Brain Research Bulletin

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood, debilitating multisystem condition. Converging evidence implicates impaired cellular bioenergetics, neuroinflammation and defective neurovascular coupling that may manifest as "virtual hypoxia" only under physiological stress. Methods We performed a single-session multimodal 3T MRI study combining brain volumetry, arterial spin labelling (ASL) and multivoxel proton magnetic resonance spectroscopy under normoxia and two controlled hypoxic challenges (oxygen saturation 87 {+/-} 3%) in 26 ME/CFS patients and 27 age- and sex-matched healthy controls. Results After intracranial-volume normalization, patients showed a reduced brainstem volume (1.46 0.14 vs. 1.55 {+/-} 0.18 % of eTIV; p = 0.013, FDR-p = 0.039), whereas deep grey matter and whole-brain parenchymal fraction did not differ between groups. Whole-brain cerebral blood flow (CBF) rose under hypoxia in both groups (controls +4.8 {+/-} 13.0%, patients +3.7 {+/-} 11.7%), with greater initial inter-individual variability in patients (patient-to-control variance ratio up to 6.94; FDR-p = 0.001). Thalamic lactate-to-creatine (Lac/tCr) ratios increased with hypoxia in controls (FDR-p = 0.028) but were already elevated at normoxia in patients (0.171 vs. 0.135; FDR-p = 0.021) and did not rise further (FDR-p = 0.38). In exploratory analyses, patients showed exaggerated inverse coupling between thalamic total N-acetylaspartate (tNAA/tCr) and white-matter CBF. Conclusions These findings provide in vivo evidence of impaired neuro-metabolic and vascular adaptive capacity in ME/CFS, supporting the virtual hypoxia hypothesis and highlighting candidate imaging markers for stratification that warrant validation.

Background: Chronic pain affects hundreds of millions worldwide and remains a major clinical challenge, despite numerous available treatments. Advances in brain imaging offer a promising path toward identifying neural signatures of chronic pain, potentially enhancing diagnosis and guiding treatment. However, while a core set of brain regions, including the insula, cingulate, and somatosensory cortices, has been repeatedly implicated, findings regarding other regions and connectivity patterns involved remain inconsistent, with limited robust replication. Objective: To address these gaps, the present work characterizes resting-state functional connectivity and gray matter volume differences between chronic pain patients and pain-free controls. Methods: In this secondary analysis of publicly available data, anatomical and resting-state functional MRI were analyzed from 56 patients with chronic knee pain due to osteoarthritis and 20 pain-free controls. Group comparisons used Network-Based Statistic (NBS) and Bayesian multivariate regression models, controlling for demographic covariates. Results: In the pain group, about 75% of parcellated brain regions exhibited increased functional connectivity compared to controls. The 30 highest degree centrality regions in the NBS network were concentrated in regions consistent with prior pain neuroimaging findings. Additionally, chronic pain patients exhibited reduced gray matter volume (-3.98%; SD 1.2%) across 33% of parcellated brain regions, including key regions implicated in pain processing. Conclusions: These findings demonstrate widespread functional and anatomical neural alterations in chronic pain, revealing a global pattern of reorganization extending beyond previously reported network-pair effects. Characterizing such alterations may contribute to ongoing efforts to identify neuroimaging markers of chronic pain, with potential translational relevance.

Background Fibromyalgia (FM) is a disorder characterized by chronic pain and somatic symptoms that are not fully understood. Central sensitization, a process by which the central nervous system amplifies pain signals, is a key aspect of the pathophysiology of fibromyalgia. Despite its prevalence, effective treatment options are limited and the underlying pathophysiological mechanisms are not fully understood. Network pharmacology, which analyzes the interactions between diseases, targets, and biological pathways, can be used to identify potential molecular targets and pathways associated with fibromyalgia. In this study, we aimed to identify potential hub genes and the underlying biological pathways involved in fibromyalgia. Methods Four online databases, GeneCards, DisGeNET, OMIM, and PharmGKB, were initially screened for genes associated with fibromyalgia. GeneCards and DisGeNET were subsequently used to identify common genes, which were used to generate a protein association network using the STRING database. Cytoscape software was used to analyze the network, and the CytoHubba plugin was used to identify hub genes based on degree and betweenness centrality. Functional enrichment analysis was performed using ShinyGO to identify significantly enriched KEGG pathways. Results TNF and IL6 were identified as the top two hub genes with the highest degree of centrality. Functional enrichment analysis identified the Toll-like receptor (TLR) signaling pathway as a significantly enriched pathway among the prioritized hub genes, with a fold enrichment of 6.78 and FDR of 0.0346. Conclusion This study identified TNF, IL6 and other highly connected genes, along with TLR signaling as an enriched pathway in the fibromyalgia-associated gene network. These findings provide potential molecular targets and pathways for further investigation into the pathophysiology of fibromyalgia. Further experimental and clinical studies are required to independently validate these findings and determine their therapeutic relevance.

Despite its high prevalence and socioeconomic costs, the condition of tinnitus shares with related neuropsychiatric disorders the characteristic that, to this day, it cannot be cured. Two contradictory views of the origin of tinnitus (peripheral hyperexcitability and central brain oscillation changes linked to prediction error) are currently discussed without any regard for one another. We now firstly used a compact 64 sensor optically pumped magnetometer (OPM)-MEG system to study a group of tinnitus subjects without co-morbidity of hyperacusis. This new technology provided an unprecedented opportunity for analyzing hemisphere-specific brain activity changes with high spatial resolution in response to pure-tones with a pitch within or outside the tinnitus frequency. We observed in tinnitus smaller ABR amplitudes (reflecting reduced cochlear output synchrony) linked with reduced alpha and enhanced gamma activity at rest (reflecting elevated excitement of intracortical circuits). In tinnitus, reduced alpha and enhanced gamma brain activity at rest were associated with reduced evoked alpha, beta, and gamma in response to pure-tones within tinnitus frequencies (reflecting low signal-to-noise ratios in auditory target regions). Furthermore, elevated gamma activity in key regions in the brain involved in attention control was observed in tinnitus subjects: hypergamma activity was seen in posterior/frontal regions, that -when hyperactive - are predicted to trigger excessive attention to irrelevant stimuli. Weakened cochlear output synchrony, possibly through lowering tonic inhibitory strength in the ascending auditory pathway, can thus reduce alpha activity (default-mode network) and unleash cortical regions that control attention to irrelevant stimuli -- tracing tinnitus to perception.

Background: Persistent COVID-19-related olfactory dysfunction (C19OD) has a significant disease burden. The underlying pathology is unclear, both at the level of the olfactory epithelium, and the higher neural networks. Functional septorhinoplasty (fSRP) is a novel intervention aimed at restoring odorant airflow to the olfactory epithelium, demonstrating clinically meaningful olfactory improvements in persistent C19OD patients. In the same cohort, we investigated the functional plasticity within the primary and higher-order olfactory brain networks using task-based functional magnetic resonance imaging (fMRI) before and after fSRP. Methods: In a prospective cohort study, patients with persistent C19OD underwent psychophysical olfactory testing, nasal airflow measurements, and olfactory task-based fMRI at baseline and 6 months post-fSRP. Whole-brain fMRI data was analysed to evaluate changes in neural activation and their correlations with clinical parameters. Results were mapped to standardized anatomical and olfactory atlases. Findings: Eight participants completed pre- and post-operative fMRI assessments. At baseline, increased deactivation was seen in the left hippocampus, and increased activation in bilateral cerebellum. Task-based activation was positively correlated with nasal volume in the right thalamus, and left cerebellum lobule VI. Post-operatively, task-based deactivation was seen in the left cerebellum crus II. Reduced task-dependent activation post- compared to pre-operatively was seen in the bilateral insula. Increased activation post- compared to pre-operatively positively correlated with change in nasal airflow in the right orbitofrontal cortex (OFC), superior and middle frontal gyrus, and frontal pole (FP). Increased post- compared to pre-operative activation correlated negatively with change in olfactory scores in bilateral insula, and left FP. Interpretation: Persistent C19OD is characterized by widespread functional alterations across higher-order cortical regions, reflecting altered central olfactory processing. fSRP elicits significant neural plasticity within these higher-order olfactory areas. The findings support the mechanism that augmenting airflow to the olfactory cleft drives olfactory recovery through

Background: Although opioids are frequently prescribed for refractory chronic neuropathic pain, few data are available on baseline factors that may identify individuals more likely to respond and inform individually tailored practice. Methods: This was a post hoc, exploratory analysis of individual-level data from a placebo-controlled trial of methadone for chronic neuropathic pain (NCT05235191). Baseline clinical, psychological, psychophysical and radiological variables were tested for association with 30% or more pain reduction in the methadone group. The correlation between expectation of improvement and pain reduction was examined in both groups. Results: Of the 81 participants completing the 8-week follow-up, 28 (70%) on methadone and 14 (34.1%) on placebo achieved 30% or more pain reduction. In the methadone group, responders had higher baseline expectation of improvement (median 100 [80-100] vs. 55 [50-81]; p=0.004), which correlated moderately with percentage pain reduction (rs=0.508; p<0.001). Neither finding was observed in the placebo group (p=0.211 and p=0.161, respectively), although the correlation did not differ significantly between groups (p for interaction=0.728). Other clinical, sociodemographic, psychological and psychophysical variables were not associated with response. In the subsample with peripheral neuropathic pain and structural MRI (n=37), lower left precentral cortex volume was associated with response to methadone (p=0.041), and lower right paracentral volume with response to placebo (p=0.003). Conclusions: Baseline expectation may influence treatment outcomes, supporting its inclusion as a covariate to improve the precision of treatment effect estimates in trials, and its use in clinical practice to help tailor treatment to individual patients. These exploratory findings require confirmation in larger studies.

Objective: Perceived injustice is a psychosocial risk factor associated with delayed recovery and poor occupational outcomes among workers with pain conditions. We examined a theory-informed pathway linking occupational stressors, perceived injustice, pain interference, depressive symptoms, and insomnia, while evaluating selected measurement properties of the Japanese Injustice Experience Questionnaire-Short Form (IEQ-SF-J). Methods: This cross-sectional online survey included 600 Japanese workers (300 with headache and 300 with low back pain). Structural validity of the IEQ-SF-J was evaluated using exploratory and confirmatory factor analyses (CFA) and item response theory. Construct validity was examined using Spearman correlations. Structural equation modelling (SEM) estimated indirect associations between job demands or low job control and pain interference, depressive symptoms, and insomnia, with perceived injustice specified as a latent intervening construct. Results: CFA supported a unidimensional structure (comparative fit index = 0.993; root mean square error of approximation = 0.080). Internal consistency was acceptable (Cronbach's ; = 0.82; McDonald's {omega}; = 0.90), and test-retest reliability was moderate (intraclass correlation coefficient = 0.60). IEQ-SF-J scores correlated significantly with pain interference, insomnia, and depressive symptoms. Job demands and low job control showed significant indirect associations with all three outcomes involving perceived injustice. Conclusions: The IEQ-SF-J showed supportive evidence for several measurement properties and occupied a theoretically coherent position in associations linking occupational stressors with pain interference, depressive symptoms, and insomnia among workers with headache or low back pain.

Atypical sensory processing is common in attention-deficit/hyperactivity disorder (ADHD), yet decreased sound tolerance has received little attention, and it remains unclear whether it reflects actual auditory sensitivity or a vulnerability to attentional breakdown under acoustic load. The only prior study provided a single overall estimate, unable to separate sensory symptoms such as avoidance and distress from attentional and fatigue-related difficulties under noisy or demanding conditions. Here, we examined whether parent-reported auditory difficulties in children with ADHD are uniform or concentrated within specific symptom domains, and whether they vary with clinical presentation or medication. A total of 226 children (ages 6-12; 162 with ADHD, 64 typically developing controls) were assessed using the parent-report adaptation of the Khalfa Hyperacusis Questionnaire (Turkish version). The ADHD cohort was stratified by medication status and clinical presentation, and total, subscale, and item-level scores were compared across groups. Our findings show that children with ADHD scored higher than controls on the total and hyperacusis-effects subscale, but not on the coping subscale. Only four of the eleven items distinguished the groups, all reflecting concentration in noise or its decline under fatigue; no item reflecting sound avoidance, sensitivity, or distress differed between groups. This pattern was independent of clinical presentation, medication, and age; it persisted after adjustment for parental education. These results suggest that elevated auditory difficulties in ADHD are better explained by attention- and fatigue-related vulnerability than by heightened auditory sensitivity and may warrant environmental rather than audiological interventions.

Background. Cerebrovascular reactivity (CVR) is a sensitive marker of vascular health, most commonly measured with BOLD fMRI during hypercapnic gas challenges. Hypoxia is a complementary but under-characterized vasoactive stimulus. We characterize a combined hypercapnic-hypoxic gas-challenge paradigm at 7 Tesla BOLD fMRI and its cross-session reproducibility. Methods. Eleven healthy adults were scanned twice at 7 Tesla during an 18-minute multi-echo, multiband BOLD acquisition, receiving fixed-inspired hypercapnic (5% CO2) and hypoxic (10% O2) gas boluses separated by medical-air recovery periods, with end-tidal gas and peripheral saturation monitoring. Hypercapnic and hypoxic CVR were estimated using three trace-based general linear models: end-tidal gas, peripheral saturation, and Severinghaus-derived arterial saturation; and a finite impulse response model. Cross-session reproducibility was assessed by region-of-interest intraclass correlation. Results. The paradigm produced robust, condition-specific gray-matter BOLD responses that reproduced across sessions. The Severinghaus-derived saturation regressor generalized significantly better than end-tidal and peripheral regressors under cross-session validation and outperformed the finite impulse response benchmark in 58% of gray-matter voxels. Reproducibility across cortical, subcortical, and brainstem atlases was moderate-to-high (median cortical intraclass correlation 0.71). Conclusion. A combined hypercapnic-hypoxic paradigm yields reproducible voxelwise cerebrovascular reactivity maps at 7 Tesla; Severinghaus-derived arterial saturation is the most generalizable regressor for hypoxic reactivity.

Abstract Background: Long COVID frequently includes post-exertional malaise, neuromuscular fatigue, internal vibrations, tremor-like symptoms, orthostatic intolerance, sleep disturbance, cognitive dysfunction, and autonomic instability. Neuroimaging studies in Long COVID and post-infectious ME/CFS have identified abnormalities across limbic, thalamic, mesiotemporal, brainstem, cerebellar, and white-matter systems, but no single established circuit accounts for this clinical phenotype. We examined whether abnormalities cluster at the mammillary body-fornix-superior tuberal hypothalamic interface and within connected brainstem-cerebellar pathways. Methods: Structural MRI and diffusion tensor imaging were analysed in 88 participants with clinician-diagnosed Long COVID and 34 healthy controls (total N = 122). Thirty-three patients were classified as bedridden. Volumetric and diffusion analyses focused on the mammillary bodies, superior tuberal hypothalamic region, fornix, dorsal and median raphe, midbrain reticular formation, and cerebellar peduncles. Fractional anisotropy was used as an index of white-matter microstructural organisation. Exploratory clinical associations included motor impairment, proprioceptive dysfunction, autonomic symptoms, fatigue, internal vibrations, and tremor-like symptoms. Results: Three mammillary-body volume phenotypes were identified: reduced, enlarged, and control-range. Left and right mammillary-body volumes differed across groups, with large effect estimates. Segmentation showed narrowing or loss of a visible internal passage at the superior tuberal-mammillary interface, while the fornix showed altered diffusion measures and reduced tract coherence in the hypothesised gate region. Additional findings included lower superior cerebellar peduncle volume, lower middle cerebellar peduncle fractional anisotropy, and lower dorsal raphe and midbrain reticular formation volumes in Long COVID. Conclusions: The findings support an exploratory mammillary body-fornix gate model in which a vulnerable periventricular hypothalamic-limbic interface may contribute to network dysfunction in a subgroup of patients with severe Long COVID. The data do not establish direct viral invasion, a coronavirus entry route, axonal destruction, or a single causal pathway. Prospective replication with standardised acquisition, preregistered regions of interest, correction for multiple comparisons, objective movement and autonomic measures, and longitudinal follow-up is required. Keywords: Long COVID; post-COVID condition; ME/CFS; mammillary body; fornix; hypothalamus; diffusion tensor imaging; internal vibrations; tremor-like symptoms; neuromuscular fatigue; dysautonomia; brainstem

Chiari I malformation (CM-I) is conventionally defined by cerebellar tonsil position, yet tonsil position is an indirect surrogate for the anatomic obstruction that impairs cerebrospinal fluid (CSF) flow across the craniocervical junction (CCJ). We hypothesized that CCJ crowding, quantified as subarachnoid space narrowing at the foramen magnum and C1, would explain CSF flow impairment more directly than tonsil position. Using non-invasive low b-value diffusion-weighted MRI (low-b dMRI), we quantified effective CSF motility, indexed by mean pseudo diffusivity (M{psi}), across the upper cervical spine, CCJ, and posterior fossa. Voxel-wise CCJ CSF pseudo-diffusion spatial statistics were integrated with CSF Waterways atlas-based regional analyses. We applied this approach in 81 pediatric and adult participants with CM I to determine how CCJ structural features shape regional CSF dynamics and clinical outcomes. Voxel wise analyses revealed that crowding at the foramen magnum was the dominant structural determinant of reduced intracranial CSF effective motility across the CCJ, basilar cisterns, and fourth ventricular outflow pathways (family-wise error corrected p < 0.05). While lower tonsil position and C1 level crowding were also associated with reduced CSF effective motility across the CCJ and fourth ventricular outflow pathways, but their associations within the basilar cisterns were spatially restricted to regions adjacent to the Liliequist membrane. Atlas-based region-of-interest analyses confirmed that greater foramen magnum crowding was associated with lower M{psi} across multiple basilar cisterns, but with higher M{psi} in the ventral spinal CSF compartment. Mediation analyses indicated that CCJ crowding at the foramen magnum and C1 accounted for the majority of the relationship between tonsil position and reduced CSF motility in the basilar cisterns. Multivariate M{psi} profiles across the CSF regions identified data-driven foramen magnum crowding thresholds of 69.5% and 77.5%, stratifying patients into mild, moderate, and severe physiological crowding groups. Exploratory analyses linked lower pre-operative CSF M{psi} to greater pain-related functional impairment, reduced cognitive function, and a higher likelihood of subsequent decompression surgery. Together, these findings demonstrate that CCJ crowding, particularly at the foramen magnum, exerts a quantifiable, region specific impact on CSF effective motility in CM I, and that low b dMRI provides a sensitive, complementary marker of CSF flow impairment. This integrative CCJ structural and CSF flow imaging framework establishes a mechanistic link between CCJ anatomy, CSF dynamics, and symptom burden, offering a scalable tool for phenotyping CM I and informing clinical decision making.

Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, fatigue and cognitive difficulties, but its underlying mechanisms remain incompletely understood. The uncertainty of the origins of FMS has hampered the development of treatments and diagnostic methods, and the available therapeutic options offer limited relief to patients, an estimated 2-4% of the population. The severe burden of FMS thus represents an urgent unmet clinical need. MicroRNAs (miRNAs), non-coding short RNAs that have vital inhibitory roles in gene expression, have been explored in FMS pathophysiology. MicroRNA signatures associated with FMS may facilitate diagnosis and reveal new insights into the cellular and molecular mechanisms of FMS. We compiled and analyzed publicly available data of dysregulated miRNAs in FMS. MiRNAs were categorized according to the direction of dysregulation (levels up or down in FMS vs health) and compared across studies. Only miRNAs identified as dysregulated in the same direction in at least two studies were included. RNA targets of at least two microRNAs were inferred using TargetScan and subjected to pathway enrichment analysis using Reactome , ShinyGo v.8, miRNA Tissue Atlas 2025 and EnrichR. This analysis revealed enrichment in pathways central to cell signaling and immune function, such as regulation of PTEN, circadian rhythm and RNA metabolic processes. Additionally, the dysregulated miRNAs in FMS were over-represented in immune-related tissues such as lymph node and spleen. Collectively, these findings support a role for immune dysregulation in FMS. By using an integrative approach, we identified candidate pathways and molecular targets that warrant further experimental validation.

Background: Fluctuations in pain intensity are intrinsic to non-specific chronic low back pain (nsCLBP). Nevertheless, pain fluctuations have rarely been considered when investigating pathophysiological mechanisms. Therefore, a novel study protocol was developed and implemented to systematically assess the impact of fluctuating pain states on pain-related measures. Methods: The final study cohort consisted of 45 nsCLBP patients and 47 age- and sex-matched healthy controls (HCs). Patients participated in three visits, conducted during different pain states (i.e. clinically relevant pain, low-intensity clinical pain / pain-free, clinically irrelevant pain induced using a Qutenza 8% capsaicin patch). Pain fluctuations were monitored through online assessments every four days and guided the pseudorandomized visit scheduling. HCs participated in a single visit. Each study visit comprised a multimodal battery of pain-related measures. Results: 93.33% of patients completed all three visit types in a pseudorandomized order (chi-squared=1.50, p=0.826). Visit scheduling was possible due to the high self-report adherence (median=93.48%), unrelated to self-report burden (rho=-0.097, p=0.53). Study visits were conducted during different pain states, as indicated by: i) the significantly higher low back pain intensity in the clinically relevant pain visit (mean[SD]: 3.98[0.90]), compared to the low-intensity clinical pain (1.03[0.86]) and clinically irrelevant pain (1.13[0.82]) visits (p-values<0.001), as well as by ii) the successful induction of a moderate-to-high clinically irrelevant pain across assessments. Conclusion: Despite scheduling complexity and pain state transition uncertainty, a pain state-dependent pseudorandomized study design is feasible and could improve the understanding of nsCLBP mechanisms.

Background: Hearing loss is a potentially modifiable risk factor for brain health, but whether it acts as a causal lever remains unclear. Methods: We constructed an ear-disease comorbidity network from NHANES 2011-2020 (N=18,939, 16 nodes, 62 edges), performed bidirectional Mendelian randomization (MR) across 24 exposure-outcome pairs, and triangulated evidence with longitudinal data from CHARLS (N=17,101). Results: Subjective hearing symptoms (prevalence 6.1%) occupied hub positions in the comorbidity network, whereas objective hearing impairment (8.0%) was sparsely connected. All forward MR estimates were null after multiple-testing correction (IVW P>.05 for 9 of 9 pairs). Reverse MR showed one nominally significant association (cognition to objective hearing beta=-0.15, P=.013) that did not survive correction. Longitudinal analysis yielded HR=1.57 (P=.00004) for subjective hearing symptoms predicting incident depression. Conclusions: Perceived hearing symptoms organize the ear-disease comorbidity network but are not a causal lever for brain health. These findings support a "flag, not lever" framework: subjective hearing symptoms warrant clinical attention as markers of systemic multimorbidity rather than intervention targets for dementia prevention.

Background Spinal manipulation therapy (SMT) is widely used for low back pain (LBP), yet comparative effectiveness findings across trials remain inconsistent. One potential explanation is incomplete separation of treatment-specific effects from natural recovery and placebo response, which may differ between acute and chronic presentations. Methods We conducted a Bayesian hierarchical analysis of 120 randomized controlled trials (298 arms; 19,059 patients) evaluating SMT, exercise, medical management, physical modalities, self-care, and control conditions. Natural history (NH) trajectories were derived from independent observational cohorts and incorporated as external model components. Treatment effects were estimated as deviations from NH, and sham-corrected effects as deviations from control conditions. Results In acute LBP, NH trajectories predicted substantial improvement by 26 weeks. Estimated treatment effects relative to NH were negative across all categories, and sham-corrected effects were near zero, with credible intervals overlapping zero. In chronic LBP, NH trajectories predicted more gradual improvement. Control conditions exceeded NH, consistent with a substantial placebo response. Exercise and SMT demonstrated positive sham-corrected effects with credible intervals excluding zero; however, estimated magnitudes were modest and did not consistently exceed commonly cited thresholds for clinical importance. Higher study quality was associated with smaller estimated effects in chronic trials. Conclusions Modeling natural history as a structural component of treatment response alters estimates of comparative effectiveness in LBP. Improvements observed in acute LBP appear largely consistent with underlying recovery processes, whereas in chronic LBP, contextual and placebo-related effects contribute substantially to observed outcomes. Explicit separation of these components may help reconcile inconsistencies in the literature and inform interpretation of treatment effects.

Purpose: Fibromyalgia involves chronic widespread pain and heightened movement evoked pain (MEP), which can limit access to resistance training's functional and psychological benefits by hindering exercise participation and adherence. This study aimed to determine whether transcutaneous electrical nerve stimulation (TENS) applied during resistance exercise reduces MEP in women with fibromyalgia. Materials and methods: 21 women with fibromyalgia performed 2 sets of 10 leg press repetitions at 60% predicted 1 RM while receiving randomized active TENS (100 Hz) or sham TENS. Pain intensity and unpleasantness (0 to 10 numerical rating scales) were assessed at baseline, immediately post exercise, 15 min post-exercise, end-of-day, and 24h later. Results: Active TENS led to a greater reduction in post-exercise pain than sham, with 90% of participants experiencing at least a 15% decrease in whole body pain 15 minutes post-exercise, compared to none in the sham group. No group differences were observed at the end of the day or 24h after the exercise session. Conclusion: These results suggest that a single session of high frequency TENS during resistance exercise can produce short term reductions in MEP in women with fibromyalgia. While effects did not persist at 24h, these short-term effects may help mitigate acute exercise related pain and support early training adherence.

Background: Temporary 60-day percutaneous peripheral nerve stimulation (PNS) can relieve pain in refractory occipital neuralgia (ON), but whether it alters acute healthcare utilization relative to the natural trajectory of the disease is unknown, because prior studies have lacked a concurrent comparator. Methods: We performed a secondary analysis of prospectively collected data from a tertiary interventional pain center. Adults with medically refractory ON (primary diagnosis occipital neuralgia, ICD-10-CM M54.81) who underwent 60-day occipital PNS (n = 42) were compared with concurrent patients who were clinically eligible for PNS but were denied insurance authorization and continued optimized non-PNS management (usual care; n = 63). Headache-related emergency department (ED) encounters - index (occipital neuralgia) and non-index (other headache/facial-pain diagnoses) - were ascertained over the 12 months before and after the treatment window via the electronic record and the statewide health information exchange. Patients were 1:1 propensity-matched on a priori confounders (age, sex, baseline total headache-related ED utilization, HIT-6, and baseline headache-medication use). The primary analysis was a difference-in-differences (DiD) comparison of the change in headache-related ED utilization, reported as the additive difference (Hodges-Lehmann estimate, distribution-free 95% CI) and, alongside, as a multiplicative rate ratio (RR). Results: Thirty-six matched pairs were well balanced. Baseline headache-related ED utilization was nearly identical between matched groups (6.3 vs. 6.2 visits/year). Over the following year, PNS patients' utilization fell to 2.5 while usual-care patients' rose to 6.9. The DiD was 5.0 fewer headache-related ED visits per patient (95% CI 3.0-6.0; p < 0.001), corresponding to a rate ratio of 0.36 (95% CI 0.27-0.48; p < 0.001). Results were consistent in the full sample, in covariate-adjusted models, and after excluding controls denied for incomplete conservative-therapy trials. The effect was driven by non-index headache visits. Conclusions: Relative to a concurrent, matched usual-care cohort whose headache related ED utilization rose over time, 60-day occipital PNS was associated with a substantial reduction in acute-care use, strengthening the case for a role of PNS on healthcare utilization in refractory ON.

Background: Sleep, pain, affect, cognition and energy (SPACE) has been described as a latent symptom-severity construct in chronic overlapping pain conditions. Its population-level structure and associations with chronic pain interference and functional disability remain uncertain. Methods: We conducted a cross-sectional analysis of UK Biobank participants. Prespecified standardised symptom domains were examined using correlation analysis, principal component analysis, exploratory factor analysis and k-means clustering. Associations with chronic pain interference, current work disability, poor self-rated health and longstanding illness or disability were assessed using covariate-adjusted logistic regression. A four-domain score excluding pain tested whether associations extended beyond the pain domain. Secondary analyses examined convergence with actigraphy, biomarkers, polygenic risk scores and brain magnetic resonance imaging phenotypes. Results: Of 501,935 eligible participants, 475,134 had complete domain data. Domains were modestly intercorrelated (r=0.04-0.46). Clustering identified lower- and higher-burden phenotypes comprising 70.5% and 29.5% of participants; current work disability occurred in 1.3% and 10.3%, respectively. Adding the four non-pain domains increased the area under the curve for chronic pain interference from 0.593 to 0.672 and for work disability from 0.748 to 0.850. Inclusion of pain increased the work-disability area under the curve to 0.863. Multimodal measures added smaller increments. Conclusions: A multidimensional symptom profile was identifiable at population scale and was concurrently associated with chronic pain interference and work disability, with non-pain domains contributing information beyond pain burden alone.

Introduction: This study aimed to characterize the neurochemical profile of Alzheimer s disease (AD) continuum stages using proton magnetic resonance spectroscopy (1H-MRS) data for brain metabolites and macromolecules. We used Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) to classify diagnostic groups and assess feature importance. Methods: Our dataset consisted of 7 T short-echo time 1H-MRS spectra of the posterior cingulate cortex/precuneus of individuals diagnosed with AD (n = 27) or Mild Cognitive Impairment (MCI, n = 27) and Healthy Controls (HC, n = 31). Classification used 100-round Monte Carlo cross-validation based on metabolite concentrations and macromolecular peak intensities. Variable importance in projection (VIP) was assessed across classification models to identify the most relevant neurochemical features. The resulting metabolite rankings were compared with previous literature to evaluate their biological plausibility. Results: Classification was strongest for AD versus HC (AUC=0.88) and lower for comparisons involving MCI. Metabolites contributing most strongly to classification included myo-inositol, ascorbate, and choline-containing compounds, consistent with previous studies on AD-related neurochemical alterations. In addition, specific macromolecular components were identified as relevant features, suggesting a potential contribution of MM signals to the characterization of AD-related neurochemistry. Discussion: These findings support the use of short-echo-time 1H-MRS as a complementary tool for characterizing neurochemical changes in the AD continuum, with potential applications in disease characterization and monitoring, warranting validation in larger cohorts.

Multimodal hypersensitivity (MMH), heightened sensitivity across multiple sensory modalities, is associated with chronic pain risk in adults. How MMH develops across adolescence and whether early pain experiences shape its trajectory remains unknown. The Early Menstrual Pain Impact on Multisensory Hypersensitivity (EMPATHY) study followed 300 premenarcheal adolescents (age M=11.29, SD=0.98 years) across the menarcheal transition with three visits comprising a comprehensive multimodal sensory testing battery: visual and auditory unpleasantness, a non-invasive bladder filling task, pressure pain thresholds, after-pain ratings, cold pain, and conditioned pain modulation. A principal component (PC) analysis of 24 baseline measures (n=214) identified three components accounting for 34.2% of variance: MMH (PC1; 16.5% of variance), a pressure-pain stimulus-response function (PC2; 9.3%), and bladder hypersensitivity (PC3; 8.4%). All experimental measures, and four self-report sensory sensitivity questionnaires projected as supplementary variables, loaded onto PC1, supporting its interpretation as MMH and replicating the component structure previously observed in adult women. Longitudinal trajectories of MMH (n=140) were modeled with linear mixed-effects regression with menstrual pain, pelvic pain, time, and their interactions as predictors, adjusting for pubertal staging. MMH decreased across the menarcheal transition (p=0.029). Pelvic pain (p=1.24x10-6), but not menstrual pain (p=0.205), was positively associated with MMH, independent of time and pubertal development. These findings establish MMH as a measurable, replicable sensory phenotype in early adolescence that covaries with non-menstrual pelvic pain, and position it as a candidate early marker of nociplastic pain risk. Future studies are needed to support interventions and screening for elevated sensory sensitivity before pain becomes clinically entrenched.