To describe the demographic, clinical, and treatment characteristics of youth diagnosed with juvenile primary fibromyalgia syndrome (JPFS) who are seen in pediatric rheumatology clinics.Information on demographics, symptoms, functioning, and treatments recommended and tried were obtained on patients with JPFS as part of a multi-site patient registry (the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry). Data were summarized using descriptive statistics. In a subset of patients completing registry follow-up visits, changes in symptoms, pain, and functioning were evaluated using growth modeling.Of the 201 patients with JPFS enrolled in the registry, most were Caucasian/White (85%), non-Hispanic (83%), and female (84%). Ages ranged from 9 to 20 years (M = 15.4 + 2.2). The most common symptoms reported were widespread musculoskeletal pain (91%), fatigue (84%), disordered sleep (82%), and headaches (68%). Pain intensity was rated as moderate to severe (M = 6.3 + 2.4/10). Scores on measures of functioning indicated mild to moderate impairment, with males observed to report significantly greater impairments. For the 37% of the initial cohort having follow-up data available, indicators of function and well-being were found to either worsen over time or remain relatively unchanged.The symptoms of JPFS remained persistent and disabling for many patients treated by pediatric rheumatologists. Further study appears warranted to elucidate gender differences in the impact of JPFS symptoms. Work also is needed to identify accessible and effective outpatient treatment options for JPFS that can be routinely recommended or implemented by pediatric rheumatology providers. Juvenile primary fibromyalgia syndrome (JPFS) is an idiopathic chronic pain syndrome thought to affect up to 6% of children and adolescents –4. CliniKnowledge about effective treatments for JPFS also remains underdeveloped. As a result, wide practice variations may exist in how pediatric rheumatologists treat patients with JPFS. A variety of classes of medications  have been tried for treating symptoms of JPFS despite limited efficacy studies . NonpharImproving knowledge about the full spectrum of characteristics and approaches to treatment of JPFS requires patient data from multiple clinical sites. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry is a prospective observational registry comprising over 9000 youth with rheumatic disease across 50 clinical sites. The current study used data from the CARRA Legacy Registry to: (a) establish the demographic and symptom characteristics of youth with JPFS presenting to pediatric rheumatologists; and (b) identify commonalities and variances in treatment recommendations for JPFS initiated by pediatric rheumatologists. In a subset of patients who returned for follow-up visits, we also sought to determine the extent to which symptoms and functioning change over time.We conducted a retrospective review of data from the CARRA Legacy Registry of JPFS patients enrolled between 2010 and 2014. Eligible patients fulfilled either the 1990 American College of Rheumatology (ACR)  diagnostA general and condition-specific standardized case report form (CRF) was used across registry sites to uniformly collect data on the study measures. Recorded information was manually entered into a registry database by site research coordinators. These data then were securely pooled and stored in an i2b2 data warehouse accessible by approved registry site investigators . The curInformation on self- or parent-reported demographics , diagnosis, date of symptom onset, and date first seen by a pediatric rheumatologist was recorded on standardized CRF at the baseline visit. Patient anthropometrics were recorded and converted to Body Mass Index (BMI).Clinicians completed checklists intended to determine the extent to which common symptoms of JPFS were present in the month leading up to the baseline visit. Checklist items included widespread musculoskeletal pain , frequent headaches, irritable bowel symptoms, subjective soft tissue swelling of the extremities, numbness and tingling of the extremities, pain modulation with physical activity, pain modulation with weather changes, pain modulation by anxiety or stress, a comorbid anxiety and/or depressive disorder, and disordered sleep. If disordered sleep was endorsed, patients were asked to further specify whether they had non-restorative sleep, increased sleep latency, hypersomnia, and/or frequent waking. The presence of hypermobility was recorded if the patient had a Beighton score > 4 on physical exam . The BeiInformation was documented on medications and non-pharmacologic treatments the patient had tried prior to the initial registry visit. Medications were categorized as nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors (SNRIs), gamma-aminobutyric acid (GABA) analogues, and opioids. Non-pharmacologic treatments queried included PT, herbals/supplements, therapeutic massage, meditation, chiropractic, acupuncture/acupressure, yoga, hypnosis, and craniosacral therapy.Average pain intensity over the past week was rated by patients who were at least 10 years of age using a 0–10 numeric rating scale (NRS) (0 = “no pain” and 10 = “very severe pain”). The NRS is a well-established measure for pediatric populations . Parent The Childhood Health Assessment Questionnaire (CHAQ) was completed by patients (or caregiver proxies if patients were less than 10 years of age) as a measure of the impact of fibromyalgia on daily functioning . This quPatients (10 years or older) or caregivers also completed two global ratings pertaining to the patient’s health status . On the Treatments recommended or provided at the baseline visit by a pediatric rheumatologist were documented by the clinician/research nurse on a CRF. Choices appearing on the form included the following: psychoeducation about chronic pain, sleep hygiene education, graduated aerobic exercise, medications for pain, PT, general counseling, cognitive-behavioral therapy (CBT), biofeedback-assisted relaxation training, and other specialty referral .For patients completing the baseline visit and returning for a follow-up visit, the checklists of disease symptoms, pain intensity rating, and functioning and quality of life measures were repeated to gauge stability of these variables over time. Patient adherence to treatment recommendations was also documented, along with reasons for the patient/family not pursuing recommendations if applicable .rbs), chi-square analyses (χ2), or independent samples t-tests as applicable. SPSS® software (IBM) version 24.0 was used for these analyses.Descriptive statistics  were used to summarize data from the baseline visit on patient demographics, symptoms, pain intensity, indices of functioning and well-being, and treatments tried and recommended. Age and sex differences in symptoms, treatments, and the indices of functioning and well-being were explored using point-biserial correlations  was used. Only those in the sample with at least one follow-up visit were included in these analyses. In these models, time elapse since the baseline visit was specified as a predictor of changes in endorsed symptoms, pain intensity, and scores/ratings on the functioning and well-being indices. For the dependent variables that were coded as binary , a logistic model was specified with a Poisson distribution and logit link function . Signifir = −.21, p = .01); no other demographic variables were significantly associated with this time elapse.Table 2 = 5.09, p = 0.03).The most commonly reported symptoms endorsed by patients at the baseline visit included widespread musculoskeletal pain (91%), fatigue (84%), disordered sleep (82%), and headaches (68%). Most patients also reported pain modulation by stress (80%), physical activity (75%), and weather changes (61%). There were no significant age or sex differences in symptoms endorsed except for numbness/tingling, which was more often endorsed in females than males  returned for a follow-up visit with their pediatric rheumatologist between 0.2 to 2.5 years from the baseline visit . The number of follow-up visits available during the time period sampled ranged from 1 (68% of the follow-up sample) to 5 (2% of the follow-up sample). Of the follow-up sample, 82% of patients were female and ranged in age from 9 to 21 years . There were no significant differences in known demographic characteristics between those in the initial cohort who did and did not return for follow-up visits.2 = 7.95, p < 0.01).Table rpb = .20, p < .01), hypnosis , and yoga . The only significant sex difference observed was that males proportionately more often reported use of herbal remedies than females .About two-thirds (67%) of patients reported no prior use of any of the listed non-pharmacologic options. The most common non-pharmacologic treatment tried was PT (21%), and the least common was craniosacral therapy (two patients). Increasing age was modestly but reliably associated with reported use of some of the non-pharmacologic strategies, including meditation (t (199) = 4.12, p < .01). Males were also found to have worse HRQOL when compared to females  = 2.01, p = .04).Pain scores at the baseline visit on average were in the moderate to severe range . Pain ratings did not significantly differ by sex or age. Scores on the functional disability and well-being measures were broad in range but on average indicated mild to moderate impairment . There were no age differences on the functioning and well-being measures. Males were found to be reliably more disabled than females based on the CHAQ measure  of patients/parents reported doing most or all of the treatments recommended from the baseline visit; 28% reported doing some of the recommended treatments, and 4% reported doing none of the recommended treatments. The most common reasons for not pursuing the recommended treatment(s) included disinterest (16%), insurance failing to cover the treatment (8%), and the treatment not being available in the patient’s area (2%).p = 0.01). Otherwise, symptoms reported at the baseline visit remained relatively constant over time. Indicators of function and well-being were found to either worsen over time since the baseline visit  = 2.05, p = 0.04; for subjective well-being: b = 0.65 ± 0.25, t (91) = 2.61, p = .01) or remain relatively consistent  = 0.53, p = .59). Duration of symptoms prior to the first rheumatologist visit did not significantly moderate these results. Whether or not patients reported following initial treatment recommendations also did not moderate these findings. Worsening of subjective well-being over time was found to be even more pronounced in male patients  = 2.63, p = ..01. There were no other significant age or sex differences in changes in symptoms and functioning over time.There was a reduced likelihood of reporting widespread pain over time since the baseline visit  = − 2.53, We sought to determine the demographic, clinical, and treatment characteristics of a representative sample of youth with JPFS patients who seek evaluation and treatment at pediatric rheumatology centers in North America. By virtue of using patient data from a registry in which multiple clinical sites participated, results of this study are thought to be relatively representative and generalizable to clinical samples of JPFS patients.The majority of the JPFS patients in the registry cohort were White, non-Hispanic, adolescent females. These characteristics are similar to those observed in all studies of youth with juvenile fibromyalgia to date , 8, 19. Results from the current study indicate that pain in youth with JPFS is generally rated as moderate to severe in intensity. Stress, physical activity, and weather were identified by the majority of patients as exacerbating pain. Other symptoms found to be most frequently reported included fatigue, disordered sleep, and headaches. Conversely, symptoms more rarely endorsed (reported by less than one-third of the sample) included hypermobility, subjective soft tissue swelling, and IBS. Symptoms were found to be associated with moderate and enduring levels of impairment in functioning and well-being. The phenotypic characteristics observed in this study are largely consistent with data from other studies. In particular, pain scores from the current study (M = 6.3 ± 2.4/10) were comparable to, or slightly higher than, those reported in other studies of JPFS , 19. GenPatients with JPFS reported about an 18 month time elapse on average between onset of symptoms and initial rheumatology evaluation. Other studies similarly have reported that symptoms may be present for many months prior to a correct diagnosis of JPFS , 21. HowTreatments recommended or implemented in pediatric rheumatology for patients with JPFS were partly consistent with evidence-based care . We are For about half of patients, pediatric rheumatologists also reported starting or changing medications. Although some medications  are Federal Drug Administration (FDA) approved for treating fibromyalgia in adults, there are no FDA-approved medications for the treatment of JPFS. There also is weak agreement  on the bResults of this study should be interpreted with consideration of known limitations. Patients enrolled in the registry were seeking treatment in pediatric rheumatology, were able to speak and read English, and were enrolled by a subset of the total sites involved in the overall CARRA Legacy Registry. Thus, the resulting sample still may not be entirely reflective of the general population of youth with JPFS. Additionally, only about one-third of the baseline sample returned to contribute data at follow-up visits. The patients who returned for follow-up visits may be those whose symptoms are most refractory to treatment. If this were the case, the observed maintenance or worsening of symptoms and poor functioning over time may not accurately reflect trajectories of most patients.Measures used to evaluate pain, functioning and well-being in the CARRA Legacy Registry also were selected for use across conditions seen in pediatric rheumatology. Although beneficial for cross-condition comparisons, some measures have less known specificity and utility for chronic pain. For example, whereas the Childhood Health Assessment Questionnaire is sensitive to the self-care and fine motor difficulties that can be common in other pediatric rheumatic diseases, it may not fully capture the range of physical, psychosocial, and academic impairments for youth with JPFS. Relatedly, a single measure of pain (pain intensity) was pragmatic to implement to quantify pain across conditions but does not fully reflect the features and dynamics of pain in JPFS. Use of other patient-reported outcome measures more commonly used in pediatric chronic pain studies to quantify pain and functional limitations, such as pain diaries and the Functional Disability Inventory,  may haveOverall, the current study further establishes that the main symptoms of JPFS are persistent and moderately disabling for many youth, with a subset of patients having minimal improvement despite at least some components of evidence-based care being implemented in pediatric rheumatology. Future research suggested by the study results should further explore gender differences among patients with JFPS, identification of barriers to timely diagnosis and treatment, and identification of effective treatment options to implement in the practice of pediatric rheumatology.


Previous research has demonstrated that patients with borderline personality disorder (BPD) are more sensitive to negative emotions and often show poor cognitive empathy, yet preserved or even superior emotional empathy. However, little is known about the neural correlates of empathy. Here, we examined empathy for pain in 20 patients with BPD and 19 healthy controls (HC) in a functional magnetic resonance imaging (fMRI) study, which comprised an empathy for pain paradigm showing facial emotions prior to hands exposed to painful stimuli. We found a selectively enhanced activation of the right supramarginal gyrus for painful hand pictures following painful facial expressions in BPD patients, and lower activation to nonpainful pictures following angry expressions. Patients with BPD showed less activation in the left supramarginal gyrus when viewing angry facial expressions compared to HC, independent of the pain condition. Moreover, we found differential activation of the left anterior insula, depending on the preceding facial expression exclusively in patients. The findings suggest that empathy for pain becomes selectively enhanced, depending on the emotional context information in patients with BPD. Another preliminary finding was an attenuated response to emotions in patients receiving psychotropic medication compared to unmedicated patients. These effects need to be replicated in larger samples. Together, increased activation during the observation of painful facial expressions seems to reflect emotional hypersensitivity in BPD. Borderline personality disorder (BPD) is a severe psychiatric disorder that occurs in 1% to 6% of the general population –4. MoreoWith regard to social cognition, a growing body of literature suggests that patients with BPD experience difficulties in “mentalizing” (or “cognitive empathy”), which refers to the ability to reflect upon one’s own and others’ mental states in terms of intentions, beliefs, desires, or feelings , 7. In cAs regard the neuronal correlates of these processes in BPD, Dziobek and colleagues examined empathy by using the multifaceted empathy test (MET) in a neuroimaging paradigm. They described decreased activation of the left superior temporal sulcus and gyrus (STS/STG) in BPD associated with cognitive empathy and increased activation of the right middle insular cortex during emotional empathy . MoreoveA novel approach to the study of empathic processes has introduced tasks in which participants are asked to put themselves into the shoes of another individual who experiences somatic pain. Research has shown that psychologically healthy participants activate a neural network comprising brain regions that strongly overlap with those areas that are involved in first-person pain processing. The core areas of this “pain matrix” include the bilateral anterior insular cortex and medial/anterior cingulate cortex, and these regions are also activated when observing someone else in a painful situation , 26. HowIn a recent study, our group aimed to investigate whether the presentation of facial emotions prior to the observed bodily pain affected the activation of the pain matrix . Since tIn the present study, we sought to examine the neuronal correlates of empathy for pain in patients with BPD. Specifically, we were interested in the question whether the presentation of facial expressions of emotions prior to the painful stimulus would alter the empathic response in participants with BPD. Aside from altered general emotional and empathic processing found in patients with BPD , previouDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria  according to  by Ref. ] were reThe Interpersonal Reactivity Index (IRI)  was usedSD = 22.5 s; range 55.2–143.7 s), between run 2 and run 3 106.75 s , and between run 3 and run 4 82.7 s . After each run, participants were asked how well they could empathize by using a visual analog scale. More detailed, participants were asked to rate their success in feeling with the presented character (“empathy character”) and with the presented painful situation (“empathy pain”). Finally, they were asked to rate their current subjective well-being (“well-being”). The paradigm was presented using the “Presentation” software  via MRI-compatible liquid crystal display (LCD) goggles .The paradigm used in the present study was similar to an empathy-for-pain task developed by Lamm and colleagues  and was 2, reconstructed to 320 × 320 mm2, field-of-view 240 × 188.8 × 192 mm3, in-plane resolution 0.8 × 0.8 mm2, slice thickness 0.8 mm, reconstructed to a final voxel size of 0.75 × 0.75 × 0.8 mm³). In total, 240 slices in transverse orientation were acquired . Functional data during the empathy for pain paradigm were collected using T2*-weighted echo-planar imaging (EPI) sequences. Thirty-two slices were acquired in interleaved order parallel to the bicommissural plane. To obtain blood-oxygen level-dependent (BOLD) contrasts, we used a sensitivity encoded single-shot echo-planar imaging protocol . The EPI sequence started with five scans that were discarded due to saturation effects. Every run contained 335 volumes and takes approximately 11 min. In total, participants completed four scanning runs.The fMRI data were recorded using a 3-tesla whole-body MRI system (Philips Achieva 3.0T TX) and a 32-channel SENSE head coil. The MRI scan started with a high-resolution T1-weighted anatomical gradient echo scan (3D TFE: matrix 300 × 235 mmhttp://www.fil.ion.ucl.ac.uk) and MATLAB 7.11 . Preprocessing of the data implies slice timing correction, realignment, coregistration, and normalization with a T1 template provided by Statistical Parametric Mapping (SPM). The images were smoothed with an isotropic 8-mm full-width half-maximum Gaussian kernel, and the final voxel size of resampled images was 2 × 2 × 2 mm³. We applied a high-pass filter  to eliminate low-frequency signal drifts. Based on our previous study  atlas (http://marsbar.sourceforge.net/) for SPM12  atlas  implemenL) atlas . Afterwaor SPM12 . In a moor SPM12 . In the t-tests. For comparison of the frequency of distribution regarding the participant’s handedness, we calculated Fisher’s exact test (two-sided). Behavioral data were investigated using mixed-model ANOVA with the factors presented “facial expression”  and identification of the emotion , that is, the response of participants and the between subject factor group . One-sample t-tests were used to assess whether category ratings differed significantly from the value 50, which was the center of the visual scale and therefore 50 indicates inconclusiveness in attribution of picture descriptions. To investigate whether habituation occurred, we calculated mixed-model ANOVAs with the within-subject factor “run” (runs 1–4) and the between-subject factor group . The ANOVA was calculated for each question separately  and for the reaction time, which was defined as the initial reaction on the first question at the end of each block.Further statistical analyses were performed using “IBM SPSS Statistics for Windows,” version 25 . The differences between groups in questionnaires were examined by independent sample t-tests were used for post hoc comparisons. All ANOVA results reported were Greenhouse–Geisser corrected. According to the work of Costantini et al., we calculated correlations between IRI scores and brain activity during painful conditions only for the supramarginal gyri , facial emotion , and group (BPD/HC), for each region separately. We calculated an additional mixed-model ANOVA including only patients with BPD and the within-subject factors pain condition (pain/no pain) and facial emotion  and the between-subject factor medication (patients with BPD receiving medication and patients free of medication), for each region separately. Dependent and independent nal gyri . In detaWe found significant differences between groups for IRI PT and PD scores see Table 2,F = 9.11, p < 0.001) and identification  = 15.81, p < 0.001) and the interaction facial expression–identification  = 391.40, p < 0.001), indicating selective rating depending on facial expression and identification. Importantly, no main effect or interaction with group appeared, showing that both patients and controls recognized the emotional content equally well. In addition, participants recognized the emotions correctly as indicated by significantly higher ratings than the “inconclusive value” of 50 (angry expressions rated as angry: t(33) = 17.49, p < 0.001; happy expressions rated as happy t(33) = 37.65, p < 0.001; neutral facial expressions rated as neutral t(33) = 7.05, p < 0.001; painful facial expressions rated as painful t(33) = 19.78, p < 0.001). All other comparisons  reached significance with values lower than 50, which stands for rebuttal of the suggested emotion category. In other words, participants did not mistake any emotion for another. For the behavioral results, ratings of one patient and four controls are missing due to timing/technical problems .The mixed-model ANOVA with the factors “facial expression” and “identification” and group revealed a significant main effect of facial expression  = 0.22, p = 0.804; interaction run–group F(1.97) = 1.92, p = 0.156; “empathy pain”: main effect “run”: F = 0.88, p = 0.432; interaction run–group F(2.25) = 1.73, p = 0.181; and “well-being”: main effect “run”: F = 1.52, p = 0.221; interaction run–group F(2.50) = 1.25, p = 0.295). Thus, rating did not change over time and did not differ between groups.The analyses of behavioral data during the fMRI task aimed to check whether participants habituated to the task over the four runs and whether a difference in subjective empathy occurred between patients with BPD and controls. First, the mixed-model ANOVA with the factors “run’’ and “group” did not show any main effects or interactions  = 1.65, p = 0.199; interaction run–group F(2.14) = 0.15, p = 0.875), which indicates that participants attended constantly to the task with no difference between groups.We further compared the reaction time of the initial reaction on the first response screen to check whether participants attended constantly to the task. Here, the ANOVA did not show any main effects or interactions  = 5.92, p = 0.020), the left thalamus  = 7.53, p = 0.030), left supramarginal gyrus  = 29.08, p < 0.001), and right supramarginal gyrus  = 10.84, p = 0.002)  = 2.08, p = 0.045, left thalamus t(38) = 2.909, p = 0.006, left supramarginal gyrus t(38) = 4.86, p < 0.001, and right supramarginal gyrus t(38) = 3.93, p < 0.001).Investigation of the contrast “effect of pain versus no pain” showed activation of the left thalamus, the left anterior insula, and bilateral supramarginal gyri Table 3.F(3.18) = 3.01, p = 0.030) and the right supramarginal gyrus (F(3.63) = 4.71, p = 0.002). Independent t-test showed differences between groups for responses to painful pictures following the presentation of painful faces [painful face+pain] (t(37) = 2.56, p = 0.015) and to nonpainful pictures after angry faces [angry face+no pain] (t(37) = −2.60, p = 0.013) for the right supramarginal gyrus  = −2.16, p = 0.044), [painful face+pain] versus [no emotion+pain] (left insula t(19) = 3.05, p = 0.007; right supramarginal gyrus t(19) = 3.29, p = 0.004), and for [neutral face+pain] versus [no emotion+pain] (left insula t(19) = 4.04, p = 0.001; right supramarginal gyrus t(19) = 2.96, p = 0.008). Further differences were found in the right supramarginal gyrus for [angry face+pain] versus [painful face+pain] (t(19) = −3.22, p = 0.005) and for [painful face+pain] versus [happy face+pain] (t(19) = 2.33, p = 0.031) In the BPD group, we found differences for [angry face+pain] versus [neutral face+pain] in the left insula t(18) = 2.18, p = 0.043), [angry face+no pain] versus [happy face+no pain] (t(18) = 2.57, p = 0.019), and [painful face+no pain] versus [no emotion+no pain] (t(18) = 2.38, p = 0.028) in the right supramarginal gyrus.Significant differences, though to a lesser degree, were also found in the control group, showing differences only within the nonpainful conditions for [neutral face+no pain] versus [no emotion+no pain] (F(3.24) = 6.07, p < 0.001) and the right supramarginal gyrus (F(2.89) = 3.13, p = 0.030). Here, independent t-tests between groups showed a significant difference for angry faces for the left supramarginal gyrus (t(37) = −2.48, p = 0.018; see post hoc comparisons within groups showed differences in activation between the emotions. These differences were apparent in both groups but showed a tendency toward more significant differences between emotions in patients with BPD . Independent t-test of medicated vs. unmedicated patients with BPD further revealed a difference in response to angry, happy, and painful faces (angry t(18) = 4.16, p = 0.001; happy t(18) = 2.47, p = 0.024; painful t(18) = 2.63, p = 0.017; An additional explorative mixed-model ANOVA with the within subject factors pain condition (pain/no pain), facial emotion , and medication (BPD with medication/BPD without medication) revealed a significant interaction of emotion–medication for the right supramarginal gyrus  = 0.409, p = 0.012).Regarding subjective reports, we found a significant correlation between the IRI subscale “perspective taking” and brain activation during “pain” trials  in the right supramarginal gyrus. Due to the small sample size and the uncontrolled nature of the comparisons regarding medication, we caution that these results need to be replicated in larger samples.The current study has several limitations. First, since we recruited only female participants, the results are not generalizable for both genders. Second, we did not include a clinical control group, so, it is unclear whether our findings are specific to BPD. Third, patients with BPD were in an inpatient psychotherapy setting, and we were unable to control for potential therapeutic effects. Fourth, the comorbidity pattern, especially the presence of comorbid depression or posttraumatic stress disorder, may have influenced our findings. Fifth, since we performed the diagnostic interview only with patients, the control group was less carefully examined for potential psychological problems. Finally, the small and heterogeneous sample  may have lowered statistical power. In summary, our study suggests that patients with BPD display heightened sensitivity to another’s somatic pain, especially when the observed pain stimulus is preceded by a painful facial expression. Future research may utilize these insights including the study of longitudinal effects of psychotherapeutic treatment on empathy for physical pain.The authors assert that all procedures contributing to this work comply with the Helsinki Declaration of 1975, as revised in 2008. All participants gave their written informed consent after the nature of the procedures had been fully explained. The study was approved by the Ethics Committee of the Medical Faculty of the Ruhr-University Bochum.VF: Study design, fMRI scanning, data analysis, manuscript writing. BE: Study design, fMRI scanning, data analysis, manuscript writing. MB: Study design, manuscript writing, and editing. All authors have approved the final article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Lateral epicondylitis or tennis elbow is a frequent condition with long-lasting symptoms. In order to identify predictors for treatment success and pain in lateral epicondylitis, we used data from a randomized controlled trial. This trial investigated the efficacy of physiotherapy alone or combined with corticosteroid injection for acute lateral epicondylitis in general practice.The outcomes treatment success and pain score on VAS were assessed at 6, 12, 26 and 52 weeks. We ran a univariate binary logistic regression with generalized estimating equations (GEE) and subsequently an adjusted multilevel logistic regression to analyze the association between potential prognostic indicators and the outcome success/ no success. To assess the changes in pain score we used a two-level multilevel linear regression (MLR) followed by an adjusted MLR model with random effects.The most consistent predictor for reduced treatment success at all time points was a high Pain Free Function Index score signifying more pain on everyday activities. Being on paid sick-leave and having a recurring complaint increased short term treatment success but gave decreased long-term treatment success. The patients reporting symptoms after engaging in probable overuse in an unusual activity, tended towards increased treatment success at all time-points, but significant only at 12 weeks. The most consistent predictor of increased pain at all time points was a higher overall complaints score at baseline.Conclusions: Our results suggest that in treating acute lateral epicondylitis, a consideration of baseline pain, a registration of the patient’s overall complaint on a VAS scale and an assessment of the patient’s perceived performance in everyday activities with the Pain Free Function Index can be useful in identifying patients that will have a more protracted and serious condition.NCT00826462. Date of registration January 22, 2009. The Trial was prospectively registrated.ClinicalTrials.gov Identifier: The online version of this article (10.1186/s12891-019-2758-y) contains supplementary material, which is available to authorized users. Lateral epicondylitis of the elbow is frequently encountered in general practice with an incidence of 5.5-person years . It is cThe objective of this paper was to identify predictors for treatment success and pain relief in acute lateral epicondylitis at 6, 12, 26 and 52 weeks follow-up using data from a recently published treatment study with stringent inclusion criteriae, a family practice setting and a 1-year follow-up .In this paper, we used data from a randomized, controlled study published in 2015 , where wP ≤ 0.20 and P ≤ 0.05 at any of the time points 6 weeks, 12 weeks, 26 weeks and 52 weeks in addition to baseline scores were used to fit two separate final models. Model selection was based on the independence model criterion (QIC), which seeks the model with the smallest estimate. Repeated measurements of pain score were obtained at baseline and at the same four follow-up time points and were assumed to be correlated within a patient. We considered a two-level multilevel linear regression (MLR) model with random effects of time (occasions) as level-1 units and patients at level-2 to assess the changes in pain score. We used the same steps as described above to model pain score. In addition, an estimate of intracluster correlation (ICC) was obtained from the adjusted final fit. The ICC helped to explain the amount of variability in pain score attributable to differences between the patients. At each stage of the model development, the Akaike Information Criteria (AIC) was used to check if the inclusion of a variable or variables improved the model fit. The AIC states that given a set of candidate models for the data, the model with the smallest AIC value should be considered a better fit. Therefore, we used the AIC to select a better fit of pain score. For both outcomes, age and gender were included in the final models as clinically relevant regardless of their significance level. All the models were fitted using StataSE 14 and the significance level of the final models were set at p = 0.05.Treatment success was registered at four follow-up time points . These repeated measurements were assumed to be correlated within a patient. Therefore, analysis methods that assume independence of observations were rendered inappropriate. We modelled the binary response of success/ no success using the binary logistic regression with generalized estimating equations (GEE) to handle the dependence in the data. The exchangeable correlation structure was considered for the GEE binary logistic models. First, we assessed the effects of each patient-level prognostic factor on success over time. Secondly, all prognostic factors in step 1 with The baseline characteristics of the patients are presented in Table The mean age at baseline was 47 years, 40% were women, and the mean duration of complaints was 7 weeks. The registered pain score on VAS was 52, the Pain Free Function score was 5.8 and the variable Overall complaints on VAS was 64. The effect of prognostic variables on treatment success is presented in Additional file Patients on paid sick leave at baseline and those having had epicondylitis earlier at baseline were more likely to have treatment success at 6 weeks follow-up  were less likely to have treatment success at 52 weeks Additional file 2:Table S3. Adjusted multilevel logistic regression showing the effects of each prognostic indicator on treatment success . (PDF 96 kb)Additional file 3:Table S4. Univariate multilevel linear regression (MLR) showing the effects of each prognostic indicator on Pain Score (VAS) at each study time point after adjusting for baseline pain on VAS. (PDF 114 kb)Additional file 4:Table S5. Adjusted MLR showing the effects of each prognostic indicator on pain (VAS) at each study time point . (PDF 192 kb)


N = 2642) and nine total RCTs (N = 1320). Using a maximum likelihood method, we estimated weekly pain scores for pregabalin-treated patients for each cluster (matched dataset); the models were validated with RCT data that did not match with OS data. We predicted novel ‘virtual’ patient pain scores over time using simulations including instance-based machine learning techniques to assign novel patients to a cluster, then applying cluster-specific regressions to predict pain response trajectories. Six clusters were identified according to baseline variables . CEM yielded 1766 patients (matched dataset) having lower covariate imbalances. Regression models for pain performed well . Simulations showed positive predictive values for achieving >50% and >30% change-from-baseline pain score improvements . Using more RCTs (nine vs. the earlier three) enabled matching of 46.7% more patients in the OS dataset, with substantially reduced global imbalance vs. not matching. This larger RCT pool covered 66.8% of possible patient characteristic combinations  and made prediction possible for a broader spectrum of patients.Prior work applied hierarchical clustering, coarsened exact matching (CEM), time series regressions with lagged variables as inputs, and microsimulation to data from three randomized clinical trials (RCTs) and a large German observational study (OS) to predict pregabalin pain reduction outcomes for patients with painful diabetic peripheral neuropathy. Here, data were added from six RCTs to reduce covariate bias of the same OS and improve accuracy and/or increase the variety of patients for pain response prediction. Using hierarchical cluster analysis and CEM, a matched dataset was created from the OS : NCT00156078, NCT00159679, NCT00143156, NCT00553475. Diabetes affects approximately 8.8% of adults worldwide , and aroPromising approaches to treatment optimization may be identified more efficiently through integration of randomized controlled trial (RCT) data with non-randomized data . Such inPreviously, we used data from three existing international RCTs and a large observational study (OS) in Germany  to asseswww.clinicaltrials.gov registration numbers: NCT00156078, NCT00159679, NCT00143156, and NCT00553475; the other trials were not registered on www.clinicaltrials.gov) [no pain and 10 = worst possible pain] over a 7-day baseline period; and have a score ≥40 mm on the 0–100 mm visual analog scale of the Short-Form McGill Pain Questionnaire at screening and randomization . Hence, the Virtual Lab included a capability for estimating whether a candidate novel patient would maintain or modify beyond the end of week 6 his/her responder status achieved at the end of week 6. We accomplished extrapolation of responder status by focusing on the monotonicity of pain trajectories. Monotonicity is a measure of the extent to which a trajectory monotonically increases or decreases  yielded six clusters (195–626 patients each) based on the semipartial clusters  with theThe OS covered 69.3% of the 192 possible combinations of the following characteristics: gender, age group , BMI group , insulin use, prior gabapentin use, and pain categories at baseline divided into moderate (4–6) or severe (7–10). The nine RCTs and the combined dataset covered 66.1% and 76.6%, respectively, of the 192 possible combinations of these patient characteristics.The Fisher’s exact test results  for the Matched dataset used for regression model calibration: gender, insulin use, past or current medical history of depression, prior gabapentin use, and pregabalin monotherapy;Validation dataset used for initial regression model evaluation: insulin use, prior gabapentin use, and pregabalin monotherapy; andMatched vs. Unmatched datasets: gender, age group, BMI group, insulin use, PRSI score at baseline, and pregabalin monotherapy.R2 ranging from 0.97 to 0.98, and root mean square errors ranging from 0.47 to 0.51 . When comparing observed pain scores in the validation dataset with those predicted using the regression models derived from the calibration dataset, two-sample t-tests found statistical similarity for all clusters . The regressions of the scatterplots of observed vs. predicted pain scores showed R2 values of 0.97, 0.98, 0.98, 0.98, 0.98, and 0.97 for clusters 1–6, respectively ; (b) decreased pain: 11.3% of patients were not responders at week 6 but became responders by week 12 or 13 (N = 106); and (c) maintained pain response from weeks 6 to 12–13: 81.2% of patients did not change their responder status between weeks 6 and week 12 or 13 (N = 358 for responders and N = 404 for non-responders) (n = 106), maintained pain response from weeks 6 to 12–13 (n = 358+404 = 762), increased pain (n = 71)] and the lowest standard deviation of the mean monotonicity.Results for the monotonicity analysis were based on the following patient groups: (a) increased pain: 7.6% of patients were responders at week 6 and became non-responders at week 12 or 13 (ponders) . We lookThe accuracy for how well we could correctly predict whether a patient would further decrease his/her pain score, maintain his/her pain score, or increase his/her pain from 6 to 12–13 weeks was 82.4%, 71.9%, and 89.5%, respectively. These results demonstrate the potential value of integrating patient data from RCT and OS sources and developing subgroup-specific regressions for prediction of therapeutic response (discussed further below). The inclusion of additional RCTs in this analysis enabled a 46.7% increase in matched OS patients (from 1204 to 1766) compared with earlier work. A high degree of imbalance often occurs in OSs because their assignments to treatments are not random. A reduction of this imbalance can be achieved, however, through a matching of OS patients with those from relevant RCTs in which the covariates are, in principle, more highly balanced owing to the randomized design. Matching is thus intended to identify a better balance in the multidimensional distribution of covariates, resulting in the lower covariate bias desired to establish better explanatory models of potential causal relationships among measured variables . Global full of energy, calm and relaxed, sad and discouraged), but rather varied in their combinations. A few were present in isolation , but they were found in various proportions in the remaining clusters. These findings demonstrate the substantial level of complexity and interaction among variables and underscore the challenge facing clinicians who are selecting appropriate treatment and dose for individual patients. The need to process enormous amounts of disparate clinical information (in the absence of effective modeling tools) may explain why clinicians often experience a great degree of uncertainty, but might also depend upon intuition rather than on a clearly defined rationale about which patients are likely to respond better to certain therapeutic approaches. For example, one could assume that the existence of females in one cluster suggests that a subgroup of females might be similar; however, most of the females are spread across five subgroups. Thus, the trait of being female combined with other characteristics is what defines their placement within a specific cluster.Consistent with prior work, the heterogeneity of patients with pDPN was confirmed by the existence, in the OS, of six clusters of patients defined by different patterns of patient variables . Most baThere were 50% pain responders and non-responders in every cluster, and all treatment doses were present in all clusters. The clusters were quite similar to the clusters from the prior work; however, there were fewer instances of clusters with only one state for the dichotomous variables. This finding might be due to the change from using Euclidean distance to Gower distance, with its ability to better identify distances with different types of variables.patterns of variables in each cluster. Some overlap was found in pairwise comparisons for some clusters within the matched OS patient dataset, within the unmatched OS patient dataset , and between the two datasets. As with the prior work, dose was not influential in defining a cluster; however, based on its presence in the majority of the cluster-specific regression equations, dose plays an important role in predicting whether a patient is likely to respond to pregabalin therapy. Since some patients require titration above a 300 mg dose and others do not [12, 13}, it is not surprising that titration was not predictive in all of the cluster-specific regressions.The pairwise comparison of variables in the six clusters  supporteR2 and root mean square error results for the regressions  even though we lacked OS data for this time period. Overall, 81.2% of the patients who had or had not achieved a 50% pain reduction at 6 weeks maintained that outcome at 12 or 13 weeks . Thus, wThese results demonstrate the potential utility of integrating patient data from RCT and OS sources to identify patient subpopulations that will manifest different degrees of therapeutic response to a particular treatment. We have shown how a combination of carefully selected modeling and microsimulation approaches can be used to predict which patients with pDPN may have a higher probability of responding to pregabalin and at which dose. These findings also highlight the importance of tracking changes over time in certain variables  after the initiation of treatment in order to adjust baseline predictions accordingly. The use of ABMS provided a mechanism for introducing patient variability into the analyses by integrating the on-treatment variables that changed over time with fixed patient characteristics and simulating the resulting on-treatment pain response. Future research can explore the range of potential applications for this approach of clustering, matching, and time series regressions with lagged variables as inputs.A limitation of our analyses is that for all studies included, we used data only from those subjects who completed the studies, so more work would be needed to determine if the results are generalizable to other patient populations . However, prior studies that occurred over a decade have found that treatment-emergent adverse events in pregabalin-treated patients infrequently lead to discontinuation  and thatSubsequent Virtual Lab work will focus on predicting discontinuations and adverse events using these same approaches, along with refining how we predict outcomes beyond 6 weeks. Also, we have not yet tried prospectively to predict actual new patient outcomes using our platform. Future work will need to examine how such efforts could work in actual practice. We need to explore how the proposed approach, including a capability for dynamic real-time updates, could be used in providing care to patients. Finally, these findings are specific to patients with pDPN, and not all patient variables associated with pDPN have yet been studied. Other clinical circumstances may require less or more complex approaches to enable prediction.The inclusion of data from six additional RCTs expanded the combinations of patient characteristics and outcomes that could be predicted using our methodological approach . In addition, matching of substantially more RCT patients to OS patients strengthened the representativeness of OS patients while maintaining strong overall predictive power. These analyses reinforced the predictive value of utilizing patient subgroups that reflect more complex patterns of fixed patient characteristics and ‘on-treatment’ variables that change over time.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig(A) Virtual Lab 2.0. (B) Virtual Lab 1.0.(TIF)Click here for additional data file.


The current longitudinal study aimed to reveal the neural correlates of changes in pain-related fear as a result of EXP. Twenty-three patients with cLBP were included in this study. Patients with cLBP underwent MRI scanning pre-treatment (pre-EXP), post-treatment (post-EXP), and 6 months after end of treatment (FU-EXP). Pain-free controls were scanned at two time points. In the scanner, participants were presented with pictures involving back-related movements, evoking pain-related fear in patients. Pre-treatment, functional MRI revealed increased activation in right posterior insula and increased deactivation in medial prefrontal cortex (mPFC) in patients compared to controls. Post-treatment, patients reported reduced fear and pre-EXP group differences were no longer present. Contrasting pre- to post- and FU-EXP in patients revealed that stimulus-evoked neural responses changed in sensorimotor as well as cognitive/affective brain regions. Lastly, exploratory analyses revealed a tendency toward an association between changes in neural activation and changes in fear ratings, including the hippocampus and temporal lobe (pre- to post-EXP changes), and mPFC and posterior cingulate cortex (pre- to FU-EXP changes). Taken together, we show evidence that neural circuitry for pain-related fear is modulated by EXP, and that changes are associated with self-reported decreases in pain-related fear.Exposure  While most of us experience acute low back pain at some point in our lives, some will develop chronic low back pain (cLBP), with persistent pain lasting more than 6 months. An estimated one in five adults is currently in chronic pain, with cLBP being the most common  and the in vivo (EXP) was developed. EXP is a cognitive-behavioral treatment based on experimental work showing that exposure to fearful activities and movements, rather than avoiding them, challenges catastrophic pain beliefs and can result in the extinction of fears and maladaptive responses  that were considered to be of particular interest due to their involvement in pain-related fear and experimental extinction learning  and/or pain chronification . We expected (I) pre-treatment group differences in neural circuitry recruited by stimuli evoking pain-related fear, correlated to fear ratings as well as pain-related outcomes in patients; (II) patient-specific pre- to post-treatment changes in regions showing pre-treatment group differences, as well as in other brain regions associated with chronic pain and with extinction ; (III) pre- to post-treatment changes associated with changes in fear and persisting at 6 months follow-up.Therefore, the current longitudinal fMRI study tested the hypothesis that EXP acts upon the neural circuitry involved in pain-related fear, using a task designed to evoke pain-related fear. We compared patients with cLBP with pain-free volunteers pre- and post-EXP treatment; the cLBP group was also examined 6 months after end of treatment. We evaluated group differences and treatment effects in evoked brain activation. Also, more exploratively, we used (changes in) fear ratings to identify neural correlates specific to (reductions in) pain-related fear. A whole-brain approach was adopted in combination with analyses in ClinicalTrials.gov [NCT02347579]. Patient recruitment was done via the department of Rehabilitation Medicine at MUMC+/Adelante rehabilitation center where patients were seen for consultation. If patients were found motivated for rehabilitation treatment and eligible for the multi-disciplinary pain screening program, they were invited by the physiatrist for the study. Recruitment was open between January 2015 and August 2017.This study presents data of a larger study investigating effects of EXP on chronic pain, “BrainEXPain”. BrainEXPain was approved by the Medical Ethical Committee of Maastricht University Hospital/Maastricht University (MUMC+/UM), and the protocol is registered at 1). The first study visit was scheduled prior to any (information on) treatment . Afterward, patients underwent a multi-disciplinary pain screening and pain education, and started the exposure sessions (if eligible for treatment) – which were all part of standard care. At the end of treatment, patients underwent a post-EXP and a follow-up study visit . Healthy controls participated in two study visits, with the time in between these visits matching the patients’ pre- to post-EXP. Participants received €15 per study visit and travel reimbursement for their participation.Participants were then contacted by the research team and were screened for in- and exclusion criteria. Informed consent was obtained at study enrollment. Prior to scanning, all participants filled in questionnaires online , and severe psychopathology (Symptom Check List-90). Of the 35 patients with cLBP invited by the physiatrist over the 2.5 years inclusion period, 23 patients with cLBP were included in BrainEXPain . Of these, three patients dropped out prior to or during the measurement (due to claustrophobia); of two patients the data analyzed here was not acquired due to technical error; three patients were excluded due to extensive motion ; and one patient was excluded due to lack of any vision-related  activity . The final sample for this study therefore consisted of 14 patients . A detailed description of the exposure-protocol for pain-related fear can be found in 2 min walking test, participants walked for 2 min on a standardized track and the covered distance was measured in meters. During staircase walking, participants walked a complete staircase (up and down), after which the average time per step was calculated.At all time-points we assessed: pain intensity using a 0–10 visual analog scale anchored with “no pain at all” and “worst pain imaginable”; pain-related fear using the PHODA short electronic version for low back , and TamIn the scanner, the participants were presented with visual stimuli, associated with one of three categories: rest (derived from a web-search – REST), movements and activities perceived as fearful for patients specifically , or pictures implying bodily damage that may be perceived as fearful in general . After a short delay (see MRI data were collected using a 3 Tesla whole body MRI scanner (Philips Gyroscan Achieva TX) using a 32-channel head coil, at the department of Radiology at MUMC+.∗-weighted standard echo-planar imaging (EPI) sequence was used to acquire 40 axial slices (3 mm isotropic) covering the entire cortical volume, using the following parameters: repetition time (TR) = 2000 ms, echo time (TE) = 25 ms, flip angle = 75°, matrix size = 120 × 240, SENSE factor = 2. In total, 225 functional volumes were collected, of which the first two volumes were dummy volumes that were discarded from subsequent analysis to avoid T1 saturation effects.For the functional images, a T2T1-weighted anatomical images were acquired using a 3D turbo field echo (TFE) sequence with the following parameters: 170 slices, 1 mm isotropic, TR = 8.1 ms, TE = 3.7 ms, flip angle = 8°, matrix size = 240 × 240.Questionnaire and performance test data were analyzed using SPSS (version 24). A general linear model (GLM) with Group  as between-subjects (BS) factor was used to examine group differences pre-EXP, as well as post-EXP. In addition, a repeated measures (rmGLM) with Time  as a within-subjects (WS) factor was used to investigate changes over time.Group comparisons in in-scanner fear ratings, focusing on MOVEMENT pictures, were evaluated using a rmGLM with Group  as BS factor and Picture Number (7 different Pictures per Category) as WS factor. In addition, the WS factor Time  was added in a separate analysis.MRI data analysis was performed using BrainVoyager 3.6 . Pre-processing of the functional data included slice scan time correction, 3D head motion correction, linear trend removal, high-pass filtering , and spatial smoothing [4 mm using a full-width at half-maximum Gaussian kernel (FWHM)]. Data was then co-registered to the corresponding anatomical image, and normalized to MNI space. The three pictures categories  plus the delay prior to the rating  were used as predictors, convolved with the hemodynamic response function (HRF). Additional information on denoising procedures can be found in x = 1, y = –29, z = –10 ]. In these ROI masks, FDR correction [q(FDR) < 0.05] and minimum cluster size of 4 voxels (108 mm3) was used for statistical thresholding.Whole-brain analyses were run within a mask that excluded the white matter and cerebral spinal fluid, based on the Harvard-Oxford atlases (probability threshold 0.25) . To specq(FDR) < 0.05] was used for map creation. In the whole-brain analysis, an initial threshold of p < 0.001 was used for contrasts across Groups and Times, after which cluster-size thresholding was performed using MonteCarlo simulations (n = 1000) to correct maps at the level of alpha 0.05. The main contrast of interest was MOVEMENT vs. baseline, plus effects of Group and Time herein, as this condition was designed to elicit pain-related fear specifically in the patient group.To compare blood-oxygen-level dependent (BOLD) responses across Groups and Times, a univariate random-effects (RFX) analysis with separate subject predictors was run at the first level, after which this data was fed into a second-level RFX analysis where group maps could be estimated and contrasted. FDR correction , where patients reported higher fear levels compared to controls  (The in-scanner fear ratings for MOVEMENT pictures showed a significant Group effect , with a significant decrease in ratings between pre- and post-EXP  and between pre- and FU-EXP , but no difference between post-EXP and FU-EXP   = 0.31, p = 0.59, ηp2 = 0.03].There was no significant effect of Time . Simple effects per time point showed that at post-EXP, there was no longer a Group difference .There was a significant Time x Group interaction , explained by a linearly decreasing response to MOVEMENT pictures over Time . The mPFC only showed a marginally significant main effect of Time , explained by linearly increasing response to MOVEMENT pictures over Time  . None of the predefined ROIs showed a group difference post-EXP. In addition, when performing a Group comparison of the extracted betas from these ROIs, no group difference was identified at post-EXP .Post-treatment, no group differences were present anymore in the whole-brain analysis  and the left temporal pole   and to decreases in pain-related disability from pre- to post-EXP .We explored whether changes in fear ratings for the MOVEMENT pictures from pre- to post-treatment were associated with specific changes in BOLD activation from pre- to post-treatment in patients. We found indications that a decrease in fear ratings from pre- to post-treatment was correlated to an increase of neural activation in the right hippocampus (MNI mm3) see . When exx = 6, y = –55, z = 10, k = 407 mm3) and mPFC . The right PCC betas additionally showed significant correlations to decreases in pain-related fear from pre- to FU-EXP . The decrease in fear ratings from pre- to FU-EXP was furthermore related to an increase in right PCC  = 0.35, p = 0.71, ηp2 = 0.04; temporal pole: F = 0.03, p = 0.94, ηp2 = 0.004; PCC: F = 2.87, p = 0.10, ηp2 = 0.26; mPFC: F = 0.29, p = 0.69, ηp2 = 0.04].None of these clusters showed a main effect of Time [hippocampus: We provide the first evidence that clinical improvements following EXP in patients with cLBP are mirrored by changes in the neural circuitry for pain-related fear, the main target of EXP. Pre-treatment, we identified group differences in in-scanner fear ratings and neural responses to pictures of back-specific movements: compared to pain-free controls, patients with cLBP showed increased activation in the right posterior insula and increased deactivation in mPFC. Post-treatment, group differences were no longer present, and the process of change continued in patients at 6 months follow-up. Apart from general changes across treatment in lateral PFC, PCC, precuneus, NAc, and pre- and post-central gyrus, patients showed neural changes specifically related to changes in in-scanner fear ratings in the temporal pole, mPFC, PCC, and hippocampus. Pain-free volunteers did not show this, indicating that these changes cannot be attributed to general habituation effects. Hence, we provide evidence for treatment-induced neural changes in chronic pain that are specific to and correlate with improvements in self-reported fear.As expected, after EXP treatment, pain-related fear and disability significantly decreased while the patient’s performance  improved significantly. Changes were maintained, or in some cases even more pronounced, 6 months after the end of treatment. We did not observe a significant effect of EXP on pain intensity, which is not uncommon nor unexpected. EXP focuses on reducing pain-related disabilities and reducing pain intensity is no explicit aim. Some studies, however, have observed significant improvements in pain intensity on a group level , and alsWe identified two brain regions showing a group difference in neural responses to pain-related fear. In the right posterior insula and mPFC, patients with cLBP showed altered neural activation compared to controls in response to our fear-evoking task. Focusing on pain-related fear, previous studies have demonstrated increased activation in the insula, as well as in other in regions including the ACC, superior parietal cortex, amygdala, orbitofrontal cortex, and striatum in patients compared to controls . A potenThe mPFC, and more specifically its ventromedial part (vmPFC), is also a core region involved in fear acquisition and extinction , and genThe increased posterior insula response to our stimuli in patients pre-treatment was reduced over the course of EXP, as was the increased mPFC deactivation. Importantly, we no longer observed group differences post-treatment. This is in accordance with normalizations observed in fear ratings as well as in most clinical measures. Treatment effects were still present or even increased at 6 months follow-up, suggesting generalization to daily life. This is in accordance with a recent RCT in complex regional pain syndrome, where EXP effect sizes were larger at 6 months follow up compared to post-treatment .pre- and post-central gyrus/supramarginal gyrus, we observed decreases from pre- to post-EXP and from pre-EXP to follow-up. Recruitment of these areas associated with motor control, sensory properties of somatosensory stimuli , involved in interoception, mentalizing, integrating information more than processing it , which we consider fair given the additional constraints of the analysis. Also note that these regions did not show main effects across treatment, suggesting individual rather than group-level differences. Future analyses will have to investigate whether there are functional connectivity alterations between mPFC and amygdala, which would be the hypothesized mechanism of extinction . However, most importantly, time-dependent changes in these regions were specific to this category . FinallyWe show the first evidence that clinical improvements in chronic pain following EXP treatment are mirrored by changes in pain-related fear neural circuitry. Group differences identified prior to treatment were no longer present after treatment. Time-dependent effects in patients continued up to 6 months after the end of EXP, and involved regions implicated in cognitive/affective, motivational as well as sensory aspects related to pain. This suggests that the effects of EXP are long-term and go above and beyond modulating fear circuitry. Lastly, explorative analyses found indications that brain regions implicated in fear extinction -including the hippocampus, PCC and mPFC- changed their neural response proportionate to the change in self-reported fear, suggesting that extinction during EXP may reflect similar working mechanisms as extinction in experimental settings. Taken together, our findings show that neural circuitry for pain-related fear is modulated by EXP, and that changes are associated with self-reported improvements in pain-related fear.The datasets generated for this study are available on reasonable request to the corresponding author.This study involving human participants was reviewed and approved by the Medical Ethical Committee of Maastricht University Hospital/Maastricht University (MUMC+/UM). All participants provided their written informed consent to participate in this study.IT, JJ, MG, JV, RS, and AK contributed to the conception and design of the study. IT and AK acquired the data and contributed to the data analysis plan. IT performed the data analysis and wrote the manuscript. All authors contributed to the manuscript, and read and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Sickle cell disease (SCD) is a hereditary blood disorder associated with many life-threatening comorbidities including cerebral stroke and chronic pain. The long-term effects of this disease may therefore affect the global brain network which is not clearly understood. We performed graph theory analysis of functional networks using non-invasive fMRI and high resolution EEG on thirty-one SCD patients and sixteen healthy controls. Resting state data were analyzed to determine differences between controls and patients with less severe and more severe sickle cell related pain. fMRI results showed that patients with higher pain severity had lower clustering coefficients and local efficiency. The neural network of the more severe patient group behaved like a random network when performing a targeted attack network analysis. EEG results showed the beta1 band had similar results to fMRI resting state data. Our data show that SCD affects the brain on a global level and that graph theory analysis can differentiate between patients with different levels of pain severity. •Graph theory used to study global impact of long term sickle cell disease on brain.•EEG and fMRI results compared to study spatial and temporal impact of disease.•More severe patients have less clustering and efficiency.•Small world values correlated with past hospitalizations, linking results to pain. AdditioFew groups have investigated abnormalities of brain connectivity in SCD patients. Increased functional connectivity to pain processing regions in these patients such as the anterior cingulate cortex, primary somatosensory cortex and periaqueductal gray matter has been reported . AlteredPrevious studies have mainly focused on specific areas related to pain processing or well-known resting state networks . We tookTherefore, we examined the effect of chronic pain and severity of SCD on brain networks using graph theory. This study was entirely data driven: regions included in a standard brain atlas were included in order to study the global brain network. Imaging was performed using both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) in order to provide high spatial and temporal resolution of resting state data. We hypothesize that graph theory would detect differences in network connectivity between healthy controls and patients, and differences among patients with less and more severe disease. Prospectively, we investigated how chronic pain can influence network connectivity. We hypothesize that greater pain intensity would cause more dysfunction in the brain network causing less organization and reduced efficiency in the network.22.1clinicaltrials.gov (registration number was NCT02212691). The patient group includes thirty-one SCD patients recruited across two sites including the University of Minnesota  and Children's National (Washington DC). Approvals from the Institutional Review Boards at the University of Minnesota and at Children's National were obtained prior to the start of the study. All patients were recruited by hematologists and gave written informed consent before participating in the study. Participants under the age of eighteen gave assent and their parent or legal guardian gave written informed consent. Written informed consent was also obtained from participants to have the research staff access medical history to obtain clinical parameters relating to the patient's general health and disease severity history, where a summary of these parameters is displayed in This study was registered as “Functional Neuroimaging of Pain Using EEG and fMRI” at n = 15, 8 female, 7 male, average age 21.4 ± 5.7 years), and patients with eight or more visits were in the more severe group . Eight visits were selected because it was the median value of the patient group. This allowed us to split the patients evenly among the two groups. Resting state fMRI data was recorded for all patients. However, due to impedance issues with EEG, two patients were removed from the resting state EEG analysis. As a result the group parameters for the total patient group , less severe group , and more severe group  changed slightly.Thirty-one patients participated in this study . Twenty-one patients were recruited at the University of Minnesota and 10 patients were recruited from the Children's National. Patients were separated into two groups based on their medical history. The sum of the number of hospitalizations and the number of emergency department visits in the past two years was used to group patients as less severe or more severe related sickle pain. Patients with less than eight total visits were placed in the less severe group  who voluntarily participated in the study. The ethnicity of the control group was diverse with 6 African Americans, 6 Caucasians, 3 Asians, and 1 Hispanic. The healthy controls were all screened prior to participation to ensure none had neurological diseases, psychiatric diseases, or chronic pain conditions. Written informed consent was obtained from each control prior to participation in the study. Resting state fMRI was recorded from all healthy controls; however, one control was removed from the EEG resting state analysis due to noise. Fifteen subjects  had EEG data and were included in the analysis. The control group did not participate in the thermal pain part of this study.2.3All of the participants in this study completed resting state fMRI acquisition and EEG recording  with a sixteen channel head coil was used to record fMRI data on fourteen subjects. The remaining seven patients recruited at the University of Minnesota used a 3 T Siemens Magnetom Prisma scanner  with a twenty channel head coil for fMRI recordings because of upgrades done at the Center for Magnetic Resonance Research. Anatomical MRI data were obtained for each patient, using a high-resolution T1 sequence with 240 contiguous sagittal slices . For functional scans, whole-brain images with blood-oxygen-level-dependent contrast were attained using a gradient echo planar imaging sequence . No MR angiography or T2 imaging was performed in this study.For experiments conducted at Children's National, a 3 T GE Discovery MR750 scanner  with a thirty-two channel head coil was used to obtain fMRI data from ten patients. Anatomical MRI data was obtained using a high-resolution T1 sequence with 360 contiguous sagittal slices . For functional scans, whole-brain images with blood-oxygen-level-dependent contrast were attained using a gradient echo planar imaging sequence .The preprocessing steps used in this study have been previously described . Essenti2.5For resting state experiments conducted at the University of Minnesota, a 64 channel MR-compatible BrainProducts EEG system was used . For resting state experiments conducted at Children's National, a 64 channel Neuroscan system was used . For thermal pain experiments, a 128 channel BioSemi Active-II EEG system was used . All electrode impedances were below 20 kΩ and all EEG data was recorded at 1 kHz.The EEG data was processed using the EEGLAB toolbox . Visual 2.6G = , where N represents the nodes or brain regions and E represents the edges or functional connections between brain regions. To eliminate potential bias, the overall functional connectivity of each subject was found. There was a significant difference between the less severe and more severe groups, and so a subset group was created that matched functional connectivity across groups  for when all subjects were included, p = .03) and the more severe group (p = .05) for the subset group analysis. This indicates that patients not only have functional neural dynamics, but also anatomical anomalies as well, which may contribute to the disruptions observed in the graph theory analysis.The gray matter voxel count did not show any significant differences between any of the groups, 4We have investigated the long-term effects of SCD severity and pain on brain dynamics using non-invasive neuroimaging by means of graph theory analysis. Significant differences were observed between the three groups . Specifically, fMRI showed that the more severe patients had less clustering coefficient and local efficiency values and behaved closer to a random network during a targeted attack. EEG source imaging demonstrated that controls significantly differed from the patient groups in the beta1 band. To our knowledge, this is the first study that uses graph theory to study the global brain network in sickle cell patients utilizing both EEG and fMRI recordings.The fMRI results found that more severe patients have reduced local efficiency and clustering coefficient compared to controls and less severe patients indicating sickle pain severity impacts global brain dynamics. Altered graph parameter values may reflect why some SCD patients have reduced cognitive abilities compared to controls . SCD patSmall world networks tend to have high clustering and low path lengths, which makes them a robust and efficient network . The smaSeveral graph parameters were correlated with the number of hospitalizations, an indirect measure of chronic pain history , during This study included both fMRI and EEG analysis for resting state data to compare how the two modalities performed. The EEG resting state data indicated significant differences only within the beta1 band. Notably, in Alzheimer's disease, a similar phenomenon was observed where beta band reflected results observed in fMRI, where patients have decreased clustering coefficient and increased path length . The betOur study has several limitations. We did not impose constraints on how long patients should abstain from taking medication prior to the experiment as it would be unethical to hold treatment for pain for a research study. This introduces a confounder, as the role of pain medication in network alteration cannot be determined. The control group was not ethnically matched to the patient groups; however, the group was ethnically diverse and a large portion of controls were African American. Other complications of SCD, such as ischemia, could cause differences in neural signals. However, we are confident our results reflect neural activity as the graph parameters showed a correlation with the number of hospitalizations and expected trends were found in the induced pain study. The lack of neuropsychology testing is another limitation as we cannot determine if other comorbidities associated with chronic pain, such as depression and anxiety, contribute to the results. Since T2 FLAIR imaging was not performed in this study, we cannot comment on the possible impact of silent cerebral infarctions on the brain network differences observed in our patients. Finally, the settings for fMRI were not the same at the two different locations. This could affect the contrast of the T1 images. An ANOVA test was conducted to determine if the overall functional connectivity was different between the two locations and no significant differences were found. Despite these limitations, we demonstrated significant differences between patients with less severe and more severe disease related pain as well as between patients and controls. We additionally showed correlations between graph parameters and hospitalizations, which reflects pain burden. Our results should be interpreted with caution, but our study provides a foundation for further exploring the long-term impacts of this disease on brain network.5This study demonstrates that graph theory can be used to assess the overall brain network of SCD patients. It is noteworthy that we found a significant difference between patients and controls, as well as between patients with less severe and more severe SCD, indicating the sensitivity and robustness of this novel non-invasive technique in determining brain function in SCD. Our graph theory results show the impact of long term chronic pain and disease severity on the brain, as the nodes with significant differences in clustering coefficient are not isolated to pain regions or major resting state network nodes. These results further support that SCD affects brain function . Neurolo


Penicillin G Benzathine (PGB) is the cornerstone of syphilis treatment. However, its intramuscular (IM) administration is associated with pain at the site of injection. The dilution of PGB with local anesthetics is recommended in some guidelines, but the evidence that supports it, particularly in adults and in HIV infection, is scarce. Preliminary clinical experience also suggests that the IM administration of PGB through increased needle gauges might improve its tolerability. The aim of the study to identify less painful ways of administering IM PGB in the treatment of syphilis in adults.Multicenter, randomized, double-blinded clinical trial in patients diagnosed with primary syphilis that required a single IM injection of PGB 2400,00 IU. Patients were randomized to receive PGB diluted with 0.5 mL mepivacaine 1% (MV) or PGB alone, and both groups either with a long 19G or short 21G IM needle. The primary objective was the effect on local pain immediately after the administration through a visual scale questionnaire on pain (0 to 10).p < 0.001; and also between short 21G group with anesthesia (MPI 3.36 [CI 95% 2.22-4.50]) vs short 21G without anesthesia (MPI 5.06 [CI 95% 3.93-6.19]), p = 0.015). No significant differences in immediate pain were observed between 19G and 21G in the presence or absence of anesthesia (p = 1.0 in both cases). No differences were found between study arms after 6 and 24 h.One hundred eight patients were included, 27 in each group. Ninety-four (94.4%) were male, and 41.7% were also HIV-infected. Mean age 36.6 years (SD 11). Significant differences in immediate pain intensity were observed when comparing the long 19G group with anesthesia  vs long 19G without anesthesia (MPI 5.56 [CI 95% 4.39-6.73), The IM administration of 1% mepivacaine-diluted PGB induces significantly less immediate local pain as compared to PGB alone. The needle gauge did not have any effect on the pain. Based on these results, we suggest anesthetic-diluted IM PGB as the standard treatment for primary syphilis.EudraCT 2014-003969-24 (Date of registration 18/09/2014). Intramuscular (IM) Penicillin G Benzathine (PGB) is the cornerstone of the treatment of primary syphilis , but itsWe conducted a randomized, double-blind clinical trial at two sites in Madrid  or PGB alone, and both groups either with a long 19G (long) or short 21G (short) IM needle. The study was performed during the first half of 2015. All patients signed informed consent. The study was approved by the local institutional review board  with approval number CEIC#14/376, and registered at the EU Clinical Trials Register with EudraCT Number: 2014-003969-24. The Consort flow diagram of the study is presented in Fig. Eligible subjects were 18 years of age or older diagnosed with primary syphilis; this diagnosis was based on both clinical and positive serological test results . Syphilis treatment required one IM dose of PGB 2400,000 million units . We excluded patients with any sensory perception diagnosis or cognitive impairment unable to understand or evaluate the visual analog score on pain. Patients with previous penicillin allergy were also excluded.PGB was diluted with 6 mL of sterile water as indicated in information pamphlet ; when MV was added to PGB, it was diluted with 5.5 mL of sterile water. A 0.5 mL dose of 1% MV was used to dilute with PGB; this corresponds to a total dose of 5 mg of MV. The study nursing team was trained to administer IM in the upper-outer quadrant of the buttock in the same way. Patients were randomly assigned to one of the four following groups: group 1, anesthetic/long 19G needle; group 2, anesthetic/short 21G needle; group 3, no anesthetic/long 19G needle; group 4, no anesthetic/short 21G needle.The study participants were randomly assigned to study groups by a computer-generated randomized number system in blocks. The randomization was done 1:1:1:1 in blocks of four. The randomization sequence was hidden for the investigators who made the selection of patients. The design of the study was double-blind: neither the patient nor the investigator who analyzed the pain results knew the assigned group.The primary objective of the study was the effect on local pain immediately after the injection; patients indicated the intensity of pain on a visual scale enumerated from 0 (no pain) to 10 (maximum pain) just after IM injection. Secondary objectives were pain intensity 6 and 24 h after the IM injection; this information was obtained by a phone call. Information was also collected on HIV status, age, sex, race, and body mass index (BMI).In the absence of any published study regarding the effect of needle gauge on pain, we estimated the sample size with data from a convenience sample of consecutive patients with syphilis treated with one dose of IM PGB 2.4 MU. We studied immediate pain after the injection, in 22 patients distributed in the same four groups; we assessed needle gauge and the effect of anesthetic with a visual pain score (0-10). We compared 19G with anesthesia vs. 21G with anesthesia; 19G without anesthesia vs. 21G without anesthesia; and 19G with anesthesia vs. 19G without anesthesia. The estimation of the global sample size was based on the larger sample required for comparisons. Based on expected mean pain intensity of 7.6 in the 19G group without anesthesia and 8.6 the 21G group without anesthesia, with a significance level of 1.7% (Bonferroni adjustment 0.05/3) and statistical power of 80%, we considered that 104 patients (26 in each group) were needed.Qualitative variables were summarized by their frequency distribution and quantitative variables by their mean and standard deviation (SD). Baseline participant characteristics were reported according to the randomly assigned intervention group with the use of descriptive statistics. To evaluate the differences in the intensity of the pain  between the study groups, a multiple linear mixed model was fitted for controlling the hospital-cluster effect with adjustment for BMI. All analyses were based on intention to treat randomization status, and the statistical significance was assessed at the Bonferroni-corrected for multiple testing (α/3 = 0.017). All analyses were performed using STATA 12.0 software.p < 0.001; and also between short 21G group with anesthesia (MPI 3.36 [CI 95% 2.22-4.50]) vs short 21G without anesthesia (MPI 5.06 [CI 95% 3.93-6.19]), p = 0.015). No significant differences in immediate pain were observed between 19G and 21G in the presence or absence of anesthesia (p = 1.0 in both cases). There were no significant differences in pain intensity between groups at 6 and 24 h. These results are shown in Fig. Patient characteristics are shown in Table The severity of pain after the IM administration of PGB may reduce the adherence to treatment and thus, improvements in tolerability might improve treatment compliance . Other sOur study shows that the administration of PGB diluted with a local anesthetic significantly reduces the intensity of pain immediately after intramuscular injection. These results are similar to those observed in a pediatric population treated with PGB for a different indication of syphilis , supportThe main strength of our study is the confirmation with a double-blind clinical trial, with adequate statistical power, of the efficacy of the PGB administered together with anesthetic in the pain control. We can, therefore, confirm that PB diluted with anesthetic significantly reduces the pain of IM administration of PGB. A limitation of our study is that most of our patients were young males (94%), and these results may not be similar in women or patients of different ages.The administration of PGB diluted with a local anesthetic significantly reduces the intensity of pain immediately after intramuscular injection; we did not find that the use of larger or longer needles exerts any influence on immediate pain. We suggest administering local anesthetic-diluted PGB as primary syphilis therapy.