The Journal of Headache and Pain

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.

Objective: Migraine 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. Methods: Adults 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. Results: The 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. Conclusions: In 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.

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.

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.

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.

IntroductionThe exploration of alternative strategies for neural tissue regeneration and repair is giving rise to a novel paradigm in neurosurgery: fusogenic therapy. This approach promises rapid restoration of peripheral nerve and spinal cord function by circumventing Wallerian degeneration and eliminating the delay associated with axonal regrowth. Its potential stems from the capacity of fusogens to induce axonal fusion and achieve immediate membrane sealing, complemented by their pronounced neuroprotective properties. However, experimental data on fusogens and their effects are inconsistent, often contentious, and derived using heterogeneous methodologies. MethodsWe present the first comprehensive systematic review covering nearly four decades of research on fusogens for axonal membrane repair and 26 years of their experimental and clinical application in mammalian and human models for peripheral and central nervous system restoration. The review includes a meta-analysis of fusogen efficacy following traumatic spinal cord and peripheral nerve injuries. ResultsConducted in accordance with the PRISMA 2020 flow protocol and PICO criteria, our analysis incorporates 86 sources, 20 of which were included in the meta-analysis. DiscussionIn summary, we have systematized the prevailing approaches and methods for fusogen application, delineated key contentious issues, and identified promising directions for the development of axonal fusion technology.

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

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.

Intervertebral disc (IVD) injury is a major cause of low-back pain and can lead to structural deficits and mechanical instability. When the IVD is compromised, neuromuscular compensation by paraspinal muscles, such as the multifidus (MF) and longissimus (ML), is critical for maintaining spine stability. However, it is unknown how IVD injury and its interaction with nociception affect neuromuscular control. This study assessed the effects of IVD injury and additional muscle-derived nociception on trunk motor control during locomotion in a rat model. IVD injury was induced via needle puncture at L4/L5. One week later, hypertonic saline was injected into the lumbar MF to induce nociception. Trunk and pelvic kinematics, bilateral EMG activity of MF and ML were recorded during treadmill locomotion at baseline, one week after IVD injury, and immediately following hypertonic saline injection. Trunk and pelvic kinematics and bilateral muscle activation patterns remained largely consistent across conditions. No significant changes were found in stride duration, pelvic, lumbar and spine angle changes, variability, or movement asymmetry. MF activation was bilaterally synchronized, whereas ML showed left-right alternating activation patterns. Following IVD injury, right MF mean activation and EMG variability increased significantly compared to baseline. When muscle-derived nociception was added in the unstable spine (IVD injury) condition, left MF minimum amplitude was significantly reduced, and instability-related increases in right MF mean activation and variability were attenuated, but not fully reversed. These findings suggest that IVD injury, alone or in combination with muscle-derived nociception, elicits localized neuromuscular adaptations without disrupting the global locomotor patterns.

ObjectiveFinding indicators of early response to antidepressant treatment in EEG signals recorded from patients suffering from major depressive disorder. MethodsFunctional brain connectivity networks based on weighted imaginary coherence and weighted imaginary mean phase coherence were computed for 176 patients for 6 different EEG frequency bands. Cross-hemispheric connectivity (CH) and lateral asymmetry (LA) were estimated from these networks based on EEG signals recorded before the beginning of treatment (V is1) and one week after the start of the treatment (V is2). Repeated measures ANOVA was used to check for statistically significant changes in connectivity based on these measures at V is2 w.r.t. V is1. Post-hoc analysis was performed with multiple pairwise comparison tests to determine which group means were significantly different. ResultsIt was found that CHV is2 was significantly reduced w.r.t. CHV is1 in the {beta}1 [12.5 - 17.5 Hz] frequency band for the responders to treatment. Also, LAV is2 was significantly increased w.r.t. LAV is1 in the {beta}1 frequency band for the responders. No such significant changes were observed for the non-responders. Brain networks constructed using both weighted imaginary coherence and weighted imaginary mean phase coherence were found to exhibit these results. For the CH connectivity changes, binarized networks and for the LA connectivity changes, weighted networks were found to be more reliable. ConclusionsResponders were found to show a reduction in cross-hemispheric connectivity and an increase in lateral asymmetry, both in the {beta}1 band while no such change was observed for the non-responders. SignificanceDecrease in cross-hemispheric connectivity and increase in lateral asymmetry in the {beta}1 band may represent candidate neurophysiological indicators of early treatment response, but they require independent replication before any clinical application can be considered.

BackgroundSpinal cord injury (SCI) triggers persistent neuroinflammation, gliosis, neuronal loss, and demyelination, leading to motor deficits and neuropathic pain. Botulinum neurotoxin type A (BoNT/A) has shown anti-inflammatory and neuroprotective effects in acute SCI, but its potential in the chronic phase remains unclear. This study investigates whether combining BoNT/A with electrical muscle stimulation (EMS) enhances recovery in chronic SCI. MethodsAdult mice with severe thoracic SCI (paraplegic) underwent EMS (30 min/day for 10 non-consecutive days starting 3 days post-injury) or no stimulation. Fifteen days after SCI, animals received a single intrathecal injection of BoNT/A (15 pg/5 L) or saline. Functional recovery was assessed up to 60 days as well as in moderate and mild SCI mice, neuropathic pain onset and maintenance were evaluated. Spinal cord tissue was analysed for astrocytic and microglial morphology, neuronal and oligodendroglia survival, myelin protein expression, and in vitro effects on oligodendrocyte precursor cells (OPCs). The phenotype of hindlimb muscles was evaluated through morphological and gene expression analyses. ResultsEMS was able to counteract muscle atrophy and fibrosis, and when combined with BoNT/A, also denervation. Moreover, the combination restored hindlimb motor function in chronic SCI, whereas BoNT/A or EMS alone were ineffective. Neuropathic pain, a common comorbidity associated with SCI, was mitigated by BoNT/A treatment even when administered in the chronic phase. BoNT/A reduced astrocytic hypertrophy and excitatory synapse association and was associated with a morphology-based redistribution of microglial profiles toward a resting-like classification, decreased apoptosis, and increased neuronal and oligodendroglia survival. Myelin basic protein expression was significantly elevated in vivo. In vitro, BoNT/A promoted OPC differentiation into myelinating oligodendrocytes, increased process complexity, and upregulated Myelin basic protein, galactocerebroside C, proteolipid protein, and myelin oligodendrocyte glycoprotein under both proliferative and differentiating conditions. Cleaved SNAP25 colocalization with OPC confirmed direct BoNT/A internalization and activity. ConclusionsBoNT/A exerts multi-cellular neuroprotective actions in chronic SCI, supporting neuronal and oligodendroglia survival, reducing neuroinflammation, enhancing remyelination and the combination with EMS promotes substantial recovery of muscle homeostasis within a permissive microenvironment shaped by early stimulation. Its efficacy depends on a permissive microenvironment achieved through EMS. These results provide strong rationale for the clinical evaluation of BoNT/A as a therapeutic strategy for chronic SCI.

Optimization of deep brain stimulation (DBS) therapy for neurological and neuropsychiatric disorders depends on objective quantitative biomarkers that can guide stimulation parameter adjustments. With the recent introduction of new-generation DBS systems capable of simultaneously stimulating brain activity and recording local field potentials (LFP), there is increasing demand for platforms that enable efficient visualization and analysis of these signals for electrophysiological biomarkers identification. To address the limitations of currently available toolboxes that require advanced signal processing skills and rely on proprietary software, we present NeoDBS, an open-source Python platform designed for ingestion and advance signal visualization and processing of LFP signals from DBS systems through an easy-to-use graphical interface. NeoDBS is a user-centered platform that offers predefined analysis pipelines with the aim of facilitating electrophysiological biomarker investigation for DBS across different brain disorders. Custom analysis pipelines are also available for users to leverage the signal analysis tools to their research needs. Critical functionalities for longitudinal biomarker research are featured in NeoDBS, such as batch file processing and event-locked analysis for in-clinic and at-home recordings. This combination of accessibility, user-experience and advanced signal processing tools makes NeoDBS an environment that propels easy and fast electrophysiological biomarker research for DBS, across patients, sessions, and stimulation parameters.

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

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

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.

Purpose: To evaluate the efficacy and safety of oral L-ergothioneine (EGT) in alleviating pain and associated symptoms in women with primary dysmenorrhea (PD). Methods: In this randomized, double-blind, placebo-controlled trial, 40 women with PD (aged 18-30 years) were randomized (1:1) to receive EGT capsules (120 mg/day) or a matching placebo for 3 consecutive menstrual cycles. Outcomes evaluated at baseline and post-cycle included peak pain (Visual Analog Scale, VAS), Dysmenorrhea Symptom Score, and the COX Menstrual Symptom Scale (CMSS). Results: EGT significantly improved PD symptoms over 3 cycles. Mean VAS for peak pain decreased from 4.80 {+/-} 1.12 to 2.32 {+/-} 1.59 in the EGT group (p < 0.001), compared to a non-significant reduction (4.10 {+/-} 1.30 to 3.45 {+/-} 1.69) in the placebo group. The between-group difference at cycle 3 was significant (p < 0.01). A linear mixed-model confirmed a significant Time x Group interaction (p < 0.001), showing an accelerated decline in symptom severity for EGT. Furthermore, 84% of EGT-treated patients achieved [&ge;]50% VAS reduction versus 35% in the placebo group (p = 0.003). Serum inflammatory biomarkers showed no significant between-group differences or correlation with VAS improvements, suggesting EGT's analgesic effects likely operate via cytoprotective pathways independent of classical inflammatory cascades. No adverse events were reported. Conclusion: Oral EGT supplementation (120 mg/day) effectively and progressively mitigates menstrual pain and systemic symptoms in PD, offering a well-tolerated, non-pharmacological intervention. Trial Registration: ChiCTR2500112557; Retrospectively registered on 2025-11-17.

ObjectivesEpidural spinal cord stimulation (SCS) is an emerging therapy for motor rehabilitation following spinal cord injury (SCI) and other motor disorders. Conventionally, SCS leads are placed along the dorsal spinal cord (SCSD), where stimulation activates large diameter afferent fibers, which indirectly activate motoneurons through reflex pathways. This leads to broad activation of flexor and extensor muscles and limited fine-tuned control of motor output. Targeting the ventral spinal cord (SCSV) may enable more direct activation of motoneuron pools, potentially improving the specificity of muscle activation; however, there is currently no established method to place leads ventrally. To address this, we evaluated the feasibility of four modified percutaneous implantation techniques to target the ventrolateral thoracolumbar spinal cord. Materials and methodsPercutaneous SCSV implantation was performed in three human cadaver torso specimens under fluoroscopic guidance. The following approaches were evaluated: sacral hiatus, transforaminal, interlaminar contralateral, and interlaminar ipsilateral. The leads in the latter 3 approaches were inserted between L1 and L5. Eighteen implants were attempted, with nine leads retained for analysis. Lead and electrode position were assessed using computed tomography (CT) with three-dimensional reconstruction, along with anatomical dissection to verify lead and electrode placement within the epidural space. ResultsSuccessful ventral epidural lead placement was achieved using all four implantation approaches. The sacral hiatus (16/16 electrodes) and transforaminal (8/8 electrodes) approaches resulted in exclusively ventrolateral placement. The interlaminar contralateral approach led to 27/32 electrodes positioned ventrolaterally and 5/32 dorsally. The interlaminar ipsilateral implantation approach led to 14/32 electrodes positioned ventrolaterally and 18/32 positioned ventromedially. ConclusionsThese findings demonstrate that ventral epidural SCS lead placement can be achieved using modified percutaneous implant techniques. The four approaches outlined here provide a clinically feasible pathway to SCSV and establishes a foundation for future clinical studies investigating SCSV for motor rehabilitation following SCI.

Background Functional neurological disorder (FND) is a common neurological condition characterised by symptoms which vary characteristically with attention. In the sensory realm, these symptoms frequently take the form of 'phantom' perception in the absence of sensation. While the condition is generally regarded not to cause auditory symptoms, tinnitus is a phantom perception which varies with symptom-focused attention, and is suggested to have similar underlying mechanisms to those proposed for FND. Based on this, we hypothesized that tinnitus might reflect the same underlying process as FND, and that it would therefore be more common in people with FND (pwFND). Methods Using an international database, we compared the proportions of pwFND who reported tinnitus with a control group. To ensure that observed differences were not attributable to agreement bias in symptom reporting, we also conducted an experiment where pwFND and controls were asked to report which symptoms they had experienced in the past month, 14 of which were symptoms of FND, and 7 of which were unrelated. Results Rates of tinnitus were significantly higher in the FND group (54% HDI 50 - 57%, n=732) than the control group (17% HDI 8.5 - 25%, n=59). In the symptom reporting experiment, pwFND (n=38) reported more FND-related symptoms than controls (n=38), but there was no between-group difference in reporting of non-FND related symptoms. Discussion Based on the markedly higher prevalence of tinnitus in pwFND than controls, and the substantial overlap in mechanisms and phenomenology, we believe tinnitus should be considered a possible symptom of FND, where both conditions reflect a failure of symptom resolution after incitement by a peripheral stimulus.

Background: Recently, a posterior pathway for fluid drainage from the retina to the meningeal lymphatics in the optic nerve (ON) sheath was identified in rodents using intravitreal imaging tracers directly injected into the ocular-globe. Fluid and solute clearance along this pathway may be associated with many diseases. However, intravitreal tracers are rarely used in clinical imaging. As intravenous Gadolinium-based-contrast-agent (GBCA) can enter the globe via the blood-ocular-barriers, it may provide an alternative approach to image this pathway. Purpose: To establish a clinically feasible intravenous GBCA-based MRI approach for tracking fluid and solute transport along the posterior lymphatic pathway in the ocular glymphatic system. Materials & Methods: This prospective study was conducted from March 2021 to September 2022 in healthy participants. Dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI was performed before, immediately and 4 hours after intravenous-GBCA administration to track GBCA distribution in aqueous humor (AH) and cerebrospinal fluid (CSF) in regions-of-interest (ROIs) in the globe (anterior-cavity, vitreous-body), in the intraorbital and extraorbital ON, and in the intracranial CSF space proximal to the ON (chiasmatic-cistern, interpeduncular-cistern). Kruskal-Wallis tests with post-hoc Dunn's tests were used for group comparisons. Results: Sixteen healthy participants (mean age +/- SD: 51 +/- 21 years, 5 men) were recruited. Intravenous-GBCA enhancement was observed in all ROIs immediately after injection. At 4-hour-post-GBCA, the vitreous body showed a trend of smaller enhancement area (55 +/- 11% versus 49 +/- 11%, P=.14) and lower GBCA-concentration (0.044 +/- 0.014 versus 0.028 +/- 0.010 mmol/L, P=.07) compared to immediate-post-GBCA. The intraorbital ON showed more widespread enhancement (39 +/- 5% versus 59 +/- 6%, P=.01) and significantly higher GBCA-concentration (0.023 +/- 0.009 versus 0.059 +/- 0.015 mmol/L, P<.001) at 4-hour-post-GBCA. Conclusion: Dynamic fluid and solute transportation along the posterior lymphatic pathway in the ocular glymphatic system in healthy participants was measured by tracking intravenous-GBCAs entering the globe via the blood-ocular-barriers using cDSC-MRI.

Purpose To determine whether clinically significant weight loss (>5% of body weight) is associated with slower 2-year knee cartilage degeneration in individuals with and without radiographic osteoarthritis. This study used a cartilage structural assessment score derived from the spatial distribution of cartilage thickness, referred to as the Cartilage Thickness Score (CTh-Score). It is based on cartilage thickness patterns and scores the cartilage between 0 and 100, with higher scores indicating greater severity. Methods We conducted a retrospective matched cohort study within the Osteoarthritis Initiative. High-resolution cartilage thickness maps (CTh-Maps), along with their corresponding CTh-Score, were extracted from a public repository. Participants with complete radiographic and MRI data at baseline and 24 months were stratified by baseline Kellgren-Lawrence (KL) grade into non-radiographic OA (non-ROA; KL<2) and radiographic OA (ROA; KL>=2). Within strata, cases (>5% 2-year weight loss) were propensity score-matched 1:2 to weight-stable controls on age, sex, height, weight, KL grade, joint space width (JSW), KOOS Pain, baseline CTh-Score, and mean cartilage thickness in the medial and lateral femoral and tibial compartments. The primary outcome was 2-year change (delta) in CTh-Score, where higher values indicate worsening. Secondary outcomes were delta JSW, delta regional mean cartilage thickness, and delta KOOS Pain. Non-parametric tests were used. Results We included 164 cases and 328 controls in non-ROA, and 266 cases and 532 controls in ROA. Median (interquartile range) weight loss was -6.10 kg (-8.90, -4.70) versus +0.30 kg (-1.30, 2.20) in non-ROA and -6.80 kg (-9.10, -5.02) versus +0.40 kg (-1.40, 2.82) in ROA (both p<0.001). Weight loss was associated with significantly smaller 2-year increases in CTh-Score: in non-ROA, median 1.58 (0.61, 6.53) vs 3.14 (0.44, 7.12) (p=0.005); in ROA, median 1.69 (0.97, 6.71) vs 2.90 (0.19, 7.38) (p=0.004). No between-group differences were detected for delta JSW or delta regional mean cartilage thickness in any of the 4 ROIs. A trend toward greater KOOS Pain improvement with weight loss was observed in ROA: 2.75 (-3.35, 13.40) vs 0.00 (-5.60, 8.40) (p=0.06). Conclusions Achieving >5% weight loss over 2 years is associated with approximately 50% lower progression in median cartilage degeneration, as assessed by CTh-Score, in both non-ROA and ROA. No change was observed with conventional structural metrics. These findings support weight management as a structural disease-modifying strategy and highlight CTh-Score as a sensitive endpoint.