Identification of traits and functional connectivity-based neurotraits of chronic pain.

Psychological and personality factors, socioeconomic status, and brain properties all contribute to chronic pain but have essentially been studied independently. Here, we administered a broad battery of questionnaires to patients with chronic back pain (CBP) and collected repeated sessions of resting-state functional magnetic resonance imaging (fMRI) brain scans. Clustering and network analyses applied on the questionnaire data revealed four orthogonal dimensions accounting for 56% of the variance and defining chronic pain traits. Two of these traits-Pain-trait and Emote-trait-were associated with back pain characteristics and could be related to distinct distributed functional networks in a cross-validation procedure, identifying neurotraits. These neurotraits showed good reliability across four fMRI sessions acquired over five weeks. Further, traits and neurotraits all related to the income, emphasizing the importance of socioeconomic status within the personality space of chronic pain. Our approach is a first step in providing metrics aimed at unifying the psychology and the neurophysiology of chronic pain applicable across diverse clinical conditions.

Hippocampal morphology mediates biased memories of chronic pain.

Experiences and memories are often mismatched. While multiple studies have investigated psychological underpinnings of recall error with respect to emotional events, the neurobiological mechanisms underlying the divergence between experiences and memories remain relatively unexplored in the domain of chronic pain. Here we examined the discrepancy between experienced chronic low back pain (CBP) intensity (twice daily ratings) and remembered pain intensity (n = 48 subjects) relative to psychometric properties, hippocampus morphology, memory capabilities, and personality traits related to reward. 77% of CBP patients exaggerated remembered pain, which depended on their strongest experienced pain and their most recent mood rating. This bias persisted over nearly 1 year and was related to reward memory bias and loss aversion. Shape displacement of a specific region in the left posterior hippocampus mediated personality effects on pain memory bias, predicted pain memory bias in a validation CBP group (n = 21), and accounted for 55% of the variance of pain memory bias. In two independent groups (n = 20/group), morphology of this region was stable over time and unperturbed by the development of chronic pain. These results imply that a localized hippocampal circuit, and personality traits associated with reward processing, largely determine exaggeration of daily pain experiences in chronic pain patients.

Translation and validation of Simplified Chinese version of the Pain Catastrophizing Scale in chronic pain patients: Education may matter.

Objective Pain catastrophizing is linked to many aspects of pain perception and defines a unique dimension in predicting pain intensity and physical disability. Pain Catastrophizing Scale (PCS) is an effective, validated,self-report measure, commonly used in clinical trials. Here, we present a Simplified Chinese PCS (SC-PCS) version developed in Chinese patients suffering from chronic pain. Methods The SC-PCS was generated in five steps and tested on an initial patient cohort (N = 30). A convenience sample (N = 200) of in-hospital patients with non-malignant pain lasting for more than 12 weeks were recruited for the study, of which 81 completed 5 additional pain questionnaires. A subset (N = 24) of the patients completed an additional SC-PCS, 10 days after the initial query to assess test-retest validation. Results Intra-class correlations coefficient indicated high reproducibility and temporal consistency, (0.97), for the total score. Cronbach's alpha determined high internal consistency across the SC-PCS total score and its three subscales (0.87, 0.85, 0.62, and 0.65). The SC-PCS total score moderately or weakly (R = -0.2 to 0.49), but significantly, correlated with other measurements, such as pain Visual Analog Scale, Beck Depression Inventory, Pain Anxiety Symptoms Scales, Positive and Negative Affect Schedule, and education. We used exploratory factor analysis to examine the dimensionality of the SC-PCS, which indicated instability of the current three-factor model. However, a confirmatory factor analysis indicated that the three-factor model had the best goodness-fitting. Conclusions We demonstrate the successful translational adaptation from English to Simplified Chinese as well as the reliability and validity of SC-PCS. An important discovery was education level significantly correlated with SC-PCS, identifying a future consideration for other cross-cultural development of self-reported measures.

Predicting placebo analgesia in patients with chronic pain using natural language processing: a preliminary validation study.

ABSTRACT: Patients with chronic pain show large placebo effects in clinical trials, and inert pills can lead to clinically meaningful analgesia that can last from days to weeks. Whether the placebo response can be predicted reliably, and how to best predict it, is still unknown. We have shown previously that placebo responders can be identified through the language content of patients because they speak about their life, and their pain, after a placebo treatment. In this study, we examine whether these language properties are present before placebo treatment and are thus predictive of placebo response and whether a placebo prediction model can also dissociate between placebo and drug responders. We report the fine-tuning of a language model built based on a longitudinal treatment study where patients with chronic back pain received a placebo (study 1) and its validation on an independent study where patients received a placebo or drug (study 2). A model built on language features from an exit interview from study 1 was able to predict, a priori, the placebo response of patients in study 2 (area under the curve = 0.71). Furthermore, the model predicted as placebo responders exhibited an average of 30% pain relief from an inert pill, compared with 3% for those predicted as nonresponders. The model was not able to predict who responded to naproxen nor spontaneous recovery in a no-treatment arm, suggesting specificity of the prediction to placebo. Taken together, our initial findings suggest that placebo response is predictable using ecological and quick measures such as language use.

Validating a biosignature-predicting placebo pill response in chronic pain in the settings of a randomized controlled trial.

ABSTRACT: The objective of this study is to validate a placebo pill response predictive model-a biosignature-that classifies chronic pain patients into placebo responders (predicted-PTxResp) and nonresponders (predicted-PTxNonR) and test whether it can dissociate placebo and active treatment responses. The model, based on psychological and brain functional connectivity, was derived in our previous study and blindly applied to current trial participants. Ninety-four chronic low back pain (CLBP) patients were classified into predicted-PTxResp or predicted-PTxNonR and randomized into no treatment, placebo treatment, or naproxen treatment. To monitor analgesia, back pain intensity was collected twice a day: 3 weeks baseline, 6 weeks of treatment, and 3 weeks of washout. Eighty-nine CLBP patients were included in the intent-to-treat analyses and 77 CLBP patients in the per-protocol analyses. Both analyses showed similar results. At the group level, the predictive model performed remarkably well, dissociating the separate effect sizes of pure placebo response and pure active treatment response and demonstrating that these effects interacted additively. Pain relief was about 15% stronger in the predicted-PTxResp compared with the predicted-PTxNonR receiving either placebo or naproxen, and the predicted-PTxNonR successfully isolated the active drug effect. At a single subject level, the biosignature better predicted placebo nonresponders, with poor accuracy. One component of the biosignature (dorsolateral prefrontal cortex-precentral gyrus functional connectivity) could be generalized across 3 placebo studies and in 2 different cohorts-CLBP and osteoarthritis pain patients. This study shows that a biosignature can predict placebo response at a group level in the setting of a randomized controlled trial.

De Novo dural arteriovenous fistulas after endovascular treatment: Case illustration and literature review.

Intracranial dural arteriovenous fistulas (dAVF) account for nearly 10-15% of all arteriovenous malformations. Although the majority of dAVF are effectively cured after endovascular intervention, there are cases of dAVFs that may recur after radiographic cure. We present the case of a 69-year-old female with de novo formation of three dAVFs in different anatomic locations after successive endovascular treatments. The patient's initial dAVF was identified in the right posterior frontal convexity region and obliterated with transarterial and transvenous embolization. The patient returned eight years later due to left-sided pulsatile tinnitus and a new dAVF in the left greater sphenoid wing region was seen on angiography. This was treated with transvenous embolization with complete resolution. One year later, she developed left sided pulsatile tinnitus again and was found to have a left carotid-cavernous dAVF. This is the first case report to our knowledge of the formation of three de novo dAVFs over multiple years in distinct anatomical locations. We also review the literature regarding de novo dAVFs after endovascular treatment which includes 16 cases. De novo dAVF formation is likely due to numerous factors including changes in venous flow and aberrant vascular development. It is important to further understand the relationship between endovascular treatment and recurrent dAVF formation to prevent subsequent malformations.

Therapeutic plasma exchange in neurological diseases: Eleven years experience at a tertiary care center in Turkey.

Therapeutic plasma exchange (TPE) is an apheresis procedure in which plasma is separated from the blood cellular components ex vivo, allocated, and replaced with another plasma or a plasma-replacing fluid. This study aimed to define the rate of complications and determine TPE distribution in various neurological diseases. Our study is a retrospective analysis of neurologic diseases requiring TPE between 2008 and 2019 that were selected using the medical records of neurology departments and apheresis units database. We performed 1459 TPE procedures on 207 patients between 2008 and 2019. TPE Procedure is most frequently applied in patients with Myasthenia-Gravis syndrome (34.7%). The complication ratio was 1.6% from a total of 1459 TPE procedures. The most commonly specified adverse event was allergic reactions 11 (5.3%), followed by hypotension 6 (2.9%). TPE was safe and tolerable, with manageable complications in experienced hands.

Quantitative language features identify placebo responders in chronic back pain.

ABSTRACT: Although placebo effect sizes in clinical trials of chronic pain treatments have been increasing, it remains unknown if characteristics of individuals' thoughts or previous experiences can reliably infer placebo pill responses. Research using language to investigate emotional and cognitive processes has recently gained momentum. Here, we quantified placebo responses in chronic back pain using more than 300 semantic and psycholinguistic features derived from patients' language. This speech content was collected in an exit interview as part of a clinical trial investigating placebo analgesia (62 patients, 42 treated; 20 not treated). Using a nested leave-one-out cross-validated approach, we distinguished placebo responders from nonresponders with 79% accuracy using language features alone; a subset of these features-semantic distances to identity and stigma and the number of achievement-related words-also explained 46% of the variance in placebo analgesia. Importantly, these language features were not due to generic treatment effects and were associated with patients' specific baseline psychological traits previously shown to be predictive of placebo including awareness and personality characteristics, explaining an additional 31% of the variance in placebo analgesia beyond that of personality. Initial interpretation of the features suggests that placebo responders differed in how they talked about negative emotions and the extent that they expressed awareness to various aspects of their experiences; differences were also seen in time spent talking about leisure activities. These results indicate that patients' language is sufficient to identify a placebo response and implie that specific speech features may be predictive of responders' previous treatment.

Hippocampus shape deformation: a potential diagnostic biomarker for chronic back pain in women.

ABSTRACT: Sex differences in the quality and prevalence of chronic pain are manifold, with women generally presenting higher incidence and severity. Uncovering chronic pain-related sex differences inform neural mechanisms and may lead to novel treatment routes. In a multicenter morphological study (total n = 374), we investigated whether the shape of subcortical regions would reflect sex differences in back pain. Given the hormone-dependent functions of the hippocampus, and its role in the transition to chronic pain, this region constituted our primary candidate. We found that the anterior part of the left hippocampus (alHP) presented outer deformation in women with chronic back pain (CBP), identified in CBP in the United States (n = 77 women vs n = 78 men) and validated in a Chinese data set (n = 29 women vs n = 58 men with CBP, in contrast to n = 53 female and n = 43 male healthy controls). Next, we examined this region in subacute back pain who persisted with back pain a year later (SBPp; n = 18 women vs n = 18 men) and in a subgroup with persistent back pain for 3 years. Weeks after onset of back pain, there was no deformation within alHP, but at 1 and 3 years women exhibited a trend for outer deformation. The alHP partly overlapped with the subiculum and entorhinal cortex, whose functional connectivity, in healthy subjects, was associated with emotional and episodic memory related terms (Neurosynth, reverse inference). These findings suggest that in women the alHP undergoes anatomical changes with pain persistence, highlighting sexually dimorphic involvement of emotional and episodic memory-related circuitry with chronic pain.

Verification and validation of an automated robot inspection cell for automotive body-in-white: a use case for the VALU3S ECSEL project.

Verification and validation (V&V) of systems, and system of systems, in an industrial context has never been as important as today. The recent developments in automated cyber-physical systems, digital twin environments, and Industry 4.0 applications require effective and comprehensive V&V mechanisms. Verification and Validation of Automated Systems' Safety and Security (VALU3S), a Horizon 2020 Electronic Components and Systems for European Leadership Joint Undertaking (ECSEL-JU) project started in May 2020, aims to create and evaluate a multi-domain V&V framework that facilitates evaluation of automated systems from component level to system level, with the aim of reducing the time and effort needed to evaluate these systems. VALU3S focuses on V&V for the requirements of safety, cybersecurity, and privacy (SCP). This paper mainly focuses on the elaboration of one of the 13 use cases of VALU3S to identify the SCP issues in an automated robot inspection cell that is being actively used for the quality control assessment of automotive body-in-white. The joint study here embarks on a collaborative approach that puts the V&V methods and workflows for the robotic arms safety trajectory planning and execution, fault injection techniques, cyber-physical security vulnerability assessment, anomaly detection, and SCP countermeasures required for remote control and inspection. The paper also presents cross-links with ECSEL-JU goals and the current advancements in the market and scientific and technological state-of-play.

Generative Adversarial Network Based Automatic Segmentation of Corneal Subbasal Nerves on In Vivo Confocal Microscopy Images.

Purpose: In vivo confocal microscopy (IVCM) is a noninvasive, reproducible, and inexpensive diagnostic tool for corneal diseases. However, widespread and effortless image acquisition in IVCM creates serious image analysis workloads on ophthalmologists, and neural networks could solve this problem quickly. We have produced a novel deep learning algorithm based on generative adversarial networks (GANs), and we compare its accuracy for automatic segmentation of subbasal nerves in IVCM images with a fully convolutional neural network (U-Net) based method. Methods: We have collected IVCM images from 85 subjects. U-Net and GAN-based image segmentation methods were trained and tested under the supervision of three clinicians for the segmentation of corneal subbasal nerves. Nerve segmentation results for GAN and U-Net-based methods were compared with the clinicians by using Pearson's R correlation, Bland-Altman analysis, and receiver operating characteristics (ROC) statistics. Additionally, different noises were applied on IVCM images to evaluate the performances of the algorithms with noises of biomedical imaging. Results: The GAN-based algorithm demonstrated similar correlation and Bland-Altman analysis results with U-Net. The GAN-based method showed significantly higher accuracy compared to U-Net in ROC curves. Additionally, the performance of the U-Net deteriorated significantly with different noises, especially in speckle noise, compared to GAN. Conclusions: This study is the first application of GAN-based algorithms on IVCM images. The GAN-based algorithms demonstrated higher accuracy than U-Net for automatic corneal nerve segmentation in IVCM images, in patient-acquired images and noise applied images. This GAN-based segmentation method can be used as a facilitating diagnostic tool in ophthalmology clinics. Translational Relevance: Generative adversarial networks are emerging deep learning models for medical image processing, which could be important clinical tools for rapid segmentation and analysis of corneal subbasal nerves in IVCM images.

Sex-Specific Pharmacotherapy for Back Pain: A Proof-of-Concept Randomized Trial.

BACKGROUND: Preventing transition to chronic back pain (CBP) is a long-sought strategy that could rescue patients from prolonged suffering. Recent rodent and human brain imaging studies suggest involvement of sexually dimorphic, dopaminergic-motivational, mesolimbic circuits in the transition to chronic pain (tCBP), and hint that the combination of carbidopa/levodopa and naproxen (LDP + NPX) may block tCBP. Here we evaluated, in people with recent-onset back pain, whether a 3-month treatment with LDP + NPX is safe, blocks tCBP, and whether its efficacy is sex-dependent. METHODS: A total of 72 participants were enrolled and stratified by risk for tCBP using brain-imaging biomarkers. Low-risk participants entered a no-treatment arm. Others were randomized to placebo + naproxen or LDP + NPX for 3 months. RESULTS: Both treatments resulted in more than 50% pain relief for approximately 75% of participants. A strong sex by treatment interaction was observed for daily pain intensity (phone NRS, P = 0.007), replicated on 4-week average pain (Pain/4w, P = 0.00001), and in intent-to-treat analysis (Pain/4w, P = 0.000004). Nucleus accumbens functional connectivity with medial prefrontal cortex, a predefined objective biomarker, showed sex dependence at baseline (P = 0.03) and sex-by-treatment interaction effect 3 months after treatment cessation (P = 0.031). Treatment modified the psychological profile of participants, and disrupted brain modeling-based predicted back pain intensity trajectories. Forty participants were queried 3.3 years from trial start; back pain ratings were similar between end of treatment and at 3.3 years (P = 0.62), indicating persistence of relief for this duration. CONCLUSIONS: These results provide the first evidence for preventing transition to chronic back pain using sex-specific pharmacotherapy. These provocative observations require confirmation in a larger study. ClinicalTrials.gov identifier: NCT01951105.

Comprehensive Treatment of Severe Periodontal and Periimplant Bone Destruction Caused by Iatrogenic Factors.

Dental implant success requires placement after periodontal therapy, with adequate bone volume, plaque control, primary stability, control of risk factors, and use of well-designed prostheses. This report describes the surgical and prosthetic management of a patient with severe iatrogenic periodontal/periimplant bone destruction. Methods. A 55-year-old female smoker with fixed partial dentures (FPDs) supported on teeth and implants presented with oral pain, swelling, bleeding, and a 10-year history of multiple implant placements and implants/prosthesis failures/replacements. Radiographs showed severe bone loss, subgingival caries, and periapical lesions. All implants and teeth were removed except implants #4 and #10 which served to retain an interim maxillary restoration. Bone defects were covered with nonresorbable dPTFE membranes. In the mandible, three new implants were placed and loaded immediately with a bar-retained temporary denture. Results. Seven months postoperatively, the bone defects were regenerated, and three additional mandibular implants were placed. All mandibular implants were splinted and loaded with a removable overdenture. Conclusions. In this case, periimplant infection and tissue destruction resulted from the lack of periodontal treatment/maintenance and failure to use evidence-based surgical and loading protocols. Combination therapy resolved the disease and the patient's severe discomfort while providing immediate function and an aesthetic solution.

Glucocorticoid receptor in rat nucleus accumbens: Its roles in propofol addictions.

Propofol has been demonstrated as a drug of abuse in humans. Our previous study indicated that dexamethasone, a potent agonist of glucocorticoid receptor (GR), inhibited propofol-maintained rat self-administration behaviors by systematic injection. However, the direct effect of GR in the nucleus accumbens (NAc) on propofol self-administration behavior has not been explored. The propofol-maintained self-administration was established in rats after a successive 3-h daily self-administration of propofol for 14days. On day 15, 30min prior to the last training, rats received one of three doses (0.3, 1.0, or 3.0µg/site) of dexamethasone or vehicle via intra-NAc injection. The number of active nose-poke responses, propofol injections, and inactive nose-poke responses was recorded. Dopamine D1 receptor and c-Fos expressions were detected. Plasma corticosterone level was measured by enzyme-linked immunosorbent assay. Intra-NAc administration of dexamethasone (1.0 and 3.0µg/site) facilitated the active nose-poke responses, which was accompanied by the upregulation of D1 receptor and c-Fos in the NAc. Plasma corticosterone level was not changed in dexamethasone-treated groups. This study provides crucial evidence that GR in the NAc plays an important role in regulating propofol self-administration behaviors in rats, which may be mediated by changes in D1 receptor and c-Fos expressions, and this also needs further examination with GR antagonist in the future.

Brain and psychological determinants of placebo pill response in chronic pain patients.

The placebo response is universally observed in clinical trials of pain treatments, yet the individual characteristics rendering a patient a 'placebo responder' remain unclear. Here, in chronic back pain patients, we demonstrate using MRI and fMRI that the response to placebo 'analgesic' pills depends on brain structure and function. Subcortical limbic volume asymmetry, sensorimotor cortical thickness, and functional coupling of prefrontal regions, anterior cingulate, and periaqueductal gray were predictive of response. These neural traits were present before exposure to the pill and most remained stable across treatment and washout periods. Further, psychological traits, including interoceptive awareness and openness, were also predictive of the magnitude of response. These results shed light on psychological, neuroanatomical, and neurophysiological principles determining placebo response in RCTs in chronic pain patients, and they suggest that the long-term beneficial effects of placebo, as observed in clinical settings, are partially predictable.