1/2 in the development of visceral hyperalgesia are sparse. Here we studied the activation of ERK1/2 in the lumbosacral spinal cord after innocuous and noxious distention of the inflamed (cyclophosphamide-treated) and noninflamed urinary bladder in mice. We also correlated the spinal ERK1/2 activation to distention-evoked bladder nociception as quantified by the abdominal visceromotor response (VMR). Cyclophosphamide treatment (bladder inflammation) evoked increased bladder hyperalgesia and allodynia to bladder distention, as evident from an upward and leftward shift of the VMR stimulus-response curve compared with that of noninflamed mice. Development of bladder hyperalgesia was associated with robust enhancement of ERK1/2 activation in the dorsal horn and deeper laminae bilaterally in the L6-S1 spinal cord. Functional blockade of spinal ERK1/2 activity via intrathecal administration of the upstream MEK inhibitor U0126 attenuated distention-evoked bladder nociception and caused a significant downward shift of the VMR stimulus-response curve. In summary, we have provided functional and immunohistochemical evidence that activation of lumbosacral spinal ERK1/2 is associated with the development of primary visceral (bladder) hyperalgesia. Our results suggest that aberrant processing of visceral nociceptive information at the level of the lumbosacral spinal cord via activation of ERK1/2 signaling may contribute to chronic bladder pain in the context of inflammation.

Keywords: Urinary bladder; Visceral pain; Inflammatory pain; Visceromotor response; ERK signaling; Central sensitization.

Intravesical dimethyl sulfoxide inhibits acute and chronic bladder inflammation in transgenic experimental autoimmune cystitis models.

Kim R, Liu W, Chen X, Kreder KJ, Luo Y. J Biomed Biotechnol. 2011:937061. doi: 10.1155/2011/937061. Epub 2010 Nov 11. [PMID: 21113298] [PMC2989383]

Abstract

New animal models are greatly needed in interstitial cystitis/painful bladder syndrome (IC/PBS) research. We recently developed a novel transgenic cystitis model (URO-OVA mice) that mimics certain key aspects of IC/PBS pathophysiology. This paper aimed to determine whether URO-OVA cystitis model was responsive to intravesical dimethyl sulfoxide (DMSO) and if so identify the mechanisms of DMSO action. URO-OVA mice developed acute cystitis upon adoptive transfer of OVA-specific OT-I splenocytes. Compared to PBS-treated bladders, the bladders treated with 50% DMSO exhibited markedly reduced bladder histopathology and expression of various inflammatory factor mRNAs. Intravesical DMSO treatment also effectively inhibited bladder inflammation in a spontaneous chronic cystitis model (URO-OVA/OT-I mice). Studies further revealed that DMSO could impair effector T cells in a dose-dependent manner in vitro. Taken together, our results suggest that intravesical DMSO improves the bladder histopathology of IC/PBS patients because of its ability to interfere with multiple inflammatory and bladder cell types.

Keywords: acute disease; autoimmune diseases; chronic disease; cystitis; dimethyl sulfoxide; dose-response relationship; epitopes; spleen/cytology; urinary bladder diseases.

2009

Evidence for overlap between urological and nonurological unexplained clinical conditions.

Rodríguez MÁ, Afari N, Buchwald DS. J Urol. 2009 Nov;182(5):2123-31. doi: 10.1016/j.juro.2009.07.036. Epub 2009 Sep 16. [PMID: 19758633] [PMC2957306]

Abstract

Purpose: Unexplained clinical conditions share common features such as pain, fatigue, disability out of proportion to physical examination findings, inconsistent laboratory abnormalities, and an association with stress and psychosocial factors. We examined the extent of the overlap among urological and nonurological unexplained clinical conditions characterized by pain. We describe the limitations of previous research and suggest several possible explanatory models.

Materials and methods: Using hallmark symptoms and syndromes as search terms a search of 12 databases identified a total of 1,037 full-length published articles in 8 languages from 1966 to April 2008. The search focused on the overlap of chronic pelvic pain, interstitial cystitis, painful bladder syndrome, chronic prostatitis/chronic pelvic pain syndrome or vulvodynia with fibromyalgia, chronic fatigue syndrome, temporomandibular joint and muscle disorders or irritable bowel syndrome. We abstracted information on authorship, type of case and control groups, eligibility criteria, case definitions, study methods and major findings.

Results: The literature suggests considerable comorbidity between urological and nonurological unexplained clinical conditions. The most robust evidence for overlap was for irritable bowel syndrome and urological unexplained syndromes with some estimates of up to 79% comorbidity between chronic pelvic pain and symptoms of irritable bowel syndrome. However, most studies were limited by methodological problems, such as varying case definitions and selection of controls.

Conclusions: The overlap between urological and selected nonurological unexplained clinical conditions is substantial. Future research should focus on using standardized definitions, and rigorously designed, well controlled studies to further assess comorbidity, clarify the magnitude of the association and examine common pathophysiological mechanisms.

Keywords: urogenital system; fatigue syndrome; chronic; fibromyalgia; irritable bowel syndrome; temporomandibular joint disorders.