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Nociceptive mechanisms in the craniofacial muscle tissue are poorly understood. The pain pattern in individual pericranial muscles has not been described before. Experimental muscle pain was induced by standardized infusions of 0.2 ml 1m hypertonic saline into six craniofacial muscles (masseter, anterior temporalis, posterior temporalis, trapezius, splenius capitis and sternocleidomastoid) in 20 healthy subjects. The pressure pain thresholds (PPTs) were determined before and after infusions. The subjects continuously reported intensity of saline-induced pain on an electronic visual analogue scale (VAS) and the perceived area of pain was drawn on anatomical maps. The pain areas were measured and the localization determined by a new centre-of-gravity method. The PPTs were lowest on the sternocleidomastoid muscle (anova: P < 0.001), but the saline-evoked VAS pain scored highest following injection into the masseter muscle (anova: P < 0.05). The centre-of-gravity measures demonstrated significantly different localization of the pain areas (anova: P < 0.001). The trigeminally vs. the cervically innervated muscles had significantly different patterns of spread and referral of pain according to trigeminally vs. cervically innervated dermatomes ( P < 0.005). In conclusion, there appear to be characteristic pain patterns and pain sensitivity in different craniofacial muscles in healthy volunteers, which may be of importance for further research on different craniofacial pain conditions. [ABSTRACT FROM AUTHOR]

Objective: In the present study, the influence of experimental muscle pain on muscle co-ordination and fatigue development during sustained isometric elbow flexion was investigated.Methods: Conventional surface electromyography (EMG) was recorded from the biceps brachii, brachioradialis, deltoideus and trapezius muscle during isometric elbow flexion at 40% maximum force. Single motor unit (MU) conduction velocity in the biceps brachii was assessed using a high spatial resolution surface EMG technique. Measurements were performed on 15 healthy subjects before, during and after (1) injection of hypertonic (pain condition) and (2) isotonic saline (control) into the biceps brachii. The pain intensity was assessed on a 10 cm visual analogue scale.Results: The experimental results showed in both experimental sessions a fatigue-related increase of the root mean square value of EMG (222±164% of the baseline), and a decrease of the median frequency (118±16% of the baseline) in all investigated muscles. A maximum pain level of in average 3.2 cm on the visual analogue scale was reached after injection of hypertonic saline during contraction. Differences between painful and control condition were seen in an increased trapezius activity (230±141%) during pain. The global EMG activity of the brachioradialis and biceps brachii was unaffected by experimental muscle pain in line with unaffected single MU conduction velocity in the biceps brachii. Differences in endurance time (mean 89.3 and 102.3 s, pain and control, respectively) were not significant.Conclusions/Significance: The findings suggest that upper extremity pain could be a possible source for overloading the trapezius muscle and as such is an important factor in occupational settings. [Copyright &y& Elsevier]

The purpose was to investigate the influence of muscle pain on work performance during computer work with digitizer and puck. Muscle pain was induced by infusion of hypertonic saline in the trapezius and the extensor carpi ulnaris (ECU) muscles on two separate days. Twelve healthy subjects participated. A computer task was performed in three 6 min sessions: baseline, pain, after pain. The computer task comprised production of drawings at maximal work pace. One drawing was defined as a work cycle. Work cycle time, number of puck button clicks, and screen pixels the cursor had moved per cycle were assessed. Shoulder pain did not influence these variables. Cycle time decreased from 13.8 (SD 2.2) to 13.0 s (SD 1.9) compared to baseline (p < 0.05) during ECU muscle pain. The increased or unchanged performance suggests that acute moderate muscle pain has minor influence on performance during computer work with digitizer and puck. [ABSTRACT FROM AUTHOR]

Background: Pain is the leading cause of disability and reduced quality of life worldwide. Despite the increasing burden for patients and healthcare systems, pain research remains underfunded and under focused. Having stakeholders identify and prioritize areas that need urgent attention in the field will help focus funding topics, reduce 'research waste', improve the effectiveness of pain research and therapy and promote the uptake of research evidence. In this study, the European Pain Federation (EFIC) developed a Pain Research Strategy for Europe., Methods: The study used multiple methods, including literature searches, multidisciplinary expert debate, a survey and a final consensus meeting. The cross-sectional survey was conducted among 628 European pain researchers, clinicians, educators and industry professionals to obtain the rating and hierarchy of pain research priorities. The final consensus meeting involved a multidisciplinary expert panel including people with lived experience from 23 countries. The survey results guided discussions where top priorities were agreed., Results: Content analysis identified nine survey themes, of which five emerged as top priorities: (i) understand the pathophysiology of pain; (ii) understand and address comorbidities; (iii) critically assess current therapies; (iv) develop new treatments; and (v) explore the biopsychosocial impacts of pain. Physical, psychological and social approaches were prioritized at the same level as pharmacological treatments. The top priorities were endorsed by a multidisciplinary expert panel. The panel emphasized the importance of also clearly communicating the concepts of prediction, prevention self-management and personalized pain management in the final strategy., Conclusions: The content of the final top research priorities' list reflects a holistic approach to pain management. The equal importance given to physical, psychological and social aspects alongside pharmacological treatments highlights the importance of a comprehensive biopsychosocial-orientated research strategy. The expert panel's endorsement of five top priorities, coupled with an emphasis on communicating the concepts of prediction, prevention, self-management and personalized pain management, provides a clear direction for future basic, translational and clinical research., Significance: EFIC has developed a Pain Research Strategy for Europe that identifies pain research areas deserving the most focus and financial support. Implementation and wide dissemination of this Strategy is vital to increase the conduct of urgent pain projects, pain research funding and the implementation of research findings into practice, to ultimately decrease the personal, societal and financial burden of pain., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Abstract: High frequency repetitive transcranial magnetic stimulation (rTMS) to the posterior-superior insula (PSI) may produce analgesic effects. However, the alterations in cortical activity during PSI-rTMS analgesia remain poorly understood. The present study aimed to determine whether tonic capsaicin-induced pain and cortical inhibition (indexed using TMS-electroencephalography) are modulated by PSI-rTMS. Twenty healthy volunteers (10 females) attended 2 sessions randomized to active or sham rTMS. Experimental pain was induced by capsaicin administered to the forearm for 90 minutes, with pain ratings collected every 5 minutes. Left PSI-rTMS was delivered (10 Hz, 100 pulses per train, 15 trains) ∼50 minutes postcapsaicin administration. Transcranial magnetic stimulation-evoked potentials (TEPs) and thermal sensitivity were assessed at baseline, during capsaicin pain prior to rTMS and after rTMS. Bayesian evidence of reduced pain scores and increased heat pain thresholds were found after active rTMS, with no changes occurring after sham rTMS. Pain (prior to active rTMS) led to an increase in the frontal negative peak ∼45 ms (N45) TEP relative to baseline. After active rTMS, there was a decrease in the N45 peak back to baseline levels. In contrast, after sham rTMS, the N45 peak was increased relative to baseline. We also found that the reduction in pain numerical rating scale scores after active vs sham rTMS was correlated with and partially mediated by decreases in the N45 peak. These findings provide evidence of the analgesic effects of PSI-rTMS and suggest that the TEP N45 peak is a potential marker and mediator of both pain and analgesia. This study demonstrates that high-frequency rTMS targeting the posterior-superior insula reduces capsaicin-induced pain and alters cortical activity, with changes in the N45 TMS-evoked potential peak mediating the analgesic effects., (Copyright © 2024 International Association for the Study of Pain.)

High-frequency repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) is used to treat several neuropsychiatric disorders, but the detailed temporal dynamics of its effects on cortical connectivity remain unclear. Here, we stimulated four cortical targets used for rTMS (M1; dorsolateral-prefrontal cortex, DLPFC; anterior cingulate cortex, ACC; posterosuperior insula, PSI) with TMS coupled with high-density electroencephalography (TMS-EEG) to measure cortical excitability and oscillatory dynamics before and after active- and sham-M1-rTMS. Before and immediately after active or sham M1-rTMS (15 ​min, 3000 pulses at 10 ​Hz), single-pulse TMS-evoked EEG was recorded at the four targets in 20 healthy individuals. Cortical excitability and oscillatory measures were extracted at the main frequency bands (α [8-13 ​Hz], low-β [14-24 ​Hz], high-β [25-35 ​Hz]). Active-M1-rTMS increased high-β synchronization in electrodes near the stimulation area and remotely, in the contralateral hemisphere (p ​= ​0.026). Increased high-β synchronization (48-83 ​ms after TMS-EEG stimulation) was succeeded by enhancement in low-β power (86-144 ​ms after TMS-EEG stimulation) both locally and in the contralateral hemisphere (p ​= ​0.006). No significant differences were observed in stimulating the DLPFC, ACC, or PSI by TMS-EEG. M1-rTMS engaged a sequence of enhanced phase synchronization, followed by an increase in power occurring within M1, which spread to remote areas and persisted after the end of the stimulation session. These results are relevant to understanding the M1 neuroplastic effects of rTMS in health and may help in the development of informed rTMS therapies in disease., Competing Interests: Declaration of competing interests The authors declare no conflict of interest related to the publication., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Noncancer chronic pain is a clinical challenge because pharmacological treatment often fails to relieve pain. Transcranial direct current stimulation (tDCS) is a treatment that could have the potential for pain relief and improvement in quality of life. However, there is a lack of clinical trials evaluating the effects of tDCS on the pain system. The aim of the present study was to evaluate the effect of 5 days of anodal tDCS treatment on the pain system in patients with chronic noncancer pain using quantitative sensory testing and quality of life questionnaires: (1) Brief Pain Inventory-short form, (2) European Organization for Research and Treatment of Life Questionnaire-C30, and (3) Hospital Anxiety Depression Scale., Methods: Eleven patients with noncancer chronic pain (51 ± 13.6 y old, 5M) participated in the study. Anodal tDCS was applied for 5 consecutive days, followed by sham stimulation after a washout period of at least 2 weeks. Pressure pain thresholds and pain tolerance thresholds (PTT) were assessed in different body regions on days 1 and 5., Results: Anodal tDCS appeared to maintain PTT at C5 (clavicle) on day 5, but sham stimulation decreased PTT ( P = 0.007). In addition, anodal tDCS increased PTT compared with sham at day 5 at Th10 ventral dermatomes ( P = 0.014). Both anodal and sham tDCS decreased the Brief Pain Inventory-short form total and interference scores, and the European Organization for Research and Treatment of Life Questionnaire-C30 fatigue score, but no interaction effect was observed., Conclusion: This study adds to the evidence in the literature that tDCS may be a potential therapeutic tool for the management of noncancer chronic pain., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Translational models of the sensitized pain system are needed to progress the understanding of involved mechanisms. In this study, long-term potentiation was used to develop a mechanism-based large-animal pain model. Event-related potentials to electrical stimulation of the ulnar nerve were recorded by intracranial recordings in pigs, 3 weeks before, immediately before and after, and 3 weeks after peripheral high-frequency stimulation (HFS) applied to the ulnar nerve in the right forelimb (7 pigs) or in control animals (5 pigs). Event-related potential recordings and peripheral HFS were done during anesthesia. Two weeks before and after the HFS, behavioral responses reflecting mechanical and thermal sensitivity were collected using brush, noxious limb-mounted pressure algometer, and noxious laser stimuli. The HFS intervention limb was progressively sensitized to noxious mechanical stimulation in week 1 and 2 compared with baseline ( P = 0.045) and the control group ( P < 0.034) but not significantly to laser or brush stimulation. The first negative (N1) peak of the event-related potential was increased 30 minutes after HFS compared with before ( P < 0.05). The N1 peak was also larger compared with control pigs 20 to 40 minutes after HFS ( P < 0.031) but not significantly increased 3 weeks after. The relative increase in N1 30 minutes after HFS and the degree of mechanical hyperalgesia 2 weeks post-HFS was correlated ( P < 0.033). These results show for the first time that the pig HFS model resembles the human HFS model closely where the profile of sensitization is comparable. Interestingly, the degree of sensitization was associated with the cortical signs of hyperexcitability at HFS induction., (Copyright © 2024 International Association for the Study of Pain.)

Long-term musical training induces adaptive changes in the functional representation of the motor cortex. It is unknown if the maladaptive plasticity associated with chronic pain, frequently affecting trained musicians, may alter the use-dependent plasticity in the motor cortex. This study investigated the interaction between adaptive and maladaptive plasticity in the motor pathways, in particular how chronic pain influences long-term use-dependent plasticity. Using transcranial magnetic stimulation (TMS), corticospinal excitability was assessed by measuring the amplitude of the motor-evoked potential (MEP), area of the motor map, volume, and center of gravity of the first dorsal interosseous muscle in 19 pain-free musicians, 17 upper limb/neck pain chronic pain musicians, and 19 pain-free non-musicians as controls. Motor map volume and MEP amplitude were smaller for both pain-free and chronic pain musicians compared to pain-free controls (P < 0.011). No significant differences were found between musicians with and without chronic pain. These findings confirm that long-term musical training can lead to focalized and specialized functional organization of the primary motor cortex. Moreover, the adaptive use-dependent plasticity acquired through fine-motor skill acquisition is not significantly compromised by the maladaptive plasticity typically associated with chronic pain, highlighting the potential of long-term sensorimotor training to counteract the effects of chronic pain in the motor system., (© 2024. The Author(s).)

Homeostatic plasticity is a mechanism that stabilizes cortical excitability within a physiological range. Most homeostatic plasticity protocols have primed and tested the homeostatic response of the primary motor cortex (M1). This study investigated if a homeostatic response could be recorded from the primary sensory cortex (S1) after inducing homeostatic plasticity in M1. In 31 healthy participants, homeostatic plasticity was induced over M1 with a priming and testing block of transcranial direct current stimulation (tDCS) in two different sessions (anodal and cathodal). S1 excitability was assessed by early (N20, P25) and middle-latency (N33-P45) somatosensory evoked potentials (SEP) extracted from 4 electrodes (CP5, CP3, P5, P3). Baseline and post-measures (post-priming, 0-min, 10-min, and 20-min after homeostatic induction) were taken. Anodal M1 homeostatic plasticity induction significantly facilitated the N20-P25, P45 peak, and N33-P45 early SEP components up to 20-min post-induction, without any indication of a homeostatic response (i.e., reduced SEP). Cathodal homeostatic induction did not induce any significant effect on early or middle latency SEPs. M1 homeostatic plasticity induction by anodal stimulation protocol to the primary motor cortex did not induce a homeostatic response in SEPs., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: An endogenous pain modulation profile, reflecting antinociceptive and pronociceptive mechanisms, may help to direct management by targeting the involved pain mechanism. For individuals with cervicogenic headache (CeH), the characteristics of such profiles were never investigated. However, the individual nature of experiencing pain demands profiling within a multidimensional framework including psychosocial lifestyle characteristics. The objective of the current protocol is to assess the pain modulation profile, which includes psychosocial lifestyle characteristics among people with CeH., Methods and Analysis: A protocol is described to map pain modulation profiles in people with CeH. A cross-sectional non-randomised experimental design will be used to assess feasibility of mapping these profiles. The pain modulation profile is composed based on results on the Depression, Anxiety, Stress Scale, Pittsburgh Sleep Quality Index, Headache Impact Test and on responses to temporal summation of pain (pinprick), conditioned pain modulation and widespread hyperalgesia (mechanical pressure pain threshold and cuff algometry). Primary analyses will report results relating to outcomes on feasibility. Secondary analyses will involve an analysis of proportions (%) of the different psychosocial lifestyle profiles and pain profiles., Ethics and Dissemination: Ethical approval was granted by the Ethics Committee Research UZ/KU Leuven (Registration number B3222024001434) on 30 May 2024. Results will be published in peer-reviewed journals, at scientific conferences and, through press releases. Protocol V.3. protocol date: 3 June 2024., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, β1, and β2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased β1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and β band oscillations and may have relevance for pain therapies., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Homeostatic plasticity (HP) is a negative feedback mechanism that prevents excessive facilitation or depression of cortical excitability (CE). Cortical HP responses in humans have been investigated by using 2 blocks of noninvasive brain stimulation with a no-stimulation block in between. A healthy HP response is characterized by reduced CE after 2 excitatory stimulation blocks and increased CE when using inhibitory stimulation. Conversely, impaired HP responses have been demonstrated in experimental and chronic pain conditions. Therefore, this systematic review aimed to provide an overview of the effect of pain on cortical HP in humans. Scopus, Embase, and PubMed were searched from inception until November 20, 2023. The included studies (1) compared experimental or clinical pain conditions with healthy controls, (2) induced HP using 2 blocks of stimulation with a no-stimulation interval, and (3) evaluated CE measures such as motor-evoked potentials. Four studies were included, consisting of 5 experiments and 146 participants, of whom 63 were patients with chronic pain and 48 were subjected to an experimental pain model. This systematic review found support for an HP impairment in pain compared with that in pain-free states, reflected by a lack of CE reduction after excitatory-excitatory HP induction over the primary motor cortex. Inhibitory-inhibitory HP induction did not produce a consistent HP response across studies, independent of pain or pain-free states. Standardization of HP induction protocols and outcome calculations is needed to ensure reproducibility and study comparison. Future HP studies may consider investigating sensory domains including nociception, which would further our understanding of abnormal HP regulation in pain conditions., Competing Interests: Center for Neuroplasticity and Pain (CNAP) is supported by the Danish National Research Foundation (DNRF121). The authors have no conflicts of interests to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: Sensitized pain mechanisms are often reported in musculoskeletal pain conditions, but population-based paediatric studies are lacking. We assessed whether adolescents with musculoskeletal pain history had evidence of increased responsiveness to experimental pressure stimuli., Methods: Data were from 1496 adolescents of the Generation XXI birth cohort. Pain history was collected using the Luebeck Pain Questionnaire (self-reported at 13, parent-reported at 7 and 10 years). Two case definitions for musculoskeletal pain were considered: (1) cross-sectional-musculoskeletal pain lasting more than 3 months at age 13 and (2) longitudinal-musculoskeletal pain at age 13 with musculoskeletal pain reports at ages 7 and/or 10. Lower limb cuff pressure algometry was used to assess pain detection and tolerance thresholds, conditioned pain modulation effects (CPM, changes in thresholds in the presence on painful conditioning) and temporal summation of pain effects (TSP, changes in pain intensity to 10 phasic painful cuff stimulations)., Results: Adolescents with musculoskeletal pain at age 13 plus a history of pain in previous evaluations (longitudinal definition) had lower pain tolerance thresholds compared to the remaining sample (40.2 v. 49.0 kPa, p = 0.02), but showed no differences in pain detection threshold, CPM effect and TSP effect. Pain sensitivity, CPM effects and TSP effects were not significantly different when the current pain only case definition (cross-sectional) was used., Conclusions: Adolescents with current musculoskeletal pain who had a history of pain since childhood had lower tolerance to cuff stimulation. This may suggest long-standing musculoskeletal pain since childhood may contribute to sensitisation, rather than the presence of current pain only., Significance: Repeated musculoskeletal pain up to age 13 years may contribute to higher pain sensitivity (particularly lowered pressure pain tolerance) in the general adolescent population. This does not seem to be the case when reported pain experiences are recent or when the outcomes are temporal pain summation or CPM. In this community-based paediatric sample, the vast majority showed no sign of altered pain processing, but a small fraction may reveal some pain sensitization at 13 years of age., (© 2023 European Pain Federation - EFIC®.)

Homeostatic plasticity (HP) regulates cortical excitability (CE) stability but is disrupted in persistent pain conditions. This study investigated how prolonged experimental pain affects HP and if pain relief modulates disrupted HP. Twenty-four healthy participants were randomised into a PainRelief or NoPainRelief group and attended four sessions; two sessions on consecutive days, separated by two weeks. Transcranial magnetic stimulation motor-evoked potentials reflecting CE and quantitative sensory testing (QST) measures were recorded. A capsaicin (pain condition) or placebo (control condition) patch was applied to the hand. HP was induced by cathodal-cathodal transcranial direct current stimulation (HP1) with CE assessment before and after. The PainRelief group had ice applied to the patch, while the NoPainRelief group waited for five minutes; subsequently another HP induction (HP2) and CE assessment were performed. After 24 h with the patch on, HP induction (HP3), QST, and CE recordings were repeated. Capsaicin reduced CE and the pain condition showed disrupted homeostatic responses at all time points (HP1: showed CE inhibition instead of facilitation; HP2 & HP3: lack of CE facilitation). Conversely, homeostatic responses were induced at all time points for the placebo condition. Capsaicin pain disrupts HP which is not restored by ice-induced pain relief. Future research may explore the prevention of HP disruption by targeting capsaicin-induced nociception but not pain perception., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Abstract: Parkinson disease (PD) affects up to 2% of the general population older than 65 years and is a major cause of functional loss. Chronic pain is a common nonmotor symptom that affects up to 80% of patients with (Pw) PD both in prodromal phases and during the subsequent stages of the disease, negatively affecting patient's quality of life and function. Pain in PwPD is rather heterogeneous and may occur because of different mechanisms. Targeting motor symptoms by dopamine replacement or with neuromodulatory approaches may only partially control PD-related pain. Pain in general has been classified in PwPD according to the motor signs, pain dimensions, or pain subtypes. Recently, a new classification framework focusing on chronic pain was introduced to group different types of PD pains according to mechanistic descriptors: nociceptive, neuropathic, or neither nociceptive nor neuropathic. This is also in line with the International Classification of Disease-11 , which acknowledges the possibility of chronic secondary musculoskeletal or nociceptive pain due to disease of the CNS. In this narrative review and opinion article, a group of basic and clinical scientists revise the mechanism of pain in PD and the challenges faced when classifying it as a stepping stone to discuss an integrative view of the current classification approaches and how clinical practice can be influenced by them. Knowledge gaps to be tackled by coming classification and therapeutic efforts are presented, as well as a potential framework to address them in a patient-oriented manner., (Copyright © 2023 International Association for the Study of Pain.)

Pain-related depression of corticomotor excitability has been explored using transcranial magnetic stimulation-elicited motor-evoked potentials. Transcranial magnetic stimulation-electroencephalography now enables non-motor area cortical excitability assessments, offering novel insights into cortical excitability changes during pain states. Here, pain-related cortical excitability changes were explored in the dorsolateral prefrontal cortex and primary motor cortex (M1). Cortical excitability was recorded in 24 healthy participants before (Baseline), during painful heat (Acute Pain), and non-noxious warm (Warm) stimulation at the right forearm in a randomized sequence, followed by a pain-free stimulation measurement. Local cortical excitability was assessed as the peak-to-peak amplitude of early transcranial magnetic stimulation evoked potential, whereas global-mean field power measured the global excitability. Relative to the Baseline, Acute Pain decreased the peak-to-peak amplitude in M1 and dorsolateral prefrontal cortex compared with Warm (both P < 0.05). A reduced global-mean field power was only found in M1 during Acute Pain compared with Warm (P = 0.003). Participants with the largest reduction in local cortical excitability under Acute Pain showed a negative correlation between dorsolateral prefrontal cortex and M1 local cortical excitability (P = 0.006). Acute experimental pain drove differential pain-related effects on local and global cortical excitability changes in motor and non-motor areas at a group level while also revealing different interindividual patterns of cortical excitability changes, which can be explored when designing personalized treatment plans., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dysmenorrhea (DYS), or recurrent menstrual pain, is a highly prevalent pain condition among otherwise healthy women. However, the progression of DYS over time and the influence of the menstrual cycle phases need to be better understood. While the location and distribution of pain have been used to assess pain mechanisms in other conditions, they are unexplored in DYS. Thirty otherwise healthy women with severe DYS and 30 healthy control women were recruited into 3 subgroups (n = 10) according to the length of their menstrual history (<5, 5-15, or>15 years since menarche). The intensity and distribution of menstrual pain were recorded. Pressure pain thresholds at abdominal, hip, and arm sites, pressure-induced pain distribution, temporal summation of pain, and pain intensity after pressure cessation over the gluteus medius were assessed at 3 menstrual cycle phases. Compared with the healthy control women, those with DYS showed lower pressure pain thresholds in every site and menstrual cycle phase (P < .05), enlarged pressure-induced pain areas during menstruations (P < .01), and increased temporal summation and pain intensity after pressure cessation in the overall menstrual cycle (P < .05). Additionally, these manifestations were enhanced during the menstrual and premenstrual phases compared to ovulation in women with DYS (P < .01). Women with long-term DYS demonstrated enlarged pressure-induced pain distribution, enlarged menstrual pain areas, and more days with severe menstrual pain compared to the short-term DYS subgroup (P < .01). Pressure-induced and menstrual pain distributions were strongly correlated (P < .001). These findings suggest that severe DYS is a progressive condition underscored by facilitated central pain mechanisms associated with pain recurrence and exacerbation. PERSPECTIVE: Enlarged pressure-induced pain areas occur in DYS, associated with the length of the condition and the distribution of menstrual pain. Generalized hyperalgesia is present throughout the entire menstrual cycle and intensifies during premenstrual and menstrual phases., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Alterations in the default mode network (DMN) connectivity across pain stages suggest a possible DMN involvement in the transition to persistent pain., Aim: This study examined whether pain-free DMN connectivity at lower alpha oscillations (8-10 Hz) accounts for a unique variation in experimental peak pain intensity beyond the contribution of factors known to influence pain intensity., Methods: Pain-free DMN connectivity was measured with electroencephalography prior to 1 h of capsaicin-evoked pain using a topical capsaicin patch on the right forearm. Pain intensity was assessed on a (0-10) numerical rating scale and the association between peak pain intensity and baseline measurements was examined using hierarchical multiple regression in 52 healthy volunteers (26 women). The baseline measurements consisted of catastrophizing (helplessness, rumination, magnification), vigilance, depression, negative and positive affect, sex, age, sleep, fatigue, thermal and mechanical pain thresholds and DMN connectivity (medial prefrontal cortex [mPFC]-posterior cingulate cortex [PCC], mPFC-right angular gyrus [rAG], mPFC-left Angular gyrus [lAG], rAG-mPFC and rAG-PCC)., Results: Pain-free DMN connectivity increased the explained variance in peak pain intensity beyond the contribution of other factors (ΔR 2  = 0.10, p = 0.003), with the final model explaining 66% of the variation (R 2  = 0.66, ANOVA: p < 0.001). In this model, negative affect (β = 0.51, p < 0.001), helplessness (β = 0.49, p = 0.007), pain-free mPFC-lAG connectivity (β = 0.36, p = 0.003) and depression (β = -0.39, p = 0.009) correlated significantly with peak pain intensity. Interestingly, negative affect and depression, albeit both being negative mood indices, showed opposing relationships with peak pain intensity., Conclusions: This work suggests that pain-free mPFC-lAG connectivity (at lower alpha) may contribute to individual variations in pain-related vulnerability., Significance: These findings could potentially lead the way for investigations in which DMN connectivity is used in identifying individuals more likely to develop chronic pain., (© 2023 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Introduction: Sitting posture may contribute to spinal pain. Effects of postures on pain, sensitivity and muscle activity during computer tasks were investigated., Methods: Twenty-five healthy participants, seated at a workstation without backrest, completed four, 15-min typing tasks: A)Upright with forearm-support; B)Upright without forearm-support; C)Slumped with forearm-support; D)Slumped without forearm-support. Participants rated pain every minute on a numerical rating scale (NRS). RMS-EMG was recorded from upper/lower trapezius (UT, LT), serratus anterior and anterior/middle deltoid. At baseline and after tasks, pressure pain thresholds (PPTs) were recorded bilaterally over the head, UT, and leg., Results: All tasks caused clinically relevant increased NRS (≥2/10) compared to baseline (P < 0.001). NRS was higher in Task-D (P < 0.003) and lower in Task-B (P < 0.005) than others. PPTs did not change from baseline. Task-D caused higher UT and LT RMS-EMG (P < 0.02) than other tasks., Conclusion: A 15-min task caused pain irrespective of posture with some causing larger changes than others., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The primary aim was to investigate the effectiveness of adding more resistance exercise to usual care on pain mechanisms (including temporal summation, conditioned pain modulation (CPM) and local pain sensitivity) and pain catastrophising in people with subacromial impingement at 16 weeks follow-up. Second, to investigate the modifying effect of pain mechanisms and pain catastrophising on the interventions' effectiveness in improving shoulder strength and disability METHODS: 200 consecutive patients were randomly allocated to usual exercise-based care or the same plus additional elastic band exercise to increase total exercise dose. Completed add-on exercise dose was captured using an elastic band sensor. Outcome measures recorded at baseline, 5 weeks, 10 weeks and 16 (primary end point) weeks included temporal summation of pain (TSP) and CPM assessed at the lower leg, pressure pain threshold at the deltoid muscle (PPT-deltoid), pain catastrophising and the Shoulder Pain and Disability Index., Results: Additional elastic band exercise was not superior to usual exercise-based care in improving pain mechanisms (TSP, CPM and PPT-deltoid) or pain catastrophising after 16 weeks. Interaction analyses showed that pain catastrophising (median split) modified the effectiveness of additional exercises (effect size 14 points, 95% CI 2 to 25), with superior results in the additional exercise group compared with the usual care group in patients with less pain catastrophising., Conclusion: Additional resistance exercise added to usual care was not superior to usual care alone in improving pain mechanisms or pain catastrophising. Additional exercise was, however, superior in improving self-reported disability in patients with lower levels of pain catastrophising at baseline., Trial Registration Number: NCT02747251., Competing Interests: Competing interests: TB has received speaking fees from Zimmer Biomet and Novartis. All authors declare no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Reduced conditioned pain modulation (CPM) and psychological distress co-occur frequently in many pain conditions. This study explored whether common negative pain cognitions and emotional factors were related to lower CPM in individuals across the spectrum from acute to chronic pain. Previously collected data on the CPM effect, pain-related cognitions (fear of movement, pain catastrophizing), and emotional distress (depression, anxiety) through questionnaires from 1142 individuals with acute, subacute, or chronic pain were used. The presence of negative psychological factors was dichotomized according to cutoff values for questionnaires. Associations between the presence of each negative psychological factor and the amplitude of pain reduction in the CPM paradigm was explored with Generalized Linear Models adjusted for sex, age, body mass index, and pain duration. A secondary analysis explored the cumulative effect of psychological factors on CPM. When dichotomized according to cutoff scores, 20% of participants were classified with anxiety, 19% with depression, 36% with pain catastrophizing, and 48% with fear of movement. The presence of any negative psychological factor or the cumulative sum of negative psychological factors was associated with lower CPM (individual factor: β between -0.15 and 0.11, P ≥ 0.08; total: β between -0.27 and -0.12, P ≥ 0.06). Despite the common observation of psychological factors and reduced CPM in musculoskeletal pain, these data challenge the assumption of a linear relationship between these variables across individuals with acute, subacute, and chronic pain. Arguably, there was a nonsignificant tendency for associations in nonexpected directions, which should be studied in a more homogenous population., (Copyright © 2023 International Association for the Study of Pain.)

Objectives: Muscle pain can be associated with hyperalgesia that may spread outside the area of primary injury due to both peripheral and central sensitization. However, the influence of endogenous pain inhibition is yet unknown. This study investigated how endogenous pain inhibition might influence spreading hyperalgesia in experimental muscle pain., Methods: Conditioned pain modulation (CPM) was assessed in 30 male volunteers by cold pressor test at the non-dominant hand as conditioning and pressure pain thresholds (PPT) at the dominant 2nd toe as test stimuli. Subjects were classified as having inhibitory or facilitating CPM based on published reference values. Subsequently, muscle pain and hyperalgesia were induced by capsaicin injection into the non-dominant supraspinatus muscle. Before and 5, 10, 15, 20, 30, 40, 50 and 60 min later, PPTs were recorded at the supraspinatus, infraspinatus and deltoid muscle, ring finger and toe., Results: Compared to baseline, PPTs decreased at the supraspinatus, infraspinatus and deltoid muscle (p≤0.03), and increased at the finger and toe (p<0.001). In facilitating CPM (n=10), hyperalgesia occurred at 5, 10, 15, 20 and 40 min (p≤0.026). In inhibitory CPM (n=20), hyperalgesia only occurred after 10 and 15 min (p≤0.03). At the infraspinatus muscle, groups differed after 5 and 40 min (p≤0.008)., Conclusions: The results suggest that facilitating CPM is associated with more spreading hyperalgesia than inhibitory CPM. This implies that poor endogenous pain modulation may predispose to muscle pain and spreading hyperalgesia after injury, and suggest that strategies to enhance endogenous pain modulation may provide clinical benefits., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Background and Aims: Nociception is the most prevalent pain mechanism in Parkinson disease (PD). It negatively affects quality of life, and there is currently no evidence-based treatment for its control. Burst spinal cord stimulation has been used to control neuropathic pain and recently has been shown to relieve pain of nociceptive origin. In this study, we hypothesize that burst transspinal magnetic stimulation (bTsMS) reduces nociceptive pain in PD., Materials and Methods: Twenty-six patients were included in a double-blind, sham-controlled, randomized parallel trial design, and the analgesic effect of lower-cervical bTsMS was assessed in patients with nociceptive pain in PD. Five daily induction sessions were followed by maintenance sessions delivered twice a week for seven weeks. The primary outcome was the number of responders (≥ 50% reduction of average pain intensity assessed on a numerical rating scale ranging from 0-10) during the eight weeks of treatment. Mood, quality of life, global impression of change, and adverse events were assessed throughout the study., Results: Twenty-six patients (46.2% women) were included in the study. The number of responders during treatment was significantly higher after active than after sham bTsMS (p = 0.044), mainly owing to the effect of the first week of treatment, when eight patients (61.5%) responded to active and two (15.4%) responded to sham bTsMS (p = 0.006); the number needed to treat was 2.2 at week 1. Depression symptom scores were lower after active (4.0 ± 3.1) than after sham bTsMS (8.7 ± 5.3) (p = 0.011). Patients' global impressions of change were improved after active bTsMS (70.0%) compared with sham bTsMS (18.2%; p = 0.030). Minor adverse events were reported in both arms throughout treatment sessions. One major side effect unrelated to treatment occurred in the active arm (death due to pulmonary embolism). Blinding was effective., Conclusion: BTsMS provided significant pain relief and improved the global impression of change in PD in this phase-II trial., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT04546529., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Repetitive movements (RM) are a main risk factor for musculoskeletal pain, which is partly explained by the overloading of musculoskeletal structures. However, RM may also drive brain plasticity, leading to maladaptive changes in sensorimotor areas and altered pain processing. This study aimed to understand whether individuals performing extensive RM (musicians) exhibit altered brain processing to prolonged experimental muscle pain. Nineteen healthy musicians and 20 healthy nontrained controls attended 3 sessions (Day 1-Day 3-Day 8). In each session, event-related potentials (ERPs) to non-nociceptive superficial and nociceptive intraepidermal electrical stimulation, reaction times, electrical detection thresholds, and pressure pain thresholds (PPTs) were recorded. In all participants, prolonged muscle pain was induced by intramuscular injection of nerve growth factor (NGF) into the right first dorsal interosseous muscle at the end of Day1. Pain intensity was assessed on a numerical rating scale (NRS) and was lower in musicians compared to non-musicians (P < .007). Moreover, in musicians, the higher amount of weekly training was associated with lower NRS pain scores on Day 3 to Day 8 (P < .037). Compared with Day1, NGF reduced PPTs on Day 3 to Day 8 (P < .001) and non-nociceptive P200 and P300 ERP amplitudes on Day 8 (P < .044) in both groups. Musicians compared to controls showed secondary hyperalgesia to electrical stimulation on Day 3 to Day 8 (P < .004) and reduced nociceptive P200 ERP amplitudes on Day 8 (P < .005). Across participants, ERP components correlated with pain detection reaction times, sensitivity (PPTs and electrical detection thresholds), and severity (NRS), (all P < .043). These results show that repetitive sensorimotor training leads to brain changes in the processing of prolonged pain, biasing the cortical response to nociceptive inputs. PERSPECTIVE: Repetitive sensorimotor training may increase the responsiveness of nociceptive inputs during the development of prolonged muscle pain. These novel data highlight the role of repetitive sensorimotor practice as a source for interindividual variability in central pain processing., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Prolonged experimental pain models can help assess cortical mechanisms underlying the transition from acute to chronic pain such as resting-state functional connectivity (rsFC), especially in early stages. This crossover study determined the effects of 24-hour-capsaicin-induced pain on the default mode network rsFC, a major network in the dynamic pain connectome. Electroencephalographic rsFC measured by Granger causality was acquired from 24 healthy volunteers (12 women) at baseline, 1hour, and 24hours following the application of a control or capsaicin patch on the right forearm. The control patch was received maximum 1 week before the capsaicin patch. Following 24hours, the patch was cooled and later heated to assess rsFC changes in response to pain relief and facilitation, respectively. Compared to baseline, decreased rsFC at alpha oscillations (8-10Hz) was found following 1hour and 24hours of capsaicin application for connections projecting from medial prefrontal cortex (mPFC) and right angular gyrus (rAG) but not left angular gyrus (lAG) or posterior cingulate cortex (PCC): mPFC-PCC (1hour:P < .001, 24hours:P = .002), mPFC-rAG (1hour:P < .001, 24hours:P = .001), rAG-mPFC (1hour:P < .001, 24hours:P = .001), rAG-PCC (1hour:P < .001, 24hours:P = .004). Comparable decreased rsFC following 1hour and 24hours (P≤0.008) was found at beta oscillations, however, decreased projections from PCC were also found: PCC-rAG (P≤0.005) and PCC-lAG (P≤0.006). Pain NRS scores following 24hours (3.7±0.4) was reduced by cooling (0.3±0.1, P = .004) and increased by heating (4.8±0.6, P = .016). However, neither cooling nor heating altered rsFC. This study shows that 24hours of experimental pain induces a robust decrease in DMN connectivity that persists during pain relief or facilitation suggesting a possible shift to attentional and emotional processing in persistent pain. PERSPECTIVE: This article shows decreased DMN connectivity that might reflect possible attentional and emotional changes during acute and prolonged pain. Understanding these changes could potentially help clinicians in developing therapeutic methods that can better target these attentional and emotional processes before developing into more persistent states., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain perception can be studied as an inferential process in which prior information influences the perception of nociceptive input. To date, there are no suitable psychophysical paradigms to measure this at an individual level. We developed a quantitative sensory testing paradigm allowing for quantification of the influence of prior expectations versus current nociceptive input during perception. Using a Pavlovian-learning task, we investigated the influence of prior expectations on the belief about the varying strength of association between a painful electrical cutaneous stimulus and a visual cue in healthy subjects (N = 70). The belief in cue-pain associations was examined with computational modelling using a Hierarchical Gaussian Filter (HGF). Prior weighting estimates in the HGF model were compared with the established measures of conditioned pain modulation (CPM) and temporal summation of pain (TSP) assessed by cuff algometry. Subsequent HGF-modelling and estimation of the influence of prior beliefs on perception showed that 70% of subjects had a higher reliance on nociceptive input during perception of acute pain stimuli, whereas 30% showed a stronger weighting of prior expectations over sensory evidence. There was no association between prior weighting estimates and CPM or TSP. The data demonstrates relevant individual differences in prior weighting and suggests an importance of top-down cognitive processes on pain perception. Our new psychophysical testing paradigm provides a method to identify individuals with traits suggesting greater reliance on prior expectations in pain perception, which may be a risk factor for developing chronic pain and may be differentially responsive to learning-based interventions., (© 2023. The Author(s).)

Background: Prolonged and repeated sensorimotor training is a crucial driver for promoting use-dependent plasticity, but also a main risk factor for developing musculoskeletal pain syndromes, yet the neural underpinnings that link repetitive movements to abnormal pain processing are unknown., Methods: Twenty healthy musicians, one of the best in vivo models to study use-dependent plasticity, and 20 healthy non-musicians were recruited. Perceptual thresholds, reaction times (RTs) and event-related potentials (ERPs) were recorded using nociceptive intra-epidermal and non-nociceptive transcutaneous electrical stimulation., Results: In response to comparable stimulus intensities, musicians compared to non-musicians showed larger non-nociceptive N140 (associated with higher activation of regions within the salience network), higher nociceptive N200 ERPs (associated with higher activation of regions within the sensorimotor network) and faster RTs to both stimuli. Non-musicians showed larger non-nociceptive P200 ERP. Notably, a similar P200 component prominently emerged during nociceptive stimulation in non-musicians. Across participants, larger N140 and N200 ERPs were associated with RTs, whereas the amount of daily practice in musicians explained non-nociceptive P200 and nociceptive P300 ERPs., Conclusions: These novel findings indicate that the mechanisms by which extensive sensorimotor training promotes use-dependent plasticity in multisensory neural structures may also shape the neural signatures of nociceptive processing in healthy individuals., Significance: Repetitive sensorimotor training may increase the responsiveness of nociceptive evoked potentials. These novel data highlight the importance of repetitive sensorimotor practice as a contributing factor to the interindividual variability of nociceptive-related potentials., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Multifocal transcranial direct current stimulation (tDCS) targeting several brain regions is promising for inducing cortical plasticity. It remains unknown whether multifocal tDCS aimed at the resting-state motor network (network-tDCS) can revert N2-P2 cortical responses otherwise attenuated during prolonged experimental pain. Thirty-eight healthy subjects participated in 2 sessions separated by 24 hours (Day1, Day2) of active (n = 19) or sham (n = 19) network-tDCS. Experimental pain induced by topical capsaicin was maintained for 24 hours and assessed using a numerical rating scale. Electrical detection and pain thresholds, and N2-P2 evoked potentials (electroencephalography) to noxious electrical stimulation were recorded before capsaicin-induced pain (Day1-baseline), after capsaicin application (Day1-post-cap), and after 2 sessions of network-tDCS (Day2). Capsaicin induced moderate pain at Day1-post-cap, which further increased at Day2 in both groups (P = .01). Electrical detection/pain thresholds did not change over time. N2-P2 responses were reduced on Day1-post-cap compared to Day1-baseline (P = .019). At Day2 compared with Day1-post-cap, N2-P2 responses were significantly higher in the Active network-tDCS group (P<.05), while the sham group remained inhibited. These results suggest that tDCS targeting regions associated with the motor network may modulate the late evoked brain responses to noxious peripheral stimulation otherwise initially inhibited by capsaicin-induced pain. PERSPECTIVE: This study extends the evidence of N2-P2 reduction due to capsaicin-induced pain from 30 minutes to 24 hrs. Moreover, 2 sessions of tDCS targeting the motor network in the early stage of nociceptive pain may revert the inhibition of N2-P2 associated with capsaicin-induced pain., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The use of high-definition transcranial direct current stimulation (HD-tDCS) has shown analgesic effects in some chronic pain patients, but limited anti-nociceptive effects in healthy asymptomatic subjects., Methods: This double-blinded sham-controlled study assessed the effects of HD-tDCS applied on three consecutive days on central pain mechanisms in healthy participants with (N = 40) and without (N = 40) prolonged experimental pain induced by intramuscular injection of nerve growth factor into the right hand on Day 1. Participants were randomly assigned to Sham-tDCS (N = 20 with pain, N = 20 without) or Active-tDCS (N = 20 with pain, N = 20 without) targeting simultaneously the primary motor cortex and dorsolateral prefrontal cortex for 20 min with 2 mA stimulation intensity. Central pain mechanisms were assessed by cuff algometry on the legs measuring pressure pain sensitivity, temporal summation of pain (TSP) and conditioned pain modulation (CPM), at baseline and after HD-tDCS on Day 2 and Day 3. Based on subject's assessment of received HD-tDCS (sham or active), they were effectively blinded., Results: Compared with Sham-tDCS, Active-tDCS did not significantly reduce the average NGF-induced pain intensity. Tonic pain-induced temporal summation at Day 2 and Day 3 was significantly lower in the NGF-pain group under Active-tDCS compared to the pain group with Sham-tDCS (p ≤ 0.05). No significant differences were found in the cuff pressure pain detection/tolerance thresholds or CPM effect across the 3 days of HD-tDCS in any of the four groups., Conclusion: HD-tDCS reduced the facilitation of TSP caused by tonic pain suggesting that efficacy of HD-tDCS might depend on the presence of sensitized central pain mechanisms., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Abstract: Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N = 120) participated in a prospective cohort study with 6-month follow-up. Candidate predictors were selected from the neurobiological (eg, sensorimotor cortical excitability assessed by sensory and motor-evoked potentials and brain-derived neurotrophic factor genotype), psychological (eg, depression and anxiety), symptom-related (eg, LBP history), and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with the presence of LBP at 6 months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress, and pain catastrophizing were the strongest predictors ( R2 = 0.47) of pain intensity at 6 months. Older age and higher pain catastrophizing were the strongest predictors ( R2 = 0.30) of disability at 6 months. When the LBP outcome was dichotomised, sensory cortex and corticomotor excitability, brain-derived neurotrophic factor genotype, depression and anxiety, LBP history and baseline pain intensity, discriminated between those who did and did not report LBP at 6 months (C-statistic 0.91). This study identifies novel risk factors for the development of future LBP. Neurobiological risk factors, when added to a multivariable linear regression model, explained a further 15% of the variance in the 6-month pain intensity., (Copyright © 2022 International Association for the Study of Pain.)

Background: A subset of osteoarthritis patients will experience chronic postoperative pain after total knee arthroplasty (TKA), but the source of pain is unclear. The aim of this exploratory study was to assess patients with and without postoperative pain after TKA using magnetic resonance imaging (MRI), quantitative sensory testing (QST), clinical assessment of pain and assessments of catastrophizing thoughts., Methods: Forty-six patients completed the 6-month postoperative assessment. MRI findings were scored according to the MRI Osteoarthritis Knee Score recommendation for Hoffa synovitis, effusion size and bone marrow lesions. QST included assessment of pressure pain thresholds (PPTs), temporal summation of pain (TSP) and conditioned pain modulation (CPM). Pain catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). Clinical pain assessment was conducted using a visual analogue scale (VAS, 0-10 cm), and groups of moderate-to-severe (VAS > 3) and none-to-mild postoperative pain (VAS ≤ 3) were identified., Results: Patients with moderate-to-severe postoperative pain (N = 15) demonstrated higher grades of Hoffa synovitis (p < 0.001) and effusion size (p < 0.001), lower PPTs (p = 0.039), higher TSP (p = 0.001) and lower CPM (p = 0.014) when compared with patients with none-to-mild postoperative pain (N = 31). No significant difference was found in PCS scores between the two groups. Multiple linear regression models found synovitis (p = 0.036), effusion size (p = 0.003), TSP (p = 0.013) and PCS (p < 0.001) as independent parameters contributing to the postoperative pain intensity., Conclusion: These exploratory findings could indicate that chronic postoperative pain after TKA is a combination of joint-related synovitis and effusion, sensitization of central pain mechanisms and potentially pain catastrophizing thoughts, but larger studies are needed to confirm this., Significance: The end-stage treatment of knee osteoarthritis is total knee arthroplasty. Some patients experience chronic postoperative pain after total knee arthroplasty, but the mechanism for chronic postoperative pain is widely unknown. The current study indicates that higher levels postoperative of synovitis and effusion, higher temporal summation of pain and higher pain catastrophizing scores could be associated with higher chronic postoperative pain., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Abstract: Classification of musculoskeletal pain based on underlying pain mechanisms (nociceptive, neuropathic, and nociplastic pain) is challenging. In the absence of a gold standard, verification of features that could aid in discrimination between these mechanisms in clinical practice and research depends on expert consensus. This Delphi expert consensus study aimed to: (1) identify features and assessment findings that are unique to a pain mechanism category or shared between no more than 2 categories and (2) develop a ranked list of candidate features that could potentially discriminate between pain mechanisms. A group of international experts were recruited based on their expertise in the field of pain. The Delphi process involved 2 rounds: round 1 assessed expert opinion on features that are unique to a pain mechanism category or shared between 2 (based on a 40% agreement threshold); and round 2 reviewed features that failed to reach consensus, evaluated additional features, and considered wording changes. Forty-nine international experts representing a wide range of disciplines participated. Consensus was reached for 196 of 292 features presented to the panel (clinical examination-134 features, quantitative sensory testing-34, imaging and diagnostic testing-14, and pain-type questionnaires-14). From the 196 features, consensus was reached for 76 features as unique to nociceptive (17), neuropathic (37), or nociplastic (22) pain mechanisms and 120 features as shared between pairs of pain mechanism categories (78 for neuropathic and nociplastic pain). This consensus study generated a list of potential candidate features that are likely to aid in discrimination between types of musculoskeletal pain., (Copyright © 2022 International Association for the Study of Pain.)

Objective: We explored differences in postural stability between subgroups of patients with low back pain (LBP) and varying risk levels for developing chronicity measured using the Subgroups for Targeted Treatment (STarT) Back Tool., Methods: This was a cross-sectional, single-session, double-blind experimental study among 65 participants who had LBP for more than 14 days. Postural stability was assessed by measuring the center of pressure (COP) range, displacement area, and velocity in anterior-posterior and mediolateral directions under four sensory and cognitive conditions: (i) eyes open and counting forward, (ii) eyes closed and counting forward, (iii) eyes closed and counting forward in multiples of seven, and (iv) eyes closed and counting backward in multiples of seven. The participants were stratified into low-/medium- (n = 53) and high-risk (n = 9) subgroups., Results: There were no significant between-group differences among patients with LBP stratified as having a low/medium or high risk of chronicity in postural stability and sensory and cognitive conditions., Conclusions: Impaired postural stability is important to consider when treating patients with LBP. However, we found that these impairments were not strongly aggravated in groups with a higher risk of chronicity, as measured using the STarT Back Tool.

High definition transcranial direct current stimulation (HD-tDCS) targeting brain areas involved in pain processing has shown analgesic effects in some chronic pain conditions, but less modulatory effect on mechanical and thermal pain thresholds in asymptomatic subjects. This double-blinded study assessed the HD-tDCS effects on experimental pain and hyperalgesia maintained for several days in healthy participants. Hyperalgesia and pain were assessed during three consecutive days following provocation of experimental pain (nerve growth factor injected into the right-hand muscle) and daily HD-tDCS sessions (20-minutes). Forty subjects were randomly assigned to Active-tDCS targeting primary motor cortex and dorsolateral prefrontal cortex simultaneously or Sham-tDCS. Tactile and pressure pain sensitivity were assessed before and after each HD-tDCS session, as well as the experimentally-induced pain intensity scored on a numerical rating scale (NRS). Subjects were effectively blinded to the type of HD-tDCS protocol. The Active-tDCS did not significantly reduce the NGF-induced NRS pain score (3.5±2.4) compared to Sham-tDCS (3.9±2.0, P > .05) on day 3 and both groups showed similarly NGF-decreased pressure pain threshold in the right hand (P < .001). Comparing Active-tDCS with Sham-tDCS, the manifestation of pressure hyperalgesia was delayed on day 1, and an immediate (pre-HD-tDCS to post-HD-tDCS) reduction in pressure hyperalgesia was found across all days (P < .05). PERSPECTIVE: The non-significant differences between Active-tDCS and Sham-tDCS on experimental prolonged pain and hyperalgesia suggest that HD-tDCS has no effect on moderate persistent experimental pain. The intervention may still have a positive effect in more severe pain conditions, with increased intensity, more widespread distribution, or increased duration and/or involving stronger affective components., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Chronic pain is the most prevalent symptomatic disease worldwide. Nonpharmacological interventions, such as noninvasive neuromodulation (NIN), have gained scientific evidence to support their use as an add-on strategy to pharmacological pain management. The most studied NIN technique is repetitive transcranial magnetic stimulation (rTMS). This review aims to identify the current indications for rTMS in the treatment of chronic pain and its new perspectives., Recent Findings: High-frequency rTMS delivered to the primary motor cortex (M1) is currently a treatment strategy with the most literature support for decreased pain intensity and alleviation of associated symptoms in peripheral neuropathic pain, fibromyalgia and migraine. It has been shown that stimulation sessions are well tolerated and tolerable, and the effects of daily stimulation sessions can be prolonged by spaced maintenance stimulation sessions. Despite its efficacy, some individuals will not respond to rTMS targeted to M1. Lines of research are currently being developed to improve rTMS efficacy either by exploring new therapeutic targets, using novel stimulation parameters or more comprehensively profiling patients who are likely to respond to this treatment modality., Summary: Noninvasive brain stimulation for chronic TMS pain is a well tolerated and reasonable add-on treatment approach for pain syndromes such as neuropathic pain, migraine and fibromyalgia. Strategies to improve its efficacy are an active field of research., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Pathophysiological causes of low back pain (LBP) remain generally unclear, so focus has shifted to psychosocial features and central pain processing. Effects of attentional and affective manipulation on conditioned pain modulation and tonic pain perception were examined in 30 patients with recurrent LBP in 2 sessions, one with and one without clinical pain, and compared with healthy participants. Phasic cuff pressure on one leg, scored on a Numerical Rating Scale, was used for test stimuli, and contralateral tonic cuff pain rated on an electronic Visual Analogue Scale was the conditioning stimulus (CS). Test stimuli were assessed before and during (1) control with no manipulation or CS, (2) 3 attentional manipulations (Flanker with or without CS or CS-Only), and (3) 3 affective manipulations (positive, neutral, and negative images) with CS. Greater inhibition of test stimuli Numerical Rating Scale scores was observed in CS-only (P = 0.028), combined CS&attention (P = 0.026), and CS&Positive (P = 0.006) than control paradigms, and greater in CS&Positive (P = 0.019) than CS&Negative paradigms. Electronic Visual Analogue Scale scores of CS pain increased throughout all paradigms with CS (P < 0.05), except the CS&Positive paradigm, and greater facilitation was observed in the CS-Only paradigm than all others (P < 0.02), and lower facilitation was additionally observed in the CS&Positive paradigm compared with CS&Attention and CS&Negative paradigms (P < 0.01). Flanker effects and interruptive effects of CS pain on attention were observed consistent with prior findings, and affective manipulation produced less shift in valence among people with recurrent LBP than controls (P < 0.05). Attention and positive affect with CS pain evoked conditioned pain modulation, and all attentional or affective tasks, especially positive affect, reduced facilitation of CS pain., (Copyright © 2021 International Association for the Study of Pain.)

Objective: To explore the associations between habitual self-reported physical activity, pain sensitivity and patient-reported outcomes (including pain intensity) in patients with chronic pain., Design: Cross-sectional, experimental study., Subjects: Patients (n = 78), age range 18-65 years, with different chronic pain conditions (> 3 months) were compared with age- and sex-matched healthy controls (n = 98)., Methods: Multivariate correlations between self-reported physical activity, pressure pain sensitivity, and patient-reported outcome measures were assessed., Results: Lower perceived health status (p < 0.001, Cohen's d = 2.34), higher levels of depression (p < 0.001, Cohen's d = 1.77), and lower pain tolerance threshold (p < 0.001, Cohen's d = 1.66) were the most prominent variables discriminating patients from controls. In patients, bivariate and multivariate analyses showed that higher pressure pain tolerance was associated with male sex, lower pain intensity and fewer painful regions, higher self-efficacy and more self-reported physical activity, but not with lower levels of anxiety and depression., Conclusion: Pain tolerance thresholds, as well as degree of depression and perceived health status discriminated between patients and controls, and there was an association between pain tolerance thresholds and level of self-reported physical activity in patients. This study highlights the importance of further research into how increased physical activity may improve pain sensitivity in patients with chronic pain.

Objectives: The posterior-superior insula (PSI) has been shown to be a safe and potentially effective target for neuromodulation in peripheral neuropathic pain (PNP) in humans and animal models. However, it remains unknown whether there is a measurable responder profile to PSI stimulation. Two factors were hypothesized to influence the response of repetitive transcranial magnetic stimulation (rTMS) of the PSI: differences in rTMS target (discrete subregions of the PSI) or PNP phenotype., Methods: This is a secondary analysis from a randomized, double-blind, sham-controlled, cross-over trial assessing PSI-rTMS in PNP (N = 31, 5 days rTMS) (10.1016/j.neucli.2021.06.003). Active PSI-rTMS true responders (>50% pain reduction from baseline after active but not after sham series of treatment) were compared with not true responders, to determine whether they differed with respect to 1) rTMS neuro-navigational target coordinates, and/or 2) specific neuropathic pain symptom inventory (NPSI) clusters (pinpointed pain, evoked pain, and deep pain) at baseline., Results: Mean rTMS target coordinates did not differ between true (n = 45.1%) and not true responders (p = 0.436 for X, p = 0.120 for Y, and p = 0.116 for Z). The Euclidian distance between true and not true responders was 4.04 mm. When comparing differences in responders between NPSI clusters, no participant within the evoked pain cluster was a true responder (p = 0.024)., Conclusion: Response to PSI-rTMS may depend on pain cluster subtype rather than on differences in targeting within the PSI., Competing Interests: Declaration of Competing Interest No conflict of interest to be reported., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The angular gyrus (AG) is a common hub in the pain networks. The role of the AG during pain perception, however, is still unclear. This crossover study examined the effect of tonic pain on resting state functional connectivity (rsFC) of the AG under eyes closed (EC) and eyes open (EO). It included two sessions (placebo/pain) separated by 24 hours. Pain was induced using topical capsaicin (or placebo as control) on the right forearm. Electroencephalographic rsFC assessed by Granger causality was acquired from 28 healthy participants (14 women) before (baseline) and 1-hour following the application of placebo/capsaicin. Subjects were randomly assigned and balanced to groups of recording sequence (EC-EO, EO-EC). Decreased rsFC at alpha-1 and beta, but not alpha-2, oscillations was found during pain compared to baseline during EC only. For alpha-1, EC-EO group showed a pain-induced decrease only among connections between the right AG and each of the posterior cingulate cortex (PCC, P = 0.002), medial prefrontal cortex (mPFC, P = 0.005), and the left AG (P = 0.023). For beta rsFC, the EC-EO group showed a bilateral decrease in rsFC spanning the connections between the right AG and mPFC (P = 0.015) and between the left AG and each of PCC (P = 0.004) and mPFC (P = 0.026). In contrast, the EO-EC group showed an increase in beta rsFC only among connections between the left AG and each of PCC (P = 0.012) and mPFC (P = 0.036). No significant change in the AG rsFC was found during EO. These results provide insight into the involvement of the AG in pain perception and reveal methodological considerations when assessing rsFC during EO and EC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)