Journal of Headache and Pain最新文献

{"title":"Source-level α periodic power in visual and default mode networks predicts topiramate treatment response in migraine.","authors":"Siyuan Xie, Chenghui Pi, Kang Jin, Longteng Ma, Yunyun Huo, Miaomiao Hu, Xiaoyan Zhang, Suyuan Tai, Jiayin Lin, Shengyuan Yu, Ye Ran, Zhao Dong","doi":"10.1186/s10194-026-02461-5","DOIUrl":"10.1186/s10194-026-02461-5","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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% of the variance in treatment efficacy.</p><p><strong>Conclusion: </strong>Periodic α activity represents a strong predictive biomarker of topiramate efficacy, with higher α power indicating poorer clinical response. These findings provide an interpretable neurobiological basis for individualized prediction in migraine preventive therapy.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Migraine is associated with altered approach-avoidance decision processing: a case control study.","authors":"Sebastian Evers, Andrea Kübler, Claudia Sommer","doi":"10.1186/s10194-026-02445-5","DOIUrl":"10.1186/s10194-026-02445-5","url":null,"abstract":"<p><strong>Background: </strong>Behavioral management of migraine has traditionally emphasized trigger avoidance, although emerging evidence supports a shift toward more confrontative coping strategies. Understanding how individuals with migraine process and respond to trigger-related information in approach-avoidance situations is critical for developing targeted interventions.</p><p><strong>Methods: </strong>Individuals with migraine and migraine-free controls were exposed to visual trigger-related and neutral stimuli prior to making approach-avoidance decisions in an adapted virtual T-maze paradigm. Behavioral measures included decision time (DT) and initial movement response (IMR). Neurophysiological activity was assessed through high-density EEG focusing on frontal alpha asymmetry (FAA), frontal midline theta activity (FMT), and functional connectivity as indexed by the debiased weighted phase lag index (dwPLI).</p><p><strong>Results: </strong>Both groups achieved comparable overall performance. Individuals with migraine exhibited significantly prolonged decision times (DTs), particularly in avoidance and high-conflict conditions, indicating increased cognitive demand. This effect was contrary to the initial hypothesis. Importantly, indirect trigger confrontation did not significantly influence avoidance behavior or decision times, nor did it modulate EEG measures, indicating a robust null effect. As secondary results, neurophysiological analyses revealed reduced FAA and FMT activity as well as situation-dependent alterations in dwPLI-based functional connectivity, providing converging evidence for altered regulatory control and increased neural excitability in migraine.</p><p><strong>Conclusions: </strong>Migraine is associated with altered approach-avoidance decision processing characterized by increased cognitive demand and impaired regulatory control. Indirect trigger confrontation appears insufficient to systematically modulate these processes within the present paradigm. These findings indicate alterations in decision-making dynamics in migraine. Further research using simpler behavioral paradigms and the utilization of neuromodulation strategies targeting FAA and FMT are required.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13377724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A delayed endothelial-glial mechanism for CGRP-induced migraine.","authors":"Jochen K Lennerz, Karl Messlinger","doi":"10.1186/s10194-026-02455-3","DOIUrl":"10.1186/s10194-026-02455-3","url":null,"abstract":"<p><p>CGRP is a key mediator in migraine and an important component of trigeminovascular signaling in primary headache disorders. Yet how CGRP induces delayed migraine-like pain after systemic infusion remains unresolved. Despite strong clinical and experimental evidence for its role, the mechanisms linking CGRP signaling to trigeminovascular nociception are still unclear. Based on a comprehensive review of the experimental literature, we propose a hypothesis, in which CGRP initiates a delayed signaling cascade that ultimately sensitizes trigeminal afferents. In this framework, CGRP promotes not only arterial vasodilatation but activates glial responses involving transcription-dependent processes and ion channel modulation that evolve over hours and provide a mechanistic explanation for the delayed onset of migraine-like pain. We further propose that peripheral endothelial-glial signaling may be amplified at ganglionic and spinal levels, contributing to trigeminovascular sensitization. In spontaneous migraine attacks, CGRP release appears as a consequence of primary afferent excitation through an excess of nitric oxide species activating transient receptor potential channels, most likely initiated by an endothelial dysfunction through metabolic disturbances including cortical spreading depression. These peripheral mechanisms do not exclude central changes that govern the periodic susceptibility of migraine and cluster headache attacks. Our model integrates existing observations regarding CGRP biology, delayed migraine induction, and glial signaling into a unified framework. We reframe migraine generation as a neuro-glial process and highlight new targets for therapeutic intervention.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Headache among children and adolescents in Benin: revised prevalence estimates, and estimates of attributed burden, from a national schools-based study.","authors":"Mendinatou Agbetou Houessou, Thierry Adoukonou, Willy Tchuenga Fokom, Nelly Dovoedo, Tayyar Şaşmaz, Fatma Bozdağ, Derya Uluduz, Andreas Kattem Husøy, Timothy J Steiner","doi":"10.1186/s10194-026-02448-2","DOIUrl":"10.1186/s10194-026-02448-2","url":null,"abstract":"<p><strong>Background: </strong>In our earlier report of headache prevalence among children (6-11 years) and adolescents (12-17) in Benin, undifferentiated headache (UdH) was defined conventionally as mild headache lasting < 1 h. In this and similar studies elsewhere in sub-Saharan Africa, we recognised diagnostic uncertainties among the many participants with short-duration headache. Here we make new estimates of prevalence using a modified definition of UdH, and, based on these, estimates of attributed burden. The study was part of the global schools-based programme conducted by the Global Campaign against Headache.</p><p><strong>Methods: </strong>In a cross-sectional survey, the child and adolescent versions of the structured HARDSHIP questionnaire, translated into West-African French, were completed by pupils in class in 16 schools representative of Benin's urban/rural divide. Headache diagnoses were based on ICHD-3 except for UdH, which we redefined as mild or moderate headache lasting < 1 h. Enquiry included multiple aspects of attributed burden, with a timeframe of 4 weeks and additional enquiry into headache yesterday (HY).</p><p><strong>Results: </strong>Of 2,488 eligible pupils, 193 (or their parents) declined, while 2,295 completed the questionnaires (males 1,156 [50.4%], females 1,139 [49.6%]; children 1,081 [47.1%], adolescents 1,214 [52.9%]; mean age 12.1 ± 3.1 years [median 12]; participating proportion 92.2%). With the modified definition, observed 1-year prevalence of UdH increased from 8.4% to 21.0%, with corresponding reductions for migraine (from 52.1% to 44.9%) and tension-type headache (TTH) (from 21.8% to 17.2%). Mean symptom burden was expressed in moderate headache on 4.2 days/4 weeks, with duration 2.8 h. All headache accounted for 4.0% lost school time according to 4-week recall, 3.3% when assessed from HY (which could not capture lost days immediately preceding weekends or holidays). Almost one in three parents (30.3%) lost time from their own work, those of children more than those of adolescents. Measures of impaired participation clearly distinguished migraine (greater burden) from TTH and UdH CONCLUSIONS: Headache is prevalent among children and adolescents in Benin. The associated lost health and impaired participation, including lost school time with, potentially, lifelong negative impact, are reliably attributed to headache. Attribution to specific headache types is less certain because of unresolved diagnostic difficulties surrounding short-duration headache.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cell levels in migraine: A systematic review and meta-analysis.","authors":"Emily Stuchfield-Denby, Samuel Adelou, Xavier Moisset, Radhouane Dallel","doi":"10.1186/s10194-026-02443-7","DOIUrl":"10.1186/s10194-026-02443-7","url":null,"abstract":"<p><strong>Background: </strong>Although recent research suggests that regulatory T (Treg) cells may be involved in migraine pathophysiology, no review has provided a comprehensive assessment of their levels in this condition. This systematic review and meta-analysis aims to assess Treg levels in migraine patients.</p><p><strong>Methods: </strong>We systematically searched PubMed, Embase and Cochrane on July 5, 2024 (updated on March 19, 2026), and included all original studies providing data on Treg levels in migraine.</p><p><strong>Results: </strong>Among 1,162 studies identified, five were included in the narrative review and four in the meta-analysis. Data were pooled using a random-effects model. Standardized mean differences (SMD) were calculated to compare peripheral whole blood Treg levels between migraine and control groups. Our narrative review showed decreased Treg levels in three of five studies comparing migraine patients and controls, and in two of three studies on interictal episodic migraine patients and controls. Our meta-analysis of few but carefully selected data suggested a significant decrease in Treg cell levels in migraine (SMD - 4.21 [-7.76; -0.66], p = 0.02, I²=98.3%).</p><p><strong>Conclusions: </strong>Our findings suggest Treg levels are decreased in migraine and of potential interest in understanding migraine pathophysiology. However, the limited data available warrant further investigations to shed light on their relevance and therapeutic potential in this condition.</p><p><strong>Trial registration: </strong>PROSPERO CRD42023490445.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective reduction of thalamic glutathione in migraine in the absence of detectable N-acetylaspartate alterations.","authors":"Rui Wang, Seungho Kim, Hongying Huang, Dafa Shi, Zhongruowen Ren, Changho Choi, Gen Yan, Yongmin Chang, Renhua Wu","doi":"10.1186/s10194-026-02456-2","DOIUrl":"10.1186/s10194-026-02456-2","url":null,"abstract":"<p><strong>Background: </strong>Oxidative stress has been implicated in migraine pathophysiology, but direct evidence of brain antioxidant alterations and their relationship to neuronal integrity remains limited.</p><p><strong>Methods: </strong>We conducted a cross-sectional proton magnetic resonance spectroscopy (¹H-MRS) study measuring seven metabolites in a single thalamic voxel of 131 participants (left or right, selected for spectral quality): 36 healthy controls, 46 migraines without aura, 17 migraines with aura, and 32 tension-type headache patients.</p><p><strong>Results: </strong>Glutathione (GSH) was the only metabolite showing significant group differences (Welch's F = 31.74, p < 0.001, η² = 0.432). Thalamic GSH was reduced in migraine without aura (1.76 ± 0.16) and migraine with aura (1.70 ± 0.13) compared to healthy controls (2.07 ± 0.20), with large effect sizes (Cohen's d = 1.70 and 2.14, respectively). N-acetylaspartate (NAA), a marker of neuronal integrity, showed no group differences (p = 0.74). Equivalence testing showed that the GSH-NAA correlation was statistically equivalent to zero within predefined bounds (TOST p = 0.015), indicating that GSH reduction occurred in the absence of a detectable linear association with NAA in this sample. GSH demonstrated good diagnostic performance (AUC = 0.895, 95% CI 0.821-0.952; sensitivity 93.7%; specificity 69.4%), validated by permutation testing (p = 0.001).</p><p><strong>Conclusions: </strong>These findings indicate selective thalamic GSH reduction in migraine in the absence of detectable NAA alterations. These observations are consistent with reduced thalamic antioxidant capacity that is not accompanied by measurable neuronal loss, although NAA cannot exclude subtle neuronal or synaptic dysfunction. Thalamic GSH may represent a candidate biomarker that requires independent validation, and the potential of antioxidant strategies remains hypothesis-generating.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13425860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sexual dimorphism in cortical excitability: repetitive nitroglycerin unmasks maladaptive spreading depolarization in female mice.","authors":"Otilia Gliga, Víctor-José Gallardo, Patricia Pozo-Rosich, Marta Vila-Pueyo","doi":"10.1186/s10194-026-02449-1","DOIUrl":"10.1186/s10194-026-02449-1","url":null,"abstract":"<p><strong>Background: </strong>Cortical excitability is maintained by a finely regulated balance between excitatory and inhibitory neurotransmission. This balance is sexually dimorphic and shapes vulnerability to pathological events such as cortical spreading depolarization (CSD), the electrophysiological correlate of migraine aura and a key phenomenon in stroke, traumatic brain injury, and seizures. Although migraine and several CSD-related disorders disproportionately affect women, most preclinical studies rely on acute, male-only paradigms, limiting understanding of how biological sex shapes cortical responses to recurrent migraine-relevant stimuli. Here, we examined whether repetitive exposure to the migraine trigger nitroglycerin (NTG) unmasks sex-specific alterations in cortical excitability and CSD recurrence dynamics.</p><p><strong>Methods: </strong>Male and female C57BL/6J mice received five systemic NTG or vehicle injections every other day to induce sustained sensitization. After the development of mechanical orofacial allodynia, in vivo electrophysiological recordings were performed to quantify CSD frequency, induction latency, and waveform characteristics. Generalized Poisson and mixed-effects models were used to assess the effects of sex, treatment, and their interaction, with model selection based on likelihood ratio tests and residual diagnostics performed using the DHARMa package.</p><p><strong>Results: </strong>Repetitive NTG induced progressive mechanical allodynia in both sexes (χ²(2) = 110.05, p < 0.001). In contrast, CSD metrics revealed marked sexual dimorphism in the adaptive response to repeated NTG stimulation. NTG increased CSD frequency by 41% in females (IRR [95% CI] = 1.41 [1.15-1.73], p = 0.001) but not in males (sex × group: p = 0.043). NTG also reduced first CSD induction latency (χ²(1) = 4.76, p = 0.029) and attenuated the prolongation of latency across successive CSD events (χ²(1) = 4.54, p = 0.033) selectively in females indicating sustained cortical hyperexcitability. CSD amplitude and duration remained unchanged across groups.</p><p><strong>Conclusions: </strong>These findings demonstrate that repetitive NTG exposure unmasks a female-specific failure of cortical homeostatic adaptation to recurrent noxious stimuli in the context of CSD-related readouts. This maladaptive response is consistent with the involvement of sex-dependent regulatory pathways, potentially involving hormonal or epigenetic mechanisms, as candidate determinants of the cortical threshold for depolarization; however, causal mechanistic attribution awaits direct experimental testing. Our results highlight sex as a fundamental determinant of cortical excitability and underscore the need for sex-inclusive, repetitive paradigms to better understand female-biased vulnerability and chronification in migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGR1-associated inflammatory and neurovascular signatures suggest a potential link between migraine and ischemic stroke.","authors":"Wenzheng Rong, Jing Xu, Bo Li, Xiaofeng Zhang, Yapeng Li, Bo Song, Yuming Xu","doi":"10.1186/s10194-026-02447-3","DOIUrl":"10.1186/s10194-026-02447-3","url":null,"abstract":"<p><strong>Background: </strong>Migraine is associated with an increased risk of ischemic stroke, but the molecular mechanisms linking these two disorders remain unclear.</p><p><strong>Methods: </strong>We performed an integrated analysis of bulk RNA-seq data from ischemic stroke and single-cell RNA-seq data from a mouse migraine model. Differential expression, Gene Ontology enrichment, cell-cell communication, protein-protein interaction, disease association, and drug-gene interaction analyses were conducted to identify shared molecular signatures and pathways. A nitroglycerin-induced migraine mouse model was further used to validate neurovascular alterations in vivo.</p><p><strong>Results: </strong>Integrated transcriptomic analysis identified shared upregulated genes between migraine and ischemic stroke, with IL1B and EGR1 emerging as key candidates. In ischemic stroke, enriched pathways were mainly related to immune and inflammatory responses, particularly immune response-regulating cell surface receptor signaling and interleukin-1-mediated signaling, with IL1B and EGR1 emerging as prominent candidates in the enriched network context. Single-cell analysis showed that EGR1 was the only significantly shared upregulated gene in migraine, with elevated expression in PEP neurons, NF neurons, vascular cells, and fibroblasts, while the interleukin-1 production pathway was activated in most of these cell types. Cell-cell communication analysis revealed enhanced interactions among neuronal, vascular, and fibroblast populations, especially through ANGPTL signaling. Network analysis highlighted EGR1, IL1B, TLR4, and ANGPTL2 as candidate hub-associated molecules. In vivo, the migraine model showed increased neuronal activation, persistent mechanical hypersensitivity, and reduced ZO-1 expression in the trigeminocervical complex, indicating vascular tight junction impairment.</p><p><strong>Conclusion: </strong>These findings identify shared inflammatory and neurovascular signatures across migraine-related and ischemic stroke-related datasets, with EGR1 emerging as a candidate molecule associated with these convergent changes. Our results support a hypothesis-generating model in which inflammatory signaling and altered neurovascular communication may represent potential links between migraine and stroke-related vascular vulnerability. Further functional studies are required to determine whether EGR1 or related pathways play a causal role.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148421627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptidomics profiling identifies endogenous peptides associated with meningeal afferent activation in a chronic migraine mouse model.","authors":"Guizeng Zhao, Chenyang Duan, Yongkun Gui, Hongmei Wang, Jun Zhao, Chen Song, Shuzhi Zang, Zhitao Gao, Chenguang Zhang, Junwei Cui, Tingmin Chang","doi":"10.1186/s10194-026-02426-8","DOIUrl":"10.1186/s10194-026-02426-8","url":null,"abstract":"<p><p>Migraine is a highly disabling disorder with a high prevalence, significantly impairing quality of life. Emerging evidence suggests that circulating endogenous peptides play critical roles in neurovascular regulation and nociceptive signaling. However, the contribution of blood-derived endogenous peptides to the activation of meningeal afferents and the pathophysiology of migraine remains poorly understood. Therefore, investigating the role of these peptides in the meninges is crucial for elucidating the mechanisms underlying migraine. To elucidate the role of endogenous peptides in activating meningeal afferents during migraine, we established a chronic migraine mouse model using nitroglycerin (NTG). Serum peptidomic analysis was performed to identify differentially expressed peptides between the Negative Group (NEG) and NTG group. Functional enrichment analysis revealed significant upregulation of pathways associated with prolactin signaling and hypoxia-inducible factor-1 (HIF-1) signaling. Subsequently, peptidomic profiling of the meninges was conducted in both groups. Integration of meningeal and serum peptidomic datasets, together with a curated set of endogenous secreted proteins, enabled cross-comparative analysis to identify circulating peptides with potential effects on the meninges. This analysis revealed a marked increase in both pituitary adenylate cyclase-activating polypeptide (PACAP) and calcitonin gene-related peptide (CGRP), two key mediators critically implicated in migraine pathophysiology.In addition, several PACAP-related short peptide fragments were identified, some of which exhibited sequence homology to known bioactive domains. Collectively, these findings suggest that PACAP and CGRP, along with their derived peptide fragments, may contribute to the activation of meningeal nociceptive fibers and thereby participate in the initiation and maintenance of migraine. Peptidomics sequencing of the TNC region was performed, and functional enrichment analysis of the differentially expressed proteins indicated the dysregulation of diverse biological pathways. These findings reveal that CGRP and PACAP may play a key role in the activation of meningeal afferents in a chronic migraine mouse model. Several protein modification sites are thought to be crucial mechanisms in endogenous peptides-mediated meningeal activation.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13628954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-response to Calcitonin Gene-Related Peptide monoclonal antibodies in a real-world setting: analysis of prospective data collected in the French FHU InovPain registry.","authors":"S Ferrao-Malheiro, R Fabre, T Jiacomini, M Lanteri-Minet","doi":"10.1186/s10194-026-02444-6","DOIUrl":"10.1186/s10194-026-02444-6","url":null,"abstract":"<p><strong>Background: </strong>Real-world data on calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are essential to determine whether a class effect exists and to assess the benefit of switching between treatments. Available data remain limited as most studies focused exclusively on patients who failed previous CGRP mAbs and evidence regarding newer agents such as eptinezumab are still scarce.</p><p><strong>Methods: </strong>This prospective real-world study included all adult patients enrolled in the FHU InovPain registry who received intravenous eptinezumab 100 mg and after prior treatment with one or more subcutaneous CGRP mAbs, regardless of their response to previous CGRP mAbs. According to the 50% response rate (in terms of monthly migraine days) after 6 months of treatment, a descriptive analysis of switching from subcutaneous CGRP mAbs to eptinezumab was performed. Patients were classified into three subgroups: cross-effectiveness (all CGRP mAbs used were effective), cross-ineffectiveness (all CGRP mAbs used were ineffective), and no cross-response (different responses across CGRP mAbs used). Factors associated with response to CGRP mAbs were investigated by comparing patients with cross-ineffectiveness (with the CGRP mAbs used) to those who responded to at least one CGRP mAb (cross-effectiveness and no cross-response), followed by multivariate logistic regression.</p><p><strong>Results: </strong>A total of 190 patients (83.7% women; mean age 52.2 ± 13.7 years) were included. The 50% responder rate to eptinezumab was 76.0% (95% CI: 67.3-83.1) in patients who had responded to at least one previously used CGRP mAb, compared with 30.4% (95% CI: 20.2-42.8) in patients with no prior response to CGRP mAbs. Cross-effectiveness, cross-ineffectiveness, and no cross-response were observed in 46.8% (95% CI: 39.6-54.2), 28.9%, (95% CI: 22.7-36.0) and 24.2% (95% CI: 18.4-31.7) of patients, respectively. Only two factors were associated with response to at least one CGRP mAb: a lower helplessness score on the Pain Catastrophizing Scale (AdjOR 0.91, 95% CI: 0.86-0.97, p=0.004) and a lower allodynia score on the ASC-12 (AdjOR 0.91, 95% CI: 0.84-0.98, p=0.010).</p><p><strong>Conclusion: </strong>This real-world study confirms the clinical benefit of switching to eptinezumab in nearly one-third of patients who did not respond to previous subcutaneous CGRP mAbs. It also demonstrates a class effect that is not absolute, as nearly one-quarter of patients showed no cross-response between CGRP mAbs.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}