In chronic pain, a number of brain regions involved in emotion  show significant functional and morphometric changes. One phenotypic manifestation of these changes is pain-related fear (PRF). PRF is associated with profoundly altered behavioral adaptations to chronic pain. For example, patients with a neuropathic pain condition known as complex regional pain syndrome (CRPS) often avoid use of and may even neglect the affected body area(s), thus maintaining and likely enhancing PRF. These changes form part of an overall maladaptation to chronic pain. To examine fear-related brain circuit alterations in humans, 20 pediatric patients with CRPS and 20 sex- and age-matched healthy controls underwent functional magnetic resonance imaging (fMRI) in response to a well-established fearful faces paradigm. Despite no significant differences on self-reported emotional valence and arousal between the two groups, CRPS patients displayed a diminished response to fearful faces in regions associated with emotional processing compared to healthy controls. Additionally, increased PRF levels were associated with decreased activity in a number of brain regions including the right amygdala, insula, putamen, and caudate. Blunted activation in patients suggests that (a) individuals with chronic pain may have deficits in cognitive-affective brain circuits that may represent an underlying vulnerability or consequence to the chronic pain state; and (b) fear of pain may contribute and/or maintain these brain alterations. Our results shed new light on altered affective circuits in patients with chronic pain and identify PRF as a potentially important treatment target. Fear of pain is considered to be a significant process in pain exacerbation and persistence . NormallA fear circuit has been defined that includes a number of brain regions in the subcortical , cortical , and brainstem regions  using a well-established fearful faces paradigm  to examiOf the 53 patients who were contacted and potentially eligible, 20 patients with CRPS (ages 8–20) were recruited from the Chronic Pain Clinic in the Pain Treatment Service at Boston Children’s Hospital (BCH) for this BCH institutional review board approved study. Written informed consent was obtained from all recruited subjects in accordance with the Declaration of Helsinki. Of the 33 patients not enrolled, 17 declined participation [32% decline rate; reasons included: not interested , overwheFigure 1). This paradigm was modeled after those used in previous studies to evoke fear circuitry . The FOPQ-C has two subscales: Fear of Pain (α = 0.89) and Avoidance of Activities (α = 0.86). Construct validity for this measure is supported with significant relations found for the FOPQ-C with child somatization, anxiety, and catastrophizing. Criterion-related validity is also supported with significant relations between higher FOPQ-C scores and greater functional disability and more frequent doctor visits in the previous 3 months. Stability of the FOPQ-C total scale score is adequate (α = 0.74) with decreases in FOPQ-C scores associated with concomitant decreases in functional disability (r = 0.45) at 1-month follow-up, suggesting sensitivity to treatment response  is a seresponse . High-feresponse .∗-weighted echo-planar pulse imaging (EPI) sequence . Subjects were instructed to look carefully at the pictures and were told that they would be asked questions about them after the MRI.Subjects underwent MRI on a 3 T  scanner using a 12-channel head coil. For each participant, we collected a 3D T1-weighted anatomical scan using a magnetization-prepared rapid acquisition gradient echo (MPRAGE) sequence . Two 5-min evoked fMRI scans were acquired using a T2All preprocessing, first-level, second-level, and third-level group analyses were performed using FMRIB Software Library (FSL).For each subject, MPRAGE images were skull-stripped using the brain extraction tool (BET).The following steps were taken within FEAT for each run of the evoked data set: (i) EPI images were skull-stripped using BET ; (ii) moOnce individual GLM FEAT analyses were completed, a fixed effects analysis was conducted combining both runs of the fearful faces paradigm to generate a mean image across runs.z = 1.96 and cluster-wise corrected at p < 0.05 for multiple comparisons. These steps were replicated for the each facial expression condition .The mean cope image for each individual was entered into an unpaired mixed-effects group analysis between patients and controls. For statistical thresholding, all whole-brain images were thresholded at n = 8), non-elevated fear individuals (n = 8), and healthy controls (n = 19). Pearson Product Moment correlations were used to examine association between percent signal change and PRF level. All ROI analyses were a priori thresholded at p < 0.05.To disentangle evoked brain response within patients by PRF level, we conducted region-of-interest (ROI) analysis using FSL Featquery for the ACC, dlPFC, amygdala , hippocampus, thalamus, putamen, caudate, and insula . Selection of these regions was based on results from recent work identifying these regions as having stronger synchronicity in activity with the amygdala at rest in pediatric CRPS , as wellGiven that age-related changes in activation have been observed for amygdala-PFC connectivity  and thatn = 6) were prescribed antiepileptic medication , 12% (n = 2) was prescribed an antiepileptic medication and a tricyclic, 6% (n = 1) was prescribed a muscle relaxant, while all other patients (n = 8) were not currently prescribed any pain medications. Three patients met criteria for an Axis I psychiatric diagnosis .A total of 20 patients and 20 age- and sex-matched healthy controls completed the emotional faces paradigm. All study participants were right-handed. Four study participants  displayed excessive motion (>3 mm) and one did not have a visual cortex response across emotional stimuli (one patient) resulting in a final group of 16 patients and 19 controls. All subsequent descriptive numbers reflect this group of patients and healthy controls. Among patients, 75% were female with an average age ± SD of 13.7 ± 3.2 years, and as expected, not significantly with the matched healthy controls . Within patients, 44% were right-side aﬄicted, 44% left-side aﬄicted, and 12% presented with bilateral lower extremity CRPS diagnosis. With regards to current medications, 38% (n = 8) reported high PRF (average PRF = 48.06 ± 3.77). PRF and pain intensity were not statistically significantly associated with one another .Among the 16 patients, 81.3% of patients self-reported moderate to severe average pain levels (average pain intensity ± SE = 6.17 ± 0.61). Median duration of pain was 7 months (average pain duration = 13.25 ± 3.87). For PRF, 50% , but not for group . Post hoc testing showed significant valence rating differences among all three types of facial expressions; fearful (-1.34 ± 0.16) vs. happy (2.31 ± 0.12), t(33) = –16.7, p < 0.01; fearful vs. neutral (–0.47 ± 0.12), t(33) = –6.00, p < 0.01, and neutral vs. happy, t(33) = –15.3, p < 0.01. Analysis of the arousal ratings revealed a significant main effect for expression , but not for group. Post hoc testing showed significantly lower arousal ratings for neutral faces (1.70 ± 1.27) vs. fearful (2.90 ± 1.33), t(33) = –5.76, p < 0.01, and happy (2.87 ± 1.29), t(33) = –5.72, p < 0.01. Arousal ratings between happy and fearful did not significantly differ.Ratings of valence and arousal were submitted to separate 2×3  analyses of variance. For valence, there was a significant main effect for expression . The first cluster was in the right hemisphere consisting of 1518 voxels including the frontal operculum cortex (FOC), insula cortex (Ins), and striatum . The second cluster was in the left hemisphere consisting of 1375 voxels including the FOC, Ins, dlPFC, MFG, thalamus , and striatum . The third cluster was in the left hemisphere consisting of 1236 voxels including the lateral occipital cortex (LOC), superior parietal lobule (SPL), supramarginal gyrus (SMG), and postcentral gyrus (PoCG). The fourth cluster was in the right hemisphere consisting of 976 voxels including the superior frontal gyrus (SFG), MFG, and precentral gyrus (PrCG). The fifth cluster was in the right hemisphere consisting of 975 voxels including the SPL and LOC. The sixth cluster was in the right hemisphere consisting of 858 voxels including the PrCG, inferior frontal gyrus (IFG), SMG, PoCG. No areas were observed to have greater activation in patients compared to controls.The whole brain analysis revealed six significant clusters with less evoked activation for patients compared to healthy controls in response to fearful faces . The first cluster was in the right hemisphere consisting of 1265 voxels including the SFG, PrCG, and MFG. The second cluster was also in the right hemisphere consisting of 1002 voxels spanning over the angular gyrus, inferior temporal gyrus, SMG, and middle temporal gyrus. No areas were observed to have greater activation in patients compared to controls.The whole brain analysis resulted in two significant clusters with less evoked activation for patients compared to healthy controls in response to happy faces . The first cluster was in the left hemisphere consisting of 1064 voxels including the PrCG, SFG, and MFG. The second cluster was also in the left hemisphere consisting of 907 voxels including the PoCG and SPL. No areas were observed to have greater activation in patients compared to controls.In the whole brain analysis, two significant clusters emerged with less evoked activation for patients compared to healthy controls in response to neutral faces (see n = 12), the majority of results were replicated. For fearful faces, differences in the left dlPFC, left MFG, and left parietal and occipital cortex were no longer significant. All other differences were replicated. For happy faces, the cluster in the right frontal/motor region was no longer significant, while the cluster in the temporal region remained significant. For neutral faces, no clusters emerged as significant. Consistent with the whole sample analysis, there were no areas where greater activation was observed in female patients compared to female controls across all emotional contexts.When limiting the analyses to only female patients  had less activation in the bilateral Pt and right Cd, right centromedial amygdala, and right anterior Ins  compared to non-elevated fear (n = 8) and healthy controls (n = 19). When examining the correlation between fear of pain level and percent signal change (n = 16), higher PRF scores were associated with attenuated responses in the right Cd , right Pt , and right Ins . Although high fear patients had less activation in the left putamen and right centromedial amygdala compared to healthy controls, the correlation between PRF and percent signal change within patients was not significant; suggesting that the differences in these brain areas was likely most driven by high fear status. The magnitude of the correlations did not change when pain level and pain duration were included as covariates. These results suggest that beyond differences between healthy individuals and patients with chronic pain, the level of PRF is associated with altered cognitive-affective brain circuit responses to emotionally relevant stimuli.To disentangle evoked brain response within patients by PRF level, we conducted ROI analysis using FSL Featquery. We observed that high-fear patients ; in other words, for patients, evoked ACC responses significantly increased across age while responses in healthy control showed a non-significant decrease across age . This decreasing response in healthy participants is consistent with prior work looking at developmental changes in response to fearful stimuli in the ACC . In a partial correlation analysis controlling for pain duration, increased activation was no longer statistically associated with older age, with the magnitude of the association medium in size , thus persistent disease state appears to be partially driving increased activation within the ACC across age.A continuous covariate interaction across patients and healthy controls was examined in relation to age, given the potential influence of age and development on evoked brain responses to fearful faces. The interaction was significant for the ACC and paracingulate gyrus (PAC) with patient slope greater than healthy controls . Despite these challenges, understanding brain alterations in youth with chronic pain is important and conclusions based on research among adults cannot serve as a replacement. (2) Sex – Although our patient sex distribution is reflective of the literature , this split pattern was consistent for the patients classified as having high PRF. We do not have strong evidence of the impact of these medications on brain activity, but importantly none of the patients were taking narcotics, which we do know has a significant impact on the brain.Our study has a number of caveats: (1) terature , the preterature , our samChronic pain is multifaceted with clear physiological, cognitive, and affective dimensions. This study provides novel evidence that pediatric patients with CRPS demonstrate altered corticolimbic circuit response in fear perception that appears to be driven or maintained by PRF levels for the striatum, centromedial amygdala, and anterior Ins. Our results suggest that the dampened response could reflect altered learning, memory, and attention in the context of a persistent and debilitating pain state. Clinically elevated PRF may reflect maladaptive aversive learning that is resistant to extinction. The dampened response observed in brain regions such as the Ins and Pt in this study may constitute important neural markers for deficit learning that leads to a pathological PRF level. Accordingly, these brain function alterations may either serve as a vulnerability factor or contribute to the persistent pain state and warrant further study.All authors contributed significantly to this work. All authors have read and reviewed this manuscript and agree on its submission to Frontiers in Behavioral Neuroscience.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.


Most diabetic patients described their pain as “slight” or “none” , while most non-diabetic patients graded their pain as “moderate” or “severe” . The quality of pain tended to be more distinct in non-diabetic patients, while diabetic patients reported mainly shortness of breath . Diabetic patients were more likely to suffer a multi-vessel disease , especially in the late arrival group. Therefore, cautious evaluation of diabetic patients and adequate education of target population could improve overall survival while well-organized care like a primary PCI Network program could significantly reduce CV mortality.The aim of our study was to determine whether diabetic ST segment elevation myocardial infarction (STEMI) patients arrive in the emergency room (ER) later than non-diabetics, compare the differences in pain quality and quantity between those groups, and measure differences in the outcome after an index hospitalization. A total of 266 patients with first presentation of STEMI were included in our study during a period of two years, 62 with diabetes and 204 without diabetes type 2. Pain intensity and quality at admission were measured using a McGill short form questionnaire. Diabetic patients did not arrive significantly later than non-diabetic (χ Cardiovascular disease, particularly coronary artery disease (CAD), is one of the leading causes of morbidity and mortality in patients with diabetes . In thosi.e., unstable angina and myocardial infarction. That atypical presentation of ACS, more frequent in diabetic patients, includes also some other anginal equivalents such as nausea, vomiting, diaphoresis, epigastric discomfort, dyspnea and an unexplained fatigue [Diabetes has a major impact on CAD development and its consequences, autonomic neuropathy, and diabetic cardiomyopathy . It has  fatigue .The purpose of our study was to assess whether diabetic patients with STEMI arrive in the emergency room (ER) later than non-diabetic patients, and whether possible differences in pain quality between those two groups could influence the arrival time to the emergency department which could be explained by diabetic polyneuropathy leading to the impaired symptom perception and causing worse clinical outcome. To confirm this hypothesis, we analyzed the hospital arrival time , the chest pain intensity and other potential symptoms’ differences between two groups. Furthermore, a comparison has been done according to survival, results of PCI, peak troponin T levels (cTnT) and duration of hospitalization.u-test, p = 0.013). There was no such difference for women . The overall significance of age difference between diabetic and non-diabetic group was present due to the greater number of men . There was no significant difference among groups with respect to sex distribution, smoking status, alcohol consumption, blood pressure, lipid profiles, renal function or use of aspirin, statins and antihypertensive drugs (data not shown).From the total of 266 patients, 204 (76.7%) were non-diabetic patients and 62 (23.3%) were diabetic patients . Men wit2; p = 0.105). The peak cardiac troponine T (cTnT) was significantly higher in diabetic compared to non-diabetic patients independently of the time of arrival , but there was no difference in cTnT levels in both groups with fatal outcome. Diabetic patients had a higher early, in-hospital mortality rate vs. non-diabetic controls (data not adjusted) but this difference was only numerical and not statistically significant. Early arrivals in general had a lower chance of lethal outcome   .2; p < 0.01). However, there was a significantly higher percentage of patients within the non-diabetic group in comparison with diabetics, reporting pain of a moderate to severe degree . Interestingly, the majority of the early arrived diabetic patients experienced “slight” or almost “no pain” at all compared to the non-diabetic group .Differences in pain scale score within early- and late-arrival groups are summarized in 2; p = 0.036), while late arrival was strongly associated with shortness of breath   and burning  both appearing more often in non-diabetic group, while shortness of breath was more common among diabetic patients . Multiple pain qualities were more prevalent among non-diabetic patients . The only reliably present symptom (>50%) in both non-diabetic and diabetic early arrivals was tugging pain.Early arrival was significantly associated with pressing pain as the leading symptom (χ= 0.011) . Regardlu-test; p = 0.008) and were associated with late hospital arrivals   .The most frequent intervention in all patients was single-vessel PCI, followed by 2-vessel PCI. PCI failure was not registered among those patients. Emergency CABG was performed in 10 patients . The mos2; p < 0.05), while a single vessel PCI was more frequent in the non-diabetic group of patients   .vs. insulin) had no appreciable influence on number of vessels involved in the intervention, neither had a correlation with any other parameter analyzed in this study.Duration of hospitalization was not significantly different between non-diabetic and diabetic patients. Patients who underwent CABG because of their ineligibility for PCI were hospitalized one day longer on average . The typIt is well known that early revascularization in ACS, particularly in STEMI, significantly improves short and long term survival and the remaining myocardial function ,12,13. Tet al. [The first parameter analyzed was the arrival to the hospital of diabetic and non-diabetic STEMI patients. Surprisingly, contrary to our hypothesis the results have shown that there was no statistically significant difference between number of diabetic and non-diabetic STEMI patients arriving at the hospital within 120 min after symptoms onset (“early”). However, while the majority of non-diabetic STEMI patients that arrived early experienced “moderate” and “severe” chest pain, even 51.7% of diabetic patients experienced “slight” or “no pain” which seemed equally indicative of serious disease as severe pain in non-diabetics. There were several important differences in pain perception between non-diabetic and diabetic patients. Analysis of individual pain qualities within the early arrival group showed a significantly higher frequency of anginal symptoms among non-diabetics and shortness of breath among diabetic patients. Shortness of breath was consistently more often reported in diabetics and that symptom seemed to be the main reason of their early hospital arrival, despite the lower intensity of pain or no pain at all. Sensations of distinct pain, like stabbing and burning, were under-reported by diabetic patients. Obviously, other atypical symptoms were incentive enough for a visit to the emergency department in patients with diabetes. This is consistent with previous studies which have shown that in the presence of myocardial ischemia, diabetic patients reported angina less frequently than non-diabetic patients and shortness of breath may be the only symptom of ischemia . In the et al.  only 45%et al. . Shortneet al. , althougi.e., by MPS). This difference was especially prominent in the late arrival group meaning that high risk diabetic patients with large areas of ischemia and developed neuropathy did reach hospital later than desirable. Obviously, the disease itself with its risk factors and complications may dictate a worse outcome despite our finding of an earlier than anticipated arrival of diabetic STEMI patients [In addition, multi-vessel disease was more common in diabetic patients. This was expected and is probably due to atherosclerotic lesions being more severe, diffuse, usually located on small blood vessels and very often not amenable to dilatation due to autonomic neuropathy and silent ischemia in diabetic patients ,17. Thatpatients ,25,26,27Peak cTnT levels were significantly higher in diabetic than non-diabetic patients, and were particularly high in diabetes patients within the early arrival group which corresponds to larger areas of damage and multi vessel disease as was previously demonstrated . Late arHowever, difference in fatal outcome was only numerical and not statistically significant between diabetic and non-diabetic patients. This could be explained that in the present study there was no difference in the arrival times between those two groups and revascularization was performed in timely manner. Furthermore, only in-hospital mortality was taken into consideration, not long-term outcomes.Incidence of silent ischemia in diabetic patients is increased in various clinical settings and in the presence of multiple risk factors ,16. The The present study has several limitations. The patient population was relatively small and recruited exclusively from a west region of Croatia which could explain absence of statistical significance in the arrival time as well as in in-hospital mortality rates between two groups. Moreover, because this was an observational study, long term outcome and prognosis in relation to specific time of arrival, type of pain and presence of diabetes remain unknown. Thus, a large-scale long-term prospective study is needed to confirm the present results and determine the relationship between hospital arrival time and pain quality in diabetic patients and the prognosis of obstructive CAD.This observational cross-sectional study complied with the Declaration of Helsinki and was approved by the ethics committee of County Hospital Čakovec. A total of 266 patients with the first presentation of acute STEMI, diagnosed by clinical symptoms, ECG criteria and elevated cTnT according to the American College of Cardiology , examinei.e., preferably within 2 h after onset of symptoms, but also later on, usually within 12 h, depending on the pain-to-first-medical-contact time.The County Hospital Čakovec, Medjimurje region, Republic of Croatia, has been involved in the Croatian 24/7 primary percutaneous coronary intervention (PCI) network for treating patients with ST-elevation myocardial infarction (STEMI) since 2005. Patients from Medjimurje are being transported to the referral PCI center in Zagreb in a way that all eligible STEMI patients are transported to the tertiary center as soon as possible Length of the hospitalization, peak Troponin T (TnT) concentrations, type of intervention (PCI or CABG) and a number of significantly occluded coronary arteries according to coronary angiography findings were acquired from hospital electronic medical records. Chest X-ray was performed to exclude dyspnea as a result of acute cardiac failure. For the purpose of this study, a fatal outcome was defined as a death within a scope of an index hospitalization (not only in the 24-hour period).Pain perception was graded using a modified McGill short form questionnaire, giving each participant a pain score between 0 (no pain) and 3 (severe pain). The quality of pain among the 6 offered categories  and shortness of breath was noted and subsequently evaluated. The questionnaire was part of the clinical examination. It was completed and evaluated by the research team. Arrival time was rated as either “early” (within 120 min of symptom onset) or “late” (more than 120 min after symptom onset).Results were analysed using descriptive statistical analysis. Significance was declared at a two-sided 0.05 level, unless otherwise specified. Statistical analyses were performed using SPSS software for Windows .Since samples in our study were relatively small and an asymmetric distribution of the analysed variables was present the difference between the two independent variables was analysed by non parametric analysis using chi square and Mann-Whitney test . Chi square test was also used to estimate the magnitude of the association between variables of interest. Calculated mortality rates were unadjusted In conclusion, the lack of difference in the arrival times between two groups, despite the tendency of less typical clinical presentation in diabetic patients, might be a result of a comprehensive health education for diabetic patients in Međimurje Region, Croatia. It seems that although diabetic STEMI patients have poorer prognosis in general, with well organized care like primary PCI Network program we can significantly reduce CV mortality. Since neuropathy and other changes in pain perception may be indicative for worse outcome in diabetic patients, an additional education should result in their increased awareness of possibility of getting ACS, even at younger age and/or with mild or atypical clinical presentation.


Objective: To determine whether topical menthol 6% gel will relieve a migraine attack.Materials and Methods: A single-center, open-label pilot trial of 25 patients with at least 1 year of diagnosed episodic migraine and <15 headache days per month. Patients treated one migraine attack with STOPAIN topical menthol 6% gel to skull base within 2 h of headache onset. Headache pain severity was assessed prior to and after gel application.Results: Thirty-two patients enrolled and 25 completed the study. Prior to treatment, 7 patients had mild pain, 13 moderate pain, and 5 severe pain. Two hours following gel application, 7 (28%) patients had no pain, 7 (28%) mild pain, 6 (25%) moderate pain, and 5 (20%) severe pain. The majority of patients had similar pain intensity  or improvement . At 24-h, only two non-rescued patients still had mild headache. Of the 25 completers, 2 patients took rescue medication prior to the 2-h period, and an additional 10 patients rescued between 2 and 24 h.Conclusion: Study results showed a significant improvement in headache intensity by 2 h after gel application. This pilot study shows STOPAIN gel may be effective in treating an acute migraine attack. Migraine is a common headache disorder with an estimated 1-year prevalence of 36 million people  in the United States . Eligible patients between 18 and 65 years of age at screening were required to have 1–10 migraine attacks and no more than 15 total headache days per month. Subjects who had a diagnosis of basilar or hemiplegic migraine were excluded. Additional exclusion criteria included medical or psychiatric conditions that would increase the risk of adverse events or interfere with study assessments, participation in an investigational drug trial in the 30 days prior to the screening visit, and pregnancy or lactation. Women of childbearing potential were required to use effective contraception during participation.Participants provided written informed consent prior to undergoing screening procedures. The screening visit (Visit 1) included a review of the patient’s medical and headache history and current medications. Vital signs and a urine pregnancy test were required for women of childbearing potential. Subjects were asked to treat a single migraine attack within 8 weeks of Visit 1. They were instructed to apply two pumps of the treatment gel from the metered dosing bottle to the area below and abutting the base of the skull to the base of the neck as well as behind and between the ears within 2 h of the onset of a migraine attack. If they had no relief after 2 h of gel application, they were permitted to use rescue medication.Subjects were provided with a take-home diary. Within 1 h of headache onset, they were instructed to record pain severity  and associated symptoms before applying the study gel, and at multiple time points  after administering the gel. They also recorded the presence or absence of photophobia, phonophobia, nausea, and vomiting. Adverse events and rescue medications, including the time of treatment and dose, were to be recorded.After treating the migraine attack and completing the diary, subjects were asked to return to Jefferson Headache Center for a final visit (Visit 2) or to return the diary and other study supplies by mail . During the final visit, the study drug and diary were collected and reviewed, and any changes in concomitant medications and/or medical conditions since the screening visit were recorded.Iris Versicolor 6× HPUS, and Sanguinaria canadensis 6× HPUS. Inactive ingredients: water (USP), ethanol (USP), cambopol polymer, propylene diglycol, and triethanolamine.Active ingredients: Mentholum (l-menthol), Belladonna 3× HPUS, Nux Vomica 6× HPUS, The primary objective is to observe the responses after topical gel application in order to determine whether larger, well-controlled trials are warranted. The primary endpoint is the headache intensity reduction 2 h after treatment. An exploratory endpoint is the headache intensity reduction at 24 h after treatment. For statistical analysis, ordinal conversion of pain levels were assigned as 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain. The Wilcoxon sign-rank test was used to compare pre-treatment pain severity with pain severity 2 h after gel application, as well as to compare pre-treatment pain severity with pain severity 24 h after gel application.Thirty-two subjects with episodic migraine met the inclusion criteria and were enrolled in the pilot study. Of these, 25 subjects completed the study and seven were lost to follow up. Of the 25 completed subjects, 7 had mild pain, 13 had moderate pain, and 5 had severe pain before the topical treatment. Figure Z = −2.18, p = 0.029) and after 24 h . Figure Using ordinal conversion of headache severity, the mean headache severity levels are at pre-treatment = 1.92 (close to moderate pain), at 2 h = 1.36 (between mild and moderate pain), and at 24 h = 0.16 (very mild pain)  required rescue medication before 2 h. This shows a potential pain-relieving property from topical menthol application. Interestingly, subjects with pre-treatment severe headache have higher rate of pain improvement after 2 h and also reported higher rate of rescue medication use within 24 h. Single application of menthol 6% gel is probably more useful for short-term ablation in migraine patients. After 24 h, most subjects, rescued or non-rescued, showed headache improvement, which could be attributed to the natural progression of the migraine.Limitations of this study include the small sample size and open-label, non-placebo-controlled design. In previous studies conducted in 2010 by Borhani Haghighi et al., a 10% menthol solution applied to the forehead and temporal area showed significant improvement in headache pain and associated symptoms at 2 h compared to placebo in patients with episodic migraine without aura . Our finThis open-label pilot study demonstrates that STOPAIN 6% menthol gel is safe and may be effective in the treatment of an acute migraine attack. Because of the limitations of this study, a larger placebo-controlled clinical trial is warranted.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.


Radio frequency induced thalamotomy has been used in patients with neuropathic pain for many years. Today, transcranial MR imaging-guided focused ultrasound (tcMRIgFUS) offers the opportunity to conduct this treatment non-invasively under closed-loop MR-imaging guidance.So far we have treated a total of 23 patients suffering from chronic neuropathic pain of various origins using tcMRIgFUS. Targeting the posterior part of the central lateral nucleus of the thalamus (pCL), we applied both unilateral and bilateral lesions, depending on the severity and extent of the clinical symptoms. Also, depending on clinical presentation, the effected lesions were created either by a single ablation cell, or, where the lesion volume of a single ablation cell seemed insufficient, by combining two to three adjoining ablation cells that were generated by electronically steering the acoustic focus a few millimetres in order to increase the lesion volume. Using a custom built eight channel phased array coil which snugly fits around the ultrasound transducer, high resolution images could be acquired during the whole intervention procedure. The temperature evolution in the target region was continuously monitored by MR-thermometry and therapeutically effective temperatures were considered to lie between 54 and 62°C.Long term effects resulting from pCL thalamotomy with tcMRIgFUS in the 23 patients evaluated here during a follow-up period of 1 to 2 years will be presented. The median pain relief is 56%, with an average reduction of subjectively felt maximal pain intensity of 34% estimated by the patients on a numerical rating scale. Here we will present important physical parameters such as lesion size and its evolution over time, as well as maximal temperature achieved during the FUS intervention. We will demonstrate the relationship between therapeutic effect and lesion size and Tmax, respectively. Apart from the pain relief, changes in quality of life and activity of daily living are at least as important for the patients. The results will also demonstrate the mutual compliment of deep brain stimulation and focused ultrasound. They form the basis for discussing possible improvements in patient management and new methodological approaches in order to allow application of tcMRIgFUS also in difficult and desperate patient situations.


The purpose was to evaluate the overlap frequency of irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and overactive bladder syndrome (OBS), as well as other gastrointestinal and systemic symptoms, in functional dyspepsia (FD). Additionally, we sought to determine whether adult Rome III FD subtypes were uniquely related to overlap syndromes or symptoms.The study was a retrospective review of 100 consecutive pediatric patients, age 8–17 years, diagnosed with FD. All had completed a standardized medical history including gastrointestinal and systemic symptoms as well as specific symptoms related to GERD and OBS. The frequency of overlap with IBS, GERD, and OBS were determined for the whole group and for those fulfilling adult FD subtype criteria. Individual symptoms were also compared by FD subtype.Overlap IBS was present in 33 % of the FD patients. At least one GERD symptom was present in 74 % of patients with 41 % reporting heartburn. At least one OBS symptom was present in 44 % of patients with 29 % reporting urinary urgency. Other than pain, the most common reported gastrointestinal symptom was nausea (86 %). Systemic symptoms were common. Overlap syndromes/symptoms did not vary by FD subtype. Postprandial distress syndrome was associated with pain with eating, weight loss, and waking at night to have a stool.FD is a heterogeneous condition in children and adolescents with significant variability in the presence of gastrointestinal and non-gastrointestinal symptoms and overlap syndromes. Varying symptom profiles need to be accounted for and analyzed in studies involving subjects with FD. There are a number of pain-associated functional gastrointestinal disorders (FGIDs) defined by Rome III for children/adolescents, namely irritable bowel syndrome (IBS), functional dyspepsia (FD), abdominal migraines, functional abdominal pain, and functional abdominal pain syndrome . In adulMost children and adolescents with chronic abdominal pain fulfill criteria for an FGID with FD and IBS being the two most common , 5, 6. TThe purpose of the current study was to evaluate the frequency of overlap IBS, potential GERD-related symptoms, and OBS-related symptoms, as well as other gastrointestinal and systemic symptoms, in a clinical sample of youth with FD. Additionally, we sought to determine the frequency of PDS and EPS in youth with FD, and whether these subtypes were uniquely related to overlap syndromes or other symptoms.The current study was a retrospective chart review of pediatric patients who were identified as being diagnosed with FD after being seen for initial evaluation of chronic abdominal pain in a subspecialty abdominal pain clinic housed within a large Midwestern children’s hospital between September, 2014 and June, 2015. All data described below were collected as part of standard care and were abstracted from the medical record and entered into a research database for analysis in the current study. The study was approved by the institutional review board at Children’s Mercy Kansas City.Helicobacter pylori on antral biopsy. Mild histologic esophagitis (peak eosinophils < 5/hpf) and/or mild chronic gastritis did not exclude the patient from selection. Patients diagnosed with other pathology, including eosinophilic gastroenteritis, celiac disease, inflammatory bowel disease, or giardiasis, were excluded from the study cohort. Eosinophilic gastritis and duodenitis were diagnosed at the discretion of the evaluating board-certified pathologist as no widely accepted criteria exist regarding eosinophil density.All patients selected for inclusion had been evaluated in a single subspecialty abdominal pain clinic. Patients were 8–17 years, inclusive, and reported pain at least weekly for a minimum of 8 weeks per standard entry criteria for the clinic. The diagnosis of FD was determined according to Rome III criteria by a single board-certified pediatric gastroenterologist based on an extensive history and physical examination conducted with each child and family during the initial clinic visit [As a prerequisite for inclusion in the study cohort, patients had to have previous biopsies to evaluate for the presence of histologic esophagitis as assessed by a board certified pediatric pathologist as part of routine care. The pathology report provided the histologic data for analysis.All patients seen for initial evaluation in the abdominal pain clinic from which the sample was selected had completed a standardized medical history. This medical history included questions regarding the presence of upper abdominal pain or discomfort, as well as any relation to a change in stool frequency or consistency or a history of relief from stooling. In addition, specific locations of the pain were obtained by asking the patient to mark pain locations on a diagram of the abdomen. The nature of the pain  was asked of each patient. Patients were specifically asked whether pain wakes them at night and whether pain increases after a meal. Patients also were asked about the presence of nausea and/or vomiting and whether nausea increases after a meal. Relevant to the issue of FD subtyping, patients were asked specifically about the presence of early satiety and postprandial bloating .Patients also are asked about the presence of a number of other gastrointestinal and systemic symptoms. Gastrointestinal symptoms that are assessed include the presence of stool symptoms such as loose stools, hard stools, mucus in stools, blood in stools, and waking at night to have a stool, as well as the presence of excessive gas. Systemic symptoms that are assessed include hayfever, fatigue, headache, fainting, dizziness, chest pain, muscle pain, joint pain, mouth sores, weight loss, and fever. In addition to the above, patients are asked about the presence of 4 symptoms related to gastroesophageal reflux  and 3 symptoms related to overactive bladder syndrome .Information from the medical history, once abstracted and entered into the research database, was used to evaluate dyspeptic symptoms and assign an FD subtype based on adult Rome III criteria. Patients were defined as having postprandial distress syndrome if they endorsed early satiety or postprandial bloating . Patientp value of <0.05 was considered statistically significant for all of the analyses. Given the exploratory nature of the current study, trends were reported for p values >0.05 but <0.07.Statistical analysis was performed using SPSS Version 20 . Frequencies were determined for individual symptoms and diagnoses. The frequencies of individual reflux symptoms were compared between patients with and without mild histologic esophagitis by chi-square analysis or Fisher’s exact tests, as appropriate given cell frequencies. The frequencies of an IBS diagnosis, reflux symptoms, and overactive bladder symptoms, respectively, were compared between genders, between patients <13 years of age and those ≥13 years of age, and between patients with and without PDS by chi-square analysis or Fisher’s exact tests, as appropriate given cell frequencies. A n = 86), the nausea occurred daily in 36 % and at least weekly in 76 %. Sixty-three percent reported that nausea increased with eating. Frequencies of other selected gastrointestinal symptoms and systemic symptoms are shown in Table One hundred patients ranging in age from 8 to 17 years with a mean age of 13 years 9 months were evaluated. Seventy-six percent were female. Pain was reported to occur daily in 76 %, several times/week in 19 %, and weekly in 5 % of patients. Pain was described as intermittent by 60 % and continuous by 40 % of patients. For patients reporting nausea , belching/burping , regurgitation , and heartburn . Frequencies for OBS-related symptoms are shown in Table p = .037).One-third (33 %) of FD patients also fulfilled criteria for IBS. Frequencies for GERD-related symptoms are shown in Table p = .001), weight loss , and waking at night to have a stool . There also were trends for patients with PDS to be more likely to report nausea with eating , pain relief with a stool , mucus in the stool , and increased gas . Although other gastrointestinal and systemic symptoms were found to be relatively common in the broader group of patients with FD, no other correlations emerged between these symptoms and the PDS subtype. PDS also did not have any significant associations with any GERD-related or OBS-related symptoms. Associations with overlap syndromes/symptoms were not examined for EPS given the low base rate (3 %) in the study cohort.Patients fulfilling criteria for PDS (as compared to those who did not) were more likely to report pain with eating (79 vs. 43 %; The current study indicates that FD is a heterogeneous condition in children and adolescents. There is significant variability in the presence of gastrointestinal, as well as non-gastrointestinal, symptoms. It is important to understand this variability within diagnostic categories, and also within individual patients as each patient appears to have a somewhat unique symptom profile within the broad category of FD.Overlap IBS was present in 33 % of the FD patients in the current study. Previously we found IBS overlap in 54 % of patients fulfilling FD criteria . ConsistEvaluating for the presence of GERD overlap in youth with FD presents a challenge, as there is no gold standard test for GERD. Symptoms and available tests lack high sensitivity or specificity. However, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines concluded, based on expert opinion, that the diagnosis of GERD can be made in adolescents with typical heartburn symptoms . HeartbuOveractive bladder symptoms were common in FD patients in the current study, with at least one symptom present in 44 %. In adults, OAB is defined as a symptom complex of urinary urgency usually with urinary frequency and nocturia . The halThe FD subtypes, PDS and EPS, are well recognized in adults but were not included in the pediatric FD criteria . In adulAdult data suggests that meal-related symptoms, including pain and nausea, may be the norm in FD . The PDSThe main strength of the current study is the relatively large population size with symptom reporting performed in a standardized fashion across a wide array of gastrointestinal and non-gastrointestinal symptoms. The main limitation is that the study design did not allow evaluation of the natural history of these symptoms. It is known that symptoms may evolve across time and patients may change FD subtype classification .In sum, pediatric FD is a heterogeneous syndrome exhibiting variable symptoms from patient to patient with many, but not all, fulfilling criteria for PDS. The clinical presentation of FD also varies with regard to non-FD symptoms, exhibiting significant overlap with IBS as well as symptoms consistent with GERD and OBS. These varying symptom profiles need to be considered in providing care to FD patients. For example, an FD patient with overlap may have a different pathogenic process or respond differently to a treatment regimen than a patient with FD alone or FD with overlap GERD. Likewise, varying symptom profiles need to be accounted for and analyzed in studies involving subjects with FD. Clinical trials need to be designed to fit the patients that are actually encountered, rather than the clean diagnostic boxes we create.EPS, epigastric pain syndrome; FD, functional dyspepsia; FGID, functional gastrointestinal disorder; GERD, gastroesophageal reflux disease; hpf, high power field; IBS, irritable bowel syndrome; OBS, overactive bladder syndrome; PDS, postprandial distress syndrome


Pain is one of the main causes leading to admission in the Emergency Department (ED) and has importance for patient satisfaction. Baseline LUP data of patient satisfaction has demonstrated that although patients are content, audit of the health care documentation of pain treatment seems insufficiently. Therefore, this study will investigate the difference between patient satisfaction, staff experience, and results from audit of the documentation of pain management in patient files. The hypothesis is that the documentation only describes a minor part of the efforts to treat the patient's pain.A qualitative investigation using a validated semi structured questionnaire of ED nurses' experience and attitude to pain management and documentation will be compared with documented care and treatment in patient files. Results will be analysed with qualitative analysis and presented as display. Baseline audit of documentation of pain treatment in 77 files and questionnaire with 5 staff nurses as indicator, followed by questionnaire of 20 nurses working 2 consecutive days.The national LUP performed in 2011-2013 shows patient satisfaction of pain management 82-85%. Baseline audit shows that 85% of all patients in the ED have been asked about pain at arrival. 30% has got VAS/NRS score > 3, which demand a documented plan and follow up of the effectiveness of treatment  although audit shows it was only documented in less than 15% of the files. The questionnaire with 20 nurses identify that nurses have a holistic approach to pain treatment but the time factor and lack of system support is the main course of this weak documentation.The study has shown that nurses work with pain management in a way that might have importance for the patient satisfaction but it is not demonstrated in their documentation. Further studies will be performed involving the patients' ideas to identify and develop a pain management report.


Achieving perceptual gains in healthy individuals or facilitating rehabilitation in patients is generally considered to require intense training to engage neuronal plasticity mechanisms. Recent work, however, suggested that beneficial outcome similar to training can be effectively acquired by a complementary approach in which the learning occurs in response to mere exposure to repetitive sensory stimulation (rSS). For example, high-frequency repetitive sensory stimulation (HF-rSS) enhances tactile performance and induces cortical reorganization in healthy subjects and patients after stroke. Patients with complex regional pain syndrome (CRPS) show impaired tactile performance associated with shrinkage of cortical maps. We here investigated the feasibility and efficacy of HF-rSS, and low-frequency rSS (LF-rSS) to enhance tactile performance and reduce pain intensity in 20 patients with CRPS type I. Intermittent high- or low-frequency electrical stimuli were applied for 45 min/day to all fingertips of the affected hand for 5 days. Main outcome measures were spatial two-point-discrimination thresholds and mechanical detection thresholds measured on the tip of the index finger bilaterally. Secondary endpoint was current pain intensity. All measures were assessed before and on day 5 after the last stimulation session. HF-rSS applied in 16 patients improved tactile discrimination on the affected hand significantly without changes contralaterally. Current pain intensity remained unchanged on average, but decreased in four patients by ≥30%. This limited pain relief might be due to the short stimulation period of 5 days only. In contrast, after LF-rSS, tactile discrimination was impaired in all four patients, while detection thresholds and pain were not affected. Our data suggest that HF-rSS could be used as a novel approach in CRPS treatment to improve sensory loss. Longer treatment periods might be required to induce consistent pain relief. The complex regional pain syndrome (CRPS) is a chronic pain syndrome, which is characterized by sensory, autonomic, and motor disturbances , 2. It iChanges of tactile abilities can be reliably induced not only by training and practice but also by brief, training-independent sensory learning through repetitive somatosensory stimulation (rSS) –19. FromA recent investigation demonstrated enhanced cortical excitability of the somatosensory and motor cortex in patients with CPRS , 35. MorWe therefore here explored the feasibility and efficacy of both a high-frequency rSS (HF-rSS) and a low-frequency rSS (LF-rSS) protocol over 45 min on five consecutive days to all fingertips of the affected hand in patients with CRPS. Primary outcome criteria were the two-point-discrimination (2PD) threshold and the mechanical detection threshold (MDT) of the index finger as measures of tactile performance. As additional secondary endpoint the potential impact on the current pain intensity was investigated.The study was approved by the Ethics Committee of the Ruhr-University Bochum, Germany 4236-12) and was performed in accordance with the Declaration of Helsinki from October 2008. All patients gave their written informed consent. A total of 26 consecutive in-patients of the Department of Pain Medicine of the University Hospital Bergmannsheil Bochum who fulfilled the Budapest diagnostic criteria for CRPS 36-12 and. Exclusin = 5; medication change: n = 1). After inclusion in the study, prior to any intervention, a detailed history was taken and each patient underwent a physical examination with focus on assessment of the Budapest Criteria . The application of the LF-rSS protocol was terminated after four patients, as impairment of the primary outcome parameter (2PD) was observed.Two-point-discrimination threshold (2PDTH) as primary outcome measure and additionally MDT as a second component of tactile performance as well as current pain intensity were assessed immediately before the start of the intervention and 1–4 h after the termination of the last rSS application.Repetitive sensory stimulation was applied on five consecutive days. Each single session lasted 45 min. Electrical stimuli were generated by a two-channel stimulation-device  and were conveyed to the fingertips of all fingers of the affected hand by a custom-made hand pad. In case of one patient  exerting forces between 0.25 and 512 mN in five ascending and descending stimulus intensities. The final threshold was calculated as the geometric mean of the resulting five suprathreshold and five subthreshold values.The MDT was assessed bilaterally on the palmar tip of the index finger using a standardized set of modified von Frey filaments , with NRS = 0 meaning no pain and NRS = 10 meaning the worst pain imaginable.n = 2) were not included. For calculation of the 2PDTH, the summed responses were plotted against distance as a psychometric function for the absolute threshold and were fitted by a binary logistic regression . Threshold criterion was 50% correct responses. After testing for normal distribution (Kolmogorov–Smirnov test), differences in 2PDTH, MDT, and current pain intensity before and after treatment were assessed by the Wilcoxon matched pairs test. Differences between affected and non-affected side were analyzed by the Mann–Whitney U test. For correlation analyses, Pearson’s partial correlation corrected for the factor age was calculated. Statistical significance was assumed if p < 0.05.All data are expressed as mean ± SEM. In case of the calculation of the mean current pain intensity, the data of patients who rated 0 for no pain (p < 0.01). Discrimination thresholds of the non-affected hand were in the same range as those reported for healthy age-matched controls , though not being statistically significant. However, MDT of the non-affected hand was substantially higher than those observed for healthy age-matched controls (unpublished). After the treatment, the mean MDT decreased significantly on the affected hand .Before the intervention, the mean MDT of the affected hand was higher than on the non-affected hand . Neither before nor after the intervention performances in both tactile tests were related to each other or to the factor pain. Concerning the percentage of change of both tactile measures and the change of pain intensity, there was no significant correlation between all measures (Table Two-point-discrimination threshold before and after the intervention, MDT before and after the intervention, as well as current pain intensity before and after the intervention were significantly correlated (2PDTH: After 5 days of LF-rSS, performance in 2PD on the affected hand was impaired in all four patients (Figure After application of HF-rSS to the affected hand of CRPS patients on five consecutive days, performance in 2PD and mechanical detection significantly improved on the affected hand. The average gain in performance was about 10% for the 2PDTH and about 28% for the MDT. The mean current pain intensity was not reduced after HF-rSS, although individual patients showed a pain relief of 30% or more. The few patients receiving LF-rSS showed further deteriorated 2PD on the affected hand.Following HF-rSS, tactile acuity as measured by 2PD was significantly improved on the affected hand with an average gain in performance of about 10%. In other studies applying HF-rSS in healthy subjects, the gain in tactile acuity was in the range of approximately 10–20%, depending on whether one single digit or all digits of the hand were stimulated and whether HFS-rSS was applied for one single session or for longer periods , 40–42. In all of the four patients stimulated with LF-rSS, impaired 2PD performance was detected. This is in line with findings in healthy individuals after LF-rSS  stimulatFrom imaging as well as from studies measuring somatosensory evoked potentials in healthy persons –23 and iThe average current pain intensity of CRPS patients was not affected by the HF-rSS treatment; however, in four patients, pain decreased by at least 30%. Since studies from amputees with phantom limb pain , 44, 45 In all but two patients rSS applied by means of the hand pad was well feasible. In one patient, the hand pad was not suitable, because one finger could not contact the stimulation area for this finger on the pad due to a flexion contracture. In this case, we used adhesive electrodes to transmit the stimuli. In a second patient, we terminated stimulation with the hand pad after 3 days because this patient experienced the rigid position of the fingers during the third session as unpleasant. None of the patients reported the electric stimulation itself to be painful or unpleasant. Thus, HF-rSS with the stimulation device used in this study is suitable for the use in patients with CRPS of the upper limb. In rare cases where no sufficient contact of all fingers with the stimulation area is possible, adhesive electrodes could be used alternatively to apply HF-rSS pulses. Since an intact somatosensory input is essential for recovery of handfunction –49, the Our results demonstrate a good feasibility and efficacy of HF-rSS in CRPS patients to improve sensory loss, therefore providing an essential prerequisite for rehabilitation of handfunction. Qualitatively, stimulation effects were similar to those observed in healthy controls, indicating intact cortical processing of rSS stimuli in patients with CRPS type I. The limited impact on pain relief might be due to the short stimulation period. In order to further evaluate this, studies with an extended period of daily stimulation are needed.Marianne David, Hubert R. Dinse, Martin Tegenthoff and Christoph Maier hold patents about repetitive sensory stimulation applications. The remaining authors have no conflict of interest to declare.


Pain-related anxiety and fear are associated with increased difficulties in attention, increased awareness of pain, impaired disengagement from pain, and can moderate the effects of attentional coping attempts. Accurately assessing the direct impact of pain-related anxiety and fear on pain behavior has proved difficult. Studies have demonstrated no or limited influence of pain-related fear and anxiety on behavior but this may be due to inherent problems with the scales used. Neuroimaging has improved the understanding of neural processes underlying the factors that influence pain perception. This study aimed to establish if a Picture and Imagination Task (PIT), largely developed from the Photographs of Daily Activity (PHODA) assessment tool, could help explore how people living with chronic pain process information about daily activities. Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to compare brain responses in patients with chronic musculoskeletal pain (CMSKP) (n = 15) and healthy controls (n = 15). Subjects were asked to imagine how they would feel mentally and physically if asked to perform daily activities illustrated in PIT. The results found that a number of regions involved in pain processing saw increased BOLD activation in patients compared with controls when undertaking the task and included the insula, anterior cingulate cortex, thalamus and inferior and superior parietal cortices. Similarly, increased BOLD responses in patients compared to controls in the frontal pole, paracingulate and the supplementary motor cortex may be suggestive of a memory component to the responses The amygdala, orbitofrontal cortex, substantia nigra/ventral tegmentum, putamen, thalamus, pallidum, inferior parietal  and cingulate cortex were also seen to have greater differences in BOLD signal changes in patients compared with controls and many of these regions are also associated with general phobic responses. Therefore, we suggest that PIT is a useful task to explore pain- and movement-related anxiety and fear in fMRI studies. Regions in the Default Mode Network remained active or were less deactivated during the PIT task in patients with CMSKP compared to healthy controls supporting the contention that the DMN is abnormal in patients with CMSKP. The way in which chronic musculoskeletal pain (CMSKP) is perceived is modified by many factors –7; the sIn 2000, Vlaeyen and Linton  introducA number of studies have examined the impact of pain- and movement- related fear, anxiety and avoidant behavior on CMSKP patients undertaking physical activities aiming to investigate the association between movement-related fear and anxiety and behavioral performance –43. PartWhile pain-related fear and anxiety have important roles in understanding and managing chronic pain, accurately assessing their direct impact on pain behavior has proved difficult. Studies have used a range of physical capacity tasks that have demonstrated no or limited influence of pain-related fear on behavior , 43–45. Neuroimaging has improved the understanding of neural processes underlying the factors that influence pain perception –48. PainShimo et al  examinedBarke et al  investigThe study was designed to investigate how people living with CMSKP process information about daily activities by using an individually tailored Picture and Imagination Task (PIT) derived from the Photographs of Daily Activity Assessment Tool (PHODA) . From thFollowing Dyfed Powys Ethics Committee approval, participants who provided informed written consent were recruited for the study. Fifteen patients were recruited from a pain management program and a multidisciplinary pain clinic in South Wales. Fifteen age and sex matched healthy controls were recruited from the Cardiff University School of Psychology’s volunteer panel. Criteria for patient inclusion in the study were: a physician-diagnosis of chronic non- malignant pain ; non-inIn an interview conducted 2–4 weeks prior to scanning, patients were asked about their current medication, intensity of pain, and depression, kinesiophobia, catastrophizing and anxiety scores were obtained. All interviews were conducted by the same researcher (AT). Using a numerical rating scale (NRS), where 0 = no pain and 100 = the worst possible pain, patients were asked to indicate the number that best described the worst pain, least pain and average pain intensity over the previous week, average pain intensity over the previous three months and the degree to which the pain interfered with activities of daily living.Depressed mood was assessed using the Beck Depression Inventory (BDI) . The BDIThe Tampa Scale of Kinesiophobia (TSK) , 66 was Catastrophizing was assessed using the catastrophizing subscale from the Coping Strategies Questionnaire (CSQ-CAT) . The CSQThe activity pictures were taken from a previously validated tool to assess kinesiophobia in low back pain populations , PHODA. However, the tool itself was not appropriate for the purpose of this study as it requested participants to rate perceived harmfulness of an activity; we did not want to bias the neural responses by suggesting the activities were harmful. To ensure the PHODA pictures were salient for the patient participants, a pilot study had been previously performed using 20 patients with chronic osteoarthritis musculoskeletal pain, age and gender matched with 20 pain-free controls outside the scanner. Participants were asked to imagine how much pain and anxiety they would feel if they were asked to complete the activity represented in the photograph and rate both on a scale of 0 to 3 . Those activity pictures that were rated the highest for both anxiety and pain in the patient group were the ones that were used in the present study. No patient or matched control from the pilot was invited to participate in the present study.Six categories of activity pictures were viewed by the participants and these included exercise, twisting, bending, pull/push, carrying and lifting. Participants viewed 40 activity-related pictures. The seventh category was of 20 resting pictures. Thirty activity pictures were common to all subjects and consisted of 5 photographs from each activity category. During informed consent (between 2–4 weeks before scanning), patients were asked about the type of activity that was most troublesome for them to perform and also how best they rested. These activities were matched to photographs from PHODA and became the ‘bespoke’ pictures  and asked to imagine performing the activity. Participants were given these instructions ‘A photograph will be presented for 3 seconds. Study the photograph carefully and imagine that after scanning we will ask you to attempt this activity. Think about how this would make you feel. Imagine how you would feel both mentally and physically during your attempt.’Participants were asked to rate how anxious they would be in undertaking the activity shown after the picture was displayed within the scanner see  using a Each trial see  lasted bPrior to scanning, subjects completed a practice version of the task in a mock scanner lasting approximately 90s and consisting of 10 trials. All pictures used in the practice session were different to those presented in the scanning session. Thus, subjects practiced the task components of button pressing but were not exposed to the pictures used in the scanner. Responses were reviewed to ensure that the subject understood the task. Participants were asked if they felt comfortable in the mock scanner and were happy to proceed to the main scanner.3  for each participant.Imaging was performed on a 3 T MRI system  using an 8-channel receive-only head coil. E-Prime was used to deliver the functional stimuli. Functional MRI data were acquired with a gradient-echo, echo-planar imaging sequence, scanning parameters were: repetition time (TR)/echo time (TE) = 3000 ms/35 ms, 20.5 cm field of view, acquired on a 64 x 64 matrix with 53 contiguous 3.2 mm slices. Each run consisted of 236 volumes. For anatomic localization, a T1-weighted, three-dimensional fast-spoiled gradient echo acquisition was performed, with a voxel resolution 1x1x1 mmwww.fmrib.ox.ac.uk/fsl). Functional data for each subject was motion corrected (MCFLIRT) [Analysis of BOLD fMRI data was performed using FSL   and fielMCFLIRT) , 72. DatMCFLIRT) . BOLD imMCFLIRT) , 74 and MCFLIRT) .A general linear model was applied to analyze functional data . The first level analysis included three regressors; (1) the time of display of the picture, (2) the time of the response, (3) the presentation of the picture modulated by the demeaned anxiety response scores reported when viewing the picture. Each of these regressors was convolved with gamma-variate haemodynamic response function.p = 0.05 [A second level mixed effects analysis (FLAME)  was perfp = 0.05 .Thirty participants were scanned , age range 25 to 83 years old, including 15 patients with pain and 15 age-matched controls. Two patients were left handed and these were also matched to left handed controls. No differences were found between groups in marital status, years in school or number of dependents. Thirteen patients had previously undergone a diagnostic MRI scan and 9 volunteers had previously been scanned as participants in previous studies or for non-pain related clinical reasons. Pain scores, demographic data and psychological variables were compared between groups. Patients’ clinical characteristics are described in Patients and controls differed in pain scores and psychological variables .All patients were receiving opioids and all had received a course of physiotherapy, 9 had received education on self-management, but no patient had attended a pain management program or an expert patient program.p< 0.001) between patients and controls for all picture types (p< 0.001) between patients and controls for all activity pictures illustrating that patients perceived that the activities would result in moderate to severe pain.The anxiety ratings performed on the button box provided statistically significant differences (re types  illustraDifferences in BOLD responses were seen with patients showing greater activation compared to controls (patients > controls) when viewing the pictures, but not for the other two regressors representing the ‘rate now’ instruction and the button press response. There were no BOLD response differences in which controls showed greater activation compared to patients (controls > patients).In the initial second level analysis , BOLD signal differences during viewing of the pictures showed greater activation in patients compared to controls (patients>controls) in a number of bilateral cortical regions as illustrated in p<0.05. Z stat refers to the peak voxel. The z-stat comes from the corrected clusters, the z-stats themselves are not corrected Anatomical locations clustered in 3 areas: cluster 1–13219 voxels, cluster 2–3063 voxels and cluster 3–3176 voxels with a resolution of 2mm x 2mm x 2mm.Anatomical locations and peak activation co-ordinates (in MNI 152 space) extracted from brain regions that were found to be significantly different between patients and controls (patients > controls) at Z>2.3 and cluster corrected p<0.05. Z stat refers to the peak voxel. The z-stat comes from the corrected clusters, the z-stats themselves are not corrected. The anxiety related anatomical locations were all in one cluster with a size of 2409 voxels with a resolution of 2mm x 2mm x 2mm. The catastrophizing related anatomical locations were in four clusters, cluster 1 689 voxels, cluster 2 709 voxels, cluster 3 748 voxels and cluster 4 904 voxel with a resolution of 2mm x 2mm x 2mm.In the supplementary second level analysis, BOLD responses during the picture task were positively correlated with higher anxiety scores and higher catastrophising scores across the group as a whole and these regions are illustrated in The accompanying analysis using TSK scores did not reveal any BOLD signal correlations across the group in either comparison .The PIT was developed, using pictures from PHODA, to investigate BOLD signal changes in patients compared to controls when viewing pictures of daily activities. We found that a number of pain processing regions including the insula, ACC and inferior and superior parietal cortices were seen to have increase BOLD responses in patients compared to controls in response to observing the photographs and rating the perceived level of anxiety at performing the activity. Similarly, increased BOLD responses in patients compared to controls in the frontal pole, paracingulate and the supplementary motor cortex may be suggestive of a memory component to the responses. The left amygdala, bilaterally the insula and the orbitofrontal cortex, substantia nigra/ventral tegmentum, putamen, thalamus, pallidum, inferior parietal  and cingulate cortex were also seen to have differences in BOLD signal changes in patients compared with controls and many of these regions are also associated with general phobic responses . TherefoA previous study by Shimo et al  in theirThe movement-related anxiety and fear associated with PIT, we believe, is part of a process that involves regions involved in the affective-motivational dimension of pain which appraises the value of the stimuli and motivates subsequent behavior and regions associated with anxiety. Regions involved in the affective-motivational dimension of pain were observed in patients compared with controls in the initial second level analysis when undertaking PIT and they include the insula cortex and rostral ventral ACC , inferioRegions involved in the cognitive-evaluative dimension, also saw increased BOLD responses in patients compared with controls during the PIT task. It has been shown that when individuals view pictures of body parts in painful situations, regions such as the inferior parietal cortex and ventral premotor areas are activated . The joiHigher anxiety ratings and catastrophizing scores correlated to BOLD activation in the lateral occipital cortex, precuneus, lingual gyrus and temporal occipital fusiform gyrus. Anxiety ratings also showed increased BOLD activation in the occipital pole, intracalcarine cortex, and cuneal cortex and higher catastrophising scores in the inferior and middle temporal gyrus, multiple regions in the cerebellum and brain stem. Since both catastrophizing and diffuse inhibitory noxious control are involved in pain processing, they may be associated with each other. Evidence does exist to support this based on connectivity between brain areas associated with catastrophizing , 89 and The occipital and calcarine regions of the visual cortex can be modulated by emotional visual stimuli , 99 withComparison of patients and controls when undertaking PIT illustrated increased BOLD activity in patients in a number of regions involved in memory processing such as the frontal pole , paracinIn their quantitative meta-analysis, Etkin and Wager  revealedThe insula is strongly interconnected with the amygdala, hypothalamus and periaqueductal gray (PAG)  regions The anterior mid cingulate cortex (aMCC) demonstrated increased BOLD signal changes in patients compared to controls, lateralised to the left, during PIT . This region is part of an intrinsic brain network that shows increased activity when stimuli in the environment are personally salient . The aMCOur patients rated themselves as low kinesiophobics on the TSK, scoring well below the cut-off point between low and high kinesiophobics at a score of 37 . This waPast reviews have suggested strong support for the Fear-Avoidance (FA) Model , 30, 123Changes in Default Mode Network (DMN) activity appear to occur as a result of chronic pain. The DMN is the network that decreases its activation during a task compared to the average brain activity at rest and includes the precuneus, PCC and medial frontal cortex , 130. RePatients continued with their routine medications and no new drugs were commenced three months prior to the study. There are problems in studying patients with severe and complex chronic pain, such as seen in those referred to specialist pain centers. Problems exist in extricating pain-related effects from those resulting in pain treatments, especially opioids . TherefoGiven the age ranges and the known interactions between age and brain structure in chronic pain, there may be an age by group interaction that would add variability to the data but the sample size was too small to test such an interaction. The heterogeneity in age, pain sites and duration of pain across patients does adds variability to the study. However, the impact of the heterogeneity is that statistical significance is harder to achieve and had the patient group been more homogenous, our results may have been more significant.The Picture and Imagination Task (PIT), largely developed from the Photographs of Daily Activity assessment tool  was desi


Katakori is a symptom name that is unique to Japan, and refers to myofascial pain syndrome-like clinical signs in the shoulder girdle. Various methods of pain relief for katakori have been reported, but in the present study, we examined the clinical effects of multi-acupuncture point injections (MAPI) in the acupuncture points with which we empirically achieved an effect, as well as the anatomical sites affected by liquid medicine. The subjects were idiopathic katakori patients (n = 9), and three cadavers for anatomical investigation. BL-10, GB-21, LI-16, SI-14, and BL-38 as the WHO notation were selected as the acupuncture point. Injections of 1 mL of 1% w/v mepivacaine were introduced at the same time into each of these points in the patients. Assessment items were the Pain Relief Score and the therapeutic effect period. Dissections were centered at the puncture sites of cadavers. India ink was similarly injected into each point, and each site that was darkly-stained with India ink was evaluated. Katakori pain in the present study was significantly reduced by MAPI. Regardless of the presence or absence of trigger points, pain was significantly reduced in these cases. Dark staining with India ink at each of the points in the anatomical analysis was as follows: BL-10: over the rectus capitis posterior minor muscle and rectus capitis posterior major muscle fascia; GB-21: over the supraspinatus muscle fascia; LI-16: over the supraspinatus muscle fascia; SI-14: over the rhomboid muscle fascia; and BL-38: over the rhomboid muscle fascia. The anatomical study suggested that the drug effect was exerted on the muscles above and below the muscle fascia, as well as the peripheral nerves because the points of action in acupuncture were darkly-stained in the spaces between the muscle and the muscle fascia. Katakori is a symptom name that is often used in Japan. There is no clear definition for katakori, but it can be summarized as "subjectively, when there is discomfort, spontaneous pain, and mild pain on motion in the neck, upper scapula region, scapula region, or interscapular region; and objectively, when these muscles tense abnormally when palpated, and there are tender points or stiffness in specific sites" [Katakori is a combination of subjective sensation and objective sensation" [katakori (stiff shoulder) in the Japanese government survey of 2013 has increased with advancing age [Katakori is higher for both males and females in the all person with subjective symptoms in Japan, is a great matter of national concern. Katakori can be induced as part of a systemic disease, but can also be induced even without organic disease [Katakori commonly affects posture/balance and lifestyle, and MPS does as well [katakori often visit medical organizations, but also may visit civilian agencies for folk therapies such as massage and chiropractic services. Therefore, it is difficult to grasp the overall picture about this symptom. In turn, MPS is characterized by pain in muscle groups associated with the presence of trigger points (TrPs). These points are small hard nodules within a firm taut band of muscle as assessed by palpation with characteristic pain patterns [katakori and MPS. Also, the active TrPs seen in MPS normally restrict the joint range of motion and produce a local twitch response (LTR) caused by mechanical stimuli as well as related pain in the muscles [katakori symptoms which do not meet the definition of MPS and TrPs. The TrPs in MPS are often known to coincide with acupuncture points, and Melzack et al reported that 71% of acupuncture points coincided with TrPs [katakori as well as the MPS. We have extensive clinical experience with the injection of the acupuncture points in numerous katakori patients. Acupuncture points in MPS, which are thus clinically important, could possibly also play a major role in the onset of katakori; therefore, we empirically performed multi-acupuncture point injections (MAPI) at various acupuncture points including BL-10, GB-21, LI-16, SI-14, and BL-38  classification names [katakori meanwhile various therapies could be available to this date. Acupuncture points in this study are conditioned not to patients’ reactions against mechanical (push) stimulations but in a matter-of–fact style on the basis of the definition of acupuncture points. We also emphasize that it is difficult katakori from MPS of the shoulder girdle by definition. A solution in MAPI would be developed into musculatures to a certainty, but has not elucidated anatomically to the present. We postulate that the muscle on the shoulder girdle takes part in katakori. The present study examined the clinical results in patients whose chief complaint was katakori, in whom organic disease was excluded, and who underwent MAPI. Injections were likewise made into cadavers, and basic anatomical research was performed in order to assist with the clinical interpretation. The approach to acupuncture points is also improved symptoms by only stimulation such as acupuncture, dry needling, or saline injection to acupuncture points [c sites" . It is unsation" , and dem as well , 5 that patterns . The synpatterns , 8. In t muscles , 10; oft muscles . We alsoith TrPs . Moreovee points , 14–19. katakori patients without an underlying disease  from January 4, 2013 to December 28, 2013. Because this study was a retrospective investigation, written/oral informed consent for participation in this study was determined to be unnecessary by the ethics committee. The clinical findings and courses were gathered from past medical records, which limited access to the participants’ backgrounds. All patients were asked about the location of any pain. They underwent general examinations based on their complaints, and were palpated for tender points (PTs) confined to the local area and for the presence or absence of TrPs with related pain. The points used for acupuncture injection were as follows: BL-10, GB-21, LI-16, SI-14, and BL-38 , we retrospectively studied nine nd BL-38 . We deciThis portion of the study concerned the dissections of three Japanese female cadavers  from the anatomy laboratory of the Tokai University School of Medicine (from the Association of Tokai University donations), Japan, during routine educational dissections carried out in 2013 . The neekatakori (without related pain) and the presence or absence of TrPs . PTs were present in nine out of nine patients, whereas TrPs were present in three out of nine patients. Similarly, katakori patients, and the change in both the PRS and effect period from this treatment. An LTR did not necessarily appear in the same places as the TrPs, and an LTR was often induced even in the absence of a TrPs. p = 0.00000296) in the nine patients, and even the three cases in which TrPs were present showed a significant decrease (p = 0.0345), with a therapeutic effect obtained regardless of the presence or absence of TrPs. This effect period was 6.33 ± 4.2 days , eye diseases, hypertension, and stress. In addition, we have encountered katakori's patients that have had shingles and cancer. The prevalence in a study of migraines of patients that were more than 15 years of age in Japan was estimated to be 8.4% [katakori appeared as a sign of migraine. Tenderness of the skull around the trapezius muscle has also been observed in tension-type headaches [katakori. Since an increase in local inflammatory factors were not observed at the tender points in the trapezius muscle with the chronic tension-type headache [katakori in chronic headache has been identified as factors of the central hypersensitivity [katakori can have a broad range of causes, and to lump all katakori together as one disease without consideration for the causes can be dangerous. Katakori in the present study is the idiopathic type rather than the symptomatic one. Therefore, the number of cases was limited (retrospective study).The number of persons who had subjective symptoms of  be 8.4% ; there headaches , 28. It eadaches . Empiricheadache , katakorsitivity . In thiskatakori. However, by definition, the presence of TrPs can be mentioned as one of the things that dictate the difference between the two. The points  where the participants in the present study who had pressure pain were therefore further divided based on whether or not there was any accompanying related pain, classified as TrPs or (in a narrower sense) PTs, respectively. Of these, TrPs were present in 33.3% (3/9) of the patients. The narrowest sense of PTs, meaning those that did not meet the definition of TrPs, were present in 100.0% (9/9) of the patients, and MPS was included in the subject patients. With MPS, it has been shown that an LTR was induced with the mechanical stimulus of TrP injection [katakori) may be closely related to the broad definition of MPS in the shoulder girdle, and MAPI for idiopathic katakori patients may be an effective means of treatment similar to the TrP injections by Graboski et al [et al [et al [et al [katakori patients, leaving room for investigation based on these points in the future. In addition, whereas the search for TrPs is technically dependent on the level of experience and expertise, treatment by MAPI would also be effective even with physicians with little experience or expertise.It is not possible to clearly differentiate MPS in the shoulder girdle from  33.3% 3/ of the pki et al , Iwama el [et al , and Kirl [et al . It is pl [et al , but amoKatakori unlike the pathogenesis of MPS, can also be induced by muscle abnormalities. The relationship of katakori and MPS may not be clear for the classification of either katakori or MPS. In this study, tenderness was present in all katakori patients, but tenderness, LTR, and TrPs did not exist together at all acupuncture points. Heine [katakori. Mepivacaine reversibly inhibited the conduction of action potentials in the somatic and autonomic nerves. Moreover, “The effect of inhibition of central sensitivity enhancement” is one of the effects of sensory nerve block. Central nerve related to the each acupuncture points  has been shown to be involved in the anterior and posterior branches of C1-C6. Effect of MAPI might be trying to suppress the sensitivity of pain by coordinated action of their central nervous system. There also seems to be a contribution to the pain relief of katakori due to a pain relief effect and muscle tension relaxation due to nerve blocking as well as an "effect of cutting off the vicious cycle of pain" that may be based on these actions. In light of the autopsy findings, traveling of the suprascapular arteries and nerves, and the vertebral arteries in the suboccipital triangle region was observed in some of the gaps, and therefore careful attention must be paid to acute local anesthetic intoxication and hematoma formation during implementation. To our knowledge, the present study is the first report on issues pertaining to the therapeutic response of MAPI for katakori including MPS.s. Heine  found ths. Heine –17, 38 as. Heine , but alss. Heine –42. Therkatakori [et al [et al [et al (≤7 days) [et al (3.0 ± 3.08 days) [et al [katakori, and they measured the tissue oxygen saturation after exercise with near-infrared spectroscopy in volunteers. They pointed out that the katakori group had a significantly greater recovery latency from circulatory impairment associated with an exercise load at the trapezius muscle, especially at a site that corresponded to GB-21, than the non-katakori group. The main feature of the integrated trigger point hypothesis is the presence of excess acetylcholine receptors at the neuromuscular junction; acetylcholine stimulates the voltage-gated sodium channels in the sarcoplasmic reticulum and persistently elevates the intracellular Ca2+ levels, therefore producing muscle contractures [2+, and inflammatory cytokine release [The flexors and extensors are physiologically regulated and controlled by the reciprocal innervation of Ia suppression and Ib suppression. However, it is believed that persistent noxious input to the skeletal muscle causes this control mechanism to fail; it also produces an energy supply shortage in the muscles, where local ischemia develops and causes the release of endogenous pain-producing substances and a decrease in the reaction threshold of polymodal receptors (an energy crisis ), leadinkatakori –47. In tkatakori –47. As si [et al  or Kirall [et al , who use≤7 days)  and Grab08 days) , who bot) [et al  speculatractures , 49. Thiractures , 50, 51. release , 52, 53, release . As such release , which i release , 56. Theet al [katakori patients in this study were not present at a high frequency compared to Melzack et al’s report [katakori and the neck and shoulder portion of MPS [katakori. Each acupuncture point is a non-anatomical pathway that leads to the empirical specific meridians of Chinese traditions. However, the connection of the trigger points has not been demonstrated. For this reason, katakori and MPS may need to be considered separately.TrPs in MPS have been often known to coincide with acupuncture points, and Melzack et al  reporteds report . Thus, tn of MPS  are diffkatakori that was subject to central sensitization in this manner. As such, though symptomatic katakori patients, who may have complex conditions, were excluded from the subjects in this study, there may be room for further investigation from this viewpoint in the future.The above considerations show that MAPI is effective for the relief of pain and muscle tension at the peripheral level. However, for example, with chronic tension-type headaches, there is no inhibitory mechanism of muscle contraction by the lateral intermediate neurons of the pontine tegmentum, which communicate with the trigeminal motor nuclei of the brain stem and spinal cord , 59, witkatakori, to which the myotonia on the shoulder girdle could contribute, from this viewpoint. Idiopathic type katakori patients do not have any organic diseases, and might relate to factors of each life background such as posture and stress. This study indicates that muscles in katakori patients are innervated by anterior and posterior branch of spinal nerve of C1-C6. These factors concerned in katakori onset might overstress to the shoulder girdle muscles. We note that subjects in this study are not symptomatic but idiopathic patients, and these conditions are not equated with. In the future studies would promise to get along with aout anatomical structures in both type of katakori.MAPI might be effective for idiopathic type S1 FigWe were allowed to wear a belt to the upper body of the cadaver (both armpits), which was lifted by a crane for 15 min.(ZIP)Click here for additional data file.