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Abstract. Introduction:. Chronic pain is a personal experience influenced by multiple biopsychosocial factors. Using a pain intensity measure alone to assess the effectiveness of a chronic pain intervention fails to fully evaluate its impact on the multifaceted chronic pain experience. The holistic minimal clinically important difference (MCID) is a composite outcome developed to provide a comprehensive assessment of chronic pain in response to intervention, across 5 outcome domains: pain intensity, health-related quality of life, sleep quality, physical, and emotional function. To focus on domains where the individual need is greatest, the holistic MCID reflects the cumulative MCID averaged over only the domains where subjects were impaired preintervention. Objectives:. To assess the internal and construct validity of the Holistic MCID score to inform its future use as an evidence-based tool. Methods:. This validation study was undertaken using data from the EVOKE trial with 111 patients up to 24-month follow-up. Internal consistency of the holistic MCID was assessed using Cronbach alpha statistic and dimensional exploration using principal component analysis. Results:. The holistic MCID measure demonstrated strong internal consistency with Cronbach alpha >0.7 at all follow-ups. Principal component analysis showed one overarching holistic dimension to be present in the composite. Construct validity was demonstrated by an increase in the holistic MCID score being associated with both increased Patients' Global Impression of Change, EuroQol visual analogue scale score, and each of the outcome domains in a “leave-one-out” analysis (all P < 0.001). Conclusion:. The holistic MCID provides a valid measure for the comprehensive, personalized assessment of response after a chronic pain intervention. The validity of the holistic MCID requires further confirmation in other chronic pain populations and with different interventions.

Background/Objectives Chronic pain is an opioid use disorder (OUD) treatment barrier and associated with poor outcomes in OUD treatment including relapse. Fibromyalgia is a chronic pain condition related to central nervous system substrates that overlap with the brain disease model of OUD. We know of no studies that have looked at non-treatment seeking individuals, to see if fibromyalgia might represent a barrier to OUD treatment. Given many non-treatment-seeking individuals previously attempted recovery before experiencing relapse, and chronic pain is a known precipitant of relapse, fibromyalgia might be a currently unappreciated modifiable factor in OUD relapse and, potentially, a barrier to treatment reengagement among those not currently seeking treatment. This study aimed to determine if fibromyalgia is associated with greater odds of agreeing that ‘I have tried to stop using opioids before, but pain caused me to relapse’ among non-treatment seeking individuals with OUD.Methods This cross-sectional study recruited non-treatment-seeking individuals with OUD (n = 141) from a syringe service program. Ordinal logistic regression was used to determine if the presence of fibromyalgia increased the odds of agreement with prior pain-precipitated relapse.Results Fibromyalgia was identified in 35% of study participants and associated with 125% greater odds of strongly agreeing that pain had previously caused them to relapse, even after accounting for relevant covariates, including age, sex, depression, anxiety, OUD severity, and pain severity.Conclusions This study provides early evidence that the presence of fibromyalgia may be associated with increased odds of pain-precipitated OUD relapse.

IMPORTANCE:. In the ICU, opioids treat pain and improve ventilator tolerance as part of an analgosedation approach. Identifying predictors of opioid consumption during the ICU course might highlight actionable items to reduce opioid consumption. OBJECTIVES:. To identify risk factors for opioid use during a postoperative ICU course. DESIGN, SETTING, AND PARTICIPANTS:. Patients enrolled in the Michigan Genomics Initiative single-center prospective observational cohort study completed baseline preoperative sociodemographic and mental/physical health questionnaires and provided blood samples for genetic analysis. Included patients were 18 years old and older, admitted to ICU postoperatively, and received opioids postoperatively. MAIN OUTCOMES AND MEASURES:. The primary outcome was ICU mean daily oral morphine equivalent (OME) use. The association between OME and phenotypic risk factors and genetic variants previously associated with pain were analyzed through univariable and multivariable linear regression models. RESULTS:. The cohort consisted of 1865 mixed-surgical patients with mean age of 56 years (sd, 15 yr). Preoperative opioid users were more likely to continue to receive opioids throughout their ICU stay than opioid-naive patients. OME (log10 scale) was most strongly associated with ICU mechanical ventilation (β = 0.27; 95% CI, 0.15–0.38; p < 0.0001; effect size 1.85 for receiving > 24 hours of mechanical ventilation), preoperative opioid use (β = 0.22; 95% CI, 0.16–0.29; p < 0.0001; effect size 1.67 for receiving preoperative opioids), major surgery (β = 0.21; 95% CI, 0.12–0.30; p < 0.0001; effect size 1.62 compared with minor surgery), and current/former illicit drug use (β = 0.12; 95% CI, 0.01–0.23; p = 0.04; effect size 1.30 for drug use). Younger age, centralized pain, and longer anesthetic duration were also significantly associated with OME but with smaller effect sizes. Selected genetic variants (FKBP5, COMT, and OPRM1) were not associated with OME use. CONCLUSIONS AND RELEVANCE:. Mechanical ventilation and preoperative opioids were the strongest risk factors for postoperative ICU opioid consumption, whereas psychologic factors and genetic variants were not associated.

Abstract Background Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD’s analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD’s effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). Methods We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). Discussion Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD’s analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. Trial registration This protocol is registered at clinicaltrials.gov under study number NCT06213233.

Objective Previous studies have demonstrated that weight loss has been shown to improve pain in weight‐bearing joints, and more recent studies suggest that weight loss may be accompanied by improvements in pain in non–weight‐bearing regions. In previous work, we demonstrated that these symptoms improve substantially in patients with obesity undergoing 12 weeks of a very low‐energy diet (VLED) restricted to 800 kcal as part of a weight‐loss program. Preclinical models also have shown analgesic effects of calorie restriction. The purpose of the current observational study was to determine the time course and trajectory of improvement in pain and other symptoms, especially during the early phase of a VLED intervention, prior to major weight loss. Methods Participants were 195 individuals with obesity who had elevated levels of pain and associated symptoms at baseline (score of ≥4 on Fibromyalgia Survey Criteria) and completed a minimum of 3 weeks of a VLED intervention. The primary outcome was improvement in Fibromyalgia Survey Criteria at week 3. In secondary analyses, we created groups of those showing little/no improvement, moderate improvement, and high improvement (little/no improvement mean, 2.21; SD, 1.02; moderate improvement mean, 2.25; SD, 0.81; high improvement mean, 2.42; SD, 0.95; F2,189 = 1.01, P = 0.37), then compared baseline characteristics. Results A large proportion of study participants (72%) experienced symptom reductions of 30% or greater by week 3, but there were no differences in the amount of weight lost at this time point. Those who showed little or no improvement (less than 30%) had a higher body mass index at baseline and were more likely to report a diagnosis of depression (both P

Abstract Background The wide heterogeneity of available cannabis products makes it difficult for physicians to appropriately guide patients. In the current study, our objective was to characterize naturalistic cannabis use routines and explore associations between routines and reported benefits from consuming cannabis. Methods We performed a mixed methods analysis of n=1087 cross-sectional survey responses from adults with self-reported chronic pain using cannabis for symptom management in the USA and Canada. First, we qualitatively analyzed responses to an open-ended question that assessed typical cannabis use routines, including administration routes, cannabinoid content, and timing. We then sub-grouped responses into categories based on inhalation (smoking, vaporizing) vs. non-inhalation (e.g., edibles). Finally, we investigated subgroups perceptions of how cannabis affected pain, overall health, and use of medications (e.g., substituting for opioids, benzodiazepines). Substitutions were treated as a count of medication classes, while responses for both pain and health were analyzed continuously, with − 2 indicating health declining a lot or pain increasing a lot and 2 indicating that health improved a lot or pain decreased a lot. Results Routines varied widely in terms of administration routes, cannabinoid content, and use timing. Overall, 18.8%, 36.2%, and 45% used non-inhalation, inhalation, and non-inhalation + inhalation routes, respectively. Those who used inhalation routes were younger (mean age 46.5 [inhalation] and 49.2 [non-inhalation + inhalation] vs. 56.3 [inhalation], F=36.1, p

Abstract Background and Purpose Many patients with chronic pain report hypersensitivity not only to noxious stimuli, but also to other modalities including innocuous touch, sound, and light, possibly due to differences in the processing of these stimuli. The goal of this study was to characterize functional connectivity (FC) differences between subjects with temporomandibular disorders (TMD) and pain‐free controls during a visual functional magnetic resonance imaging (fMRI) task that included an unpleasant, strobing visual stimulus. We hypothesized the TMD cohort would exhibit maladaptations in brain networks consistent with multisensory hypersensitivities observed in TMD patients. Methods This pilot study included 16 subjects, 10 with TMD and 6 pain‐free controls. Clinical pain was characterized using self‐reported questionnaires. Visual task‐based fMRI data were collected on a 3T MR scanner and used to determine differences in FC via group independent component analysis. Results Compared to controls, subjects with TMD exhibited abnormally increased FC between the default mode network and lateral prefrontal areas involved in attention and executive function, and impaired FC between the frontoparietal network and higher order visual processing areas. Conclusions The results indicate maladaptation of brain functional networks, likely due to deficits in multisensory integration, default mode network function, and visual attention and engendered by chronic pain mechanisms.

Abstract Background Rapid and irregular ventricular rates (RVR) are an important consequence of atrial fibrillation (AF). Raw accelerometry data in combination with electrocardiogram (ECG) data have the potential to distinguish inappropriate from appropriate tachycardia in AF. This can allow for the development of a just-in-time intervention for clinical treatments of AF events. The objective of this study is to develop a machine learning algorithm that can distinguish episodes of AF with RVR that are associated with low levels of activity. Methods This study involves 45 patients with persistent or paroxysmal AF. The ECG and accelerometer data were recorded continuously for up to 3 weeks. The prediction of AF episodes with RVR and low activity was achieved using a deterministic probabilistic finite-state automata (DPFA)-based approach. Rapid and irregular ventricular rate (RVR) is defined as having heart rates (HR) greater than 110 beats per minute (BPM) and high activity is defined as greater than 0.75 quantile of the activity level. The AF events were annotated using the FDA-cleared BeatLogic algorithm. Various time intervals prior to the events were used to determine the longest prediction intervals for predicting AF with RVR episodes associated with low levels of activity. Results Among the 961 annotated AF events, 292 met the criterion for RVR episode. There were 176 and 116 episodes with low and high activity levels respectively. Out of the 961 AF episodes, 770 (80.1%) were used in the training data set and the remaining 191 intervals were held out for testing. The model was able to predict AF with RVR and low activity up to 4.5 min before the events. The mean prediction performance gradually decreased as the time to events increased. The overall Area under the ROC Curve (AUC) for the model lies within the range of 0.67–0.78. Conclusion The DPFA algorithm can predict AF with RVR associated with low levels of activity up to 4.5 min before the onset of the event. This would enable the development of just-in-time interventions that could reduce the morbidity and mortality associated with AF and other similar arrhythmias.

Abstract. The concept that a regional musculoskeletal pain may occur in the absence of identifiable tissue abnormality may be puzzling. Previously these regional complaints were generally categorized as myofascial pain syndromes, or prior to the formalization of the nociplastic pain concept, as musculoskeletal pain with a neuropathic component, and treatments were anatomically focussed. Chronic primary musculoskeletal pain is now identified under the chronic primary pain stem category with the mechanistic descriptor of nociplastic pain. It is possible that many patients previously diagnosed with myofascial pain do in fact suffer from chronic primary musculoskeletal pain, requiring a paradigm shift in management towards more centrally directed treatment strategies. Many questions remain, including validation of the proposed examination techniques, prevalence, ideal treatment, and uptake and acceptance by the healthcare community. This new classification should be welcomed as an explanation for regional pain conditions that previously responded poorly to physically focussed treatments.

Abstract Background Studies suggest an increased prevalence of cognitive impairment (CI) among people with rheumatoid arthritis (RA). However, most prior studies have used convenience samples which are subject to selection biases or have failed to adjust for key confounding variables. We thus examined the association between CI and RA in a large national probability sample of older US adults. Methods Data were from interviews with 4462 participants in the 2016 wave of the nationally representative U.S. Health and Retirement Study with linked Medicare claims. RA diagnoses were identified via a minimum of two ICD-9CM or ICD-10 codes in Medicare billing records during the prior 2 years. The Langa-Weir Classification was used to classify cognitive status as normal, cognitively impaired non-dementia (CIND), or dementia based on a brief neuropsychological battery for self-respondents and informant reports for proxy respondents. We compared the odds of CI between older adults with and without RA using logistic regression, adjusted for age, education, gender, and race. Results Medicare records identified a 3.36% prevalence of RA (150/4462). While age, gender, education, and race independently predicted CI status, controlling for these covariates we found no difference in CI prevalence according to RA status (prevalent CI in 36.7% of older adults with RA vs. 34.0% without RA; adjusted OR = 1.08, 95% CI 0.74–1.59, p = .69). Conclusion There was no association between RA and CI in this national sample of older U.S. adults.

Abstract. Introduction:. Central sensitization (CS) involves dysfunctional central nervous system pain modulation resulting in heightened pain perception. Central sensitization is not commonly assessed among patients with opioid use disorder (OUD), despite the fact that pain has been implicated in the development, maintenance, and relapse of OUD and chronic opioid use may produce opioid-induced hyperalgesia. Central sensitization is a plausibly important mechanism underlying the complex relationship between OUD and chronic pain. However, this premise is largely untested. Methods:. Participants with OUD (n = 141) were recruited from an academic addiction treatment center in Columbus, Ohio. An established surrogate measure of CS, the American College of Rheumatology 2011 Fibromyalgia Survey Criteria, was administered using electronic survey. Participants also responded to questions about pain interference (Brief Pain Inventory), quality of life (RAND-36), and items regarding pain beliefs and expectations of pain and addiction treatment. Descriptive analyses, Spearman rho correlations, and Mann–Whitney U tests were performed. Results:. Hypothesized relationships were confirmed between degree of CS, pain interference, and health-related quality of life. Degree of CS was also positively correlated with greater endorsement of pain as a reason for the onset, maintenance, and escalation of OUD; treatment delay; and OUD relapse. Participants with the American College of Rheumatology 2011 Fibromyalgia Survey Criteria ≥13 had significantly greater endorsement of pain as a reason for delaying OUD treatment, continuing and increasing opioid use, and precipitating OUD relapse. Conclusions:. This study provides early evidence CS may underlie previously observed connections between clinically salient features of chronic pain and OUD, potentially informing future mechanistic research and precision treatment.

Objective Perceived cognitive dysfunction in people with fibromyalgia (FM), “fibrofog,” is commonly reported and has been demonstrated in neurocognitive testing. Distractibility and inattention have been implicated as potential contributors to fibrofog, but the role of environmental distractions has not been explored. In this study, ambulatory assessment methods were used to examine whether FM is related to more environmental distractions and to examine the impact of distractions on subjective and objective cognitive functioning. Methods Fifty people with FM and 50 age‐, sex‐, and education‐matched controls without FM completed 8 consecutive days of ambulatory assessments. Five times per day, participants reported perceived cognitive functioning and environmental distractions and completed validated tests of processing speed and working memory. Results The FM group reported distractions in a higher proportion of the ambulatory cognitive testing sessions (40.5%) compared with the group without FM (29.8%; P < 0.001) and more often reported multiple simultaneous distractions. For both groups, sound was the most common distraction. The group with FM reported more distractions caused by light, and the group without FM reported more social distractions. Group differences in subjective and objective cognitive functioning were not augmented during distraction relative to during periods of no distraction. There were no group differences in within‐person changes in cognitive functioning as a function of distraction. Conclusion The group with FM reported more distractions than the group without FM; both groups reported poorer processing speed when distracted, and the effects of distraction on test performance did not differ significantly by group. Findings suggest that sensitivity to environmental distractions may play a role in the experience of cognitive dysfunction in FM.

Neuroimaging has enhanced our understanding of the neural correlates of pain. Yet, how neural circuits interact and contribute to persistent pain remain largely unknown. Here, we investigate the mesoscale organization of the brain through intrinsic functional communities generated from resting state functional MRI data from two independent datasets, a discovery cohort of 43 Fibromyalgia (FM) patients and 20 healthy controls (HC) as well as a replication sample of 34 FM patients and 21 HC. Using normalized mutual information, we found that the global network architecture in chronic pain patients is less stable (more variable). Subsequent analyses of node community assignment revealed the composition of the communities differed between FM and HC. Furthermore, differences in network organization were associated with the changes in the composition of communities between patients with varying levels of clinical pain. Together, this work demonstrates that intrinsic network communities differ substantially between patients with FM and controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.

OBJECTIVES/GOALS: Over 30% of patients with rheumatoid arthritis (RA) exhibit fibromyalgianess, a symptom cluster associated with increased pain sensitivity. Up to half of RA patients use oral glucocorticoids (GCs) long-term despite their known, dose-dependent toxicity. We examined the association between fibromyalgianess and oral GC persistence in RA patients. METHODS/STUDY POPULATION: We used data from the Central Pain in Rheumatoid Arthritis (CPIRA) cohort to follow participants with active RA on oral prednisone who initiated a new disease-modifying anti-rheumatic drug. We measured fibromyalgianess using the Fibromyalgia Survey Questionnaire (FSQ), previously shown to correlate with key fibromyalgia features often superimposed upon RA. We stratified fibromyalgianess severity as follows: FSQ10 high/very high. We defined GC persistence as GC use at 3 month followup visit. We assessed the association between baseline fibromyalgianess (exposure) and GC persistence at followup (outcome) using multiple logistic regression, adjusted for demographics, RA duration, serostatus, and inflammatory activity measured by swollen joint count and C reactive protein. RESULTS/ANTICIPATED RESULTS: Of 97 participants on prednisone at baseline, 65% were taking prednisone at follow-up. Fifty-seven percent of participants with low baseline fibromyalgianess had persistent GC use, compared to 84% with high or very high fibromyalgianess. After adjustment as outlined above, participants with high/very high baseline fibromyalgianess remained more likely to be on prednisone at follow-up, relative to those with low fibromyalgianess (OR 4.99 [95% CI 1.20 – 20.73]). DISCUSSION/SIGNIFICANCE: In this cohort of patients with active RA, high fibromyalgianess is associated with persistent GC use, independent of inflammatory activity. This finding suggests non-inflammatory pain related to fibromyalgianess may be misclassified as inflammatory pain related to RA disease activity.

Many diseases, such as rheumatoid arthritis, are characterized by a chronic inflammatory state, but it is not clear whether or how this affects the brain. Here, the authors show that the severity of on-going inflammation predicts altered functional brain connectivity in people with rheumatoid arthritis.

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

ABSTRACT IMPACT: Glucocorticoid steroids are commonly used despite known dose-dependent cardiovascular toxicity, yet little is known about a) how patients with other cardiovascular risk factors use glucocorticoids, and b) how risks of glucocorticoid treatment might vary depending on a patient’s baseline cardiovascular risk. OBJECTIVES/GOALS: Up to one-third of RA patients use long-term glucocorticoids (GCs) despite a known, dose-dependent association with increased risk of major adverse cardiovascular events (MACE). We aim to evaluate patterns of GC use among RA patients with other MACE risk factors (i.e. diabetes, smoking), and examine how GC use may potentiate these risk factors. METHODS/STUDY POPULATION: We used claims data from Veterans Health Administration to identify 6,090 RA patients with ≥1 rheumatology clinic visit during 2013-2017. We used logistic regression to evaluate associations between incident MACE between 2013-2018, recent long-term GC use, and 5 MACE risk factors: hypertension, diabetes, hyperlipidemia, smoking, and prior MACE. We included two-way interaction terms between GC use and each risk factor. We used a claims-based algorithm to define MACE as any of acute MI, ischemic stroke, TIA, sudden death, or coronary revascularization, between index date and 12/31/2018. We defined index date as first rheumatology visit after meeting RA diagnostic criteria, and recent long-term GC use as ≥90 days’ supply dispensed over 2 years prior to index date. RESULTS/ANTICIPATED RESULTS: Among 2,884 eligible patients,1,553 (54%) had MACE risk factors, and 97 (3%) had prior MACE (Table 1). Overall, 16% of patients recently used long-term GC, compared to 17% of patients with MACE risk factors, and 22% of patients with prior MACE. Incident MACE occurred in 308 (11%) patients, 24% of whom had recent long-term GC use. Recent long-term GC use was independently associated with increased incident MACE (Table 2). While no interaction term was statistically significant overall, differences in odds of incident MACE were seen across levels of recent GC use for several risk factors, particularly diabetes (OR 2.10, 95% CI [0.93-4.77]), tobacco use (OR 2.88, 95% CI [1.16-7.14]) and prior MACE (OR 2.41, 95% CI [0.73-7.95]). DISCUSSION/SIGNIFICANCE OF FINDINGS: Long-term GC use is common among RA patients with MACE risk factors. In this cohort, 25% of patients with incident MACE had recently used long-term GC. Long-term GC use may potentiate effects of comorbidities like diabetes and smoking, disproportionately increasing MACE risk in certain patients.

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.

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.

Abstract. Introduction:. Neuroimaging reveals increased glutamate within the insula of patients with fibromyalgia (FM), suggesting a link between FM symptoms and increased central excitatory neurotransmission. Many patients with FM also present with decreased intraepidermal nerve fiber density (IENFD), consistent with small fiber pathology. It remains unknown, however, whether either of these mechanistic findings represent a cause or a consequence of the other. This study tests the hypothesis that an excitatory imbalance within the insula leads to small fiber pathology. Objectives:. This is a proof-of-concept study to examine whether a chronic, bilateral increase in insular glutamate can be a causal factor in the development of small fiber neuropathy in FM. Methods:. The glutamate transport inhibitor l-trans-Pyrrolidine-2,4-dicarboxylic acid (PDC), which increases endogenous levels of glutamate, was dissolved in Ringer solution and bilaterally delivered into the insula of rats for 6 weeks. Naive rats that did not undergo any surgery or treatment and rats administered Ringer vehicle solution into the insula served as controls. Multimodal nociceptive sensitivity was assessed weekly. Hind paw tissue biopsies were collected for IENFD assessment, at the end of the experiment. Results:. Compared with controls, increasing endogenous glutamate in the insula with PDC caused sustained decreases in mechanical paw withdrawal threshold and thermal paw withdrawal latency, increased aversion to noxious mechanical stimulation, and a decrease in IENFD. Cold reactivity was not altered by PDC administration. Conclusion:. Bilateral insular PDC administration produced a persistent increase in multimodal pain behaviors and a decrease in peripheral nerve fibers in rat. These preclinical findings offer preliminary support that insular hyperactivity may be a casual factor in the development of small fiber pathology in FM.