Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unclear pathogenesis. This study aimed to investigate the possible molecular mechanisms of ALS by analyzing protein structure and dynamics in a rapidly progressing ALS patient carrying the N87D mutation. A patient with the N87D mutation experienced rapid disease progression and died within one year. We reviewed all known mutations at the 87th position of the superoxide dismutase (SOD1) gene and the clinical characteristics. To investigate the molecular basis of the severe phenotype, we performed protein structure modeling and molecular dynamics (MD) simulations, and compared wild type homodimers, mutant homodimers, and heterodimers in terms of energy, residue fluctuation, number of hydrogen bonds, radius of gyration (Rg), principal component analysis (PCA), free energy landscape (FEL), the contribution of dimer interface residues, solvent-accessible surface area, and metal ion coordination. Our analysis revealed that patients with mutations at the 87th position of the SOD1 gene typically exhibited rapid disease progression. Protein structure modeling and MD simulations demonstrated that the N87D mutation significantly increased the energy and RMSF of SOD1 heterodimers compared to homodimers. Furthermore, Rg, FEL and PCA analyses showed that the heterodimers had a broader and more unstable conformational energy distribution, along with a stronger tendency for aggregation. Additionally, the N87D mutation disrupted metal ion coordination, further destabilizing the heterodimer and promoting protein misfolding. These findings suggest a potential molecular mechanism underlying ALS and support a protein structure based approach for investigating the pathogenic mechanisms of disease causing mutations.

Background Chronic migraine imposes a large disease burden; however, its underlying mechanisms remain poorly understood. The paraventricular thalamus (PVT), traditionally linked to arousal, has recently been shown to regulate pain and negative emotions. However, the role of the PVT and its related neural circuits in migraine remains insufficiently investigated. The neglect of the PVT could be due to its high basal neuronal activity under physiological conditions, complicating the isolation of disease-specific changes. Methods A mouse model of chronic migraine was established by repeated intraperitoneal injection of nitroglycerin (NTG) i.p. The mechanical hyperalgesia, anxiety, and depression-like behaviors of the mice were evaluated using the von Frey test, open field test, elevated plus maze test, and tail suspension test. The activation status of the posterior PVT (pPVT) was determined via the FosTRAP strategy, and behavioral tests were performed after its neurons were inhibited chemogenetically. Neural circuits potentially involved in regulation were subsequently identified by combining anterograde tracing with activity mapping in downstream regions. Finally, chemogenetic manipulation was employed to further verify the role of the circuit in NTG-induced chronic migraine. Results Mice with chronic migraine exhibited mechanical hyperalgesia and anxiety-like behavior, whereas depression-like behavior was not observed. Compared with the control group, the model group showed increased activation in the pPVT, as indicated by the results of the FosTRAP strategy. Chemogenetic inhibition of pPVT glutamatergic neurons can alleviate mechanical hyperalgesia in model mice without affecting anxiety-like behaviors. Projections from the pPVT innervate multiple regions, including the central amygdala (CeA). The model group showed increased activation in the CeA and its afferent input from the pPVT (pPVT(glu)- CeA). Chemogenetic inhibition of CeA GABAergic neurons alleviated both mechanical hyperalgesia and anxiety-like behavior in model mice. However, chemogenetic inhibition of both pPVT(glu)- CeA and CeA GABAergic neurons receiving input from the pPVT (pPVT- CeA(GABA)) can ameliorate mechanical hyperalgesia in model mice without affecting anxiety-like behaviors. Conclusions The pPVT(glu)- CeA(GABA) circuit is involved in mechanical hyperalgesia behaviors in chronic migraine, and could be a promising candidate for chronic migraine treatment.

OBJECTIVE:Data on the long-term efficacy and safety of rituximab (RTX) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are scarce. The potential for a relapsing-remitting disease course in patients with MOGAD also requires further investigation. The study aimed to evaluate the long-term clinical outcomes in relapsing MOGAD patients receiving RTX maintenance therapy. METHODS:A retrospective analysis was performed on MOGAD patients. Clinical features, relapse frequency, and Expanded Disability Status Scale (EDSS) scores were evaluated pre- and post-administration of 0.5g RTX. RESULTS:Thirty-five MOGAD patients who met inclusion criteria were identified with a median RTX duration of 1.25 (0.5-4) years. RTX reduced both annualized relapse rate (ARR) (from 1.64 to 0.1; P <0.0001) and person-year relapse rate (PRR) (from 0.61 to 0.12). 74 % (26/35) of patients remained relapse-free; 26 % (9/35) experienced relapses, of whom 78 % (7/9) had B-cell repopulation or discontinuation of RTX maintenance treatment. Most relapsing patients had mild clinical symptoms, with mean EDSS scores increasing to 1.65 (range, 1-4). All patients who reinfused ≥2 RTX after relapse remained relapse-free. Seroconversion to MOG-IgG negativity occurred in 43 % (15/35), with 6 patients exhibiting recurrent seropositivity, and 3 of whom experienced relapses. Three patients who discontinued RTX after seroreversion maintained relapse-free status. Importantly, no serious adverse events were observed, except that three patients suffered from infection or a rash during infusion. CONCLUSION:RTX treatment is associated with lower recurrence rates and high seroconversion rates in MOGAD patients. Post-treatment relapses did not exacerbate disability severity, supporting RTX as a favorable therapeutic option to prevent relapse.

Migraine is a debilitating primary headache disorder characterized by significant sex differences in epidemiology, clinical features, comorbidities, and treatment response, yet the underlying mechanisms remain obscure. This study aims to dissect the sex difference map in chronic migraine models and explore the underlying mechanisms driving these specific phenotypes. A mouse model of chronic migraine was established by intraperitoneal injection of nitroglycerin (NTG, 10 mg/kg, 5 times in 9 days). Both male and female mice were included. Mechanical withdrawal thresholds (MWTs) were measured to assess migraine-related hyperalgesia. Anxiety-like behaviors and acute malaise were evaluated using the Open Field Test (OFT), Elevated Plus Maze (EPM), and Light-Dark Box (LDB). Neuronal activation was mapped via c-Fos immunofluorescence. Medullary TNF-α levels were quantified by ELISA. 16S rRNA sequencing and targeted metabolomics characterized the gut microbiota composition and fecal metabolites, respectively. Although male and female mice showed comparable responses in acute and chronic mechanical pain hyperalgesia, significant sex differences were observed in other migraine-like behaviors: only male mice exhibited significant acute-phase motor inhibition and anxiety-like behavior in the chronic phase. These phenotypic differences coincided with a male-restricted elevation of medullary TNF-α following NTG administration. In terms of regional brain activation, the AP stood out in males for its markedly elevated c-Fos cell. This sexual dimorphism extended to the gut-brain axis: while the female NTG group microbiome was enriched with g-Akkermansia, the male profile was dominated by g-Parabacteroides. Metabolomic profiling identified 29 differential metabolites (NTG vs. VEH) in males but only 3 in females. In males, these alterations were primarily enriched in the pentose and glucuronate interconversions and biosynthesis of unsaturated fatty acids pathways that are involved in neuropsychiatric disorders. The NTG-induced chronic migraine model exhibits significant sexual dimorphism, with male mice showing greater sensitivity to acute discomfort and chronic emotional comorbidities. This exploratory study identifies the specific activation of the AP brain region, medullary neuroinflammation, and more severe disturbances in the gut microbiota-metabolic axis as potential contributors to this sex-dependent phenotype.

BackgroundAlthough diagnostic criteria and treatment guidelines for migraine are well-established, care remains suboptimal due to frequent misdiagnosis and undertreatment. This Delphi consensus aimed to explore how clinicians in the Asia-Pacific region approach migraine diagnosis and management.MethodsThis study used a modified-Delphi method, involving two rounds of surveys and a virtual scientific meeting with 14 headache-specialists from seven countries in Asia-Pacific. Consensus on statements was measured using a Likert scale ranging from 1 to 9, with consensus threshold set at 75%.ResultsThe study had 100% participation in both surveys, and the scientific meeting was attended by 64.3% of participants. Out of 21 closed-ended statements, 12 reached consensus. Notably, 93% of participants reported using only ICHD-3 for migraine diagnosis, and 79% found the criteria easy to apply. For the diagnosis of migraine, all participants evaluated migraine-related disability and depression; 93% anxiety, and 86% sleep disturbances. Neck pain and dizziness were recognised as migraine-associated symptoms by 93% of respondents, with 85% reporting that 25–75% of their patients experience neck pain. Anti-CGRP mAbs were considered effective and addressed unmet needs for chronic or episodic migraine by 86% of participants. Efficacy (100%) was the primary deciding factor in selecting a specific anti-CGRP mAb, followed by safety (93%) and tolerability (86%). Factors such as frequency of administration (43%), perceived wearing-off effect (43%), availability and reimbursement (57%), and cost (58%) were less influential in decision-making. While 79% of the participants would consider anti-CGRP mAbs as first-line treatment, 93% believed these therapies would improve safety, adherence, and compliance outcomes. Only 7% of the participants favoured the use of gepants. Participants unanimously supported the use of anti-CGRP mAbs in adolescents (13–17 years), but not in children (6–12 years).ConclusionConsensus was reached on key aspects of migraine diagnosis and management. Participants endorsed the ICHD-3 criteria as the diagnostic standard and favoured using headache diaries, followed by MIDAS and HIT-6 for assessment. Anti-CGRP mAbs were recognised as effective in addressing unmet needs in migraine prevention. The panel advised against using anti-CGRP mAbs in children under 12 due to insufficient evidence, highlighting the need for more paediatric data.

The comorbidity between endometriosis and migraine has long been recognized clinically, yet a unifying pathophysiological explanation has remained elusive. Traditional models, centered on hormonal fluctuations or secondary inflammation are lacking to explain the fundamental predisposition underlying their co-occurrence. This review synthesizes the evidence from genetic epidemiology that is reshaping this narrative, positing that shared molecular genetic mechanisms provide the missing link. This review paper aims to present a review of the current literature surrounding genetic overlap between EM and migraine. Critically, Mendelian Randomization analyses refute a causal relationship, instead pointing to pleiotropy as the core principle. We delve into the specific shared risk loci, such as TRIM32 and SLC44A4, and demonstrate how they converge on dysregulated biological pathways, notably IL-1, TNF-α, and MAPK/ERK signaling that drive both peripheral inflammation in endometriosis and neuroinflammation in migraine. Central sensitization emerges as a critical amplifier, functionally coupling the two conditions and exacerbating chronic pain. By integrating these findings, we propose a novel model where endometriosis and migraine are parallel manifestations of a shared genetic architecture. Finally, we discuss the translational implications of this paradigm, including the potential for genetic stratification of high-risk patients and the repurposing of therapeutics targeting these shared inflammatory pathways. This genetic reframing may move the field beyond symptomatic management toward a future of mechanism-based, personalized medicine for this underserved patient population.

Migraine is the leading cause of years lived with disability (YLDs) in young and middle-aged populations globally. Despite strategic initiatives to standardize headache care in China, large-scale real-world evidence regarding clinical management patterns remains sparse. The China Migraine Registry (CHIME) was established to bridge this gap. This study aims to delineate the CHIME methodology and report the baseline clinical characteristics, diagnostic accuracy, and therapeutic patterns of its initial cohort. CHIME is a nationwide, multi-center, prospective, longitudinal cohort study involving over 100 specialized headache centers across 28 provinces in China. Initiated in May 2024, the study utilizes a proprietary digital health platform integrated with a clinical decision support system (CDSS 2.0) for headache disorders. Data collection encompasses structured clinical profiles, patient-reported outcomes, and specialized sub-study cores. This baseline analysis details the cross-sectional characteristics of patients enrolled through February 15, 2026. Among 11,814 participants (79.43

Background Migraine affects nearly one billion people worldwide and remains a major global health burden with inadequate treatment options. In this study, transcranial low-intensity focused ultrasound (LIFU) targeting the medial prefrontal cortex (mPFC) was assessed as a novel, non-invasive neuromodulatory strategy for migraine abortive treatment. The therapeutic potential and safety of LIFU were evaluated in animal models to support its future clinical translation.Methods Male C57BL/6 mice were administered intraperitoneally with nitroglycerin (NTG) to induce an acute migraine model, whereas control animals received vehicle (VEH). Following model induction, mice were subjected to either mPFC-targeted LIFU or sham stimulation, which underwent an identical protocol without ultrasonic output. A series of behavioral, histological, and molecular assays was performed to evaluate the therapeutic effects and neuromodulatory mechanisms of LIFU. Mechanical allodynia was assessed using the von Frey test; anxiety-like behavior was evaluated in the elevated plus maze. Neuronal activation was examined via c-Fos immunofluorescence and GABA/glutamate co-staining. Tissue safety was assessed by HE staining and TUNEL assay. All quantitative analyses were conducted under blinded conditions.Results NTG injection induced significant allodynia and anxiety-like behaviors. LIFU stimulation significantly attenuated cephalic and plantar allodynia and ameliorated anxiety-like behaviors compared to the sham group. The NTG-induced migraine model exhibited significant mPFC c-Fos hyperactivation, which LIFU stimulation effectively suppressed. NTG injection significantly increased the proportion of activated glutamatergic neurons (GLU-N) and decreased activated GABAergic neurons (GABA-Ns) among total c-Fos-positive cells in the mPFC. This imbalance was reversed by LIFU, i.e., it was characterized by a decrease in activated GLU-Ns and an increase in activated GABA-Ns. No significant histopathological damage or apoptosis was detected following LIFU exposure.Conclusions Aberrant activation and excitatory and inhibitory (E/I) imbalance of neurons in mPFC were involved in acute NTG-induced episodes. The LIFU targeting mPFC could alleviate NTG-induced mechanical allodynia and anxiety-like behavior by restoring E/I balance. LIFU is a novel, safe, non-invasive neuromodulatory strategy offering a potential migraine treatment.

The investigation into the association between histamine and headache has persisted for nearly a century. Nevertheless, the functional role of the central histaminergic system in headache pathophysiology remains inadequately characterized. This study aims to elucidate the activation status of tuberomammillary nucleus (TMN) histaminergic neurons in mice during acute headache episodes and their impact on headache-related behavioral alterations. Using transgenic mouse models, immunofluorescence staining, and chemogenetic manipulation, we systematically evaluated the functionality of histaminergic neurons in acute headache. c-Fos expression analysis and calcium signaling measurements were utilized to assess TMN neuronal activation. Our findings indicated that nitroglycerin (NTG) stimulation did not significantly alter the activation level of TMN histaminergic neurons, with no statistically significant differences observed between NTG-treated and control groups (p = 0.48, p = 0.92). Furthermore, calcium probe and histamine probe techniques revealed no substantial changes in neuronal activity during acute headache phases, suggesting a non-critical role for these neurons in acute headache responses. Anatomical tracing confirmed sparse projections from TMN histaminergic neurons to the trigeminal complex (TCC), reinforcing their limited involvement in pain signal transmission. Collectively, our results challenge the purported significance of central histaminergic neurons in acute headache pathophysiology within the NTG-induced mouse model and suggest that TMN histaminergic neurons do not show detectable activation and are not required for the behavioral endpoints tested in an NTG-induced acute headache mouse model.

Erenumab is a fully human monoclonal antibody targeting the calcitonin gene-related peptide receptor. Several double‐blind studies have demonstrated the clinical benefits of erenumab in migraine prevention. However, long-term studies on safety and effectiveness of erenumab are lacking in Asian population. To evaluate the long-term safety and continued clinical benefit of erenumab 70 mg in adult patients with chronic migraine (CM) in China and other Asian countries. This was an open-label extension of the Phase 3 DRAGON study. Upon completion of the 12-week, double-blind treatment phase (DBTP) of the DRAGON study, randomized patients who met the inclusion criteria and provided consent transitioned into an open‐label treatment phase (OLTP) lasting until erenumab approval in the patient’s country. During OLTP, patients received once-monthly subcutaneous injection of erenumab 70 mg, irrespective of their initial treatment allocation in DBTP. Safety was assessed by collecting all adverse events (AEs) and serious AEs (SAEs) including their severity and relationship to study treatment. Effectiveness outcomes included clinical global impression (CGI) [severity (CGI-S), improvement (CGI-I), and efficacy index (CGI-E)]. Of the 557 randomized patients (DBTP), 456 from 50 centers participated and 226 (49.6

Migraine is highly heterogeneous, and patients exhibit substantial variability in their responses to preventive treatment. The dose-escalation strategy of topiramate further complicates early evaluation of therapeutic efficacy. Identifying neurobiological markers that can predict treatment response is therefore essential for individualized therapy. In this study, we constructed predictive models based on individualized periodic and aperiodic power features derived from source-reconstructed electroencephalography (EEG) to identify electrophysiological indicators associated with topiramate efficacy, thereby providing a foundation for personalized prediction in migraine prevention. In total, 112 patients with episodic migraine without aura received baseline EEG assessment and subsequently completed 3 months of topiramate treatment. EEG signals were source-reconstructed, and periodic and aperiodic components were separated using FOOOF with adjustment by each participant’s individual α frequency (IAF). Predictive models were developed using XGBoost, with stratified cross-validation and 0.632 + bootstrap used to estimate generalization performance. Shapley Additive exPlanations (SHAP) analysis quantified feature contributions. Correlation analysis and Leave-One-Out Cross-Validation (LOOCV) regression were subsequently performed to examine the relationships between key features and treatment outcomes. The model achieved an area under the receiver operating characteristic curve (AUROC) of 0.859 in identifying treatment responders. SHAP analysis indicated that the most influential features were periodic α-band power localized to the cuneus, pericalcarine cortex, medial orbitofrontal cortex, frontal pole, and precuneus. Principal component analysis (PCA) of the functional brain networks comprising these regions showed that the principal components of the visual network (VN) and default mode network (DMN) were significantly associated with headache improvement, and their joint inclusion in a LOOCV regression model explained 26.1

Sex differences in the clinical characteristics of cluster headache (CH) remain controversial in both Eastern and Western studies, and such differences have not been thoroughly investigated among Chinese patients. This large-scale, multicenter cohort study included 1,206 patients from 31 provinces across China diagnosed with CH between May 2021 and December 2024, and was conducted within the framework of the Chinese Cluster Headache Register Individual Study. Demographic and clinical data were systematically collected from each participant using an electronic structured questionnaire, and compared all variables between sexes. In total, 1,206 patients were enrolled, with a female-to-male ratio of 1:3.94. Demographic analysis revealed that female patients had an earlier mean age of onset, higher educational attainment, and fewer unhealthy lifestyle factors compared to male patients. Female patients were also more likely to have comorbidities such as migraine (28.28

Background Preventing migraine chronification is a key treatment goal, yet environmental and lifestyle contributors remain understudied in Asian populations. We investigated predictors of the transition from episodic migraine (EM) to chronic migraine (CM) in a prospective Chinese clinical-based cohort.Methods This multicenter, prospective study involved 1642 participants with EM meeting ICHD-3 criteria. Baseline characteristics, including environmental factors and psychological scales, were captured via a Clinical Decision Support System (CDSS). Longitudinal follow-up was conducted using a web-based mini-program. Risk factors were identified using multi-variable Cox proportional hazards models, validated by LASSO and stepwise regression.Results During a median 6-month follow-up, 47 (2.9%) patients progressed to CM. Multivariable analysis identified anxiety symptoms [Generalized Anxiety Disorder-7 (GAD-7) score: Hazard Ratio (HR) 1.15, 95% Confidence Interval (CI) 1.06-1.25], baseline analgesic use frequency (HR 1.07, 95% CI 1.01-1.14), and age (HR 1.04, 95% CI 1.01-1.06) as independent risk factors. Conversely, weekly physical activity duration emerged as a significant protective factor (HR 0.66, 95% CI 0.45-0.98).Conclusion Anxiety and higher frequency of analgesic use are independent risk factors of migraine chronification in this Chinese cohort, while regular physical activity offers protection. These findings support an integrated management strategy combining psychological intervention, medication education, and exercise therapy.

AimFremanezumab is approved for migraine prevention in Europe, the United States (US), Japan, South Korea, and several other countries; however, there are no data available on fremanezumab as a migraine preventive treatment in a Chinese population. This study evaluated the efficacy and safety of fremanezumab in Chinese adults with migraine.MethodsThis randomized, multicenter, Phase 3 trial consisted of a 4-week screening period, a 12-week double-blind period (DBP), and a 12-week open-label extension (OLE). Chinese adults with episodic and chronic migraine were randomized 1:1:2 to receive fremanezumab monthly (225 mg), fremanezumab quarterly (675 mg), or matched monthly placebo during the DBP. During the OLE, all participants received fremanezumab monthly (225 mg). The primary endpoint was mean change from baseline in monthly migraine days (MMD) during the DBP. Secondary endpoints included mean change from baseline in migraine days during the first 4 weeks of treatment and in monthly number of days with acute headache medication use during the DBP. Similar endpoints were assessed during the OLE. Safety assessments included, but were not limited to, adverse event (AE) reporting.ResultsIn total, 365/454 screened participants were randomized to fremanezumab (n = 182 [monthly, n = 91; quarterly, n = 91]) or placebo (n = 183). Significantly greater changes from baseline in MMD were observed with fremanezumab versus placebo during the DBP (-4.6 vs -2.8; p < 0.0001) and in mean migraine days during the first 4 weeks of treatment (-4.5 vs -2.2; p < 0.0001). The mean change from baseline in days of acute headache medication use during the DBP was -3.0 with fremanezumab and -1.1 for placebo (p < 0.0001). During the OLE, the mean change from baseline in MMD was -6.8 and -7.2 for those assigned to fremanezumab and placebo, respectively, during the DBP. The percentage of participants with any AE was similar between fremanezumab and placebo groups during the DBP (47% vs 43%); serious AEs were infrequent (fremanezumab, 1%; placebo, <1%). Similar trends in AEs were observed during the OLE.ConclusionIn this study, fremanezumab demonstrated significant improvements over placebo with respect to reductions in MMD and days with acute headache medication use, with these reductions being maintained over the OLE. Fremanezumab demonstrated a favorable safety profile, with no safety signals. These results are comparable to pivotal adult trials in Europe and the US, supporting the use of fremanezumab in Chinese adults living with migraine.Clinical trial pre-registrationClinicalTrials.gov identifier: NCT05458011; submitted: 11 July 2022; first participant enrolled: 30 September 2022; available at: https://clinicaltrials.gov/study/NCT05458011; first submitted: 11 July 2022).

Sleep deprivation is a common phenomenon in modern society and can influence pain perception. However, inconsistencies have emerged in mechanistic studies investigating this relationship. We hypothesize that these discrepancies may stem from the use of different animal models of sleep deprivation. Therefore, we evaluated the effects of three commonly used and one newly improved sleep deprivation paradigms on pain responses and explored the underlying mechanisms contributing to their different effects. Our findings revealed that distinct sleep deprivation paradigms exert varying effects on pain sensitivity in mice, with corresponding differences in the stress responses elicited by each model. Among the four acute 6-hour sleep deprivation paradigms tested, multiple platform-induced sleep deprivation induced the most pronounced stress response. The activation levels of locus coeruleus noradrenergic neurons were identified as a biomarker reflecting the effect of sleep deprivation on stress in mice. Consequently, research examining the comorbidity of acute sleep deprivation and pain should carefully consider the differences between different sleep deprivation models and employ appropriate experimental designs to minimize potential biases.

Migraine with aura is clinically linked to cognitive impairment, yet sex differences and underlying mechanisms are unclear. Cortical spreading depression (CSD) is widely regarded as the electrophysiological correlate of migraine aura. Therefore, we utilized a mouse model of repetitive CSD to model recurrent aura events and investigate how this phenomenon modulates behavior and cognition in a sex-dependent manner. CSD was repeatedly induced in both male and female mice via epidural KCl application, using six consecutive stimuli at 20-minute intervals. Behavioral tests were performed to assess pain sensitivity, photophobia, anxiety, and cognitive function. Hippocampal neurogenesis and synaptic plasticity were examined via immunofluorescence and electrophysiology respectively. Repetitive CSD induced transient allodynia, which was most prominent on day 1 and fully recovered by day 5. This effect was more pronounced and longer-lasting in female mice. In contrast, photophobia observed in the CSD group was more prevalent in male mice. Repetitive CSD did not trigger anxiety-like behavior on either day 1 or day 7. During the Morris water maze probe trial on day 11, female mice in the CSD group exhibited a reduced number of platform crossings and decreased exploration distance in the target quadrant, while no such difference was observed in male mice. Conversely, in the novel location recognition test conducted on day 9 (with a 30-min interval), the CSD group showed a higher discrimination index than the SHAM group, specifically in female mice. These changes were accompanied by increased hippocampal neurogenesis. Moreover, enhanced long-term potentiation at the perforant path–dentate gyrus synapse was observed in females only. All cognitive alterations had recovered by 21 days post-CSD. Our study demonstrates that repetitive CSD stimulation elicits distinct, sex-dependent phenotypes. Allodynia was more pronounced and longer-lasting in female mice than in males. Moreover, cognitive alterations were observed only in female mice and exhibited a bidirectional pattern. While repetitive CSD impaired the consolidation or retrieval of long-term reference memory, it transiently enhanced short-term episodic memory. These changes occurred shortly after CSD stimulation and were reversible. Together, these results offer a novel perspective for investigating sex differences in migraine with aura and highlight the dual, dynamic influence of CSD on brain cognitive function.

Abstract Background Our recent estimate of the global 1-year prevalence of headache among those aged 18–65 years was 65%: considerably higher than previous estimates, but based solely on high-quality epidemiological data derived from a large population-based sample. Here we present complementary estimates of 1-day prevalence. Methods We performed a meta-analysis of individual participant data from cross-sectional surveys among population-representative samples (age range 18–65 years) from 15 countries and all world regions. All used the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, including the question “did you have a headache yesterday?”, from which 1-day prevalence was determined. An algorithmic process applying modified ICHD criteria yielded separate estimates for migraine, tension-type headache (TTH) and probable medication-overuse headache (pMOH: the association of headache on ≥ 15 days/month and medication overuse). We analysed associations with age, gender and country-income level, and adjusted prevalence estimates for these factors. We calculated predicted 1-day prevalence from 1-year prevalence and reported headache frequency. Results Among the 38,512 participants, females (53.4%) and participants from low- (17.1%) or lower-middle-income countries (64.6%) were overrepresented, but age distribution fairly matched that of the world. Overall, 13.7% (95% CI: 13.3–14.0) reported headache yesterday, females (17.1% [16.6–17.6]) more than males (9.7% [9.3–10.2]). Migraine was the most common headache type yesterday (6.0% [5.8–6.3]), followed by TTH (4.1% [3.9–4.3]) and pMOH (2.3% [2.2–2.5]). One-day headache prevalence was higher in low/lower-middle-income countries (13.9% [13.6–14.3]) than in high/upper-middle-income countries (12.4% [11.6–13.2]). Predicted 1-day prevalence (10.9% [10.7–11.1]) was considerably lower than observed 1-day prevalence (13.7% [13.3–14.0]), although not among those with pMOH (3.1% [3.0-3.3] versus 2.3% [2.2–2.5]). Adjusted for age, gender and country-income level, global 1-day prevalence estimates were 13.1% (12.8–13.5) for any headache, 5.7% (5.5–5.9) for migraine, 3.9% (3.7–4.1) for TTH and 2.4% (2.3–2.6) for pMOH, with 1.0% undiagnosed. Conclusion Assuming yesterday was no different from any other day, an estimated 13.1% (N = 641,900,000) of the world’s population aged 18–65 years will have headache tomorrow; almost half will be migraine. People with migraine or TTH underestimate the frequency of headache episodes. Since headache-attributed burden is usually estimated from recalled frequency over 1–12 months, this also may be underestimated.

ObjectiveCurrent fractional flow (FF) approaches in quantifying the hemodynamic severity of intracranial atherosclerotic stenosis (ICAS) are invasive or require angiography. This study primarily evaluated a noninvasive FF method derived from magnetic resonance angiography (MRA-FF) against established reference standards, with an exploratory assessment of its ability to reflect hemodynamically relevant impairment.MethodsIn this retrospective study of 50 patients with ICAS, MRA-FF was computed from 3D vascular models using patient-specific flow boundary conditions. Agreement with invasive pressure-wire-derived FF (PW-FF, n = 18) and angiography-based FF (DSA-FF, n = 50) was assessed using intraclass correlation coefficients (ICC). Equivalence to DSA-FF was evaluated using the two one-sided tests procedure (TOST; δ = ±0.05). An exploratory analysis examined the ability of MRA-FF to discriminate hypoperfusion using receiver operating characteristic (ROC) analysis in the subset of patients with available perfusion imaging (n = 38).ResultsMRA-FF showed moderate-to-good agreement with PW-FF (ICC = 0.743; 95% CI, 0.437–0.895) and good agreement with DSA-FF (ICC = 0.784; 95% CI, 0.649–0.871). Equivalence to DSA-FF was confirmed by TOST (90% CI of difference, −0.016 to 0.035; p < 0.01). In the perfusion subset, MRA-FF was lower in patients with hypoperfusion than in those without (p = 0.022). The area under the ROC curve for discriminating hypoperfusion was 0.723 (95% CI, 0.54–0.90). Within this dataset, the exploratory optimal cutoff value was 0.855.ConclusionMRA-FF demonstrates good agreement with invasive and angiographic reference methods and shows the ability to discriminate hypoperfusion in an exploratory analysis. These findings support the feasibility and potential clinical utility of a fully noninvasive FF approach for functional assessment and hemodynamic characterization, although further external validation is required.

Medication overuse headache (MOH) is a chronic disorder due to excessive acute headache treatment use. Neuroimaging studies suggest the involvement of the orbitofrontal cortex (OFC) in the pathophysiology of MOH, particularly its connections with the periaqueductal gray (PAG). The OFC-vlPAG circuit has been well-established as a critical neural substrate in pain regulation; while its role in triptan-related MOH pathogenesis remains unclear. This study aims to investigate the role of the OFC-vlPAG circuit and its underlying mechanisms in regulating mechanical hypersensitivity using a triptan-induced MOH mouse model. Male C57BL/6J mice (along with a female exploratory cohort) were used to develop a triptan-induced MOH model through repeated rizatriptan (RIZ) administration. Behavioral assessments of cutaneous allodynia were conducted using von Frey filaments. Immunofluorescence staining was performed to examine neuronal activity and 5-HT1D receptor (5-HT1DR) expression in the OFC. Chemogenetic and optogenetic techniques were employed to modulate vlOFC glutamatergic neurons or the vlOFC-vlPAG pathway, and pharmacological methods were utilized to target the vlOFC’s 5-HT1DR. Repeated RIZ administration induced cutaneous allodynia in the MOH mouse model, with significant reductions in hind paw and head withdrawal thresholds. Elevated c-Fos expression in the vlOFC CaMKII-α+ neurons of triptan-induced MOH mice indicated increased glutamatergic neuronal activity. Chemogenetic and optogenetic glutamatergic neuron activation in the vlOFC alleviates allodynia in the triptan-induced MOH model. Furthermore, glutamatergic vlOFC-vlPAG circuit activation significantly improved pain thresholds in these MOH mice. The observed downregulation of 5-HT1DR in the vlOFC of these MOH mice was functionally associated with inhibition relief in this circuit. This adaptation may create a permissive state, allowing for robust analgesic effects upon targeted exogenous activation. Activating the glutamatergic OFC-vlPAG circuit elicits robust analgesia in triptan-induced MOH mice. 5-HT1DR downregulation is hypothesized to unmask the circuit’s analgesic potential by elevating vlOFC baseline activity, providing a highly responsive therapeutic target for triptan-related allodynia. Not applicable.