Pain

Background: Transcranial temporal interference stimulation (tTIS) is an emerging noninvasive neuromodulation approach that enables focal, frequency-specific modulation of deep brain regions, offering a novel method for investigating therapeutic mechanisms underlying brain and mental health disorders. Pain is a key target because it is a feature of multiple disorders and is increasingly understood to depend on brain circuits. Here, we tested the effects of tTIS on bilateral evoked pain, capitalizing on converging evidence from human and animal studies indicating that the primary motor cortex (M1) contains body-wide inter-effector regions and has descending projections to regions implicated in nociceptive, motivational, and autonomic processing, making it a key cortical target for pain modulation. Methods: We conducted a pre-registered, triple-blind, randomized crossover study (N = 32, 160 study sessions), investigating frequency-dependent effects of tTIS applied to the left M1 on experimentally evoked thermal pain in healthy adults. We tested four stimulation frequencies (10 Hz, 20 Hz, 70 Hz, and sham) on separate days (>10,000 pain trials total). Noxious heat was applied to both the right and left forearms using individually calibrated temperatures both pre- and post-stimulation. Results: Active tTIS produced significant analgesia at all stimulation frequencies (10 Hz, 20 Hz, and 70 Hz) relative to sham (Cohens d = 0.46-0.82, all p < 0.05). 10 Hz produced the greatest reduction (d = 0.82), and both 10 Hz and 20 Hz produced more analgesia than 70 Hz (d = 0.44 and 0.38, respectively; p < 0.05). Stimulation-related sensations were equivalent across frequencies, and participants were blind to condition. Pain reductions remained stable over a [~]40-min post-stimulation period and were bilateral, consistent with stimulation of body-wide inter-effector regions. Conclusions: These results provide the first evidence that tTIS can reliably reduce experimental pain perception in humans in a frequency-dependent manner, providing a foundation for noninvasive pain modulation with tTIS.

Pain captures attention and interferes with executive and motor processes but task performance may be preserved at the cost of more effort. In a preregistered fMRI study, 40 participants performed a visuomotor force-matching task at two force levels under individually calibrated painful or non-painful thermal stimulation, while reporting the intensity of perceived effort. Maintaining task performance under pain was associated with increased perceived effort and recruited brain regions involved in pain modulation and cognitive control. Region-of-interest analysis showed perceived effort was consistently linked to decreased anterior midcingulate cortex activity, whereas supplementary motor area contributions varied depending on its role in motor execution or pain processing. Across experimental condition, motor, pain-modulatory and cognitive-control regions were associated with effort perception. Independently of condition, effort perception was modulated by ventromedial prefrontal cortex and ventral striatum. These findings indicate that effort perception reflects brain activity within areas involved in motor, executive and valuation processes.

STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSSexual dysfunction can occur after midurethral sling (MUS) and transvaginal prolapse surgery. It remains unclear whether these procedures impact the clitoris, despite its role in sexual function and proximity to the MUS and vagina. ObjectivesTo compare postoperative sexual function and clitoral features by MUS and vaginal surgery approach after transvaginal prolapse repair with/without concomitant MUS. DesignCross-sectional ancillary study of magnetic resonance imaging (MRI) and sexual function data from the Defining Mechanisms of Anterior Vaginal Wall Descent study. SettingEight clinical sites in the US Pelvic Floor Disorders Network. Participants: 88 women with uterovaginal prolapse who underwent vaginal mesh hysteropexy or vaginal hysterectomy with uterosacral ligament suspension with/without MUS between 2013-2015. Data were analyzed between September 2021-June 2023. ExposuresBetween June 2014-May 2018, participants underwent pelvic MRI 30-42 months after surgery, or earlier if reoperation was desired. Sexual activity and function at baseline and 24-48-month follow-up were evaluated using the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR). Clitoral features were obtained from postoperative MRI-based 3-dimensional models. Main Outcomes and MeasuresPISQ-IR scores and clitoral features (size, position). ResultsEighty-two women (median [range] age, 65 [47-79] years) were analyzed: 45 MUS (22 hysteropexy, 23 hysterectomy) and 37 No-MUS (19 hysteropexy, 18 hysterectomy). Postoperatively, 25 MUS, 12 No-MUS, 20 hysteropexy, and 17 hysterectomy patients were sexually active (SA). Overall, within the MUS and vaginal surgery groups, sexual function remained unchanged or improved (most PISQ-IR change from baseline scores were [&ge;]0) among SA and NSA women. Among SA women after surgery, the MUS group (vs No-MUS) had a poorer PISQ-IR arousal/orgasm (SA-AO) score (median, 3.5 vs 4.3; P=.02). The hysteropexy group (vs hysterectomy) had less improvement in PISQ-IR SA-AO score (median, 0.0 vs 0.3; P=.01). Women with MUS (vs without) had a smaller clitoral glans thickness (median, 9.0 mm vs 10.0 mm; P=.008) and clitoral body volume (median, 2783.5 mm3 vs 3587.4 mm3; P=.01). Conclusions and RelevanceSA women with MUS (vs without) or hysteropexy (vs hysterectomy) experienced poorer postoperative sexual function. MUS was linked to a smaller clitoris. Future studies should explore surgery-induced changes in clitoral anatomy and sexual function. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow do sexual function and clitoral anatomy differ by midurethral sling placement and vaginal surgery approach? FindingsThis cross-sectional study compared patient-reported sexual function outcomes and 30-42-month postoperative magnetic resonance imaging-based 3-dimensional clitoral models of 82 women after vaginal prolapse surgery with or without concomitant midurethral sling. Midurethral sling (vs no sling) and vaginal mesh hysteropexy (vs vaginal hysterectomy) were associated with poorer postoperative sexual function outcomes. Additionally, midurethral sling was associated with a smaller clitoral glans and body. MeaningMidurethral sling and vaginal mesh hysteropexy were associated with, and may adversely alter, postoperative sexual function and/or clitoral anatomy. VISUAL ABSTRACT/PROMOTIONAL IMAGE O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/26351291v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@904497org.highwire.dtl.DTLVardef@187514aorg.highwire.dtl.DTLVardef@e9e799org.highwire.dtl.DTLVardef@640f1a_HPS_FORMAT_FIGEXP M_FIG C_FIG

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

ImportanceMigraine attacks often occur unpredictably, limiting the ability of individuals to initiate timely preventive or preemptive treatment. Short-term probabilistic forecasting of migraine risk could enable more targeted management strategies. ObjectiveTo externally validate the previously developed Headache Prediction Model (HAPRED-I), evaluate an updated continuously learning model (HAPRED-II), and assess the feasibility and short-term safety of delivering individualized probabilistic migraine forecasts directly to patients. Design, Setting, and ParticipantsProspective 8-week cohort study conducted remotely at two academic medical centers in the United States (Massachusetts General Hospital and Wake Forest Health Sciences) between 2015 and 2019. Adults with recurrent migraine or tension-type headache completed twice-daily electronic diaries. A total of 230 participants contributed 23,335 diary entries across 11,862 participant-days of observation. Main Outcomes and MeasuresOccurrence of a headache attack within 24 hours following each evening diary entry. Model performance was evaluated using discrimination (area under the receiver operating characteristic curve [AUC]) and calibration. ResultsExternal validation of HAPRED-I demonstrated modest discrimination (AUC, 0.59; 95% CI, 0.57-0.61) and poor calibration, with predicted probabilities consistently exceeding observed headache risk. In contrast, the continuously updating HAPRED-II model demonstrated progressive improvement in predictive performance as participant-specific data accumulated. Discrimination increased from an AUC of 0.59 (95% CI, 0.57-0.61) during the first 14 days to 0.66 (95% CI, 0.63-0.70) after the first month, accompanied by improved calibration across predicted risk levels. Over the study period, 6999 individualized forecasts were delivered directly to participants. No evidence suggested that receipt of forecasts was associated with increasing headache frequency or worsening predicted headache risk trajectories. Conclusions and RelevanceA static migraine forecasting model demonstrated limited transportability to new individuals. In contrast, models that continuously update within individuals may improve predictive accuracy over time and enable real-time delivery of personalized migraine risk forecasts. Further work incorporating richer physiologic and contextual predictors will likely be necessary before such systems can reliably guide clinical treatment decisions.

Short-interval intracortical inhibition (SICI) is the most widely used neurophysiological index of GABAergic inhibition in the human cortex. However, it is an indirect measure, inferring synaptic inhibition from suppression of peripherally recorded motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In the standard protocol, a subthreshold conditioning pulse suppresses the MEP evoked by a suprathreshold test pulse delivered 1-5 ms later. Interpretation is further complicated by temporal overlap with short-interval intracortical facilitation (SICF), reflecting excitatory interactions at interstimulus intervals of [~]1.5 and 2.7 ms. To overcome these limitations, we recorded immediate TMS-evoked EEG potentials (iTEPs; 1-10 ms post-stimulus) as a more direct measure of motor cortical activity in 16 healthy volunteers (20-35 years; 7 male). The conventional SICI protocol suppressed only later components of the iTEP, likely corresponding to late corticospinal volleys previously identified in epidural spinal recordings after suprathreshold TMS, while the earliest iTEP component was unaffected. Importantly, later iTEPs were suppressed to a similar extent whether conditioning-test intervals coincided with SICF peaks or troughs, and the magnitude of iTEP suppression correlated with concurrently recorded paired-pulse MEP suppression. SICI also reduced an early TEP component (N15; 10-20 ms), but paired-pulse N15 suppression showed a different dependence on stimulus intensity and did not correlate with MEP suppression. These findings demonstrate that SICI measured via MEPs does not reflect a global index of cortical GABAergic motor cortical inhibition but instead reflects inhibition within specific cortical circuits that can be investigated directly with iTEPs.

BackgroundDespite advances in therapy, optimal management of juvenile idiopathic arthritis (JIA) remains challenging. The ability to predict disease progression in JIA can improve personalized treatment decisions, but few reliable clinical predictors have been identified. We developed machine learning approaches to predict disease trajectories in children with JIA. MethodsUsing data from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry (years 2015-2024), we developed machine learning models to predict attainment of inactive disease in children with non-systemic JIA. We applied Dynamic Bayesian Networks (DBN) to model temporal dependencies and causal relationships, and Convolutional Neural Networks (CNN) to capture complex non-linear patterns. Model input included demographic factors, longitudinal clinical factors, and medication use in the preceding 12 months. FindingsA total of 8,093 participants were included. When tested on an independent test cohort, both DBN (AUC:0.76; precision:0.73; recall:0.83; F1-score:0.78; accuracy:0.71) and CNN (AUC:0.76; precision:0.71; recall:0.63; F1-score:0.67; accuracy:0.70) models achieved comparable performance in predicting inactive disease. Disease activity levels in the preceding 12 months, presence of enthesitis and uveitis were the strongest predictors. Causal relationships captured in the DBN model revealed suboptimal care patterns, likely shaped by insurance constraints and a predominantly reactive approach to JIA management. InterpretationOur study demonstrates that machine learning approaches can predict disease trajectories in JIA with good discriminative performance. Unlike prior studies that predict outcomes at single timepoints, our models are the first to predict inactive disease longitudinally. However, suboptimal care patterns in retrospective data limit models capacity to learn treatment-outcome relationships, underscoring critical opportunities to improve JIA care and the need for prospective comparative studies to better inform prediction models. FundingPatient-Centered Outcomes Research Institute (PCORI) Award (ME-2022C2-25573-IC). RESEARCH IN CONTEXT Evidence before this studyNumerous studies have sought to identify clinical predictors of JIA progression and outcomes. However, few reliable predictors have emerged and existing prediction models demonstrate limited performance. As a result, our ability to personalize treatment decisions based on individual risk of severe disease course remains limited. Added value of this studyWe developed novel machine learning models that predict individualized disease trajectories in children with polyarticular and oligoarticular JIA using data from their preceding 12-month clinical course. These models demonstrated strong discriminative performance and outperformed previously published machine learning approaches in JIA. Unlike prior studies limited to single time-point predictions, our models are the first to predict inactive disease longitudinally, enabling a patient-specific projection of disease progression over time. Importantly, our findings also bright to light patterns of suboptimal care, likely driven by insurance constraints and a reactive treatment paradigm, underscoring critical opportunities to improve JIA management. Implications of all the available evidenceOur models have the potential to support clinical decision-making by enabling early identification of children with JIA at risk for unfavorable disease trajectories. In addition, the suboptimal care patterns and systems-level barriers identified through our analyses highlight priority areas for quality improvement initiatives and policy interventions to reduce gaps in JIA care delivery.

Chronic pain and nicotine use frequently co-occur, and individuals with chronic pain often experience greater difficulty quitting. Therefore, we examined nicotine withdrawal behaviors and analgesic-like effects in pain-naive and chronic pain conditions. Adult male and female rats underwent chronic constriction injury or sham surgery. After pain establishment, rats received twice-daily subcutaneous nicotine (0.3 or 0.7 mg/kg) or saline for 14 days. 24 h after the final injection, withdrawal was assessed, including physical signs and anxiety-like behavior. Depressive-like responses were evaluated at 72 h. Pain sensitivity and nicotines analgesic-like effects were assessed throughout. Chronic pain increased physical signs of withdrawal in both sexes, with greater effects in females. It also induced anxiety-like behavior in controls of both sexes. In rats with comorbid chronic pain and withdrawal, anxiety-like behavior was further enhanced in males, whereas females showed variable responses across assays, with increases or decreases depending on the test. Chronic pain induced depressive-like behavior in males but not in females. During withdrawal, depressive-like responses in males with chronic pain were not greater than those in the chronic pain alone group, while chronic nicotine exposure reduced depressive-like behavior in females. Nicotine produced acute analgesic-like effects that diminished over time in both pain-naive and chronic pain conditions, indicating tolerance. In pain-naive rats, repeated nicotine exposure induced mechanical hypersensitivity. Chronic pain intensified nicotine withdrawal severity in a nicotine concentration- and sex-dependent manner. These findings highlight the importance of considering pain status and sex when developing effective cessation strategies, particularly for individuals with comorbid chronic pain. SummaryChronic pain exacerbates nicotine withdrawal severity. Chronic nicotine exposure induces pain hypersensitivity and tolerance to analgesic effects. These effects vary by nicotine concentration and sex.

Introduction Large language models are increasingly being used in healthcare. In interventional pain medicine, clinical reasoning is essential for procedural planning. Prior studies show that simplified prompts reduce clinical detail in AI-generated responses. It remains unclear whether this reflects knowledge loss or simply prompt-driven suppression of information. Methods We performed a controlled comparative study using 15 standardized low back pain questions representing common interventional pain questions. Each question was submitted to ChatGPT under three conditions, professional-level prompt (DP), fourth-grade reading-level prompt (D4), and clinician-directed rewriting of the D4 response to a medical level (U4[-&gt;]MD). No follow-up prompting was allowed. Three physicians independently rated responses for accuracy using a 0-2 ordinal scale. Clinical completeness was determined by consensus. Word count and Flesch-Kincaid Grade Level (FKGL) were also measured. Paired t-tests compared conditions. Results Accuracy was highest with professional prompting (1.76). Accuracy declined with the fourth-grade prompt (1.33; p = 0.00086). When simplified responses were rewritten for clinicians, accuracy returned to baseline (1.76; p {approx} 1.00 vs DP). Clinical completeness followed the same pattern showing DP 80.0%, D4 6.7%, U4[-&gt;]MD 73.3%. Fourth-grade responses were shorter and less complex. Upscaled responses were more complex and similar in length to professional responses. Inter-rater reliability was low (Fleiss {kappa} = 0.17), but trends were consistent across conditions. Conclusions Reduced clinical detail under simplified prompts appears to reflect constrained output rather than loss of knowledge. Clinician-directed reframing restores omitted content. LLM performance in interventional pain depends strongly on prompt design and intended audience.

Scratching provides transient relief from itch, yet the neural circuit mechanisms that transform scratching into itch relief remain poorly understood. Midbrain dopaminergic neurons and their downstream targets in the lateral shell of the nucleus accumbens (NAc LaSh) are implicated in itch-scratch processing. Previous studies show that pharmacological manipulation of dopamine D1 and D2 receptors in the NAc LaSh alters scratching behavior, but the specific contributions of D1R- and D2R-expressing neurons during acute and chronic itch remain unclear. Here, we show that NAc LaShD1R and D2R neurons bidirectionally regulate scratching behavior across itch states. NAc LaShD1R neurons activity promotes scratching bouts, whereas NAc LaShD2R neurons preferentially facilitate scratch termination. Anterograde viral tracing revealed distinct brain-wide projection patterns of NAc LaShD1R and D2R neurons, which we functionally tested using projection-specific optogenetic manipulations. We found that NAc LaShD2R neurons terminate scratching by inhibiting neurons in the lateral parabrachial nucleus (LPBN), a key hub for itch processing. Furthermore, dopamine levels in the NAc LaSh were elevated during chronic itch compared with acute itch, suggesting enhanced dopaminergic signaling contributes to persistent scratching. Together, these findings identify circuit mechanisms linking reward pathways to itch regulation.

BackgroundLasers have wide applications in medicine and dermatology, but are associated with pain and anxiety, particularly in younger patients. Pain mitigation is often limited to topical anesthetics in the outpatient setting. Distraction techniques are limited by the need for ocular protection, which can include adhesive eye patches that can completely occlude vision. Virtual reality is effective at managing procedural pain and anxiety under other short medical procedures and is a promising tool for this population. ObjectiveThis trial aims to assess the safety, feasibility, and efficacy of Virtual Reality Pain Alleviation Therapeutic (VR-PAT) for pain management during outpatient laser procedures. Methods40 patients requiring outpatient laser therapy for at least two sessions will be recruited from a pediatric hospital in the midwestern United States for this crossover randomized, two-arm clinical trial with a 1:1 allocation ratio. During the first laser visit, the participant will be randomly assigned to either play the VR-PAT game during their procedure or wear the headset with a dark screen. Participants will answer questions about their pain (Numeric Rating Scale (NRS) 0-10), anxiety (State Trait Anxiety Inventory for Children, NRS 0-10, Modified Yale Preoperative Anxiety Scale (mYPAS)), and pain medication usage. Those playing the VR-PAT will additionally report simulator sickness symptoms and their experience playing the game. At their second laser visit, participants will crossover to the opposite intervention from their first visit. The primary outcomes are the difference in self-reported pain and anxiety between the two interventions. Feasibility outcomes include the proportion of screened patients who are eligible, consent, and complete both visits and adverse events reported. To evaluate the efficacy of pain reduction, composite scores of pain score, pain medication will be calculated for each laser visit. To evaluate the efficacy of anxiety reduction, the change of mYPAS scores will be compared between control and VR groups at each visit using Wilcoxon rank sum tests. All statistical analyses will follow the intention-to-treat principle in regard to intervention assignment at each visit. ResultsThe study was funded in January 2023 and began enrollment at that time. A total of n=44 participants were recruited and data collection was completed in November 2025, with n=40 subjects completing both visits. The sample was balanced with n=40 subjects using the intervention and participating in the control condition. The age range of the complete sample was 6 to 21 years at recruitment and was 55% female sex. Data analysis is in progress with final results planned for June 2026. ConclusionsFindings from this innovative randomized clinical trial will provide early evidence on the efficacy of the VR-PAT for reducing self-reported pain and anxiety during outpatient laser procedures. The results from this trial will inform a large-scale, multisite study. Trial RegistrationClinicalTrials.gov: NCT05645224 [https://clinicaltrials.gov/study/NCT05645224]

BackgroundThere is a close correlation between neuroendocrine regulation and pulpitis progression. This study aims to identify key neuroendocrine regulation-related genes in pulpitis, providing insights for its treatment. MethodsGSE77459 and GSE92681 datasets were used to validate experimental findings. Key neuroendocrine regulation-related genes were identified via Cytoscape plugin cytoHubba and expression validation. Gene set enrichment analysis, RNA-binding protein regulatory networks, post-translational modifications, molecular regulatory networks, and drug prediction were performed. Key gene expression was experimentally verified in clinical samples. ResultsTop 10 genes were obtained via cytoHubba; 4 (IL6R, OSM, IL1RN, CCL4) with significant differences between pulpitis and control samples and consistent trends in both datasets were identified as key genes. Gene set enrichment analysis showed key genes participate in pathways like cytokine-cytokine receptor interaction. Related RNA-binding proteins were ELAVL1 and HNRNPA1, with phosphorylation as the main post-translational modification. Core regulatory microRNAs included miR-519, miR-765, miR-23, and regulatory factors included FOXC1, PRRX2. Targeted drugs (e.g., sarilumab, haloperidol decanoate, cyclosporine) were predicted, and clinical sample verification confirmed consistent expression trends. Conclusion4 key neuroendocrine regulation-related genes were identified, which may have clinical significance for the diagnosis and treatment of pulpitis.

We completed a video-based, four-night, in-home, level 3 sleep apnea study of healthy, low-risk pregnant participants and their bed partners in order to characterize sleep physiology in the third trimester of pregnancy. Demographic, anthropometric, and baseline sleep health characteristics were recorded, and the NightOwl home sleep apnea test device was used to measure sleep breathing, posture, and architecture parameters. Symptoms of restless legs syndrome were elicited in the exit interview. Forty-one pregnant participants and 36 bed partners completed the study. Bed partners had a significantly higher prevalence of sleep apnea than their pregnant co-sleepers (31% vs. 5.9%). Bed partners also had more severe sleep apnea than their pregnant co-sleepers, and this persisted on an adjusted analysis for baseline differences in factors known to increase risk of sleep apnea. In pregnant participants, increasing gestational age was found to be protective against mild respiratory events but not more severe events. While the correlation between STOP-Bang score and measures of sleep apnea severity was weak, an affirmative response to the witnessed apneas item on the STOP-Bang questionnaire was a strong predictor of more severe sleep apnea for all participants. Smoking history also increased sleep apnea risk. Pregnant participants had lower sleep efficiency and longer self-reported sleep onset latency. Restless legs syndrome was experienced by 39.5% of the pregnant participants but no bed partners. From a sleep breathing perspective, people with healthy, low-risk pregnancies have better sleep than their bed partners despite lower sleep efficiency and higher rates of restless legs syndrome.

Pregnancy complications such as preeclampsia are associated with circulating cell-free mitochondrial DNA (mtDNA), a damage-associated molecular pattern capable of activating Toll-like receptor 9 (TLR9). We hypothesized that acute mtDNA exposure induces maternal inflammation and endothelial dysfunction during pregnancy via TLR9 activation. Non-pregnant and pregnant rats (gestational days 14-15) were treated intravenously with saline or purified mtDNA and euthanized 4 h after treatment. mtDNA increased cytokine mRNA expression in lung and liver of non-pregnant and pregnant rats, with magnitude varying by pregnancy status and organ. Aortas from pregnant, but not non-pregnant, rats exhibited reduced acetylcholine (ACh)-induced relaxation following mtDNA treatment (Emax, saline: 90.1 {+/-} 3.9 % vs. mtDNA: 62.1 {+/-} 20.7 % KClmax, p<0.05), while uterine artery function was preserved, indicating vascular bed-specific effects. Ex vivo incubation of aortic rings with mtDNA {+/-} white blood cells did not replicate in vivo findings, implicating systemic rather than direct vascular mechanisms. Nuclear DNA did not affect ACh-induced relaxation (p>0.05), confirming that the vascular effects were mtDNA-specific. Pharmacological antagonism of TLR9 with ODN2088 partially attenuated mtDNA-induced maternal endothelial dysfunction. Although overt vascular ROS increases were not detected, aortas from pregnant rats had reduced sod-1 expression (p<0.05) and increased eNOS protein abundance (p<0.05). Acute mtDNA exposure during pregnancy induces maternal organ inflammation and impairs endothelium-dependent vasodilation, with partial TLR9 involvement. In conclusion, aortic transcriptional changes in antioxidant pathways and increased eNOS abundance were also observed, though their functional significance remains to be determined. New & NoteworthyTo our knowledge, this is the first study to demonstrate that acute exposure to circulating mtDNA induces pregnancy-specific maternal endothelial dysfunction and organ-selective inflammatory responses. Our findings reveal pregnancy- and vascular-bed specific responses of the maternal vasculature to mitochondrial danger signals, with partial TLR9 involvement. Aortic transcriptional changes in antioxidant pathways and increased nitric oxide synthase abundance were identified as molecular correlates of this dysfunction.

BackgroundClinical and genetic evidence on the association between atopic dermatitis (AD) and subsequent psoriasis remains conflicting, and it is unclear whether this risk is modified by systemic treatments. Recent reports suggest type 2-targeted biologics may unmask psoriasis in AD patients, but data are limited. We thus aimed to assess whether AD is associated with incident psoriasis and whether this risk differs by systemic treatment, particularly biologics versus conventional systemic immunosuppressants (cvIS). MethodsScoping analyses informed a locked analytic design, preregistration at OSF, and confirmatory execution. Propensity score-matched analyses compared AD with non-AD controls and biologics with cvIS. Sensitivity analyses, Cox model triangulation, and control outcomes assessed robustness. FindingsAmong [~]300,000 matched pairs, AD was associated with increased psoriasis risk (primary HR 3.81, 95% CI 3.35-4.34), consistent across all 8 sensitivity analyses and model triangulation. Biologic treatment was associated with reduced psoriasis risk versus cvIS (primary HR 0.20, 95% CI 0.11-0.35), consistent across 6 of 7 evaluable sensitivity analyses and Cox triangulation. Positive and negative control outcomes showed expected directional patterns. InterpretationAcknowledging limitations including residual confounding and coding misclassification, AD was associated with increased psoriasis risk and biologics with lower psoriasis risk than cvIS. FundingDFG (EXC2167, SFB1526, LU877/25-1), Schleswig-Holstein Excellence-Chair Program, Swedish Society for Dermatology and Venereology, and the Tore Nilson Foundation. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAtopic dermatitis (eczema) and psoriasis are the two most common chronic inflammatory skin diseases worldwide. For a long time, doctors and researchers assumed these two conditions could not occur in the same person, as they were thought to involve opposing immune responses. However, this view has been challenged over the past decade. Some large studies, including population-based cohorts from Taiwan and the United Kingdom, have found that people with eczema may be at higher risk of developing psoriasis over time, while other studies, including genetic analyses, have suggested the opposite: that the two diseases may actually protect against each other. This conflicting picture has left clinicians uncertain about the true relationship between the two diseases in everyday clinical practice. A separate but related concern has emerged with the introduction of a new class of highly effective treatments for eczema, biologics, particularly dupilumab. Case reports and observational studies, including a large study published in JAMA Dermatology in 2025, have raised the possibility that these medications might trigger psoriasis in some patients, potentially by shifting the immune system from one inflammatory pattern to another. However, prior studies on this question had important methodological limitations: they were not pre-planned and registered before data collection, they did not always tightly link treatment use to an eczema diagnosis, and critically, none compared biologic treatment directly against conventional immunosuppressant medications, the most relevant clinical comparator. Added value of this studyThis study is a large and methodologically rigorous investigation of both questions: whether eczema itself increases the risk of developing psoriasis, and whether the type of systemic treatment used for eczema influences that risk. Using a database of over 110 million electronic health records from across the United States, we matched approximately 300,000 patients with eczema to 300,000 patients without eczema and followed them for up to seven years. We also compared nearly 5,500 patients treated with biologics to an equal number treated with conventional immunosuppressants. Crucially, our study was pre-registered before any data were analyzed, meaning the research questions, methods, and analyses were locked in advance and could not be adjusted based on what the data showed. We also used a range of additional analyses to test whether our findings were robust, including checks using outcomes that should not be affected by eczema or its treatment (such as appendectomy and hearing loss), which confirmed that our results were not likely explained by bias alone. We found that eczema was associated with an increased risk of developing psoriasis, but that this risk was substantially influenced by the choice of comparison group, ranging from approximately 1.4-fold to nearly 4-fold depending on the analytical approach. More strikingly, we found that patients treated with biologics had a markedly lower risk of developing psoriasis compared with those treated with conventional immunosuppressants, the opposite of what prior reports had suggested. This finding was consistent across nearly all additional analyses performed. Implications of all the available evidenceTaken together with existing evidence, these findings suggest two important conclusions. First, clinicians should be aware that eczema, particularly moderate-to-severe eczema requiring systemic treatment, may carry an elevated risk of developing psoriasis over time. This does not mean that all patients with eczema need to be screened for psoriasis routinely, but it does support clinical awareness and monitoring in higher-risk patients. Second, and perhaps most importantly for treatment decisions, biologics do not appear to increase the risk of psoriasis compared with conventional immunosuppressants and may in fact be associated with a lower risk. This provides reassurance for patients and clinicians considering biologic therapy and challenges the narrative that these medications trigger psoriasis. Future research should aim to confirm these findings in other populations, investigate the biological mechanisms underlying the relationship between eczema and psoriasis, and examine whether specific biologic agents differ from one another in their effects on psoriasis risk.

GLP-1 agonists are an emerging treatment for disorders of consumption. They are most prominent as treatments for obesity, but recent literature suggests that they are effective at reducing the consumption of all types of hedonic substances. This clearly suggests a central, cognitive, mechanism rather than a peripheral mechanism or an interaction with a single signalling pathway, but the specific site or sites for this mechanism remain to be discovered. Candidate brain regions for this reward-modulating activity have a relative paucity of GLP-1 receptors, with the exception of lateral septum, which expresses an abundance of them. In these experiments we recorded local field potential from lateral septum while animals received either saline control or the GLP-1R agonist liraglutide. We find that liraglutide significantly reduced the power of both high-frequency oscillations and theta rhythm in the lateral septum, suggesting that GLP-1R agonism changes how lateral septum communicates with its network. In addition, we show that liraglutide causes animals to wait longer to respond for reward in a differential reinforcement of low rates paradigm. Together, these results suggest that a primary region in the control of the anticonsumptive action of GLP-1 agonists is the lateral septum, and that the coding of reward by this region is a central node in the network responsible for cognition about and behaviour with respect to reward.

Preconception weight loss by metabolic-bariatric surgery (MBS) improves maternal-fetal outcomes, but little is known about its impact on offspring growth and health. The preconception bariatric surgery and child health outcomes (POSIT) study aims to estimate the effects of maternal MBS-induced preconception weight loss on infant and childhood body size, growth, and related outcomes. This report presents the methods used to construct the POSIT cohort and its baseline characteristics. This retrospective cohort study sampled members from a United States healthcare system aged 18 and older with a singleton, live birth to create three study groups: 1) a treatment group including women who underwent preconception MBS and subsequently became pregnant (n=1,374); 2) a control group matched to the MBS pre-surgery body mass index (BMI) (pre-surgery controls, n=13,740); and 3) a second control group matched to the MBS post-surgical, pre-pregnancy BMI (pre-pregnancy controls, n=13,740). MBS and pre-surgery BMI controls showed slight imbalances in that pre-surgery BMI controls were on average ~6 months younger, had 0.6 lower BMI (44.5 kg/m2) at the time of their pregnancy and were more likely to have become pregnant in earlier years than the MBS group prior to surgery. MBS and pre-pregnancy controls had comparable age (mean {+/-} SD 33 {+/-} 5 years), pre-pregnancy BMI (33 {+/-} 6 kg/m2), and year of delivery. Following matching, the MBS group had similar socioeconomic and health disparities as the pre-surgery control group, and both were worse than pre-pregnancy control group. Pregestational maternal comorbidity index improved after MBS and matched the pre-pregnancy controls. Upon extraction of offspring growth patterns and mediation analyses of maternal weight loss and metabolic responses to MBS, study findings will investigate effects of preconception weight loss by MBS on short- and long-term child health outcomes. Results will guide future studies focusing on improving maternal preconception weight and maternal-fetal outcomes.

The central role of microglia in CNS function in health and disease has resulted in large interest in targeting microglial as treatments for neurodegenerative disease; understanding the factors that regulate microglial gene expression will be crucial to this goal. microRNAs (miRNAs) are among the most abundant post transcriptional regulators of gene expression. miRNAs suggests miRNA were likely key to significant evolutionary events as regulators of gene expression. The miRNAome of microglia is critical to their correct functioning but the miRNA that define microglia identity and regulate key functions have not been fully defined. In this study we performed a detailed analysis of the microglial miRNAome to identify miRNA enriched in microglia that are conserved across species (human, mouse, and xenopus). We further characterised the expression of these conserved miRNAs during demyelination and remyelination and identified conserved function of a microglial-enriched miRNA across species. These findings reveal evolutionary conservation of specific miRNAs, suggesting an important role in establishing and maintaining microglial identity. They also highlight miRNAs that may be critical for microglial function in the central nervous system in both health and disease. Overall, this work advances our understanding of the factors that regulate microglial gene expression.

ObjectivePathological beta-band oscillations (13 to 30 Hz) in the subthalamic nucleus (STN) are a hallmark of Parkinsons disease and a primary target for deep brain stimulation therapy, yet the specific pattern of synaptic reorganization that drives their emergence remains incompletely understood. We developed a GPU-accelerated computational framework to systematically investigate combinations of synaptic changes across basal ganglia pathways that produce Parkinsonian beta oscillations while satisfying literature-based electrophysiology constraints. ApproachWe implemented a biophysically detailed spiking network model of the STN, external globus pallidus (GPe), and internal globus pallidus (GPi) in JAX (a high-performance numerical computing Python library), achieving a 490-fold speedup over conventional CPU-based simulation. Using the Covariance Matrix Adaptation Evolution Strategy (CMA-ES) we optimized 10 network parameters across two stages: first establishing a healthy baseline matching primate electrophysiology data, then searching within biologically motivated bounds for synaptic modifications that reproduce Parkinsonian firing rates and beta power. Fixed in-degree connectivity ensured optimized parameters produced scale-invariant dynamics from 450 to 45000 neurons. All simulations ran on a single cloud GPU instance at 84 cents per hour. Main ResultsThe optimizer converged on a coordinated pattern of synaptic reorganization dominated by asymmetric changes within the STN-GPe reciprocal loop: STN to GPe excitation increased 2.21-fold while GPe to STN inhibition collapsed to 0.11-fold of its healthy value. STN to GPi and GPe to GPi pathways changed minimally (1.06-fold and 1.45-fold respectively). This configuration transformed asynchronous firing (beta: 0.4 percent of spectral power) into synchronized bursting with prominent beta oscillations (49.4 percent), with firing rate changes matching experimental observations. Network dynamics were invariant across a 100-fold range of network sizes (firing rate deviation less than 2.4 Hz; all metrics p less than 0.001 across 10 random seeds at 45000 neurons). We implemented a simplified deep brain stimulation model for validation purposes, which achieved complete beta suppression (49.4 percent to 0.0 percent) and restored GPi output to healthy levels. SignificanceThese results suggest that pathological beta oscillations emerge from a specific pattern of synaptic reorganization, namely the reduction of GPe inhibitory feedback to STN. The GPU-accelerated optimization framework, running on commodity cloud infrastructure, demonstrates an accessible platform for parameter exploration in neural circuit models and a foundation for generating synthetic training data for adaptive deep brain stimulation algorithms.

Endurance exercise imposes extreme metabolic demands on the adult human brain, raising the question of how core brain function is preserved under physiological challenge. We previously showed that marathon running induces reversible reductions in myelin within specific white-matter tracts, suggesting adaptive structural change under metabolic stress. Here, we asked whether this process is functionally tolerated. Neurophysiological recordings revealed maintained conduction latencies across motor, somatosensory, visual, and auditory pathways within 48 hours after race completion, indicating intact axonal signal transmission despite reduced myelin content. Cognitive testing revealed selective and transient modulation of higher-order processing, including attenuated practice-related gains in processing speed and short-lived increases in interference, whereas visuomotor speed and executive flexibility were preserved. All cognitive measures normalized one month after the race, supporting an adaptive framework linking myelin change with preserved brain function under extreme metabolic stress.