The Journal of Headache and Pain

Mild traumatic brain injury (mTBI) often leads to migraine-like post-traumatic headache (PTH), yet effective treatments are limited. Clinical and preclinical studies have shown that mTBI disrupts glymphatic transport of cerebrospinal fluid in the brain. We hypothesized that altered glymphatic transport might underlie facial allodynia commonly associated with migraine and PTH. A closed-head impact model was used to induce mTBI in mice. Facial allodynia, a symptom of PTH and migraine, was evaluated using periorbital von Frey testing. Glymphatic influx was assessed using slice-based imaging of a fluorescent tracer injected into the cisterna magna. Here we show that prazosin (PZN), an 1-noradrenergic receptor antagonist, restores glymphatic function and treats facial allodynia induced by calcitonin gene-related peptide (CGRP) and a nitric oxide donor in mice. In contrast, propranolol, a {beta}-noradrenergic receptor antagonist, was ineffective. Even in the absence of mTBI, CGRP reduced glymphatic function and PZN was able to restore glymphatic function in the dorsal cortex. Importantly, the role of glymphatic function was confirmed by the lack of PZN efficacy in aquaporin-4 knockout mice. These findings indicate that targeting 1-noradrenergic receptors to enhance glymphatic transport may offer a therapeutic strategy for treating migraine and PTH.

Migraine is a common and disabling neurological disorder linked to alterations in neuronal activity and waste clearance in the brain. MRI-visible perivascular spaces (PVS) are key components of the glymphatic system which may serve as imaging biomarker of such disorder. We hypothesised that higher frequency of migraine episodes would be associated with increased PVS burden, reflecting greater levels of impaired glymphatic clearance. In this retrospective case-control study of 90 participants (20 episodic migraineurs, 18 chronic migraineurs, and 52 age- and sex-matched healthy controls; 58 females, median [Q1, Q3] age=28.6 [25.1, 39.4] years) we investigated PVS alterations in episodic migraineurs (n=20) and 18 chronic migraineurs (n=18). PVS volumes and cluster counts were quantified in the white matter (WM), basal ganglia (BG), midbrain, and hippocampus. We stratified PVS metrics by white matter lobes and arterial vascular territories. After adjusting for age, sex, and total brain volume, episodic migraineurs exhibited significantly lower BG-PVS volumes (exp({beta})=0.76, 95%CI [0.61, 0.94], p=0.01) compared to controls. Chronic migraineurs exhibited significantly lower PVS cluster counts in the parietal (exp({beta})=0.8, 95%CI [0.68, 0.94], p=0.01) and temporal lobes (exp({beta})=0.72, 95%CI [0.53, 0.96], p=0.03) and middle cerebral artery territory (exp({beta})=0.82, 95%CI [0.68, 0.97], p=0.03) compared to healthy controls. Within migraineurs, those with aura (n=20) exhibited significantly lower PVS burden in all brain regions, vascular territories, and across the frontal, parietal, and temporal lobes (all pFDR<0.05). Our findings suggest that the aura symptom, rather than the migraine disorder itself, may primarily drive changes in perivascular spaces, with effects varying across brain regions.

IntroductionVestibular migraine is a major cause of recurrent vertigo, yet its mechanisms and diagnostic markers remain limited. Abnormal vestibular-cervical integration and convergence insufficiency, reflected by impaired near point convergence (NPC),suggest multisensory dysfunction. This study tested whether cervical proprioceptive perturbation provokes vertigo and nystagmus in vestibular migraine and evaluated NPC as a predictor of these responses. MethodsFifty-one vestibular migraine patients and 12 controls underwent interictal vestibular testing. Peripheral function was assessed with vHIT. Participants received randomized 100-Hz cervical (proprioceptive) and mastoid (vestibular) vibration without visual fixation, with eye movements recorded via video Frenzel goggles and NPC measured using standard methods. Analyses included McNemars, Wilcoxon signed-rank, Mann-Whitney U, correlations, and multivariable logistic regression. ResultsNeck vibration provoked vertigo in all vestibular migraine patients and none of the controls, producing nystagmus in 76.5%. Horizontal, ipsiversive nystagmus predominated, while less frequent vertical responses showed higher velocities. Mastoid vibration elicited no nystagmus. NPC was the only independent predictor of nystagmus and correlated with slow-phase velocity and bilateral responses. Age correlated with drift velocity, whereas vestibulo-ocular reflex gain showed no association. DiscussionNeck vibration elicits vertigo and nystagmus in vestibular migraine, providing the first objective physiological marker. NPC predicts and correlates with nystagmus severity, highlighting its value as a surrogate of multisensory dysfunction. Together, these findings implicate abnormal cervical-vestibular integration and position NPC and neck-vibration testing as practical tools for diagnosis and phenotyping. Key pointsO_LIVestibular migraine affects [~]3% of population yet remains highly controversial. C_LIO_LIObjective measures reveal reproducible vertigo and nystagmus in vestibular migraine. C_LIO_LIImpaired convergence strongly predicts vibration-induced nystagmus in VM patients. C_LIO_LIFindings support sensory mismatch model linking cervical proprioception to vertigo. C_LI

ObjectiveTo describe the design, feasibility, and baseline characteristics of the Migraine Impact on Neurocognitive Dynamics (MIND) study, a 30-day smartphone-based cohort for high-frequency assessment of cognition and symptoms in adults with migraine. BackgroundCognitive symptoms are an important component of migraine burden, but they are difficult to measure using single-visit testing or retrospective questionnaires. Repeated smartphone-based assessment may better capture real-world variability in cognition and symptoms. MethodsAdults meeting International Classification of Headache Disorders, 3rd edition, criteria for migraine were enrolled remotely and completed 30 days of once-daily ecological momentary assessments and mobile cognitive tasks delivered through the Mobile Monitoring of Cognitive Change platform. Baseline measures assessed demographics, migraine characteristics, disability, mood, stress, and treatment patterns. Feasibility was evaluated using enrollment, completion, and retention metrics. ResultsA total of 177 participants enrolled (mean age 38.8 {+/-} 11.9 years; 79.7% female), including 80/177 (45.2%) with chronic migraine. Across the 30-day protocol, 3688 daily assessments were completed, representing 70.8% of all possible study days, and 70.6% of participants completed at least 20 days of monitoring. Completion remained above 60% across study days. At baseline, chronic migraine was associated with greater burden than low-frequency and high-frequency episodic migraine, including higher MIDAS scores (98.6 vs. 38.7 and 70.3), more days with concentration difficulty (16.0 vs. 7.9 and 11.5), and more days with functional interference (18.5 vs. 7.6 and 13.0). ConclusionsThe MIND study demonstrates the feasibility of high-frequency smartphone-based assessment of cognition and symptoms in migraine and provides a methodological foundation for future analyses of within-person cognitive and symptom dynamics across the migraine cycle.

Background: Post-dural puncture headache (PDPH) affects up to 11.2% of patients after neuraxial anesthesia. The sphenopalatine ganglion block (SPGB) is a promising minimally invasive intervention, but high-quality randomized trial data are limited. We conducted a pilot randomized controlled trial to assess feasibility and inform a future definitive trial. Methods: Twenty-six patients with PDPH following accidental dural puncture with 17G Tuohy needles were randomized to conservative management (bed rest, hydration) or SPGB (bilateral intranasal 2% lidocaine). Primary outcomes were feasibility (recruitment, retention, protocol adherence). Secondary outcomes included pain intensity (Numeric Rating Scale, NRS 0-10) at 30 minutes, 12 hours, and 24 hours; rescue analgesia requirements; mobilization time; and adverse events. Results: Feasibility was confirmed: 100% recruitment of target sample, 100% retention, 100% protocol adherence. At 30 minutes, all SPGB patients reported complete pain resolution (NRS=0) versus median NRS 3 (IQR 2) in controls (p<0.001), though this finding is limited by lack of blinding and baseline assessment. No SPGB patients required rescue analgesia or experienced adverse events. Conservative group patients had prolonged hospitalization (46%). Sample size calculation for a definitive trial (90% power, =0.05) yields 120 participants (60/group). Conclusions: A definitive RCT comparing SPGB to conservative management for PDPH is feasible. Preliminary efficacy data suggest rapid analgesia with SPGB, but rigorous confirmation in a sham-controlled trial is required. Trial registration: ClinicalTrials.gov -NCT07494383 (retrospectively registered). Keywords: Post-dural puncture headache, sphenopalatine ganglion block, pilot study, feasibility, regional anesthesia, randomized controlled trial

Background. Calcitonin gene-related peptide (CGRP)-targeted therapies, including injectable monoclonal antibodies (mAbs: erenumab, fremanezumab, galcanezumab, eptinezumab) and oral gepants (atogepant, rimegepant), represent a paradigm shift in episodic migraine prevention. No direct head-to-head trials across the full drug class exist. We conducted a PRISMA-NMA-compliant Bayesian network meta-analysis (NMA) to compare the relative efficacy and tolerability of all approved CGRP-targeted preventive therapies. Methods. PubMed, Embase, and Cochrane CENTRAL (inception to January 2026) were searched for doubleblind RCTs in episodic migraine. A Bayesian random-effects NMA used Markov Chain Monte Carlo simulation. Primary outcome: change in monthly migraine days (MMD). Secondary outcomes: 50% or greater responder rate, TEAEs, and DAEs. SUCRA probabilities quantified treatment rankings. Transitivity was formally assessed. Publication bias was evaluated using comparison-adjusted funnel plots and Egger test. GRADE certainty was rated for all key comparisons. Results. Thirty-two RCTs (24,418 participants; mean age 39.2 years; 84% female; mean baseline 8.2 MMD) were included (Table 1). All active treatments significantly reduced MMD versus placebo. Eptinezumab 300 mg ranked highest for MMD reduction (MD 2.40 MMD, 95% CrI 3.10 to 1.70; SUCRA 91.2%), followed by galcanezumab 240 mg (SUCRA 85.4%) and erenumab 140 mg (SUCRA 79.8%). For the 50% responder rate, galcanezumab 240 mg ranked highest (OR 3.12, 95% CrI 2.22 to 4.38; SUCRA 92.1%). Oral gepants demonstrated significant but more modest efficacy: atogepant 60 mg (SUCRA 38.4%) and rimegepant (SUCRA 28.9%). The absolute mAb-versus-gepant efficacy difference of approximately 1.1 MMD exceeded the accepted minimal clinically important difference. Gepants demonstrated placebo-comparable tolerability (TEAE RR 1.02, 95% CrI 0.93 to 1.12; SUCRA 93 to 96%). Heterogeneity was low to moderate (I-squared 14 to 31%); no significant network inconsistency (node-split p greater than 0.29); and no significant publication bias (Egger test p = 0.24). GRADE certainty was high for class-versus-placebo comparisons and moderate for indirect mAb-versus-gepant comparisons. Conclusion. CGRP mAbs provide superior efficacy over oral gepants for episodic migraine prevention. Oral gepants offer placebo-comparable tolerability. An individualized, patient-centered approach guided by symptom burden, comorbidities, administration preference, and the efficacy-tolerability tradeoff of each drug class is recommended.

ObjectiveMigraine attacks are frequently accompanied by patient-reported "subjective" cognitive symptoms, but objective findings have been inconsistent. We used high-frequency, smartphone-based cognitive testing to assess within-person changes in subjective and objective cognition across migraine phases using daily diaries. MethodsAdults with migraine were recruited through social media. Eligible participants met ICHD-3 migraine criteria and had 3 to 22 monthly headache days. For 30 days, they completed daily smartphone-based reports on headache features, cognitive symptoms, and three smartphone-based objective cognitive tasks. Objective tests included Symbol Search (processing speed/visual search), Color Dots (visual working memory/attention), and Grid Memory (visuospatial working memory). Primary analyses contrasted assessments on current headache days (ictal) versus days with no headache (nonictal). When possible, non-ictal days were subclassified using information from adjacent days as pre-ictal, post-ictal, and interictal days. Outcomes included subjective cognition, reaction time (mean across correctly scored trials), accuracy, and a speed-accuracy composite (Reaction Time/Accuracy). Mixed-effects models adjusted for age, sex, and practice effects. ResultsThe 139 eligible participants (84.9% female; mean age 38.2 years) contributed 3,014 person-days for ictal versus nonictal comparisons (2,097 nonictal; 917 ictal); for 1,828 person-days precise phase classification was possible. Subjective cognitive symptoms were worse on ictal days, with higher odds of more severe brain fog (OR=3.39, 95% CI 2.70-4.27) and task forgetting (OR=2.82, 95% CI 2.29-3.49). In adjusted models, reaction times were slower on ictal days for Symbol Search (reaction time ratio =1.043, 95% CI 1.028-1.059) and Color Dots (ratio=1.015, 95% CI 1.003-1.026) but not Grid Memory (reaction time ratio =1.006, 95% CI 0.985-1.028). Grid Memory accuracy was lower on ictal days (OR=0.867, 95% CI 0.823-0.914). In analyses based on phase, most nonictal phases showed faster reaction time and lower subjective symptom burden relative to ictal days, with limited differentiation among preictal, postictal, and interictal periods. ConclusionsIn persons with migraine, daily smartphone assessments revealed subjective cognitive impairment on ictal vs nonictal days in brain fog and forgetfulness. Objective testing revealed slowing in processing speed and attention and modest differences in the accuracy of working-memory. High-frequency digital cognition appears feasible and may provide scalable functional endpoints for real-world monitoring and treatment evaluation.

Inflammatory bowel disease (IBD) is characterised by chronic pain, a debilitating symptom for which effective treatments are few and far between. IBD pathogenesis includes the prevalence of a variety of pro-inflammatory cytokines, including the Interleukin-6 (IL-6) family members Il-6 and Oncostatin M (OSM). Previous research has shown disruption of OSM signaling can modulate nociceptor sensitization and activation, however the downstream signalling pathway is unknown. When an in silico analysis of murine colonic sensory neuronal populations was undertaken for receptor expression for OSM and other factors necessary for intracellular signaling, we can find diverse expression indicative of functional signaling. We were able to observe that hyper Il-6 (Il-6 bound to the soluble Il-6 receptor) and OSM can elicit activation of a subset of murine sensory neurons by finding an increase in calcium mobilization following superfusion. This could then be attenuated by the pharmacologic inhibition of all janus kinases or interestingly, TYK2 alone. Furthermore, inhibition of transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 ion channels, which are known to be sensitized by OSM in other sensory neurons also reduced the proportion of OSM-responsive neurons. This further understanding of OSM signaling in sensory neurons creates avenues for more extensive research into the molecular mechanisms occurring as well as the potential to exploit these therapeutically to induce analgesia in a subset of neurons.

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.

Background Migraine prevalence is higher among individuals with attention deficit hyperactivity disorder (ADHD). However, most research has focused on single-disease studies. This study used Global Burden of Disease (GBD) data to analyze co-occurrence patterns and related risk factors. Methods This study extracted the incidence and age-standardized incidence rate (ASIR) of migraine and ADHD among individuals across 204 countries and territories in GBD 2021, as well as exposure values for risk factors. To explore the co-occurrence patterns of migraine and ADHD and their spatial heterogeneity in global distribution, the incidence of both diseases was classified into quartiles, and countries and territories were categorized into three regional types: consistent regions, migraine-dominant regions, and ADHD-dominant regions. Global groupings by economy and risk factors were analyzed separately for co-occurrence patterns, and disease burden projections were made for 2050. Results In 2021, countries and regions were categorized into three distinct groups based on disease prevalence patterns: the majority exhibited an ADHD-dominant profile, predominantly found in high-SDI regions; a consistent pattern, where both diseases occurred at comparable levels, was primarily observed across South Africa and the Middle East, while a migraine-dominant pattern was identified in North Africa. Co-occurrence patterns were generally less prevalent in areas with lower socioeconomic development. Across all three patterns, high temperature exposure, iron deficiency, and metabolic risks emerged as the primary contributing factors. Looking ahead to 2050, the global burden of migraine was projected to stabilize, whereas the prevalence of ADHD was expected to experience a slight yet consistent increase. Conclusion This study systematically identifies the co-occurrence patterns of ADHD and migraine, along with their socioeconomic and environmental drivers, offering evidence-based insights for early prevention and targeted intervention in disease populations globally. Keywords GBD, migraine, ADHD, incidence, disease burden

Pain perception is initiated upon activation of nociceptors of the dorsal root ganglia (DRG) and trigeminal ganglia. We identified G protein-coupled receptors (GPCRs) expressed in CGRP+ mouse and human nociceptors and found that agonists of several identified Gi/o-coupled and orphan GPCRs attenuated neuronal excitability. Experiments focusing on the Gi/o-coupled serotonin receptor Htr1b, which is expressed in mouse and human CGRP+ DRG neurons, revealed that Htr1b/1d agonists, the triptans sumatriptan and zolmitriptan, attenuated CGRP+ neuron excitability in vitro and exhibited analgesia across several pain models, including neuropathic pain. Conditional genetic deletion experiments showed that triptan-induced analgesia is mediated by Htr1b expressed in A-fiber mechanonociceptors. Also, triptan-associated adverse effects are partially mediated by Htr1b-independent targets. Further testing identified the GPCR Gpr19 as an additional promising target for treating pain. These findings establish a preclinical screening platform for identifying novel analgesics and reveal nociceptor GPCRs that may be targeted to treat pain.

Intervertebral disc degeneration (IVDD) compromises disc structures and mechanics, yet systematic evaluations of the mechanical responses and their relationship to morphological changes in preclinical models remain limited. This systematic review and meta-analysis synthesized mechanical and morphological alterations following experimental disc injury in in vivo animal models. Searches of MEDLINE, EMBASE and Web of Science databases were conducted in accordance with PRISMA guidelines. Study quality and risk of bias were assessed using modified CAMARADES and SYRCLE tools. Twenty-eight studies were included. Pooled analyses showed significant reductions in stiffness, Youngs modulus, and disc height, and significant increases in range of motion and degeneration grade, indicating both mechanical and structural deterioration. Youngs modulus appeared to be the most sensitive marker of functional degeneration. By contrast, creep and other viscoelastic responses showed non-significant changes. High heterogeneity was evident across studies, reflecting variability in injury models, species, timepoints, and testing methods. Evidence of publication bias was detected in several domains, and moderate methodological quality was noted with overall insufficient blinding and lack of sample size calculations. In vivo animal models of IVDD demonstrate robust and consistent mechanical and morphological degeneration after injury. Youngs modulus is a sensitive mechanical indicator, supporting its use in future preclinical research. Standardization of outcome definitions, methodology, and reporting is essential to improve comparability and enhance translation of preclinical findings to clinical research.

Previous brain decoding studies indicate that an individuals pain experience can be robustly predicted from distributed patterns of brain activity. Two brain decoders have notably been associated respectively with the nociceptive and cognitive aspects of pain experience, the Neurologic Pain Signature (NPS) and the Stimulus-Intensity Independent Pain Signature (SIIPS). Yet, we still do not know if these brain patterns are also causally related to pain experience. To evaluate this possibility, we used high-field (7-Tesla) fMRI to test whether humans can alter their pain experience by bidirectionally modulating their pain-related brain activity in decoded neurofeedback paradigm. In a double-blind design, participants were trained to up- and down-regulate the NPS or the SIIPS. Our results indicate that participants can achieve bidirectional control of both signatures. NPS expression reliably increased during pain stimulation and covaried with both stimulus intensity and subjective ratings. In contrast, SIIPS expression did not show consistent stimulus-locked effects in the primary analyses. Importantly, reduction in pain rating was specific for SIIPS-training, whereas NPS has failed to show any consistent behavioral effect. Based on these preliminary findings, we hereby preregister a follow-up study, with specified rationale, hypotheses, experimental design, and analysis protocols.

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.

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.

The severity stratification of carpal tunnel syndrome (CTS) relies on ultrasound morphological markers and electromyography. However, it remains unclear how structural imaging can reliably infer functional impairment. Clarifying the structure-function relationship is critical for efficient diagnostic pathways. A retrospective cohort of 55 patients with symptoms related to CTS was analyzed at the Shanghai Sixth Peoples Hospital. All patients were subjected to ultrasound and EMG. 72.7% cases were diagnosed with CTS with a female predominance and equal left-right involvement. Random-forest classifiers were trained using surrogate splits, and performance was evaluated using predictions outside the bag. A full-feature model (34 candidate variables) was compared against a simplified model (8 core variables) capturing the core morphological and electrophysiological features. A residual-based framework was then used to characterize the structure-function mismatch within severity grades (1a-3c). The simplified model improved discriminative performance compared to the full-feature model (AUC 0.789 to 0.824). The simplified model achieved an overall accuracy of 77.3%. Analysis of predicted probability distributions and 10-bin calibration curves indicated stable and clinically interpretable risk estimation in most probability ranges. Permutation-based importance analysis confirmed that both ultrasound and electrophysiological features contributed substantively to prediction. Residual-based grading further revealed structure- function heterogeneity within each main severity grade. CTS severity can be stratified using a limited set of complementary morphological and electrophysiological features. Structure-function mismatch supports an imaging-led initial screening, with electrophysiology reserved for selected patients.

Individual variability in pain perception raises fundamental questions about how biological and experiential factors shape pain processing. Cognitive-demanding motor training is a key driver of use-dependent brain plasticity and may contribute to differences in pain responses. Using musicians as a model of cognitive-motor expertise, we examined how such experience influences cortical dynamics and pain perception during experimentally induced prolonged musculoskeletal pain. Resting-state electroencephalography (EEG) was recorded in musicians and non-musicians before (Day 1) and during pain development (Days 3 and 8) following intramuscular nerve growth factor (NGF) administration. We parameterized periodic (alpha peak frequency, power, frontal asymmetry) and aperiodic (exponent, offset) components of the EEG signal to characterize intrinsic cortical activity. During pain development, non-musicians exhibited slowing of peak alpha frequency, a neural marker associated with ongoing pain. In contrast, musicians showed preserved alpha dynamics and greater left frontal asymmetry, reflecting resilient top-down pain regulation. Musicians also displayed higher aperiodic exponent across sessions, suggesting that musical training shapes the excitation-to-inhibition (E:I) balance potentially reflecting a shift toward greater inhibitory activity. Notably, across all participants, only aperiodic features improved the prediction of pain severity, with higher exponents and higher offsets associated with lower pain ratings. These findings demonstrate that cognitive-motor training shapes cortical dynamics during sustained pain, supporting more stable, resilient cortical responses to pain. Such training also contributes to inter-individual variability in pain processing. Moreover, this study identifies aperiodic EEG components as predictors of pain severity and resilience.

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.

Nerve injury causes an imbalance of glutamatergic excitation over GABAergic inhibition, contributing thereby to lasting neuropathic pain. Transgenic GAD67-GFP knock-in reporter mice were developed to visualize GABAergic interneurons. The knock-in into glutamate decarboxylase (GAD67) causes haploinsufficiency that manifest in low GABA levels. In this model, we studied if diminished GABA exacerbates neuropathic pain after nerve injury. Adolescent male and female GAD67-GFP knock-in mice were subjected to Spared Sciatic Nerve Injury (SNI). At baseline, nociception and thermal preferences were equal but after SNI, GAD67-GFP mice developed thermal allodynia which was not detected in wildtype littermates. At the electrophysiology level, SNI caused a partial decrease in the excitability in layer 2/3 pyramidal neurons in the projection-hemisphere in wildtype mice. This effect was exacerbated in GAD67-GFP, affecting both sides, and was accompanied with imbalance of field-potential (FP) amplitudes between projection and non-projection hemisphere, which did not occur in wildtype mice. The results suggest that GABA deficiency can be compensated to protect from hyperexcitability at baseline, but it cannot be further upscaled, ultimately leading to network hyperactivity after injury. Metabolomic studies confirmed the moderate loss of GABA in ipsi- and contralateral cortex and lumbar spinal cord of GAD67-GFP mice and failure to raise GABA in the ipsilateral dorsal horn after injury. Carnosine, cystathionine, and glutathione, three important anti-oxidative metabolites, were co-reduced with GABA suggesting that GABAergic activity and anti-oxidative capacity are interconnected and failure of this axis contributes to neuropathic "pain".

Deficient descending pain inhibition assessed by conditioned pain modulation (CPM) is considered a common feature of various chronic pain disorders. Typically, CPM studies focus on one particular disorder making direct comparisons between disorders difficult. This cross-sectional study aimed to compare CPM effects between three clearly distinct chronic pain disorders and pain-free controls. Furthermore, patients were pooled with controls to explore whether subgroups showing different CPM effects could be separated independent of cohort membership. One hundred and forty participants (patients: 53 non-specific chronic low back pain [nsCLBP], 15 complex regional pain syndrome [CRPS], 14 neuropathic pain after spinal cord injury [painSCI]; 58 controls) were included. CPM effects were assessed in a remote, pain-free area using pressure pain thresholds as test stimulus and a cold water bath as conditioning stimulus. Cohort differences in CPM effects were analyzed using linear mixed models. The presence of subgroups showing different CPM effects was tested using latent class linear mixed models. CPM effects differed between cohorts (p = 0.011), driven mainly by reduced inhibitory CPM effects in patients with nsCLBP compared to patients with painSCI. Latent class analysis detected 3 subgroups with varying degrees of significant inhibitory CPM effects (ps [&le;] 0.002). All subgroups comprised patients and controls. These results oppose deficient descending pain inhibition as a common feature of chronic pain disorders. Additionally, the failure to identify subgroups without inhibitory CPM effects within a heterogenous patient/control sample challenges the utility of deficient CPM as predictor of chronic pain or treatment efficacy. PerspectiveInhibitory conditioned pain modulation, a measure of descending pain inhibition, is not consistently impaired across distinct chronic pain disorders. Furthermore, identifying individuals with impaired conditioned pain modulation within a heterogenous sample is difficult. Thus, for conditioned pain modulation to be clinically useful, its variability needs to be better understood.