Journal of Headache and Pain最新文献

{"title":"Trigeminal nociceptive somatotopy across brainstem and cortex and their functional interactions.","authors":"Adrian Scutelnic, Kuan-Po Peng, Kristina Kokian, Arne May, Jan Mehnert","doi":"10.1186/s10194-026-02476-y","DOIUrl":"10.1186/s10194-026-02476-y","url":null,"abstract":"<p><strong>Background: </strong>The trigeminal nerve innervates the face and the meninges via its three branches, with central relay neurons located in the brainstem's spinal trigeminal nucleus. We have shown a somatotopic organization on human brainstem level and aimed, using an independent new sample, to characterize the functional somatotopy with a focus on within-brainstem and brainstem-cortical connectivity.</p><p><strong>Methods: </strong>Electrical stimulation was applied to the three branches of the trigeminal nerve at two intensities (high and low) to examine the somatotopic organization in healthy participants during fMRI. Neuroimaging was preregistered (NCT06534880) and covered the upper spinal cord, brainstem, thalamus, insula, primary somatosensory cortex (S1), S2/parietal operculum, and cingulate cortex. Activation patterns following stimulation of each trigeminal branch were analyzed. Branch-specific functional connectivity was estimated within the brainstem as well as between brainstem and cortical targets.</p><p><strong>Results: </strong>In a cohort of 30 healthy participants (mean age 32.1 ± 8.8 years, 18 female (60%)), spatially distinct brainstem representations of the trigeminal branches were identified, replicating previous reports. Activation at the cortical level was largely bilateral and symmetric, except in the primary somatosensory cortex and the insula, where it was predominantly contralateral. Within the brainstem, functional connectivity was strongest between the left and right subnuclei at the same level and was independent of the stimulated branch (all F(2,116) ≤ 5.67, threshold F = 8.00, α = 0.05/90). Brainstem-cortex connectivity showed a robust rostrocaudal gradient that was modulated by the stimulated branch across insular, somatosensory, and opercular regions (significant in 37/48 ROIs, F-Range 2.46-5.19, P_FWE<0.05).</p><p><strong>Conclusion: </strong>We replicated somatotopic representation of the three trigeminal branches in the brainstem and revealed distinct bilateral activation and branch-specific functional connectivity across multiple levels of the afferent neuraxis.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865373","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 disorders and the Global Burden of Disease study: deficiencies, challenges and opportunities for betterment.","authors":"Andreas Kattem Husøy, Latifa Adarmouch, Amalie Berring-Uldum, Raquel Gil-Gouveia, Rigmor Jensen, Risako Shirane, Timothy J Steiner","doi":"10.1186/s10194-026-02490-0","DOIUrl":"10.1186/s10194-026-02490-0","url":null,"abstract":"","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706688","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":"Pain in Parkinson's disease: bridging pathophysiology, clinical features, and personalized management.","authors":"Thalis Asimakopoulos, Iliana Psychari, Martina Rekatsina, Zinovia Kefalopoulou","doi":"10.1186/s10194-026-02416-w","DOIUrl":"10.1186/s10194-026-02416-w","url":null,"abstract":"<p><p>Pain is a highly prevalent and disabling non-motor symptom of Parkinson's disease (PD), yet it remains underrecognized and frequently undertreated in clinical practice. Although long considered a secondary consequence of motor dysfunction, pain in PD is now increasingly understood as a manifestation of disease-related alterations in nociceptive processing. These changes extend beyond dopaminergic deficiency and involve broader neurotransmitter imbalances and impaired descending inhibitory control across different neuroanatomical regions, providing a framework for understanding pain as an intrinsic feature of PD rather than a purely peripheral or motor-related phenomenon. We also summarize the main categories of pain experienced in PD, each with distinct clinical features and underlying pathophysiological mechanisms, and link them with current management strategies. A multimodal, mechanism-informed approach that integrates optimization of dopaminergic therapy with non-dopaminergic pharmacological treatments, neuromodulation, rehabilitation, and complementary interventions is key to a personalized treatment plan for pain in patients with PD. Finally, we highlight emerging translational directions, including candidate biomarkers that may help objectify pain and its related dysfunction in the PD population. Focusing on the neurobiological basis of pain in PD, this review aims to support a shift toward mechanism-based assessment and management, with an ultimate goal of improving pain outcomes and quality of life for individuals living with the disease.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712678","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":"Botulinum toxin type A attenuates trigeminal neuralgia-like pain by suppressing CGRP release and modulating NaV1.7-associated signaling.","authors":"Min-Hua Yao, Hai-Chao Chen, Xiao-Yu Zhang, Si-Wei Zhou, Chuan-Xiong Li, Yan-Yu Lu, Zi-Rui Liao, Lei Wang, Ruo-Hui Zhang, Yu-Hong Jing","doi":"10.1186/s10194-026-02454-4","DOIUrl":"10.1186/s10194-026-02454-4","url":null,"abstract":"<p><strong>Background: </strong>Trigeminal neuralgia (TN) is a disabling facial pain disorder, and current treatments remain insufficient for a substantial proportion of patients. Botulinum toxin type A (BoNT/A) has shown therapeutic benefit in TN, but its peripheral analgesic mechanisms remain incompletely understood. We aimed to determine whether BoNT/A alleviates TN-like pain by modulating the calcitonin gene-related peptide (CGRP)-extracellular signal-regulated kinase (ERK)-NaV1.7 pathway in trigeminal ganglion neurons.</p><p><strong>Methods: </strong>TN-like pain was induced in mice by chronic constriction injury of the infraorbital nerve (CCI-ION). On postoperative day 14, BoNT/A (10 U) or saline was injected intradermally into the whisker pad. Evoked and spontaneous pain-like behaviors were assessed using von Frey testing, the Ugo Basile facial pain test, and spontaneous scratching recordings; anxiety-like behavior was evaluated using the elevated plus maze. Myelin pathology was examined by Luxol fast blue staining and transmission electron microscopy. CGRP, NaV1.7/NaV1.8, and ERK/MAPK signaling were examined in trigeminal ganglion neurons using immunofluorescence, Western blotting, RT-qPCR, ELISA, calcium-influx assays, and whole-cell patch-clamp recordings. Olcegepant and PD98059 were used to interrogate CGRP receptor- and ERK-dependent mechanisms.</p><p><strong>Results: </strong>BoNT/A significantly attenuated CCI-ION-induced mechanical allodynia, increasing the facial withdrawal threshold from 0.11 to 1.29 g, and reducing spontaneous pain-like behaviors. BoNT/A also improved anxiety-like behavioral measures in CCI-ION mice. Histological and ultrastructural analyses shown partial amelioration of myelin pathology, accompanied by increased myelin basic protein expression and a lower g-ratio. Mechanistically, BoNT/A reduced CGRP-associated activity in TRPV1-positive trigeminal ganglion neurons, accompanied by lower serum CGRP levels and attenuated capsaicin-evoked calcium influx. These changes were associated with a preferential reduction in NaV1.7 membrane localization, without a comparable reduction in NaV1.8, and with a marked decrease in sodium current density, with peak sodium current reduced by 78.6%. Pharmacological inhibition of CGRP receptors or ERK phosphorylation reproduced the effects of BoNT/A on NaV1.7 membrane localization.</p><p><strong>Conclusions: </strong>These findings suggest that BoNT/A alleviates CCI-ION-induced TN-like pain, at least in part, by suppressing CGRP-dependent ERK activation and subsequent NaV1.7 membrane recruitment in trigeminal ganglion neurons. The CGRP-ERK-NaV1.7 pathway may represent a peripheral mechanism of BoNT/A-mediated analgesia and a potential target for neuropathic facial pain.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706709","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":"Evaluating clinical associations of immediate post-traumatic headache: a prospective multicenter study.","authors":"Mansoureh Togha, Maryam Bahreini, Sepideh Aarabi, Elham Jafari, Soroor Advani, Nahid Beladi-Moghadam, Narges Yazdi, Muhammad Hussain Ahmadvand","doi":"10.1186/s10194-026-02478-w","DOIUrl":"10.1186/s10194-026-02478-w","url":null,"abstract":"<p><strong>Background: </strong>Post-traumatic headache (PTH) is a frequent early consequence of head traumatic injury, yet emergency departments (EDs) lack practical tools to identify high-risk patients. Whether routinely documented trauma characteristics are associated with immediate PTH beyond established clinical factors remains uncertain.</p><p><strong>Methods: </strong>This prospective, multicenter observational study evaluated patients aged ≥ 18 years presenting with head and/or neck trauma to the ED between 2022 and 2025. To adhere strictly to ICHD-3 criteria and prevent severity measurement bias, the primary analysis was restricted exclusively to a homogeneous cohort of 495 patients with mild traumatic head injury (GCS 13-15, no traumatic brain CT abnormalities). The primary outcome was immediate PTH occurring directly following the traumatic event. To prevent overfitting, candidate variables were restricted a priori to 9 core features. We utilized multivariable logistic regression and evaluated internal validity via 500 bootstrap resamples.</p><p><strong>Results: </strong>Immediate PTH occurred in 62.8% of patients with mild head trauma. Prior headache history showed the strongest association with PTH. Several trauma-related characteristics, including posterior, frontal, and temporal impact locations, scalp hematoma, and traffic accident mechanism, were independently associated with higher odds of PTH. Variance Inflation Factor (VIF) confirmed no significant multicollinearity (< 1.85). The parsimonious 9-variable model demonstrated robust discrimination and stability, with an apparent AUC of 0.855 and an optimism-corrected AUC of 0.843.</p><p><strong>Conclusions: </strong>An association model based on 9 routine ED variables identified several clinical and specific trauma features strongly associated with immediate PTH in mild head trauma patients. These findings highlight important early prognostic factors and maintain statistical stability; however, external validation is required before widespread clinical application.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684809","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":"Impact of semaglutide introduction on the use of triptans: an interrupted-time series.","authors":"Noémie Roland, Heidi Sonne, Lanfranco Pellesi, Maja Bramming, Lise Gehrt Cardél, Anton Pottegård, Helene Kildegaard","doi":"10.1186/s10194-026-02462-4","DOIUrl":"10.1186/s10194-026-02462-4","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence suggests that glucagon-like peptide-1 receptor agonist (GLP-1RA) may be associated with reduced migraine burden. We aimed to evaluate whether semaglutide for weight management initiation is associated with changes in triptan consumption.</p><p><strong>Methods: </strong>We conducted a nationwide interrupted time series analysis using Danish health registers. All adults initiating semaglutide between December 2022 and December 2024 were included. The first dispensing date served as the index date, establishing a 24-month baseline and a 12-month follow-up period. The primary outcome was monthly triptan consumption (defined daily doses (DDD)/10,000 individuals). Analyses were conducted for new and prevalent triptan users, and stratified by sex, age group, and prior use of prophylactic antimigraine medication.</p><p><strong>Findings: </strong>During the study period, 189,392 individuals initiated semaglutide (68% females, median age 50 years). Before initiation, triptan use increased over time; after initiation, this trend reversed, showing a decline of -13 DDD/month/10,000 (95% CI: -25 to -1.3), corresponding to a 7% relative reduction at 12 months (RR 0.93; 0.88-0.97). This decrease primarily reflected a reduction in DDD consumption among prevalent users (RR 0.86; 0.82-0.90) rather than a change in monthly rates of new users. A sex-specific effect was observed, with female users demonstrating an 8% reduction (RR 0.92; 0.88-0.97) and males showing no statistically significant change. The largest reductions occurred in individuals aged 18-35 years (RR 0.86; 0.78-0.94) and previous users of prophylactic antimigraine medications (RR 0.88; 0.82-0.94).</p><p><strong>Conclusions: </strong>Weight-loss semaglutide initiation was associated with a modest, gradual reduction in triptan use, particularly among females and individuals with history of migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678828","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":"Genome-wide association susceptibility loci for cluster headache support a role for inflammation in the pathophysiology.","authors":"Caroline Ran, Clémence Deborgies Sanches, Julia Swedblom, Katrin Wellfelt, Alessandro Antoniazzi, Joseph Lloyd, Felicia Jennysdotter Olofsgård, Stefan Spulber, Elisabet Waldenlind, Maria Lantz, Anna Steinberg, Anna Sundholm, Christina Sjöstrand, Andrea Carmine Belin","doi":"10.1186/s10194-026-02485-x","DOIUrl":"10.1186/s10194-026-02485-x","url":null,"abstract":"<p><strong>Background: </strong>Recent genetic findings have broadened the perspectives of cluster headache pathophysiology. Genes identified by genome wide association studies are likely to be involved in the pathophysiological mechanisms underlying the disease. In this study, we performed validation and characterization of eight loci corresponding to nine genes identified in previous genome wide association studies.</p><p><strong>Methods: </strong>Genetic loci were validated by means of a case-control study using TaqMan genotyping in 671 individuals, and a meta-analysis using previously genotyped data. Pyrosequencing methylation analysis and reverse transcription quantitative PCR gene expression studies was performed in a subset of individuals with cluster headache and healthy controls.</p><p><strong>Results: </strong>Genetic associations were found with functional variants in two genes; FHL5 and MERTK. The minor allele of the FHL5 variant rs2273621 was associated with an increased risk of cluster headache in the genotyped samples (odds ratio = 1.42, P = 0.03) and in a meta-analysis (odds ratio = 1.29, confidence interval: 1.09-1.52), and the minor allele of the rs2230515 variant in MERTK was associated with lower risk in the meta-analysis (odds ratio = 0.69, confidence interval: 0.52-0.92). Methylation analysis further revealed altered methylation status of MERTK. Moreover, changes in relative gene expression were found for several candidate genes: a decrease in the mRNA expression of DUSP10 (P < 0.001), CAPN2 (P < 0.001), UFL1 (P < 0.001) and LRP1 (P = 0.007) in blood, and a decrease of CAPN2 (P < 0.001) as well as an increase in the mRNA expression of FTCDNL1/FONG (P = 0.004) in fibroblasts in CH vs. controls. Only two genes; PLCE1 and WNT2, could not be validated in the biological tissue studied; WNT2, possibly due to limited power, while PLCE1 was not expressed in the available tissue.</p><p><strong>Conclusions: </strong>These results confirm the validity of seven candidate genes for cluster headache identified through GWAS. Furthermore, five of the candidate genes are abundantly expressed in both immune and blood cells, converge functionally on inflammatory signalling pathways and suggest a potential role for inflammasomes in cluster headache.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678894","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-attributed burden among children and adolescents in Nepal: a national schools-based cross-sectional study.","authors":"Rajeev Ojha, Ragesh Karn, Bikram Prasad Gajurel, Reema Rajbhandari, Niraj Gautam, Bikash Deo, Aakarshan Timilsina, Anushka Adhikari, Ravi Raj Timasina, Gaurav Nepal, Derya Uludüz, Tayyar Şaşmaz, Bengü Nehir Buğdaycı Yalçın, Andreas Kattem Husøy, Timothy J Steiner","doi":"10.1186/s10194-026-02472-2","DOIUrl":"https://doi.org/10.1186/s10194-026-02472-2","url":null,"abstract":"<p><strong>Background: </strong>We recently published estimates of 1-year headache prevalence among children (6-11 years) and adolescents (12-17) in Nepal. Adjusted for age and gender, these were 83.9% for all headache, 39.5% for migraine, 31.7% for undifferentiated headache (UdH), 10.0% for tension-type headache (TTH), 0.3% for probable medication-overuse headache (pMOH) and 1.9% for other headache on ≥ 15 days/month (other H15+). Here we present estimates of attributed burden.</p><p><strong>Methods: </strong>We followed the Global Campaign's standardised protocol. In nine schools representative of the country, the child and adolescent versions of the structured HARDSHIP questionnaire were completed by pupils in class under supervision. Headache diagnoses followed ICHD-3, except for UdH, defined here as mild or moderate headache with usual duration < 1 h. Burden enquiries were in multiple domains, with timeframes of 4 weeks and 1 day, the latter based on reports of headache yesterday (HY).</p><p><strong>Results: </strong>There were 2,352 participants (1,040 children [44.2%]; 1,312 adolescents [55.8%]) from 2,360 eligible (participating proportion 99.7%). Symptom burden was expressed as moderate headache on an average of 2.9 days/4 weeks, lasting for 2.0 h. Mean proportion of time in ictal state (pTIS) was 1.0%, but much higher among those with pMOH (11.0%) or other H15+ (9.4%). Except for pMOH, only one third of headache episodes were medicated. Lost school time was 3% estimated from recall over the preceding 4 weeks, with similar time lost from other (social and leisure) activities. Actual absences from school yesterday because of HY were more (4.5%), suggesting losses were underestimated by recall, but, since recorded absences yesterday failed to capture absences on days preceding weekends or holidays, true losses might have been 5-6%. More than one fifth (21.7%) of parents lost time from their own work. Both emotional impact and quality-of-life (QoL) scores were sensitive to headache (and headache type), showing gradients of negative impact (pMOH and other H15+ > migraine > TTH and UdH).</p><p><strong>Conclusions: </strong>Symptom burden appeared to be relatively modest except for pMOH and H15+, but measures of impaired participation (including lost time from school), emotional impact and QoL all indicated material impact. Parents, teachers, health-care providers and policy makers should be aware of this.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794085","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":"Integrative genetic analysis identifies shared regulation of DNA methylation and gene expression in migraine risk.","authors":"Ammarah Ghaffar, Dale R Nyholt","doi":"10.1186/s10194-026-02469-x","DOIUrl":"10.1186/s10194-026-02469-x","url":null,"abstract":"<p><strong>Background: </strong>Migraine affects approximately 14% of adults, but the molecular mechanisms underlying susceptibility remain incompletely understood. Although genome-wide association studies (GWAS) have identified many migraine risk loci, translating these associations into biological insight remains challenging. Environmental and physiological migraine triggers, including hormones, diet and stress, may act partly through epigenetic mechanisms such as DNA methylation. Because many migraine risk variants are non-coding and may influence disease through regulatory effects, integrating genetic association data with DNA methylation and gene expression may help refine migraine-associated loci into candidate molecular mechanisms.</p><p><strong>Methods: </strong>We performed a novel methylome-wide association study (meWAS) of migraine, imputing genetically regulated DNA methylation at 86,518 cytosine-phosphate-guanine (CpG) sites using GWAS summary statistics derived from 102,084 migraine cases and 771,257 controls of European ancestry. We then linked DNA methylation signals to imputed gene expression using transcriptome-wide association study (TWAS) evidence across 49 Genotype-Tissue Expression tissues. Bayesian colocalisation analyses were used to prioritise CpGs and genes supported by shared causal variants with migraine risk, and to map shared regulatory signals between methylation and expression quantitative trait loci.</p><p><strong>Results: </strong>We identified 258 migraine-associated CpG sites after Bonferroni correction (P < 5.78 × 10^-7), of which 177 colocalised with migraine GWAS variants (PP4 > 0.5) and mapped to 69 independent genomic loci, including 58 established and 11 putative novel loci. Integration with TWAS evidence prioritised 199 genes (candidate-set Bonferroni-corrected TWAS P < 7.84 × 10^-5) near these CpG sites, including 91 genes with evidence of colocalisation with migraine GWAS variants. Further colocalisation between methylation and expression quantitative trait signals mapped shared regulatory signals to 120 CpGs and 78 genes across 40 independent genomic loci, comprising 32 established and eight putative novel migraine risk loci. Protein-protein interaction analysis showed modest but significant network enrichment, with local modules implicating signalling organisation, mitochondrial function, oxidative stress, and related regulatory processes.</p><p><strong>Conclusions: </strong>These findings show that migraine susceptibility is partly shaped by shared genetic regulation of DNA methylation and gene expression. By refining GWAS loci into candidate genes and molecular signals, this integrative multi-omic framework highlights distributed molecular pathways relevant to neuronal and vascular responsiveness and identifies candidates for future functional characterisation.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818462","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-attributed burden among children and adolescents in Georgia: estimates from a national cross-sectional schools-based study.","authors":"Nana Nino Tatishvili, Zaza Katsarava, Teona Shatirishvili, Tamar Kipiani, Tinatin Giuashvili, Mariam Lomsianidze, Aleksandre Kotetishvili, Anano Kvernadze, Irakli Tugushi, Salome Maghlakelidze, Vera Nemsadze, Ana Bedoshvili, Tamar Bitskinashvili, Giorgi Sakvarelidze, Derya Uludüz, Tayyar Şaşmaz, Deniz Erdal, Andreas Kattem Husøy, Timothy J Steiner","doi":"10.1186/s10194-026-02451-7","DOIUrl":"https://doi.org/10.1186/s10194-026-02451-7","url":null,"abstract":"<p><strong>Background: </strong>We recently published an account of headache prevalence among children (6-11 years) and adolescents (12-17) in Georgia, reporting an age- and gender-adjusted 1-year estimate of 66.3% for all headache. With undifferentiated headache (UdH) defined as mild or moderate headache lasting < 1 h, age- and gender-adjusted prevalence of migraine was 22.2%, of tension-type headache (TTH) 9.5%, of UdH 30.2%, of probable medication-overuse headache (pMOH) 0.5%, and of other headache on ≥ 15 days/month (other H15+) 3.6%. Here, using the same definition of UdH, we present data on attributed burden, collected contemporaneously from the same participants. The study was within the worldwide programme of cross-sectional schools-based studies undertaken by the Global Campaign against Headache.</p><p><strong>Methods: </strong>We used the Global Campaign's standardized protocol, selecting schools representative of the country. The child and adolescent versions of the structured Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, translated into Georgian language, were completed by pupils under supervision in class. Headache diagnoses followed International Classification of Headache Disorders, edition 3 (ICHD-3), except for UdH, which was defined as mild or moderate headache lasting < 1 h. Burden enquiry was in multiple domains, including symptom burden, impaired participation and quality of life (QoL), with timeframes of 4 weeks and 1 day (the latter based on headache yesterday [HY]).</p><p><strong>Results: </strong>Symptom burden was evidenced by mean headache frequency of 4.3 days/4 weeks, duration 1.6 h, proportion of time in ictal state 1.5% and intensity 1.7 (mild to moderate). Of episodic headaches, migraine was the most frequent, longest lasting and most intense. Pupils with pMOH reported headache on 78.9% of all days. Except for pMOH, fewer than half of headache days were medicated. Headache was blamed for 0.7 days/4 weeks of missed school (3.5% of 20 days), although only 1.5% of the 1,910 pupils with headache in the last year were absent yesterday because of HY (this analysis could not capture lost days immediately preceding weekends or holidays, so underestimated by at least 20%). Almost one in five parents (18.3%) of children lost time from their own work because of their child's headache, but only 4.5% of parents of adolescents. Emotional impact and QoL scores both showed gradation across headache types (pMOH and other H15 + worse than migraine worse than TTH and UdH).</p><p><strong>Conclusions: </strong>Headache among children and adolescents in Georgia is associated with individual- and population-level burdens that measurably and adversely affect health, wellbeing, education and participation in leisure activities. These findings are available to inform national education and health policies.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760627","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}