Journal of Headache and Pain最新文献

{"title":"State-of-the-art preclinical techniques to study the impact of spreading depolarizations in awake rodents.","authors":"Alejandro Labastida-Ramirez, Neela K Codadu, Kagan Agan, Robert C Wykes","doi":"10.1186/s10194-025-02121-0","DOIUrl":"https://doi.org/10.1186/s10194-025-02121-0","url":null,"abstract":"<p><strong>Background: </strong>Understanding the mechanisms of pathological brain network activity and the efficacy of therapies requires testing hypothesis in vivo, where brain circuitry remains preserved. Therefore, animal models are a key tool in the study of primary neurological disorders such as migraine, stroke and epilepsy. These models not only have advanced our understanding of the underlying neurobiology of these disorders but have also provided novel pharmacological targets and insights on shared pathophysiological processes such as spreading depolarizations (SD). SD, the electrographic correlate of migraine with aura, are transient waves of near-complete neuroglial depolarization associated with transmembrane ionic and water shifts. BODY: Many studies investigating the impact of SD in preclinical models have done so in the presence of anesthesia. However, the use of anesthesia is a well-known confounding factor that not only influences SD threshold or frequency but also SD-evoked hemodynamic responses as common anesthetics affect cerebral blood flow and neurovascular coupling, limiting translation. Therefore, here we discuss research methods that have recently been developed or refined to allow the study of SD in awake rodents with a focus on migraine with aura. We discuss advantages, limitations and also efforts made to transition towards minimally-invasive procedures. Methods include optogenetic approaches to induce SD, multisite high-fidelity DC-coupled electrophysiological recordings, and measurements of neurovascular signals detected at both mesoscopic/macroscopic (e.g., fluorescent reporters, functional ultrasound system) and microscopic levels (e.g., two-photon microscopy, miniscopes). Additionally, we discuss continuous wireless telemetry recordings to detect spontaneous SD frequency over weeks to months in freely moving animals.</p><p><strong>Conclusion: </strong>Implementation of these methods in awake brain will close the translational gap and improve the relevance of preclinical animal models.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"188"},"PeriodicalIF":7.9,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957057","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":"Oral atogepant mitigates spreading depolarization-induced pain and anxiety behavior in mice.","authors":"Melih Z Kaya, Pradeep Banerjee, Cenk Ayata, Andrea M Harriott","doi":"10.1186/s10194-025-02125-w","DOIUrl":"https://doi.org/10.1186/s10194-025-02125-w","url":null,"abstract":"<p><strong>Background: </strong>Spreading depolarization (SD) is the most likely cause of migraine aura and may be linked to trigeminal nociception. Using minimally invasive optogenetic SD induction (opto-SD), we previously showed that SD triggers acute periorbital mechanical allodynia-like behavior, supporting SD-induced activation of migraine-relevant trigeminal pain pathways. Here, we tested whether selective oral calcitonin gene-related peptide (CGRP) receptor antagonist, atogepant, could ameliorate SD-evoked pain and anxiety phenotypes.</p><p><strong>Methods: </strong>Thirty-two adult male and female Thy1-ChR2-EYFP transgenic mice (3-5 months, 18-30 g) housed in 12/12-hr light/dark cycles were used. Under brief isoflurane anesthesia, a thin glass panel was placed on intact skull one week before the experiment to achieve translucency. A single SD was evoked using 10 s, 10 mW blue light stimulation over the motor cortex. One hour before SD or sham stimulation, atogepant (ato; 30 mg/kg in 100% PEG400) or vehicle (veh; 100% PEG400) was administered by oral gavage (4 mL/kg). Mechanical periorbital thresholds were measured 1 h after SD using von Frey monofilaments. Mouse grimace was then quantified using PainFace, an open convolutional neural network platform. Lastly, anxiety-like behavior was examined in an open field. Groups were randomly assigned and the investigator blinded to group allocation (n = 8/group, balanced by sex), p < 0.05 was considered significant.</p><p><strong>Results: </strong>There was a significant main effect of SD (p < 0.001) and atogepant (p = 0.015) on the periorbital threshold with an interaction (p < 0.001). A single opto-SD lowered periorbital threshold compared with sham (veh sham vs. veh SD: p < 0.001). SD also increased the total grimace score compared with sham (veh sham vs. veh SD: p = 0.014). Oral atogepant (30 mg/kg) alleviated SD-induced periorbital allodynia-like behavior (veh SD vs. ato SD: p < 0.001) but did not completely reverse SD-induced periorbital allodynia-like behavior (ato sham vs. ato SD: p < 0.001). Atogepant abolished the SD-induced facial grimace (ato sham vs. ato SD: p = 0.238). SD increased thigmotaxis score compared with sham (veh sham vs. veh SD: p = 0.016). Following atogepant treatment, there was no difference in thigmotaxis score in SD versus sham groups (ato sham vs. ato SD: p = 0.200).</p><p><strong>Conclusions: </strong>These data suggest SD provokes a reproducible and robust facial pain phenotype in mice that is alleviated by pre-administration with atogepant. There was also improvement in SD-induced anxiety-like behavior following atogepant.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"187"},"PeriodicalIF":7.9,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957016","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":"The epidemiology, management, and the associated burden of migraine in Australian primary care: a retrospective analysis of electronic health record data.","authors":"Nicole Limberg, Jason C Ray, Benjamin Harvey, Giles Stratton, Angus Cuskelly, Charmaine S Tam, David Witcombe","doi":"10.1186/s10194-025-02103-2","DOIUrl":"10.1186/s10194-025-02103-2","url":null,"abstract":"<p><strong>Background: </strong>Migraine accounts for more disability than all other neurologic conditions combined. Despite this, more than 40% of people with migraine do not seek medical care. Migraine is associated with a higher risk of comorbidities, adding to the symptom burden. Currently, there is limited epidemiological data available on the prevalence and incidence of migraine in the Australian primary care setting. This study aimed to describe the epidemiology (prevalence and incidence) of diagnosed migraine within the Australian general practice population.</p><p><strong>Methods: </strong>Electronic health record data captured by national clinical practice management software over a 14-year index period (2010-2024) was analysed. The point prevalence of diagnosed migraine was estimated. The incidence of diagnosed migraine was estimated based on patients with new onset migraine during the index period. Estimates were stratified by age and sex. Differences by sociodemographic groups, patterns of treatment, and referral pathways were also evaluated.</p><p><strong>Results: </strong>The study encompassed a total of 37,579 eligible migraine prevalent cases. The overall adjusted point prevalence of diagnosed migraine was estimated as 7.02 per 1,000 persons (95% confidence interval (CI) 6.79 to 7.25), which equates to 0.702% after adjusting for the interaction of age and sex. The overall incidence rate (IR) was estimated as 3.48 per 1,000 person-years (95% CI 3.38 to 3.58) after adjusting for the interaction of age and sex. Depression and anxiety were reported four times more frequently in the migraine population. High use of opioids and opioid combinations (54.75%) was noted in the migraine population, as well as a lower-than-expected use of triptans (51.06%). Among those with migraine, 32.03% had been referred to a physiotherapist and 18.64% had been referred to a neurologist.</p><p><strong>Conclusions: </strong>This is the first study to describe the IR, accounting for life-years, in the Australian general practice population. The point prevalence of diagnosed migraine and incidence were lower than population-based estimates from other regions. The findings indicate that migraines are frequently underdiagnosed in the Australian primary care setting, with a possible lack of awareness of potential presentations for migraine, including neck pain, and highlight the need for further patient and clinician education.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"186"},"PeriodicalIF":7.9,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883008","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":"Unveiling migraine subtype heterogeneity and risk loci: integrated genome-wide association study and single-cell transcriptomics discovery.","authors":"Shuxu Wei, Yan Quan, Xinyi Li, Suiqin Zhong, Ling Xiao, Chao Yang, Ronghuai Shen, Xiaojia Lu, Lingbin He, Youti Zhang, Xianxi Huang","doi":"10.1186/s10194-025-02128-7","DOIUrl":"10.1186/s10194-025-02128-7","url":null,"abstract":"<p><strong>Background: </strong>Migraine, a debilitating neurological disorder with distinct subtypes (migraine with aura [MA] and migraine without aura [MO]), exhibits genetic and spatial heterogeneity that remains poorly understood. While genetic correlations between subtypes are established, spatially resolved molecular mechanisms driving their divergent clinical phenotypes-particularly in tissue microenvironments-are unclear, limiting targeted therapeutic development.</p><p><strong>Methods: </strong>We integrated genome-wide association study (GWAS) data from FinnGen R11 and international cohorts with transcriptomic, epigenomic, and spatially resolved single-cell spatial transcriptomics (sc-ST) profiles. Genetic correlations and functional annotations were assessed using Linkage Disequilibrium Score Regression (LDSC), High-Definition Likelihood (HDL), and partitioned heritability analyses. A multi-omics framework combined Summary Mendelian Randomization (SMR) for expression and methylation quantitative trait loci (eQTL/mQTL), Functional Summary-based Imputation (FUSION), Multi-marker Analysis of GenoMic Annotation (MAGMA), Joint-Tissue Imputation Enhanced PrediXcan Analysis (JTI-PrediXcan), and the Polygenic Priority Score (PoPS) to systematically prioritize genes based on methodological robustness (≥ 2 analytical approaches) and cross-subtype consistency. Tissue-enriched specificity was validated via genetically informed spatial mapping of cells for complex traits (gsMap), a novel algorithm integrating sc-ST and GWAS data to map subtype-associated cellular architectures at single-cell resolution across embryonic tissues.</p><p><strong>Results: </strong>LDSC and HDL confirmed strong genetic correlations between MA and MO. But they showed divergent functional architectures in functional genomic annotations, with MA enriched in conserved regulatory elements (e.g., Backgrd_Selection_StatL2_0, enrichment = 1.38, P = 5.47 × 10^-6) and MO in vascular pathways (e.g., GERP.NSL2_0, enrichment = 2.12, P = 1.04 × 10^-6). Sc-ST revealed spatially divergent niches: MA showed prenatal enrichment in neural crest-derived tissues (jaw primordium, p = 0.0039) and hypothalamic microglial adjacencies, aligning with neuroimmune regulation, while MO exhibited peripheral tropism in vascular smooth muscle and gut-brain interfaces, corroborated by LDSC-SEG/MAGMA vascular pathways. Multi-omics integration identified high-confidence cross-subtype genes (LRP1 [PoPS: Overall = 3.67, MO = 0.80], PHACTR1 [PoPS: Overall = 2.65, MA = 0.33, MO = 1.28], STAT6 [PoPS: Overall = 3.00, MO = 2.29], RDH16, TTC24, ZBTB39, FHL5, MEF2D, NAB2, UFL1, and REEP3) supported by ≥ 2 methods. Subtype-specific genes included MA-associated neuronal regulators (CACNA1A, KLHDC8B) and MO-specific vascular/metabolic genes (e.g., ACO2, BCAR1, CCDC134).</p><p><strong>Conclusion: </strong>Our study delineates spatially constrained mechanisms underlying migraine heterogeneity: MA ari","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"185"},"PeriodicalIF":7.9,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873506","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":"Longitudinal assessment of migraine burden in resistant and refractory migraine - Data from the prospective REFINE study.","authors":"Umberto Pensato, Raffaele Ornello, Chiara Rosignoli, Valeria Caponnetto, Agnese Onofri, Mark Braschinsky, Olga Sved, Raquel Gil-Gouveia, Renato Oliveira, Christian Lampl, Jakob Paungarttner, Paolo Martelletti, William David Wells-Gatnik, Isabel Pavao Martins, Dimos D Mitsikostas, Loukia Apostolakopoulou, Aynur Ozge, Dilan Bayar Narin, Patricia Pozo-Rosich, Albert Munoz-Vendrell, Maria Pia Prudenzano, Martino Gentile, Kristina Ryliskiene, Jurgita Vainauskiene, Margarita Sanchez-Del-Rio, Fabrizio Vernieri, Gianmarco Iaccarino, Marta Waliszewska-Prosół, Sławomir Budrewicz, Marta Carnovali, Zaza Katsarava, Simona Sacco","doi":"10.1186/s10194-025-02126-9","DOIUrl":"10.1186/s10194-025-02126-9","url":null,"abstract":"<p><strong>Background: </strong>Some individuals with migraine fail to respond adequately to preventive treatments, bearing most of migraine burden. The European Headache Federation (EHF) classifies these individuals into resistant migraine (ResM) or refractory migraine (RefM) according to treatment failures, debilitating headache days, and disease duration. We investigated the evolution of these categories over six months in patients treated at tertiary headache centers and whether they accurately reflect disability and burden.</p><p><strong>Methods: </strong>Participants from the multicenter, prospective REFINE study were classified into three categories of treatment responsiveness, namely RefM, ResM, and non-refractory non-resistant migraine (NRNRM). The primary objective was to determine the trajectories of category changes over six months. Secondary outcomes included changes in the 6-item Headache Impact Test (HIT-6), Headache-Attributed Lost Time (HALT), and Hospital Anxiety and Depression Scale (HADS-A and HADS-D) scores.</p><p><strong>Results: </strong>Overall, 489 participants were included with a median age of 45 years (IQR = 36-53); 389 participants (79.7%) were female; 256 (52.4%) had NRNRM, 178 (36.4%) ResM, and 55 (11.2%) RefM. At follow-up, 200/256 (78.1%) NRNRM remained stable, while 56/256 (21.9%) progressed to ResM. Among those with ResM, 98/178 (55.1%) remained stable, 72/178 (40.5%) improved to NRNRM, and 8/178 (4.5%) worsened to RefM. Among participants with RefM, 37/55 (67.3%) remained stable, while 18/55 (32.7%) improved to NRNRM. Participants with RefM and ResM presented significantly higher scores at baseline than those with NRNRM. Over time, HIT-6, HALT, and HADS-A scores improved substantially in the overall cohort (p < 0.001, p < 0.001, and p = 0.006, respectively). Improvements were observed in participants with ResM across all scores and HIT-6 and HALT for NRNRM, but no improvement was noted in participants with RefM.</p><p><strong>Conclusions: </strong>Over six months, ~ 40% of ResM and ~ 30% of RefM individuals improved to NRNRM, while ~ 20% of NRNRM developed treatment resistance after receiving care in tertiary headache centers. Participants with ResM had a better prognosis than those with RefM. While both ResM and RefM reflect high migraine disability burden, they might present relevant differences in their management and prognosis.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"184"},"PeriodicalIF":7.9,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859194","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":"Neural signature of chronic migraine mice model and related photophobia in the primary visual cortex.","authors":"Kai-Bo Zhang, Cheng Peng, Zhen Liu, Sheng-Lin Zhao, Chen-Lu Zhu, Shou-Yi Wu, Tian-Xiao Wang, Zhi-Lei Li, Jing-Gui Gao, Yun-Hao Xu, Tian-Hua Fan, Hong Xie, Ji-Song Guan, Yong-Gang Wang","doi":"10.1186/s10194-025-02123-y","DOIUrl":"10.1186/s10194-025-02123-y","url":null,"abstract":"<p><strong>Background: </strong>Migraine episodes are known to induce heightened photosensitivity. Neuroimaging investigations have revealed that the primary visual cortex exhibits abnormal activation patterns both during and between migraine attacks. Growing evidence suggests that altered cortical activity patterns may underlie the pathophysiology of neurological disorders. This study explored whether and how chronic migraine affects cortical activity patterns at single-cell resolution in the primary visual cortex during its progression.</p><p><strong>Methods: </strong>Longitudinal in vivo two-photon calcium imaging was performed in the primary visual cortex of a chronic migraine mouse model across multiple time points. Cortical circuit activity patterns and behavioral correlates were assessed through combined chemogenetic manipulation and pharmacological interventions, with a particular focus on primary visual cortex functional modulation.</p><p><strong>Results: </strong>Following chronic migraine induction, spontaneous hyperactivation emerged in cortical activity patterns within the primary visual cortex. Layer II/III neurons appeared as major contributors to this neural dysregulation, with layer V neurons showing less pronounced involvement. Prophylactic topiramate treatment attenuated allodynia and light aversion behaviors while reducing pathological cortical hyperactivity. Chemogenetic inhibition of primary visual cortex layer II/III neurons ameliorated light aversion without attenuating pain sensitization, while modulating aberrant spontaneous cortical activity patterns.</p><p><strong>Conclusions: </strong>These findings provide preliminary evidence for dynamic alterations in spontaneous cortical neural signatures within the primary visual cortex throughout chronic migraine progression. Modulation of these neural adaptations appears to show the potential to alleviate associated light sensitivity, providing insight into potential pathophysiological mechanisms underlying light sensitivity in chronic migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"182"},"PeriodicalIF":7.9,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835270","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":"Substrate-selective COX-2 inhibition by IMMA attenuates posttraumatic headache via endocannabinoid modulation and neuroinflammatory suppression.","authors":"Jie Wen, Mikiei Tanaka, Yumin Zhang","doi":"10.1186/s10194-025-02116-x","DOIUrl":"10.1186/s10194-025-02116-x","url":null,"abstract":"<p><strong>Background: </strong>Posttraumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), characterized by neuroinflammation and pain hypersensitivity. Current treatments are limited, and novel therapeutics are needed. Indomethacin morpholinamide (IMMA), a substrate-selective cyclooxygenase-2 (COX-2) inhibitor, enhances endocannabinoid signaling without disrupting prostaglandin homeostasis and may offer a mechanistically distinct approach to managing PTH.</p><p><strong>Methods: </strong>Male C57BL/6J mice were subjected to repetitive mild TBI (rmTBI) using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) and treated with IMMA (10 mg/kg, i.p.) daily for 7 days post-injury. Mechanical allodynia was assessed using von Frey stimulation of the periorbital region. Neuroinflammation was evaluated through immunohistochemistry in the trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Endocannabinoid and prostaglandin levels were quantified by mass spectrometry and enzyme immunoassay, respectively.</p><p><strong>Results: </strong>IMMA significantly reduced rmTBI-induced periorbital allodynia, microglial and astrocyte activation, and CGRP expression in the TG and TNC. It also preserved meningeal mast cell integrity and elevated cortical anandamide (AEA) levels without altering prostaglandin E₂ (PGE₂) production, supporting a mechanism that enhances cannabinoid signaling while sparing COX-2-mediated prostaglandin synthesis.</p><p><strong>Conclusion: </strong>IMMA effectively attenuates neuroinflammation and pain hypersensitivity in the acute phase of PTH through a distinct mechanism that preserves endocannabinoid tone without suppressing physiological prostaglandins. While these results highlight its promise as a novel therapeutic strategy, further studies are warranted to determine its efficacy during the chronic phase of PTH and across anatomically targeted regions.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"183"},"PeriodicalIF":7.9,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835271","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":"Vascular responses to molecular migraine triggers: a systematic review of magnetic resonance angiography studies.","authors":"Robin Arquizan, Anna G Melchior, Rune H Christensen, Haidar M Al-Khazali, Messoud Ashina, Håkan Ashina","doi":"10.1186/s10194-025-02105-0","DOIUrl":"10.1186/s10194-025-02105-0","url":null,"abstract":"<p><strong>Objective: </strong>To synthesize and interpret magnetic resonance angiography (MRA) findings on vascular changes after administration of established molecular migraine triggers in adults with migraine and in healthy individuals, focusing on the middle meningeal artery (MMA) and middle cerebral artery (MCA).</p><p><strong>Methods: </strong>A systematic review of experimental studies using MRA to assess extracerebral and intracerebral arterial responses to established molecular migraine triggers was conducted. Eligible studies included adults with migraine or healthy volunteers, use of MRA, and oral ingestion or intravenous infusion of an established molecular migraine trigger. Studies not meeting these criteria, as well as conference abstracts, preprints, reviews, case reports, and case series, were excluded.</p><p><strong>Results: </strong>Sixteen eligible MRA studies were identified. The triggers used included calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptides (PACAP-27 and PACAP-38), vasoactive intestinal polypeptide, nitroglycerin, cilostazol, sildenafil, and levcromakalim. All triggers induced extracerebral (meningeal) arterial dilation, often accompanied by headache or migraine attacks. Dilation induced by neuropeptides was confined to extracerebral arteries, consistent with limited blood-brain barrier penetration. In contrast, nitroglycerin and levcromakalim also dilated cerebral arteries. Across all studies, sumatriptan consistently reversed extracerebral arterial dilation and alleviated migraine pain.</p><p><strong>Conclusions: </strong>Established molecular triggers reliably induce extracerebral arterial dilation, an effect reversed by sumatriptan. These findings support the hypothesis that sustained meningeal vasodilation might contribute causally to migraine pathogenesis. Standardized MRA protocols, rigorous methodological designs, and well-controlled studies are needed to further refine our understanding of these vascular mechanisms and to guide the development of more targeted therapies for migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"181"},"PeriodicalIF":7.9,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12341203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821556","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":"Compromised PGF2α signaling in the paraventricular hypothalamic nucleus contributes to the central sensitization of the nitroglycerin-induced chronic migraine in male mice.","authors":"Xianrong Hu, Lunquan Wu, Li Wang, Congxue Peng, Yunyun Tian, Qian Zhu, Hongwei Zhu, Liang Nie, Li Yin, Yuehui Zhang, Jiang Bian","doi":"10.1186/s10194-025-02124-x","DOIUrl":"10.1186/s10194-025-02124-x","url":null,"abstract":"<p><p>Impaired descending inhibitory controls are now understood to exacerbate central sensitization of chronic migraine, yet the underlying neural and molecular mechanisms remain largely elusive. Herein, a paraventricular hypothalamic nucleus (PVN) ^{oxytocin (OXT)} → trigeminal nucleus caudalis (TNC) ^GABA neural circuit was identified through the application of a rigorous anterograde tracing strategy and RNAscope in situ hybridization techniques, involved in regulating trigeminal nociceptive transmission. In both episodic and chronic migraine mouse models induced by nitroglycerin (NTG) injections, increased activity of the PVN ^OXT → TNC ^GABA circuit was observed. However, the activity of PVN ^OXT neurons decreased in chronic migraine mice when compared to episodic migraine mice. Chemogenetic activation of PVN ^OXT neurons alleviated migraine hyperalgesia and enhanced the release of OXT and GABA in TNC in chronic migraine mice, while these beneficial effects were abrogated by the intra-TNC administration of OXT receptor antagonist. Interestingly, the expression of prostaglandin F2α receptor (FP) in PVN ^OXT neurons decreased with the chronification of migraine despite upregulation of PVN prostaglandin F2α (PGF2α) levels. Targeting FP overexpression in PVN ^OXT neurons restored neuronal activity and ameliorated chronic migraine hyperalgesia. Overall, our study reveals a novel neural and molecular mechanism for descending modulation of trigeminal central sensitization, thereby providing a basis for treating chronic migraine.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"179"},"PeriodicalIF":7.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794611","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":"Atrophy of hypothalamic subregions increases migraine risk: cross-sectional study and mendelian randomization analysis.","authors":"Zhonghua Xiong, Lei Zhao, Geyu Liu, Dong Qiu, Yanliang Mei, Xiaoshuang Li, Zhi Guo, Peng Zhang, Mantian Zhang, Tianshuang Gao, Jinju Sun, Xin Liu, Yonggang Wang","doi":"10.1186/s10194-025-02119-8","DOIUrl":"10.1186/s10194-025-02119-8","url":null,"abstract":"<p><strong>Background: </strong>The hypothalamus is a versatile structure comprising several nuclei that play key roles in regulating various biological processes associated with migraine, including hormone secretion, metabolism, circadian rhythm, and autonomic nervous system functions. However, the involvement of hypothalamic subregions in migraine remains unclear.</p><p><strong>Methods: </strong>Based on T1-weighted MRI data from 76 migraine patients (23 episodic migraine [EM], 53 chronic migraine [CM]) and 35 healthy controls (HCs), we examined group differences in the volume of five hypothalamic subregions. To clarify causal relationships between migraine and hypothalamic volume, we conducted Mendelian randomization (MR) analyses. Mediation analysis was further performed to assess the role of gut microbiota composition in this association.</p><p><strong>Results: </strong>Compared to HCs, migraine patients exhibited significantly reduced total hypothalamic volume (813.53 ± 66.46 mm³ vs. 831.86 ± 57.91 mm³; FDR q = 0.048) and inferior tuberal hypothalamic volume (255.26 ± 30.17 mm³ vs. 265.29 ± 23.32 mm³; FDR q = 0.046). These reductions were particularly pronounced in patients with CM, whereas no significant differences were observed in those with EM. MR analysis revealed causal effects of total hypothalamic volumes (OR = 0.80, FDR q = 7.28 × 10^-5) and inferior tuberal hypothalamic volumes (OR = 0.85, FDR q = 2.61 × 10^-2) on migraine, providing causal evidence to support the observational findings from the cross-sectional study. Furthermore, specific gut microbiome (genus DefluviitaleaceaeUCG011, genus Eubacteriumruminantiumgroup, and family FamilyXIII) were identified as partial mediators of the hypothalamus-migraine link (FDR q < 0.05).</p><p><strong>Conclusions: </strong>This study suggests that atrophy of the inferior tuberal subregion of the hypothalamus plays a pivotal role in increasing migraine risk, and that this effect is partially mediated through alterations in gut microbiome composition.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":"26 1","pages":"178"},"PeriodicalIF":7.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12326839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794610","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}