The Journal of Headache and Pain

Migraine is a disabling neurological disorder that frequently co-occurs with depression and anxiety. While prior research suggests a genetic association between these conditions, little is known about the genetic relationships underlying specific migraine subtypes. Bivariate genetic correlations between migraine with depression and anxiety were estimated using Linkage-Disequilibrium Score Regression (LDSC), drawing on publicly available large-scale Genome-Wide Association Study data for these traits. In addition, PGS were constructed using the same data and applied to two target cohorts for out-of-sample prediction of migraine and its subtypes. These were a depression-enriched cohort (Australian Genetics of Depression Study; N=12,601), and an unselected population cohort (QSkin Study of Sun and Health; N=16,532). Migraine subtypes were defined according to standard criteria and comprised a broad migraine without aura phenotype and three nested subtypes: migraine with aura, and chronic migraine with and without aura. We found significant genetic correlations between migraine and depression (rg=0.29), as well as between migraine and anxiety (rg=0.32). Across both cohorts, Migraine (OR{approx}1.35) and Depression PGS (OR{approx}1.12) were significantly associated with all measures of migraine and its subtypes. Depression PGS remained significantly associated with all non-chronic migraine subtypes after controlling for migraine and anxiety PGS, suggesting an independent contribution of depression genetic risk on migraine. Anxiety PGS were significantly associated with all non-chronic migraine subtypes (OR{approx}1.09). However, these associations did not persist after adjustment for migraine and/or depression PGS. These results provide insight into the genetic relationships between migraine and its subtypes with depression and anxiety.

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.

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.

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.

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.

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.

Objective: To compare first-line emergency department (ED) treatment classes for acute headache on short-term all-cause ED return and index admission across two independent health systems. Background: ED trials of acute headache treatment are judged on in-ED pain relief, a documented endpoint that is recorded incompletely and shifts with the scoring rule, and is a weak surrogate for what happens after discharge. All-cause ED return after an index headache visit (any subsequent ED encounter within the window) has not been used to compare first-line treatments at scale, and society guidance favors dopamine-receptor antagonists while recommending against routine opioids. Methods: Retrospective two-center cohort of adults treated for headache in the ED, using MIMIC-IV-ED (Beth Israel Deaconess Medical Center, 2011-2019) and MC-MED (Stanford, 2020-2022). The first-line class was the earliest qualifying acute agent. The primary contrast was opioids versus dopamine-receptor antagonists (the guideline-preferred class). Outcomes were 72-hour and 7-day all-cause ED return (among discharged patients; any subsequent ED encounter within the window) and index hospital admission. Confounding by indication was addressed with propensity overlap weighting; associations are reported as adjusted risk ratios (RRs) with bootstrap 95% CIs and E-values. Estimates were pooled with a site term and examined per site. Results: Among 13,285 treated adults (10,799 MIMIC-IV-ED; 2,486 MC-MED), opioid recipients were older and higher-acuity than dopamine-antagonist recipients (index admission 38.1% vs 16.4%). In the MIMIC-IV-ED discharged primary-contrast population, overlap weighting reduced the maximum standardized mean difference from 0.35 to 0.002; pooled and site-specific balance diagnostics are provided in the Supplement. First-line opioids remained associated with a higher 72-hour all-cause ED return (6.8% vs 3.8%; adjusted RR 1.79; 95% CI 1.31 to 2.33), 7-day return (10.7% vs 6.6%; RR 1.62; 95% CI 1.28 to 1.98), and index admission (RR 2.32; 95% CI 2.11 to 2.58, consistent with strong residual severity differences in patients selected for opioids). The direction of association was concordant across both health systems, although MC-MED return estimates were imprecise given the smaller opioid-treated discharged sample. In MIMIC-IV-ED, the cumulative all-cause return incidence by treatment class separated by day 3 and persisted through 30 days. The direction was consistent, though attenuated and no longer statistically significant, when the outcome was restricted to a headache-specific return (72-hour RR 1.31; 95% CI 0.91 to 1.88); the direction persisted for the composite of admission or 72-hour return, which does not condition on discharge but is influenced by the more confounded admission component (RR 2.16; 95% CI 1.98 to 2.39). Conclusion: Across two health systems, first-line opioid treatment for ED headache was associated with higher all-cause short-term ED return among discharged patients and higher index admission than dopamine antagonists. These observational associations reflect downstream all-cause ED utilization after an index headache visit rather than confirmed headache recurrence or treatment failure; they are consistent with guideline-concordant, opioid-sparing first-line treatment and warrant prospective confirmation. Plain Language Summary: Emergency departments treat headaches with several different medicines, but the usual way of judging which works, the pain score recorded during the visit, is often missing or inconsistent. Using two large hospital systems and a clearer outcome, whether patients came back to the emergency department for any reason, we found that patients first treated with opioids returned within 72 hours about 1.8 times as often as those given the guideline-preferred dopamine-blocking medicines and were admitted more than twice as often. These patterns pointed the same direction in both hospital systems after adjustment for the measured differences available in both databases. Because this was an observational comparison and returns were counted for any reason, the findings are consistent with using guideline-preferred non-opioid medicines first, rather than proof that opioids worsen headache.

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.

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.

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.

People differ widely in their sensitivity to pain, and this variability is clinically relevant, yet the underlying structural brain mechanisms remain poorly understood. White matter hyperintensities (WMH), a common imaging marker of cerebral small vessel disease, are associated with microstructural abnormalities in white matter tracts and have also been linked to pain related outcomes; however, the mechanisms linking WMH to altered pain perception remain unclear. We investigated whether WMH are linked to pain sensitivity through tract specific microstructural alterations and cortical structural differences. We analysed data from 1,448 participants (mean age 73 years; 53% women) in the population based Rotterdam Study and independently replicated the findings in 1,522 participants (mean age 63 years; 52% women) from the population based Tromso Study. Pain sensitivity was quantified using the cold pressor test. Multimodal magnetic resonance imaging, including T1 weighted, fluid attenuated inversion recovery and diffusion tensor imaging, was used to map WMH to predefined white matter tracts, derive tract specific fractional anisotropy (FA), and estimate cortical measurements. Cox proportional hazards models assessed associations with pain sensitivity, and tract specific mediation analyses evaluated whether white matter microstructure or tract connected cortical regions mediated the relationship between white matter hyperintensities and pain sensitivity. WMH were present in 20 of 27 predefined tracts and were associated with reduced FA in 18 tracts. Higher WMH burden was associated with greater pain sensitivity, particularly in the left anterior thalamic radiation and left superior thalamic radiation, while lower FA in the anterior thalamic radiation, medial lemniscus, superior thalamic radiation and inferior fronto occipital fasciculus was associated with greater pain sensitivity. Mediation analyses showed that white matter microstructural disruption was the principal pathway linking WMH to pain sensitivity, with the strongest indirect effects observed through the inferior fronto occipital fasciculus (44.6% mediated) and anterior thalamic radiation (32.6% mediated). Cortical atrophy in the precentral and postcentral gyri provided a smaller secondary pathway, mediating approximately from 3 to 6% of the association between corticospinal or superior thalamic radiation WMH and pain sensitivity. Replication analyses supported these cortical mediation pathways, and meta analysis strengthened the tract specific associations. Together, the results suggest that vascular white matter injury is associated with pain perception through specific structural pathways, with DTI based markers appearing particularly sensitive to these relationships.

Background: Whether a patient's pain improved after emergency department (ED) treatment is read from the record to benchmark EDs, compare drugs, and label research outcomes. It is interpretable only if a post-treatment score is recorded, appropriately timed, and chosen by a fixed rule; its stability across these choices is unknown. Methods: Retrospective measurement study of adult headache visits in a de-identified ED database (MIMIC-IV-ED, 2011-2019). Among treated visits, we quantified reassessment completeness by time window, estimated meaningful relief (a reduction of at least 2 points) under score-selection rules and missing-data assumptions, tested whether reassessment was predictable at treatment, and compared headache with other painful presentations. Results: Among 19,501 visits (15,273 patients), 13,682 (70.2%) were treated. A post-treatment pain score appeared at any time for 77.1% (95% CI, 76.4 to 77.8), but within 2 hours of the analgesic for only 47.9% and within 1 hour for 27.5%. Meaningful relief was 66.9% using the first post-treatment score but 81.0% and 83.4% using the last or lowest score; it was 67.5% under inverse-probability weighting and could be bounded only between 51.8% and 74.4%. Whether a score was recorded was weakly predictable at treatment (area under the curve, 0.566) and unrelated to baseline pain. Completeness was similar across headache strata and comparator painful presentations. In an independent ED (MC-MED, a different EHR), the score-selection effect replicated: relief rose from 71.1% (first) to 80.6% (last) and 83.4% (lowest). Conclusions: Documented pain relief after ED headache treatment was not a stable outcome: it varied with the reassessment window and score-selection rule, was not point-identified for unreassessed patients, and behaved like other painful ED presentations. Programs and research that use documented relief should prespecify the reassessment window, score-selection rule, completeness denominator, and a missing-data range, and favor protocol-timed reassessment.

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.

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.

PurposeMild therapeutic hypothermia (MTH) preserves cochlear function in animal models and is now entering early-phase human trials for hearing preservation. However, the extent to which the human cochlea can actually be cooled, and the mechanisms underlying MTH, remain unclear, in part because blood perfusion is expected to oppose localized cooling. In this study we evaluated the impact of blood flow on human cochlear temperature exposed to the MTH device using a combined experimental and computational approach. MethodsTemperature measurements were obtained from a human cadaver skull exposed to a commercial MTH device. These data were used to validate a three-dimensional bioheat transfer model incorporating realistic skull anatomy. The validated model was subsequently extended to include physiological blood perfusion in the internal carotid artery; a major heat source located near the cochlea. Finally, the in silico model was further expanded to incorporate the surrounding skin and brain tissues. ResultsIncorporating blood flow in internal carotid artery substantially altered predicted cochlear temperature distributions, highlighting the importance of localized vascular heat transport in the human cochlea during MTH. Although cochlear cooling was attenuated in the presence of perfusion, the therapeutic effects of MTH may not depend solely on the magnitude of local intracochlear temperature reduction. Additional mechanisms, such as reduced facial surface temperature, may also contribute to its efficacy. ConclusionThe validated in silico model provides a physiologically realistic framework for evaluating human cochlear thermal responses, investigating MTH mechanisms, and optimizing temperature-based strategies for hearing preservation.

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.

Background and Purpose-Aneurysmal subarachnoid hemorrhage (aSAH) remains a devastating cerebrovascular event, with delayed cerebral ischemia (DCI) representing its most feared complication. High-altitude environments induce profound cerebrovascular adaptations, yet no study has systematically examined aSAH outcomes in chronically hypoxic populations. We characterized clinical features and identified DCI predictors among aSAH patients on the Tibetan Plateau. Methods-This single-center retrospective cohort included 256 consecutive aSAH patients admitted at a tertiary neurosurgical center in Tibet (altitude 2,330-4,920 m) between 2013 and 2015. The primary outcome was DCI per consensus criteria. Multivariable logistic regression identified independent predictors; receiver operating characteristic analysis evaluated model performance. Altitude and hemoglobin were specifically evaluated as altitude-related risk factors. Results-DCI occurred in 26 patients (10.2%). In-hospital mortality was 1.6%. Most patients presented with good-grade aSAH (Hunt-Hess I-II, 73.0%; Fisher I-II, 73.1%). On multivariable analysis, only Fisher grade independently predicted DCI (odds ratio, 3.63 [95% CI, 1.14-11.52]; P=0.029). Neither altitude (P=0.697) nor hemoglobin concentration (P=0.858) was associated with DCI risk. The predictive model achieved an area under the curve of 0.812. At 1-year follow-up, 77.8% achieved favorable functional outcomes (modified Rankin Scale 0-2). Conclusions-Fisher grade is the sole independent predictor of DCI in high-altitude aSAH patients, while chronic hypoxia and compensatory hemoglobin elevation do not significantly modify DCI risk. Established sea-level prognostic frameworks remain valid in high-altitude settings, supporting their continued use for clinical risk stratification. Keywords: aneurysmal subarachnoid hemorrhage; high altitude; delayed cerebral ischemia; Fisher grade; Tibetan Plateau; prognosis

Nociplastic pain represents a major burden across immune-mediated inflammatory diseases (IMIDs). It is hypothesised, but not yet demonstrated, that peripheral inflammation promotes nociplastic pain by bottom-up sensitisation of the central nervous system (CNS). In rheumatoid arthritis (RA), a prototypic IMID, we used ultra-high field (7T) brain resting-state functional MRI to evaluate whether peripherally targeted anti-inflammatory therapies alter a biomarker of bottom-up CNS sensitisation: inferior parietal lobule (IPL)--insula connectivity. In discovery and replication cohorts, JAK-STAT pathway inhibitors significantly shifted IPL--insula connectivity toward a normalised pattern. This effect was not seen with placebo or anti-TNF therapy. Moreover, after performing an agnostic whole-brain multivariate analysis of functional connectivity change related to JAK-STAT inhibition, the posterior cingulate cortex (PCC) was identified; like the IPL, a major hub of the default mode network (DMN). We then probed the DMN with transcranial magnetic stimulation in an independent RA cohort. Active, but not sham, stimulation altered DMN connectivity and reduced peripheral blood monocyte pSTAT3 function, a surrogate of immune inactivation, suggesting a bi-directional brain-immune circuit. Together, these findings provide the first human experimental evidence that peripheral JAK-STAT pathways contribute to nociplastic pain in IMIDs.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, often infection-triggered illness with no cure and no effective treatment. Marked symptom heterogeneity hampers diagnosis, disease management, and trial design. Using phenotype data from the world's largest ME/CFS cohort, this study aimed to identify groups of patients with similar symptom profiles using cluster analysis, to assess the association between cluster membership and onset type, and to explore genetic associations with cluster membership. Methods: This study included 19,019 DecodeME participants, ages 16 and over, with ME/CFS in the UK, from 2022-2024. We performed a k-modes cluster analysis of individuals based on similar symptoms. Cluster metrics identified the optimal number of clusters, which were characterised and compared. A sex-stratified subgroup analysis explored differences between clusters among males and females. The association between ME/CFS onset type (infectious, non-infectious, or unknown) and cluster membership was assessed with logistic regression models, adjusting for sex, age, deprivation, and ethnicity. Genetic associations with cluster membership were assessed using a genome-wide association study. Results: We identified two clusters in our study population: a high symptom burden cluster (HSBC; 57% of participants) and a lower symptom burden cluster (LSBC; 43%). The HSBC was characterised by higher prevalence of symptoms across all domains, more comorbidities, and greater illness severity. Individuals with infectious and unknown onset had 1.24 times (95% CI: 1.15-1.35) and 1.30 times (95% CI: 1.18-1.43) higher adjusted odds of HSBC membership relative to non-infectious onset, respectively. A similar pattern was observed in the sex-stratified analyses, although it showed an overall higher symptom prevalence for females and a higher proportion of females in the HSBC compared to males. No genetic variant was significantly associated with cluster membership. Conclusions: This large-scale cluster analysis of DecodeME symptom data reinforces that ME/CFS is a heterogeneous condition with clinical subtypes. The identification of symptom-based phenotypes, along with sex-based differences in symptom burden and cluster characteristics, highlights the importance of incorporating symptom burden and sex in future research, clinical decision-making, and public health strategies. Tailoring future interventions to these subgroups could enhance patient management and improve outcomes.

Background: Cerebral vasospasm is a frequent complication after aneurysmal subarachnoid hemorrhage (aSAH) and is associated with delayed cerebral ischemia (DCI) and unfavorable outcome. While CTA-based vasospasm grading is frequently used, its relationship with actual cerebral perfusion remains incompletely understood. This study investigates the association between vasospasm severity and distribution and territorial perfusion deficits. Methods: In this retrospective single-center study, 513 CT examinations (CTA and CT perfusion) from 194 patients with aSAH were analyzed. Vasospasm was graded per vessel segment using the CTA Vasospasm Score, and perfusion deficits were assigned to corresponding vascular territories (left/right anterior circulation, posterior circulation). Vasospasm distribution was further classified by severity and multifocality. Associations between vasospasm score and perfusion deficits were assessed using a generalized linear mixed model with binomial distribution, adjusting for Hunt & Hess grade, modified Fisher score, and days since hemorrhage. Results: Vasospasm was detected in 79.3% of examinations, and a perfusion deficit in at least one territory was present in 62.6%. The proportion of perfusion deficits increased progressively with both vasospasm severity and multifocality, ranging from 21.7-25.0% in the absence of vasospasm to 81.2-82.2% in severe multifocal vasospasm. The CTA Vasospasm Score was significantly associated with perfusion deficits in all territories (OR 1.36-1.50), with stronger associations in the anterior than posterior circulation. Conclusion: Vasospasm severity and distribution are strongly associated with perfusion deficits, supporting a continuum model of ischemic risk. However, the substantial proportion of perfusion deficits occurring independent of vasospasm suggests additional microcirculatory mechanisms not captured by CTA. CT perfusion should be considered complementary to CTA, particularly in clinically deteriorating or non-assessable patients.