Journal of Headache and Pain最新文献

{"title":"Functional characterisation of dura mater αCGRP degradation fragments at vascular, immune, and CGRP receptor targets.","authors":"Mette N Jensen, Jens B Kristensen, Maria Castrillo, Philip V Reducha, Karin M L Nordahl, Debbie L Hay, Kristian A Haanes","doi":"10.1186/s10194-026-02390-3","DOIUrl":"10.1186/s10194-026-02390-3","url":null,"abstract":"<p><strong>Objective: </strong>Calcitonin gene related peptide (CGRP) is a central mediator in migraine and can trigger attacks in susceptible individuals. Therapies targeting CGRP or its receptor provide clinical benefit, but treatment responses vary. This suggests that local factors regulating CGRP availability and signalling within migraine relevant tissues may influence its biological effects. The extent and functional relevance of CGRP degradation at the dura mater, including possible effects on biomarker detection, remain insufficiently characterised.</p><p><strong>Methods: </strong>Proteomic analyses were used to identify human αCGRP (hαCGRP) degradation fragments generated in rat meningeal preparations. Functional properties of full-length hαCGRP and selected degradation fragments were assessed at the dura mater, in isolated arteries, in mast cell degranulation assays, and at CGRP receptors in vitro. Fragment interactions with a CGRP ELISA were examined to assess potential interference with detection of full-length CGRP. Male Sprague Dawley rats were used for the ex vivo experiments.</p><p><strong>Results: </strong>hαCGRP disappeared rapidly in the meningeal environment and reduced transdural resistance in the dura mater. Seven predominant degradation fragments accounted for ~ 81.5% of the detected fragment pool. None of the fragments showed agonist activity at the CGRP receptor or altered dural resistance or mast cell degranulation. In vascular assays, the fragments were likewise inactive, with the exception of the C-terminal fragment hαCGRP_11-37, which displayed weak competitive antagonism at the CGRP receptor. This was confirmed at both the human and rat CGRP receptor in vitro. Although the identified fragments were not directly detected by the CGRP ELISA, selected fragments interfered with intact hαCGRP measurements, indicating that degradation products can influence biomarker readout.</p><p><strong>Conclusion: </strong>Local degradation of hαCGRP at the dura mater primarily generates fragments without measurable vascular, immune, or receptor activating effects. The main consequence of this processing appears to be reduced hαCGRP bioavailability rather than formation of secondary bioactive signalling peptides. At the same time, fragment dependent interference in ELISA based detection indicates that local hαCGRP metabolism may affect interpretation of CGRP biomarker measurements in migraine relevant tissues.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"27 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987814","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":"Methodology and baseline characteristics of the China Migraine registry (CHIME): a nationwide, multi-center, prospective cohort study of 11,814 patients.","authors":"Ye Ran, Zizi He, Xun Han, Hui Su, Mingjie Zhang, Shuhua Zhang, Longteng Ma, Shengyuan Yu, Zhao Dong","doi":"10.1186/s10194-026-02389-w","DOIUrl":"10.1186/s10194-026-02389-w","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Among 11,814 participants (79.43% female; mean age 37.42 ± 10.94 years), 10,123 (85.7%) had episodic migraine (EM), 1,019 (8.6%) had chronic migraine (CM), and 672 (5.7%) had probable migraine. A profound diagnostic-therapeutic gap was identified: only 31.0% of patients had received a correct prior diagnosis. Paradoxically, 91.43% had undergone auxiliary investigations, primarily cranial imaging (87.36%). Acute treatment relied heavily on non-specific analgesics (NSAIDs: 59.77% EM, 51.03% CM). Among patients meeting clinical criteria for prophylaxis, only 26.59% were receiving preventive therapy, and the treatment maintenance rate was critically low (12.56% for ≥3 months). CM patients exhibited significantly higher disability (MIDAS Grade IV: 52.2% vs. 26.9%) and psychiatric comorbidities compared to EM patients (p < 0.001).</p><p><strong>Conclusions: </strong>The CHIME study reveals a paradoxical \"treatment odyssey\" in China characterized by a low correct diagnosis rate, pervasive diagnostic over-investigation, alongside a systemic under-utilization of evidence-based therapies. These findings highlight the urgent need for standardized diagnostic implementation and improved prophylactic maintenance in China's headache care system.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982071","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":"Abnormal structural connectivity-functional connectivity coupling beyond the cortex in patients with chronic migraine.","authors":"Yan Li, Yixuan Hu, Chenyu Dai, Fangwang Fu, Yungang Cao, Keyang Chen, Jinming Cheng, Xiaozheng Liu","doi":"10.1186/s10194-026-02397-w","DOIUrl":"10.1186/s10194-026-02397-w","url":null,"abstract":"<p><strong>Background: </strong>Studies have shown that patients with chronic migraine exhibit abnormalities in structural and functional brain networks. However, the underlying brain mechanisms that govern structural-to-functional connectivity coupling in this population remain unclear.</p><p><strong>Methods: </strong>Multimodal functional MRI data were collected from 36 patients with chronic migraine without aura, 94 patients with episodic migraine without aura and 51 healthy controls. Spearman's correlation analysis was used to calculate SC-FC coupling. The Kruskal-Wallis test was used to compare differences in SC-FC coupling between the three groups. We also performed a correlation analysis to investigate the associations between SC-FC coupling and clinical variables.</p><p><strong>Results: </strong>Compared with the healthy control group, patients with episodic migraine exhibited abnormal SC-FC coupling in the right rolandic operculum, left lingual gyrus, left pallidum, and vermis 7. In contrast, patients with chronic migraine exhibited abnormal SC-FC coupling in the left cerebellum 3, vermis 7, and pulvinar nucleus of the thalamus. Patients with chronic migraine exhibited abnormal SC-FC coupling in the left pulvinar nucleus of the thalamus compared with patients with episodic migraine. SC-FC coupling in the left cerebellum 3 of patients with chronic migraine was significantly associated with disability scores (r = -0.3731, p = 0.0250).</p><p><strong>Conclusion: </strong>Our study identified SC-FC coupling alterations associated with chronic migraine. This suggests that abnormalities in SC-FC coupling in subcortical nuclei and the cerebellum may represent underlying mechanisms of chronic migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147973028","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":"Medial prefrontal cortex-targeted low-intensity focused ultrasound alleviates migraine-related allodynia and affective symptoms via modulating glutamate/GABA balance in mice.","authors":"Jiayi Liu, Mingjie Zhang, Qiuquan Cai, Chunxiao Yang, Yajin Wu, Weinan Na, Deqi Zhai, Huijuan Yuan, Ya Cao, Xiaoya Chen, Yingji Li, Wenjing Tang, Dengfa Zhao, Ruozhuo Liu, Zhao Dong, Jiajia Yang, Dong Ming, Shengyuan Yu","doi":"10.1186/s10194-026-02377-0","DOIUrl":"10.1186/s10194-026-02377-0","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147973021","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":"Brain structural MRI changes before and after 6 months of preventive treatment with erenumab and onabotulinumtoxinA in migraine.","authors":"Joana Rosell-Mirmi, Edoardo Caronna, Víctor J Gallardo, Deborah Pareto, Alicia Alpuente, Marta Torres-Ferrús, Eulalia Giné-Ciprés, Àlex Rovira, Patricia Pozo-Rosich","doi":"10.1186/s10194-026-02393-0","DOIUrl":"10.1186/s10194-026-02393-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Structural neuroimaging findings in migraine remain heterogeneous, and the impact of preventive treatments such as erenumab and onabotulinumtoxinA (OnabotA) on brain plasticity is poorly understood. We aimed to comprehensively characterize brain morphology, including less explored regions such as the cerebellum and corpus callosum (CC), compare people with migraine with healthy controls (HC), identify baseline predictors of treatment response, and evaluate longitudinal structural trajectories following preventive therapy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This prospective study included participants with migraine with ≥ 8 headache days/month eligible for erenumab or OnabotA, together with HC. T1-weighted MRI was acquired on 3T MRI scanners at baseline (M0) in all participants and repeated at 6 months (M6) in eligible participants with migraine. Regions of interest (ROIs) were segmented, and cortical thickness (CTh), cortical surface area (SA) and brain volume values were extracted using FastSurfer. Data were analysed using generalized linear mixed models (GLMM). Response was defined as a ≥ 50% reduction in monthly headache days at M6.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We included 189 participants with migraine and 63 HC; 87.9% were female (222/252), and age was similar between groups (adjusted-p = 0.627). Compared with HC, individuals with migraine showed larger volumes in the mid-posterior (adjusted-p = 0.001) and central CC segments (adjusted-p = 0.030). 2) At baseline, non-responders (NR) showed higher CTh in the left parahippocampal gyrus than responders (R) (adjusted-p = 0.008). In addition, a significant response-by-treatment interaction was observed in the bilateral caudate volume: post-hoc contrast showed higher caudate volumes in OnabotA responders than in OnabotA NR (adjusted-p = 0.041 for both hemispheres), whereas no such difference was obsvered with erenumab. Longitudinally, several time-by-treatment interactions indicated different structural trajectories between treatments. In most of these regions, post-hoc contrasts showed lower M6 values in the erenumab group, including SA in the left fusiform, left pericalcarine, left rostral anterior cingulate, and right lingual regions, and volume in the bilateral cerebellar cortex, right hippocampus, and left amygdala. The left choroid plexus showed an opposite pattern, with increased volume in the erenumab group. Comparable longitudinal changes were not observed in the OnabotA group.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our results identify CC alterations and baseline parahippocampal and caudate morphometry as potential markers of migraine and treatment response. Erenumab and OnabotA showed different longitudinal structural trajectories, with more evident changes observed in the erenumab group in regions related to in pain, limbic, memory, and cerebellar processing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Trial registration information: &lt;/strong&gt;EudraCT: 2019-002224-32, Date: 2019-11-12. ID","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959860","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":"Rimegepant for the acute treatment of migraine: a systematic review and meta-analysis.","authors":"Melissa Istoc, Basit A Chaudhry, Rune H Christensen, Haidar M Al-Khazali, Messoud Ashina, William K Karlsson, Håkan Ashina","doi":"10.1186/s10194-026-02388-x","DOIUrl":"10.1186/s10194-026-02388-x","url":null,"abstract":"<p><strong>Objective: </strong>To determine the efficacy and tolerability of a single 75 mg oral dose of rimegepant compared with placebo for the acute treatment of migraine attacks in adults.</p><p><strong>Methods: </strong>A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines, with the protocol prospectively registered in PROSPERO (Identifier: CRD420251042015). Comprehensive searches of CENTRAL, ClinicalTrials.gov, EMBASE, EUCTR, PubMed, and WHO ICTRP were performed from database inception to December 2025, without language restrictions. Supplementary sources were also reviewed, including regulatory and sponsor materials such as FDA and EMA submissions and entries in the Pfizer and Biohaven clinical trial registries. Eligible studies were double-blind randomized controlled trials enrolling adults (≥ 18 years) with migraine (with or without aura) who received a single 75 mg oral dose of rimegepant compared with placebo for the acute treatment of migraine attacks. The co-primary outcomes were pain freedom at 2 h post-dose and sustained pain freedom from 2 to 24 h post-dose. Tolerability outcomes included all non-serious adverse events (AEs) following dosing, whereas safety outcomes comprised serious adverse events. Risk of bias was evaluated using the Cochrane RoB 2 tool, and certainty of evidence was assessed using the GRADE framework. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model, and heterogeneity was quantified using the I² and τ² statistics.</p><p><strong>Results: </strong>Seven double-blind RCTs (one phase II, five phase III, one phase IV) comprising 6,734 participants met the inclusion criteria. Two hours post-dose, 19.8% of participants receiving rimegepant and 10.7% receiving placebo achieved pain freedom (RR, 1.93; 95% CI, 1.51-2.47; P < 0.001; NNT = 10). Sustained pain freedom from 2 to 24 h was achieved by 14.2% of those receiving rimegepant, compared with 6.3% receiving placebo (RR, 2.39; 95% CI, 1.75-3.27; P < 0.001; NNT = 11). AEs occurred in 14.3% of rimegepant-treated and 12.7% of placebo-treated participants (RR, 1.14; 95% CI, 1.00-1.30; P = 0.056; NNH = 55). Risk of bias was judged as low across the included trials.</p><p><strong>Conclusions: </strong>Rimegepant 75 mg provides modest yet clinically meaningful efficacy with favorable short-term tolerability for the acute treatment of migraine attacks. These findings support its use as an effective treatment option for adults with inadequate response, contraindications, or intolerance to first- or second-line therapies.</p><p><strong>Clinical trials number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959830","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":"Multimodal serum and MRI signatures of neuroaxonal injury in high-frequency migraine.","authors":"Víctor J Gallardo, Edoardo Caronna, Joana Rosell-Mirmi, Laila Asskour, Deborah Pareto, Marta Torres-Ferrús, Alicia Alpuente, Eulàlia Giné-Ciprés, Nara Ikumi, Àlex Rovira, Patricia Pozo-Rosich","doi":"10.1186/s10194-026-02392-1","DOIUrl":"10.1186/s10194-026-02392-1","url":null,"abstract":"<p><strong>Background: </strong>It remains unclear whether high-frequency migraine is associated with objective markers of possible neuroaxonal injury and potential expression of neurodegenerative hallmarks. We compared serum and MRI biomarkers in high-frequency migraine versus healthy controls (HC) and tested whether baseline profiles predict 6-month response to erenumab.</p><p><strong>Methods: </strong>Adults with migraine (≥ 10 monthly headache days) and age- and sex-matched healthy controls (HC) were prospectively recruited at a tertiary center in Spain (2020-2021). Serum neurofilament light (sNf-L) was measured, and susceptibility-weighted MRI (SWI; iron-related signal) and diffusion MRI (fractional anisotropy, FA) were acquired within 7 days of blood sampling; headache status on the scan day was recorded via an eDiary. Migraine participants received erenumab 140 mg monthly for 24 weeks; response was defined as a ≥ 50% reduction in monthly headache days. Mixed-effects models adjusted for demographic and clinical covariates, with modality-wise FDR correction.</p><p><strong>Results: </strong>We included 134 participants (68 migraine, 66 HC); median migraine duration was 25.0 years. sNf-L was higher in migraine (β[SE] = 0.139[0.052]; adj.P = 0.028). In the MRI subcohort (n = 102), left rostral ACC SWI signal was higher (0.863[0.275]; adj.P = 0.027) and right cuneus FA lower (- 0.202[0.061]; adj.P = 0.017). A multivariable model including clinical and biomarker variables identified depressive symptoms as the strongest predictor, while elevated sNf-L and reduced FA in the right cuneus remained independent biomarkers distinguishing migraine from HC (Accuracy [95% CI]: 0.739 [0.516-0.898]). None of these biomarkers predicted erenumab response after 6 months.</p><p><strong>Conclusions: </strong>High-frequency migraine was associated with higher sNf-L and focal SWI/FA differences versus HC, consistent with possible neuroaxonal involvement, but these measures did not predict erenumab response at 6 months.</p><p><strong>Trial registration: </strong>EudraCT 2019-002224-32 (Registration Date: 2019-11-12).</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147941454","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":"Impaired glymphatic function and advanced brain age gap in chronic migraine: a multimodal MRI study.","authors":"Chenyu Dai, Fangwang Fu, Yu Guo, Xiaoqing Liu, Zi Tao, Xiaojie Zhang, Xinhao Li, Chenyu Lin, Mengqian Ye, Mei Huang, Yixuan Hu, Kun Liu, Yungang Cao, Keyang Chen, Beilei Hu, Xiaozheng Liu, Yan Li","doi":"10.1186/s10194-026-02384-1","DOIUrl":"10.1186/s10194-026-02384-1","url":null,"abstract":"<p><strong>Objectives: </strong>This study investigated whether the coupling between cortical blood-oxygen-level-dependent (BOLD) signals and cerebrospinal fluid (CSF) flow, a physiologically motivated but indirect proxy related to glymphatic-associated dynamics, moderates the relationship between migraine disability (MIDAS) and brain age gap (BAG).</p><p><strong>Methods: </strong>Patients with episodic migraine (EM), chronic migraine (CM), and healthy controls were recruited. BAG was estimated using a deep learning-based framework, and glymphatic-related hemodynamic-CSF dynamics were assessed using BOLD-CSF coupling. A moderation model, adjusted for sleep quality (PSQI) and biological covariates using HC3 robust standard errors, evaluated the statistical moderating role of BOLD-CSF coupling on the MIDAS-BAG association.</p><p><strong>Results: </strong>A network-specific pattern of altered BOLD-CSF coupling was identified, with higher-order network abnormalities observed specifically in CM (p = 0.037). CM patients exhibited a significantly greater BAG than EM patients and healthy controls (p = 0.007). BOLD-CSF coupling significantly moderated the association between MIDAS and BAG (interaction β = -0.104, p = 0.035; Wald test p = 0.036). In individuals with relatively stronger coupling, MIDAS was more strongly associated with BAG (β = 0.066, p < 0.001), whereas this association was attenuated in those with weaker coupling (β = 0.035, p = 0.005).</p><p><strong>Conclusions: </strong>Altered higher-order network BOLD-CSF coupling may represent a relevant imaging feature of migraine chronification. BOLD-CSF coupling was associated with interindividual differences in the relationship between migraine-related disability and BAG, independent of sleep quality. These findings support the potential relevance of glymphatic-related physiological processes in chronic migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13340348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147930415","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 neural substrate for targeted analgesia associated with attenuated serotonergic transmission in a mouse model of medication overuse headache.","authors":"Deqi Zhai, Chunxiao Yang, Zihua Gong, Yingyuan Liu, Yu Wang, Huijuan Yuan, Weinan Na, Huanxian Liu, Shuqing Wang, Longteng Ma, Shengyuan Yu, Zhao Dong","doi":"10.1186/s10194-026-02391-2","DOIUrl":"10.1186/s10194-026-02391-2","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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-HT_1D receptor (5-HT_1DR) 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-HT_1DR.</p><p><strong>Results: </strong>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-HT_1DR 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.</p><p><strong>Conclusions: </strong>Activating the glutamatergic OFC-vlPAG circuit elicits robust analgesia in triptan-induced MOH mice. 5-HT_1DR 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.</p><p><strong>Clinical trail number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147930318","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":"Adrenal gland dysfunction in males with cluster headache.","authors":"Connar Stanley James Westgate, Tanja Lylloff, David Møbjerg Kristensen, Thomas Folkmann-Hansen, Nunu Lund, Mads Barloese, Marie-Louise Kulas Søborg, Sophie Bryde Laursen, Trine Holm Johannsen, Hanne Frederiksen, Anders Juul, Rigmor Højland Jensen, Anja Sofie Petersen","doi":"10.1186/s10194-026-02386-z","DOIUrl":"10.1186/s10194-026-02386-z","url":null,"abstract":"<p><strong>Background: </strong>Cluster headache is associated with compensated hypogonadism in males, suggesting impaired testicular steroidogenesis. It is unknown if adrenal steroidogenesis is dysregulated and how this is linked to cluster headache pathophysiology. We therefore aimed to define the adrenal steroid profile in cluster headache and define the differences between the phases of episodic cluster headache. We secondarily aimed to assess whether the steroid profile could distinguish between chronic cluster headache and episodic cluster headache.</p><p><strong>Methods: </strong>A prospective case-control study containing adult males with chronic cluster headache (n = 60), paired episodic cluster headache in and out of bout (n = 60) and healthy controls (n = 60). A fasted serum steroid profile for 16 steroid hormones was assessed via liquid chromatography tandem mass-spectrometry, assessing mineralocorticoids, glucocorticoids, and androgens. Explorative machine learning was used to segregate the cluster headache states.</p><p><strong>Results: </strong>The mineralocorticoids 11-deoxycorticosterone (P < 0.05), corticosterone (P < 0.05) and aldosterone (P < 0.05) were lower in those with episodic cluster headache compared to controls. 11-deoxycorticosterone (P < 0.01), corticosterone (P < 0.01), and the glucocorticoids 11-deoxycortisol (P < 0.01) and cortisol (P < 0.05) and cortisol/DHEAS ratio (P < 0.001) are lower in episodic in bout compared to their paired remission state. Those with chronic cluster headache had lower concentrations of 17-OH pregnenolone (P < 0.05) and DHEAS (P < 0.001) and a higher cortisol/DHEAS ratio (P < 0.01). The steroid hormone profile distinguished between chronic and episodic cluster in bout with a specificity of 86% (95%CI: 69%-90%), sensitivity of 81% (95%CI: 73%-93%) and AUC of 0.92 (P < 0.0001). Attack frequency and time from last attack correlated with the degree of steroid dysfunction in episodic cluster headache but not in chronic cluster headache.</p><p><strong>Conclusion: </strong>We identify distinct steroid hormone profiles in episodic and chronic cluster headache. Episodic in bout was associated with reduced adrenal steroid synthesis that resolves in remission. Chronic cluster headache was associated with stress induced androgen suppression. Together, these differences are likely secondary to cluster headache and may reflect distinct neurobiological bases underlying episodic and chronic cluster headache.</p><p><strong>Clinical trail number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147930294","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}