Chronic pelvic pain is a substantial clinical challenge that profoundly impacts quality of life for many women. The Neuro Emotional Technique (NET) is a novel mind-body intervention designed to attenuate emotional arousal of distressing thoughts and pain. This study evaluated functional connectivity changes in key areas of the brain in patients with chronic pelvic pain receiving the NET intervention. The goal was to assess whether the NET intervention was associated with functional connectivity (FC) changes in the brain related to reductions in emotional distress and pain, particularly in the limbic areas, sensory/pain regions, and cerebellum.

This is a prospectively designed study that included twenty-six patients with a diagnosis of chronic pelvic pain who were randomised to either the NET intervention or a waitlist control. To evaluate the primary outcome of neurophysiological effects, all participants received resting state functional blood oxygen level dependent (BOLD) magnetic resonance imaging (rs-fMRI) before and after the NET intervention or waitlist control period. Pain, mood, anxiety, and quality of life also were assessed.

Compared to the control group, the NET group demonstrated significant improvements in pain interference and pain intensity, and in emotional measures such anxiety and depression. Functional connectivity in the NET group compared to controls, was significantly decreased in the amygdala, cerebellum, and postcentral gyrus. There were also significant correlations between FC changes and changes in clinical measures.

This study is an initial step towards describing a neurological signature of reducing emotional distress in women with chronic pelvic pain. Specifically, FC changes between the cerebellum and the amygdala and sensory areas appears to be associated with a reduction in pain and the effects of that pain. Future, larger clinical trials are warranted to further evaluate these mechanisms and NET as a potential therapeutic intervention in patients with chronic pelvic pain.

Chronic ocular surface pain (COSP) refers to interrelated symptoms such as burning, aching, and irritation and can occur as an isolated condition or comorbid with numerous ocular disorders, including dry eye syndrome Treatments for COSP are largely aimed at the ocular surface and modulating pain arising from damaged corneal nerves; however, the average impact of these treatments on COSP are low to absent. A potential explanation for this is that, in a subset of patients with COSP, individuals have amplified and/or dysregulated neural signaling and sensory processing within the central nervous system (CNS). As in other chronic pain conditions, this might be the pathogenic mechanism primarily responsible for maintaining pain - a phenomenon now referred to as nociplastic pain. The key clinical features of nociplastic pain include symptoms out of proportion to signs, regional or widespread pain, the presence of other chronic pain conditions, and non-pain CNS mediated symptoms (e.g., sleep disorders). We provide an overview for eye care clinicians of nociplastic pain and delineate the emerging evidence for the presence of nociplastic pain among some individuals with COSP. We highlight gaps in our current understanding of nociplastic pain in COSP and provide clinicians with specific tools that may aid in the assessment and management of nociplastic pain.

Effective prevention and management strategies for chronic pain remain elusive. This has prompted investigations into biomarkers to better understand the mechanisms underlying pain development and persistence. One promising marker is low peak alpha frequency (PAF), an electroencephalography (EEG) measure that has been associated with increased sensitivity during acute experimental pain. However, findings regarding the relationship between PAF and chronic pain are variable, potentially due to disparate levels of central sensitization among chronic pain populations. This is evidenced by the variable extent of widespread pain, a phenotypic marker for central sensitization, observed across individuals with chronic pain.

To explore the impact of widespread pain on PAF among people with chronic pain.

Thirty-eight individuals with urologic chronic pelvic pain syndrome were categorized as having widespread (n = 24) or localized (n = 14) pain based upon self-reported body maps. Electroencephalography data were collected under resting conditions, and PAF was determined using spectral analysis.

Participants with widespread pain had a significantly lower global average PAF than those with localized pain, after controlling for age and sex. This relationship persisted even when accounting for pain intensity and duration. Peak alpha frequency differences were observed across all EEG electrodes, particularly in the sensorimotor and occipital regions.

Preliminary findings suggest that PAF may represent a potential biomarker for central sensitization in chronic pain, highlighting the importance of considering pain distribution in chronic pain research. Future studies with larger samples should investigate the neural mechanisms underlying these observations and the clinical utility of PAF in diverse chronic pain populations.

Maladaptive brain plasticity has been reported in chronic pain (CP) conditions, though it remains unclear if there are common alterations across pathologies. Therefore, we systematically synthesized literature comparing resting-state functional magnetic resonance imaging (rs-fMRI) in CP patients and healthy controls (HC), and meta-analyzed data whenever applicable. Separate meta-analyses were performed for each method - (fractional) amplitude of low-frequency fluctuations (fALFF, ALFF), regional homogeneity (ReHo), seed-based connectivity (according to the seed) and independent component analysis (according to the network). In qualitative synthesis, sensory-discriminative pain processing - thalamus, insula, temporal and sensory cortices - and cognitive and emotional processing - cingulate, prefrontal and parietal cortices and precuneus - regions concentrated CP/HC differences. Meta-analyses revealed decreased ALFF and increased ReHo in the precuneus, increased fALFF in the left posterior insula and disrupted within- and cross-network connectivity of default mode network (DMN) nodes, as well as altered connectivity in top-down pain modulation pathways. Specifically, it showed decreased anterior and increased posterior components' representation within DMN, enhanced connectivity between the medial prefrontal cortex (mPFC, part of the DMN) and anterior insula (part of the salience network), and decreased mPFC connectivity with the periaqueductal gray matter (PAG). Collectively, results suggest that CP disrupts the natural functional organization of the brain, particularly impacting DMN nodes (mPFC and precuneus), insula and top-town pain modulation circuits.

Low peak alpha frequency (PAF) is an electroencephalography (EEG) outcome associated reliably with high acute pain sensitivity. However, existing research suggests that the relationship between PAF and chronic pain is more variable. This variability could be attributable to chronic pain groups typically being examined as homogenous populations, without consideration being given to potential diagnosis-specific differences. Indeed, while emerging work has compared individuals with chronic pain to healthy controls, no previous studies have examined differences in PAF between diagnoses or across chronic pain subtypes.

To address this gap, we reanalysed a dataset of resting state EEG previously used to demonstrate a lack of difference in PAF between individuals with chronic pain and healthy controls. In this new analysis, we separated patients by diagnosis before comparing PAF across three subgroups: chronic widespread pain (n = 30), chronic back pain (n = 38), and healthy controls (n = 87).

We replicate the original finding of no significant difference between chronic pain groups and controls, but also find that individuals with widespread pain had significantly higher global average PAF values than those of people with chronic back pain [p = 0.028, β = 0.25 Hz] after controlling for age, sex, and depression.

These novel findings reveal PAF values in individuals with chronic pain may be diagnosis-specific and not uniformly shifted from the values of healthy controls. Future studies should account for diagnosis and be cautious with exploring homogenous 'chronic pain' classifications during investigations of PAF.

Our work suggests that, contrary to previous hypotheses, inter-individual differences in PAF reflect diagnosis-specific mechanisms rather than the general presence of chronic pain, and therefore may have important implications for future work regarding individually-tailored pain management strategies.

Pain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been tested in clinical trials for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). We explored this hypothesis using data from 3 previously published trials testing treatments for IC/BPS, which suggested modest benefits but did not meet a priori primary outcome statistical significance criteria. Importantly, these studies also collected symptom questionnaire data that allowed us to retrospectively identify participants with and without widespread pain. Analyzing the treatment by the degree of widespread pain revealed a difference in outcome and statistical significance level for each trial. Participants with predominately local pain (ie, limited widespread pain symptoms) responded to therapy targeting local symptoms, whereas those with widespread pain did not. Alternatively, participants with widespread pain beyond their local pelvic pain responded to more centrally acting treatments. Our results suggest that differentiating patients based on widespread vs more localized pain is a key consideration for designing future clinical trials for conditions with variable pain profiles, such as IC/BPS and potentially other pain-based syndromic disorders.

Chronic pain is a pervasive and debilitating condition with increasing implications for public health, affecting millions of individuals worldwide. Despite its high prevalence, the underlying neural mechanisms and pathophysiology remain only partly understood. Since its introduction 35 years ago, brain diffusion magnetic resonance imaging (MRI) has emerged as a powerful tool to investigate changes in white matter microstructure and connectivity associated with chronic pain. This review synthesizes findings from 58 articles that constitute the current research landscape, covering methods and key discoveries. We discuss the evidence supporting the role of altered white matter microstructure and connectivity in chronic primary pain conditions, highlighting the importance of studying multiple chronic pain syndromes to identify common neurobiological pathways. We also explore the prospective clinical utility of diffusion MRI, such as its role in identifying diagnostic, prognostic, and therapeutic biomarkers. Furthermore, we address shortcomings and challenges associated with brain diffusion MRI in chronic primary pain studies, emphasizing the need for the harmonization of data acquisition and analysis methods. We conclude by highlighting emerging approaches and prospective avenues in the field that may provide new insights into the pathophysiology of chronic pain and potential new therapeutic targets. Because of the limited current body of research and unidentified targeted therapeutic strategies, we are forced to conclude that further research is required. However, we believe that brain diffusion MRI presents a promising opportunity for enhancing our understanding of chronic pain and improving clinical outcomes.

Central sensitization is an important mechanism underlying many chronic pain conditions. Chronic pain and alcohol use disorder (AUD) are highly comorbid. Despite great scientific interest in brain mechanisms linking chronic pain and AUD, progress has been impeded by difficulty assessing central sensitization in AUD.

The present study is the first to employ a validated surrogate measure to describe central sensitization in a clinical sample with AUD.

Participants with AUD (n = 99) were recruited from an academic addiction treatment center. A well-established surrogate measure of central sensitization, The American College of Rheumatology Fibromyalgia Survey Criteria (ACRFMS) was administered. Participants also responded to questions about quality of life (RAND-36), and AUD. Descriptive analyses and Spearman's rho correlations were performed.

Chronic pain and evidence of central sensitization were prevalent. Greater central sensitization was associated with worse health-related quality of life. Participants higher in central sensitization expressed greater endorsement of pain as a reason for AUD onset, maintenance, escalation, treatment delay, and relapse.

The present study bolsters prior assertions that AUD and chronic pain might compound one another via progressive sensitization of shared brain circuitry. These results may inform future mechanistic research and precision AUD treatment.

Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes mellitus (T2DM) and is often accompanied by a variety of cognitive and emotional deficits, but the neurologic mechanisms underlying these deficits have not been fully elucidated. Therefore, this study aimed to use independent component analysis to explore the changes in the characteristics within the intrinsic network and to reveal patterns of interactions between networks in patients with DPN. Forty-one patients with T2DM who showed DPN, 37 patients with T2DM who did not show DPN (NDPN group), and 43 healthy controls (HC) underwent a neuropsychological assessment and resting-state functional magnetic resonance imaging examinations to examine the patterns of intra- and inter-network variations in the patients with T2DM at different clinical stages (with and without DPN). The relationships of intra- and inter-network functional connectivity (FC) with clinical/cognitive variables were also examined. In comparison with the NDPN group and HC, patients with DPN showed decreased FC within the visual network and sensorimotor network (SMN). Moreover, in comparison with the HC group, patients with DPN showed decreased FC within the anterior default mode network and increased FC within the basal ganglia network. Inter-network analysis showed decreased FC between the SMN and salience network in patients with DPN relative to the NDPN and HC groups. The decreased FC within the bilateral paracentral lobule (BA 6) of SMN was associated with Color Trails Test part 1 scores (r = -0.302, P = 0.007) and disease duration (r = -0.328, P = 0.003) in all patients with T2DM. In conclusion, the results revealed that patients with DPN have abnormal FC in multiple resting-state intrinsic networks in addition to the SMN, and that decreased FC between the SMN and salience network may be involved in the neural basis of abnormal sensorimotor function in patients with DPN.

Few neuroimaging studies have investigated structural brain differences associated with variations in pain distribution.

To explore structural differences of the brain in fibromyalgia (FM), temporomandibular disorder pain (TMD) and healthy pain-free controls (CON) using structural and diffusion MRI.

A case-control exploratory study with three study groups with different pain distribution were recruited: FM (n = 16; mean age [standard deviation]: 44 [14] years), TMD (n = 17, 39 [14] years) and CON (n = 10, 37 [14] years). Participants were recruited at the University Dental Clinic in Malmö, Sweden. T1-weighted and diffusion MRIs were acquired, clinical and psychosocial measures were obtained. Main outcome measures were subcortical volume, cortical thickness, white matter microstructure and whole brain grey matter intensity.

Patients with FM had smaller volume in the right thalamus than patients with TMD (p = .020) and CON (p = .030). The right thalamus volume was negatively correlated to pain intensity (r = -0.37, p = .022) and pain-related disability (r = -0.45, p = .004). The FM group had lower cortical thickness in the right anterior prefrontal cortex than CON (p = .005). Cortical thickness in this area was negatively correlated to pain intensity (r [37] = - 0.48, p = .002).

This study suggests that thalamus grey matter alterations are associated with FM and TMD, and that anterior prefrontal cortex grey matter alterations are associated with FM but not TMD. Studies on chronic overlapping pain conditions are needed in relation to possible nociplastic pain mechanisms in the brain and central nervous system.

The effect of chronic pain on brain-predicted age is unclear. We performed secondary analyses of a large cross-sectional and 3-year longitudinal data set from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network to test the hypothesis that chronic pelvic pain accelerates brain aging and brain aging rate. Brain-predicted ages of 492 chronic pelvic pain patients and 72 controls were determined from T1-weighted MRI scans and used to calculate the brain-predicted age gap estimation (brainAGE; brain-predicted - chronological age). Separate regression models determined whether the presence of chronic pelvic pain could explain brainAGE and brain aging rate when accounting for covariates. We performed secondary analyses to understand whether brainAGE was associated with factors that subtype chronic pelvic pain patients (inflammation, widespread pain, and psychological comorbidities). We found a significant association between chronic pelvic pain and brainAGE that differed by sex. Women with chronic pelvic pain had higher brainAGE than female controls, whereas men with chronic pelvic pain exhibited lower brainAGE than male controls on average-however, the effect was not statistically significant in men or women when considered independently. Secondary analyses demonstrated preliminary evidence of an association between inflammatory load and brainAGE. Further studies of brainAGE and inflammatory load are warranted.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a highly prevalent condition with incompletely understood pathophysiology, especially in relation to the systemic symptoms experienced. The role of autonomic nervous system dysfunction in IC/BPS remains poorly understood.

The purpose of this study was to assess the relationship between autonomic symptom severity and clinical characteristics of patients with IC/BPS.

This is a retrospective cohort study of 122 IC/BPS patients who completed the Composite Autonomic Symptoms Score (COMPASS-31) questionnaire. Data were collected on anesthetic bladder capacity (BC), Hunner lesion (HL) status, results for validated IC/BPS symptom questionnaires (O'Leary Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index (ICSI/ICPI) and the Pelvic Pain and Urgency/Frequency (PUF) scale), and comorbid nonurologic associated syndromes. Using the first quartile of COMPASS-31 scores as the cutoff, we compared patients within the first quartile (low symptom load; n = 30), to the remainder of the patients (high symptom load; n = 92).

Patients scoring ≥20.36 were significantly less likely to be HL positive (10.9% vs 26.7%; P = 0.043) and had a significantly higher BC (823.10 ± 396.07 vs 635.00 ± 335.06; P = 0.027), higher scores on the PUF questionnaire (23.80 ± 4.98 vs; 19.61 ± 5.22 P < 0.001), and a higher number of nonurologic associated syndromes (5.65 ± 2.90 vs 2.60 ± 1.89; P < 0.001).

Patients with IC/BPS experience widespread symptoms associated with autonomic nervous system dysfunction. A higher symptom load strongly correlates with a nonbladder-centric phenotype. These findings provide further evidence that total body nervous system dysfunction is present in patients with nonbladder centric IC/BPS.

Degenerative cervical myelopathy (DCM) is a debilitating condition characterized by compression of the cervical spinal cord, leading to neurological deficits. This study aimed to investigate the association between comorbidities like diabetes mellitus (DM) and obesity and quality of life (QOL) in preoperative patients with DCM, and to examine the distribution of pain and numbness.

A cross-sectional study with 86 preoperative patients with DCM was conducted. Patient-reported outcome measures (PROMs) including Core Outcome Measure Index for the neck (COMI-Neck), Neck Disability Index (NDI), EQ-5D-3L, SF-12v2 assessed QOL, and baseline characteristics were collected. Patients were categorized by diabetic and obesity status, resulting in 17 with and 69 without DM, and 27 obese, 59 nonobese patients. In the statistical analysis, we compared PROMs and baseline characteristics, and conducted MANCOVA to investigate the association of DM and obesity with PROMs.

The study found no significant differences in preoperative QOL between patients with and without DM or obesity. Additionally, the results of MANCOVA indicated that neither DM nor obesity alone, nor their combination, had an association with the total scores of PROMs. In each group, the Symptom-specific well-being score on the COMI-Neck was notably high, implying distressing current symptoms (median: 10). On the NDI, the median score for pain intensity, lifting, work, and recreation subitems was 3. Pain was predominantly reported in the neck and lower back, while numbness was more prevalent in the peripheral regions of the upper and lower limbs.

Preoperative QOL was not significantly affected by the presence of DM and/or obesity. DCM-related symptoms may mask the associations with these comorbidities. Regardless of the preoperative condition, it is important to address the PROMs items that posed challenges before surgery.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an at least 6-mo noninfectious bladder inflammation of unknown origin characterized by chronic suprapubic, abdominal, and/or pelvic pain. Although the term cystitis suggests an inflammatory or infectious origin, no definite cause has been identified. It occurs in both sexes, but women are twice as much affected.

To systematically review evidence of psychiatric/psychological changes in persons with IC/BPS.

Hypothesizing that particular psychological characteristics could underpin IC/BPS, we investigated in three databases the presence of psychiatric symptoms and/or disorders and/or psychological characteristics in patients with IC/BPS using the following strategy: ("interstitial cystitis" OR "bladder pain syndrome") AND ("mood disorder" OR depressive OR antidepressant OR depression OR depressed OR hyperthymic OR mania OR manic OR rapid cyclasterisk OR dysthymiasterisk OR dysphoriasterisk).

On September 27, 2023, the PubMed search produced 223 articles, CINAHL 62, and the combined PsycLIT/ PsycARTICLES/PsycINFO/Psychology and Behavioral Sciences Collection search 36. Search on ClinicalTrials.gov produced 14 studies, of which none had available data. Eligible were peer-reviewed articles reporting psychiatric/psychological symptoms in patients with IC/BPS, i.e. 63 articles spanning from 2000 to October 2023. These studies identified depression and anxiety problems in the IC/BPS population, along with sleep problems and the tendency to catastrophizing.

Psychotherapies targeting catastrophizing and life stress emotional awareness and expression reduced perceived pain in women with IC/BPS. Such concepts should be considered when implementing treatments aimed at reducing IC/BPS-related pain.

Nociplastic pain is a mechanistic term used to describe pain that arises or is sustained by altered nociception, despite the absence of tissue damage. Although nociplastic pain has distinct pathophysiology from nociceptive and neuropathic pain, these pain mechanisms often coincide within individuals, which contributes to the intractability of chronic pain. Key symptoms of nociplastic pain include pain in multiple body regions, fatigue, sleep disturbances, cognitive dysfunction, depression and anxiety. Individuals with nociplastic pain are often diffusely tender - indicative of hyperalgesia and/or allodynia - and are often more sensitive than others to non-painful sensory stimuli such as lights, odours and noises. This Review summarizes the risk factors, clinical presentation and treatment of nociplastic pain, and describes how alterations in brain function and structure, immune processing and peripheral factors might contribute to the nociplastic pain phenotype. This article concludes with a discussion of two proposed subtypes of nociplastic pain that reflect distinct neurobiological features and treatment responsivity.

In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only.

A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site.

Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations.

These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes.

Exploring the relationship between underlying pain mechanisms and physical activity could inform interventions to optimize physical activity in persons with multiple sclerosis (PwMS). This cross-sectional nationwide survey examined whether pain phenotype is a significant predictor of self-reported physical activity in PwMS. The study included 938 persons with a self-reported diagnosis of MS (93% reported neurologist-diagnosed MS) who completed surveys of demographic, clinical information, pain intensity, indicators of underlying pain mechanisms (Fibromyalgia Survey Criteria and painDETECT), and physical activity (Godin Leisure-Time Exercise Questionnaire). Responses were used to categorize pain phenotypes as widespread pain with nociplastic features (WPNF), neuropathic, nociceptive, or mixed (neuropathic/WPNF). Following current physical activity guidelines, self-reported physical activity was categorized as active or insufficiently active/sedentary. Applying multivariable logistic regression, participants with no chronic pain had 2.30 higher odds of being physically active when compared to participants with chronic mixed pain. Similarly, participants with neuropathic and nociceptive pain had, respectively, 1.90 and 1.66 higher odds of being physically active compared to individuals with mixed pain. Higher scores on the fibromyalgia survey criteria (operationalized in this study as an indicator of WPNF) were a significant independent predictor of insufficient physical activity (OR = .93, P < .01). Findings indicate that experience and phenotype of chronic pain, in particular WPNF, are associated with physical inactivity in PwMS. This suggests that assessing pain phenotype may be important to identify individuals at risk of inadequate physical activity and may guide the tailoring of behavioral therapeutic approaches to help PwMS achieve the recommended level of physical activity. PERSPECTIVE: This study examines the association between pain mechanism and physical activity in multiple sclerosis. These findings highlight the possibility that a basic screening for pain mechanism could offer clinically useful information without requiring extensive neurobiological phenotyping and may inform the development of behavioral interventions to enhance physical activity in multiple sclerosis.

Placebo and nocebo effects have been well documented for nearly two centuries. However, research has only relatively recently begun to explicate the neurobiological underpinnings of these phenomena. Similarly, research on the broader social implications of placebo/nocebo effects, especially within healthcare delivery settings, is in a nascent stage. Biological and psychosocial outcomes of placebo/nocebo effects are of equal relevance. A common pathway for such outcomes is the endogenous opioid system. This chapter describes the history of placebo/nocebo in medicine; delineates the current state of the literature related to placebo/nocebo in relation to pain modulation; summarizes research findings related to human performance in sports and exercise; discusses the implications of placebo/nocebo effects among diverse patient populations; and describes placebo/nocebo influences in research related to psychopharmacology, including the relevance of endogenous opioids to new lines of research on antidepressant pharmacotherapies.

First-line pain treatment is unsatisfactory in more than 50% of chronic pain patients, likely because of the heterogeneity of mechanisms underlying pain chronification.

This cross-sectional study aimed to better understand pathomechanisms across different chronic pain cohorts, regardless of their diagnoses, by identifying distinct sensory phenotypes through a cluster analysis.

We recruited 81 chronic pain patients and 63 age-matched and sex-matched healthy controls (HC). Two distinct chronic pain cohorts were recruited, ie, complex regional pain syndrome (N = 20) and low back pain (N = 61). Quantitative sensory testing (QST) was performed in the most painful body area to investigate somatosensory changes related to clinical pain. Furthermore, QST was conducted in a pain-free area to identify remote sensory alterations, indicating more widespread changes in somatosensory processing.

Two clusters were identified based on the QST measures in the painful area, which did not represent the 2 distinct pain diagnoses but contained patients from both cohorts. Cluster 1 showed increased pain sensitivities in the painful and control area, indicating central sensitization as a potential pathomechanism. Cluster 2 showed a similar sensory profile as HC in both tested areas. Hence, either QST was not sensitive enough and more objective measures are needed to detect sensitization within the nociceptive neuraxis or cluster 2 may not have pain primarily because of sensitization, but other factors such as psychosocial ones are involved.

These findings support the notion of shared pathomechanisms irrespective of the pain diagnosis. Conversely, different mechanisms might contribute to the pain of patients with the same diagnosis.

In complex regional pain syndrome (CRPS), the representation area of the affected limb in the primary sensorimotor cortex (SM1) reacts abnormally during sensory stimulation and motor actions. We recorded 3T functional magnetic resonance imaging resting-state data from 17 upper-limb CRPS type 1 patients and 19 healthy control subjects to identify alterations of patients' SM1 function during spontaneous pain and to find out how the spatial distribution of these alterations were related to peripheral symptoms. Seed-based correlations and independent component analyses indicated that patients' upper-limb SM1 representation areas display (i) reduced interhemispheric connectivity, associated with the combined effect of intensity and spatial extent of limb pain, (ii) increased connectivity with the right anterior insula that positively correlated with the duration of CRPS, (iii) increased connectivity with periaqueductal gray matter, and (iv) disengagement from the other parts of the SM1 network. These findings, now reported for the first time in CRPS, parallel the alterations found in patients suffering from other chronic pain conditions or from limb denervation; they also agree with findings in healthy persons who are exposed to experimental pain or have used their limbs asymmetrically. Our results suggest that CRPS is associated with a sustained and somatotopically specific alteration of SM1 function, that has correspondence to the spatial distribution of the peripheral manifestations and to the duration of the syndrome.

Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain, tenderness, and fatigue. Patients with FM have no effective medication so far, and their activity of daily living and quality of life are remarkably impaired. Therefore, new therapeutic approaches are awaited. Recently, exercise therapy has been gathering much attention as a promising treatment for FM. However, the underlying mechanisms are not fully understood, particularly, in the central nervous system, including the brain. Therefore, we investigated functional connectivity changes and their relationship with clinical improvement in patients with FM after exercise therapy to investigate the underlying mechanisms in the brain using resting-state fMRI (rs-fMRI) and functional connectivity (FC) analysis.

Seventeen patients with FM participated in this study. They underwent a 3-week exercise therapy on in-patient basis and a 5-min rs-fMRI scan before and after the exercise therapy. We compared the FC strength of sensorimotor regions and the mesocortico-limbic system between two scans. We also performed a multiple regression analysis to examine the relationship between pre-post differences in FC strength and improvement of patients' clinical symptoms or motor abilities.

Patients with FM showed significant improvement in clinical symptoms and motor abilities. They also showed a significant pre-post difference in FC of the anterior cingulate cortex and a significant correlation between pre-post FC changes and improvement of clinical symptoms and motor abilities. Although sensorimotor regions tended to be related to the improvement of general disease severity and depression, brain regions belonging to the mesocortico-limbic system tended to be related to the improvement of motor abilities.

Our 3-week exercise therapy could ameliorate clinical symptoms and motor abilities of patients with FM, and lead to FC changes in sensorimotor regions and brain regions belonging to the mesocortico-limbic system. Furthermore, these changes were related to improvement of clinical symptoms and motor abilities. Our findings suggest that, as predicted by previous animal studies, spontaneous brain activities modified by exercise therapy, including the mesocortico-limbic system, improve clinical symptoms in patients with FM.

Widespread pain hypersensitivity and enhanced temporal summation of pain (TSP) are commonly reported in patients with complex regional pain syndrome (CRPS) and discussed as proxies for central sensitization. This study aimed to directly relate such signs of neuronal hyperexcitability to the pain phenotype of CRPS patients.

Twenty-one CRPS patients and 20 healthy controls (HC) were recruited. The pain phenotype including spatial pain extent (assessed in % body surface) and intensity were assessed and related to widespread pain hypersensitivity, TSP, and psychological factors. Quantitative sensory testing (QST) was performed in the affected, the contralateral and a remote (control) area.

CRPS patients showed decreased pressure pain thresholds in all tested areas (affected: t(34)  = 4.98, P < .001, contralateral: t(35) = 3.19, P = .005, control: t(31) = 2.65, P = .012). Additionally, patients showed increased TSP in the affected area (F(3,111) = 4.57, P = .009) compared to HC. TSP was even more enhanced in patients with a high compared to a low spatial pain extent (F(3,51) = 5.67, P = .008), suggesting pronounced spinal sensitization in patients with extended pain patterns. Furthermore, the spatial pain extent positively correlated with the Bath Body Perception Disturbance Scale (ρ = 0.491; P = .048).

Overall, we provide evidence that the pain phenotype in CRPS, that is, spatial pain extent, might be related to sensitization mechanism within the central nociceptive system. This study points towards central neuronal excitability as a potential therapeutic target in patients with more widespread CRPS.

Endogenous pain modulation in humans is frequently investigated with conditioned pain modulation (CPM). Deficient pain inhibition is a proposed mechanism that contributes to neuropathic pain (NP) after spinal cord injury (SCI). Recent studies have combined CPM testing and neuroimaging to reveal neural correlates of CPM efficiency in chronic pain. This study investigated differences in CPM efficiency in relation to resting-state functional connectivity (rsFC) between 12 SCI-NP subjects and 13 age- and sex-matched healthy controls (HC). Twelve and 11 SCI-NP subjects were included in psychophysical and rsFC analyses, respectively. All HC were included in the final analyses. Psychophysical readouts were analysed to determine CPM efficiency within and between cohorts. Group differences of rsFC, in relation to CPM efficiency, were explored with seed-to-voxel rsFC analyses with pain modulatory regions, e.g. ventrolateral periaqueductal gray (vlPAG) and amygdala. Overall, pain inhibition was not deficient in SCI-NP subjects and was greater in those with more intense NP. Greater pain inhibition was associated with weaker rsFC between the vlPAG and amygdala with the visual and frontal cortex, respectively, in SCI-NP subjects but with stronger rsFC in HC. Taken together, SCI-NP subjects present with intact pain inhibition, but can be differentiated from HC by an inverse relationship between CPM efficiency and intrinsic connectivity of supraspinal regions. Future studies with larger cohorts are necessary to consolidate the findings in this study.

The relationship between external lumbar, hip, and/or pelvic girdle pain and internal vaginal pelvic floor myofascial pain is not well described. We assessed this relationship in a cohort of adult women.

The cohort included women ≥ 18 years old who received care for external lumbar, hip, and/or pelvic girdle pain (reported or elicited on physical examination) who then underwent internal vaginal myofascial levator ani pain assessments, in a tertiary care Female Pelvic Medicine and Reconstructive Surgery pelvic pain clinic over a 2-year period (2013 and 2014).

The cohort of 177 women had an average age of 44.9±16.0 years, an average body mass index of 27.2±7.0 kg/m2, and the majority (79.2%) were white. Most patients presented with a chief complaint of pelvic (51.4%), vulvovaginal (18.6%), and/or lumbar (15.3%) pain. Women who reported symptoms of lumbar, hip, or pelvic girdle pain were more likely to have pain on vaginal pelvic floor muscle examination than women without this history (OR, 7.24; 95% CI, 1.95-26.93, p=0.003). The majority (85.9%) of women had bilateral internal vaginal pelvic floor myofascial pain on examination.

Although participants did not describe "vaginal pelvic floor myofascial pain," the high detection rate for internal vaginal pelvic floor myofascial pain on clinical examination highlights an opportunity to improve treatment planning. These findings suggest that the vaginal pelvic floor muscle examination should be part of the assessment of all women with lumbar, hip, and/or pelvic girdle pain. The relationship between this finding and clinical outcomes following directed treatment warrants additional study.

Although primary motor cortex (M1) transcranial direct current stimulation (tDCS) has an analgesic effect in fibromyalgia (FM), its neural mechanism remains elusive. We investigated whether M1-tDCS modulates a regional temporal variability of blood-oxygenation-level-dependent (BOLD) signals, an indicator of the brain's flexibility and efficiency and if this change is associated with pain improvement.

In a within-subjects cross-over design, 12 female FM patients underwent sham and active tDCS on five consecutive days, respectively. Each session was performed with an anode placed on the left M1 and a cathode on the contralateral supraorbital region. The subjects also participated in resting-state functional magnetic resonance imaging (fMRI) at baseline and after sham and active tDCS. We compared the BOLD signal variability (SDBOLD), defined as the standard deviation of the BOLD time-series, between the tDCS conditions. Baseline SDBOLD was compared to 15 healthy female controls.

At baseline, FM patients showed reduced SDBOLD in the ventromedial prefrontal cortex (vmPFC), lateral PFC, and anterior insula and increased SDBOLD in the posterior insula compared to healthy controls. After active tDCS, compared to sham, we found an increased SDBOLD in the left rostral anterior cingulate cortex (rACC), lateral PFC, and thalamus. After sham tDCS, compared to baseline, we found a decreased SDBOLD in the dorsomedial PFC and posterior cingulate cortex/precuneus. Interestingly, after active tDCS compared to sham, pain reduction was correlated with an increased SDBOLD in the rACC/vmPFC but with a decreased SDBOLD in the posterior insula.

Our findings suggest that M1-tDCS might revert temporal variability of fMRI signals in the rACC/vmPFC and posterior insula linked to FM pain. Changes in neural variability would be part of the mechanisms underlying repetitive M1-tDCS analgesia in FM.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a common and debilitating disease with poor treatment outcomes. Studies from the multidisciplinary approach to the study of chronic pelvic pain research network established that IC/BPS patients with chronic overlapping pain conditions (COPCs) experience poorer quality of life and more severe symptoms, yet the neurobiological correlates of this subtype are largely unknown. We previously showed that ex vivo toll-like receptor 4 (TLR4) cytokine/chemokine release is associated with the presence of COPCs, as well as widespread pain and experimental pain sensitivity women with IC/BPS. Here, we attempt to confirm these findings in the multisite multidisciplinary approach to the study of chronic pelvic pain Symptom Patterns Study using TLR4-stimulated whole blood (female IC/BPS patients with COPC n = 99; without n = 36). Samples were collected in tubes preloaded with TLR4 agonist, incubated for 24 hours, and resulting supernatant assayed for 7 cytokines/chemokines. These were subject to a principal components analysis and the resulting components used as dependent variables in general linear models. Controlling for patient age, body mass index, and site of collection, we found that greater ex vivo TLR4-stimulated cytokine/chemokine release was associated with the presence of COPCs ( P < 0.01), extent of widespread pain ( P < 0.05), but not experimental pain sensitivity ( P > 0.05). However, a second component of anti-inflammatory, regulatory, and chemotactic activity was associated with reduced pain sensitivity ( P < 0.01). These results confirm that the IC/BPS + COPCs subtype show higher levels of ex vivo TLR4 cytokine/chemokine release and support a link between immune priming and nociplastic pain in IC/BPS.

Microstructural alterations have been reported in patients with urologic chronic pelvic pain syndrome (UCPPS). However, it isn't clear whether these alterations are reproducible within 6 months or whether long-term symptom improvement is associated with specific microstructural changes. Using data from the MAPP-II Research Network, the current study performed population-based voxel-wise DTI and probabilistic tractography in a large sample of participants from the multicenter cohort with UCPPS (N = 364) and healthy controls (HCs, N = 61) over 36 months. While fractional anisotropy (FA) differences between UCPPS patients and HCs were observed to be unique at baseline and 6-month follow-up visits, consistent aberrations in mean diffusivity (MD) were observed between UCPPS and HCs at baseline and repeated at 6 months. Additionally, compared to HCs, UCPPS patients showed stronger structural connectivity (SC) between the left postcentral gyrus and the left precuneus, and weaker SC from the left cuneus to the left lateral occipital cortex and the isthmus of the left cingulate cortex at baseline and 6-month. By 36 months, reduced FA and MD aberrations in these same regions were associated with symptom improvement in UCPPS. Together, results suggest changes in white matter microstructure may play a role in the persistent pain symptoms in UCPPS. PERSPECTIVE: This longitudinal study identified reproducible, "disease-associated" patterns in altered mean diffusivity and abnormal microstructural connectivity in UCPPS comparing to HCs over 6 months. These differences were found in regions involved in sensory processing and integration and pain modulation, making it potentially amenable for clinical interventions that target synaptic and/or neuronal reorganization.

Clinical trials of pain are notoriously difficult and inefficient in demonstrating efficacy even for known efficacious treatments. Determining the appropriate pain phenotype to study can be problematic. Recent work has identified the extend of widespread pain as an important factor in the likelihood of response to therapy, but has not been tested in clinical trials. Using data from three previously published negative studies of the treatment of interstitial cystitis/ bladder pain with data on the extent of widespread pain, we examined the response of patients to different therapies base on the amount of pain beyond the pelvis. Participants with predominately local but not widespread pain responded to therapy targeting local symptoms. Participants with widespread and local pain responded to therapy targeting widespread pain. Differentiating patients with and without widespread pain phenotypes may be a key feature of designing future pain clinical trials to demonstrate treatments that are effective versus not.

Preliminary evidence suggests that there are sex differences in microstructural brain organization among individuals with irritable bowel syndrome (IBS). The aim of this study was to further investigate sex-dependent differences in brain microstructure and organization in a large sample of well-phenotyped participants with IBS compared with healthy controls. We hypothesized that female patients with IBS would show evidence for increased axonal strength and myelination within and between brain regions concerned with pain and sensory processing, when compared with males with IBS. We also hypothesized that female compared with male IBS subjects show greater levels of somatic awareness and sensory sensitivity consistent with multisystem sensory sensitivity. Diffusion tensor images and clinical assessments were obtained in 100 healthy controls (61 females) and 152 IBS (107 females) on a 3T Siemens Trio. Whole brain voxel-wise differences in fractional anisotropy, mean, radial and axial diffusivity, and track density as differences in somatic awareness and sensory sensitivity were assessed using the general linear model. Female compared with male IBS participants showed extensive microstructural alterations in sensorimotor, corticothalamic, and basal ganglia circuits involved in pain processing and integration of sensorimotor information. Together with the observed increases in symptom severity, somatic awareness, and sensory sensitivity, the findings support the hypotheses that the etiology and maintenance of symptoms in females with IBS may be driven by greater central sensitivity for multiple sensory stimuli.

The purpose of this paper is to evaluate the efficacy of a multimodal, outpatient neuromuscular protocol in treating remaining sensitization and myofascial pain in endometriosis patients post-surgical excision.

A retrospective longitudinal study was conducted for women aged 22 to 78 with a history of surgically excised endometriosis. 60 women with an average duration of pain of 8.63 ± 7.65 years underwent a treatment protocol consisting of ultrasound guided trigger point injections, peripheral nerve blocks, and pelvic floor physical therapy for 6 weeks. Concomitant cognitive behavioral therapy once weekly for a total of 12 weeks was also undertaken. Pain intensity and pelvic functionality were assessed at new patient consults and 3-month follow ups using Visual Analogue Scale (VAS) and Functional Pelvic Pain Scale (FPPS).

At new patient consults, average VAS and FPPS were 7.45 ± 2.11 (CI 6.92-7.98) and 14.35 ± 6.62 (CI 12.68 -16.02), respectively. At 3-month follow ups, average VAS and FPPS decreased to 4.12 ± 2.44 (CI 3.50-4.73; p < 0.001) and 10.3 ± 6.55 (CI 8.64-11.96; p < 0.001), respectively. Among FPPS categories, sleeping, intercourse, and working showed the highest statistical significance.

Data suggests the multimodal protocol was effective in treating the remaining underlying sensitization and myofascial pain seen in Endometriosis patients post-surgical excision, particularly in decreasing pain and improving function during work and intercourse.

Dysmenorrhea is characterized by high rates of transition to chronic pain. In a previous study using structural equation modeling, we demonstrated that several symptom domains associated with the emerging concept of nociplastic pain can be described using 2 symptom groups: generalized sensory sensitivity (GSS; composed of widespread pain, interceptive sensitivity, and environmental sensitivity) and SPACE (composed of unrefreshing sleep, pain, affective disturbances, cognitive issues, and reduced energy). Here, we perform a secondary cross-sectional analysis examining the same symptoms groups in a cohort of patients with dysmenorrhea without a diagnosis of chronic pain. Our purpose is to determine if the same symptom patterns are apparent and if they are associated with the presence and severity of comorbid pain. Participants were 201 women with dysmenorrhea. We replicated the hypothesized 2-factor structure in this cohort (comparative fit index = 0.971 and root mean square error of approximation =0.055; 90% CI: 0.000-0.097). Generalized sensory sensitivity was associated with the severity of bladder, bowel, and overall pain in multivariable models including SPACE, patient age, and BMI (all β > 0.32, all P < 0.05). Sleep, pain, affective disturbances, cognitive issues, and reduced energy were associated with menstrual pain during nonsteroidal anti-inflammatory drug use, whereas GSS was associated with the same in the absence of nonsteroidal anti-inflammatory drug use (both P < 0.05). This 2-factor model of symptoms seems to be replicable and valid in a cohort of women at risk for developing chronic pain conditions. These symptom groups are promising potential markers of future pain chronification and may point to patients in need of earlier or more aggressive intervention.

The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is imperfectly understood. Recent studies reported that small-fiber polyneuropathy (SFPN) is common in fibromyalgia, a condition commonly comorbid with IC/BPS.

The objective of this study was to determine the prevalence of SFPN in a large cohort of IC/BPS patients.

Adults diagnosed with IC/BPS scheduled to undergo either therapeutic hydrodistention (n = 97) or cystectomy with urinary diversion (n = 3) were prospectively recruited to this study. A skin biopsy obtained from the lower leg was used for intraepidermal nerve fiber density measurement. Small-fiber polyneuropathy (+/-) status was determined by comparing linear intraepidermal nerve fiber density (fibers/mm2) with normative reference values. Demographic information, medical history, and diagnoses for 14 conditions (both urologic and nonurologic) known to co-occur with IC/BPS were documented from self-report and electronic medical record.

In this large cohort of patients with IC/BPS, 31% (31/100) were positive for SFPN. Intraepidermal nerve fiber density was below the median for age and sex in 81% (81/100) of patients. Approximately one-third (31%) of SFPN+ patients reported co-occurring chronic fatigue syndrome, compared with 10.6% of the SFPN- group (P = 0.034). Small-fiber polyneuropathy-positive patients reported significantly fewer allergies than SFPN- patients (37.9% vs 60.6%; P = 0.047). There were no significant differences in bladder capacity or Hunner lesion status between the SFPN+ and SFPN- subgroups.

Small-fiber polyneuropathy is a common finding in patients with IC/BPS, and SFPN status is significantly correlated with co-occurring chronic fatigue syndrome and negatively correlated with the presence of allergies in this population.

Central sensitization is considered a key mechanism underlying neuropathic pain (NP) after spinal cord injury (SCI).

Two novel proxies for central sensitization were investigated in thoracic SCI subjects with (SCI-NP) and without NP (SCI-nonNP) compared to healthy controls (HC). Specifically, temporal summation of pain (TSP) was investigated by examining pain ratings during a 2-min tonic heat application to the volar forearm. Additionally, palmar heat-induced sympathetic skin responses (SSR) were recorded in order to reveal changes in pain-autonomic interaction above the lesion level. Pain extent was assessed as the percentage of the body area and the number of body regions being affected by NP.

Enhanced TSP was observed in SCI-NP (+66%) compared to SCI-nonNP (-75%, p = 0.009) and HC (-59%, p = 0.021). In contrast, no group differences were found (p = 0.685) for SSR habituation. However, pain extent in SCI-NP was positively correlated with deficient SSR habituation (body area: r = 0.561, p = 0.024; body regions: r = 0.564, p = 0.023).

These results support the value of TSP and heat-induced SSRs as proxies for central sensitization in widespread neuropathic pain syndromes after SCI. Measures of pain-autonomic interaction emerged as a promising tool for the objective investigation of sensitized neuronal states in chronic pain conditions.

We present two surrogate readouts for central sensitization in neuropathic pain following SCI. On the one hand, temporal summation of tonic heat pain is enhanced in subjects with neuropathic pain. On the other hand, pain-autonomic interaction reveals potential advanced measures in chronic pain, as subjects with a high extent of neuropathic pain showed diminished habituation of pain-induced sympathetic measures. A possible implication for clinical practice is constituted by an improved assessment of neuronal hyperexcitability potentially enabling mechanism-based treatment.

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.