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.

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.

The Urinary Proteomic Profile Implicates Key Regulators for Urologic Chronic Pelvic Pain Syndrome (UCPPS): A MAPP Research Network Study.

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.

Research on the Properties of Mineral-Cement Emulsion Mixtures Using Recycled Road Pavement Materials.

The reduction in natural resources and aspects of environmental protection necessitate alternative uses of waste materials in the area of construction. Recycling is also observed in road construction where mineral-cement emulsion (MCE) mixtures are applied. The MCE mix is a conglomerate that can be used to make the base layer in road pavement structures. MCE mixes contain reclaimed asphalt from old, degraded road surfaces, aggregate improving the gradation, asphalt emulsion, and cement as a binder. The use of these ingredients, especially cement, can cause shrinkage and cracks in road layers. The article presents selected issues related to the problem of cracking in MCE mixtures. The authors of the study focused on reducing the cracking phenomenon in MCE mixes by using an innovative cement binder with recycled materials. The innovative cement binder based on dusty by-products from cement plants also contributes to the optimization of the recycling process in road surfaces. The research was carried out in the field of stiffness, fatigue life, crack resistance, and shrinkage analysis of mineral-cement emulsion mixes. It was found that it was possible to reduce the stiffness and the cracking in MCE mixes. The use of innovative binders will positively affect the durability of road pavements.

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.

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.

Novel research approaches for interstitial cystitis/bladder pain syndrome: thinking beyond the bladder.

Despite years of basic and clinical research focused on interstitial cystitis/bladder pain syndrome (IC/BPS), including clinical trials of candidate therapies, there remains an insufficient understanding of underlying cause(s), important clinical features and a lack of effective treatments for this syndrome. Progress has been limited and is likely due to many factors, including a primary focus on the bladder and lower urinary tract as origin of symptoms without adequately considering the potential influence of other local (pelvic) or systemic factors. Traditionally, there has been a lack of sufficiently diverse expertise and application of novel, integrated methods to study this syndrome. However, some important insights have been gained. For example, epidemiological studies have revealed that IC/BPS is commonly associated with other chronic pain conditions, including fibromyalgia, irritable bowel syndrome and chronic fatigue syndrome. These observations suggest that IC/BPS may involve systemic pathophysiology, including alterations of the central nervous system in some patients. Furthermore, there may be multiple causes and contributing factors that manifest in the symptoms of IC/BPS leading to multiple patient sub-groups or phenotypes. Innovative research is necessary to allow for a more complete description of the relationship between this syndrome and other disorders with overlapping symptoms. This report provides examples of such innovative research studies and their findings which have the potential to provide fresh insights into IC/BPS and disorders associated with chronic pain through characterization of broad physiologic systems, as well as assessment of the contribution of the bladder and lower urinary tract. They may also serve as models for future investigation of symptom-based urologic and non-urologic disorders that may remain incompletely characterized by previous, more traditional research approaches. Furthermore, it is anticipated a more holistic understanding of chronic urologic pain and dysfunction will ensue from productive interactions between IC/BPS studies like those described here and broader cutting-edge research endeavors focused on potentially related chronic pain disorders. A more comprehensive vision for IC/BPS inquiry is anticipated to yield new insights into basic disease mechanisms and clinical characteristics that will inform future research studies that will lead to more effective therapies and improved clinical care for these patients.

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

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.