The Journal of Pain

Objective: Myofascial pain (MP) is a leading cause of disability globally. Pain quality and severity vary widely for people with MP, making it difficult to accurately assess the spectrum of symptoms and develop appropriate treatments. We assessed potential contributors to variability in the clinical spectrum of unexplained neck/shoulder pain and associated myofascial component(s). Design: Prospective cross-sectional study of adults reporting neck/shoulder pain and pain-free individuals. Outcomes Measures: Pain intensity and interference (PEG); Symptom burden measured using patient-reported outcomes and objective measures: pain catastrophizing (PCS); PROMIS physical function (PF); sleep disturbance; anxiety (GAD-2); depression (PHQ-2); hypermobility (Beighton/Brighton); Objective measures in the medial upper trapezius: pressure pain threshold (PPT) and quantitative sensory testing (QST). Results: Of the 96 adults recruited for the study, 82 had complete records (age 32.2 +/-13.1 years, 57% women). On physical exam, 23 were assessed to be in an active group (those with spontaneous MP without provocation), 38 in a latent group (those with MP upon provocation), and 21 in a normal group (no MP in neck and shoulder). The symptom burden explained 75% of the variance in PEG in the overall sample, 85% in the active group and 92% in the normal group. PF and PCS are key predictors of PEG. Network analysis identified unique symptom clusters in the active and latent groups. Conclusions: The symptom burden explains the variability in the clinical spectrum of pain intensity and interference in unexplained neck/shoulder MP. Network analysis can further improve clinical risk stratification. These findings represent a step towards an eventual goal of developing multidisciplinary clinical guidance for managing the whole patient, rather than the current emphasis on regional pain contributors in MP.

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 low back pain (CLBP) is persistent and refractory, affecting 20-30% of population worldwide. Neurofeedback has been explored as a potential non-pharmacological intervention for chronic pain, although evidence in CLBP remains limited. This study evaluated PainWaive, a consumer-grade digitally-delivered neurofeedback intervention targeting multiple pain-related frequency bands recorded over the sensorimotor cortex in individuals with CLBP. In a multiple-baseline experimental design, four participants completed daily assessments of pain severity and pain interference during randomly-assigned baseline phases of 7, 10, 14, and 20 days, followed by 20 sessions of the PainWaive intervention over four weeks. Daily pain assessments continued during the post-intervention and follow-up phases. Participants rated PainWaive's usability and acceptability at post-intervention. Anxiety, depression, wellbeing, and sleep disturbance were assessed at three timepoints. Aggregated Tau-U analyses indicated a large effect (-0.67) on pain severity from baseline to intervention and very large from baseline to post-intervention (-0.92) and follow-up (-0.92) phases. Large effects (-0.63, -0.62, and -0.70) were also observed for pain interference. Individual-level analyses showed significant reductions across all participants, with visual inspection confirming progressive decreases over time. The intervention was rated usable and acceptable by all participants, while psychological outcomes were mixed and varied across participants. The findings provide promising evidence that the PainWaive neurofeedback intervention may reduce pain severity and pain interference in some individuals with CLBP. By prioritising accessibility, usability, and self-administration, PainWaive supports a foundation for more patient-centred, technology-enabled approaches to chronic pain management. Further evaluation of this approach in randomised trials is required to establish efficacy.

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.

Introduction: Adults with spinal cord injury (SCI) often experience reduced or lost sensation and movement, impairing the ability of the brain to locate paralyzed body parts, which, in turn, compromises sensorimotor recovery. This disruption of the internal body map of the brain, or mental body representations (MBR), also contributes to neuropathic pain in about 69% of adults with SCI. Medications for neuropathic pain are often ineffective and can cause adverse reactions. Our previous pilot clinical trial showed that Cognitive Multisensory Rehabilitation (CMR), a physical therapy that restores MBR, produced significant, lasting reductions in neuropathic pain, improved sensorimotor function, and enhanced brain function. Building on these results, we examined whether 8 weeks of CMR or adaptive fitness (1) improved sensorimotor function and reduced pain; (2) greater brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Sixteen participants (52+/-8 years old, 13+/-10 years post-SCI) were randomized to 8 weeks of CMR or adaptive fitness (45 min, 3x/week). Ten participants had neuropathic pain of 3/10 or greater. Pain and sensorimotor function were assessed at baseline, post-intervention, and 3-month follow-up using the Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS). Functional MRI included resting-state and 4 tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR, participants improved on AIS with large effect sizes (touch: d=1.54; pinprick: d=1.83; lower limb motor function: d=1.32), while adaptive fitness had small/moderate effects (touch: d=0.49; pinprick: d=0.53; lower limb motor function: d=0.74). CMR also showed larger effect sizes for NRS (core: d=2.19; upper limb: d=0.69; lower limb: d=0.74) than fitness (core: d=0.73; upper limb: d=0.34; lower limb: d=0.00). Benefits persisted at follow-up. Highest neuropathic pain intensity reduced post-CMR and at 3-month follow-up (d=0.48; d=0.63). Pain increased slightly after fitness (n=6; d=-0.19; d=-0.41). CMR increased brain connectivity and activation during the leg imagery task. Increased activation during whole-body imagery was greater after CMR than fitness. Discussion: These preliminary results support the potential of CMR to improve function and reduce neuropathic pain in adults with SCI, warranting larger confirmatory trials. Clinicaltrial.gov: NCT05167032

IntroductionCannabis is increasingly used for pain management, with many patients reporting relief from chronic pain that did not respond to conventional treatments. However, cannabis is also associated with unwanted side effects including psychomimetic effects and the potential of developing a cannabis use disorder. To circumvent the central nervous system effects, we investigated whether a peripherally restricted cannabinoid receptor (CB1) agonist, PrNMI [(4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3yl]ethyl}morpholine] attenuated pain hypersensitivity associated with nerve injury and profiled its abuse potential. Materials and MethodsMice with chronic constriction injury (CCI) of the sciatic nerve developed hypersensitivity to mechanical stimulation. Paw withdrawal thresholds were assessed following administration of PrNMI (i.p. 0.3 mg/kg and 0.6 mg/kg) or vehicle in CCI and sham mice. The conditioned place preference model was used to measure drug-reward to 0.6 mg/kg i.p. PrNMI in CCI and sham-injury control animals. We further assessed abuse potential to determine if PrNMI (0.5 mg/kg) would reinstate drug-seeking behavior in mice trained to self-administer intravenous fentanyl (10 g/kg/infusion). ResultsPrNMI administration transiently increased paw withdrawal thresholds in mice with CCI-induced allodynia in a dose-dependent manner. PrNMI conditioning did not produce a conditioned place preference in mice with either CCI or sham injury. Mice who had learned to self-administer fentanyl and went through extinction training did not reinstate drug-seeking behavior when administered PrNMI. DiscussionThe systemic CB1 receptor agonist PrNMI demonstrated analgesic benefit in alleviating mechanical allodynia associated with chronic constriction injury of the sciatic nerve without increasing addiction related behaviors associated with the establishment of addiction.

Chronic pain presents a leading challenge in the world today for both clinicians and researchers. Because chronic pain is difficult to explain and treat, it is often managed with opioids despite providing limited relief and contributing to dependence and misuse. Persistent pain can be maintained by altered central nervous system processing even in the absence of distinct tissue damage or disease, which may limit the efficacy of conventional pharmacological therapies that target nociceptive signal transmission rather than maladaptive central nervous system dynamics often present in those with chronic pain. Although neuroimaging studies have identified this shift from nociceptive to emotional circuits during pain chronification, a quantitative framework linking these neural changes to longitudinal pain trajectories or recovery is lacking. We present a parsimonious firing-rate model that can account for the development of and recovery from chronic pain, which is based on the theoretical framework established by Wilson and Cowan. The model provides a quantitative explanation of how sensitization, anxiety, and fear maintain pain even after an injury has healed, and how calming stimulus downregulates these processes to facilitate recovery. A study applying the same principles as the model produced an average pain decrease of 3.5 on the Visual Analog Scale (VAS), with all subjects experiencing a reduction in pain. These results, coupled with our model and findings in prior studies, suggest that increasing calming stimulus can reduce pain without necessitating pharmacological or invasive, resource-intensive interventions.

Background: Transcranial temporal interference stimulation (tTIS) is an emerging noninvasive neuromodulation approach that enables focal, frequency-specific modulation of deep brain regions, offering a novel method for investigating therapeutic mechanisms underlying brain and mental health disorders. Pain is a key target because it is a feature of multiple disorders and is increasingly understood to depend on brain circuits. Here, we tested the effects of tTIS on bilateral evoked pain, capitalizing on converging evidence from human and animal studies indicating that the primary motor cortex (M1) contains body-wide inter-effector regions and has descending projections to regions implicated in nociceptive, motivational, and autonomic processing, making it a key cortical target for pain modulation. Methods: We conducted a pre-registered, triple-blind, randomized crossover study (N = 32, 160 study sessions), investigating frequency-dependent effects of tTIS applied to the left M1 on experimentally evoked thermal pain in healthy adults. We tested four stimulation frequencies (10 Hz, 20 Hz, 70 Hz, and sham) on separate days (>10,000 pain trials total). Noxious heat was applied to both the right and left forearms using individually calibrated temperatures both pre- and post-stimulation. Results: Active tTIS produced significant analgesia at all stimulation frequencies (10 Hz, 20 Hz, and 70 Hz) relative to sham (Cohens d = 0.46-0.82, all p < 0.05). 10 Hz produced the greatest reduction (d = 0.82), and both 10 Hz and 20 Hz produced more analgesia than 70 Hz (d = 0.44 and 0.38, respectively; p < 0.05). Stimulation-related sensations were equivalent across frequencies, and participants were blind to condition. Pain reductions remained stable over a [~]40-min post-stimulation period and were bilateral, consistent with stimulation of body-wide inter-effector regions. Conclusions: These results provide the first evidence that tTIS can reliably reduce experimental pain perception in humans in a frequency-dependent manner, providing a foundation for noninvasive pain modulation with tTIS.

Background Chronic pain and depression are leading causes of disability and frequently co-occur. Depression presents with diverse symptoms, but despite this variability, the prevalence of individual depressive symptoms in chronic pain and the genetic and causal associations linking these traits remain poorly characterised. Methods Using data from 142,688 age- and sex-matched UK Biobank participants, we compared depressive symptom severity levels and item-level Patient Health Questionnaire-9 (PHQ-9) prevalences, spanning affective, cognitive and somatic domains, between participants with and without chronic pain. Using genome-wide association study (GWAS) summary statistics of multisite chronic pain (MCP), major depressive disorder (MDD), and individual symptoms of depression, genetic correlations and bidirectional causal effects between MCP and depressive phenotypes (MDD and individual symptoms) were estimated via linkage disequilibrium score regression (LDSC) and two-sample Mendelian randomisation (MR), respectively. Results Depression (at every severity level) was more common in the chronic pain group compared to controls, with the largest between-group difference for severe symptoms (7.50-fold increase). All individual depressive symptoms were at least 2.79 times as prevalent in chronic pain. Additionally, chronic pain had a significant and positive genetic correlation with MDD (rg = 0.59) and all depressive symptoms (rg = [0.24, 0.55]). MR supported a bidirectional causal association between MCP and MDD (MCP[-&gt;]MDD: OR = 1.85, pFDR < 0.001, MDD[-&gt;]MCP: {beta} = 0.17, pFDR < 0.001). At the symptom level, MR indicated bidirectional effects between MCP and anhedonia (MCP[-&gt;]anhedonia: OR = 1.60, pFDR < 0.001, anhedonia[-&gt;]MCP: {beta} = 0.08, pFDR = 0.005), and unidirectional effects of MCP on appetite/weight gain (OR = 1.90, pFDR = 0.022) and appetite/weight loss (OR = 1.63, pFDR = 0.005), concentration problems (OR = 1.63, pFDR = 0.044), and suicidal thoughts (OR = 1.46, pFDR = 0.021). Additionally, genetic liability to concentration problems was associated with a lower risk of MCP ({beta} = -0.04, pFDR = 0.022). Conclusion Chronic pain is associated with a marked depressive burden spanning all symptom domains. Shared genetic architecture and symptom-specific causal pathways, particularly involving anhedonia, highlight potential targets for improved treatment of comorbid chronic pain and depression.

Traumatic Brain Injury (TBI) patients may suffer from a number of long-term complications after injury such as impaired motor skills, cognitive decline, and sensory abnormalities including chronic pain. Disruption of endogenous pain modulatory pathways likely contributes to development of chronic pain in a wide range of conditions including TBI. Aerobic exercise has been shown to impact pain syndromes. Here we investigate the effect of exercise on pain outcome measures after TBI using a lateral fluid percussion (LFP) model and voluntary running wheels in male and female rats. We tested mechanical nociceptive reactivity with von Frey fibers and descending control of nociception (DCN) using hindpaw sensitization with PGE2 followed by a capsaicin-test stimulus to the forepaw. Pharmacological studies employed the administration of noradrenergic (NA) and serotoninergic receptor blockers. Neuropathological studies quantified neuroinflammatory changes and axonal damage. We found that exercise decreased the duration of the acute phase of pain from [~]5 weeks to 2-3 weeks in female and male TBI rats respectively, gains that could be reversed using the 1-adrenoceptor (1AR) antagonist, prazosin. Exercise also prevented the loss of DCN for at least 180 days post-injury in both male and female TBI rats. The intact DCN response in male and female TBI rats provided by exercise could be blocked using prazosin. Surprisingly, exercise-mediated restoration of the DCN response in male TBI rats was not blocked by the 5-HT7 receptor antagonist, SB-267790, the receptor system through which serotonin reuptake inhibitors restore DCN after TBI in male rats. Therefore, the transition from a noradrenergic to a serotonergic inhibitory pain pathway that we typically see in male TBI rats, was blocked by exercise. Assessment of neuropathology, acutely after TBI, reveals that both the astrocyte and microglial response to injury is significantly greater in male TBI compared to female TBI, regardless of exercise. The effect of exercise on the extent of neuroinflammation after injury was minimal in TBI rats of both sexes. In contrast, exercise significantly decreased the amount of axonal loss in the corpus callosum in both male and female TBI rats compared to sedentary TBI rats. However, the extent of axonal loss after TBI in both exercise and sedentary male rats was greater than in female exercise and sedentary groups respectively. These results demonstrate that exercise is a promising treatment for chronic pain after TBI in both male and females. It also highlights that dysfunction of the endogenous pain modulatory pathways observed in male rats after TBI can be prevented by exercise, possibly by reducing axonal loss.

The vagus nerve conveys interoceptive information, yet how specific vagal sensory afferents regulate pain remains unclear. Here, we tested whether vagus nerve stimulation (VNS) modulates temporomandibular disorder (TMD)-related pain. In a mouse model of TMD, auricular VNS (aVNS) attenuated temporomandibular joint (TMJ) pain behaviors and suppressed sensitization of trigeminal nociceptors. We identified a subset of vagal sensory afferents with dopaminergic features that was sufficient to mediate these effects, as selective activation of these afferents recapitulated the analgesic actions of aVNS. These findings highlight an underappreciated peripheral interoceptive pathway and provide a mechanistic framework for targeted neuromodulation in chronic craniofacial pain.

Background Trials in occupational populations, such as surgeons, face feasibility challenges due to high workload, restricted availability, and clinical heterogeneity, which may compromise recruitment, adherence, and retention. Objective To prespecify the feasibility framework and progression criteria for an internal pilot phase embedded within a pragmatic randomized controlled trial (RCT) comparing Mechanical Diagnosis and Therapy with generalized exercise in surgeons with chronic spinal pain. Design Protocol for a prespecified internal pilot phase embedded within a pragmatic, two-arm, parallel-group RCT. Methods The internal pilot will include the first four months of recruitment and aims to randomize at least 12 participants. Feasibility will be assessed across predefined domains, i.e., recruitment, eligibility, consent, intervention uptake, adherence, retention, data completeness, and treatment fidelity. Each domain is operationally defined and linked to prespecified progression criteria to ensure interpretability and decision-making utility. Criteria will be interpreted collectively to guide trial continuation. A minimal qualitative process evaluation will be embedded. Ethics and dissemination The host trial has received ethical approval (N-20240046) and is registered at ClinicalTrials.gov (NCT07293130). The findings from the internal pilot will be reported in a separate feasibility manuscript.

The central nucleus of amygdala (CeA) comprises diverse populations of neurons, forming a complex network responsible for regulating various behavioral responses. Among these, neurons expressing calcitonin gene-related peptide receptors (CGRPR) have emerged as key players in CGRP neuropeptide-mediated pain modulation. While previous studies emphasize CGRPs key role in synaptic plasticity and its connection with pain behavior in the CeA, the precise functional attributes and contributions of CeA-CGRPR-expressing neurons in pain processing remain elusive. This study reveals the co-localization of CGRPR-expressing neurons in the CeA with phosphorylated extracellular signal-regulated kinase (pERK), a marker indicating pain plasticity, in a neuropathic pain model. Electrophysiological assessments of these neurons in slice preparations unveiled heightened intrinsic excitability after sciatic nerve cuff implantation, contingent upon their rostro-caudal positioning within the CeA. Furthermore, our behavioral experiments using chemogenetic inhibition of CeA-CGRPR neurons demonstrated the ability to reverse nerve injury-induced hypersensitivity. Conversely, activating these neurons induced pain-related hypersensitivity even in the absence of injury. Our findings also highlight a sex-specific role of CeA-CGRPR neurons in formalin-induced spontaneous pain response. Collectively, these data reinforce the involvement of CeA-CGRPR neurons in pain processing, contributing to a better understanding of how neural circuits are affected in persistent pain conditions. Significance StatementOur study shows the role of CGRPR-expressing neurons within the CeA during pain processing. Using a cuff-implanted neuropathic mouse model, we discovered that CGRPR-expressing neurons co-localize with phosphorylated extracellular signal-regulated kinase (pERK), a hallmark of pain plasticity, in both male and female mice. Furthermore, our electrophysiological investigations reveal that posterior CeA-CGRPR neurons exhibit increased excitability following sciatic nerve cuff implantation. Importantly, we demonstrate that CeA-CGRPR neurons exert bidirectional effects on pain behavior in mice, irrespective of sex differences in nerve injury-induced pain responses while showing sex-specific spontaneous pain responses in the formalin-induced model. These findings show the role of CeA-CGRPR neurons in pain modulation, underscoring their potential significance in understanding and addressing persistent pain conditions.

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a genetic connective tissue disorder characterized by hypermobile joints, chronic pain, fatigue, brain fog, orthostatic intolerance, and GI symptoms and dysmotility. Its heterogeneous presentation contributes to poor quality of life, inappropriate interventions, and prolonged diagnostic delays, often up to 10 years. This study primarily aimed to determine if physiological signals captured by a medical-grade wrist wearable could characterize autonomic patterns in hEDS and relate them to symptoms. Individuals with hEDS (n=30) and healthy controls (n=28) wore a medical grade smartwatch for 30 days, collecting continuous heart rate variability, activity, oxygen saturation, and blood pressure, alongside initial baseline symptom and quality-of-life surveys. Individuals with hEDS showed greater instability and variability in both systolic and diastolic blood pressure as well as the HRV metric LF/HF ratio, in comparison to healthy controls (p-values: 0.04, 0.02, 0.02). During sleep, metrics of parasympathetic activity (HRV measures: HF power, pNN50, RMSSD) trended lower in hEDS than healthy in comparison. As expected, survey domains assessing physiologic symptoms and quality-of-life were significantly worse in the hEDS cohort (p-values < 0.05). Notably, autonomic metrics correlated with GI symptoms in the hEDS cohort (Spearman's {rho} range: 0.38-0.60), and psychological symptoms in the healthy cohort (Spearman's {rho} range: -0.47-0.41). Principal component analysis (PCA) of physiologic and symptom features clearly separated groups, supporting distinct physiologic profiles. Combination of GI symptom index and wearable monitoring show promise as a hybrid screening approach that could substantially shorten the time to diagnosis in this population.

ObjectiveThe objective of this study is to assess the quality, empathy, and readability of large language model (LLM) responses regarding otologic questions from patients as they compare to verified physician responses in other patient-driven forums. This study aims to predict the potential utility of LLMs in patient-centered communication. Study DesignComparative study SettingsInternet MethodsA sample of 49 otology-related questions posted on Reddit r/AskDocs1 between January 2020 and June 2025 were selected using search terms including "hearing loss," "ear infection," "tinnitus," "ear pain," and "vertigo." Posts were retrieved using Reddits "Top" filter. Each question was answered by a verified doctor on Reddit and three AI LLMs (ChatGPT-4o, ClaudeAI, Google Gemini). Responses were scored by five evaluators. ResultsCommon otologic concerns posed in patient questions were otalgia (38.7%), vertigo (28.6%), tinnitus (24.5%), hearing loss (22.4%), and aural fullness (20.4%). LLM responses were longer than physician responses (mean 145 vs 67 words; p < .05) and rated higher in quality (10.95 vs 9.58), empathy (7.26 vs 5.18), and readability (4.00 vs 3.73); (all p < .05). Evaluators correctly identified AI versus physician responses in 89.4% of cases with higher sensitivity for detecting physician responses (93.5%). By Flesch-Kincaid grade level, ChatGPT produced the most readable content (mean 7.25), while ClaudeAI responses were more complex (11.86; p < .05). ConclusionLLM responses received higher ratings in quality, empathy, and readability than those of physicians in response to a variety of otologic concerns. When appropriately implemented, such systems may enhance access to understandable otologic information and complement clinician-delivered care.

Background Lumbar fusion and decompression procedures are widely used for degenerative spine conditions but are associated with substantial health care costs and variable outcomes. Orthobiologic treatments, including platelet rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), have emerged as less invasive options for select patients who meet surgical criteria. However, concerns remain that orthobiologic care may delay rather than avert surgery, potentially increasing downstream utilization and costs. Comparative evidence on real world utilization and costs is limited. Methods We conducted a retrospective, observational study using linked commercial insurance claims and a national orthobiologic treatment registry. Adults with lumbar degenerative disc disease (DDD) who met criteria for lumbar fusion or laminectomy, foraminotomy, discectomy, and facetectomy (LFDF) procedures, and who received PRP injection (with or without BMAC) or surgery between 2016 and 2023 were included. Two comparisons were evaluated: PRP versus lumbar fusion and PRP versus lumbar decompression procedures. Propensity score matching was used to balance cohorts on demographic characteristics, comorbidities, spine related diagnoses, prior health care use, and severity proxies. Outcomes included spine-related health care resource use and aggregate costs at 12 and 24 months, with exploratory analyses at 36 and 48 months. Costs were estimated using multiple approaches, including Medicare based estimates and commercial payer methods. Results After matching, 133 patients receiving PRP were compared with 2,560 patients undergoing fusion, and 198 patients receiving PRP were compared with 3,960 patients undergoing LFDF. Rates of subsequent spine surgery following PRP were low and below cell suppression thresholds through 24 months, with similar findings in exploratory longer-term analyses. Compared with surgical cohorts, patients receiving PRP had lower rates of postoperative imaging, home health services, and outpatient visits, with no consistent differences in opioid use, magnetic resonance imaging, or physical therapy. At 12 and 24 months, mean aggregate costs were significantly higher for fusion and LFDF cohorts across most costing methods. Cost differences were largest for fusion comparisons and were driven primarily by index procedure costs and higher reoperation and imaging rates in surgical cohorts. Findings were generally consistent across sensitivity and exploratory analyses. Conclusions Among select patients with degenerative spine conditions who meet surgical criteria, PRP was associated with lower health care utilization and substantially lower costs compared with lumbar fusion or LFDF, without evidence of increased progression to surgery. These findings support consideration of orthobiologic options for appropriately selected patients when surgery is not the only viable treatment option. Limitations include selection bias, absence of patient reported outcomes, and claims-based severity measures.

Neuropathic pain after spinal cord injury reflects persistent hyperexcitability in the spinal cord dorsal horn, yet the molecular drivers sustaining this maladaptive state are unknown. Using an antibody microarray of dorsal horn tissue from mice six weeks after cervical contusion spinal cord injury, we found persistent upregulation of Eph-ephrin signaling, including increased EphB1, EphB2 and EphB3 expression and phosphorylation. Reversible chemogenetic inhibition of EphB kinase activity, using an EphB1/2/3 analog-sensitive knock-in mouse, selectively reversed established mechanical allodynia without affecting thermal hyperalgesia or motor function and also shifted dorsal horn signaling away from pain sensitization-associated pathways. Among EphB receptors, EphB2 showed the most consistent and robust injury-induced increase in expression within dorsal horn. Although EphB2 transcript levels increased in both dorsal horn neurons and astrocytes, conditional deletion of EphB2 only in dorsal horn neurons, but not in astrocytes, reversed established mechanical allodynia and reduced dorsal horn neuronal activation. These findings identify EphB signaling, and neuronal EphB2 in particular, as a mechanism that actively maintains pain hypersensitivity after spinal cord injury.

Introduction: Pudendal nerve stimulation is a promising therapy for urinary incontinence, however stimulation can evoke off-target activity. We aimed to determine whether multi-contact cuff electrodes can selectively recruit motor fibers of the pudendal nerve trunk in preclinical feline and ovine models. Methods: Multi-contact cuff electrodes were implanted around the pudendal nerve in anesthetized felines and ovines. Structured variations in electrode contact configurations and stimulation amplitudes were applied to evoke external urethral sphincter (EUS) and external anal sphincter (EAS) pressure responses. We calculated selectivity indices, EUS Scores, and EAS Scores to quantify selective recruitment and the magnitude of evoked pressure changes. Results: We achieved selective motor activation, with preferential recruitment of the EUS or EAS in all three feline experiments and one of three ovine experiments. In felines, at least four electrode combinations selectively evoked EUS responses (EUS Score 0.5) and at least one combination targeted the EAS. In ovines, one EUS-selective and six EAS-selective combinations obtained comparable scores. In preliminary tests, we observed functional increases in leak point pressure and incontinence prevention with selective stimulation. Conclusions: This study shows that multi-contact cuff electrodes can selectively activate EUS and EAS motor fibers in the pudendal nerve. Future work should focus on optimizing stimulation parameters to enhance selectivity and assess the translational potential of this approach for restoring pelvic organ control.

Background Chronic pain and depression are common disorders and leading causes of disability worldwide. They frequently co-occur and show substantial genetic correlation, indicating a shared genetic basis. However, the locus-specific architecture of this overlap remains poorly characterised and may yield important insights into the pathophysiology of their comorbidity. Methods Using the largest currently available European-ancestry genome-wide association studies of major depressive disorder (MDD) (n = 1,639,572) and multisite chronic pain (MCP) (n = 387,649), we estimated the polygenic overlap between traits using the bivariate causal mixture model (MiXeR), identified shared loci via conjunctional false discovery rate (conjFDR), and tested colocalisation with each trait and genetically regulated gene expression in 13 brain tissues. Results MiXeR analysis demonstrated a high degree of directionally consistent polygenic overlap between MDD and MCP. Subsequent conjFDR analysis identified 375 shared loci, 22 of which showed cross-trait colocalisation between the MDD and MCP signals. Gene mapping and enrichment of shared loci implicated several biological processes, including cadherin-mediated cell-cell adhesion and translational initiation. Gene expression colocalisation in brain tissue highlighted protein phosphatase 6 catalytic subunit (PPP6C) and suppressor of cancer cell invasion (SCAI) in both disorders. Conclusion Overall, these findings have enhanced our understanding of the complex relationship between chronic pain and depression by identifying shared molecular mechanisms that warrant further study as targets for prevention and treatment.

Background: Lumbar spinal stenosis (LSS) can cause pain and severe walking limitation. Although surgery aims to improve walking, many patients do not achieve clinically meaningful gains. Rehabilitation can improve outcomes, yet existing programmes lack robust evidence and theoretical underpinning. This study aimed to (1) co-design a theory-informed rehabilitation programme to improve walking after LSS surgery, and (2) evaluate feasibility of conducting a future trial and acceptability of the intervention. Methods: A multi-methods study included intervention co-design followed by a single-arm feasibility study. Co-design used an adapted Experience-Based Co-Design approach with patients, carers, and healthcare professionals (n=39), integrating the Behaviour Change Wheel. This resulted in STructured Rehabilitation and InDividualised Exercise and Education (STRIDE), delivered over 12-week pre- and 12-weeks post-surgery, targeting knowledge, expectations, perceived control, physical capability, and fears. Adults aged [&ge;]50 years awaiting LSS surgery were recruited to a before-after feasibility study. Feasibility outcomes included recruitment and retention. Acceptability was assessed using the Theoretical Framework of Acceptability questionnaire (0-5 (high acceptability)) and focus groups. Clinical outcomes measured at baseline, post-prehabilitation, and post-rehabilitation included 6-minute walk distance (6MWD) and mean daily step count over 7 days. Results: Fifteen of 31 eligible participants were recruited (48%; mean age 70 years), with 80% retained to study end (2 decided against surgery, 1 unable to complete final assessment). Acceptability was high (median 5/5, IQR 0). Participants valued the personalised, supportive approach and reported improved motivation and preparation for surgery, though travel was burdensome. Small pre-operative and moderate-to-large post-operative improvements were observed in 6MWD (+49.9 m and +81.6 m) and daily step count (+868 and +1405 steps/day). Conclusions: This co-designed, physiotherapy-led, behaviour-change rehabilitation programme was acceptable to participants, with encouraging recruitment, retention, and signals of improved walking following LSS surgery. The findings support progression to a future trial.