Pain

Nav1.7 voltage-gated sodium channels are strongly expressed in human primary painsensing neurons (nociceptors) and selective Nav1.7 inhibitors have been developed as possible therapeutic agents for treating pain, so far with disappointing clinical results. In contrast, a selective Nav1.8 channel inhibitor (suzetrigine) has had successful clinical trials. Because nociceptors express both Nav1.7 and Nav1.8 channels, it is of interest to compare effects of Nav1.7 and Nav1.8 inhibitors on the excitability of human nociceptors. To compare with previous results with suzetrigine, we characterized the effects of a selective Nav.7 inhibitor, AM-2099, on action potential generation and repetitive firing of dissociated human dorsal root ganglion neurons, studied at 37{degrees}C. Inhibition of Nav1.7 channels by 600 nM AM-2099 generally produced a substantial depolarizing shift of action potential threshold, an increase in rheobase, a decrease in action potential upstroke velocity, decrease in action potential peak, and prolongation of refractory period. Compared to inhibition of Nav1.8 channels, inhibition of Nav1.7 channels had larger effects on threshold and maximal upstroke velocity, while action potential peak was reduced similarly by both. Nav1.8 inhibition produced much more dramatic reduction of repetitive firing than Nav1.7 inhibition. The results show that although the excitability of human DRG neurons is affected by inhibition of Nav1.7 channels, most notably by an increase in threshold and increase in refractory period, repetitive firing of the neurons in response to strong stimuli is little affected. Significance statementNav1.7 sodium channels are highly expressed in primary pain-sensing neurons and humans with null mutations in Nav1.7 channels have loss of pain sensation. However, unlike the Nav1.8 inhibitor suzetrigine, Nav1.7 inhibitors have so far not reached clinical use. We compared effects of Nav1.7 on electrical excitability of human dorsal root ganglion neurons with those of suzetrigine and found that while Nav1.7 inhibition affects spike threshold more than suzetrigine, there is little effect on repetitive firing with strong stimuli.

BackgroundPersistent Spinal Pain Syndrome (PSPS) type II represents a challenging clinical entity with limited therapeutic options. Various spinal cord stimulation (SCS) modalities have emerged as potential treatments, but their comparative effectiveness remains unclear. ObjectiveOur goal in this paper is to systematically evaluate and compare the efficacy of different SCS modalities in patients with PSPS type II through meta-analysis of available randomized controlled trials. Evidence ReviewWe conducted a systematic review following PRISMA guidelines, searching major databases for randomized controlled trials evaluating SCS modalities in PSPS type II patients until the end of May 2025(search updated on October 3rd). Primary outcomes included pain intensity (VAS) and functional disability (ODI) at 6 and 12 months. Subgroup analyses compared tonic versus burst stimulation and high-frequency versus low-frequency SCS. FindingsNine randomized controlled trials were included, encompassing 565 patients across different SCS modalities. For the primary outcome of clinically meaningful pain relief ([&ge;]50% reduction), pooled analysis demonstrated that 45% (95% CI: 18-75%, I{superscript 2} = 92.2%) of patients achieved this threshold for back pain and 55% (95% CI: 45-65%, I{superscript 2} = 0%) for leg pain. Subgroup analysis revealed significant differences in back pain responder rates by stimulation modality: High-frequency SCS demonstrated responder rates of 92% (95% CI: 79-98%) versus 28% (95% CI: 13-49%) for conventional frequencies (p < 0.001). For leg pain, no significant difference was observed between tonic (51%, 95% CI: 37-65%) and burst stimulation (60%, 95% CI: 45-74%, p = 0.36) and mean VAS scores demonstrated significantly lower pain with high-frequency SCS (13.30, 95% CI: 8.82-17.78) compared to conventional frequency (28.42, 95% CI: 24.02-32.88, p<0.0001). For back pain, mean VAS scores decreased from a baseline of 73.03 to 41.67 (95% CI: 36.12-47.22, I{superscript 2}=22.8%) at 6 months and remained stable at 35.66 (95% CI: 25.39-45.93, I{superscript 2}=75.0%) at 12 months. Leg pain showed more pronounced improvement, with VAS scores declining from a baseline of 61.81 to 23.75 (95% CI: 17.69-29.81, I{superscript 2}=78.8%) at 6 months and 29.16 (95% CI: 24.81-33.52, I{superscript 2}=0%) at 12 months). Meta-regression identified longer pain duration and older age as positive predictors of response, while higher baseline leg pain predicted lower responder rates. Serious adverse events occurred in 10%, with a 16% revision surgery rate. Only two studies demonstrated a low risk of bias across all domains. ConclusionsCurrent evidence demonstrates that various SCS modalities provide clinically meaningful pain relief in PSPS type II patients, with approximately half achieving [&ge;]50% pain reduction. High-frequency SCS shows significantly superior responder rates for back pain compared to conventional tonic stimulation, while burst stimulation yields significantly superior reductions in continuous pain intensity metrics. However, the limited number of studies, substantial heterogeneity, and lack of head-to-head comparisons prevent definitive recommendations regarding optimal stimulation parameters. Future large-scale randomized trials with standardized protocols and responder-based outcomes are needed to establish evidence-based treatment algorithms for PSPS type II patients.

ObjectivesSensitization of C-fiber nociceptors plays a critical role in spontaneous and ongoing pain in patients with chronic pain. We recently demonstrated that C-fiber afferents can be reversibly blocked through activity-dependent conduction slowing, suggesting that selective activation of C-fiber afferents may represent a novel strategy for pain relief. We hypothesized that electrical peripheral nerve stimulation (ePNS) and dorsal root ganglion (DRG) stimulation exhibit distinct activation thresholds for unmyelinated C-fiber afferents. Materials and MethodsWe characterized the activation thresholds of A- and C-fiber afferents during ePNS and DRG stimulation using single-fiber electrophysiological recordings from split nerve filaments and optical GCaMP6f imaging of intact DRGs. We further quantified the distribution of the sodium channel subtype NaV1.6 in afferent axons and somata and evaluated its contribution to neuronal excitability using NEURON-based computational modeling. ResultsSingle-fiber recordings showed that activation of C-fiber axons required approximately tenfold higher stimulus amplitudes than A/{beta}-fiber axons during ePNS. In contrast, DRG stimulation within a narrow amplitude range robustly activated both small- and large-diameter DRG neurons, with putative C-fiber afferents comprising 57% of the activated population, indicating markedly reduced differential activation thresholds compared with ePNS. Analysis of published single-cell RNA-sequencing datasets revealed high NaV1.6 expression in TRPV1-positive C-fiber nociceptors. Immunohistochemical staining demonstrated prominent clustering of NaV1.6 in the stem axons of most DRG neurons, including small-diameter C-fiber afferents, whereas NaV1.6 was absent from C-fiber axons in the sciatic nerve. NEURON simulations further showed that NaV1.6 clustering at the stem axon is a key determinant of activation thresholds during DRG stimulation. ConclusionsThese findings identify a structural and molecular mechanism underlying the efficient activation of C-fiber afferents by DRG stimulation and provide mechanistic insight into the superior therapeutic efficacy of DRG stimulation for the treatment of C-fiber-mediated chronic pain.

New-onset chronic pain is a common and debilitating symptom of Long COVID (LC) that remains not fully understood in terms of pathophysiology and therapeutic targets. A growing body of evidence in chronic pain syndromes similar to LC demonstrates an association between EEG alpha oscillatory activity and the experience of pain, with clinical studies showing maladaptive changes in oscillatory activity, particularly a slowing of alpha activity. This study aims to investigate the association between EEG alpha oscillatory activity and pain perception in new-onset LC-chronic pain. We recruited 31 individuals (20 females) with a clinical diagnosis of LC reporting new-onset chronic pain and 31 healthy pain-free age-and sex-matched controls. Participants completed questionnaires regarding symptoms and psychological functioning prior to recording eyes-open resting-state EEG. Peak alpha frequency (PAF) and spectral power within the alpha band (8-13 Hz) were extracted from EEG signals. Lower PAF over the posterior scalp region was significantly associated with higher LC-chronic pain severity when controlling for age and depression. This observation was consistent across PAF estimation methods. PAF was significantly increased, particularly in the posterior region, in the moderate pain LC subgroup compared to both severe pain subgroup and controls, while alpha power did not differ between the three groups and was not associated with pain severity. Our findings highlight associations between PAF and pain symptoms in a new post-infection chronic pain syndrome. PAF can thus be explored as a potential biomarker and therapeutic target for EEG-based neuromodulation interventions in LC-chronic pain. These results may have implications for other similar chronic pain syndromes. SummaryLower resting-state EEG peak alpha frequency in posterior scalp region is associated with higher severity of new-onset Long COVID chronic pain.

BackgroundStress and pain are two adaptive mechanisms, driving human behavior and cognition. They are bidirectionally related, and modulating factors such as sleep or physical activity were identified. However, how stable individual differences in pain-related distress, including individual dispositions for pain catastrophizing, and person-specific pain sensitivities relate to the strength of stress responses remains unclear. This preregistered study closes this gap by investigating how trait pain-related distress and pain sensitivity changes relate to individuals stress response. MethodsTrait pain-related distress was assessed in 148 healthy males with the Pain Catastrophizing Scale, the Tampa Scale of Kinesiophobia, and the Fear of Pain Questionnaire. Baseline blood pressure, pulse rate, alpha-amylase, and cortisol were obtained as well as initial heat pain thresholds and tolerances. One participant group underwent the Maastricht Acute Stress Task, while a control group performed the placebo version of this task, and consecutively all stress- and experimental pain indicators were examined again. ResultsIndividuals with lower kinesiophobia demonstrated higher stress-induced increases in alpha-amylase. Furthermore, stress-induced changes in pain sensitivity showed high individual variability, but were not associated with the stress response. Finally, in individuals with a higher tendency to catastrophize and to fear pain, stronger alpha-amylase increases were associated with larger post-stressor increases in pain threshold, indicating reduced pain sensitivity. ConclusionOur study suggests that stable individual differences influence the stress-pain link beyond physiology. This underscores the importance of considering trait differences in future research on stress-pain interactions with the goal of better tailoring preventions and treatments for patients with chronic pain.

Placebo analgesia reduces pain through psychosocial mechanisms, yet the neuromodulators involved remain incompletely understood, limiting clinical translation. Endogenous opioids contribute to placebo analgesia, but do not fully account for inter-individual differences. We tested whether circulating levels of the endocannabinoid (eCB) 2-arachidonoylglycerol, the eCB and fatty acid amide hydrolase (FAAH) substrate anandamide, and FAAH substrates N-palmitoylethanolamide and N-oleoylethanolamide, contribute to placebo analgesia, and whether these effects depend on endogenous opioid activity. Forty-eight healthy adults underwent a validated placebo paradigm with blood sampling. Placebo analgesia was associated with increases in FAAH substrates, but not with 2-arachidonoylglycerol or {beta}-endorphin alone. Critically, {beta}-endorphin levels moderated the relationship between FAAH substrates and analgesia: when {beta}-endorphin elevations were low, FAAH substrate increases strongly predicted pain reduction; when {beta}-endorphin elevations were high, this relationship was absent. These findings indicate that eCB and opioid systems interact in a state-dependent manner to produce placebo analgesia in humans, with implications for harnessing endogenous analgesic mechanisms to personalize pain treatment.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to propose a composite meta-analytic risk index for interventional pain medicine requiring prospective validation. Methods: We searched PubMed/MEDLINE, Scopus, and the Cochrane Library through March 2026 for studies reporting adjusted odds ratios linking (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, and (4) preoperative opioid use/polypharmacy to chronic pain chronification or treatment failure. DerSimonian-Laird random-effects meta-analyses were performed per loop. Publication bias was assessed via Egger's test (k>=8). Effect sizes were integrated into a logistic regression model--the Pain Amplifier Loop Framework (PALF). Neurobiological convergence on TLR4/NF-kB microglial signaling was examined. Results: Forty-four studies (>500,000 participants) were included. Pooled odds ratios: sleep disturbance 1.80 (95% CI 1.65-1.96; k=16; I2=51%), pain catastrophizing 2.11 (1.71-2.61; k=8; I2=0%), metabolic/fat mass 2.02 (1.32-3.09; k=7), preoperative opioid use 4.48 (2.87-6.97; k=6; I2=84%), and opioid-benzodiazepine co-prescription 2.62 (1.76-3.89; k=7; I2=79%). Egger's test showed no significant asymmetry for sleep (p=0.21) or catastrophizing (p=0.84). All loops converge on TLR4/NF-kB microglial signaling. The PALF yields a Systemic Load Score and failure probability P=1/(1+e^-theta), enabling low (<0.30), moderate (0.30-0.60), and high (>=0.60) risk stratification. Conclusions: Four biopsychosocial amplifier loops independently and substantially increase chronic pain risk. The PALF proposes a transparent, hypothesis-driven composite risk index anchored in meta-analytic evidence from >500,000 participants. As a meta-analytic synthesis rather than a fitted prediction model, the PALF requires prospective multicenter validation with individual patient data before clinical application.

Background: Chronic pain affects millions of patients globally and remains therapeutically chal-lenging. While conventional pharmacological approaches have limitations and side effects, pulsed electromagnetic field (PEMF) therapy represents a non-invasive biophysical approach. However, the biological mechanisms underlying PEMF efficacy remain poorly understood. Objective: This study starting from a multi-center post-market surveillance (PMS) data of 81 patients treated with Synth&eacuteXer (a CE-marked Class IIa PEMF device) proposes a mechanistic framework that links ob- served clinical effects to epigenetic modulation via the histone demethylase KDM6B. Materials and Methods: Patients with inflammatory and degenerative disorders causing chronic pain were treated with Synth&eacuteXer across four Italian rehabilitation centers. Pain was assessed using the Numerical Pain Rating Scale (NPRS) before and after treatment. Statistical analysis included descriptive statistics, ANOVA, correlations, and Cohen d effect size. Proposed mechanisms were based on and extrapolated from molecular and biochemical studies demonstrating KDM6B-dependent epigenetic changes in response to specific PEMF sequences. Results: Mean NPRS score decreased significantly from 8.07 {+/-} 1.65 (PRE) to 1.79 {+/-} 1.67 (POST), representing a 6.28-point reduction (p < 0.001; Cohen d = 3.1). Ninety-eight percent of patients showed pain reduction [&ge;] 2 points. No adverse effects were reported. Subset analysis revealed consistent responses across inflammatory (n=19) and degenerative (n=62) pathologies. Discussion: While the observational nature of these data precludes definitive causal attribution, the magnitude of clinical response combined with emerging evidence of KDM6B-mediated epigenetic remodeling suggests a plausible biological basis for PEMF efficacy. Specifically, sequence-depend- ent electromagnetic stimulation may promote the production of and release of anti-inflammatory cytokines and pain resolution through histone demethylation and chromatin remodeling ultimately acting on the expression modulation of such regulatory cytokines. Conclusions: These post-market surveillance data provide clinical evidence of PEMF effects in chronic pain management. The proposed epigenetic mechanism, while requiring further experimental validation and mechanistic confirmation, offers a science-based framework for understanding PEMF biological action and guiding future investigations.

High-impact chronic pain (HICP), defined as persistent pain that substantially limits daily activities, affects millions of adults and poses a public health challenge. Yet relatively little is known about how HICP manifests in people's daily lives. To address this gap, this study used the comprehensive Ecological Momentary Assessment of pain (cEMAp) to assess pain-related experiences four times per day over 7 days in individuals with chronic low back pain. Based on the classification using the Graded Chronic Pain Scale-Revised, we compared individuals with HICP (n = 66) with those in the next most severe pain category, bothersome chronic pain (n = 41), defined as having similar pain frequency but less frequent interference with daily activities. On each prompt, participants completed 2-hour assessments of pain intensity, interference, catastrophizing, behaviors, coping strategies, and pain characteristics. In line with prior research, both groups reported similar pain intensity levels, but the HICP group reported more frequent interference with physical, mental, and social activities. There were no group differences in daily mood or catastrophizing. Exploratory analyses suggested that many daily experiences were similar across groups, with differences observed in selected pain qualities, coping strategies, and pain behaviors. Additional analyses of response distributions showed some similarity across groups in many experiences. Overall, although individuals with HICP on average experience higher pain interference in daily life, levels of many day-to-day experiences are similar between the two groups. Data obtained with cEMAp complement traditional retrospective assessment by providing a detailed view of chronic pain in everyday life.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to develop a logistic regression-based risk stratification tool for interventional pain medicine. Methods: We searched PubMed, Scopus, and Cochrane Library through March 2026 for studies reporting adjusted odds ratios for associations between (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, (4) preoperative opioid use/polypharmacy, and chronic pain chronification or treatment failure. Random-effects meta-analyses (DerSimonian-Laird) were performed for each loop. Effect sizes were translated into a composite logistic regression model, the Pain Amplifier Loop Framework (PALF), using ln(OR) as first-order coefficient approximations. Results: Forty-four studies with over 500,000 participants were included. Pooled odds ratios were: sleep disturbance OR=1.80 (95% CI 1.65-1.96; k=16), pain catastrophizing OR=2.11 (95% CI 1.71-2.61; k=8), metabolic/fat mass OR=2.02 (95% CI 1.32-3.09; k=7), preoperative opioid use OR=4.48 (95% CI 2.87-6.97; k=6), and opioid-benzodiazepine co-prescription OR=2.62 (95% CI 1.76-3.89; k=7). All four loops converge on TLR4/NF-kB microglial signaling. The PALF model produces a probability of interventional failure enabling stratification into low, moderate, and high risk categories. Conclusions: Four amplifier loops independently increase chronic pain risk. The PALF provides a transparent, clinically actionable risk score requiring prospective validation.

Neuropathic pain (NP) affects approximately 60% of individuals with spinal cord injury (SCI). Existing pharmacological treatments provide only modest relief and are often limited by adverse effects, while non-pharmacological options show small effects at best. As such, there remains a need for accessible, mechanism-informed treatments for SCI-NP. This protocol describes a trial evaluating two promising home-based neuromodulatory interventions for SCI-NP - electroencephalography neurofeedback (EEG-NF) and transcranial direct current stimulation (tDCS) - tested both independently and when applied in combination. We will employ a partially double-blinded (i.e. 1 treatment blinded, the other not), 2x2 factorial randomised controlled trial. Adults with chronic SCI-NP (N=192) will be randomised to: (1) EEG-NF + active tDCS, (2) EEG-NF + sham tDCS, (3) active tDCS alone, or (4) sham tDCS alone, in addition to treatment as usual. Participants will complete 20 home-based sessions over 5 weeks. The primary outcome is change in overall pain severity with the primary endpoint being 6 weeks post-randomisation, with secondary endpoints at 16, 26 and 52 weeks post-randomisation. Secondary outcomes (worst pain intensity, pain interference, sleep, depressive symptoms, health-related quality of life) will be assessed at 6 weeks, 16 weeks, 26 weeks and 52 weeks post-randomisation. This will be the first large-scale trial of home-based EEG-NF and tDCS for SCI-NP. If found to be effective, these scalable interventions could be integrated into routine care and inform further optimisation of neuromodulation strategies for managing SCI-NP.

Chronic pain involves natural intensity fluctuations that patients cannot control, contributing to learned helplessness and functional impairment. Detecting spontaneous pain decreases could enable precisely timed interventions that enhance perceived control. However, existing research on objective pain assessment has focused primarily on estimating static intensity from short, predictable stimuli rather than detecting moment-to-moment changes in ongoing pain. This study investigated whether pain decreases can be detected objectively using easily obtainable physiological signals during fluctuating pain. We recorded multiple physiological signals (8-channel EEG, electrodermal activity, heart rate, pupil diameter, facial expressions) from 42 healthy participants (Mage = 26.2 years, SD = 5.1) during calibrated tonic heat pain stimulation on the left forearm with unpredictable intensity fluctuations (0-70 on visual analogue scale; twelve 3-minute trials). Temperature changes lasted 5-20 seconds. Using minimal preprocessing suitable for real-time applications, we trained state-of-the-art deep learning models to classify pain decreases versus non-decreases from brief temporal windows on a held-out test set (9 participants). Combining electrodermal activity, heart rate, and pupil diameter yielded optimal classification performance using a transformer-based architecture (AUROC = 0.854, accuracy = 76.8%). Electrodermal activity emerged as the most informative single predictor. Continuous stream analysis demonstrated median detection latency of 5.75 seconds with 70.4% sensitivity, reducible to 4.25 seconds at the cost of increased false positives. Results indicate that electrodermal activity and heart rate enable straightforward practical deployment, while highly variable signals such as EEG and facial expressions require personalized fine-tuned models. These findings establish a basis for closed-loop interventions targeting spontaneous pain changes. SummaryDeep learning models detect pain decreases using electrodermal activity, heart rate, and pupil diameter (AUROC=0.854, 5.75s latency), facilitating precisely timed interventions for fluctuating tonic pain.

Chronic pain and post-traumatic stress symptoms (PTSS) frequently co-occur. However, how they interact in the brain to influence cognition and emotion is not well understood. Here, we examined how PTSS affects working memory-related networks during an N-back task. In addition, we examined how these networks interact with subcortical threat regions and influence working memory and pain symptoms. Fifty-three chronic low back pain participants completed the N-back task during fMRI. Brain activation was analyzed in relation to PTSS as both a continuous measure and as high-versus-low groups, using whole-brain parcellation across task loads (FDR corrected). We also examined whether abnormally activated regions were functionally connected to periaqueductal gray subregions, the amygdala, or hippocampus, and how these connections related to PTSS. Although higher PTSS did not affect task performance, it was associated with reduced activation in dorsal and inferior lateral frontal regions during the 3-back condition. PTSS was also associated with increased functional connectivity between the dorsolateral prefrontal cortex and periaqueductal gray, but not with the amygdala or hippocampus. Reduced prefrontal activations and high connectivity with periaqueductal gray predicted higher depression and catastrophizing symptoms. Thus, in chronic pain, PTSS selectively disrupts prefrontal circuits, suggesting that greater trauma symptoms interact with prefrontal circuits when cognitive demand is high. PTSS strengthens coupling between prefrontal regions and brainstem threat/pain circuits, suggesting cognitive-affective coupling. These neural alterations occur even when working memory performance is intact and are linked to higher depression and pain catastrophizing. Larger studies are needed to confirm and clarify these mechanisms.

Suzetrigine, a selective Nav1.8 blocker, despite its significant role as a non-opioid analgesic, exhibits modest efficacy. The potential enhancement of Nav1.8 blocker efficacy through engagement of Nav1.8 at central terminals remains uncertain. We established a donor-derived human organotypic nociceptive circuit to determine where and how clinically relevant analgesics suppress pain signaling. Using ELISA and immunohistochemistry, we quantified calcitonin gene-related peptide (CGRP) release from acute explants of adult human spinal cord, dorsal root ganglia (DRG), and an intact DRG-spinal cord preparation preserving primary afferent anatomy and directional signaling. In isolated spinal cords, capsaicin evoked concentration-dependent spinal CGRP release without compromising viability, and clinically used analgesics inhibited it, validating the assay. In the intact circuit, the application of capsaicin to the DRG cell bodies triggered CGRP release exclusively in the spinal cord, consistent with compartmentalized neuropeptide release at central terminals. Selective Nav1.8 inhibition with suzetrigine reduced spinal CGRP release only when applied to the DRG or nerve root, not the spinal cord, indicating that Nav1.8 regulates peripheral action potential propagation rather than presynaptic transmitter release. These findings establish the first intact human pain circuit-based assay to study analgesics and demonstrate that the analgesic efficacy of Nav1.8 inhibitors is unlikely to increase with improved CNS penetration.

BackgroundThe transition from acute to chronic pain represents a failure of physiological resolution. While systemic immune cell counts and androgen levels have been associated with this transition, the specific molecular mediators remain poorly understood. We sought to identify the functional proteomic drivers of long-term pain persistence and determine their independence from systemic factors. MethodsWe identified a longitudinal persistence cohort (N=3,221) within the UK Biobank who reported acute pain at baseline and were followed for resolution or persistence. Using the Olink Explore 3072 platform, we screened 2,923 serum proteins. Multivariable competition models were employed to evaluate the independent predictive power of top proteomic hits alongside systemic monocyte counts and circulating free testosterone levels, adjusted for age and sex. ResultsOur proteome-wide screen identified Lactoperoxidase (LPO) as a dominant and highly significant predictor of pain persistence. In the fully adjusted competition model, each standard deviation increase in LPO was associated with a 59% increase in the odds of persistence (OR 1.59, 95% CI 1.25-2.07, p < 0.001). Notably, after accounting for LPO, systemic monocyte counts (OR 0.93, p = 0.55) and testosterone levels (OR 0.82, p = 0.46) were no longer significant predictors. Nogo Receptor (RTN4R) also remained a significant predictor in independent models (OR 1.44, p = 0.002). ConclusionsThese exploratory findings demonstrate that long-term pain persistence is associated with specific functional molecular signatures rather than broad systemic cell quantity. The dominance of LPO suggests that secretory peroxidase-driven pathways may be a primary barrier to pain resolution. Furthermore, the association of RTN4R identifies neural repair inhibition as a candidate driver of persistence. These proteins are candidates for further mechanistic investigation.

In this randomized, double-blind, controlled trial of 8 weeks of repetitive transcranial magnetic stimulation (rTMS) for chronic pain, we compared the classic primary motor cortex (M1) rTMS with a novel target-selection strategy based on pre-therapy cortical connectivity. Guided by principles of homeostatic plasticity, we tested whether stimulating the cortical site with the lowest pre-therapy global connectivity would be more effective than two active comparators: stimulating the site with the highest pre-therapy global connectivity or stimulating M1 independent of connectivity. Before starting rTMS treatment, TMS-evoked EEG potentials were recorded from four cortical targets: M1, the dorsolateral prefrontal cortex, the anterior cingulate cortex, and the posterosuperior insular cortex. For each target, global connectivity was quantified using a distance-weighted, phase-based index (debiased weighted phase lag index, wPLI) derived from pre- and post-TMS-evoked EEG activity, capturing both the magnitude and spatial extent of TMS-induced oscillatory phase locking across cortical regions. Target allocation in the Low- and High-Connectivity groups was based on this global connectivity measure. Ninety patients with chronic pain were randomized to Low-Connectivity, High-Connectivity, or Classic-M1 groups. Treatment consisted of 12 rTMS sessions delivered over 8 weeks to the assigned target. The primary outcome was the proportion of patients achieving [&ge;] 30% reduction in pain intensity. Secondary outcomes included continuous change in pain intensity, pain interference, sleep, fatigue, mood, quality of life, and patient global impression of change. No between-group differences were observed for primary or secondary outcomes (p > 0.05). In prespecified exploratory analyses, we examined whether pre-therapy local connectivity (within-target wPLI) predicted treatment response. In the Classic-M1 group, lower pre-therapy local M1 connectivity was associated with a greater reduction in pain intensity (r = 0.50, p = 0.005). This association was not observed in the Low- or High-Connectivity groups. A regression model including group-by-connectivity interaction indicated that the relationship between local connectivity and pain reduction differed between the Classic-M1 and High-Connectivity groups (p = 0.038). The results of this clinical trial showed that connectivity-based target allocation using global connectivity did not improve clinical outcomes. However, lower local M1 connectivity was associated with greater pain reduction following Classic-M1 stimulation, suggesting that local M1 connectivity may serve as a potential biomarker of response.

Background Chronic pain is associated with structural and functional brain alterations, particularly within prefrontal, insular, and cingulate cortices. The dorsolateral prefrontal cortex (DLPFC) shows consistent structural abnormalities across chronic pain conditions, whereas findings on intrinsic functional connectivity (FC) remains inconsistent. Anchoring FC analyses to structural alterations may help identify consistent patterns across chronic pain conditions. Methods We employed a voxel-based morphometry (VBM)-guided, seed-based resting-state FC approach. Structural and functional MRI data were obtained from patients with chronic neck pain (CNP; n=21) and healthy controls (HC; n=25). Regions showing significant gray matter volume (GMV) differences were used as seeds for whole-brain FC analysis. Associations with pain intensity and pain-related fear were examined. Findings were further evaluated in an independent cohort with chronic primary pain (CPP; n=38). Results VBM revealed reduced GMV in the left DLPFC in CNP compared with HC, replicated in CPP. Seed-based FC analysis demonstrated reduced connectivity between the left DLPFC and the right hippocampus in CNP, with a similar pattern in CPP. In CNP, GMV in the DLPFC was positively associated with DLPFC-hippocampal connectivity (r = 0.45, 95% CI 0.02 to 0.74, p = 0.043). Reduced DLPFC-hippocampal connectivity was associated with higher activity avoidance (r = -0.50, 95% CI -0.77 to -0.09, p = 0.021), whereas no associations were observed with pain intensity. Conclusions These findings indicate consistent structural and functional alterations across chronic pain cohorts. Reduced DLPFC-hippocampal connectivity may reflect altered interactions between prefrontal and hippocampal circuits involved in pain-related cognitive and affective processes.

Cognitive dysfunction is increasingly recognized as an important feature of chronic pain (CP). However, subjective cognitive complaints and objectively measured cognitive performance frequently diverge. Whether and how these two aspects of cognitive functioning differentially relate to the broad symptomatology and brain function in CP remains unclear. Here, 114 individuals with CP completed patient-reported outcome measures on cognitive functioning and multidimensional CP symptoms, as well as a visuospatial working memory task, and resting-state EEG. Bayesian correlations, network analyses, and Bayesian regression models examined how subjective and objective cognitive functioning relate to multidimensional CP symptoms and EEG activity/connectivity, while controlling for age and sex. Additional models tested whether EEG associations were independent of broader symptom burden. Results indicated that subjective and objective cognitive functioning were uncorrelated. Subjective cognitive functioning was strongly associated with psychosocial symptoms, whereas objective cognitive functioning was largely independent of broader symptom burden. EEG revealed associations between subjective cognitive functioning and bilateral frontotemporal beta connectivity; however, these relationships were substantially attenuated after accounting for broader CP symptom burden. Objective cognitive functioning showed no robust associations with EEG. These findings indicate a dissociation between subjective cognitive complaints and objective cognitive performance in CP. Subjective cognitive complaints were primarily associated with psychosocial symptom burden and beta-band hypoconnectivity. In contrast, objective cognitive performance was unrelated to the broader symptomatology of CP and EEG measures. This dissociation may inform more targeted interventions, optimize the allocation of cognitive assessment resources, and ultimately improve long-term functional outcomes in CP.

Pain is commonly described in sensory terms, yet its spatial characteristics-localization and distribution-are rarely quantified. We investigated whether lay beliefs about pain distribution (PD) influence theoretical decisions to seek care and treatment preferences. In a representative cross-sectional survey (N=503; 49% with pain), participants completed thought experiments in which both visually presented PD patterns (small, moderate or large) and pain intensity (NRS 2, 5, 8/10) were systemically varied. For each scenario, they rated the likelihood of (i) seeking professional help (LoSH) and (ii) taking analgesic medication (LoTM). Participants also completed a spatial-intensity trade-off task (SITT), in which they chose between a fixed 20% reduction in intensity and variable reductions in PD (20-80%). A reversed version contrasted a fixed 80% reduction in PD with variable reductions in pain intensity. LoSH and LoTM increased significantly with greater PD (p<0.001), mirroring the gradient observed for pain intensity. In the SITT, participants' choice followed a sigmoid-like function (p<0.001): 1% reduction in intensity was treated as equivalent to approximately a 3% reduction in distribution, indicating a systematic valuation of PD. This ratio was lower in individuals experiencing pain compared to pain-free individuals. Moreover, 63% reported that PD should be routinely considered in pain management alongside intensity. Results suggest that PD is not merely a trivial descriptor, but a meaningful determinant of healthcare-related decision-making beliefs. Incorporating spatial metrics into clinical assessment and research may better capture how individuals implicitly evaluate pain severity.

Chronic pain is often accompanied by cognitive complaints, but evidence for global working memory problems is mixed. We tested whether working memory performance differences in chronic pain are global or task-specific and whether model-based analysis could help distinguish differences in processing efficiency, response caution or sensory/motor speed. In a preregistered online case-control study, 99 adults with mixed chronic pain conditions and 87 pain-free controls completed visuo-verbal, visuo-spatial and auditory-temporal n-back tasks at low (0/1-back) and high (2-back) load. Accuracy and reaction times were analysed with mixed effects models. Drift diffusion modelling decomposed performance into processing efficiency (drift rate), response caution (threshold separation) and non-decision (sensory/motor) time. Higher load reduced accuracy and slowed responses in both groups. There was no evidence of a global working-memory deficit in the chronic pain group. The clearest group difference was a larger load-related drop in accuracy in the auditory-temporal task (odds ratio 0.64, 95% CI 0.56 to 0.73), persisting after adjustment for mood, sleep and fatigue. Load-related slowing in visuo-verbal (6.7% slower, 5.1% to 8.2%) and auditory-temporal tasks (3.6% slower, 1.7% to 5.4%) were attenuated after adjustment. Diffusion modelling showed no evidence for sensory/motor slowing, but rather greater response caution in the auditory-temporal task and small efficiency (drift rate) reductions in low-load visual conditions. The results do not support a global working-memory capacity loss account in this mixed chronic pain sample. Rather, they suggest task-specific performance differences, most evident in auditory-temporal processing, with response caution as a plausible contributor.