Frontiers in Human Neuroscience

BackgroundUnderstanding the associations among biopsychosocial factors is essential for improving research and treatment of chronic low back pain (CLBP). Here we characterized interrelations among biopsychosocial domains using network analysis and identified the most influential features in CLBP. MethodsData came from Quebec Low Back Pain Study, comprising 4,489 CLBP participants. We modeled relationships among baseline biopsychosocial features as networks, where nodes represent features and edges encode statistical or causal dependencies among them. Undirected network was inferred using distance correlation. Directed network was constructed using the Linear Non-Gaussian Acyclic Model, which estimates plausible causal directions. Influence maximization was performed using the Independent Cascade (IC) model to identify the most influential features in each network. ResultsIn the undirected network, physical function and pain interference were the most central nodes, followed by depression. In the directed network, fear of movement, catastrophizing, and widespread pain emerged as key downstream hubs receiving multiple causal inputs, whereas pain interference, physical function, and depression acted as major upstream drivers exerting broad causal influence. IC diffusion simulations further identified pain interference and physical function as the most influential features in the undirected and directed networks, respectively. ConclusionsPain interference, physical function, and depression consistently emerged as key components of the CLBP biopsychosocial network. These features exert causal effects on fear of movement, catastrophizing, and widespread pain, with diffusion analyses confirming their roles as system-wide drivers. Interventions targeting functionality and pain interference, rather than pain intensity alone, may yield broader benefits across psychological and functional domains.

New-onset chronic pain is a common and debilitating symptom of Long COVID (LC) that remains not fully understood in terms of pathophysiology and therapeutic targets. A growing body of evidence in chronic pain syndromes similar to LC demonstrates an association between EEG alpha oscillatory activity and the experience of pain, with clinical studies showing maladaptive changes in oscillatory activity, particularly a slowing of alpha activity. This study aims to investigate the association between EEG alpha oscillatory activity and pain perception in new-onset LC-chronic pain. We recruited 31 individuals (20 females) with a clinical diagnosis of LC reporting new-onset chronic pain and 31 healthy pain-free age-and sex-matched controls. Participants completed questionnaires regarding symptoms and psychological functioning prior to recording eyes-open resting-state EEG. Peak alpha frequency (PAF) and spectral power within the alpha band (8-13 Hz) were extracted from EEG signals. Lower PAF over the posterior scalp region was significantly associated with higher LC-chronic pain severity when controlling for age and depression. This observation was consistent across PAF estimation methods. PAF was significantly increased, particularly in the posterior region, in the moderate pain LC subgroup compared to both severe pain subgroup and controls, while alpha power did not differ between the three groups and was not associated with pain severity. Our findings highlight associations between PAF and pain symptoms in a new post-infection chronic pain syndrome. PAF can thus be explored as a potential biomarker and therapeutic target for EEG-based neuromodulation interventions in LC-chronic pain. These results may have implications for other similar chronic pain syndromes. SummaryLower resting-state EEG peak alpha frequency in posterior scalp region is associated with higher severity of new-onset Long COVID chronic pain.

In this randomized, double-blind, controlled trial of 8 weeks of repetitive transcranial magnetic stimulation (rTMS) for chronic pain, we compared the classic primary motor cortex (M1) rTMS with a novel target-selection strategy based on pre-therapy cortical connectivity. Guided by principles of homeostatic plasticity, we tested whether stimulating the cortical site with the lowest pre-therapy global connectivity would be more effective than two active comparators: stimulating the site with the highest pre-therapy global connectivity or stimulating M1 independent of connectivity. Before starting rTMS treatment, TMS-evoked EEG potentials were recorded from four cortical targets: M1, the dorsolateral prefrontal cortex, the anterior cingulate cortex, and the posterosuperior insular cortex. For each target, global connectivity was quantified using a distance-weighted, phase-based index (debiased weighted phase lag index, wPLI) derived from pre- and post-TMS-evoked EEG activity, capturing both the magnitude and spatial extent of TMS-induced oscillatory phase locking across cortical regions. Target allocation in the Low- and High-Connectivity groups was based on this global connectivity measure. Ninety patients with chronic pain were randomized to Low-Connectivity, High-Connectivity, or Classic-M1 groups. Treatment consisted of 12 rTMS sessions delivered over 8 weeks to the assigned target. The primary outcome was the proportion of patients achieving [≥] 30% reduction in pain intensity. Secondary outcomes included continuous change in pain intensity, pain interference, sleep, fatigue, mood, quality of life, and patient global impression of change. No between-group differences were observed for primary or secondary outcomes (p > 0.05). In prespecified exploratory analyses, we examined whether pre-therapy local connectivity (within-target wPLI) predicted treatment response. In the Classic-M1 group, lower pre-therapy local M1 connectivity was associated with a greater reduction in pain intensity (r = 0.50, p = 0.005). This association was not observed in the Low- or High-Connectivity groups. A regression model including group-by-connectivity interaction indicated that the relationship between local connectivity and pain reduction differed between the Classic-M1 and High-Connectivity groups (p = 0.038). The results of this clinical trial showed that connectivity-based target allocation using global connectivity did not improve clinical outcomes. However, lower local M1 connectivity was associated with greater pain reduction following Classic-M1 stimulation, suggesting that local M1 connectivity may serve as a potential biomarker of response.

Resting-state electroencephalography (EEG) has been proposed as a scalable source of biomarkers for chronic pain, but its clinical potential remains uncertain. To systematically evaluate this potential, we benchmarked nine modeling strategies, spanning conventional machine learning with handcrafted features to state-of-the-art deep learning. Across 72 configurations of signal representations and model architectures, we trained models to predict self-reported pain intensity, using chronological age decoding as a positive control. Pain prediction performance was limited (R=0.15), with the best results achieved by conventional connectivity-based models. In contrast, age was robustly decoded from the same dataset (R=0.53), confirming technical efficacy. These findings indicate that resting-state EEG contains limited information about inter-individual differences in chronic pain intensity, making it unlikely to yield clinically actionable biomarkers in cross-sectional settings. Instead, its potential may lie in intra-individual modeling of pain dynamics, which could advance individualized mechanistic insights and more personalized treatment of chronic pain.

IntroductionChronic pain in fibromyalgia may be driven by abnormal ongoing activity in a subclass of C-fibre nociceptors known as Type1B or CMi nociceptors. As is common in C-nociceptor microneurography studies, the modest patient numbers in these prior studies generate large confidence intervals around the point estimate of the prevalence of this abnormal activity. This complicates the interpretation of the relative importance of this ongoing nociceptor activity as a pain generating mechanism in fibromyalgia. The study aims to improve precision via an adaptive Bayesian protocol that maximises the yield and quality of data collection whilst minimising patient burden. MethodsThe study employs an optimised microneurography protocol with an adaptive study design. The microneurography protocol incorporates early identification of CMi nociceptors via an abbreviated activity dependent slowing protocol to increase yields enabling efficient collection of the primary outcome data. The adaptive study design will use Bayesian principles to iteratively assess the predictive probability of futility, and terminate early if there is high confidence that the hypothesis is false. Furthermore, the study will employ questionnaires to explore links with pain in the area under study to the electrophysiology data. Finally, quantitative sensory testing will be used to investigate whether the irritable nociceptor phenotype is associated with abnormalities in CMi nociceptor physiology. Ethics & DisseminationThis study has received HRA REC approval in the UK. Participants will provide written informed consent, and may withdraw at any time without consequence. At the end of the study, the results will be disseminated through peer-reviewed publication, and the data made available via a data repository. Strengths & limitations of this studyBayesian predictive probability of futility to minimise patient burden in microneurography Microneurography for objective interrogation of the peripheral nervous system Optimised microneurography protocol to efficiently answer primary hypotheses Subjective elements of early termination criteria of the study assessed and co-developed with Patient and Public Inclusion and Engagement Group

BackgroundPersistent Spinal Pain Syndrome (PSPS) type II represents a challenging clinical entity with limited therapeutic options. Various spinal cord stimulation (SCS) modalities have emerged as potential treatments, but their comparative effectiveness remains unclear. ObjectiveOur goal in this paper is to systematically evaluate and compare the efficacy of different SCS modalities in patients with PSPS type II through meta-analysis of available randomized controlled trials. Evidence ReviewWe conducted a systematic review following PRISMA guidelines, searching major databases for randomized controlled trials evaluating SCS modalities in PSPS type II patients until the end of May 2025(search updated on October 3rd). Primary outcomes included pain intensity (VAS) and functional disability (ODI) at 6 and 12 months. Subgroup analyses compared tonic versus burst stimulation and high-frequency versus low-frequency SCS. FindingsNine randomized controlled trials were included, encompassing 565 patients across different SCS modalities. For the primary outcome of clinically meaningful pain relief ([&ge;]50% reduction), pooled analysis demonstrated that 45% (95% CI: 18-75%, I{superscript 2} = 92.2%) of patients achieved this threshold for back pain and 55% (95% CI: 45-65%, I{superscript 2} = 0%) for leg pain. Subgroup analysis revealed significant differences in back pain responder rates by stimulation modality: High-frequency SCS demonstrated responder rates of 92% (95% CI: 79-98%) versus 28% (95% CI: 13-49%) for conventional frequencies (p < 0.001). For leg pain, no significant difference was observed between tonic (51%, 95% CI: 37-65%) and burst stimulation (60%, 95% CI: 45-74%, p = 0.36) and mean VAS scores demonstrated significantly lower pain with high-frequency SCS (13.30, 95% CI: 8.82-17.78) compared to conventional frequency (28.42, 95% CI: 24.02-32.88, p<0.0001). For back pain, mean VAS scores decreased from a baseline of 73.03 to 41.67 (95% CI: 36.12-47.22, I{superscript 2}=22.8%) at 6 months and remained stable at 35.66 (95% CI: 25.39-45.93, I{superscript 2}=75.0%) at 12 months. Leg pain showed more pronounced improvement, with VAS scores declining from a baseline of 61.81 to 23.75 (95% CI: 17.69-29.81, I{superscript 2}=78.8%) at 6 months and 29.16 (95% CI: 24.81-33.52, I{superscript 2}=0%) at 12 months). Meta-regression identified longer pain duration and older age as positive predictors of response, while higher baseline leg pain predicted lower responder rates. Serious adverse events occurred in 10%, with a 16% revision surgery rate. Only two studies demonstrated a low risk of bias across all domains. ConclusionsCurrent evidence demonstrates that various SCS modalities provide clinically meaningful pain relief in PSPS type II patients, with approximately half achieving [&ge;]50% pain reduction. High-frequency SCS shows significantly superior responder rates for back pain compared to conventional tonic stimulation, while burst stimulation yields significantly superior reductions in continuous pain intensity metrics. However, the limited number of studies, substantial heterogeneity, and lack of head-to-head comparisons prevent definitive recommendations regarding optimal stimulation parameters. Future large-scale randomized trials with standardized protocols and responder-based outcomes are needed to establish evidence-based treatment algorithms for PSPS type II patients.

BackgroundArthroscopic release for elbow stiffness is considered a minimally invasive and effective treatment. However, the extent to which each intraoperative step contributes to improvement in range of motion (ROM) has not been well investigated. PurposeTo sequentially evaluate the relationship between intraoperative surgical steps and changes in elbow ROM during arthroscopic release for severe elbow stiffness, and to identify the key procedural stage contributing most significantly to ROM improvement. MethodsFive elbows in five patients with severe elbow stiffness following fracture or dislocation were retrospectively reviewed. Arthroscopic release was performed using a stepwise posterior-based approach, starting from the posterior soft-spot portal, followed by exposure of the olecranon fossa and progression into the posteromedial compartment. Changes in elbow ROM were assessed at each intraoperative step, and ROM at final follow-up was also evaluated. ResultsAll patients demonstrated improvement in elbow ROM at final follow-up. Intraoperative ROM improvement did not occur in a continuous manner but rather in a stepwise fashion. Gradual improvement was observed with establishment of the posterior and posteromedial working spaces, followed by the most substantial increase in ROM immediately after release of the soft tissue attached to the posterior aspect of the humeral medial epicondyle. Although the maximum ROM achieved intraoperatively was not fully maintained at final follow-up, no patient experienced deterioration to preoperative ROM levels. ConclusionsIn arthroscopic release for severe elbow stiffness, improvement in elbow ROM occurs in a stepwise rather than continuous pattern. Release of the posteromedial structures attached to the posterior aspect of the humeral medial epicondyle may represent a critical turning point contributing significantly to ROM improvement.

BackgroundReverse total shoulder arthroplasty (rTSA) is an increasingly common surgical procedure often performed to treat pain related to glenohumeral osteoarthritis or to rotator cuff arthropathy. Although surgical outcomes are generally excellent, recent evidence has found that postoperative pain ([&ge;] 3/10) two years following surgery is reported by an estimated 18% of patients. Recently, the NIH Acute-to-Chronic Pain Signatures program recommended longitudinal studies using select biomarkers to describe and predict individual patient responses to surgery. These data are not yet available for rTSA procedures. MethodsThis was a longitudinal cohort study performed at a single academic medical center. Twenty participants undergoing rTSA surgery were included, recruited from a tertiary hospital system in the southern United States. The first objective of this study was to describe changes in general pain intensity (Numerical Pain Rating Scale), widespread body pain, anxiety (General Anxiety Disorder-7), depression (Patient Health Questionnaire-9), neuropathic pain symptoms (painDETECT), and quantitative sensory testing from baseline to 6 weeks following rTSA. The second objective was to identify the baseline demographic and pain-related factors associated with 6-week postsurgical improvements in pain intensity. ResultsFrom before to after surgery, our cohort demonstrated significant improvement in shoulder pain intensity, widespread body pain, PainDETECT score, and temporal summation magnitude measured at the surgical deltoid. Degree of 6-week pain intensity improvement was associated with baseline pain intensity (F=18.79, p=0.0004) and temporal summation magnitude of the tibialis anterior (F=5.06, p=0.0380). ConclusionsPain intensity, location, nature, and mechanism can serve as biomarkers of the short-term postsurgical changes that can be expected following rTSA. Baseline pain intensity and temporal summation magnitude of the tibialis anterior were associated with the degree of pain improvement, suggesting their use for preoperative risk assessment. Future research should evaluate whether these 6-week biomarker changes are associated with the development of chronic postoperative pain at longer durations after surgery. Level of EvidenceLevel I, Prognostic Study

IntroductionPatients undergoing anterior cruciate ligament (ACL) reconstruction experience substantial postoperative pain, which delays recovery and leads to both immediate and long-term opioid use. In other knee procedures, infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) has demonstrated analgesic and opioid reducing effects. However, the effect in patients undergoing ACL reconstruction has not been investigated. We aimed to investigate the real-world effect of IPACK in patients undergoing ACL reconstruction on immediate postoperative opioid consumption. ParticipantsIn this single-centre difference-in-differences cohort study, all patients who underwent ACL reconstruction surgery at Bispebjerg Hospital, Denmark, from 1 February 2024 to 30 June 2025 are included. The study further includes a similar reference cohort, comprising all patients who underwent trochleaplasty, Elmslie-Trillat, or medial patellofemoral ligament reconstruction during the same period, and at the same hospital. InterventionThe primary exposure is the implementation of IPACK as part of perioperative management for ACL reconstruction on 1 January 2025. The IPACK was performed under ultrasound guidance, immediately before surgery, administering 20 mL of ropivacaine 0.5% between the popliteal artery and the posterior knee capsule. OutcomesThe primary outcome is the cumulative opioid consumption from surgical incision to 2 hours postoperatively. Secondary outcomes include the cumulative opioid consumption from incision to 24 hours postoperatively, the worst reported pain score at 0-24h postoperatively, occurrence of postoperative nausea or vomiting (PONV) 0-24h postoperatively, length of PACU stay, length of hospital stay, and nerve injuries. As an exploratory outcome, carbon dioxide emissions will be investigated. Statistical analysisThe main analysis will be a standard two-way fixed effects DiD regression assessing the changes occurring at the time of implementation of IPACK in the ACL cohort, with adjustment for the underlying time trend. Continuous outcomes are reported as mean difference (95% confidence interval [CI]), and binary outcomes as absolute and relative risks (95% CI).

BackgroundTotal knee arthroplasty (TKA), partial knee arthroplasty (pKA), and arthroscopic meniscectomy are among the most commonly performed procedures for knee osteoarthritis and degenerative meniscal tears in the United States, yet concerns persist regarding overuse, variable clinical benefit, and high costs. Orthobiologic treatments, including platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC), have emerged as less invasive alternatives, but downstream health care resource use (HCRU) and costs associated with these treatments relative to surgery are not well established. MethodsWe conducted a retrospective, observational cohort study using linked commercial insurance claims data and a national orthobiologic treatment registry to compare downstream HCRU and costs following orthobiologic versus surgical treatment of knee conditions. Two comparisons were evaluated separately: (1) PRP versus arthroscopic meniscectomy among patients with degenerative meniscal pathology and minimal osteoarthritis, and (2) BMAC with or without PRP versus TKA or pKA among patients with knee osteoarthritis. Eligible procedures occurred between 2016 and 2023. Propensity score matching was used to balance demographic and clinical confounders. Co-primary outcomes were total health care costs at 12 and 24 months post-procedure, with exploratory analyses at 36 and 48 months. Costs were estimated using multiple approaches, including Medicare-based estimates, commercial payer estimates, and aggregate allowed amounts. HCRU outcomes included outpatient visits, physical therapy, imaging, opioid use, repeat injections, and subsequent surgery. ResultsAfter matching, analyses included 167 PRP-treated patients matched to 1,670 meniscectomy patients and 165 BMAC/PRP-treated patients matched to 1,650 TKA/pKA patients, with good balance across pre-specified confounders. Progression to subsequent surgery after orthobiologic treatment was rare at 12 and 24 months in both cohorts. Compared with TKA/pKA, BMAC/PRP was associated with lower overall health care use for several services, including outpatient visits, physical therapy, knee radiographs, and opioid prescriptions, although magnetic resonance imaging was more frequent following orthobiologic treatment. Total costs at 12 and 24 months were consistently higher for TKA/pKA than for BMAC/PRP across all costing methods. In the PRP versus meniscectomy comparison, differences in health care use were modest, and costs were similar or lower for PRP depending on the costing approach. Exploratory analyses through 48 months showed similar patterns, with persistently low rates of subsequent surgery after orthobiologic treatment and generally higher cumulative costs following surgical intervention. ConclusionsIn this real-world, propensity-matched analysis of commercially insured patients, orthobiologic treatments with PRP or BMAC were associated with similar or lower downstream health care costs compared with commonly performed surgical alternatives for selected patients with degenerative meniscal tears or knee osteoarthritis. Progression to surgery following orthobiologic treatment was uncommon through two years and remained low in longer-term exploratory analyses. These findings support the consideration of orthobiologic therapies as potentially lower-cost alternatives to surgery for appropriately selected patients and may inform shared decision-making and payer policy.

BackgroundThe cognitive demands of medical education require optimal learning environments. While the influence of background music on cognition has been widely studied, existing research exhibits a significant Eurocentric bias, predominantly focusing on Western classical music like the "Mozart Effect." This leaves a critical gap in understanding the impact of culturally salient, non-Western musical traditions on learning within their native contexts. MethodsA single-blind, randomized controlled trial was conducted with 147 clinical (4th, 5th and 6th) year medical students stratified by ethnicity at the Faculty of Medicine, Nnamdi Azikiwe University, Nnewi Campus, Anambra State, Nigeria between March and September 2025. Participants were randomly assigned to one of three background music conditions: Igbo Highlife (instrumental), Western classical (Mozarts Sonata K.448), or silence (control with pink noise masking). Cognitive performance was assessed through a short-term memory recall test of 20 medical terms and a timed clinical problem-solving task comprising 20 multiple-choice questions. Baseline mood was controlled for using the Positive and Negative Affect Schedule (PANAS). Data were analyzed using ANOVA and post-hoc Tukey HSD tests. ResultsMusic condition had a highly significant effect on student performance (p < 0.001). The Igbo Highlife group demonstrated superior outcomes, achieving the highest scores in memory recall (mean = 16.7) and problem-solving accuracy (mean = 15.7), alongside the fastest completion time (23.4 seconds/question), significantly outperforming both the classical and silence groups. A significant correlation was found between cultural familiarity with Highlife and enhanced cognitive performance (accuracy: {rho} = 0.268, p = 0.001). ConclusionsIncorporating music that holds cultural significance and familiarity to learners, specifically Igbo Highlife, is a highly effective auditory stimulus for enhancing learning efficiency in medical education. Students and educational institutions should consider integrating culturally familiar instrumental music into study environments to optimize cognitive performance and learning outcomes. Competing Interest StatementThe authors have declared no competing interest.

BackgroundArthroscopic rotator cuff repair (RCR) is a common surgical intervention used to address rotator cuff-related pain after other conservative interventions have been exhausted. With a continuing increase in procedures, evidence-based outcomes research is needed to identify key parameters of postoperative rehabilitation planning. ObjectiveWe aim to identify rehabilitation planning factors leading to better outcomes while also providing clinicians with reference data to describe the magnitude of pain and functional improvement following RCR. MethodsFor this observational study of patients undergoing RCR surgery and physical therapy, demographic variables and patient-reported outcome measures (PRO) were collected preoperatively and up to 12 months postoperatively Four multiple linear regression models were created, one for 12-month Visual Analog Scale (VAS) score, the second for VAS improvement, the third for 12-month American Shoulder and Elbow Surgeons (ASES) function score, and the fourth for ASES function improvement. ResultsThe 29 participants had a median age of 62 years, median baseline VAS of 4.9, ASES composite score of 45, and Veterans-Rand 12 Mental Component Score of 53.5. In univariate analysis, one variable was associated with 12-month VAS score and two were associated with 12-month VAS improvement. No associations were found with 12-month ASES function score, and one variable was associated with ASES function improvement. With our sample, multivariable analyses provided no significant association or predictor for VAS or ASES function scores. ConclusionsOur hypothesis was not supported, and we did not find an association between physical therapy wait time prior to evaluation or visit frequency and PRO measures or improvements. We observed that 12-month PRO measures and improvements can be predicted using baseline measures among this population.

The neural signature of rhythm and tempo remains difficult to study in both humans and non-human primates. Here we recorded from the motor cortex of human participants implanted with intracortical microelectrode arrays while they performed a series of rhythmic tapping tasks. We found that rhythmic tapping elicited low-dimensional rotational neural dynamics whose radii varied in a tempo-dependent manner and axes related to kinematic properties. Moreover, we observed a spectrum of kinematic and neural behavior as participants shifted from low tempo punctuated taps to high tempo smoother, continuous taps. Surprisingly, we observed that tactile feedback strengthened the rotational dynamics despite reduced kinematic range. Moreover, while tempo preparation did not produce dynamics of their own, motor cortex encoded it in an orthogonal dimension. Finally, we found that switching tempos was achieved with smooth neural transitions that could only be separated in higher dimensions. These results show that motor cortex directly encodes a multitude of rhythm related features.

BackgroundDystonia is a debilitating movement disorder that is difficult to assess when co-existing with spasticity, as is typical in cerebral palsy (CP). Querying caregivers about their childrens movements is known to increase clinical dystonia identification. However, beyond identification, determining whether dystonia is the predominant vs. accompanying movement feature in a child with CP can guide clinical decision making, particularly regarding surgical candidacy. ObjectiveTo determine whether caregivers movement descriptions differed between children with predominant dystonia, predominant spasticity with accompanying dystonia, and predominant spasticity without dystonia. MethodsIn this cross-sectional study, we used conventional content analysis to codify caregivers descriptions of triggered involuntary movements in children with CP seen in a tertiary care CP center between 4/2023 and 12/2024. Movement feature frequencies were compared across tone types using Chi-square tests with Bonferroni corrections for multiple comparisons. ResultsOf 180 children with CP (mean age 9.2, 47.8% male), caregivers of children with predominant dystonia (50/180, 27.8%) more frequently described movements triggered by negative emotions (p<0.002) and affecting their back, trunk, and whole body (p<0.04). Caregivers of children with predominant spasticity with dystonia (99/180, 55.0%) more frequently described movements affecting a single limb (p<0.04). Caregivers of children without dystonia (31/180, 17.2%) described movements as being slight or small (p<0.008). These differences persisted even for caregivers unaware their child had dystonia (77/149, 51.6%). ConclusionsCaregivers movement descriptions differ between children with different combinations of dystonia and spasticity, which may help inform clinical management and guide communication with families about dystonia.

Oscillatory coupling between respiration, heart rate, and cortical function is fundamental to physiological regulation yet remains poorly characterized in humans. Diminished respiratory heart rate variability (RespHRV)--the rhythmic heart rate modulation accompanying respiration--has emerged as a transdiagnostic biomarker of mental and physical health, reduced in anxiety, depression, cardiovascular disease, and aging (Beauchaine & Thayer, 2015; Menuet & Gourine et al., 2025). However, the cortical substrates that coordinate rhythmic cardiovascular-respiratory coupling are not well understood. Our current findings highlight the involvement of the left orbitofrontal cortex (OFC) in oscillatory cardiorespiratory dynamics. In adults aged 50-70 (N = 55; mean age = 60.1 {+/-} 6.0 years; 29 female), across both a slow-paced breathing condition and a random-paced breathing condition, greater heart rate oscillatory power during 9-week breathing training sessions predicted OFC volume increases. OFC changes were most strongly linked with upper low-frequency range power during practice (0.09-0.13 Hz; p < 0.005, cluster-corrected) but were not tightly constrained by precise breathing frequency. These effects covaried with improved attentional and executive performance, including reduced pupil responses to distractors and enhanced working-memory and associative-memory scores. Our findings identify the orbitofrontal cortex as a key site of cortical plasticity linked to rhythmic cardiovascular-respiratory engagement. By delineating how oscillatory body-brain coupling supports cognitive control-related processes, including attentional filtering and memory updating, this work bridges mechanistic neuroscience and translational intervention science, suggesting a frequency-general pathway through which simple breathing practices may enhance neurovisceral integration and cognitive resilience in aging. SummaryO_LIGreater oscillatory heart rate power during breathing training, particularly within the upper low-frequency range (0.09-0.13 Hz), predicted increases in left orbitofrontal cortex (OFC) volume. C_LIO_LIOFC volume increases were associated with improved attentional and executive performance, including reduced pupil reactivity to distractors and enhanced working-memory and associative-memory scores. C_LIO_LIThese findings suggest that rhythmic cardiovascular-respiratory coupling supports cortical plasticity and cognitive resilience, providing a frequency-general mechanism through which breathing practices enhance neurovisceral integration in aging. C_LI

PurposeTo investigate the effects of morning and evening narrowband blue light exposure on axial length, and to examine the short-term effect of morning blue light combined with myopic defocus on axial length. MethodsFor objective 1, 18 individuals underwent 60 minutes of narrowband blue light exposure (460nm) in the morning (9:00-11:00AM) and evening (5:00-7:00PM) of the same day. The axial length values were normalized to the average of the morning and evening axial length values. For objective 2, 27 young adults were exposed to 60 minutes of narrowband blue light and broadband white light while wearing a +3.00 D lens over the right eye. Axial length was measured using Lenstar LS900. ResultsA significant reduction in axial length was observed after exposure to morning blue light compared to evening blue light (-10.0{+/-}3.96{micro}m vs.-0.67{+/-}3.30{micro}m; p=0.02), whereas no such effect was observed with broadband white light exposure (0.0{+/-}3.53 {micro}m vs. -2.50{+/-}4.23{micro}m, p=0.70). While the broadband white light exposure did not alter the normal diurnal variation in axial length (+2.35{+/-}1.82{micro}m vs.-6.25{+/-}2.21{micro}m, p=0.04), blue light diminished such a pattern (-4.12{+/-}1.72{micro}m vs. - 2.00{+/-}2.00{micro}m, p=0.48). The myopic defocus did not influence axial length under either narrowband blue or broadband white light conditions. ConclusionThe short-term narrowband blue light exposure led to a significant decrease in axial length in the morning than evening exposure, with a likely influence on the diurnal rhythm of axial length. Morning blue light exposure with lens-induced myopic defocus did not provide additional short-term modulation of axial length.

BackgroundOscillations underpin a large spectrum of brain function. Brain oscillations are altered by neuromodulation approaches including deep brain stimulation (DBS), but a mechanistic understanding of the brain oscillation - DBS interaction is missing. DBS is predominantly used in the treatment of Parkinsons disease. DBS can induce or alter pre-existing narrow frequency band gamma oscillations at half the stimulation frequency. Such half-harmonic responses have been interpreted as entrainment of endogenous oscillations by an exogenous oscillator with an associated Arnold tongue structure. However, half-harmonic responses are not exhibited by all patients. MethodsHere, a Wilson-Cowan model of subcortical neuronal populations is used to set out a broad theoretical framework explaining the heterogeneity of observed responses. ResultsIn the absence of stimulation, the model exhibited either damped oscillations or self-sustained oscillations, depending on parameter values. Off-stimulation behaviour determined observed stimulation response. When oscillations were strongly damped, the only observed response was a driven oscillation at the stimulation frequency. When off-stimulation oscillations were weakly damped, additional half-harmonic responses occurred for sufficiently large amplitude stimulation. When self-sustained oscillations were present they were entrained by the stimulation frequency leading to harmonic, half-harmonic and many other subharmonic responses. Varying stimulation amplitude highlighted hysteresis with the onset and offset of half-harmonic responses appearing at different thresholds. Such two-threshold systems present challenges for adaptive control systems. ConclusionsThis framework captures observed heterogeneity and will help guide future therapeutic practices and the development of adaptive neuromodulation techniques for more effective promotion of physiological rhythms and suppression of abnormal rhythms.

Osteoporosis is a silent yet debilitating disease that often remains undetected until fractures occur. While early prediction is crucial, most studies combine male and female datasets to train a single model, introducing bias since osteoporosis risk and progression differ by gender. This study aims to develop gender-specific machine learning models that leverage longitudinal data to predict osteoporosis risk, providing tailored insights for men and women. Data were obtained from two large longitudinal cohorts: the Study of Osteoporotic Fractures (SOF) for women and the Osteoporotic Fractures in Men Study (MrOS) for men. Multiple ML algorithms were trained and evaluated for each sex, with model performance assessed using the area under the receiver operating characteristic curve (AUC-ROC). Among the tested models, the XGBoost model demonstrated the best performance for women, achieving an AUC-ROC of 0.93 using SOF data. For men, the Random Forest model achieved an AUC-ROC of 0.89 using MrOS data. Feature importance analysis identified sex-specific osteoporosis risk factors, underscoring the need for tailored prediction and management. By revealing male and female risk factors and reducing bias from combined datasets, the work advances personalized care and supports earlier, effective clinical intervention to prevent fractures and improve health outcomes.

Background and objectives STXBP1-related disorder (STXBP1-RD), caused by pathogenic variants in the STXBP1 gene, is a rare neurodevelopmental condition, characterized by early-onset seizures, developmental delay, intellectual disability (ID), and prominent motor dysfunction. Despite the high prevalence of motor symptoms, systematic gait characterization remains limited. We therefore aimed to quantitively assess gait in individuals with STXBP1-RD. Methods In this cross-sectional study, we included ambulatory patients aged 6 years or older with genetically confirmed STXBP1-RD. Instrumented 3D Gait Analysis (i3DGA) was performed to objectively quantify gait. Functional mobility was assessed with the Functional mobility scale (FMS) and Mobility Questionnaire 28 (MobQues28). Caregiver health-related quality of life was evaluated using the PedsQL-Family Impact Module (PedsQL-FIM). We explored associations between gait, functional mobility, STXBP1-variant type and clinical features (ID, age at seizure onset, seizure frequency, age at onset of independent walking). Correspondence between i3DGA and the Edinburgh Visual Gait Score (EVGS), an observational gait assessment, was investigated. Results Eighteen participants were included. Compared to typically developing peers, individuals with STXBP1-RD had significantly reduced walking speed, step and stride length. Gait patterns were highly variable, with the most frequent pattern being an externally rotated foot progression angle (FPA), present in 11/18 participants. At home, 93.75% of the participants (16/18) walked independently, yet community mobility was more variable: 11/16 (68.75%) walked independently, 2/16 (12.50%) with aid and 3/16 (18.75%) used a wheelchair, indicating increasing limitations with distance and environmental complexity. Earlier acquisition of independent walking strongly predicted later unassisted ambulation at community level (p<0.001). Median MobQues28 score was 57.14% and median PedsQL-FIM score was 60.42%, indicating a moderate level of mobility limitations and reduced health-related quality of life of caregivers. EVGS was highly positive correlated with i3DGA (p= 0.001). Discussion Quantitative gait analysis in individuals with STXBP1-RD demonstrates heterogenous kinematic deviations, with an externally rotated FPA emerging as the most common pattern. Age at independent walking was a clinically relevant predictor of later functional mobility. EVGS showed strong correspondence with i3DGA and may offer a more practical, semi-quantitative assessment for broader use. These findings inform clinical decision-making and guide the selection of scalable outcome measures for natural history studies and interventional trials.

IntroductionTraditional bone-setting remains a culturally significant healthcare practice in low- and middle-income countries, particularly in regions like Sudan where modern orthopedic services are often inaccessible or unaffordable .This study examines the role of traditional healing practices in orthopedic care in White Nile State, Sudan, assessing patient perceptions, treatment effectiveness, and sociocultural factors influencing healthcare choices. MethodsA cross-sectional analytical study was conducted among 147 patients, 7 traditional healers, and 4 orthopedic practitioners in urban and rural areas of White Nile State. Data were collected using structured questionnaires and interviews, focusing on treatment preferences, perceived effectiveness, and barriers to integration. Descriptive and inferential statistics were used to analyze quantitative data, while thematic analysis was applied to qualitative responses from healers and practitioners. ResultsFractures (45.6%) and arthritis (23.1%) were the most common orthopedic conditions. 30.6% of patients initially sought traditional treatment, all eventually utilized modern care (medication 71.4%, surgery 42.9%). Traditional healing was perceived as somewhat effective by 40% of users, whereas 59.9% rated modern care as very effective. Key factors influencing treatment choices included cultural beliefs (29.9%), accessibility (18.4%), and cost (16.3%). No significant demographic associations were found with treatment preference or effectiveness (p > 0.05). Traditional healers predominantly treated dislocations (100%) and fractures (71.4%) using manual techniques, with 57.1% referring complex cases to modern practitioners. Barriers to collaboration included lack of communication (85.7% of healers) and differing treatment philosophies (50% of practitioners). ConclusionThis study highlights the persistent dual reliance on traditional and modern orthopedic care in Sudan, with modern treatments perceived as more effective yet traditional methods remaining culturally entrenched especially in rural areas. The path forward requires bridging these systems through mutual respect, shared protocols, and community engagement to ensure safe, equitable, and effective musculoskeletal care for all Sudanese patients.