European Journal of Pain

Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique with a favorable safety profile in healthy volunteers. Participant-experienced symptoms however remain inconsistently measured, and prospective benchmarks are lacking. Here, we prospectively characterized symptoms associated with LIFU neuromodulation across eight studies using a standardized Report of Symptoms (ROS). We compiled 629 sessions (472 LIFU, 157 sham) in 106 healthy adults (28.1 +/- 9.8 years) across eight cortical and subcortical targets (500 kHz; extracranial ISPPA 3.9-33.3 W/cm2; mechanical index 0.5-1.4). The ROS rated 17 symptom domains from 0 (absent) to 3 (severe) before and after each session. New-onset incidence, symptom severity, and total symptom burden were compared between LIFU and sham. The same instrument was applied in 35 patients with chronic pain. Symptom profiles after LIFU were indistinguishable from sham across all 17 domains. Total symptom burden averaged approximately one domain per session and did not increase after LIFU (0.94 to 1.03; p = 0.120). Post-intervention burden was predicted by baseline burden (beta = 0.347, p < 0.001) but not by stimulation condition (p = 0.222). New-onset symptoms did not increase across up to 27 LIFU sessions (OR = 0.99, p = 0.73) and were weakly, non-significantly related to acoustic intensity (rho = 0.37). Across a prospective, sham-controlled dataset, LIFU added no measurable symptom burden and was well tolerated in healthy adults, with comparable tolerability in patients. These findings establish a benchmark for the safety of human LIFU neuromodulation and a foundation for its therapeutic translation.

Background. Pain influences motor function and has been proposed to reduce corticospinal and intracortical excitability. At the same time, performance can be maintained during pain, at the cost of increased perceived effort, a centrally generated signal reflecting resource engagement. Here, we tested whether contralateral thermal heat pain-related changes in corticospinal and intracortical excitability contribute to increased effort perception. Methods. In this preregistered transcranial magnetic stimulation (TMS) study, twenty-one healthy participants received single and paired pulse TMS at rest and during submaximal isometric right wrist flexions performed at 20% maximal peak force. Trials were conducted under a control condition or during contralateral thermal stimulation (painful or non-painful warm) applied to the left forearm. After each contraction, participants rated the intensity of their perceived effort. Corticospinal and intracortical excitability of the right wrist flexor was assessed at rest and during submaximal contractions. Results. Contralateral heat pain significantly increased perceived effort compared with the control and warm conditions. Contralateral heat pain did not reduce corticospinal or intracortical excitability. Conversely, contralateral heat pain increased corticospinal excitability, reflected primarily in decreased cortical silent period duration. Perceived effort was associated with the subjective experience of pain rather than with TMS-derived variables. Conclusions. These findings suggest that increased effort during contralateral heat pain cannot be attributed to inhibition of the primary motor cortex or the corticospinal pathway. The higher perceived effort in the presence of contralateral heat pain likely reflects the cognitive cost of pain rather than alterations in the transmission of the motor command.

Low back pain is a prevalent issue with few reliable treatments. Although there is great variation in clinical presentation within the low back pain population, little is known about the neurobiological mechanisms underlying these differences. In this study, we sought to stratify chronic low back pain patients (N = 275) into phenotypes characterized by correlated patterns of resting-state brain activity and sensory abnormalities (pain, numbness, and pins and needles) indicated on hand-drawn body maps. Our cross-decomposition analysis yielded phenotypes that resemble previously documented mechanistic pain types, revealing distinct brain connectivity patterns associated with different clinical presentations. Our model was then used to predict pain body maps from fMRI data in a small novel dataset of chronic pain subjects, suggesting that these relationships may generalize to other chronic pain conditions. Our results support the utility of resting-state fMRI in understanding the heterogeneity of chronic pain, which may be leveraged to develop more targeted pain treatments.

Background: Chronic pain is associated with impaired muscle health, but whether these changes reflect site-specific factors, broader systemic factors, or both remains unclear. The purpose of this study is to determine whether normative markers of muscle health derived from MRI show site-specific patterns in chronic pain. Methods: UK Biobank participants who underwent whole-body MRI from 2006 to 2010 were included in this retrospective cross-sectional study. The MuscleMap Toolbox quantified volume and intramuscular fat (IMF) in 42 muscles of the abdomen, pelvis, and thigh. Normative models trained on a no pain group generated muscle-specific deviations from normal (i.e., Z-scores) for single- and multi-site chronic and acute pain. Results: Of 17,843 participants, the primary site-specific analysis included 9,704 no pain, 885 single-site chronic back pain (CBP), 438 single-site chronic hip pain (CHP), and 1,315 single-site chronic knee pain (CKP) participants (n=12,342; mean age 63.7{+/-}7.5 years; 52.7% female). Additional analyses included single-site chronic neck/shoulder pain, acute pain, and multi-site chronic pain groups. In CBP, deviations were localized to abdominal muscles, with decreased volume in 6/8 and increased IMF in 6/8. In CHP, deviations were broad, with decreased volume in 3/8 of the abdominal and 14/26 of the thigh muscles, and increased IMF in 6/8 of the abdominal, 5/8 of the pelvic, and 4/26 of the thigh muscles. In CKP, deviations were localized to thigh muscles, with decreased volume in 8/26 and increased IMF in 6/26. Acute pain groups showed no significant differences except for decreased volume in one thigh muscle in acute knee pain. With each additional chronic pain site, volume decreased ({beta}=-.078;IQR:-0.100-0.051), and IMF increased ({beta}=.085;IQR:0.066-0.101). Combined Z-scores classified chronic pain groups better than chance (accuracy: 48.6%;p<.001), but not acute pain groups (accuracy: 39.0%;p=.20). Conclusions: Whole-body MRI combined with AI-driven muscle segmentation and normative modeling revealed site-specific patterns of muscle health in single-site chronic pain.

Nociceptive pain is the most common pain condition, and moderate-to-severe nociceptive pain substantially impacts daily functioning, constituting a significant public health burden. Despite this, most studies investigating the neural mechanisms underlying somatosensory processing and inhibition have focused on other pain conditions (e.g., neuropathic, nociplastic, or mixed pain). Thus, the extent to which neural aberrancies detected in these other populations extend to or differentiate from nociceptive pain conditions remains largely unknown. In this study, 29 individuals with moderate-to-severe nociceptive pain (MSNP) and 47 pain-free (PF) controls underwent magnetoencephalography (MEG) alongside a paired-pulse somatosensory stimulation paradigm to examine somatosensory cortical processing and functional inhibition. Pain status and intensity were determined using validated pain questionnaires, painDETECT and PROMIS-29, respectively. MEG oscillatory responses were source localized via a beamformer to the primary somatosensory cortex (S1) and time series data were extracted from the peak voxel to quantify the dynamics of somatosensory gating (SG; index of cortical inhibitory processing), oscillatory response power, and spontaneous power. We found that adults with MSNP exhibit aberrant theta SG in contralateral S1 compared to PF controls, reflecting reduced functional inhibition of innocuous stimulus processing in this region. Additionally, individuals with MSNP demonstrated exaggerated gamma responses but blunted alpha responses in contralateral S1 to innocuous stimulation. Finally, individuals with MSNP were characterized by weaker spontaneous alpha in contralateral S1 that scaled with self-reported pain intensity. Together, these findings suggest that experiencing MSNP is associated with disrupted somatosensory and cortical inhibitory processing.

Introduction: Pain catastrophizing and pain self-efficacy are well-established predictors of health outcomes in chronic pain. Higher pain catastrophizing, a maladaptive cognitive process, predicts worse health outcomes, whereas higher pain self-efficacy, an adaptive cognitive process, predicts better health outcomes. This study examined whether pain catastrophizing and pain self-efficacy interactions predict physical and psychosocial health outcomes at 3 months and their change over 3-months among patients with chronic pain who sought care at a tertiary pain clinic. Methods: Adults with chronic pain (N = 181; 66.7% female; Mage = 58.7) completed baseline assessments of the Pain Catastrophizing Scale (PCS), Chronic Pain Self-Efficacy Scale (CPSS), and PROMIS measures of physical (pain intensity, pain interference, physical function) and psychosocial health (depression, anxiety, anger, loneliness). PROMIS measures were repeated at 3 months. Hierarchical multiple regression analyses tested PCS, CPSS, and their interaction as predictors of outcomes at 3 months and change scores from baseline to 3 months. Results: The PCS by CPSS interaction significantly improved prediction for physical function (Change in R2 = 0.02, p = .02). Higher baseline self-efficacy predicted better physical function (Beta = 0.65, p < .001), but this effect weakened with higher levels of pain catastrophizing. The interaction also predicted change scores in physical function (p = .025) but was marginal after false discovery rate correction (p = .059). Additionally, a significant interaction emerged for loneliness change scores (p = .01): higher self-efficacy predicted greater reductions in loneliness, attenuated by higher catastrophizing. Conclusion: Pain self-efficacy interacted with pain catastrophizing to predict physical function and loneliness at 3 months. Greater self-efficacy was associated with better outcomes, with associations diminished with higher levels of pain catastrophizing. Findings highlight the moderating role of adaptive and maladaptive cognitions and suggest interventions should address both processes to optimize recovery in physical and social functioning.

The anterior cingulate cortex (ACC) is a key brain center involved in cognitive and emotional processing that is implicated in a variety of neuropsychiatric disorders including chronic pain and depression. Circuit-targeted diagnosis and treatment of these disorders will require the capacity to precisely modulate ACC subregions. Toward that end, we recently developed and validated a novel low-intensity transcranial focused ultrasound device that can noninvasively and directly modulate ACC subdivisions in humans with millimeter precision. Here we describe the subjective reports of 36 individuals diagnosed with either chronic pain or major depression who received repeated brief stimulation trials (807 active, 797 sham; duration 30s-3min) spanning the dorsoventral extent of the ACC. Sonication immediately altered cognitive-emotional states (odds ratio 5.6, active versus sham), eliciting a positive-valence experience more often than negative (29% versus 8%) in both diagnostic groups. Sham-adjusted response rate varied across ACC targets, with the largest effects (Cohen's d ~ 0.8) observed in pregenual and subgenual ACC in subjects with chronic pain and depression, respectively. These rapid trial-by-trial responses to ACC stimulation predicted subsequent improvements in pain and depression severity at 24 hours. Collectively, these findings reveal that transcranial ultrasound can robustly evoke immediate, target-specific, clinically meaningful changes in cognitive-emotional state, demonstrating the potential of ultrasonic neuromodulation as a tool for individualized probing of circuit function and dysfunction.

Background: Chronic pain is a multidimensional condition that often persists despite conventional treatment and adversely affects multiple domains of daily life. Music listening has emerged as a promising non-pharmacological intervention, with accumulating evidence supporting its beneficial effects on pain and associated psychological outcomes. However, despite growing evidence of efficacy, the translation of music listening into routine clinical practice remains limited, partly because intervention reporting has received comparatively little attention. Objective: To evaluate the effectiveness of music listening interventions for chronic pain and systematically assess the methodological quality and completeness of intervention reporting to identify barriers to reproducibility and clinical implementation. Methods: Systematic searches were conducted in PubMed, Cochrane Library, CINAHL, and Web of Science through June 2025, with no date restrictions on publication. Randomized controlled trials involving adults with chronic pain receiving music listening interventions were included. Two independent reviewers screened studies, extracted data, and assessed risk of bias. Intervention reporting was evaluated using the TIDieR checklist, and a random-effects meta-analysis was performed for pain intensity outcomes. Results: Ten RCTs involving 538 participants were included. Music listening interventions varied substantially in delivery, duration, and music selection procedures, reflecting considerable heterogeneity in intervention design. Most studies reported significant improvements in pain and psychological outcomes. Meta-analysis of eight trials (10 effect estimates), demonstrated a moderate reduction in pain intensity (SMD = -0.53, 95% CI: -0.96 to -0.11, p = 0.014; I2 = 76.2%). Although intervention rationale and procedures were generally well described, reporting of intervention modifications, treatment fidelity, and adherence was frequently incomplete. These reporting deficiencies may compromise reproducibility and limit translation into clinical practice. Conclusions: Music listening appears to be a safe, accessible, and scalable non-pharmacological intervention for chronic pain management, with benefits extending beyond pain reduction to psychological wellbeing, quality of life, and functioning. However, incomplete reporting of key intervention components may limit reproducibility and hinder clinical implementation. Future trials should adopt standardized and transparent reporting standards to facilitate implementation into clinical practice.

Spinal cord injury (SCI) results in dysfunction of both motor and sensory systems, which can be characterized by neuropathic pain, hypersensitivity, muscular spasticity and rigidity. Most SCIs result from incidents such as vehicle accidents or falls, resulting in polytraumatic SCI that includes peripheral injuries in addition to direct CNS damage. Recent findings suggest that spinal cord synaptic plasticity plays a crucial role in neuropathic pain pathophysiology, specifically in association with spinal sensitization and the consequent onset of AMPA-related maladaptive plasticity. Further findings have demonstrated that nociceptive peripheral stimulation in the acute phase of SCI results in maladaptive spinal synaptic plasticity by overdriving GluA2-lacking calcium-permeable AMPARs (CP-AMPARs). Here, we investigated the effect of a spared nerve injury (SNI) in conjunction with SCI to determine the effect of polytraumatic SCI on maladaptive plasticity in the spinal cord. Near-IR quantitative Western blot analysis demonstrated that SCI+SNI increases spinal GluA1 expression, but not GluA2. Patch-clamp confirmed that AMPAR currents in spinal motorneurons increase after SCI with SNI, and decrease after the administration of NASPM, a CP-AMPAR antagonist. Data-driven analysis using non-linear principal components analysis (NL-PCA) also demonstrated that SCI with SNI produces a multivariate signature of AMPAR plasticity that is observed in other forms of nociceptive peripheral input, indicating a general mechanism for maladaptive plasticity in spinal motor systems in response to polytraumatic SCI.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and painful side effect of paclitaxel (PTX) treatment. The most common measures of painful neuropathy focus on evoked mechanical hypersensitivity, but clinically relevant ongoing pain remains understudied in preclinical models. Automated machine learning methods for pose estimation and behavioral classification have been proposed to capture non-evoked pain-like behaviors, though these approaches have primarily been applied to unilateral injury models such as spared nerve injury or unilateral inflammatory compound injection. Here, we evaluated the extent to which paclitaxel-induced CIPN affects the posture and spontaneous behavior of freely moving mice using a commercially available automated recording system (BlackBox). We found that paclitaxel-treated mice develop a broad and reproducible behavioral and postural phenotype relative to vehicle-treated controls, characterized by reduced front paw luminance and print size, increased front paw lifting, and altered body measurements consistent with a guarded posture. This phenotype was replicated across two independent cohorts and was detectable at both day 2 and day 6 following the final paclitaxel injection. To identify behavioral features specific to CIPN, we administered gabapentin, an analgesic often used to treat neuropathic pain in patients, to determine whether paclitaxel-induced behavioral changes could be attenuated. Gabapentin reduced several behavioral features in both paclitaxel-treated and vehicle-treated animals, suggesting that its effects on posture and gait are not specific pain in CIPN. These findings demonstrate that automated behavioral recording captures a robust paclitaxel-induced postural phenotype but question whether captured behaviors are indicative of ongoing pain as alleviated by gabapentin.

Abstract Background: Non-specific chronic low back pain (NSCLBP) is associated with persistent pain, reduced health-related quality of life (HRQoL), and low-grade systemic inflammation. This study examined associations among changes in inflammatory biomarkers, pain intensity, and HRQoL following a 12-week aerobic exercise programme. Methods: This secondary analysis used data from a randomized controlled trial involving 41 participants with NSCLBP (intervention, n = 21; control, n = 20). Participants received either supervised aerobic exercise plus health education or health education alone for 12 weeks. Change scores for tumour necrosis factor-alpha (TNF-), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), pain intensity, and HRQoL domains were analysed using correlation and multiple regression analyses. Results: Improvements in IL-6 (r = 0.434, p = 0.005) and hs-CRP (r = 0.444, p = 0.004) were significantly associated with improvements in pain intensity. No significant associations were observed between biomarker changes and HRQoL domains. Treatment allocation was the strongest independent predictor of improvement in physical HRQoL ({beta} = 0.492, p = 0.017) and pain intensity ({beta} = -0.512, p = 0.006). Conclusions: Improvements in IL-6 and hs-CRP were associated with reductions in pain intensity but not with improvements in HRQoL. Treatment allocation was the strongest predictor of clinical improvement, suggesting that mechanisms beyond systemic inflammation may contribute to the benefits of aerobic exercise in NSCLBP. Keywords: non-specific chronic low back pain; aerobic exercise; inflammation; interleukin-6; high-sensitivity C-reactive protein; pain intensity; health-related quality of life.

Cerebral Palsy (CP) is the most common motor disability in childhood, and the most frequent comorbidity is pain. Rabbit kits subjected to prenatal hypoxia-ischemia (HI) exhibit allodynia and an expansion of nociceptive afferents in the lumbar spinal cord at postnatal day (P5). In this study, we examined how HI alters the development of multiple sensory modalities and its effect on psychosocial measures and C-fiber distribution in the spinal cord. To do this, we performed an HI surgery to occlude blood flow to fetal New Zealand White rabbits for 40 minutes, or a sham surgery. We performed von Frey, Hargreaves, and a cold allodynia test at P1, P5, P11, and P18. Additionally, we performed open field, a two-texture preference test, and immunofluorescence assays at P18. HI kits exhibit altered development and allodynia in von Frey and Hargreaves and minor decreased sensitivity in cold allodynia. HI kits spend less time on the aversive side of the two-texture preference apparatus and more time in the center of an open field but a higher ratio of that time immobile. This is accompanied by changes in the distribution of C-fibers in the dorsal horn of the cervical and lumbar spinal cord. A principal components analysis revealed altered nociception and psychosocial changes are important for differentiating between control and HI kits but not distribution of C-fibers. Overall, HI rabbits kits exhibit altered sensory development, allodynia, anxiety-like behavior, and changes to the distribution of nociceptive afferents in the dorsal horn of the spinal cord.

Objective: To characterise the symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Method: 1028 adults with ME/CFS completed The Index of ME Symptoms (TIMES) online. Raw ordinal data were Rasch transformed into interval data so parametric statistics were used. Results: Mean TIMES score was 57.2/100 (sd 5.4) indicating a severe symptom burden affecting multiple body systems. The correlations between symptom burden, age and duration were negligible, and moderate with ME/CFS severity. Women had a greater symptom burden than men. All participants experienced fatigue, neurological symptoms and dysautonomia. The mean Fatigue Scale score was severe (67.7 (sd 19.9)) and moderate for the Neurological Scale (mean 45.11 (sd 9.45)) and Dysautonomia Scale (43.98 (sd 8.42)). Over 90% experienced cognitive, pain, motor-sensory, sleep, cardio-respiratory, cranial nerve and gastro-intestinal symptoms to some degree. They were mild-moderately troublesome overall, except cognitive symptoms which were severe. Conclusions. ME/CFS causes a heavy multi-system symptom burden. Although most individual symptoms were mild-moderately troublesome, the cumulative effect was severe or very severe. Fatigue was the most common and troublesome problem followed by cognitive symptoms, sleep disturbance and pain. Women experienced a greater symptom burden than men, and there was a moderate relationship between symptom burden and disease severity.

Evaluation of the effectiveness of therapeutic interventions for dentine hypersensitivity is limited by a lack of standardisation and objectivity in measuring the associated pain. To address this, we investigated whether electroencephalography (EEG) can provide an objective, quantitative measure of the condition. Participants with and without dentine hypersensitivity underwent evaporative (air puff) and thermal (cooling probe) tooth stimulation during continuous recording of EEG activity. Sensitivity scores (Schiff Sensitivity score for air puff stimuli, and Visual Analogue Scale score (VAS) for thermal stimuli) were recorded, and participants' responses to the Dentine Hypersensitivity Experience Questionnaire (DHEQ) collected. There were strong positive correlations between the Schiff and VAS scores, and also between both sensitivity scores and the impact of dentine hypersensitivity on quality of life (DHEQ). Additionally, EEG data analysis revealed significant differences in event-related potentials (ERP) following evaporative stimulation between participants with different Schiff scores, and in cortical activity between traces where participants indicated discomfort and those where participants did not indicate discomfort during thermal stimulation trials. Topographical maps of EEG band power during thermal stimulation showed progressive cortical recruitment and focal activation emerging in the 3 seconds prior to indication of discomfort. Comparison of EEG band power between response and no response trials to thermal stimulation showed significantly higher delta frequency band power in response trials than in no-response trials. Peak-to-peak amplitude of cortical response during thermal stimulation correlated with DHEQ and VAS scores, and the probe temperature at which participants indicated discomfort. These findings suggest that components of EEG responses align with other measures of dentine sensitivity (DHEQ, Schiff and VAS scores) and can serve as objective neurophysiological markers for evaluating the severity of dentine hypersensitivity.

Chronic postsurgical pain (CPSP) prevalence after total knee arthroplasty (TKA) is >20%. Circulating immune biomarkers are known factors of musculoskeletal pain but poorly understood as CPSP predictors. This prospective, longitudinal study of 203 patients s/p TKA tested presurgical plasma biomarkers associated with 6-month CPSP, using promising approaches from geriatrics biomarker research: expected recovery differential (ERD; resilience outcome) and penalized, machine-learning regularization modeling (elastic net and LASSO regression). Forty-nine presurgical candidate biomarkers were considered. CPSP was operationalized using ERDs built around PROMIS pain intensity and pain interference, which quantified the difference between observed and expected recovery after accounting for demographic, comorbidity, reserve, and perioperative factors. Plasma/ERDs from ~130 patients revealed 13 biomarkers with the highest selection stability criteria, and either positive or negative (+/-) associations with ERDs. Interleukin (IL) 5 (-) and Lipopolysaccharide-Binding Protein (LBP; +) were associated with both ERDs. Unique associations with pain intensity ERD included Cytomegalovirus-Specific IgG Negative (CMV IGg-; -), Macrophage Inflammatory Protein-1 Beta (MIP1b; -), IL12p70 (-, Cluster of Differentiation 30 (sCD30;-), Interferon alpha 2a (IFN2a;+), and Leukemia Inhibitory Factor (LIF;+). Unique associations with pain interference ERD included Lipopolysaccharide (LPS;-), Activin A (-), IL8 (-), Serum Amyloid A (SAA;-), and IL7 (+). Protein-protein interaction analyses and topology motifs suggest a centralized network with higher-than-expected connectivity, involving IL5, IL7, IL8, MIP1{beta}, and IFN2a, among others. This study proposes rigorous yet feasible approaches to expedite pain biomarker research, and introduces presurgical biomarkers t0 consider in future TKA-CPSP biosignature derivation.

Introduction Chronic musculoskeletal pain (CMSKP) in adolescence is associated with physical, psychological, social, and academic impairment and increased risk for chronic pain in adulthood. Although physical activity interventions are an evidence-based approach for managing pediatric chronic pain, many adolescents with CMSKP avoid physical activity due to fear of increased pain, low confidence in physical functioning, and other pain-avoidance behaviors. Resilience-focused interventions targeting self-efficacy, motivation, and mental flexibility may improve engagement in valued activities despite pain. This study describes the design and protocol of the Pain REsilience Promotion for Youth (PREP-Y) intervention, a resilience-focused physical activity intervention for adolescents with CMSKP. Methods and analysis This single-site, pilot phase 2, single-group, non-randomized clinical trial will enroll 40 adolescents aged 12-17 years with CMSKP from Nationwide Childrens Hospital in Columbus, Ohio, USA. Participants complete questionnaires, objective physical functioning assessments, and physical activity monitoring using activPAL devices as baseline measures. Participants then complete 4 virtual resilience-focused intervention sessions targeting pain resilience, self-efficacy, motivation, and adaptive coping related to physical activity. Garmin watches are used to track activity during the intervention period. Follow-up assessments occur post-intervention and at 3 months post-intervention. Primary outcomes include feasibility and acceptability, assessed through recruitment, retention, attendance, intervention fidelity, and completion of study measures. Exploratory outcomes include physical activity, sedentary behavior, pain-related functioning, pain catastrophizing, kinesiophobia, self-efficacy, and resilience-related constructs. Ethics and dissemination The study was approved by the Nationwide Childrens Hospital Institutional Review Board. Findings will inform a future randomized clinical trial. This manuscript reflects protocol version 5.0 dated 23 March 2026. Trial registration ClinicalTrials.gov: NCT06923891.

Myofascial pain syndrome (MPS) is a major cause of chronic neck pain, with tissue ischemia implicated as a contributing factor. This prospective, single-arm interventional study evaluated the analgesic effect of ultrasound-guided fascia hydrorelease (US-FHR) performed around arteries supplying the neck in patients with chronic neck MPS. Thirteen adults (median age 53.0 years; 38.5% female) underwent US-FHR targeting the perivascular fascia of either the transverse cervical or dorsal scapular artery using 2 mL of normal saline. Pain intensity was assessed by visual analog scale (VAS) at rest and during movement; disability by the 5-item Pain Disability Index, Japanese version (PDI-5-J); and arterial blood flow volume before and after the procedure. The primary outcome, pain VAS during movement, decreased from 49.0 mm (interquartile range [IQR], 44.5-64.0) at baseline to 22.0 mm (IQR, 14.5-31.5) at 15 min and 22.0 mm (IQR, 14.0-34.0) at 1 week (Hodges&-Lehmann median difference, 30.5 mm [95% CI, 24.5 to 36.5] and 28.5 mm [95% CI, 18.5 to 37.0]; both P < 0.001). Pain VAS at rest improved from 21.0 mm (IQR, 13.0-43.5) to 8.0 mm at 15 min and 1 week (median difference, 14.5 mm [95% CI, 9.0 to 24.0; P = 0.001] and 13.5 mm [95% CI, 6.0 to 21.0; P = 0.007]). PDI-5-J decreased from 17.0 (IQR, 10.5-23.0) to 13.0 (IQR, 4.0-17.5) at 1 week (median difference, 5 [95% CI, 2 to 8; P = 0.004]). Blood flow volume increased from 11.2 mL/min (IQR, 4.5-14.4) to 17.2 mL/min (IQR, 6.1-23.7) immediately after US-FHR (median difference, +4.1 mL/min [95% CI, +2.5 to +8.9; P = 0.001]), although transient. One patient experienced transient bleeding that was promptly controlled. In this single-arm feasibility study, US-FHR around the target artery was simple and safe to perform and was associated with reduced neck pain. Because the study lacked a control group, these preliminary findings should be regarded as hypothesis-generating and require confirmation in controlled trials; they may also inform the future evaluation of MPS in other anatomical regions. Trial registration: UMIN Clinical Trials Registry, UMIN000053612.

ObjectiveLateral spinal cord stimulation (LSCS) is a promising approach for restoring somatosensory feedback in lower-limb amputees, but its spatial selectivity remains limited. Percepts often spread to unintended regions of the residual limb, and reducing electrode contact size may not improve focality. This study investigated whether the anatomical organization of lumbar dorsal rootlets (DR) imposes fundamental constraints on LSCS selectivity. ApproachAcute neurophysiology experiments were performed in six adult cats. Both LSCS and individual DR stimulation were conducted in the same animals. For DR stimulation, bipolar hook electrodes were used to stimulate individual DR, while antidromic compound action potentials (CAPs) were recorded from femoral and sciatic nerve branches instrumented with nerve cuffs. For LSCS, custom 32-contact epidural paddle electrodes were placed over the lateral surface of the spinal cord at corresponding vertebral levels. Recruitment thresholds, dynamic ranges, and response patterns were analyzed across spinal levels, and DR recruitment patterns were directly compared to those evoked by LSCS within the same animals. Main resultsA clear rostrocaudal organization was observed across spinal levels during stimulation of individual DR, with femoral branches predominantly recruited at L4-L5 and sciatic branches at L6-L7. However, no somatotopic organization was found across DR within each spinal level; individual DR frequently co-activated multiple branches within the same group, and selective recruitment could only be maintained over a narrow dynamic range (median [~]10 {micro}A). LSCS exhibited even a narrower dynamic range ([~]5 {micro}A) but closely mirrored DR recruitment patterns, indicating that LSCS activates sensory afferents in a manner determined by the organizational structure of the DR. SignificanceThese findings demonstrate that the limited spatial selectivity of LSCS can largely be attributed to the coarse organization of DR within each root level rather than due to limitations of epidural electrode design. Moving electrodes intradurally or reducing contact size further is unlikely to substantially improve focality. Instead, improving paddle stability to ensure consistent placement over the appropriate spinal levels may be a more effective strategy for enhancing percept localization.

Background: Cutaneous microvascular responses to local heating and acetylcholine perfusion are widely used to assess nitric oxide (NO)-mediated endothelium-dependent dilation in human health and disease. Despite the increasingly common usage of these approaches, no studies have directly compared responses to these stimuli within individuals. Therefore, we assessed endothelium- and NO-dependent dilation in 80 young adults (40 males/40 females; 22{+/-}3 years) to determine the extent to which microvascular responses to these endothelium-dependent stimuli are comparable within an individual. Methods: We examined cutaneous vascular conductance responses to (1) standardized local heating protocols to 39{degrees}C and 42{degrees}C, and (2) graded infusions of acetylcholine (10-10-10-1 M) alone or with 15 mM NG-nitro-l-arginine methyl ester (L-NAME; NO synthase inhibitor). Endothelium- and NO-dependent dilation were calculated and expressed in multiple ways based on commonly published analyses to allow for a thorough comparison within and between each stimulus. Results: Local heating-induced endothelium- and NO-dependent dilation were lower at 39{degrees}C compared with 42{degrees}C (P<0.001). The magnitude of local heating-induced endothelium-dependent dilation was significantly related to the NO-dependent contribution of that response at 39{degrees}C (R2= 0.79) and 42{degrees}C (R2= 0.56). Local heating-induced NO-dependent dilation at 39{degrees}C was not related to that at 42{degrees}C (P>0.05). Acetylcholine-induced endothelium- and NO-dependent dilation were not related to local heating-induced responses (all P>0.05). Conclusions: These data demonstrate that while local heating and acetylcholine perfusion produce robust endothelium- and NO-dependent cutaneous vasodilation, these responses are not comparable within an individual.

The excitability of afferents involved in nociceptive signaling reflects the interaction of several co-expressed membrane receptors. Current studies have shown that Toll-like receptor-4 (TLR-4) signaling can exacerbate excitation evoked by transient receptor potential vanilloid type 1 (TRPV1) activity, and this interaction plays a key role in driving and sustaining facilitated pain states. The mechanism by which this potentiated TRPV1 activity secondary to TLR-4 agonism occurs in sensory neurons remains unknown, although intracellular kinase activity is a strong candidate. To address this hypothesized linkage, neuronal cell cultures prepared from dorsal root ganglia (DRG) of male wildtype (WT) and Tlr4-/- mice were used to evaluate calcium transients of neurons after capsaicin administration in culture, pre-treated for 30 minutes with the TLR-4 agonist, lipopolysaccharide (LPS). TRPV1 protein expression at the neuron surface in cultured DRG cells with or without LPS treatment was quantified by flow cytometry assay. The roles of protein kinase A (PKA) and C were assessed using selective inhibitors (KT5720 for PKA and Chelerythrine chloride for PKC) applied to WT-DRG neurons or administered in vivo by intraplantar or intrathecal injection, prior to LPS and capsaicin administration. Behavioral effects of in vivo TRPV1 activation were assessed through paw flinch responses evoked by intraplantar capsaicin injection and by hind paw tactile thresholds measured by von Frey filaments. LPS incubation in cultured DRG neurons enhances the intensity of calcium influx following TRPV1 activation in WT but not Tlr4-/ cells. The augmented calcium influx evoked by capsaicin was prevented by the inhibition of PKA but not PKC. Similarly, mice treated with LPS in the hind paw displayed greater nociceptive responding after capsaicin and increased tactile allodynia. The facilitated component was prevented by the local pre-treatment with the PKA inhibitor. Correspondingly, lumbar spinal blockade of PKA resulted in temporary reversal of hyperalgesia induced by intrathecal LPS injection in mice. Together, these results demonstrate the relevance of TLR-4 in modulating the excitability of nociceptor signaling by regulating TRPV1, thereby influencing pain transmission through PKA signaling.