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The remodeling of functional neuronal connectivity in chronic widespread pain (CWP) patients remains largely unexplored. This study aimed to investigate functional connectivity in CWP patients in brain networks related to chronic pain for changes related to pain sensitivity, psychological strain, and experienced pain. Functional connectivity strength of the default mode network (DMN) and the salience network (SN) was assessed with functional magnetic resonance imaging. Between-group differences were investigated with an independent component analysis for altered connectivity within the whole DMN and SN. Then, changes in connectivity between nodes of the DMN and SN were investigated with the use of a seed-target analysis in relation to the covariates clinical pain intensity, pressure pain sensitivity, psychological strain, and as an effect of experienced experimental cuff-pressure pain. CWP patients showed decreased connectivity in the inferior posterior cingulate cortex (PCC) in the DMN and increased connectivity in the left anterior insula/superior temporal gyrus in the SN when compared to controls. Moreover, higher pain sensitivity in CWP when compared to controls was related to increased connectivity within the SN (between left and right insula) and between SN and DMN (between right insula and left lateral parietal cortex). This study shows that connectivity within the DMN was decreased and connectivity within the SN was increased for CWP. Furthermore, we present a novel finding of interaction of pain sensitivity with SN and DMN-SN functional connectivity in CWP.

The mechanisms involved in musculoskeletal pain include peripheral and central sensitization, the latter of which might cause the chronification of widespread pain conditions. These mechanisms are discussed in this Review, along with methods to assess muscloskeletal pain, such as pressure algometry, cuff-algometry and repeated pressure stimulation. The aim of this Review is to give a short presentation of the manifestations, assessment methods, and mechanisms underlying localized and widespread musculoskeletal pain, deep somatic tissue hyperalgesia and chronification. Hyperalgesia can be explained by increased pain sensitivity of nociceptors located in deep tissue (peripheral sensitization) or by increased responses from dorsal horn neurons (central sensitization). The spreading of pain and sensitization is related to increased synaptic activity in central neurons and to changes in descending control from supraspinal centers. Manifestations related to the different aspects of sensitization can be assessed quantitatively using sensory tests, such as pressure algometry (quantitative palpation) and cuff-algometry. Repeated pressure stimulation can evaluate the degree of temporal summation, which is a proxy for the level of central sensitization, as is expanded referred muscle pain area. The transition of acute localized musculoskeletal pain into chronic widespread pain is related to the progression of peripheral and central sensitization. This sensitization for the chronification of pain should be assessed by adequate pain biomarkers. Furthermore, pain prevention should target early intervention strategies and new anti-hyperalgesic compounds should be developed. Key Points The different manifestations of localized, regional and widespread musculoskeletal pain involve different peripheral and central mechanisms Methodologies are available for quantitative assessment of musculoskeletal pain targeting specific mechanisms such as hyperalgesia, spreading sensitization, temporal summation and pain referral Peripheral and central sensitization are key neurophysiologic mechanisms in musculoskeletal pain Central sensitization is a likely reason for the chronification of widespread pain conditions The transition of acute localized musculoskeletal pain into chronic widespread pain is probably related to the progression of peripheral and central sensitization

Unaccustomed eccentric exercise leads to impaired microvascular function but the underlying mechanism is unknown. In this study, we evaluated the role of oxidative stress and of nitric oxide (NO) bioavailability. Thirty young men and women performed eccentric contractions of the tibialis anterior (TA) muscle (ECC), with the contralateral leg serving as nonexercising control (CON). Participants were randomized into three groups ingesting an antioxidant cocktail (AO), beetroot juice (BR) or placebo 46 h postexercise. At baseline and 48 h postexercise, hyperemic responses to brief muscle contractions and 5 min of cuff occlusion were assessed bilaterally in the TA muscles using blood oxygen level dependent (BOLD) magnetic resonance imaging. Eccentric contractions resulted in delayed time‐to‐peak (~22%; P < 0.001), blunted peak (~21%; P < 0.001) and prolonged time‐to‐half relaxation (~12%, P < 0.001) in the BOLD response to brief contractions, with no effects of AO or BR, and no changes in CON. Postocclusive time‐to‐peak was also delayed (~54%; P < 0.001) in ECC, with no effects of AO or BR, and no changes in CON. Impaired microvascular reactivity after eccentric contractions is confined to the exercised tissue, and is not restored with acute ingestion of AO or BR. Impairments in microvascular reactivity after unaccustomed eccentric contractions may result from structural changes within the microvasculature that can diminish muscle blood flow regulation during intermittent activities requiring prompt adjustments in oxygen delivery. Eccentric muscle contractions result in impaired microvascular function. Oxidative stress and reduced nitric oxide (NO) availability were hypothesized to play a role in impaired microvascular function after eccentric muscle contractions. Acute ingestion of antioxidants (to reduce oxidative stress) and dietary nitrate (to enhance NO availability) did not preserve microvascular function 48 h after eccentric muscle contractions.

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. We used a novel approach that combines transcranial magnetic stimulation with an electroencephalogram (known as TMS‐EEG) to study evoked‐oscillatory cortical activity during acute pain. Our main findings showed that alpha oscillations, evoked by M1 probing, were reduced during acute pain, which correlated with individual trait pain sensitivity.

Abstract Objective Exercise increases pressure pain thresholds (PPTs) in exercising and nonexercising muscles, known as exercise-induced hypoalgesia (EIH). No studies have investigated the test-retest reliability of change in PPTs after aerobic exercise. Primary objectives were to compare the effect on PPTs after an incremental bicycling exercise compared with quiet rest and to investigate the relative and absolute test-retest reliability of the test stimulus (PPT) and the absolute and relative EIH response in exercising and nonexercising muscles. Setting Laboratory. Methods In two sessions, PPTs in the quadriceps and trapezius muscles were assessed before and after 15 minutes of quiet rest and 15 minutes of bicycling in 34 healthy subjects. Habitual physical activity was assessed by the International Physical Activity Questionnaire (IPAQ). Results Bicycling increased PPTs in exercising and nonexercising muscles in both sessions (P < 0.05). The magnitude of the EIH response in the exercising muscle was, however, larger in the second compared with the first session (P < 0.015). PPTs showed excellent (intraclass correlation [ICC] ≥ 0.84) within-session and between-session test-retest reliability. The EIH response in exercising and nonexercising muscles demonstrated fair (ICC = 0.45) between-session relative test-retest reliability, but agreement in EIH responders between sessions was not significant (quadriceps: κ = 0.24, P = 0.15; trapezius: κ = 0.01, P = 0.97). Positive correlations between the IPAQ score and PPTs were found (quadriceps: r = 0.44, P = 0.009; trapezius: r = 0.31, P = 0.07) before exercise. No significant association was found between IPAQ and EIH. Conclusions Incremental bicycling exercise increased PPTs with fair relative and absolute reliability of the EIH response. These data might have an impact on future studies investigating EIH and for clinicians designing exercise programs for pain relief.

Based on reciprocal connections between the dorsolateral prefrontal cortex (DLPFC) and basal-ganglia regions associated with sensorimotor cortical excitability, it was hypothesized that repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC would modulate sensorimotor cortical excitability induced by muscle pain. Muscle pain was provoked by injections of nerve growth factor (end of Day-0 and Day-2) into the right extensor carpi radialis brevis (ECRB) muscle in two groups of 15 healthy participants receiving 5 daily sessions (Day-0 to Day-4) of active or sham rTMS. Muscle pain scores and pressure pain thresholds (PPTs) were collected (Day-0, Day-3, Day-5). Assessment of motor cortical excitability using TMS (mapping cortical ECRB muscle representation) and somatosensory evoked potentials (SEPs) from electrical stimulation of the right radial nerve were recorded at Day-0 and Day-5. At Day-0 versus Day-5, the sham compared to active group showed: Higher muscle pain scores and reduced PPTs (P < 0.04); decreased frontal N30 SEP (P < 0.01); increased TMS map volume (P < 0.03). These results indicate that muscle pain exerts modulatory effects on the sensorimotor cortical excitability and left DLPFC rTMS has analgesic effects and modulates pain-induced sensorimotor cortical adaptations. These findings suggest an important role of prefrontal to basal-ganglia function in sensorimotor cortical excitability and pain processing. •Experimental muscle soreness facilitated the sensory cortical excitability.•Facilitated sensory cortical excitability was reverted by rTMS on the DLPFC.•The corticomotor maps representing the sore muscle was enlarged..•Soreness-induced enlarged corticomotor maps were reduced by rTMS on the DLPFC.•Experimental muscle soreness was reduced by rTMS applied on the DLPFC.

BackgroundAn 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 analysisA 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 disseminationEthical 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.

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.

Multi-site pain has not been investigated among adolescents suffering from knee pain. This study aimed to examine the trajectory of pain in adolescents with knee-pain, to determine if multi-site pain in adolescents together with other established prognostic factors (frequency of pain, sex, sports participation, Health Related Quality of Life (HRQoL)) was associated with five-year prognosis of knee-pain and function. This prospective cohort study included 504 adolescents with knee pain and 252 controls. At five-year follow-up, participants responded to an questionnaire which documented prescence and severity of knee pain and co-occurring pain. At follow-up, 358 (71.0%) of those with knee-pain at baseline, and 182 (72.2%) controls responded. Female sex, low HRQoL, daily pain, and multi-site pain were associated with an increased odds of knee pain after 5 years (odds ratio: 1.41-3.37). Baseline multi-site pain was not associated with problems running at follow-up, whereas higher sports participation at baseline was associated with less problems running at follow-up (odd ratio 0.49). Among those with knee-pain at inclusion, the number of pain sites increased from a median of 2 (IQR 1-3) to 4 (IQR 2-6) at follow-up (P<0.05). Those with multi-site pain at follow-up score significantly worse in self-reported knee function, compared to those with one pain site only. This study identified a set of factors that appeared to be associated with an increased risk of knee pain at five years follow up. Research is needed to understand and help direct treatment of adolescents with multi-site pain.

Abstract Objective Nerve growth factor (NGF) is essential for generating and potentiating pain responses. This double-blinded crossover study assessed NGF-evoked pain in healthy humans after repeated NGF injections in the tibialis anterior (TA) muscle compared with control injections of isotonic saline. Subjects Twenty healthy subjects participated in two experimental phases; each consisted of seven sessions over 21 days. Methods At day 0, day 2, and day 4, a low-dose NGF (1 µg) was injected. Data on daily self-reported muscle pain (using a Likert scale) were collected. Data on pressure pain thresholds (PPTs), pain evoked by nonischemic and ischemic muscle contractions (using a numerical rating scale [NRS]), pressure pain detection (PDT), and pain tolerance thresholds (PTTs) to cuff algometry were recorded before day 0 and at 1, 2, 4, 7, 10, and 21 days after the first injection. Temporal summation of pain (TSP) and conditioned pain modulation (CPM) were recorded to assess central pain mechanisms. Results Likert scores remained elevated for 9 days after NGF injection (P<0.05). PPTs at the TA muscle were decreased at day 1 until day 7 after NGF injection compared with day 0 (P=0.05). In subjects presenting with NGF-induced muscle hyperalgesia, pain NRS scores evoked by nonischemic contractions were higher after NGF injection at day 4 and day 7 (P<0.04) compared with the control condition. At all time points, higher pain NRS scores were found with ischemic compared with nonischemic contractions (P<0.05). The pain NRS after ischemic contractions was elevated following prolonged NGF hyperalgesia at day 7 compared with the control condition and day 0 (P<0.04). The PDT, PTT, TSP, and CPM remained unchanged during the period of NGF-induced hyperalgesia. Conclusions Repeated low-dose NGF injections maintain muscle pain and potentiate pain evoked by ischemic contractions during prolonged NGF hyperalgesia.