In the search for chronic pain biomarkers, functional magnetic resonance imaging (fMRI) provides crucial insights into the neurobiological underpinnings of pain. Characterizing these mechanisms is challenging due to pain's dynamic nature. Analyzing pain-evoked brain responses conventionally assumes alignment with the onset of a noxious stimulus. However, the dynamic and subjective nature of pain challenges this assumption's accuracy. We hypothesized that incorporating the temporal delay between a noxious stimulus and the onset of perceptible pain improves the precision of fMRI responses. In a two-part study, we recruited pain-free twenty-seven individuals (14 females, mean age = 23.2 yrs). The first part aimed to establish the pain experience's temporal profile using noxious heat stimuli applied outside the scanner. The stimuli followed a 20-second on and 20-second off block design, maintaining a predetermined moderately painful temperature. Subjects continuously rated pain intensity, detailing the delay in perception relative to each block's onset. In the second part, subjects underwent fMRI scans with simultaneous noxious heat stimuli presentation. The BOLD scans were preprocessed, including slice-timing and motion artifact correction. The FSL FEAT's general linear model tool estimated brain responses to stimuli, comparing models aligning timings with actual stimulus periods and those accounting for the delay. Results revealed an average 8-second delay between thermal stimulus onset and non-negligible pain. Incorporating this delay in the analysis substantially enhanced BOLD signals within canonical pain-processing areas, such as thalamus and somatosensory cortices, compared to the strictly aligned model. This evidence suggests that considering the dynamics of the pain experience improves pain-evoked experiments.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that is often severely painful due to nociceptive mechanisms (i.e., stimulation of cutaneous nociceptors). However, patient-reported pain character suggests that neuropathy may also drive HS pain in a subset of patients. Quantitative sensory testing (QST) can help identify neuropathic pain by testing for heightened and paradoxical pain responses in patients, but it is less feasible for routine clinical use compared with brief questionnaires. We therefore tested the suitability of a standardized neuropathic questionnaire (PainDETECT; PD-Q) for use as a surrogate clinical measure by directly comparing it with QST-identified neuropathic pain in HS. Methods: This observational, cross-sectional study included 22 adults with painful HS lesions who completed the PD-Q and underwent QST. A receiver operating characteristic curve was generated and Cohen’s Kappa, sensitivity, and specificity were examined at three scoring thresholds. Results: Of the 22 participants, 14 (64%) exhibited dynamic mechanical allodynia and/or paradoxical thermal sensations in QST, which are characteristically found in neuropathic pain. According to the PD-Q, 8 participants (36%) were unlikely, 8 (36%) were possible, and 6 (27%) were likely to have neuropathic pain. A PD-Q Score indicating possible or likely neuropathic pain (i.e., ≥13) demonstrated 82% agreement with QST-determined neuropathic pain (Cohen’s Kappa = 0.61 [p = 0.004]; sensitivity = 86%; specificity = 75%). Conclusion: The PD-Q demonstrates moderate agreement with QST in screening for neuropathic pain in HS and may be a helpful clinical tool.

Introduction:Notalgia paresthetica (NP) is a chronic condition characterized by pruritus and other unpleasant dysesthetic sensations unilaterally on the subscapular back. Its specific underlying mechanisms are largely unknown, though hypothesized to be neuropathic. Determination of possible somatosensory contributors to the condition could pave the way for novel treatments.Objectives:Given the potential involvement of non-pruritic mechanisms in NP, our objective was to broadly characterize the somatosensory function in NP-affected and unaffected skin using methods that have been standardized in pain-free controls and painful neuropathic disorders. We hypothesized that if NP is caused by neuropathic mechanisms not targeted directly to pruritoceptors in the skin, somatosensory abnormalities would not be itchspecific. Second, given the lack of symptoms on the contralateral side of the back, we hypothesized that this region would be normally sensitive.Methods:In this study, quantitative sensory testing (QST) was used to comprehensively assess the somatosensory function in 15 adult patients with NP. Standardized QST metrics were performed in the NP-affected region and compared with the contralateral asymptomatic skin and itch-free individuals using an age, gender, and site-matched reference data set.Results:There were no significant differences in sensitivity between symptomatic and asymptomatic skin, except for increased mechanical-evoked itch on the itchy side. However, reference data set comparisons revealed bilateral hyposensitivity to innocuous cold and noxious pinprick and higher temporal summation of pain in patients with NP. In addition, compared with reference data, patients with NP demonstrated decreased sensitivity to cold and pinprick, presence of paradoxical heat sensations, and increased wind-up of pain.Conclusion:These results suggest a role for Aδ fiber pathways and central sensitization in NP-associated itch. More research is needed to determine whether sensory differences extend beyond the NP-affected dermatomal level and what might cause neuropathy specifically targeting Aδ fibers.

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.

Importance:Pain is the most impactful symptom in patients with hidradenitis suppurativa (HS). Characterization of sensory profiles may improve understanding of pain mechanisms in HS and facilitate identification of effective pain management strategies. Objective:To characterize somatosensory profiles in patients with HS at clinically affected and nonaffected sites compared with pain-free reference data. Design, Setting, and Participants:This cross-sectional study was conducted at the Emory University Dermatology Clinic. It was hypothesized (1) that patients with HS would demonstrate hypersensitivity to pain in HS lesions and (2) that some patients would have sensory profiles consistent with complex pain mechanisms. Therefore, adults with dermatologist-diagnosed HS and at least 1 painful HS lesion at the time of testing were enrolled between September 10, 2020, and March 21, 2022. Patients with other diagnoses contributing to pain or neuropathy were excluded. Data analysis was conducted between March and April 2022. Exposure:Quantitative sensory testing was performed on HS lesions and control skin according to a standardized protocol. Main Outcomes and Measures:Quantitative sensory testing outcomes included innocuous thermal and mechanical sensitivity (cold, warmth, and light touch detection thresholds), noxious thermal and mechanical sensitivity (cold, heat, pinprick, and deep pressure pain thresholds and suprathreshold pinprick sensitivity), temporal summation of pinprick, paradoxical thermal sensations, and dynamic mechanical allodynia (pain upon light stroking of the skin). Sensitivity in HS lesions was compared with sensitivity in a control location (the hand) and in pain-free controls using t tests. Results:This study included 20 participants with a median age of 35.5 (IQR, 30.0-46.5) years, the majority of whom were women (15 [75%]). In terms of race and ethnicity, 2 participants (10%) self-identified as Asian, 11 (55%) as Black, 6 (30%) as White, and 1 (5%) as more than 1 race or ethnicity. Compared with site-specific reference values from healthy, pain-free control participants, HS lesions were insensitive to innocuous cold and warmth, noxious heat, and light touch (t = -5.69, -10.20, -3.84, and 4.46, respectively; all P < .001). In contrast, HS lesions also demonstrated significant hypersensitivity to deep pressure pain (t = 8.36; P < .001) and cutaneous pinprick (t = 2.07; P = .046). Hypersensitivity to deep pressure pain was also observed in the control site (t = 5.85; P < .001). A subset of patients with HS displayed changes in pain processing that are often seen in neuropathic and nociplastic pain conditions, including hypersensitivity to repetitive pinprick (5 [26%]), paradoxical thermal sensations (3 [15%]), and pain upon light stroking of the skin (10 [50%]). Conclusions and Relevance:The findings of this cross-sectional study suggest that HS involves local changes in the skin or its free nerve endings, possibly leading to peripheral neuropathy and alterations in the transduction of innocuous and noxious thermal and mechanical stimuli. For some patients, central nervous system changes in somatosensory processing may also occur, but confirmatory evidence is needed. Better understanding of neuropathic and nociplastic mechanisms in HS pain could lead to individually tailored treatments.

Temporomandibular disorders (TMD) involve chronic pain in the masticatory muscles and jaw joints, but the mechanisms underlying the pain are heterogenous and vary across individuals. In some cases, structural, functional, and metabolic changes in the brain may underlie the condition. In the present study, we evaluated the functional connectivity between 86 regions of interest (ROIs), which were chosen based on previously reported neuroimaging studies of pain and differences in brain morphology identified in an initial surface-based morphometry analysis. Our main objectives were to investigate the topology of the network formed by these ROIs and how it differs between individuals with TMD and chronic pain (n = 16) and pain-free control participants (n = 12). In addition to a true resting state functional connectivity scan, we also measured functional connectivity during a 6-min application of a noxious cuff stimulus applied to the left leg. Our principal finding is individuals with TMD exhibit more suprathreshold correlations (higher nodal degree) among all ROIs but fewer “hub” nodes (i.e., decreased betweenness centrality) across conditions and across all pain pathways. These results suggest is this pain-related network of nodes may be “over-wired” in individuals with TMD and chronic pain compared to controls, both at rest and during experimental pain.

Objective: To evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS). Materials & methods: This was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-one veterans with fibromyalgia were randomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST with auricular PENFS (ST + PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2 weeks post-treatment. Clinical pain and physical function were also assessed at these timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness. Results: Both the ST + PENFS and ST groups reported a decrease in pain with treatment. Volumetric: Cortical thickness significantly decreased in the left middle posterior cingulate (p = 0.018) and increased in the left cuneus (p = 0.014) following ST + PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (p = 0.02) inversely correlated with pain scores. ST + PENFS group right hemisphere posterior dorsal cingulate size significantly (p = 0.044) positively correlated with pain scores. GABA: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (p = 0.083) using a linear mixed effects model. Conclusions: Results suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.

Purpose: A proportion of subjects with internal derangements of the temporomandibular joint (TMJ) may have a central sensitization disorder that may affect pain perception after surgery. This study aims to estimate the association between fibromyalgianess (FMness) score, a summed score of the Widespread Pain Index (WPI) and Symptom Severity Sore (SSS), and outcomes following TMJ arthroscopy. Methods: A retrospective cohort study including individuals who received arthroscopy for TMJ internal derangement at Michigan Medicine between 2011 and 2020 was performed. A predictor variable, FMness score, was assigned via the sum of WPI and SSS. Univariate and bivariate analyses were performed. Linear-mixed effects models were used to analyze 6 different outcomes, each in their own model: pain, jaw functional limitation scale (JFLS), JFLS-mobility domain, pain-related disability, comfortable maximum interincisal opening, and active maximum interincisal opening. Covariance structure was selected based on null model fit separately for each outcome. Results: Thirty-one subjects were included in the study sample. Twenty-eight subjects were female. Average age was 45.9 years. Bivariate analysis demonstrated that subject's FMness score was not correlated with pain (b = 0.03 [- 0.10, 0.17] P = .59) or JFLS score (b = 1.00 [-.80, 2.81] P = .27). However, subject's FMness score was significant for predicting JFLS-mobility domain score (b = .61, [0.05, 1.18] P = .04). Conclusion: A greater extent of central sensitization was associated with lower comfortable mouth opening after surgery, greater limitations in opening wide enough to eat various foods (higher JFLS-mobility scores), and higher pain-related disability. Future studies with larger sample sizes and reconstructive TMJ operations such as total TMJ arthroplasty may help clarify the impact of SSS and WPI scores on outcomes of TMJ surgery. (C) 2022 American Association of Oral and Maxillofacial Surgeons

Introduction: Myocardial ischemia with no obstructive coronary arteries (INOCA) is more common in women and associated with adverse cardiovascular outcomes. INOCA patients have recurrent chest pain and reduced quality of life, and therapeutic strategies are poorly defined. Central nervous system factors can promote and maintain spontaneous clinical pain. We explored central sensitization in INOCA. Methods: Twenty-nine women diagnosed with INOCA based on coronary angiography were enrolled. Baseline demographics, risk factors, and angina burden by the Seattle Angina Questionnaire (SAQ) was assessed. Generalized pain hypersensitivity was assessed using the validated Central Sensitization Inventory (CSI), with scores ≥40 indicating the presence of central sensitization. Functional capacity was determined by Duke Activity Status Index (DASI). A DASI score ≤34 is prognostic of major adverse cardiac events. Depressive symptoms were assessed using the Beck Depression Inventory. Descriptive statistics and Pearson correlations were performed; p-value ≤.05 was considered significant. Results: Mean age was 55.4±10 years and body mass index (BMI) was 30.1±7 kg/m 2 . Cardiac risk factors were prevalent with 59% hypertension, 55% hyperlipidemia, and 21% diabetes. SAQ scores indicated a high angina burden: 49.3±25.7 (angina frequency) and 39.3±27.6 (angina stability). Mean CSI score was 40.5±17, and 62% had CSI scores ≥40, indicating central sensitization. Mean DASI score was 33.3±18.6. A majority (52%) had a DASI score ≤34, indicative of guarded prognosis. CSI scores correlated positively with depression (r=0.78, p=0.00001) and BMI (r=0.39, p=0.04), and negatively with DASI (r=-0.36, p=0.05), indicating impaired physical functioning in those with higher levels of central pain sensitivity. Conclusions: Nearly two-thirds of women with INOCA have central sensitization. Central pain amplification is associated with angina, depression, obesity, and a limited functional capacity in mid-life INOCA women. The role of the central nervous system in persistent chest pain should be further investigated and may lead to novel therapeutic strategies.

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.

BACKGROUND:Mounting evidence suggests that central nervous system amplification, similar to that seen in fibromyalgia (FM), contributes to the pain experience in a subset of patients with temporomandibular disorders (TMD). METHODS:In this prospective observational study, patients with TMD completed the 2011 FM survey questionnaire, a surrogate measure of "centralized" pain. The influence of centralized pain on TMD pain, dysfunction, and disability was assessed dichotomously by determining the incidence of FM-positive cases in the sample and by using FM survey scores as a continuous measure of "fibromyalgia-ness" ("FM-ness"). RESULTS:The patients meeting criteria for FM diagnosis (17 of 89) had significantly more disease burden on numerous measures. FM-ness was positively associated with pain at rest, negative mood, tenderness to palpation, perceived jaw functional limitation, and pain-related disability, and it was negatively associated with comfortable pain-free jaw opening. The impact of FM-ness on perceived jaw functional limitation and disability was mediated by levels of spontaneous, ongoing pain in the orofacial region. Importantly, this pattern of findings was still present even in those not meeting the criteria for FM diagnosis. CONCLUSION:Together, these results imply that higher FM-ness increases TMD patient burden by amplifying spontaneous pain and further hampering painless jaw function, even in patients who do not meet criteria for FM diagnosis. These results are highly relevant for the clinical management of TMD, as they imply that targeting the central nervous system in the treatment of patients with TMD with evidence of pain centralization may help ameliorate both pain and jaw dysfunction.

Objective There is increasing demand for prediction of chronic pain treatment outcomes using machine‐learning models, in order to improve suboptimal pain management. In this exploratory study, we used baseline brain functional connectivity patterns from chronic pain patients with fibromyalgia (FM) to predict whether a patient would respond differentially to either milnacipran or pregabalin, 2 drugs approved by the US Food and Drug Administration for the treatment of FM. Methods FM patients participated in 2 separate double‐blind, placebo‐controlled crossover studies, one evaluating milnacipran (n = 15) and one evaluating pregabalin (n = 13). Functional magnetic resonance imaging during rest was performed before treatment to measure intrinsic functional brain connectivity in several brain regions involved in pain processing. A support vector machine algorithm was used to classify FM patients as responders, defined as those with a ≥20% improvement in clinical pain, to either milnacipran or pregabalin. Results Connectivity patterns involving the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) individually classified pregabalin responders versus milnacipran responders with 77% accuracy. Performance of this classification improved when both PCC and DLPFC connectivity patterns were combined, resulting in a 92% classification accuracy. These results were not related to confounding factors, including head motion, scanner sequence, or hardware status. Connectivity patterns failed to differentiate drug nonresponders across the 2 studies. Conclusion Our findings indicate that brain functional connectivity patterns used in a machine‐learning framework differentially predict clinical response to pregabalin and milnacipran in patients with chronic pain. These findings highlight the promise of machine learning in pain prognosis and treatment prediction.

Pain is a hallmark symptom of osteoarthritis (OA). In the past, chronic OA pain has been thought to arise solely from peripheral mechanisms in affected joints. However, there is a poor relationship between radiographic evidence of joint damage and pain, and emerging evidence suggests that some patients with OA exhibit a centralized pain phenotype in which central nervous system mechanisms augment their pain. In the present study, we hypothesized that patients with knee OA who have symptoms suggestive of centralized pain would display altered connectivity between brain regions implicated in pain processing. 40 females (mean age ± SD = 58.9 ± 8.1 years) with idiopathic knee OA completed self-report measures and resting state functional connectivity magnetic resonance imaging (fcMRI). Patients completed the ACR 2011 fibromyalgia (FM) survey criteria as a surrogate measure of centralized pain and were divided into 3 score tertiles: low (0–3), moderate (4–8), high (>8). (Higher scores indicate greater spatial distribution of pain and symptom burden.) fcMRI was performed using a seed-based approach targeting both pro- and anti-nociceptive regions and was then analyzed utilizing a one-way ANOVA in SPM8. 32 patients passing fcMRI quality control were analyzed. Results were significant at a cluster level corrected false discovery rate P value < .05, and were correlated with clinical data. The high tertile (n = 10) displayed increased connectivity between the anterior insula and the precuneus (P < .001) when compared to the low tertile (n = 7). Insula-precuneus connectivity for all patients was correlated with pain DETECT scores (r = .428, P = .015). We demonstrate that OA patients with symptoms reflective of centralized pain have altered connectivity between brain regions involved in pain processing, and those with greater connectivity report increased neuropathic pain symptoms. These findings suggest that non-peripheral mechanisms contribute to the pain experience in a subset of OA patients and may have important clinical implications. Supported by: Midwest Pain Consortium.

Conditioned pain modulation (CPM), a psychophysical paradigm that is commonly used to infer the integrity of endogenous pain-altering systems by observation of the effect of one noxious stimulus on another, has previously identified deficient endogenous analgesia in fibromyalgia (FM) and other chronic pain conditions. The mechanisms underlying this deficiency, be they insufficient inhibition and/or active facilitation, are largely unknown. The present cross-sectional study used a combination of behavioral CPM testing, voxel-based morphometry, and resting state functional connectivity to identify neural correlates of CPM in healthy controls (HC; n = 14) and FM patients (n = 15), and to probe for differences that could explain the pain-facilitative CPM that was observed in our patient sample. Voxel-based morphometry identified a cluster encompassing the periaqueductal gray (PAG) that contained significantly less gray matter volume in FM patients. Higher resting connectivity between this cluster and cortical pain processing regions was associated with more efficient inhibitory CPM in both groups, whereas PAG connectivity with the dorsal pons was associated with greater CPM inhibition only in HC. Greater PAG connectivity to the caudal pons/rostral medulla, which was pain-inhibitory in HC, was associated with pain facilitation in FM patients. PERSPECTIVE:These findings indicate that variation in the strength of the PAG resting functional connectivity can explain some of the normal variability in CPM. In addition, pain-facilitative CPM observed in FM patients likely involves attenuation of pain inhibitory as well as amplification of pain facilitative processes in the central nervous system.

Abstract Dentists regularly employ a variety of self‐report and sensory techniques to aid in the diagnosis and treatment of tooth‐related disease. Many of these techniques leverage principles borrowed from psychophysics, the quantitative measurement of the relationship between stimuli and evoked sensations, which falls under the larger umbrella of quantitative sensory testing (QST). However, most clinicians fail to meet the bar for what could be considered quantitative sensory testing, and instead focus on qualitative and dichotomous “yes/no” aspects of sensory experience. With our current subjective measurements for pain assessments, diagnosis and treatment of dental pain in young children and individuals (any age) with severe cognitive impairment rely extensively on third‐party observations. Consequently, the limitation of inadequate pain diagnosis can lead to poor pain management. In this review, it discusses mechanisms that underlie acute and chronic dental pain. It details the measurement of somatosensory responses and pulpal blood flow as objective measures of tooth health and pain. It proposes that bridging these varied methodologies will significantly improve diagnosis and treatment of orofacial pain and pathology. It concludes that improving the precision of sensory measurements could yield important improvements in diagnostic challenges in pulpal pathology for noncommunicative and cognitively impaired individuals.

Chronic overlapping pain conditions (COPCs) are characterized by aberrant central nervous system processing of pain. This "centralized pain" phenotype has been described using a large and diverse set of symptom domains, including the spatial distribution of pain, pain intensity, fatigue, mood imbalances, cognitive dysfunction, altered somatic sensations, and hypersensitivity to external stimuli. Here, we used 3 cohorts, including patients with urologic chronic pelvic pain syndrome, a mixed pain cohort with other COPCs, and healthy individuals (total n = 1039) from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to explore the factor structure of symptoms of centralized pain. Using exploratory and confirmatory factor analysis, we identified 2 general factors in all 3 cohorts, one characterized by a broad increased sensitivity to internal somatic sensations,environmental stimuli, and diffuse pain, termed Generalized Sensory Sensitivity, and one characterized by constitutional symptoms-Sleep, Pain, Affect, Cognition, Energy (SPACE). Longitudinal analyses in the urologic chronic pelvic pain syndrome cohort found the same 2-factor structure at month 6 and 1 year, suggesting that the 2-factor structure is reproducible over time. In secondary analyses, we found that Generalized Sensory Sensitivity particularly is associated with the presence of comorbid COPCs, whereas SPACE shows modest associations with measures of disability and urinary symptoms. These factors may represent an important and distinct continuum of symptoms that are indicative of the centralized pain phenotype at high levels. Future research of COPCs should accommodate the measurement of each factor.

Effusions are common among patients with disorders of the temporomandibular joint (TMJ), but publications are limited and results inconsistent about the correlation between them and important clinical variables, in particular severity of pain and degenerative disease. We organised a retrospective study of patients who presented for the evaluation and management of arthralgia of the TMJ and myofascial pain at the University of Michigan between 2011 and 2014. Inclusion criteria were: patients who had pain that was primarily arthrogenous, and coexisting myogenous pain, who had had initial non-surgical treatment, and arthroscopy of the TMJ with or without intramuscular injection of onabotulinumtoxinA (Botox,® Allegan, Weston, Fl, USA). The primary outcome variables were pain at rest as measured by visual analogue score (VAS) and the presence of degenerative disease of the joint. The secondary outcome variables included the position of the disc and whether it was perforated, signs of synovitis, maximal interincisal opening (MIO), and duration of symptoms. We studied 47 patients (94 TMJ) who met the inclusion criteria. We found no significant differences in pain at rest before or after arthroscopy, between patients with and without effusions, or in maximal MIO or duration of symptoms between the two groups. There was, however, a significant relation between effusions and degenerative joint disease. Effusions were also associated with a lower probability of the disc being in a normal position and a higher probability of anterior disc displacement without reduction.

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.