Chronic Pain Research Research Articles

Recruitment and retention challenges of underrepresented populations in chronic pain research: A systematic review and evidence-based recommendations

Recruitment and retention challenges of underrepresented populations in chronic pain research: A systematic review and evidence-based recommendations

Blood Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate as Pathophysiological Correlates of Chronic Pain: Analyses Using a National Sample of Midlife Adults in the United States.

Identifying biomarkers is a priority in translational chronic pain research. Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, are adrenocortical steroids in the blood with neuroprotective properties that also produce sex hormones. They may capture key sex-specific neuroendocrine mechanisms of chronic pain. Cross-sectional study. Using data from 1,216 community-dwelling adults aged 34-84 from the Midlife in the United States (MIDUS) cohort, we examined blood DHEA and DHEA-S levels in association with chronic pain in men and women, adjusting for demographics, chronic diseases, medications including opioids, and psychosocial factors. If an association was found, we further explored dose-response relationships by the number of pain locations and the degree of pain interference. In women, chronic pain was associated with 0.072 lower (95% confidence interval [CI], -0.127 to -0.017) log10 DHEA-S µg/dL, with pain in one to two locations associated with 0.068 lower (95% CI, -0.131 to -0.006) and in three or more locations 0.071 lower (95% CI, -0.148 to 0.007) log10 DHEA-S (P for trend = 0.074). Furthermore for women, low-interference pain was associated with 0.062 lower (95% CI, -0.125 to -0.000), whereas high-interference pain was associated with 0.138 lower (95% CI, -0.233 to -0.043) log10 DHEA-S (P for trend = 0.004). Chronic pain was not associated with DHEA or DHEA-S levels in men or DHEA levels in women. Chronic pain and its functional interference correspond to lower blood DHEA-S levels in women.

Characterizing Chronic Pain Episodes in Clinical Text at Two Health Care Systems: Comprehensive Annotation and Corpus Analysis.

BackgroundChronic pain affects more than 20% of adults in the United States and is associated with substantial physical, mental, and social burden. Clinical text contains rich information about chronic pain, but no systematic appraisal has been performed to assess the electronic health record (EHR) narratives for these patients. A formal content analysis of the unstructured EHR data can inform clinical practice and research in chronic pain.ObjectiveWe characterized individual episodes of chronic pain by annotating and analyzing EHR notes for a stratified cohort of adults with known chronic pain.MethodsWe used the Rochester Epidemiology Project infrastructure to screen all residents of Olmsted County, Minnesota, for evidence of chronic pain, between January 1, 2005, and September 30, 2015. Diagnosis codes were used to assemble a cohort of 6586 chronic pain patients; people with cancer were excluded. The records of an age- and sex-stratified random sample of 62 patients from the cohort were annotated using an iteratively developed guideline. The annotated concepts included date, location, severity, causes, effects on quality of life, diagnostic procedures, medications, and other treatment modalities.ResultsA total of 94 chronic pain episodes from 62 distinct patients were identified by reviewing 3272 clinical notes. Documentation was written by clinicians across a wide spectrum of specialties. Most patients (40/62, 65%) had 1 pain episode during the study period. Interannotator agreement ranged from 0.78 to 1.00 across the annotated concepts. Some pain-related concepts (eg, body location) had 100% (94/94) coverage among all the episodes, while others had moderate coverage (eg, effects on quality of life) (55/94, 59%). Back pain and leg pain were the most common types of chronic pain in the annotated cohort. Musculoskeletal issues like arthritis were annotated as the most common causes. Opioids were the most commonly captured medication, while physical and occupational therapies were the most common nonpharmacological treatments.ConclusionsWe systematically annotated chronic pain episodes in clinical text. The rich content analysis results revealed complexity of the chronic pain episodes and of their management, as well as the challenges in extracting pertinent information, even for humans. Despite the pilot study nature of the work, the annotation guideline and corpus should be able to serve as informative references for other institutions with shared interest in chronic pain research using EHRs.

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

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.

Metabolomics in chronic pain research.

Metabolomics deals with the identification and quantification of small molecules (metabolites) in biological samples. As metabolite levels can reflect normal or altered metabolic pathways, their measurement provides information to improve the understanding, diagnosis and management of diseases. Despite its immense potential, metabolomics applications to pain research have been sparse. This paper describes current metabolomics techniques, reviews published human metabolomics pain research and compares successful metabolomics research in other areas of medicine with the goal of highlighting opportunities offered by metabolomics to advance pain medicine. Non-systematic review. Our search identified 19 studies that adopted a metabolomics approach in: fibromyalgia (7), chronic widespread pain (4), other musculoskeletal pain conditions (5), neuropathic pain (1), complex regional pain syndrome (1) and pelvic pain (1). The studies used either mass spectrometry or nuclear magnetic resonance. Most are characterized by small sample sizes. Some consistency has been found for alterations in glutamate and testosterone metabolism, and metabolic imbalances caused by the gut microbiome. Metabolomics research in chronic pain is in its infancy. Most studies are at the pilot stage. Metabolomics research has been successful in other areas of medicine. These achievements should motivate investigators to expand metabolomics research to improve the understanding of the basic mechanisms of human pain, as well as provide tools to diagnose, predict and monitor chronic pain conditions. Metabolomics research can lead to the identification of biomarkers to support the development and testing of treatments, thereby facilitating personalized pain medicine.

I. Indices of Pain Intensity Derived From Ecological Momentary Assessments: Rationale and Stakeholder Preferences

Pain assessment that fully represents patients’ pain experiences is essential for chronic pain research and management. The traditional primary outcome measure has been a patient's average pain intensity over a time period. In this series of 3 articles, we examine whether pain assessment can be enhanced by considering additional outcome measures capturing temporal aspects of pain, such as pain maxima, duration, and variability. Ecological momentary assessment makes the assessment of such indices readily available. In this first article, we discuss the rationale for considering additional pain indices derived from ecological momentary assessment and examine which are most important to stakeholders. Patients (n = 32), clinicians (n = 20), and clinical trialists (n = 20) were interviewed about their preference rankings for Average, Worst, and Least Pain, Time in High Pain, Time in No/Low Pain, Pain Variability, and Pain Unpredictability. Each stakeholder group displayed a distinct preference hierarchy for different indices, and there were few commonalities between groups. Patients favored Worst Pain and Time in High Pain, followed by Pain Variability and Unpredictability. Trialists favored Average Pain, whereas clinicians favored Worst Pain. Results suggest that multiple temporal aspects of pain are relevant for stakeholders and should be considered when evaluating the efficacy of pain management. PerspectiveExamining which aspects of pain are most important to measure from the perspective of different stakeholders can facilitate efforts to include all relevant treatment outcomes. Our study suggests that multiple temporal aspects of pain intensity are important to stakeholders. This should be considered when evaluating the efficacy of pain management.

“It’s like she’s talking about me” — Exploring the value and potential impact of a YouTube film presenting a qualitative evidence synthesis about chronic pain: An analysis of online comments

ABSTRACT Background There is very limited research exploring the value and impact of qualitative research in chronic pain despite the large volume of research. Aims The aim of this study was to find out whether viewers’ comments in response to a YouTube film, portraying findings from a qualitative evidence synthesis about living with pain, revealed any potential value or impact to viewers. Methods We collected online data posted in response to the film Struggling to Be Me. We used themes from a large review of qualitative research as an a priori analytic framework. We used inductive thematic analysis to distil the essence of data that did not fit this framework. A thematic analysis of online comments to evaluate the impact of an arts-based health research film on people living with chronic pain is presented. Results We developed two inductive themes that explored the value and potential impact of watching the film online: (1) It has given voice to our suffering and (2) it makes me feel that I am not alone. Two subthemes added insight to the a priori framework: First, I have had enough of me added insight to the theme my life is impoverished and confined; second, I am treated like a criminal because I take opioids added insight to the theme lost personal credibility. Conclusions Our findings indicate that watching the YouTube film has potential value and impact, giving voice to suffering and making people feel that they are not alone. There are specific ethical challenges relating to internet-mediated research.

Central Nervous System Targets: Glial Cell Mechanisms in Chronic Pain.

Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.

DOD announces $4.8M for chronic pain research

DOD announces $4.8M for chronic pain research

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

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. 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. 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. 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.

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.

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. 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. 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. 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.

Fear in the context of pain: Lessons learned from 100 years of fear conditioning research

Human fear conditioning research since Watson's case study on “Little Albert” has vastly evolved and its impact today is reaching far beyond phobic anxiety. This review focuses on how fear conditioning research, mainly using exteroceptive conditioned stimuli (CSs) and aversive, non-noxious stimuli as unconditioned stimuli (USs), has been extended and translated to chronic pain research. We describe the different pain-related fear conditioning paradigms using proprioceptive and interoceptive CSs and painful stimuli as USs that have been developed to study specific forms of pain-related fear (i.e. fear of movement, fear of touch, fear of visceral sensations, and fear of penetration) that are relevant for different chronic pain conditions (i.e. musculoskeletal pain, neuropathic pain, visceral pain, and genital pain). We present evidence that patients with chronic pain demonstrate impaired safety learning and excessive fear generalization; learning anomalies that have also been observed in anxiety disorders. Extinction-based protocols (exposure in vivo) have been developed to reduce pain-related fear and increase daily functioning in various chronic pain disorders. Finally, we outline some challenges and future directions to further our understanding of learning mechanisms underlying the development, persistence, and treatment of chronic pain disability.

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.

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. 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. 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. 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.

MP07-09 ESTIMATED NATIONAL PREVALENCE OF IC/BPS UTILIZING VETERANS HEALTH ADMINISTRATION DATA

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Interstitial Cystitis (MP07)1 Apr 2020MP07-09 ESTIMATED NATIONAL PREVALENCE OF IC/BPS UTILIZING VETERANS HEALTH ADMINISTRATION DATA Jennifer Anger*, Catherine Bresee, Kai Dallas, Amanda De Hoedt, Kelsey Haywood, Emily Wiggins, Kelsey Hoggatt, Marc Goodman, Jayoung Kim, and Stephen Freedland Jennifer Anger*Jennifer Anger* More articles by this author , Catherine BreseeCatherine Bresee More articles by this author , Kai DallasKai Dallas More articles by this author , Amanda De HoedtAmanda De Hoedt More articles by this author , Kelsey HaywoodKelsey Haywood More articles by this author , Emily WigginsEmily Wiggins More articles by this author , Kelsey HoggattKelsey Hoggatt More articles by this author , Marc GoodmanMarc Goodman More articles by this author , Jayoung KimJayoung Kim More articles by this author , and Stephen FreedlandStephen Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000827.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The burden of interstitial cystitis/painful bladder syndrome (IC/BPS) is immense. A key challenge in managing IC/BPS is a lack of clear diagnostic criteria, with even its prevalence being difficult to determine. Literature estimates IC/BPS prevalence to be (0.045%-6.5%) for women and (0.008%-4.2%) for men. We aim to improve prevalence estimates of IC/BPS by uniquely combining analysis of a population based dataset and individual chart review of the nation’s largest health care system the Veterans Health Administration (VA). METHODS: The Veterans Affairs Informatics and Computing Infrastructure (VINCI) was used to identify all living patients with at least 2 clinic visits in the past 2 years with ICD-9/10 codes for IC/BPS or similar conditions that may represent undiagnosed IC/BPS (“IC/BPS-like”). Random gender-balanced samples were made these groups, as well as controls, for detailed manual chart review to confirm presence of IC/PBS (Figure 1). Based on sampling weights, prevalence was estimated for the VA population. Further gender and age adjustments were calculated to estimate the US prevalence based on 2010 Census data. RESULTS: Of the 5,263,124 patients identified, IC/BPS was confirmed in 588/1,673 sampled charts with an ICD code for IC/BPS, 10/396 charts with an ICD-like code, and 4/813 controls. After adjustment for the size of the sampling pools, the overall prevalence of IC/BPS in the VA population was estimated to be 0.32% (95% CI: 0.00-0.83) with the female and male prevalence of 1.49% (95% CI: 0.00-6.08) and 0.23% (95% CI: 0.00-0.65), respectively. These values translated to national prevalence estimates of 0.99% (95% CI: 0.97-1.01), with female and male prevalence of 1.40% (95% CI: 1.37-1.44) and 0.55% (95% CI: 0.54-0.55), respectively (Figure 1). CONCLUSIONS: We estimate the national prevalence of IC/BPS to be 0.99% which is lower than the 2.7% from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network, and higher than other administrative studies with rates of as low as 0.05%. We believe our findings potentially represent the most accurate estimates to date given the broader and more heterogeneous population studied and unique strategy of combining administrative population-based data with individual chart reviews. Source of Funding: CDC © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e99-e99 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jennifer Anger* More articles by this author Catherine Bresee More articles by this author Kai Dallas More articles by this author Amanda De Hoedt More articles by this author Kelsey Haywood More articles by this author Emily Wiggins More articles by this author Kelsey Hoggatt More articles by this author Marc Goodman More articles by this author Jayoung Kim More articles by this author Stephen Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Walking the Tightrope: A Proposed Model of Chronic Pain and Stress.

Pain and stress are both phenomena that challenge an individual’s homeostasis and have significant overlap in conceptual and physiological processes. Allostasis is the ability to adapt to pain and stress and maintain homeostasis; however, if either process becomes chronic, it may result in negative long-term outcomes. The negative effects of stress on health outcomes on physiology and behavior, including pain, have been well documented; however, the specific mechanisms of how stress and what quantity of stress contributes to the maintenance and exacerbation of pain have not been identified, and thus pharmacological interventions are lacking. The objective of this brief review is to: 1. identify the gaps in the literature on the impact of acute and chronic stress on chronic pain, 2. highlight future directions for stress and chronic pain research; and 3. introduce the Pain-Stress Model in the context of the current literature on stress and chronic pain. A better understanding of the connection between stress and chronic pain could provide greater insight into the neurobiology of these processes and contribute to individualized treatment for pain rehabilitation and drug development for these often comorbid conditions.

4C Influence of Neighborhood Disorder on Perceived Control Over Pain and Pain-Related Function in African Americans

The purpose of these studies was to determine the influence of neighborhood disorder on pain-related function as mediated by perceived control over pain in urban residing African Americans. Neighborhood disorder is characterized by physical and social features of a neighborhood that may signal the breakdown of order and social control, and may include high poverty, increased crime, poor building condition, housing instability, and low educational levels of residents. Current knowledge in chronic pain research is extended by addressing gaps linking neighborhood disorder and perceived control over pain as a mediator to pain-related function. This research has shown that as pain severity decreases, pain-related function increases. Disparity in chronic pain is especially true of African Americans living in neighborhoods with high levels of disorder. For those who experience little control over adversities surrounding neighborhood disorder, perceived control over pain and resulting pain-related function may also be influenced.

Biocybernetic model for the diagnosis and treatment of chronic pain

Purpose The biopsychosocial model (BPSM) on chronic pain is an interactive psychophysiological behavior pattern that cannot be separated into different independent components. However, the epistemological analysis of the classic BPSM, based on “biopsychosocial factors,” can be reduced to a list of biological, psychological and social factors, which can be addressed simultaneously, but independently, where simultaneity is seen as relationality. The purpose of this paper is to achieve a systemic and transdisciplinary vision of the idea of simultaneity and multidisciplinarity of the BPSM and propose a new model for the diagnosis and treatment of chronic pain. Design/methodology/approach Based on the following conceptual triad, co-autonomy, centralization and non-requisite variety, to constitute systemic indicators, the authors design a new conceptual model of cohesion, communication, conduction and coordination (CO4) model to deal with the relational system of chronic pain patients. Findings The indicators of the CO4 system as transdisciplinary structure create and focus a completely new relationship regarding the relational system of the chronic pain patients. This new conceptual framework transcends the objects and frameworks of each discipline separately, going beyond the multidisciplinary model. Originality/value The CO4 model allows a diagnostic and therapeutic standardization as a new model on chronic pain, improving therapeutic efficiency, resource use and laying the foundation for a common language in future chronic pain research.

Proteomic profiling of proteins in the dorsal horn of the spinal cord in dairy cows with chronic lameness

Chronic lameness affects bovine welfare and has a negative economic impact in dairy industry. Moreover, due to the translational gap between traditional pain models and new drugs development for treating chronic pain states, naturally occurring painful diseases could be a potential translational tool for chronic pain research. We therefore employed liquid chromatography tandem mass spectrometry (LC-MS/MS) to stablish the proteomic profile of the spinal cord samples from lumbar segments (L2-L4) of chronic lame dairy cows. Data were validated and quantified through software tool (Scaffold® v 4.0) using output data from two search engines (SEQUEST® and X-Tandem®). Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis was performed to detect proteins interactions. LC-MS/MS identified a total amount of 177 proteins; of which 129 proteins were able to be quantified. Lame cows showed a strong upregulation of interacting proteins with chaperone and stress functions such as Hsp70 (p < 0.006), Hsc70 (p < 0.0079), Hsp90 (p < 0.015), STIP (p > 0.0018) and Grp78 (p <0.0068), and interacting proteins associated to glycolytic pathway such as; γ-enolase (p < 0.0095), α-enolase (p < 0.013) and hexokinase-1 (p < 0.028). It was not possible to establish a clear network of interaction in several upregulated proteins in lame cows. Non-interacting proteins were mainly associated to redox process and cytoskeletal organization. The most relevant down regulated protein in lame cows was myelin basic protein (MBP) (p < 0.02). Chronic inflammatory lameness in cows is associated to increased expression of stress proteins with chaperone, metabolism, redox and structural functions. A state of endoplasmic reticulum stress and unfolded protein response (UPR) might explain the changes in protein expression in lame cows; however, further studies need to be performed in order to confirm these findings.

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.

Hub disruption in patients with chronic neck pain: a graph analytical approach.

Chronic pain is known to alter the brain's network dynamics. These dynamics are often demonstrated by identifying alterations in the brain network topology. A common approach used for this purpose is graph theory. To date, little is known on how these potentially altered networks in chronic pain relate to the symptoms reported by these patients. Here, we applied a graph theoretical approach to identify network changes in patients suffering from chronic neck pain, a group that is often neglected in chronic pain research. Participants with chronic traumatic and nontraumatic neck pain were compared to healthy pain-free controls. They showed higher levels of self-reported symptoms of sensitization, higher levels of disability, and impaired sensorimotor control. Furthermore, the brain suffering from chronic neck pain showed altered network properties in the posterior cingulate cortex, amygdala, and pallidum compared with the healthy pain-free brain. These regions have been identified as brain hubs (ie, regions that are responsible for orchestrating communication between other brain regions) and are therefore known to be more vulnerable in brain disorders including chronic pain. We were furthermore able to uncover associations between these altered brain network properties and the symptoms reported by patients. Our findings indicate that chronic neck pain patients reflect brain network alterations and that targeting the brain in patients might be of utmost importance.