Building on the recent finding that chronic pain patients with impaired functioning of the descending nociceptive inhibitory system (DNIS) present lower resting heart rate variability (HRV), this study aims to investigate the impact of Spinal Cord Stimulation (SCS) on HRV in patients with Failed Back Surgery Syndrome (FBSS). More precisely, we hypothesize that SCS influences the DNIS, with increased parasympathetic tone as a consequence, as measurable by HRV analysis.Twenty-two patients diagnosed with FBSS and treated with SCS participated in this study. HRV was measured with a 2-lead ECG registration tool during on and off states of SCS. HRV analysis for time, frequency, time-frequency and nonlinear domain parameters was based on a 5-minute recording segment.The mean heart rate and low frequency power were significantly lower when SCS was activated. HRV, absolute and normalized high frequency power significantly increased during SCS compared to without SCS. The ratio of low frequency/high frequency ratios, as parameter for global sympathetic-parasympathetic equilibrium, significantly decreased when SCS was activated.When SCS is switched off, patients with FBSS present relatively stronger sympathetic tone and weaker parasympathetic activity. Activation of the SCS, possibly via stimulation of the DNIS, restores this disbalance of autonomic activity. It has previously been suggested that traditional, paresthesia-generating, Spinal Cord Stimulation (SCS) induces several changes in modulation circuits located in the cerebrum and brainstem. An inhibitory effect of traditional SCS on somatosensory evoked potentials, and potential key regions like the thalamus and the anterior cingulate cortex, could play a role in the mechanism of action of SCS as well –4. SeverIn healthy subjects, the autonomic nervous system (ANS) is in harmonic balance between the excitatory sympathetic and inhibitory parasympathetic systems. Dysregulation of the ANS has been suggested in chronic pain patients with an overweight of sympathetic activation , 17. ThiHeart rate variability (HRV) is the variability in the interval between successive heart beats and is a sensitive predictor of the capacity to regulate emotional responses to threatening intrinsic and extrinsic stressors . HRV hasRecently, the relationship between the DNIS and HRV has been investigated for chronic pain patients, showing that patients with impaired DNIS presented lower resting HRV . EndogenUp to now, only a very small case series with only 7 patients with chronic pain (among which 2 patients with FBSS) is available, with promising results towards the influence of SCS on the ANS . TherefoFBSS patients (at least 18 years old) who are treated with SCS at the department of Neurosurgery of Universitair Ziekenhuis Brussel were invited to participate in this study. Patients were excluded if they had one or more coexisting conditions known to affect HRV analysis  .Of the 40 patients who were contacted to participate, 26 patients agreed to take part in this study. Patient recruitment started on 29/11/2018 and lasted until 21/12/2018. Three patients cancelled their visit on the day of the study visit, wherefore only 23 patients were included. One patient had not switched off the neurostimulator and was therefore excluded, resulting in a total study population of 22 patients. The flow chart of this study is presented in Six males and 16 females participated in this study with an average age of 55.09 ± 7.63 years. The mean duration that patients were implanted with SCS was 937 ± 648 days. All patients received SCS at level (D8)-D9-D10 and were implanted with either a Senza rechargeable system  with 2*8 contacts or a Restore SensorTM SureScan system connected with a SpecifyTM 5-6-5 SureScan MRI surgical lead . SCS was delivered with a median charge per pulse of 0.105 (0.06–0.7) μC, median charge per seconds of 550 (49.5–750) μC/sec and a median duty cycle of 30 (25–30) %. Twelve patients supplemented their pain treatment with opioid use and 8 patients were also taking beta-blockers .The study protocol was approved by the local ethics committee of Universitair Ziekenhuis Brussel (B.U.N. 1423201837785) on 21/11/2018 and registered on clinicaltrials.gov (NCT03768791) on 28/11/2018 (released on 7/12/2018). The authors confirm that all ongoing and related trials for this drug/intervention are registered. All patients provided written informed consent before participation. The study was conducted according to the revised Declaration of Helsinki (1998).The study consisted of a single outpatient visit. Patients were asked to switch off their SCS 12 hours before the study visit. All patients were verbally asked to confirm that they switched off SCS 12 hours before the study visit. This statement was also controlled with the aid of the device programming systems. During the study visit, a 5-minute inter-beat (RR) interval measurement was recorded, where after patients were asked to provide a pain intensity score for their back and leg pain. After having filled in the questionnaire, the neurostimulator was switched on again. After a resting period of 40 minutes, RR intervals were registered for 5 minutes and patients again rated their pain intensity. Blinding of patients was not possible, due to the pain relieving effect of SCS that patients felt.Patients were asked to refrain from alcohol, tobacco, caffeine and drug consumption 24 hours before the study visit . There wAll participants completed a visual analogue scale (VAS) for assessment of the pain intensity. Pain intensity scores were provided separately for back, left leg and right leg pain. The VAS ranged from no pain to the maximal pain and is expressed in cm from 0 to 10. Patients completed this pain intensity score twice; once after RR registration when SCS was switched off and once after RR registration when SCS was activated. The VAS pain score is broadly accepted as a reliable and valid tool that is sensitive to change –35.RR recordings were made with a non-invasive 2-lead ECG registration tool ). The eMotion device is validated for individuals without arrhythmia  and has The ECG signals were saved as text (.txt) files in the eMotion LAB software and a 5 minute segment was selected for off-line analysis using the heart rate variability analysis software (HRVAS) . PreprocHRV analysis was performed in the four major domains being the time, frequency, time-frequency and nonlinear domain. In the time domain mean inter beat interval (IBI), heart rate (HR), standard deviation of normal-to-normal R-R intervals (SDNN), root-mean-square of successive differences of normal-to-normal heart beat interval (RMSSD), HRV triangular index (TI) and triangular interpolation of normal-to-normal heart beat interval histogram (TINN) were calculated.In the frequency domain, spectral power was computed and divided into four frequency bands: ultra low frequency (ULF) from 0 to 0.0033 Hz, very low frequency (VLF) from 0.003 to 0.04 Hz, low frequency (LF) from 0.04 to 0.15 Hz and high frequency (HF) from 0.15 to 0.4 Hz . These fTime-frequency analysis, which enables viewing time and frequency information, was performed with a windowed Burg periodogram (window 30 sec with 15 sec overlap). This procedure consists of resampling the data series and breaking into consecutive segments of equal length . The powNonlinear techniques such as Poincaré plot analysis , sample entropy  and detrended fluctuation analysis (to assess self-similar properties of non-stationary time series) were also calculated , 47. Poi2 were used in the current calculation. The minimal total sample size should reach 24 patients, based on two-tailed testing with alpha = 0.05 and a desired power of 0.95.Sample size calculation was performed using G*Power 3.1.3  based on the HF HRV component of a previously reported study in patients with FBSS . Mean HFAll analyses were performed in R Studio version 0.99.903. Normality was controlled with the Shapiro Wilk test and QQ-plots and equality of variances by Levene’s tests. Descriptive statistics are provided as mean (± SD) or as median (interquartile range). Differences in pain intensity scores between the on and off state of SCS were calculated with Wilcoxon tests. HRV data in the four domains between the on and off state was compared with paired t-tests or Wilcoxon tests. P values of 0.05 or less, were considered statistically significant.There was a significant decrease in back pain intensity when SCS was switched on (VAS when SCS off: 6.2 (Q1-Q3: 4.3–7.5); VAS when SCS on: 4.3 (Q1-Q3: 1.4–5.8) . Leg pain intensity at the symptomatic side revealed a significant decrease when SCS was functioning (off: 5.5 (Q1-Q3: 4.3–7.6), on: 4.3 (Q1-Q3: 1.8–5.8) ).Individual data on HRV parameters can be found in The mean HR was significantly lower when SCS was switched on (SCS off: 65.9 beats per minute (bpm) (60.33–70.88); SCS on: 61.55 bpm (55.15–70.33))  . There w2 (33.67–163.22) and SCS on: 114.17 ms2 (27.5–285.21); . Post hoc analyses through an unpaired Wilcoxon tests revealed that the differences in absolute HF power were not explainable by sex , nor the use of beta-blockers  or opioids . Normalized HF significantly increased with SCS (t(21) = -2.52, p = 0.02). No differences were found in LF/HF between both states   = 2.52, p = 0.02), yet absolute LF power was not significantly different between both states . Both absolute and normalized HF power were significantly higher when SCS was switched on: absolute HF power with SCS off: 66.48 ms = 0.13) .Normalized LF significantly decreased when SCS was switched on compared to switched off (t(21) = 3.04, p = 0.006) , while aNo statistically significant differences could be revealed when comparing SCS on versus SCS off in the nonlinear domain .This study investigates the influence of SCS on various HRV parameters by comparing cardiovascular autonomic modulation between the on and off states of SCS in patients with FBSS. The predefined hypothesis that SCS leads to an increase of the parasympathetic component, which is captured by HF power, can be confirmed by the increase in HF and decrease in LF oscillations when patients activate their SCS.Besides the well-known spinal segmental mechanisms of SCS, supraspinal loops were already postulated as important contributors to the inhibitory effect of SCS in 1986 . An incrHRV offers a minimally-invasive measurement for the autonomic nervous system activity. HF oscillations are often denoted as a surrogate measure of vagal activity while LF oscillation are considered as a combination of sympathetic and vagal activity . The ratTransmission of nociceptive information from the periphery is suppressed by the DNIS and the interface between autonomic and sensory systems . ImpaireCurrent literature on this topic is limited to a small case series exploring the effect of SCS on HRV parameters in seven patients with chronic pain, among which two patients with FBSS . A decreIn the time domain, an increased HRV and decreased HR were found when SCS was enabled. Both parameters have an overlapping distribution when comparing these variables during on and off modes of SCS. This demonstrates that both measurements are highly individually determined . SCS is HRV holds the potential to objectify pain intensity since an increase in parasympathetic nervous activity, as measured by HRV parameters, may indicate pain relief . The useWe report the largest cross-over study investigating the effect of SCS on HRV in a population of patients with FBSS. The study was conceived with a very specific working hypothesis in mind, which has been confirmed. Though this is the largest study population reported in literature, we need to acknowledge that the sample size is insufficient to evaluate the effect of confounders or mediators on the relation between SCS and HRV parameters. Future studies are required for confirmation of the beneficiary effects of SCS on HRV in patients with FBSS and also to evaluate the role of potentially influencing factors . Additionally, the authors did not correct for multiple testing, which could have resulted in false positive results. When applying the Simes procedure to correct for multiple testing, the normalized LF and HF in the frequency domain and the rLF/HF in the time-frequency domain are not statistically significant anymore . This meRelying on the assumption that HRV measurements provide information on the sympathetic and parasympathetic system, patients with FBSS present a dominant sympathetic tone and “under-utilization” of the parasympathetic system when SCS is switched off. SCS reduces this dominance of the sympathetic system and increases the parasympathetic influence. Activation of SCS may influence HRV via activation of the DNIS.


In particular, the multiscale nature of local connectivity properties in various brain regions is still unclear. Here, we used voxelwise Kendall's coefficient of concordance (KCC) and coherence (Cohe) regional homogeneity (ReHo) in the typical (0.01–0.1 Hz) and five specific frequency (slow-6 to slow-2) bands to analyze individual whole-brain resting-state functional magnetic resonance imaging scans in 25 persistent LBLP patients (duration: 36.7 ± 9.6 months) and 26 healthy control subjects. Between-group differences demonstrated significant alterations in the KCC- and Cohe- ReHo of the right cerebellum posterior lobe, brainstem, left medial prefrontal cortex and bilateral precuneus in LBLP patients in the typical and five specific frequency bands, respectively, along with interactions between disease status and the five specific frequency bands in several regions of the pain matrix and the default-mode network . The altered ReHo in the five specific frequency bands was correlated with the duration of pain and two-point discrimination, which were assessed using partial correlational analysis. These results linked the course of disease to the local connectivity properties in specific frequency bands in persisting LBLP. In future studies exploring local connectome association in pain conditions, integrated frequency bands and analytical methods should be considered.Increasing evidence has suggested that central plasticity plays a crucial role in the development and maintenance of (chronic) nonspecific low back pain. However, it is unclear how local or short-distance functional interactions contribute to persisting low back-related leg pain (LBLP) due to a specific condition ( •This study demonstrated significant interactions between disease status and five specific frequency bands in several regions.•The alterations in ReHo of five specific frequency bands were related to the duration of disease and 2-PD in LBLP patients.•It is useful to select specific frequency or the method of analyses to improve the detection of LBLP-related brain activity. Most paIn previous neuroimaging studies of low back pain, white matter structural damage , corticaIn more recent studies, resting-state functional magnetic resonance imaging (rs-fMRI) has become a state-of-the-art method for decoding the local and remote functional properties of physiological and pathological conditions, including autism, depression, schizophrenia, chronic pain and others . FunctioIn this study, we hypothesize that the local property of intrinsic brain activity is impaired when LBLP patients experience persistent pain and paresthesia (numbness). For this aim, two ReHo methods for rs-fMRI based on Kendall's coefficient of concordance (KCC) and coherence (Cohe), proposed by In accordance with the abovementioned situation, we used KCC- and Cohe-ReHo to explore local features of the resting brain connectome across multiple frequencies in patients with LBLP. Moreover, associations between ReHo and clinical evaluations of pain intensity and tactile discrimination ability were assessed.22.1e.g., sneezing, coughing); and (4) failure to respond to conservative treatment with medications within at least the month prior, e.g., anti-inflammatory drugs  and acetaminophen  without opioids, exercise and physical therapy  were recruited from our hospital and from the local community from Oct. 2016 to Jun. 2017. The LBLP patients were included according to the following criteria: (1) age 35–65 years old and volunteered to enroll in the study; (2) clinically and radiologically diagnosed with clear evidence of discogenic compression on a lumbar CT and/or MRI (>1 ruptured annulus fibrosus with compressed soft tissue); (3) pain  score > 4) with radiating pain in the buttock(s) and lower limb(s), particularly under increased abdominal pressure  sequence (repetition time (TR)/echo time (TE) = 1900 ms/2.26 ms, field of view (FOV) = 215 mm × 230 mm, matrix = 240 × 256, thickness/gap = 1.0/0 mm and 176 sagittal slices) and rs-fMRI  were acquired.All MR images were acquired with a Trio 3.0-Tesla Siemens scanner with a standard 8-channel head coil . Foam padding was used to minimize head motion and machine noise, and subjects were asked to keep their eyes closed and not to fall asleep  questionnaire). A high- resolution 3D-T2-weighted and T2-fluid-attenuated inversion recovery (FLAIR) sequences were acquired to screen all subjects for anatomical brain abnormalities. Sagittal and axial conventional T1-weighted, T2-weighted and T2-fat suppression sequences were acquired for the lumbar spine and discs from L1 to S3 for the diagnosis of LBLP.Additional conventional T2.33 cube voxels; and head motion estimation, >2.0 mm of the maximal translation or 2.0° of the maximal rotation, was excluded from the final analysis. Linear detrending and nuisance linear regression  based on statistical parametric mapping , which was run on MATLAB 8.4.0 .The main preprocessing steps of rs-fMRI included the following: the first 10 volumes were discarded for signal stabilization and subject adaptation; then, slice timing, spatial realignment, head motion correction, individual registration between high-resolution T1 and echo planar imaging (EPI) images, T1 segmentation with the Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra (DARTEL) and spatial normalization to register rs-fMRI data sets to the Montreal Neurological Institute (MNI) space were performed, along with resampling to 3 × 3 × 3 mmer model ) were peer model  (http://2.4(1) Predefined settings were used to calculate the ReHo; to investigate local features of the resting brain connectome in patients with LBLP, the preprocessing of the rs-fMRI data divided the data into a typical frequency band (0.01–0.1 Hz) and five specific frequency bands: slow-6 (0–0.01 Hz), slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), slow-3 (0.073–0.198 Hz) and slow-2 (0.198–0.25 Hz), according to the Buzsáki framework .http://restfmri.net/forum/RESTplusV1.2). The KCC-ReHo detailed mathematical formula was as follows . According to this equation, a larger value of a given voxel (node) indicated higher local FC or network centrality in three aspects with the following advantages: acquired the connectivity strength interaction with nearest neighboring nodes; high-efficiency rank-based computation; and robust against noise by integrating the spatial domain (the mean-rank filter) and noise-filtering of the temporal domain (the order-rank filter) .(2) Individual KCC-ReHo mapping: KCC of the predefined frequency band time series of each voxel relative to nearest neighbors (26 in this study) was calculated within the whole brain using the Resting-State fMRI Data Analysis Toolkit plus V1.2 KCC=∑XnT)((λ) is the discrete Fourier transform of the nth segment of timeseries x(t). Second, estimation of coherence across predefined frequency bands and their band-averaged estimates of the cross spectrum and power spectra were calculated (in (3) Individual Cohe-ReHo mapping: calculating the Cohe-ReHo of the predefined frequency band time series of each voxel included the three following steps . First, lated in :(4)CohxyK=27):Finally, the averaged coherence coefficient of the cluster within the given cluster was calculated to represent the Cohe-ReHo of its center voxel  for pain intensity, the Japanese Orthopaedic Association (JOA) Back Pain Evaluation questionnaire (−6 to 29) to examine the impact of neuropathic or nociceptive pain on quality of life , the Fug2.6via Fisher's r-to-z standardization within a whole-brain mask; then, the resulting data were further spatially smoothed using a 6-mm isotropic full width at half maximum (FWHM) Gaussian kernel.Before statistical analysis, the individual KCC-ReHo and Cohe-ReHo maps were generated t-tests were performed on individual zReHo data with smoothing in a voxel-by-voxel manner  theory correction with cluster-level P < .05). To calculate the interactions between pain status and the five specific frequency bands on the ReHo map, we performed an ANOVA  using SPM12 with the groups (LBLP and HC) as the between-subject factor and the frequency band (slow-2 to slow-6) as the within-subjects factor . All significant clusters were reported on the MNI coordinates, and T-values of the peak voxel were determined. Cohen's d was computed using a between-groups t-test value for effect size analysis. Cohen's d can be interpreted in terms of the percent of nonoverlap between two groups, while “d = 0.2,” “d = 0.5,” “d = 0.8” and “d = 2.0” indicated nonoverlaps of 14.7%, 33.3%, 47.4% and 81.1% in the two distributions, respectively.Group mean z-values of KCC-ReHo or Cohe-ReHo were calculated for estimating the spatial patterns or distribution of the predefined frequency bands in the patients with LBLP and HC. To explore the differences in the KCC-ReHo or Cohe-ReHo between the LBLP and HC groups in the typical frequency band and five specific frequency bands, second-level random-effects two-sample t-tests and chi- square tests in SPSS  to explore differences between groups.Clinical characteristics and index statistics were analyzed using two-sample P < .05 with Bonferroni corrections).In addition, clinical associations were analyzed by partial correlational analyses in the SPSS 13.0 software between the clinical evaluation and zReHo values for brain areas that exhibited significant differences between the LBLP and HC groups, with the effects of age, gender and mean head motion as covariates  subjects were selected for the group ReHo comparison. Among these patients, 25 (100%) patients presented with low back pain (duration: 36.72 ± 9.63 months), 23 (92%) patients also presented with pain and numbness in a unilateral lower limb and 2 (8%) patients also presented with pain and numbness in bilateral lower limbs. Among the patients, the significantly low JOA Back Pain Evaluation scores  indicated an effect on quality of life due to neuropathic or nociceptive pain, and high VAS scores  indicated tolerable or moderate pain. The mean Fugl-Meyer score was 19.2 ± 4.3 (range from 15.0 to 24.0). In the tactile spatial resolution ability assessment, decreased 2PD test scores in LBLP patients were observed in the right (30.60 ± 1.62 mm) and left (30.00 ± 1.17 mm) feet and the right (24.96 ± 1.22 mm) and left (26.24 ± 1.27 mm) hands, which indicated cortical reorganization of, for instance, somatosensory cortices. Finally, there were no significant differences in age , gender  or head motion  between the patients and HCs.Among the participants, 3 patients and 4 healthy subjects were excluded due to excessive head motion. In addition, 2 patients were excluded for a vascular malformation and an infarction. Ultimately, a total of 25 persistent LBLP patients and 26 HC , the patients with LBLP were observed to have a roughly similar spatial distribution of KCC-ReHo or Cohe-ReHo to that of the HCs and higher KCC-ReHo and Cohe-ReHo in the regions (including the PCC/precuneus (PCUN), medial prefrontal cortex (mPFC) and bilateral inferior parietal lobule (IPL)) belonging to the DMN, indicating higher local connectedness . In the 3.3P < .01, GRF correction). In the KCC- and Cohe-ReHo analyses of the typical frequency band, identical commonly altered regions were mainly found in the right cerebellum posterior lobe (CPL), brainstem, left mPFC and bilateral PCUN . KCC-ReHo detected more regions  and several regions of the DMN  in both the KCC- and Cohe-ReHo analyses  and the Cohe-zReHo of the bilateral Rec at slow-6 (P = .035) significantly correlated with duration of disease; the Cohe-zReHo in the CPL/brainstem (CPL/BS) at slow-2 significantly correlated with Fugl-Meyer scores (P = .016); and the Cohe-zReHo of the left PFC at slow-4 (P = .025) and the Cohe-zReHo of the bilateral Rec at slow-6 (P = .031) significantly correlated with 2PD values of the left foot. However, in the altered regions of KCC-ReHo, more alterations, similar to those in the bilateral PFC at slow-2 (P = .023), in the bilateral anterior cingulate cortex (ACC) at slow-5 (P = .037) and in the bilateral PFC/ACC at slow-6 (P = .033) significantly correlated with the 2PD of the right hand; values in the bilateral ACC at slow-5 (P = .038) and in the bilateral PFC/ACC at slow-6 (P = .047) significantly correlated with the 2PD of left hand; and values in the bilateral PFC/ACC at slow-6 correlated with the 2PD of the left foot (P = .006) (etc.) and altered KCC- or Cohe-ReHo in the typical frequency bands.Within the LBLP group , the Coh = .006) . No corr4In this study, we first investigated the local FC property in the typical and then five specific frequency bands using KCC- and Cohe-ReHo analyses; we then further demonstrated significant interactions between disease status and the five specific frequency bands in the right CPL, brainstem, BG and several regions of the DMN . Moreover, there were pain-related alterations in ReHo in the five specific frequency bands related to disease duration and 2PD assessments. Together, these findings provided a full view of the local connectivity property observed in BOLD waves, which is potentially useful for selecting specific frequencies or the method of ReHo analysis to improve the detection of LBLP-related brain activity.4.1As one subgroup of LBP, leg pain due to nerve root involvement is usually considered an obstacle to recovery or a marker of severity, particularly when associated with evidence of positive neurological findings. Although the mechanisms of intrinsic activity underlying the local connection disruptions observed in patients with LBLP are uncertain, several candidates should be considered. According to one hypothesis, LBLP patients may have both nociceptive and neuropathic pain. In this study, we demonstrated decreased ReHo in the left mPFC and bilateral PCUN and increased ReHo in the right CPL/BS in LBLP patients in typical frequency band analyses of KCC- and Cohe-ReHo. The PCUN and mPFC form a hub (or core) node of the DMN, and increased ReHo in experimentally induced low back pain  and disri.e., either positive cooperativity in regional activity due to abnormal information inputs or negative “side effects”, followed by structural injury to inhibitory interneurons. Similarly, increased ReHo or hyperactivation has been observed in other pain disorders  and parabrachial nucleus (PB), which receive nociceptive input through the spinoreticular pathways . The CPLisorders . In this4.2vs. eyes closed (EC)] ]  and deteontrols] . In the ontrols] . However4.3post hoc analyses of the region of interactions. In a previous study, the neuronal oscillations in the human brain proposed a spectrum of oscillatory bands for the implementation of functioning in human cognition. Zuo et al. (2013) and Song In this study, significant interactions were identified between frequency-based ReHo in the five specific frequency bands and disease status in the pain matrix  and the DMN , suggesting that different frequency bands may have specific pathological relevance in this region. This notion was demonstrated in post hoc ReHo analyses of the five specific frequency bands, the altered pattern in LBLP patients implied an interaction of pain (nociceptive and neuropathic) and paresthesia (numbness) in the frequency-related alterations in specific brain regions, including distributed changes in processing long-distance neural activity and local neural activity in the patients with LBLP. Therefore, in the Our finding may underlie the neurophysiological basis of the local BOLD activities and the functional specificity of different brain regions. These findings suggest that specific frequency ranges, even high-frequency bands, should be selected to detect pain-related intrinsic activity in future studies of LBLP patients.4.4etc.) in LBLP patients, implying the lower clinical relevance of ReHo in the typical frequency bands.For LBLP patients, the KCC-ReHo in several brain regions, such as the bilateral ACC, at slow-5 correlated with the 2PD of the right and left hands, while the Cohe-zReHo of the left PFC at slow-4 correlated with the 2PD of the left foot. Together, these results suggest that decreased local connectivity is associated with decreased tactile spatial resolution ability. There were no correlations between the KCC-ReHo or Cohe-ReHo of the typical frequency bands with the clinical variables  by extending the computation onto the cortical mantle. Third, the study's cross-sectional design might have an impact on determining cause-effect relationships.5In this study, we showed disease-related differences in the ReHo in the pain matrix and DMN within the typical and five specific frequency bands and interactions between disease status and the five specific frequency bands. Associations between the altered KCC- and Cohe- ReHo and the clinical assessment scores in the specific frequency bands are potentially useful for selecting specific frequencies or the method of ReHo analyses to improve the detection of LBLP-related brain activity.FZ and YZ designed the study. LW, LG and YZ acquired the data. XZ and FZ processed the neuroimaging data. FZ performed the statistical analyses. All authors contributed to data interpretation and writing of the article.The authors declare no conflicts of interest with respect to the publication of this article.


Background and Objectives: Pain is one of the most common symptoms that weighs on life’s quality and health expenditure. In a reality where increasingly personalized therapies are needed, the early use of genetic tests that highlights the individual response to analgesic drugs could be a valuable help in clinical practice. The aim of this preliminary study is to observe if the therapy set to 5 patients suffering of chronic or acute pain is concordant to the Pharmacogenetic test (PGT) results. Materials and Methods: This preliminary study compares the genetic results of pharmacological effectiveness and tolerability analyzed by the genetic test Neurofarmagen Analgesia®, with the results obtained in clinical practice of 5 patients suffering from acute and chronic pain. Results: Regarding the genetic results of the 5 samples analyzed, 2 reports were found to be completely comparable with the evidences of the clinical practice, while in 3 reports the profile of tolerability and effectiveness were partially discordant. Conclusion: In light of the data not completely overlapping with results observed in clinical practice, further studies would be appropriate in order to acquire more information on the use of Neurofarmagen in routine clinical settings. Pain is the most common factor motivating healthcare use, as well as one of the main health care system spending factors. In particular, chronic pain is such a diffuse and disabling condition that it is considered a syndrome and not merely a symptom ,2. IndivIn recent years an increased interest in the genetic and epigenetic correlates of pain was observed both for the genetic origin of pain’s sensitivity threshold, and for the individual response to analgesic treatments ,13. A beThe aim of this preliminary study is to observe if the therapy set to 5 patients suffering of chronic or acute pain is concordant to the pharmacogenetic test (PGT) results.This naturalistic study had foreseen a preliminary assessment of 5 patients affected by acute and chronic pain referring to Gaetano Pini Orthopedic Institute. Patients had to fulfill the following inclusion criteria: to be older than 18 years; to suffer from acute or chronic pain; to subscribe a generic written informed consent.Patients were evaluated during an outpatient visit at the Gaetano Pini Institute. All patients were already taking pain medication at the time of assessment. The genetic test was performed by two investigators who did not know the clinical response at the therapy, while clinicians were not aware of the test results, carried out subsequently.All patients provided a general written informed consent for processing personal data as part of the routine diagnostic assessment procedure and quality check processes. Assessment tools and scales were administered by clinicians at the patient’s facilities, as part of clinical routine practice. As patient data was made anonymous, obscuring sensitive information used in the research to protect the recognizability of the patients, according to the Italian legislation , the Provincial Health Ethical Review Board, consulted prior to the beginning of the study, confirmed that it did not need authorization from the Board. The study was carried out in accordance with the ethical principles of Declaration of Helsinki (with amendments) and Good Clinical Practice.® kit. This test scans the genetic polymorphisms linked to the pharmacokinetics of analgesic drugs belonging to the NSAIDs, opioids, antidepressants, antiepileptic, triptans, 5HT-3 receptor antagonists, and ergotamine’s derivatives. The test examines the isoforms of cytochrome CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, which are responsible for the metabolism of each of the drugs considered. The test allows us to determine the patient response both to peripheral analgesics like NSAIDs and cox-2, and to central analgesics as paracetamol, tricyclics, serotonin reuptake inhibitors (SSRI), anticonvulsants, opioids, and triptans. The genetic test’s administration is carried out by taking a patient’s saliva sample in an amount equal to about 1 ml. Given the same possibility to obtain the genetic information from biological material, use of saliva samples allow for greater practicality in the execution of the test, and it is less invasive. DNA was extracted from patient saliva samples with the genomic DNA Isolation kit . DNA quality was evaluated by microvolume spectrometry. The sample is collected by the patient under the doctor’s guidance through the kit provided and remains stable at room temperature for a maximum of 15 days, the time required for sending it off to the laboratory to be analyzed. During the 30 min before sample collection the patient should not consume food, drink or chewing gum, must not smoke and must have completely removed the presence of any lipstick. The results are available within 10 working days from the date of arrival of the sample at Neurofarmagen laboratory  which is declared by the company as having the necessary authorization to operate as a health laboratory using biological samples. Genotyping of single nucleotide polymorphisms was performed by OpenArray® Technology on the QuantStudio™ 12K Flex Real-Time PCR System  using a custom designed array. Saliva samples were marked with an electronic numerical barcode associated with the patient, and the identification code was archived at the Gaetano Pini Orthopedic Institute in Milan. The archive in question contains the correspondences necessary to associate the clinical and demographical data of each patient with the Neurofarmagen genetic record. In that way no sample was sent in association of personal data. The collected data have been used exclusively for research purposes. The test evaluates 6 different genes, putting them in relation to active 48 drugs. For each patient the report provides a table in which the molecule evaluated correspond to a color coding: (1) green—expectation of higher likelihood of the good response to treatment or a good tolerability profile than average; (2) white—index of a standard response, not different from the general population; (3) yellow—requiring more careful dose monitoring; and (4) red—for high risk of adverse effects or not expected efficacy.The genetic analysis was performed by the Neurofarmagen AnalgesiaMcGill Pain Questionnaire-Short Form—MGPQ-SF : this isVisual Analogue Scale—VAS : the VASNumerical Rating Scale—NRS : the NRSPatients were evaluated with algometric scales:Clinical characteristics of the patients and treatments prescribed are shown in The second patient (P2) was a 22-year-old woman suffering from chronic pain resulting from Ewing’s femoral sarcoma resection and mega prosthesis implant replacement at the age of 16. The patient had taken several different analgesic molecules . In this case a substantial correspondence between the report provided by the genetic analysis and effectiveness and tolerability profile observed in clinical practice was found.The third patient (P3) was a 45-year-old woman with a diagnosis of end stage renal failure in systemic lupus erythematosus (SLE) with contraindication to the use of NSAIDs and a short-term program of renal transplantation. The patient underwent a laparoscopic abdominal operation with analgesia performed with a high dose of tramadol and without side effects, while in the post-transplant a low dose of morphine and subsequently 2 mg/day of Paracetamol for 5 days, were successfully used. Regarding tramadol, the test indicated the patient as a slow metabolizer (CYP2D6) and recommended reducing the dose by 30%, along with paying particular attention to the occurrence of adverse effects such as nausea, vomiting, constipation, respiratory depression, confusion, and urinary retention, or to choose an alternative drug (yellow response). The drug was instead used at maximal doses intravenously with complete response to pain and without collateral or treatment emergent adverse events—TEAE . With regard to the use of morphine, the test showed the presence of a variant of COMT and OPRM1 that resulted in a reduced response to opioid agonists: the patient may have needed higher dosage or more frequent administration of the drug for adequate pain control. The patient was instead subjected to post-operative therapy with morphine at minimum therapeutic doses with optimal and rapid response. With regard to paracetamol, the PGT indicated a standard response, meaning a risk of undesirable effects not higher than general population. The patient, instead, showed signs of severe hepatic toxicity as a result of maximum therapeutic antalgic dose for 5 days of treatment. The situation required clinical and instrumental hepatological monitoring; the normalization of the liver enzyme required about 60 days. In this case some discordances between the clinical setting and the PGT’ suggestion emerged.The fourth patient, (P4) was a 75-year-old woman affected by persistent osteoarthritis (OA) pain poorly responsive to common NSAIDs. The patient was clinically known as non-responsive to NSAIDs and discreetly responsive to paracetamol-codeine combination without evidence of significant adverse effects at a common therapeutic dosage. The result of the genetic test was indicative for standard response to NSAIDs and highlighted the need for specific dose monitoring and/or lower probability of positive response to codeine (yellow response). The PGT indicated the patient as an intermediate metabolizer of codeine due to the CYP2D6 gene. For the same patient, the test suggested the possibility of using major opioids (with specific reference to morphine).The last patient (P5) was a 55-year-old man suffering from chronic pain caused by early OA. The patient presented an excellent response to the analgesic drugs used (paracetamol-codeine and NSAIDs) at the doses commonly used in clinical practice. In this case the genetic test showed a standard profile of efficacy and tolerability for the molecules used, confirming the clinical level.Total scores of algometric scales for pain evaluation are reported for each patient in Pain is a syndrome that has a major impact on life’s quality. It is intended as a complex phenomenon characterized by a huge subjective component and dependent on different endogenous and external factors ,25. An ePain treatment is a significant challenge for clinicians and could hesitate in poor outcome, particularly among patients treated with multiple drugs, in complications and adverse drug effects ,32, no iLimitations of this study include the small sample size due to the pilot nature of the study and a lack of control group. The measures presented are primarily descriptive.There is no doubt that genetic variations that involve gene coding for enzymes involved in drug metabolism, absorption, distribution, and elimination can significantly modify the therapeutic effects and tolerability profile of the drugs, and that knowing these polymorphisms would potentially allow us to customize therapy, maximize therapeutic efficacy, and minimize unwanted or adverse effects ,44,45,46


Lateralized pain is a core diagnostic feature of migraine. In previous research, left-sided spinal pain was more frequent and associated with greater emotional distress and healthcare use than right-sided pain. We hypothesized therefore that patients with left-sided head pain might experience higher levels of distress or healthcare use than those with right-sided or bilateral pain.  Medical record information was extracted for 477 randomly selected patients with migraine seen in 2011 in a tertiary headache clinic. This included demographic data, pain location, handedness, comorbid psychiatric diagnoses, medical and emergency department visits, and use of selected headache medications. p=0.001), while 56 (24.5%) reported unilateral pain with no side predominance. Contrary to expectations, with the exception of self-reported posttraumatic stress disorder, there were no statistically significant differences between left and right in measures of psychiatric distress, emergency department visits, or healthcare use.  Two hundred twenty-eight of four hundred seventy-seven (47.8%) patients reported lateralized pain, of which 107 (47.9%) patients were right sided compared with 65 (28.5%) left-sided patients ( Although unilateral pain location can be helpful in making a migraine diagnosis, it does not appear to have additional clinical implications. Additionally, its absence does not rule out a diagnosis of migraine since more than half of migraineurs have bilateral head pain. A substantial body of research supports the view that trigeminal pain processing, like many other brain functions, is strongly lateralized to the right side. Functional imaging and other studies in a variety of pain disorders show greater activation of the right than left cerebral hemispheres –5. Such The “right hemisphere hypothesis of emotion” proposes that cognitive processes are preferentially handled by the left hemisphere and emotional processes by the right hemisphere, although the results of recent research have been conflicting. An alternative hypothesis, referred to as the “valence asymmetry hypothesis,” holds that positive emotions are lateralized to the left hemisphere and negative emotions to the right. Yet another hypothesis, referred to as “region-specific functional lateralization,” suggests that emotional processing is frequently lateralized, but that the direction of lateralization depends upon the region of the brain , 9. SincIn prior research involving healthy subjects, pain thresholds for mechanical, thermal, or electrical stimulation were found to be lower on the left side of the body compared with the right –13. LeftUnilateral pain location is a characteristic feature of migraine, but it is not present in all patients. To satisfy diagnostic criteria for migraine, patients must report two of the following four pain characteristics: unilateral location, moderate to severe intensity, throbbing quality, and aggravation by physical activity . PreviouBecause migraine is a highly prevalent chronic disorder, it is an ideal condition in which to explore the association of pain laterality with distress, disability, and healthcare use. The association between pain lateralization and clinical outcomes has not previously been studied in headache. Additionally, the extent to which patients with lateralized head pain can be identified in routinely collected medical record data is unknown.Based on these observations, we hypothesized that patients with head pain occurring exclusively or principally on the left side of the head would be having higher levels of distress, as measured by diagnoses of depression, anxiety, or other psychiatric comorbidities and would be more likely to use ED and other healthcare services. In the context of this paper, we use the word “distress” to mean “pain or suffering affecting the body, a bodily part, or the mind” . These hFollowing approval by the Institutional Review Board of Brigham and Women's Faulkner Hospital, the proprietary Partners Healthcare Physician On-Line Reporting (POLR) system database was used to obtain medical record numbers for a representative sample of patients listed as having received ICD-9 diagnostic codes for migraine, cluster headache, or hemicrania continua at the John R. Graham Headache Center of the Brigham and Women's Faulkner Hospital in Boston. The system captures physician-assigned diagnostic codes and other administrative information from all visits to Partners Healthcare facilities and can be queried to obtain information for specific practice locations, diagnoses, physicians, and dates. To obtain pilot data for a predetermined sample size calculation, medical record information was examined on 50 randomly selected patients with these diagnoses seen in 2009. For the final sample, the data used was from 500 randomly selected patients with these diagnoses seen in 2011.Brigham and Women's Faulkner Hospital is part of the Partners Healthcare network, which provides care to approximately 50% of patients in the greater Boston metropolitan area. The headache clinic is a tertiary clinic providing care to patients referred from the Partners network. Some patients are referred from within the New England region or other parts of the United States. In 2011, there were 3619 patient visits to the Headache Center, consisting of 966 new patient visits and 2653 return visits. Clinic administrative staff enter demographic information and diagnostic codes into POLR for all patients seen in the headache clinic. Clinic physicians assign a diagnostic code or codes at every patient encounter, using the International Classification of Diseases, Ninth Revision (ICD-9).For the pilot phase of the project, 50 patients were randomly selected by entering medical record numbers of all patients with diagnoses of interest seen in 2009 into a Microsoft Excel® spreadsheet. To generate a random sample of these patients, each record was assigned a random number, after which records were sorted by random number, and the first 50 were chosen for the pilot study. For the principal data collection phase of the study, this procedure was repeated to generate a random sample of 500 patients with diagnoses of interest seen in the clinic in 2011.Medical records for these patients were identified in the Longitudinal Medical Record (LMR) system. LMR is a proprietary electronic medical record system developed by Partners Healthcare and used in Partners facilities. It captures information traditionally included in paper medical records, including demographic information and detailed, clinician-generated notes for medical encounters. The system records medications, allergies, medical problem lists, and other information and includes prescribing software that allows clinicians to electronically prescribe medications and other treatments.A data collection form was created using Research Electronic Data Capture (REDCap) software. A single investigator (EW) abstracted information from each patient record using this data collection form. A subset of 50 records was reviewed by a second investigator (EL) to establish consensus about data extraction. For each patient record, the first headache consultation was identified. The diagnosis at this visit was verified as migraine, cluster headache, or hemicrania continua. Additional information was collected from the medical record and entered into the REDCap database. Information included basic demographic data . Physician notes were obtained on (1) the location of headache pain, (2) handedness, (3) comorbid psychiatric diagnoses, (4) patient-initiated interactions with the healthcare system, (5) emergency department visits, and (6) use of selected headache medications.Location of headache was determined using a two-stage process: First, it was noted whether in the initial consultation the pain was described as unilateral, even if only occasionally, or as bilateral. If the pain was ever unilateral, additional information was collected whether the pain was recorded as “always,” “usually,” “sometimes,” or “never” on the right side of the head, and also whether the pain was “always,” “usually,” “sometimes,” or “never” on the left side of the head.To provide quantitative information for statistical analysis, we used a commonly used method to assess asymmetry in studies of lateralized phenomena . Two latTo illustrate, a patient with unilateral headache who “sometimes” had pain on the left and “usually” had pain on the right would receive a left laterality score of 2 and a right laterality score of 3, for a net score of 1, indicating a slight predominance of right-sided head pain. Alternatively, a patient with unilateral headache who “always” had left-sided head pain and “never” had right-sided head pain would receive a left laterality score of 4 and a right laterality score of 1, for a net score of −3, indicating side-locked left-head pain.In addition to examining cases in which headache was exclusively one sided, the categories of always, usually, and sometimes as well as always and usually for both left and right pain location were collapsed. This procedure made it possible to examine the association of outcomes with varying degrees of unilaterality.Psychiatric diagnoses were identified by searching the medical record for physician diagnoses of substance use disorder, anxiety disorder, depression, bipolar disorder, cognitive/dementia disorder, eating disorder, psychotic disorder, PTSD, and/or a past history of trauma or abuse. Patients were considered to have these disorders if these diagnoses appeared in problems lists or were described in physician notes, especially the past medical history section of the record. Psychiatric diagnoses could have been assigned by any of the clinicians who saw the patient. In many cases, these were psychiatrists or psychologists, although diagnoses also could be made by primary care physicians or other healthcare providers. Psychiatric diagnoses also were inferred from prescriptions for medications principally or only used to treat psychiatric illnesses . A psychiatric diagnosis was not inferred in patients using benzodiazepines or tricyclic antidepressants because those classes of medications are often used for nonpsychiatric indications.Use of healthcare resources was measured using data from the LMR, first by determining whether a patient received primary medical care within the Partners healthcare system, as indicated by having a Partners primary care provider note listed in their medical record. Those who did not have a primary care provider within the Partners system were excluded because of inability to confirm the accuracy of their medical record or information about healthcare use. Beginning one year before the first headache consultation and up to the time of the headache consultation, the number of times patients initiated contact with a physician was counted.Patient-initiated telephone calls, emails, appointments, urgent care visits, and procedures were counted as contacts. Laboratory and imaging reports or calls or emails initiated by healthcare providers were not included because they were not initiated by the patient. Emergency department visits were counted separately and were not included in the measures of general healthcare use. The same process was used to measure healthcare use in the year following the first headache consultation. The headache consultation itself was not counted in either the “before” or “after” contacts. In some cases, patients only had primary care notes visible in the medical record in the year following their headache consultation, indicating that they had moved their care to the Partners system. Data from these patients contributed to measures of healthcare use only for the year after consultation.Information was collected on emergency department visits occurring in the year before and the year after the initial headache consultation visit. Visits were categorized as due to headache or for other reasons, based on information contained in physician or nursing notes. Urgent care visits were not included in these counts.Preliminary data analyses were conducted after collecting information on 50 patients during the pilot portion of the study. Power calculations indicated that a sample size of 500 patients would be sufficient to detect a difference of 20% in the proportion of patients with depression or anxiety in the group with left-lateralized pain compared with the group with right-lateralized pain. Pilot patients were not included in the final analyses.© 2011, SAS Institute Inc, Cary, NC. The p values for the distress measurements were obtained by subtracting the right from the left score and using the Jonckheere–Terpstra test.For the actual study, demographic information was obtained and logistic regression was used to evaluate the relationship between demographic and other factors including markers of healthcare use  and distress (such as depression or anxiety). All analyses were generated using SAS software v 4.3Of the 500 patient records identified for the actual study, 2 did not contain a consultation note and were excluded from the analysis. Of the 498 nonpilot patients for whom consultation notes were available, 477 (95.8%) patients had migraine. Sixteen (3.2%) patients had cluster headache, and five (1%) patients had hemicrania continua. The 21 patients with cluster headache or hemicrania continua were removed from the final analyses of migraine patients.Of the 91.6% of patients who provided handedness information at the initial consultation, 33/437 (7.6%) of patients were left handed. The majority of patients were Caucasian, married, with over 80% having more than a high school diploma. 13.7% of patients were unemployed or disabled. Within this sample, the majority (81.5%) of patients reported onset of headaches before the age of 26.p < 0.001). 56 of 228 (24.5%) patients with unilateral headache had pain that was equally distributed between the right and left side of the head. Among patients with migraine, 228 of the 451 (50.6%) patients with available information reported some lateralized pain, whether it was strictly side-locked pain, usually, or always lateralized. Of the 228 subjects with lateralized pain, 72 of 228 (31.6%) patients had side-locked pain, with twice as many (24 L and 48 R) reporting right side-locked pain compared with left side-locked pain. Thus, of the entire 451 subjects, only 72 (15.9%) patients had side-locked pain. When considering patients with any amount of right- or left-sided pain predominance, 107 of 228 (47%) patients had right pain predominance and 65 of 228 (28.5%) patients had a predominance of left-sided headaches (p=0.34). One hundred forty-three of four hundred twenty-four (33.7%) females and fourteen of fifty-three (26.4%) males had depression, which was not a statistically significant difference (p=0.29).p=0.15). Twenty-nine of two hundred sixty (11%) females went to the ED in the year after the first consultation, versus two of thirty-eight (5%) males, which was not statistically significant (p=0.27).15.2% of migraine patients visited the emergency department (ED) for headache in the year before their first consultation visit, compared with 10.4% in the year after the first consultation. ED visits for other reasons also declined. Moreover, the average number of ED visits for headache in the year prior to consultation was 0.32 (range 0–22) and in the year after consultation was 0.18 (0–6). Thirty-one of two hundred twenty-one females (14%) and seven of twenty-nine (24%) males went to the ED in the year before the first consultation, with no significant sex differences .Tables p=0.008, Pearson chi-square).The single exception was that patients with left-lateralized pain were statistically significantly more likely than those with right-lateralized pain to have a diagnosis of posttraumatic stress disorder. Specifically, for those with information on both variables, 6 of 65 (9.2%) patients with any degree of left-predominant head pain had a history of PTSD compared with 1 of 107 with right-predominant pain (p < 0.001).Bivariate correlation between ED visits for migraine in the year before the first consultation and healthcare visits in general showed a slight negative correlation that was not statistically significant. In the year after the first consultation, the number of ED visits was positively correlated with the overall number of patient-initiated healthcare contacts.  the pain does not strictly concern one-half the head” [Fewer than half of patients with migraine report that their pain is unilateral. This observation is remarkable given that migraine is commonly thought of as a lateralized pain disorder—in fact, the word migraine is derived from Latin via the Greek term hemikrania, which means “half of the cranium”. Unilateral location of pain also is a key criterion for the diagnosis of migraine. As early as 1933, the eminent neurologist Macdonald Critchley, then an assistant physician at Queen Square in London, pointed out that the headache of migraine was “often not unilateral,” characterizing this as one of the “certain incorrect or exaggerated statements commonly made.” Writing in the he head” .Only about half of patients with migraine reported unilateral pain. About a quarter of these patients say that their unilateral headaches are equally likely to occur on the right or the left. The remaining three quarters note a side preference. Among patients whose headache pain is lateralized, almost twice as many report that the pain location is more commonly or always on the right compared to the left side, and this difference is statistically significant. It is not clear whether this asymmetry is the result of hemispheric lateralization or other factors, which should be evaluated separately. This right-sided predominance is seen in many other lateralized head pain disorders and also exists for chewing-side preference. For example, the right side is more commonly involved than the left in trigeminal neuralgia and temporomandibular joint dysfunction , 22. AddIn general our findings that only about half of migraine patients reported unilateral pain are broadly consistent with other studies; for example, previous research did not examine asymmetry in laterality as we did using a laterality index. Rather, they simply asked patients whether headaches were typically unilateral and if so on whether there was side predominance. Lipscombe and Prior found that 66% of those with migraine had unilateral headache, and two-thirds of those reported a side preference in their headaches . CompareOur hypothesis was based on the assumption that cortical activation and pain processing associated with headache pain are strongly lateralized, which could lead to differential effects depending on whether head pain arose on the right or the left. However, recent work by others, in addition to our finding of no major differences, is not consistent with this hypothesis. Other possibilities include bilateral cortical activation, or that decussation of the cranial nerves, particularly the trigeminal, may be more complex than is currently appreciated .In contrast to our hypothesis that left-sided head pain would be associated with more psychopathology than right-sided pain, we found no evidence of left-sided migraine pain being more associated with psychopathology than right-sided pain. With the exception of PTSD, there was no evidence of a relationship between left-sided pain and measures of healthcare utilization or psychological distress. The statistically significant association of greater left- than right-sided head pain with PTSD may be spurious but could be explored in subsequent studies. Emergency department visits and patient-initiated contacts with the medical system declined following consultation, suggesting the value of specialty treatment for headache. There was no evidence that ED use, depression, or anxiety were more common in those with left-sided headache compared with right-sided headache.A major strength of this study is the detailed and carefully documented information on a large number of patients with migraine, diagnosed by headache experts in a large, integrated healthcare system. These findings are likely to be generalizable to other clinical settings. The design and implementation of this study were based on hypotheses derived from previous work, with analyses based on a protocol developed before data collection, and sample size was determined based on a preliminary pilot study.This study also has a number of limitations. Data were collected as part of a retrospective study of medical records and clinical notes of patients seeking treatment for migraine headaches in the context of routine clinical practice. Standardized data collection instruments were not used. Rather, physician notes included narrative descriptions of headache and other patient characteristics, which often lacked information such as standardized measures of pain intensity or duration. The completeness and quality of information varied among providers, requiring some subjectivity in classifying the degree of sidedness, although information in the chart was almost always adequate to make a valid basic distinction between pain that was predominantly right or left sided. It seems very likely, therefore, that the reported findings are valid. The presence of comorbid conditions such as depression was inferred based on the use of specific antidepressant or other medications, or on a mention of these diagnoses in the chart. Similarly, it was only possible to collect information on ED visits and healthcare contacts that occurred within the Partners Healthcare System. Because these methods are somewhat imprecise, it is possible that the hypothesized right versus left differences in the frequency of these outcomes may have been overlooked or underestimated.Retrospective analysis of patient records is not an ideal way to make a diagnosis of psychiatric comorbidity, since an accurate measure of severity is not available.Psychiatric comorbidity may not be a good measure of distress from a neural perspective. Psychiatric conditions are common and are of varying severity. Some patients with formal psychiatric diagnoses may not be particularly distressed, while others with important distress may not receive a psychiatric diagnosis. Even if not the best measure, however, we think it is reasonable to assume that severe distress would be associated with an increased likelihood of having a psychiatric diagnosis compared to matched controls and would be clinically important. Unfortunately, validated tools to assess headache impact, such as the Migraine Disability Assessment (MIDAS) or Headache Impact Test (HIT-6), were not routinely obtained.We assessed ED utilization as a marker of distress but were unable to control for migraine severity or duration, or control for use of triptans or preventive medications, which may be confounders. Unfortunately, such information was not sufficient to calculate these factors. It seems reasonable, however, to assume that since all patients included in the study were seen and diagnosed by headache specialists in a tertiary care setting, they represent a relatively homogeneous population of treatment-seeking patients with migraine.Our results, although very useful for the purposes of our study, highlight the shortcomings of information contained in medical records. In the future, a systematic way of collecting data, perhaps using structured questionnaires with data entered directly by patients, should be considered as a way to improve data quality and completeness.Taken as a whole, our data do not support the view that left-sided migraine pain is more distressing than right-sided pain. Although unilateral pain location can be helpful in making a migraine diagnosis, it does not appear to have additional clinical implications. Additionally, its absence does not rule out a diagnosis of migraine since more than half of migraineurs have bilateral head pain.


Background and purpose — Little is known about heterogeneity in early recovery after primary total hip arthroplasty (THA). Therefore, we characterized subgroups of patients according to their hip function trajectory during the first 6 weeks after THA in a fast-track setting.Patients and methods — 94 patients  from a single hospital participated in a diary study. Patients recorded their severity of hip problems  weekly for 6 weeks after THA. Latent class growth modelling (LCGM) was used to identify patients with the same hip function trajectory and to compare these subgroups on patient characteristics.Results — LCGM revealed a fast (n = 17), an average (n = 53), and a slow (n = 24) recovery subgroup. Subgroups differed on the estimated weekly growth rate during the first 2 weeks , with fewer differences between groups in the last 4 weeks . Patients in the slow recovery group could be characterized as women of older age (mean age =69) who rated their health as lower preoperatively, needed more assistance during recovery, and were less satisfied with the outcomes of the surgery.Interpretation — We identified distinct recovery trajectories in the first 6 weeks after fast-track primary THA which were associated with patient characteristics. Between 7% and 15% of patients are dissatisfied with the results of total hip arthroplasty (THA)   by the same orthopedic surgeon.Discharge criteria for all patients were functional and evaluated by a doctor, a physiotherapist, and a nurse. Patients had to be able to walk 30 meters with crutches or walker, to climb stairs if they were able to walk with crutches, to dress independently, and to go to the toilet independently. Adequate pain relief had to be achieved by means of oral medication before discharge, assessed with a numeric rating scale  for pain below 3 at rest and below 5 during mobilization. Last, the wound had to be dry, or nearly dry, and the patient should not experience dizziness or nausea.A diary method was used for data collection; patients received a booklet after discharge with a variety of questions regarding their recovery, which they had to complete every day. To reduce patient burden not all questions were assessed daily. Preoperatively (approximately 1 week before surgery) a subset of questions was probed as part of standard routine.Patients who were planned for primary unilateral THA between February 2015 and October 2015 were considered eligible for inclusion. Exclusion criteria were an insufficient command of the Dutch language, being mentally disabled, and a prosthesis in another joint of the ipsilateral or contralateral lower limb placed within 6 months before THA surgery. Of the 144 eligible patients, 43 did not participate in the study . Of the 101 included patients, 7 were excluded from analyses for various reasons.The main outcome measure of this study was reported severity of problems with the operated hip, as measured with the Oxford Hip Score (OHS). Higher scores (0–48) indicate better functioning and less pain. Patients had to complete the OHS questionnaire at 1 week before surgery and once every week starting on the 7th day after discharge.We assessed a variety of patient characteristics to explore whether the identified subgroups based on OHS trajectories match the profile of a “typical” patient. These variables can be divided into preoperative or pre-discharge characteristics, healthcare utilization and assistance during the 6-week recovery period, and postoperative patient-reported experience measures (PREMs) after the 6-week recovery period.Preoperative demographic and patient characteristics included age, sex, BMI, and whether the patient lived alone. Preoperative radiographic OA severity was assessed by the last author (SV) using the Kellgren–Lawrence (K–L) grading (0–4) system. The Charlson comorbidity index (CCI) and the American Society of Anesthesiologists (ASA) physical status classification system (1–4) were used as co-morbidity measures. Health-related quality of life was measured with the EQ-5D (5L). All 5 individual domain scores (1–5) were used, where a higher score indicated more problems, as well as the overall health Visual Analog Scale . Length of stay (LOS) in hospital was recorded, as well as surgical complications.Once a week patients recorded in their diary whether they had a physiotherapy session, a visit to the doctor, whether they needed aids  to walk inside or outside their house and whether they received help  with personal hygiene or with housekeeping. Pain medication was recorded daily.At the end of the 6-week recovery period patients completed the PREMs in their diary. They indicated on an 11-point scale how satisfied they were with the results of surgery (0–10). On several 5-point scales they indicated their satisfaction with the general result of surgery, current pain, activities of daily living, and their quality of life. In addition, we asked whether they would opt for THA surgery again if needed (yes/no) and if they would recommend it to others (yes/no). Patient’s attitude towards fast-track THA, provided support during recovery, and the information provided were also assessed through yes/no questions.https://www.statmodel.com/version6.12.shtml) was used to handle missing data. LCGM is an extension to latent growth curve models, which are commonly used to assess inter-individual differences in intra-individual change   old and 56 were women . Almost Supplementary data). The entropy values all exceeded the minimum of 0.8, indicating that the classes were sufficiently distinct from each other.As can be seen from the BIC values and the outcomes of the BLRT, model fit improved by adding classes up to the 4-class model , as well as an average (Class 2) and fast recovery group (Class 1), and statistical fit improved. Even though fit improved even further in a 4-class model, clinical interpretability did not improve. In this model the average recovery subgroup in the 3-class model was divided into 2 separate subgroups (Class 1 and 2) differing only marginally from each other in their initial growth rate. We therefore chose the 3-class model for further analyses.The average change in OHS from baseline until week 6 for the fast recovery group was 23, for the average recovery group 19, and for the slow recovery group 9.9 . The biggest difference between the classes became apparent in the first 2 weeks of recovery. Both the fast (Class 1) and average recovery group (Class 2) showed a steep initial increase in reported functioning of the operated hip in the first 2 weeks, levelling off in the subsequent 4 weeks. The levelling off phase was a little more pronounced in the fast recovery group. In stark contrast, the slow recovery group showed a slow and steady improvement, lacking the exponential increase in the first 2 weeks. In addition, growth seemed to already level off after week 4. It is also notable that the classes were similar in their preoperative baseline OHS.There were distinct differences between the 3 different early recovery trajectory classes in preoperative characteristics, healthcare utilization and assistance during recovery, and postoperative PREMs.The largest class of patients  can be characterized as slightly overweight patients (average BMI =27) with an average age of 65, having an average preoperative movement-evoked NRS pain score of 7 and staying on average 1 night in hospital after surgery. Patients in this class on average did not report mental health problems preoperatively or problems with self-care, but they did report slight problems with mobility, usual activities, and pain. For the majority of the 6-week recovery period they used walking aids, attended weekly physical therapy sessions, and took pain medication. After 6 weeks they were highly satisfied with the results of the surgery. In the subsequent analyses we compared the other smaller classes with this dominant class.The patients in Class 1 (fast recovery) were younger (mean age =59) and were operated more often in an outpatient setting. During the 6-week recovery they used pain medication and required walking aids for a shorter period (median =3 weeks) than patients in the average trajectory class (median =5 weeks).Patients in Class 3 (slow recovery) were more often female (four-fifths) and older (mean age =69) than patients classified in the average recovery trajectory. They were less often operated on in an outpatient setting and rated their overall health as lower and reported more hip pain at rest before the surgery. More patients already had another prosthesis, and although not statistically significant, co-morbidities (ASA and CCI) were more common. Compared with the average recovery class patients required more weeks with personal hygiene assistance (median =6 weeks) and longer use of walking aids outside (median =5 weeks). After the 6-week recovery period patients were less satisfied with the results of the surgery and were also less positive about the support provided during recovery.In this prospective cohort study we identified 3 different trajectories of early recovery after primary unilateral THA in a fast-track setting.In the slow recovery group, healthcare utilization and assistance during recovery was higher, in combination with lower satisfaction of provided care. Preoperatively, health perception was more negative and patients reported more pain at rest. Together with being older and having more co-morbidities, clinicians might describe this group of patients as being more “difficult” (Hahn et al. At the other end of the spectrum the subgroup of patients displaying a fast recovery presented a very different profile. The majority of these patients left hospital on the day of surgery. In line with their pronounced improvement in pain and function during the first 2 weeks after discharge, they used pain medication and walking aids for a much shorter period of time than the average patient subgroup. Their quick recovery may in part be explained by having fewer co-morbidities and their younger age. However, these patients did not rate their health as better, or have less pain preoperatively. Perhaps being scheduled for the outpatient treatment and meeting the discharge criteria to leave on the same day as the surgery may have instilled more positive recovery expectations. Positive outcome expectations can enhance the effects of medical treatments (Crow et al. Our results underscore the need for tailored care and provide directions to achieve such an outcome. Patients fitting the slow recovery trajectory were less satisfied with the surgery and less positive about the support provided during recovery. Although we are not able to tell what kind of support this subgroup of patients wanted, their higher healthcare utilization suggests unfulfilled needs when it comes to pain management and assistance with daily activities. This is in line with previous work stressing the importance of postoperative pain management after THA to improve patient satisfaction (Bergés et al. The most important limitations concern the generalizability of our findings and that we did not try to identify potentially important preoperative psychosocial predictors of early recovery. Being an exploratory study with a relatively small sample size, replication of our findings in other larger samples in different settings is essential.Previous studies have pointed to the importance of psychosocial predictors of responses to arthroplasty, such as pain catastrophizing or psychological distress (Vissers et al. In summary, 3 distinct subgroups of patients were identified with markedly different recovery rates. By comparing these groups we were able to develop preliminary patient profiles of early recovery. Our study demonstrates the necessity to further explore the specific needs of these different subgroups, as well as clinical and psychosocial predictors of early recovery.supplementary data in the online version of this article, http://dx.doi.org/ 10.1080/17453674. 2018.1519095The authors are grateful to all the patients for their efforts in completing their diaries, and especially thank N. de Esch for her help during the study.JP performed data analysis, wrote and revised the manuscript, NM designed the study, supported data analysis and reviewed the manuscript. LK supported data collection and reviewed the manuscript. JE helped composing the diary, performed data collection, and reviewed the manuscript. MM supported the data analysis and reviewed the manuscript. SV designed the study, operated on all patients and reviewed the manuscript.Acta thanks Henrik Husted for help with peer review of this study.


Loin Pain Hematuria Syndrome (LPHS) remains a rare disease but has a significant impact on those affected by it. Patients diagnosed with LPHS experience severe, constant or intermittent flank pain that radiates to the groin and may be exacerbated even by a gentle touch. These patients often require significant narcotic regimens for pain control and are unable to maintain a functional lifestyle. Previously, diagnosis has been made based on clinical presentation. One treatment for this syndrome is renal autotransplant; however, success rates are varied. Therefore, patient selection for this procedure is important. We have developed the UW-LPHS test as a diagnostic maneuver in order to determine which patients with LPHS would benefit from renal autotransplant. To perform this diagnostic test, bupivacaine is instilled into the ureter on the affected side and left to dwell. Patients who experience pain relief following this test are deemed to benefit from renal autotransplant. Here we describe this novel diagnostic test and initial success rates following renal autotransplant. As a result of this debilitating pain, patients often require large quantities of narcotics for pain control.5 Additionally, patients may experience micro- or macroscopic hematuria. LPHS has previously been differentiated as type 1 or type 2 LPHS. Type 1 LPHS can be attributed to identifiable causes including nutcracker syndrome, nephrolithiasis, polycystic kidney disease, recurrent renal papillary necrosis with ureteral obstruction, renal thromboembolism, or renal artery dissection. Cases in which diagnostic work-up does not reveal an etiology have been categorized as type 2 LPHS.5 Although the pathophysiology of type 2 LPHS remains largely undetermined, Taba Taba Vakili and colleagues describe one possibility that postulates that the pain and hematuria seen in LPHS may be related to renal vascular disease, coagulopathy, and renal vasospasm with microinfarction among other abnormalities in the urogenital system.8 However, renal function is usually unchanged in these patients.11 As a result of the fact that pathology cannot be established in a subset of patients with LPHS, these patients are often labeled as having a somatoform pain disorder or drug-seeking behavior.12Loin pain hematuria syndrome (LPHS) describes a constellation of symptoms that is estimated to have a prevalence of approximately 0.012% and primarily occurs in women.Loin Pain Hematuria Syndrome describe the pathophysiology, diagnosis, and treatment of this disease. Overwhelmingly, the diagnosis of LPHS was made clinically with the findings of severe flank pain, hematuria, and an exclusion of other causes of these symptoms.2 Additionally, this review includes an overview of treatment options and associated success rates including renal denervation, unilateral nephrectomy, and renal autotransplant.19 Specifically, they address renal autotranplant as a potential treatment option; however, pain recurrence varied greatly as indicated in multiple case series. One potential explanation for varied success rates following renal autotransplant is improper patient selection. Therefore, it is imperative to have a reliable diagnostic test in order to determine who may benefit from renal autotransplant.Taba Taba Vakili and colleagues in their 2014 review article 20 This case highlights the fact that ultimately, the ureter may be the origin of pain in LPHS. To support this hypothesis, we developed the UW-LPHS test as a diagnostic study to identify patients who may experience pain relief following renal autotransplant.A case report in 2015 described a male patient who presented with symptoms consistent with LPHS. After receiving tadalafil , which functions as a smooth muscle relaxant of the urogenital system, the patient experienced a dramatic improvement in his pain.5 Pain is assessed prior to discharge following the procedure, later in the evening by telephone, and in clinic the following day. Patients who have pain relief for at least 12 hours following the test and have no other anatomical abnormalities are considered to have a positive test and would likely benefit from renal autotransplant. Patients typically state they have pain relief immediately after waking up from general anesthesia, which can then last up to 48 hours following the test.The UW-LPHS test utilizes bupivacaine in order to determine if the ureter is the origin of pain. Under general endotracheal anesthesia, patients undergo cystoscopy and 0.5% bupivacaine is injected into the ureter on the effected side and left to dwell there for 5 minutes. At this time the bladder is also inspected in order to rule out other pathology. Patients are then awoken and their pain is assessed several hours following the procedure before discharge and later in the evening on the same day of procedure. Patients are not given any additional analgesics or relaxants. If patients have relief of their pain, then they are deemed to be candidates for renal autotransplant.5At our institution, we have utilized the UW-LPHS test in order to identify who may benefit from renal autotransplant for LPHS. Six patients underwent the test and reported significant improvement in their pain. Additionally, two patients did not experience pain relief following bupivacaine infusion. One of these patients was found to have interstitial cystitis, which was diagnosed on cystoscopy, and the other patient was later diagnosed with pudendal neuralgia. The patients who were found to have a positive UW-LPHS test underwent renal autotransplant. The kidney on the affected side is removed with the remaining distal ureter completely removed to the level of the bladder. The kidney is then re-implanted on the right side in standard fashion.Pre-operatively all six patients required pain medication prior to autotransplant with 50% (n=3) of patients requiring narcotics. Pain medication usage significantly declined at 3 months post-transplant and at present, none of these patients require narcotics. All patients have returned to school or work.21 However, smaller series have reported pain recurrence up to 73%.14 We believe one key explanation to this discrepancy in outcomes is patient selection. Since we have identified the ureter as a contributor to pain through ureteral spasm, we have developed the UW-LPHS test as a method to identify patients who may benefit from renal autotransplant. Although additional follow-up is required, our current results indicate that it is a reliable method to identify these patients. As a result, we support the UW-LPHS test as a simple and reliable diagnostic tool in order to help determine the best treatment for patients with LPHS.Loin Pain Hematuria Syndrome continues to be not only a rare disease, but also it is incompletely understood. Nevertheless, patients who are affected by it experience life-altering pain, which frequently leads to disability. Although conservative management and surgical intervention have varied results, multiple case series have reported high success rates with renal autotransplant. As reported in Vakili and associates, Burke and Chin presented a series of 48 patients who under renal autotransplant with sustained pain relief in 70% of these patients.


Stable chest pain is a common clinical presentation that often requires further investigation using noninvasive or invasive testing, resulting in a resource-consuming problem worldwide. At onset of 2016, the National Institute for Health and Care Excellence (NICE) published an update on its guideline on chest pain. Three key changes to the 2010 version were provided by the new NICE guideline. First, the new guideline recommends that the previously proposed pretest probability risk score should no longer be used. Second, they also recommend that a calcium score of zero should no longer be used to rule out coronary artery disease (CAD) in patients with low pretest probability. Third, the new guideline recommends that all patients with new onset chest pain should be investigated with a coronary computed tomographic angiography (CTA) as a first-line investigation. However, in real world the impact of implementation of CTA for the evaluation of new onset chest pain remains to be evaluated, especially regarding its cost effectiveness. The aim of the present report was to discuss the results of the studies supporting new NICE guideline and its comparison with European and US guidelines. In the last two years a great debate occurs about the value of anatomical information by coronary computed tomographic angiography (CTA) in comparison to functional imaging tests on the evaluation of patients with new onset chest pain and unknown coronary artery disease (CAD) –5. StablIn current era of modern cardiology, the diagnostic workup test for patients with suspicion of CAD remains matter of debate –8. WhateSpecifically, the NICE guideline update (2016) makes three key changes to the 2010 version . The firThe 2013 European Society of Cardiology (ESC) guideline on stable chest pain recommends the use of a PTP RS that is calculated using age, gender, and typicality of chest pain, but not cardiovascular risk factors . This RSThe PTP model was based on USA cohorts of patients undergoing invasive coronary angiography (ICA) in the 1970s who had a much higher prevalence of CAD than current rapid access chest pain clinic populations. Thus, in the latest guidance, NICE has parted from its PTP model; it may overestimate the risk in current rapid access chest pain clinic populations , 29. SinThe advance in management and the adoption of modern effective treatment have reduced the cardiovascular mortality for patients with acute coronary syndrome worldwide, but not for patients with stable CAD. Currently, healthcare system focused their efforts on delivering management of stable CAD that is both clinical and cost effective. Notably, the populations with stable CAD increase in age and consequently their access to the healthcare system may increase exponentially worldwide. This picture of stable CAD is true worldwide; thus the treatment for stable CAD should be not only efficacious but also sustainable for healthcare system. Moreover, differently to the previous two decade, now the rapid clinical assessment of patients with suspected angina is necessary for the community of cardiology to select out high-risk individuals . In thisThe practical implementation of the new guidelines will meet many challenges. The recommendations are in part based on the assumption that the radiation dose of CTA is in the order of 1–2 mSv, which is achievable in most patients with the latest generation CT scanners –62. HoweCTA is an excellent rule-out test for CAD when used in the appropriate disease prevalence population. Despite the good performance of CTA in recent PROMISE, SCOT-HEART, and EVINCI trials, there is little clinical or health economic data to support the use of CTA over other noninvasive imaging tests in patients at intermediate-high risk of CAD in real world. Furthermore, the availability of latest generation scanners in European country is limited. Thus the potential for high cumulative radiation dose exposure from multiple serial CTA investigations could be a big problem. Finally, in real world the implementation of CTA for the evaluation of new onset chest pain fundamentally depends on the new health strategy based on the reconfiguration of current finances and staffing levels.