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

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.

Correlation of tryptophan metabolites with connectivity of extended central reward network in healthy subjects.

OBJECTIVE: A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions play an important role in human health and disease, including hedonic food intake and obesity. We performed a tripartite network analysis based on graph theory to test the hypothesis that microbiota-derived fecal metabolites are associated with connectivity of key regions of the brain's extended reward network and clinical measures related to obesity. METHODS: DTI and resting state fMRI imaging was obtained from 63 healthy subjects with and without elevated body mass index (BMI) (29 males and 34 females). Subjects submitted fecal samples, completed questionnaires to assess anxiety and food addiction, and BMI was recorded. RESULTS: The study results demonstrate associations between fecal microbiota-derived indole metabolites (indole, indoleacetic acid, and skatole) with measures of functional and anatomical connectivity of the amygdala, nucleus accumbens, and anterior insula, in addition to BMI, food addiction scores (YFAS) and anxiety symptom scores (HAD Anxiety). CONCLUSIONS: The findings support the hypothesis that gut microbiota-derived indole metabolites may influence hedonic food intake and obesity by acting on the extended reward network, specifically the amygdala-nucleus accumbens circuit and the amygdala-anterior insula circuit. These cross sectional, data-driven results provide valuable information for future mechanistic studies.

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

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.

Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females.

Early adverse life events (EALs) have been associated with regional thinning of the subgenual cingulate cortex (sgACC), a brain region implicated in the development of disorders of mood and affect, and often comorbid functional pain disorders, such as irritable bowel syndrome (IBS). Regional neuroinflammation related to chronic stress system activation has been suggested as a possible mechanism underlying these neuroplastic changes. However, the interaction of genetic and environmental factors in these changes is poorly understood. The current study aimed to evaluate the interactions of EALs and candidate gene polymorphisms in influencing thickness of the sgACC. 210 female subjects (137 healthy controls; 73 IBS) were genotyped for stress and inflammation-related gene polymorphisms. Genetic variation with EALs, and diagnosis on sgACC thickness was examined, while controlling for race, age, and total brain volume. Compared to HCs, IBS had significantly reduced sgACC thickness (p = 0.03). Regardless of disease group (IBS vs. HC), thinning of the left sgACC was associated with a significant gene-gene environment interaction between the IL-1ß genotype, the NR3C1 haplotype, and a history of EALs (p = 0.05). Reduced sgACC thickness in women with the minor IL-1ß allele, was associated with EAL total scores regardless of NR3C1 haplotype status (p = 0.02). In subjects homozygous for the major IL-1ß allele, reduced sgACC with increasing levels of EALs was seen only with the less common NR3C1 haplotype (p = 0.02). These findings support an interaction between polymorphisms related to stress and inflammation and early adverse life events in modulating a key region of the emotion arousal circuit.

Pain and Interoception Imaging Network (PAIN): A multimodal, multisite, brain-imaging repository for chronic somatic and visceral pain disorders.

The Pain and Interoception Imaging Network (PAIN) repository (painrepository.org) is a newly created NIH (NIDA/NCCAM) funded neuroimaging data repository that aims to accelerate scientific discovery regarding brain mechanisms in pain and to provide more rapid benefits to pain patients through the harmonization of efforts and data sharing. The PAIN Repository consists of two components, an Archived Repository and a Standardized Repository. Similar to other 'open' imaging repositories, neuroimaging researchers can deposit any dataset of chronic pain patients and healthy controls into the Archived Repository. Scans in the Archived Repository can be very diverse in terms of scanning procedures and clinical metadata, complicating the merging of datasets for analyses. The Standardized Repository overcomes these limitations through the use of standardized scanning protocols along with a standardized set of clinical metadata, allowing an unprecedented ability to perform pooled analyses. The Archived Repository currently includes 741 scans and is rapidly growing. The Standardized Repository currently includes 433 scans. Pain conditions currently represented in the PAIN repository include: irritable bowel syndrome, vulvodynia, migraine, chronic back pain, and inflammatory bowel disease. Both the PAIN Archived and Standardized Repositories promise to be important resources in the field of chronic pain research. The enhanced ability of the Standardized Repository to combine imaging, clinical and other biological datasets from multiple sites in particular make it a unique resource for significant scientific discoveries.

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.

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.

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

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.

Multivariate morphological brain signatures predict patients with chronic abdominal pain from healthy control subjects.

Irritable bowel syndrome (IBS) is the most common chronic visceral pain disorder. The pathophysiology of IBS is incompletely understood; however, evidence strongly suggests dysregulation of the brain-gut axis. The aim of this study was to apply multivariate pattern analysis to identify an IBS-related morphometric brain signature that could serve as a central biological marker and provide new mechanistic insights into the pathophysiology of IBS. Parcellation of 165 cortical and subcortical regions was performed using FreeSurfer and the Destrieux and Harvard-Oxford atlases. Volume, mean curvature, surface area, and cortical thickness were calculated for each region. Sparse partial least squares discriminant analysis was applied to develop a diagnostic model using a training set of 160 females (80 healthy controls and 80 patients with IBS). Predictive accuracy was assessed in an age-matched holdout test set of 52 females (26 healthy controls and 26 patients with IBS). A 2-component classification algorithm comprising the morphometry of (1) primary somatosensory and motor regions and (2) multimodal network regions explained 36% of the variance. Overall predictive accuracy of the classification algorithm was 70%. Small effect size associations were observed between the somatosensory and motor signature and nongastrointestinal somatic symptoms. The findings demonstrate that the predictive accuracy of a classification algorithm based solely on regional brain morphometry is not sufficient, but they do provide support for the utility of multivariate pattern analysis for identifying meaningful neurobiological markers in IBS.

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

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.

Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain.

Resting-state functional magnetic resonance imaging has been used to investigate intrinsic brain connectivity in healthy subjects and patients with chronic pain. Sex-related differences in the frequency power distribution within the human insula (INS), a brain region involved in the integration of interoceptive, affective, and cognitive influences, have been reported. Here we aimed to test sex and disease-related alterations in the intrinsic functional connectivity of the dorsal anterior INS. The anterior INS is engaged during goal-directed tasks and modulates the default mode and executive control networks. By comparing functional connectivity of the dorsal anterior INS in age-matched female and male healthy subjects and patients with irritable bowel syndrome (IBS), a common chronic abdominal pain condition, we show evidence for sex and disease-related alterations in the functional connectivity of this region: (1) male patients compared with female patients had increased positive connectivity of the dorsal anterior INS bilaterally with the medial prefrontal cortex (PFC) and dorsal posterior INS; (2) female patients compared with male patients had greater negative connectivity of the left dorsal anterior INS with the left precuneus; (3) disease-related differences in the connectivity between the bilateral dorsal anterior INS and the dorsal medial PFC were observed in female subjects; and (4) clinical characteristics were significantly correlated to the insular connectivity with the dorsal medial PFC in male IBS subjects and with the precuneus in female IBS subjects. These findings are consistent with the INS playing an important role in modulating the intrinsic functional connectivity of major networks in the resting brain and show that this role is influenced by sex and diagnosis.

Early adverse life events and resting state neural networks in patients with chronic abdominal pain: evidence for sex differences.

BACKGROUND: Early adverse life events (EALs) and sex have been identified as vulnerability factors for the development of several stress-sensitive disorders, including irritable bowel syndrome (IBS). We aimed to identify disease and sex-based differences in resting state (RS) connectivity associated with EALs in individuals with IBS. METHOD: A history of EALs before age 18 years was assessed using the early trauma inventory. RS functional magnetic resonance imaging was used to identify patterns of intrinsic brain oscillations in the form of RS networks in 168 people (58 people with IBS, 28 were female; 110 healthy controls, 72 were female). Partial least squares, a multivariate analysis technique, was used to identify disease and sex differences and possible correlations between EALs and functional connectivity in six identified RS networks. RESULTS: Associations between EALs and RS networks were observed. Although a history of EALs was associated with altered connectivity in the salience/executive control network to a similar extent in male and female patients with IBS (bootstrap ratio = 3.28-5.61; p = .046), male patients with IBS demonstrated additional EAL-related alterations in the cerebellar network (bootstrap ratio = 3.92-6.79; p = .022). CONCLUSIONS: This cross sectional study identified correlations between RS networks and EALs in individuals with IBS. These results suggest that exposure to EALs before age 18 years can shape adult RS in both male and female patients in the salience/executive control network, a brain network that has been implicated in the pathophysiology of central pain amplification.

Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain.

Regional cortical thickness alterations have been reported in many chronic inflammatory and painful conditions, including inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), even though the mechanisms underlying such neuroplastic changes remain poorly understood. In order to better understand the mechanisms contributing to grey matter changes, the current study sought to identify the differences in regional alterations in cortical thickness between healthy controls and two chronic visceral pain syndromes, with and without chronic gut inflammation. 41 healthy controls, 11 IBS subjects with diarrhea, and 16 subjects with ulcerative colitis (UC) underwent high-resolution T1-weighted magnetization-prepared rapid acquisition gradient echo scans. Structural image preprocessing and cortical thickness analysis within the region of interests were performed by using the Laboratory of Neuroimaging Pipeline. Group differences were determined using the general linear model and linear contrast analysis. The two disease groups differed significantly in several cortical regions. UC subjects showed greater cortical thickness in anterior cingulate cortical subregions, and in primary somatosensory cortex compared with both IBS and healthy subjects. Compared with healthy subjects, UC subjects showed lower cortical thickness in orbitofrontal cortex and in mid and posterior insula, while IBS subjects showed lower cortical thickness in the anterior insula. Large effects of correlations between symptom duration and thickness in the orbitofrontal cortex and postcentral gyrus were only observed in UC subjects. The findings suggest that the mechanisms underlying the observed gray matter changes in UC subjects represent a consequence of peripheral inflammation, while in IBS subjects central mechanisms may play a primary role.

Irritable bowel syndrome in female patients is associated with alterations in structural brain networks.

Alterations in gray matter (GM) density/volume and cortical thickness (CT) have been demonstrated in small and heterogeneous samples of subjects with differing chronic pain syndromes, including irritable bowel syndrome (IBS). Aggregating across 7 structural neuroimaging studies conducted at University of California, Los Angeles, Los Angeles, CA, USA, between August 2006 and April 2011, we examined group differences in regional GM volume in 201 predominantly premenopausal female subjects (82 IBS, mean age: 32±10 SD, 119 healthy controls [HCs], 30±10 SD). Applying graph theoretical methods and controlling for total brain volume, global and regional properties of large-scale structural brain networks were compared between the group with IBS and the HC group. Relative to HCs, the IBS group had lower volumes in the bilateral superior frontal gyrus, bilateral insula, bilateral amygdala, bilateral hippocampus, bilateral middle orbital frontal gyrus, left cingulate, left gyrus rectus, brainstem, and left putamen. Higher volume was found in the left postcentral gyrus. Group differences were no longer significant for most regions when controlling for the Early Trauma Inventory global score, with the exception of the right amygdala and the left postcentral gyrus. No group differences were found for measures of global and local network organization. Compared to HCs, in patients with IBS, the right cingulate gyrus and right thalamus were identified as being significantly more critical for information flow. Regions involved in endogenous pain modulation and central sensory amplification were identified as network hubs in IBS. Overall, evidence for central alterations in patients with IBS was found in the form of regional GM volume differences and altered global and regional properties of brain volumetric networks.

The perfect neuroimaging-genetics-computation storm: collision of petabytes of data, millions of hardware devices and thousands of software tools.

The volume, diversity and velocity of biomedical data are exponentially increasing providing petabytes of new neuroimaging and genetics data every year. At the same time, tens-of-thousands of computational algorithms are developed and reported in the literature along with thousands of software tools and services. Users demand intuitive, quick and platform-agnostic access to data, software tools, and infrastructure from millions of hardware devices. This explosion of information, scientific techniques, computational models, and technological advances leads to enormous challenges in data analysis, evidence-based biomedical inference and reproducibility of findings. The Pipeline workflow environment provides a crowd-based distributed solution for consistent management of these heterogeneous resources. The Pipeline allows multiple (local) clients and (remote) servers to connect, exchange protocols, control the execution, monitor the states of different tools or hardware, and share complete protocols as portable XML workflows. In this paper, we demonstrate several advanced computational neuroimaging and genetics case-studies, and end-to-end pipeline solutions. These are implemented as graphical workflow protocols in the context of analyzing imaging (sMRI, fMRI, DTI), phenotypic (demographic, clinical), and genetic (SNP) data.

Sex-related differences of cortical thickness in patients with chronic abdominal pain.

BACKGROUND & AIMS: Regional reductions in gray matter (GM) have been reported in several chronic somatic and visceral pain conditions, including irritable bowel syndrome (IBS) and chronic pancreatitis. Reported GM reductions include insular and anterior cingulate cortices, even though subregions are generally not specified. The majority of published studies suffer from limited sample size, heterogeneity of populations, and lack of analyses for sex differences. We aimed to characterize regional changes in cortical thickness (CT) in a large number of well phenotyped IBS patients, taking into account the role of sex related differences. METHODS: Cortical GM thickness was determined in 266 subjects (90 IBS [70 predominantly premenopausal female] and 176 healthy controls (HC) [155 predominantly premenopausal female]) using the Laboratory of Neuro Imaging (LONI) Pipeline. A combined region of interest (ROI) and whole brain approach was used to detect any sub-regional and vertex-level differences after removing effects of age and total GM volume. Correlation analyses were performed on behavioral data. RESULTS: While IBS as a group did not show significant differences in CT compared to HCs, sex related differences were observed both within the IBS and the HC groups. When female IBS patients were compared to female HCs, whole brain analysis showed significant CT increase in somatosensory and primary motor cortex, as well as CT decrease in bilateral subgenual anterior cingulate cortex (sgACC). The ROI analysis showed significant regional CT decrease in bilateral subregions of insular cortex, while CT decrease in cingulate was limited to left sgACC, accounting for the effect of age and GM volume. Several measures of IBS symptom severity showed significant correlation with CT changes in female IBS patients. CONCLUSIONS: Significant, sex related differences in CT are present in both HCs and in IBS patients. The biphasic neuroplastic changes in female IBS patients are related to symptom severity.

Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain.

Abnormal responses of the brain to delivered and expected aversive gut stimuli have been implicated in the pathophysiology of irritable bowel syndrome (IBS), a visceral pain syndrome occurring more commonly in women. Task-free resting-state functional magnetic resonance imaging (fMRI) can provide information about the dynamics of brain activity that may be involved in altered processing and/or modulation of visceral afferent signals. Fractional amplitude of low-frequency fluctuation is a measure of the power spectrum intensity of spontaneous brain oscillations. This approach was used here to identify differences in the resting-state activity of the human brain in IBS subjects compared with healthy controls (HCs) and to identify the role of sex-related differences. We found that both the female HCs and female IBS subjects had a frequency power distribution skewed toward high frequency to a greater extent in the amygdala and hippocampus compared with male subjects. In addition, female IBS subjects had a frequency power distribution skewed toward high frequency in the insula and toward low frequency in the sensorimotor cortex to a greater extent than male IBS subjects. Correlations were observed between resting-state blood oxygen level-dependent signal dynamics and some clinical symptom measures (e.g., abdominal discomfort). These findings provide the first insight into sex-related differences in IBS subjects compared with HCs using resting-state fMRI.