Journal of Headache and Pain最新文献

{"title":"Early life stress induces brain-wide electrical network predisposition to migraine.","authors":"Micah Johnson, Maureen Eberle, Ian Hultman, Xinyu Zhang, Yassine Filali, Benjamin Hing, Molly Matkovich, Alli Jimenez, Sara Mitchell, Anjayooluwa Adegboyo, Radha Velamuri, Julia Miller, Kung-Sik Chan, Sanvesh Srivastava, Rainbo Hultman","doi":"10.1186/s10194-026-02399-8","DOIUrl":"10.1186/s10194-026-02399-8","url":null,"abstract":"<p><strong>Background: </strong>Migraine is a disorder of severe, recurrent headaches and debilitating sensory, cognitive and affective symptoms, often triggered by stress. Early life stress in childhood has been shown to increase the likelihood of migraine in adulthood in humans. Calcitonin gene-related peptide (CGRP) has been shown to reliably and acutely induce migraine or migraine-like behavior in both humans and rodent models. Here we investigate the impact of early life stress and CGRP on migraine-related neural circuitry in order to better understand the mechanisms by which early life stress predisposes neural circuitry to migraine brain network activity.</p><p><strong>Methods: </strong>We implemented an early life stress paradigm in the outbred strain of mice, CD1. We evaluated the impact of peripheral CGRP on migraine-like behavior and employed multi-site in vivo neurophysiology in freely behaving mice. A changepoint analysis was used to dissect differences in individual CGRP-induced responses.</p><p><strong>Results: </strong>We found that early life stress exacerbated migraine-related behavioral and network physiology. CGRP alone caused disruptions in neural oscillatory activity across a network of brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), thalamus (Po, VPM, and MDthal), and parabrachial nucleus (PBN). We found that power across the network was lowered within 10 minutes of peripheral CGRP exposure, which was sustained for ~40-50 min. Coherence was mostly disrupted in amygdalar brain region pairings, and took on a shorter timecourse, with partial rescue of these responses by migraine abortive, sumatriptan. We found that early life stress exacerbated most of these responses, especially AMY-thalamic coherence pairings, although early life stress in the absence of CGRP demonstrated no impact on the network overall. We further identified individual mice with brain-network activity hypersusceptible to migraine.</p><p><strong>Conclusions: </strong>Our findings demonstrate that early life stress confers vulnerability to migraine, simultaneously impacting behavior and brain network activity responses to peripheral CGRP.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251816","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":"Efficacy and safety of eptinezumab in adults with chronic migraine and medication-overuse headache who also received patient education: 24-week results of the randomized RESOLUTION trial.","authors":"Henrik W Schytz, Rigmor H Jensen, Christofer Lundqvist, Cristina Tassorelli, Fabrizio Vernieri, Michel Lantéri-Minet, Gisela M Terwindt, Andrew Blumenfeld, Stewart J Tepper, Mette Krog Josiassen, Gary Jansson, Anders Ettrup, Aurélia Mittoux, Richard B Lipton","doi":"10.1186/s10194-026-02423-x","DOIUrl":"10.1186/s10194-026-02423-x","url":null,"abstract":"<p><strong>Background: </strong>The phase 4 RESOLUTION trial showed that the first 12 weeks of treatment with eptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody, reduced migraine frequency, severity, and disease burden, and improved quality of life (QOL) versus placebo in participants with chronic migraine (CM) and medication-overuse headache (MOH) who also received patient education. Here, we present 24-week eptinezumab efficacy and safety in the RESOLUTION trial.</p><p><strong>Methods: </strong>RESOLUTION was a randomized, parallel-group, multinational clinical trial that included a 12-week double-blind, placebo-controlled period and a 12-week open-label extension period (OLE). Adults (18-75 years) with CM and MOH (excluding opioid-overuse headache) received a brief educational intervention about MOH at baseline and were randomized (1:1) to IV eptinezumab 100 mg or placebo. At Week 12, all participants received eptinezumab 100 mg. Measures used for primary and key secondary efficacy endpoints were also captured during the OLE: mean changes from baseline in monthly migraine days (primary endpoint: Weeks 1-4), monthly headache days, monthly days with acute medication use, average daily pain, and participants no longer meeting threshold criteria for CM nor MOH. Secondary endpoints (including patient-reported-outcomes [PROs] assessing disease-related burden and health-related QOL) and treatment-emergent adverse events (TEAEs) were also captured during the OLE.</p><p><strong>Results: </strong>Of 608 participants randomized, 593 (97.5%) were treated with eptinezumab in the OLE, and 584/608 (96.1%) completed the trial. Reductions in migraine frequency and active CM/MOH diagnosis, and improvements across multiple PROs observed in post hoc analyses during the placebo-controlled period were sustained during the OLE for participants initially treated with eptinezumab, with similar levels of improvement gained for those initially receiving placebo. The proportion of participants with TEAEs in the OLE was similar between eptinezumab-eptinezumab and placebo-eptinezumab treatment sequence groups (30% vs 34%); no new safety signals were identified.</p><p><strong>Conclusions: </strong>In participants with CM and MOH who received patient education, reductions in disease burden and improvements in QOL during the first 12 weeks with eptinezumab treatment were sustained for up to 24 weeks following a second eptinezumab infusion, with similar improvements observed in participants switched from placebo to eptinezumab. Eptinezumab was generally well tolerated, with no new safety signals.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT05452239 (https://clinicaltrials.gov/study/NCT05452239); EudraCT Number: 2021-003049-40 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2021-003049-40).</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13274074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251809","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":"Consistency of response to rimegepant for the acute treatment of migraine among real-world users - findings from the prospective observational CONFIDENCE study.","authors":"Richard B Lipton, Lucy Abraham, Alexandre Urani, Giorgio Lambru, Peter J Goadsby, Patricia Pozo-Rosich, Todd J Schwedt, Kristina M Fanning, Feng Dai, Karin Hygge Blakeman","doi":"10.1186/s10194-026-02421-z","DOIUrl":"10.1186/s10194-026-02421-z","url":null,"abstract":"<p><strong>Background: </strong>Real-world data on the effectiveness of rimegepant for the acute treatment of migraine is limited, particularly regarding consistency of response over multiple attacks.</p><p><strong>Methods: </strong>CONFIDENCE was a prospective observational survey study with screening and baseline questionnaires; a 28-day observational period where participants completed daily assessments on migraine occurrence, treatment, and outcomes; and an end of study questionnaire. Adults in the United States with 3-14 headache days in the last 30 days, a rimegepant prescription for the acute treatment of migraine, and plans to use rimegepant in the next 30 days were recruited in phases via the Migraine Buddy® app; firstly, those with/without preventive therapies, and then, those taking specific preventive therapies. A primary outcome of CONFIDENCE was consistency of rimegepant response across multiple attacks at the population and participant levels regardless of preventive migraine therapy. Positive treatment outcomes were defined as (1) meaningful pain relief (MPR) within 2 hours, (2) meaningful improvement in function (MIF) within 2 hours, and (3) attacks where participants reported being 'satisfied' or 'extremely satisfied' with rimegepant (treatment satisfaction).</p><p><strong>Results: </strong>416 participants recorded data for 2169 rimegepant-treated migraine attacks (median: 7/participant). Participants' mean age was 40 years, 91% were female, 90% were White, and 84% took ≥ 1 preventive therapy. At baseline, participants reported a median (IQR) of 8 (5, 10) headache days/month and 40% had very severe migraine-related disability as measured by the Migraine Disability Assessment score ≥ 41. Among all rimegepant-treated migraine attacks recorded in the study, 61% achieved MPR and 58% achieved MIF within 2 hours, while 68% achieved treatment satisfaction. Of the 349 participants who treated ≥ 3 attacks, favorable outcomes were achieved in ≥ 2 of their first 3 recorded attacks for MPR within 2 hours in 65%, MIF within 2 hours in 60%, and treatment satisfaction in 74%. 55%, 48%, and 66% of participants achieved these outcomes in ≥ 3 of their first 4 attacks (n = 289 participants with ≥4 attacks).</p><p><strong>Conclusions: </strong>Consistently positive treatment outcomes were observed at the population (all attacks) and participant levels in this real-world observational study of > 400 participants and >2000 migraine attacks treated with rimegepant.</p><p><strong>Trial registration: </strong>NCT06467370.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239508","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":"CD4⁺T cells mediate systemic and local immune changes and pain symptoms in the rat model of temporomandibular disorders related pain.","authors":"Jianquan He, Yuzhuo Hei, Lin Li, Xiaojun Xia, Zhihui Mai, Xiayun Chen","doi":"10.1186/s10194-026-02422-y","DOIUrl":"10.1186/s10194-026-02422-y","url":null,"abstract":"<p><strong>Background and purpose: </strong>Immune cells involved in pain has received increasing attention, but the available literature on the role of T cells in temporomandibular disorders (TMD) related pain is limited. Our previous study has showed that elevated expression of HLA DR⁺ CD4⁺ T cell may increase the risk of TMD-related pain. In the present study, we aimed to investigate CD4⁺ T cell-mediated systemic and local immune changes in the rat model of TMD-related pain via CD4⁺ T cell depletion, and clarify the immunological contribution of CD4⁺ T cell on TMD-related pain.</p><p><strong>Methods: </strong>A rat model of occlusal interference was established to induce TMD-related pain. Animals were divided into three Groups: control (Group1), occlusal interference (Group2), and occlusal interference with CD4⁺ T cell depletion (Group3). Systemic CD4⁺ T cell proportions were verified by flow cytometry at day3, 6, 14. Pain-related behavior was assessed by von Frey testing daily, and the circulating levels of cortisol, TNF-α, IL-6, IL-17 A, and IFN-γ levels quantified by ELISA at day 3, 10, 15. In the end, local inflammatory cytokine expression patterns in condylar tissues were examined by immunofluorescence staining.</p><p><strong>Results: </strong>Occlusal interference model successfully mimicked significant TMD-related pain with a sharply increase reaching its peak at day 6 followed by a gradual decline, but at lower level of pain in Group3. The circulating level of IL-17 A rapidly rise at the initial phase, then stabilized and declined eventually despite of CD4⁺ T cell depletion or not. Levels of cortisol and TNF-α were significantly decreased at the end of the study in Group 3. Immunofluorescence analysis of condylar tissues revealed substantial up-regulation of TNF-α, IL-6 and IFN-γ in Group 2, which was significantly alleviated in Group 3.</p><p><strong>Conclusion: </strong>This study demonstrated IL-17 A increased with pain independent of CD4⁺T cells at the early stage. But consistently lower pain sensitivity, reduced systemic and local inflammatory cytokines in the later were identified after CD4 + T cell depletion. So we suggest that CD4⁺ T cells are important to maintain TMD-related pain and central to the late-phase immunological cascade in this model. More underlying mechanism of CD4⁺ T cells involved in TMD-related pain warrant further investigations.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239480","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":"Oscillatory edge connectivity in pain-related regions supports machine learning identification of migraine.","authors":"Fu-Jung Hsiao, Kuan-Lin Lai, Wei-Ta Chen, Yen-Feng Wang, Shih-Pin Chen, Gianluca Coppola, Shuu-Jiun Wang","doi":"10.1186/s10194-026-02420-0","DOIUrl":"10.1186/s10194-026-02420-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Objective and interpretable brain signatures for migraine diagnosis and phenotyping remain limited. Edge-centric connectivity treats interregional connections as primary analytical units and captures higher-order, frequency-resolved coordination patterns that may not be detected by conventional node-based functional connectivity approaches. This study investigated whether resting-state magnetoencephalography-derived oscillatory edge-connectivity features within pain-related regions may provide mechanistic insights into migraine neuropathology and inform future research on complementary approaches to migraine diagnosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study included 250 individuals, stratified into healthy controls (n = 72), patients with chronic migraine (CM; n = 98), and patients with episodic migraine (EM; n = 80). Resting-state 306-channel magnetoencephalography activity was source-analysed in predefined pain-related regions: the bilateral insula, primary somatosensory cortex, secondary somatosensory cortex, primary motor cortex, and anterior cingulate cortex (ACC). Dynamic connectivity was estimated using amplitude envelope correlation, with symmetric orthogonalisation to reduce leakage. Edge-centric functional connectivity was calculated from co-fluctuation time series across frequency bands. Seven classifiers were trained using fivefold nested cross-validation with independent testing (80/20 split). Model predictions were further interpreted using Shapley values to identify candidate neurophysiological signatures at the edge-and frequency-band levels.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Compared with HCs, both migraine groups exhibited significantly higher anxiety and depression scores (all p &lt; 0.001), whereas the CM group demonstrated greater headache frequency and migraine-related disability than did the EM group. Using oscillatory edge-connectivity features derived from resting-state magnetoencephalography, multiple machine-learning models successfully discriminated patients with migraine from healthy controls. In the validation and independent test datasets, six models, particularly support vector machine, k-nearest neighbour, and ensemble approaches, achieved the predefined performance criteria (accuracy and weighted F1-score ≥ 0.75). Receiver operating characteristic analysis demonstrated good discriminative performance, with area under the curve values ranging from 0.783 to 0.841 in the validation dataset and from 0.808 to 0.854 in the independent test dataset. Shapley analysis consistently revealed that elevated ACC-centred edges linking the somatosensory cortex, insula, and motor cortex to the ACC contributed most strongly to migraine classification, particularly within alpha-to-gamma frequency bands. Region-level contribution analyses further demonstrated that the ACC and primary somatosensory cortex together accounted for more than 60% of the total feature importance. By contrast, machine learning","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217765","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":"Blood-brain barrier integrity and brain entropy in reversible cerebral vasoconstriction syndrome.","authors":"Chia-Hung Wu, Tun-Wei Hsu, Yu-Hsiang Ling, Yen-Feng Wang, Chien-Yuan Lin, Chia-Wei Lee, Jiing-Feng Lirng, Shuu-Jiun Wang, Shih-Pin Chen","doi":"10.1186/s10194-026-02409-9","DOIUrl":"10.1186/s10194-026-02409-9","url":null,"abstract":"<p><strong>Background: </strong>Elucidating functional brain dynamics under different blood-brain barrier (BBB) permeabilities may resolve the enigmatic pathophysiology of reversible cerebral vasoconstriction (RCVS); however, relevant investigations are lacking. We aimed determine the relationship between brain functional dynamics and BBB permeability in patients with RCVS.</p><p><strong>Methods: </strong>We prospectively recruited RCVS patients and healthy controls (HCs) from November 2016 to January 2023 in Headache Center in a tertiary medical center (> 3000 beds) and adjacent communities. RCVS patients who were diagnosed according to the International Headache Society criteria, and age- and sex-matched HCs were enrolled. Normalized entropy, derived from resting-state fMRI (rs-fMRI), was compared at the network and parcel levels between RCVS patients with and without BBB disruption. Dynamic contrast-enhanced MRI (DCE-MRI)-derived K^trans BBB permeability and ultrasonographic findings were analyzed.</p><p><strong>Results: </strong>In total, 188 subjects (100 RCVS + 88 HCs) were enrolled. Compared with the HCs, the RCVS patients had greater entropy (p = 0.014), which was greater in the RCVS patients without than in those with (adjusted p = 0.040) BBB disruption. Compared with HCs, patients without BBB disruption had greater entropy between 60 and 90 days after headache onset (adjusted p = 0.006). No significant differences in entropy were noted between disease stages in BBB-disrupted patients. Parcels within subnetworks of the Default mode network (Default A and C) exhibited higher entropy in patients without BBB disruption. In specific anatomical locations, entropy values were negatively correlated with ultrasonographic Lindegaard index vasoconstriction severity (p = 4.3 × 10^- 6; within the Default A network) and DCE-MRI K^trans BBB permeability (p = 0.005; within the Default C network).</p><p><strong>Conclusion: </strong>The differential changes in normalized entropy suggest that increased rs-fMRI signal complexity may reflect a compensatory functional response to abrupt vasoconstriction. In contrast, the loss of entropy fluctuations in the context of severe BBB disruption indicates a state of impaired cerebral autoregulation in patients with RCVS. The compensatory capacity decreased as vasoconstriction or BBB disruption exacerbated.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217820","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 multi-omics analysis identifies endocrine-disrupting chemical-related molecular mechanisms in migraine.","authors":"Yinfan Ren, Ziqi Xu, Zifei Xu, Guifang Zhang, Huanjie Huang, Chuhuai Wang, Xiao-Qian Hu","doi":"10.1186/s10194-026-02412-0","DOIUrl":"10.1186/s10194-026-02412-0","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Migraine is a highly prevalent, heritable neurological disorder with a marked female predominance, indicating substantial hormonal contributions to disease pathophysiology. Endocrine-disrupting chemicals (EDCs) are ubiquitous environmental contaminants that interfere with hormonal signaling and have been linked to multiple diseases, yet their molecular contribution to migraine remains unclear. This study aims to identify EDC-related genes contributing to migraine risk and explore underlying mechanisms using an integrative multi-omics and causal inference framework.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We curated 181 EDCs and identified 1,116 EDC-related genes through chemical-gene interaction network analysis, followed by integration of multi-omics quantitative trait loci datasets (eQTL, sQTL, mQTL, and pQTL) to derive genetic instruments. Summary data-based Mendelian randomization (SMR) was performed to assess the effects of genetically predicted molecular traits on migraine risk using genome-wide association study (GWAS) data from the OpenGWAS and GWASCatalog. HEIDI testing and Bayesian colocalization analyses were conducted to distinguish pleiotropy from linkage and to prioritize genes with shared causal variants, followed by transcriptome-wide association study (TWAS) for validation. Multi-omics integration and differential gene expression analysis were used to characterize regulatory mechanisms. Finally, molecular docking and molecular dynamics simulations were performed to evaluate interactions between prioritized EDCs and molecular targets implicated in migraine pathophysiology.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Eight EDC-related genes were identified as significantly associated with migraine risk, of which MEF2D, OSBPL10, B9D2, HTRA1 and PRDM16 were classified as high- or medium-evidence genes. Notably, PNKP and B9D2 demonstrated consistent cross‑tissue evidence across multiple molecular layers, including TWAS, gene expression, DNA methylation, and alternative splicing. PNKP, prioritized through integrative analyses of EDC-related genes and migraine-associated omics datasets, exhibited limited individual differential gene expression but significant enrichment of pathways related to hypothalamic-pituitary axis dysfunction, blood circulation, and pain signaling. Molecular docking and dynamics simulations further suggested stable binding between migraine-related target proteins and prioritized EDCs, including triphenyl phosphate (TPP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and benzo(a)pyrene (B[a]P), providing preliminary connections between EDC exposure and migraine at the molecular level.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study provides integrative genetic and multi-omics evidence suggesting that EDC-related genes may be associated with to migraine susceptibility, highlighting the potential role of environmental factors to migraine risk. These findings identify a set of candidate EDCs and molecular ","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204183","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":"Sex-dependent central amygdala physiology after supradural CGRP exposure is associated with migraine-like behaviors.","authors":"Nico Antenucci, Sambantham Shanmugam, Mariacristina Mazzitelli, Kenichi Tanaka, Caroline Kopruszinski, Igor Ponomarev, Edita Navratilova, Frank Porreca, Volker Neugebauer","doi":"10.1186/s10194-026-02417-9","DOIUrl":"10.1186/s10194-026-02417-9","url":null,"abstract":"<p><strong>Background: </strong>Calcitonin gene-related peptide (CGRP) is a key mediator of migraine, but the mechanisms through which meningeal CGRP engages central circuits involved in the sensory and affective dimensions of migraine remain incompletely understood. Here, we tested if supradural CGRP is sufficient to induce migraine-like sensory and affective behaviors and if these effects are associated with sex-dependent changes in parabrachial-central amygdala (PB-CeA) signaling.</p><p><strong>Methods: </strong>Adult male and female C57BL/6J mice received supradural CGRP or vehicle. Behavioral testing, whole-cell patch-clamp recordings, and qPCR analyses were performed 3 h later.</p><p><strong>Results: </strong>CGRP induced robust periorbital mechanical allodynia selectively in females, while hindpaw mechanical thresholds were reduced in both sexes, with a greater effect in females. CGRP also increased avoidance-like behavior in both sexes, reflected by decreased open-arm exploration in the elevated plus maze and decreased time spent in the light compartment of the light-dark box. Whole-cell patch-clamp recordings from neurons in the right latero-capsular central amygdala in CGRP-exposed mice revealed higher excitability and larger PB-evoked excitatory postsynaptic currents in females than males. Ex vivo bath application of the CGRP receptor antagonist CGRP₈₋₃₇ was used to test local CGRP receptor sensitivity and selectively decreased excitability and PB-evoked excitatory transmission in females, while paired-pulse ratio remained unchanged in both sexes. In addition, qPCR analysis identified region- and sex-dependent transcriptional changes after supradural CGRP, with the most consistent molecular effects observed in the right PBN and more limited changes in the right CeA.</p><p><strong>Conclusions: </strong>Together, these findings show that supradural CGRP is sufficient to produce sex-differentiated mechanical hypersensitivity and avoidance-like behavior and is associated with sex-dependent physiological and transcriptional changes, including a right-sided pattern of transcriptional effects. These results identify the PB-CeA pathway as a candidate substrate linking meningeal CGRP signaling to central mechanisms relevant to hypersensitivity and amygdala plasticity that is more pronounced in females.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194782","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":"Transcriptional correlates of structure-function coupling plasticity in trigeminal neuralgia: unveiling the synaptic and metabolic associations.","authors":"Jian Zhang, Xujing Nie, Shuyue Fu, Yinping Lu, Tiantian Liu, Zhilin Zhang, Jinglong Wu, Xuezhi Tong, Tianyi Yan","doi":"10.1186/s10194-026-02419-7","DOIUrl":"10.1186/s10194-026-02419-7","url":null,"abstract":"<p><strong>Background: </strong>Trigeminal neuralgia (TN) is characterized by severe facial pain, transitioning from peripheral vascular compression to central sensitization. However, the core central pathophysiological mechanisms-particularly how the brain structurally and functionally reorganizes to maintain pain or recover after surgical treatment (primarily microvascular decompression or percutaneous interventions)-remain to be fully elucidated.</p><p><strong>Methods: </strong>We employed a longitudinal multi-scale design using a graph harmonic model to quantify structure-function (S-F) coupling, a metric reflecting brain network integrity. We analysed multimodal magnetic resonance imaging data from 87 patients with TN and 42 healthy controls (HCs). Post-treatment follow-up data were acquired for 46 patients, of whom 39 had complete longitudinal paired data. We further utilised partial least squares (PLS) regression with rigorous spatial permutation testing (spin-tests) to bridge macroscopic imaging changes with microscopic transcriptomic data from the Allen Human Brain Atlas.</p><p><strong>Results: </strong>Patients exhibited significantly reduced global S-F coupling, particularly in the somatomotor and dorsal attention networks. Notably, this decoupling was negatively correlated with baseline pain severity and disease duration. Following treatment, global S-F coupling returned to levels statistically indistinguishable from healthy baselines ([Formula: see text]). Crucially, the magnitude of postoperative reorganization ([Formula: see text]S-F coupling) significantly correlated with postoperative pain reduction percentages and long-term follow-up NRS scores. This recovery extended beyond focal repair, involving extensive adaptive reorganization in the visual and default mode networks. Molecularly, disease-related decoupling was spatially associated with genes linked to neuronal energy metabolism, cellular ionic homeostasis, and neuroinflammation. Conversely, treatment-induced plasticity strongly correlated with genes modulating chemical synaptic transmission and endogenous opioid signaling.</p><p><strong>Conclusions: </strong>TN pathophysiology is closely linked to ion channel-mediated neuronal metabolism and progressive network decoupling. Effective treatment restores homeostatic brain network coupling primarily by facilitating synaptic plasticity-based adaptive reorganization rather than merely through focal repair. This work offers a new perspective on the neural circuits underlying pain maintenance and provides potential imaging indicators for developing brain network-targeted therapeutic strategies.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13251101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194790","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 glutamatergic ventrolateral periaqueductal gray-lateral habenula pathway is associated with depression-like behavioral measures in young adult male mice with trigeminal neuropathic pain.","authors":"Lulu Zhang, Yizhen Yao, Chengmao Zhou, Minhui Wu, Fucheng Zhang, Jiwei Yao, He Zhu","doi":"10.1186/s10194-026-02415-x","DOIUrl":"10.1186/s10194-026-02415-x","url":null,"abstract":"<p><strong>Background: </strong>Depression is a clinically important comorbidity of trigeminal pain disorders, including trigeminal neuralgia, yet the neural circuits linking persistent trigeminal nerve injury to negative affect remain incompletely understood. The present study aimed to investigate the involvement of the ventrolateral periaqueductal gray (vlPAG)-lateral habenula (LHb) pathway in depression-like behavioral measures in a young adult male mouse model of trigeminal neuropathic pain.</p><p><strong>Methods: </strong>A mouse model of trigeminal neuropathic pain was established in young adult male mice using infraorbital nerve chronic constriction injury (IoN-CCI). Spontaneous facial pain-related behavior and depression-like behavioral measures were assessed using facial grooming analysis, the sucrose preference test, the open field test, and the tail suspension test. c-Fos mapping, cell-type analysis, viral tracing, and chemogenetic manipulation of vlPAG glutamatergic neurons and the vlPAG-LHb pathway were performed to examine neuronal recruitment, anatomical connectivity, and behavioral relevance.</p><p><strong>Results: </strong>In young adult male mice, IoN-CCI induced persistent facial grooming behavior as an index of spontaneous facial pain-related behavior and, by 4 weeks after surgery, was associated with depression-like behavioral changes without detectable alterations in body weight, general locomotor activity, or hindpaw mechanical and thermal sensitivity. c-Fos mapping and cell-type analyses showed a progressive increase in c-Fos expression in vlPAG neurons following IoN-CCI, with most labeled neurons identified as glutamatergic, suggesting recruitment of vlPAG glutamatergic neurons in this model. Chemogenetic inhibition of vlPAG glutamatergic neurons decreased depression-like behavioral measures, whereas chemogenetic activation increased these measures, without significantly altering facial grooming behavior used as an index of spontaneous facial pain-related behavior. Viral tracing provided anatomical evidence for a projection from the vlPAG to the LHb, and c-Fos expression in LHb neurons increased following IoN-CCI. Chemogenetic inhibition of the vlPAG-LHb pathway decreased depression-like behavioral measures, whereas chemogenetic activation increased these measures in IoN-CCI mice and was associated with similar behavioral changes in naive mice.</p><p><strong>Conclusion: </strong>These findings suggest that the vlPAG-LHb pathway is functionally associated with behavioral measures related to negative affect in a young adult male mouse model of trigeminal neuropathic pain, providing a circuit-level framework for understanding pain-associated affective disturbances.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":16013,"journal":{"name":"Journal of Headache and Pain","volume":" ","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194822","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}