Chronic migraine is characterized by recurrent trigeminovascular activation, cutaneous allodynia, and central sensitization. Mitochondrial dysfunction and impaired calcium handling may contribute to migraine chronification, but whether these processes are modified by Yangxue Qingnao (YXQN), a traditional Chinese medicine used for headache disorders, remains unclear. Here, a chronic migraine mouse model was induced by intraperitoneal nitroglycerin (NTG) injections on alternate days for 9 days. Migraine-like behaviors, trigeminal nucleus caudalis (TNC) neuropeptide expression, neuronal activation, proteomic profiling, mitochondrial function, and electrophysiological properties were assessed. YXQN attenuated migraine-like phenotypes, reduced TNC calcitonin gene-related peptide (CGRP) levels and c-Fos neuronal activation in TNC region. Proteomic analysis identified exploratory changes in mitochondrial- and calcium-transport-related pathways. YXQN treatment was accompanied by improvements in selected mitochondrial structural and functional measures, reduced calcium-associated fluorescence signals, and attenuated TNC neuronal hyperexcitability. These findings support further investigation of mitochondrial calcium handling and TNC neuronal excitability as potential contributors to the effects of YXQN.
Trigeminal neuralgia (TGN) is a disabling neuropathic pain condition. Neurovascular compression of the trigeminal nerve root is the widely accepted cause, yet a proportion of patients derive no lasting benefit from microvascular decompression or pharmacotherapy with carbamazepine (CBZ), suggesting the involvement of additional pathogenic mechanisms. Neuroimmune dysregulation has been increasingly implicated, but the peripheral immune landscape across the full clinical trajectory of TGN—from drug-naïve to treatment-refractory—has not been systematically characterized. Here we constructed a single-cell immune atlas spanning this continuum to identify cell-type-specific programs linked to CBZ response and resistance. Peripheral blood mononuclear cells from 11 donors (healthy controls, untreated TGN, CBZ-responsive, and CBZ-non-responsive patients) were profiled by single-cell RNA sequencing with paired T/B cells receptor sequencing. An intradural trigeminal nerve compression mouse model was used for flow cytometric validation. Analyses included trajectory inference, metabolic pathway scoring, and intercellular communication network modeling. Across 122,582 high-quality cells, immune remodeling followed a gradient of severity rather than a simple on/off pattern. Untreated patients showed acute cytotoxic CD8⁺ T cells expansion and pro-inflammatory monocytes activation; these changes partially reverted in CBZ responders. Non-responders, however, exhibited a qualitatively distinct state of cross-lineage functional remodeling: a pro-inflammatory CD8_T_TNF population emerged and expanded, cytotoxic CD8_T_GZMB cells switched from an acute effector program to a sustained NF-κB-centered inflammatory program, regulatory T cells were selectively depleted in association with elevated YBX1, inflammatory B_CD80 cells expanded alongside transitional B_ZBTB16 cells, and monocytes polarized toward a CTNNB1-associated pro-fibrotic and angiogenic phenotype. Intercellular communication analysis identified an “inflammation–matrix remodeling–angiogenesis” signaling pattern enriched in the non-responsive group. CBZ treatment resistance in TGN is accompanied by systemic, cross-lineage immune reprogramming into a sustained treatment-non-responsive configuration rather than by quantitative changes in cell abundance alone. The transcriptional checkpoints identified here may offer candidate biomarkers and potential therapeutic targets for refractory TGN.
Cognitive dysfunction is increasingly recognized as a major contributor to disability in chronic migraine (CM), yet the mechanisms linking neuroinflammation to synaptic dysfunction and cognitive decline remain poorly understood. Interleukin-17A (IL-17A) has emerged as an important regulator of neuroimmune interactions in neurological disorders; however, its role in migraine-associated cognitive impairment remains unknown. A nitroglycerin (NTG)-induced mouse model of CM was combined with behavioral testing, transcriptomic profiling, immunohistochemistry, molecular analyses, and in vitro microglial studies. IL-17A neutralization, Il17ra knockdown, antioxidant treatment, and pharmacological inhibition of STING were used to dissect the underlying mechanisms. Repeated NTG administration induced mechanical hypersensitivity, cognitive impairment, and elevated cortical IL-17A expression. Neutralization of IL-17A significantly alleviated both nociceptive sensitization and cognitive deficits. Transcriptomic analyses revealed activation of IL-17 and cytosolic DNA-sensing pathways, accompanied by suppression of synaptic-related programs. Mechanistically, IL-17RA was predominantly upregulated in cortical microglia, where IL-17A promoted oxidative stress, mitochondrial dysfunction, and mitochondrial DNA (mtDNA) release. Cytosolic mtDNA subsequently activated the cGAS/STING pathway, driving inflammatory microglial remodeling and excessive synaptic engulfment. Pharmacological or genetic interruption of this signaling cascade attenuated cGAS/STING activation, reduced microglial inflammatory responses, and preserved synaptic integrity. Importantly, STING inhibition markedly suppressed microglial synaptic engulfment and rescued synaptic deficits in repeated NTG-treated mice. Our findings identify an IL-17A/IL-17RA-ROS-mtDNA-cGAS/STING signaling cascade in microglia that links neuroinflammation to synaptic pathology chronic migraine-like conditions. By driving inflammatory microglial remodeling and excessive synaptic pruning, this pathway contributes to migraine-associated cognitive dysfunction and represents a potential therapeutic target for preventing migraine chronification and its cognitive impairments. Not applicable.
Headache disorders are major contributors to non-fatal health loss in adolescents, but epidemiological data from Vietnam are lacking. This study aimed to estimate the prevalence of headache disorders among Vietnamese high school pupils and examine their associations with demographic and school-level characteristics. This cross-sectional, school-based study was conducted in Vietnam from January to March 2026 using the standardized methodology of the Global Campaign against Headache. Pupils aged 15–17 years from seven high schools representing diverse geographic and socioeconomic settings completed the Vietnamese-translated adolescent version of the HARDSHIP questionnaire under supervision. Headache diagnoses were assigned using the HARDSHIP diagnostic algorithm according to two approaches: the original criteria, defining UdH as mild headache lasting < 1 h, and modified criteria, defining undifferentiated headache (UdH) as mild-to-moderate headache lasting < 1 h. Enquiry timeframes were 1 year, 4 weeks, and 1 day, the latter assessed using the headache-yesterday (HY) question. Prevalence estimates were calculated with 95
The trigeminal nerve innervates the face and the meninges via its three branches, with central relay neurons located in the brainstem’s spinal trigeminal nucleus. We have shown a somatotopic organization on human brainstem level and aimed, using an independent new sample, to characterize the functional somatotopy with a focus on within-brainstem and brainstem–cortical connectivity. Electrical stimulation was applied to the three branches of the trigeminal nerve at two intensities (high and low) to examine the somatotopic organization in healthy participants during fMRI. Neuroimaging was preregistered (NCT06534880) and covered the upper spinal cord, brainstem, thalamus, insula, primary somatosensory cortex (S1), S2/parietal operculum, and cingulate cortex. Activation patterns following stimulation of each trigeminal branch were analyzed. Branch-specific functional connectivity was estimated within the brainstem as well as between brainstem and cortical targets. In a cohort of 30 healthy participants (mean age 32.1 ± 8.8 years, 18 female (60
Classical trigeminal neuralgia (CTN) is characterized by transient, stimulus-evoked pain attacks, but post-stimulation changes in local brain synchronization remain unclear. We characterized static and dynamic local functional synchronization at baseline and during resting-state scans initiated after a single trigger-zone stimulation. Baseline analyses included 44 healthy controls (HC), 80 CTN patients with stimulation-evoked pain (CTN_pain), and 68 CTN patients without evoked pain (CTN_no_pain). Longitudinal analyses included 39 HC, 75 CTN_pain patients, and 64 CTN_no_pain patients completed all the three resting-state fMRI sessions: baseline, a scan initiated within 5 seconds after stimulation, and a scan initiated 30 minutes later. The first 20 seconds of each time series were discarded. Regional homogeneity, coherence-based regional homogeneity, and their dynamic measures (ReHo, CoReHo, dReHo, and dCoReHo) were assessed using voxel-wise group/time analyses; exploratory region of interest (ROI)-level mixed-effects models tested group × time interactions. At baseline, group differences were observed in Frontal_Med_Orb_R, Insula_L/R, and Hippocampus_R/L. Insula_R dReHo and Frontal_Med_Orb_R ReHo differed between CTN_pain and CTN_no_pain patients. Within-group post-stimulation changes were limited in HC and broader in both CTN subgroups. Exploratory ROI-level sensitivity analyses identified seven group × time interactions that remained significant after metric-specific Bonferroni correction. Exploratory imaging-clinical analyses indicated that imaging measures associations with pain scores in CTN_pain patients and quality of life, anxiety and depression scores in CTN_no_pain patients. CTN subgroups defined by the observed pain-evocation outcome differed in baseline and temporal measures of resting-state local synchronization. Baseline Insula_R dReHo was the subgroup-associated measure but should not be interpreted as causal or predictive. Exploratory group × time interactions and imaging-clinical correlations provide preliminary evidence that requires independent replication. These findings reflect post-stimulation resting-state alterations rather than acute activation.
Cluster headache is one of the most painful known disorders. Cluster headache sufferers compare the extreme unilateral pain to labour pains and gunshot wounds. Given the many logistical challenges of capturing spontaneous cluster headache attacks, only a handful of neuroimaging studies have successfully captured such attacks. Intravenous nitroglycerin (NTG) reliably induces cluster headache attacks in a controlled setting, thereby enabling investigation of resting-state functional connectivity during the attack stage. Cluster headache patients aged 18–60 years were recruited from both the population and tertiary headache clinics. Consented participants received either 0.5 µg/kg/min NTG or placebo infusion for 20 min. Structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependent contrast (BOLD) time series were obtained at baseline (pre-infusion) and during headache. A total of 16 paired headache (NTG-infusion) and placebo scans were analysed. The functional connectivity was assessed for three pre-determined seeds: thalamus, ACC and insula. A two-factor (time and treatment), repeated measures 2 × 2 ANOVA model was used to assess main effects and interactions. Significant changes in functional connectivity between the contralateral amygdala (T = 3.47, peak connectivity change at 30, 0, -20, P < 0.001), and hippocampus (T = 4.33, peak connectivity change at 28, -8, -20, P < 0.001) and ipsilateral cerebellum culmen (T = 5.13, peak connectivity change at -14, -30, -18, P < 0.001), with respect to the anterior insula ipsilateral to the pain side. These findings suggest reconfiguration of salience, limbic, cerebellar and default mode networks during the cluster headache attack state and implicate the cerebellum in trigeminal nociceptive processing.
Circadian syndrome (CircS) integrates metabolic abnormalities, short sleep duration, and depressive symptoms, and may reflect multidimensional circadian-related health dysregulation. Migraine is a disabling neurological disorder that is frequently accompanied by gastrointestinal symptoms, but evidence on the association between CircS and migraine-related symptom phenotypes in middle-aged and older adults remains limited. This study examined the associations between CircS and headache accompanied by stomach pain, a self-reported symptom co-occurrence phenotype, and explored the mediating role of frailty. Data were obtained from the China Health and Retirement Longitudinal Study. A total of 9,342 participants were included in the cross-sectional analysis, and 5,895 participants without headache accompanied by stomach pain at baseline were included in the longitudinal analysis. CircS was defined as the presence of at least four of seven components. Logistic regression and Cox proportional hazards models were used to examine the associations of CircS with prevalent and incident headache accompanied by stomach pain, respectively. Sensitivity analyses included complete-case analyses, a 2-year lag analysis, age-restricted analysis, propensity score matching, and E-value analysis. Time-dependent receiver operating characteristic curves and bootstrap mediation analysis were also performed. CircS was associated with higher odds of prevalent headache accompanied by stomach pain after full adjustment (OR = 1.38, 95
Pain is a highly prevalent and disabling non-motor symptom of Parkinson’s disease (PD), yet it remains underrecognized and frequently undertreated in clinical practice. Although long considered a secondary consequence of motor dysfunction, pain in PD is now increasingly understood as a manifestation of disease-related alterations in nociceptive processing. These changes extend beyond dopaminergic deficiency and involve broader neurotransmitter imbalances and impaired descending inhibitory control across different neuroanatomical regions, providing a framework for understanding pain as an intrinsic feature of PD rather than a purely peripheral or motor-related phenomenon. We also summarize the main categories of pain experienced in PD, each with distinct clinical features and underlying pathophysiological mechanisms, and link them with current management strategies. A multimodal, mechanism-informed approach that integrates optimization of dopaminergic therapy with non-dopaminergic pharmacological treatments, neuromodulation, rehabilitation, and complementary interventions is key to a personalized treatment plan for pain in patients with PD. Finally, we highlight emerging translational directions, including candidate biomarkers that may help objectify pain and its related dysfunction in the PD population. Focusing on the neurobiological basis of pain in PD, this review aims to support a shift toward mechanism-based assessment and management, with an ultimate goal of improving pain outcomes and quality of life for individuals living with the disease. Not applicable.
Growing evidence implicates the hypothalamus as a key structure in migraine pathophysiology; however, our understanding of its precise role and of the specific nuclei involved remains limited. We combined MRI data from our laboratory with publicly available MRI datasets from OpenNeuro to examine hypothalamic subunit volumes in episodic migraine and to assess whether comparable alterations were observed in available chronic pain datasets. Structural MRI combined with an automated atlas-based segmentation algorithm was employed to investigate cross-sectional volumetric differences across 5 bilateral hypothalamic subunits in two independent migraine cohorts: DS1-MIG (DS1-MIG-base, n = 111 patients, n = 35 controls) and DS2-MIG (n = 28 patients, n = 31 controls). The adjusted volumes were compared between groups using MANOVA as an omnibus test, followed by Welch t-tests to test univariate follow-up. Longitudinal volumetric changes were additionally assessed in DS1-MIG participants with available follow-up scans using linear mixed models. To examine whether comparable hypothalamic alterations were observed in available clinical comparison datasets, the same cross-sectional pipeline was applied to two chronic pain datasets, one including patients with fibromyalgia (DS-FM, n = 33 patients, n = 33 controls) and the other including patients with trigeminal neuralgia (DS-TN, n = 119 patients, n = 55 controls). MANOVA revealed significant multivariate group differences in both independent migraine cohorts (DS1-MIG-base: p = .006 ; DS2-MIG: p = .008 ). Follow-up univariate analyses identified a consistent enlargement of the left anterior-superior subunit across both cohorts ( p_FDR = .023 in DS1-MIG-base and p_FDR = .046 in DS2-MIG), representing the only cross-cohort replication finding. Beyond this shared signature, DS2-MIG exhibited additional significant enlargements of the right anterior-inferior and right inferior tubular subunits. Longitudinal analyses in DS1-MIG showed no significant group-by-time interactions in hypothalamic subunit volumes over the available follow-up period. No significant volumetric alterations were detected in the fibromyalgia or trigeminal neuralgia cohorts, either in multivariate or univariate analyses. These findings provide evidence for subunit-specific hypothalamic structural alterations in migraine localized to the left anterior-superior hypothalamic subunit. The absence of detectable differential longitudinal change over the available follow-up period, together with the absence of comparable alterations in the available fibromyalgia and trigeminal neuralgia datasets, supports a migraine-related pattern of hypothalamic structural organization. However, this finding does not establish diagnostic specificity and should be confirmed in harmonized multi-diagnostic cohorts.
Trigeminal neuralgia (TN) is a disabling facial pain disorder, and current treatments remain insufficient for a substantial proportion of patients. Botulinum toxin type A (BoNT/A) has shown therapeutic benefit in TN, but its peripheral analgesic mechanisms remain incompletely understood. We aimed to determine whether BoNT/A alleviates TN-like pain by modulating the calcitonin gene-related peptide (CGRP)–extracellular signal-regulated kinase (ERK)–NaV1.7 pathway in trigeminal ganglion neurons. TN-like pain was induced in mice by chronic constriction injury of the infraorbital nerve (CCI-ION). On postoperative day 14, BoNT/A (10 U) or saline was injected intradermally into the whisker pad. Evoked and spontaneous pain-like behaviors were assessed using von Frey testing, the Ugo Basile facial pain test, and spontaneous scratching recordings; anxiety-like behavior was evaluated using the elevated plus maze. Myelin pathology was examined by Luxol fast blue staining and transmission electron microscopy. CGRP, NaV1.7/NaV1.8, and ERK/MAPK signaling were examined in trigeminal ganglion neurons using immunofluorescence, Western blotting, RT-qPCR, ELISA, calcium-influx assays, and whole-cell patch-clamp recordings. Olcegepant and PD98059 were used to interrogate CGRP receptor- and ERK-dependent mechanisms. BoNT/A significantly attenuated CCI-ION-induced mechanical allodynia, increasing the facial withdrawal threshold from 0.11 to 1.29 g, and reducing spontaneous pain-like behaviors. BoNT/A also improved anxiety-like behavioral measures in CCI-ION mice. Histological and ultrastructural analyses shown partial amelioration of myelin pathology, accompanied by increased myelin basic protein expression and a lower g-ratio. Mechanistically, BoNT/A reduced CGRP-associated activity in TRPV1-positive trigeminal ganglion neurons, accompanied by lower serum CGRP levels and attenuated capsaicin-evoked calcium influx. These changes were associated with a preferential reduction in NaV1.7 membrane localization, without a comparable reduction in NaV1.8, and with a marked decrease in sodium current density, with peak sodium current reduced by 78.6
Migraine has been linked to structural brain alterations that may deviate from normative aging patterns. Recent brain-age modeling studies have reported elevated brain age gap (BAG) values in migraine populations, but the clinical factors associated with individual variation in BAG remain incompletely characterized. This study quantified BAG in patients with migraine and identified demographic, lifestyle, and clinical factors independently associated with structural brain-age deviation. This cross-sectional study enrolled 128 patients with migraine (ICHD-3 criteria) and 35 non-migraine controls. Brain age was estimated using a support vector regression model trained on T1-weighted MRI scans from an independent multicenter dataset of 1,410 healthy adults. The primary outcome was the bias-corrected BAG. Multivariable linear regression analysis identified independent predictors of BAG within the migraine cohort across headache, psychiatric, sleep, and lifestyle domains. An exploratory extreme-group comparison contrasted migraine patients in the upper and lower BAG tertiles using binary logistic regression. Patients with migraine exhibited a significantly higher bias-corrected BAG than controls (9.76 ± 8.97 vs. 4.88 ± 8.25 years; ANCOVA adjusted for age, age², and total intracranial volume: F = 6.795, p = 0.010, partial η²=0.041). In multivariable linear regression analysis, depressive symptom severity (Beck Depression Inventory-II [BDI-II]: β = 0.39, 95
Neuropathic pain (NP) is a subtype of refractory chronic pain that currently presents three major difficulties in diagnosis and therapy in that clinicians must depend on patient complaints for the diagnosis, physicians find it difficult to recognize the disease early, and the evaluation of efficacy is slow. This review surveys the research on NP biomarkers conducted to date and aims to provide a scientific basis and reference for the exact diagnosis and treatment of NP. Studies indicate that the core pathological mechanism producing NP and its changes is the pathological plastic changes which have occurred in the sensory nervous system and that distinct etiologies of NP are associated with unique pathological mechanisms. NP biomarkers exist in such facets of investigation as biochemical, electrophysiological, imaging, genetic and epigenetic studies. Each category of biomarkers can provide specific utility for the diagnosis and prognostic assessment of NP. However, the high heterogeneity of NP limits the clinical translatability of individual biomarkers. Therefore, a multimodal integration of biomarkers is required for NP diagnosis and treatment, utilizing strategies including multicenter clinical research and therapeutic interventions, integrated multi-omics data analysis, to progressively develop an increasingly precise diagnostic and therapeutic system. These efforts will progressively facilitate the transition of the NP diagnostic and therapeutic model from traditional empirical medicine to a data-driven paradigm.
Post-traumatic headache (PTH) is a frequent early consequence of head traumatic injury, yet emergency departments (EDs) lack practical tools to identify high-risk patients. Whether routinely documented trauma characteristics are associated with immediate PTH beyond established clinical factors remains uncertain. This prospective, multicenter observational study evaluated patients aged ≥ 18 years presenting with head and/or neck trauma to the ED between 2022 and 2025. To adhere strictly to ICHD-3 criteria and prevent severity measurement bias, the primary analysis was restricted exclusively to a homogeneous cohort of 495 patients with mild traumatic head injury (GCS 13–15, no traumatic brain CT abnormalities). The primary outcome was immediate PTH occurring directly following the traumatic event. To prevent overfitting, candidate variables were restricted a priori to 9 core features. We utilized multivariable logistic regression and evaluated internal validity via 500 bootstrap resamples. Immediate PTH occurred in 62.8
Trigeminal neuropathic pain (TNP) is a chronic, debilitating pain disorder affecting the orofacial region. Patients often experience concomitant cognitive impairment, severely impacting their quality of life. The principal neural circuit mechanisms that link TNP to cognitive dysfunction remain unclear. The piriform cortex (PIR), primarily recognised for its role in olfaction, has not been systematically investigated in trigeminal neuropathic pain processing or pain-related cognitive dysfunction. This study utilised pseudorabies virus-mediated multisynaptic retrograde tracing to map whole-brain anatomical connectivity associated with orofacial sensory pathways. c-Fos immunofluorescence staining and in vivo fibre-optic calcium signalling recordings were used to detect alterations in glutamatergic neuronal activity within the PIR of TNP model mice. Chemogenetic and optogenetic techniques were employed to manipulate PIR glutamatergic (PIRGlu) neurons in a bidirectional manner, validating their functional roles in pain and cognitive regulation. Anterograde viral tracing was integrated with circuit-specific chemogenetic intervention to elucidate downstream regulatory pathways. This study identified the PIR as a previously unrecognized brain region anatomically associated with trigeminal neuropathic pain-related pathways, providing evidence for its potential involvement in TNP. PIRGlu neurons in TNP model mice exhibited marked burst-like activation, with in vivo calcium activity intensity exhibiting considerable synchronisation with facial pain-sensitive behaviour. Chemogenetic inhibition of PIRGlu neurons significantly increased pain thresholds and ameliorated cognitive deficits in TNP mice, whereas selective activation of PIRGlu neurons in sham mice recapitulated the pain–cognition comorbidity phenotype, demonstrating the essential role of these neurons in mediating pain-related cognitive dysfunction. Viral tracing identified the mediodorsal thalamus (MD) as a critical downstream target of PIRGlu neurons. Electrophysiological recordings further confirmed that PIRGlu neurons establish direct excitatory monosynaptic connections with MD neurons, with fast glutamatergic transmission predominantly mediated by AMPA receptor-dependent signalling. Specific disruption of the PIRGlu–MD circuit simultaneously alleviated pain and cognitive impairment in model mice, while inhibition of PIRGlu neurons markedly reduced calcium activity in downstream MD neurons. This study highlights the PIRGlu–MD circuit as an important pathway contributing to TNP–cognitive impairment comorbidity. Furthermore, it augments our understanding of the non-olfactory physiological functions of the PIR, offering a novel potential target for investigating the mechanisms underlying the association of chronic pain with cognitive impairment.
Emerging evidence suggests that glucagon-like peptide-1 receptor agonist (GLP-1RA) may be associated with reduced migraine burden. We aimed to evaluate whether semaglutide for weight management initiation is associated with changes in triptan consumption. We conducted a nationwide interrupted time series analysis using Danish health registers. All adults initiating semaglutide between December 2022 and December 2024 were included. The first dispensing date served as the index date, establishing a 24-month baseline and a 12-month follow-up period. The primary outcome was monthly triptan consumption (defined daily doses (DDD)/10,000 individuals). Analyses were conducted for new and prevalent triptan users, and stratified by sex, age group, and prior use of prophylactic antimigraine medication. During the study period, 189,392 individuals initiated semaglutide (68
White matter hyperintensities (WMHs) are prevalent in migraine, yet their relationship to specific migraine features remains poorly defined. Prior studies have used coarse phenotyping and linear methods, leaving potential threshold effects and the broader migraine phenotype unexplored. We applied an explainable machine-learning framework to characterise associations between migraine features and WMH volume and to identify data-driven phenotypes. Baseline data from two ongoing randomised controlled trials in Hong Kong Chinese women with episodic migraine were used for analyses. Participants underwent 3T brain magnetic resonance imaging (MRI) and WMH were quantified from manually corrected segmentations by radiologists. Migraine features (attack frequency, duration, pain intensity, aura subtypes, accompanying symptoms, triggers, and acute medication use) were derived from prospective three-month diaries and structured interviews. An XGBoost model was developed with nested five-fold cross-validation and interpreted using SHapley Additive exPlanations (SHAP). Unsupervised K-means clustering on patient-level SHAP values identified phenotypes. The analytic sample comprised 171 women (median age 52.0 years [IQR 38.5–60.0]) with a median WMH volume of 0.90 mL (IQR 0.56–1.31). The model explained modest variance (R² = 0.221) and achieved an area under the curve of 0.801 (95
Recent genetic findings have broadened the perspectives of cluster headache pathophysiology. Genes identified by genome wide association studies are likely to be involved in the pathophysiological mechanisms underlying the disease. In this study, we performed validation and characterization of eight loci corresponding to nine genes identified in previous genome wide association studies. Genetic loci were validated by means of a case-control study using TaqMan genotyping in 671 individuals, and a meta-analysis using previously genotyped data. Pyrosequencing methylation analysis and reverse transcription quantitative PCR gene expression studies was performed in a subset of individuals with cluster headache and healthy controls. Genetic associations were found with functional variants in two genes; FHL5 and MERTK. The minor allele of the FHL5 variant rs2273621 was associated with an increased risk of cluster headache in the genotyped samples (odds ratio = 1.42, P = 0.03) and in a meta-analysis (odds ratio = 1.29, confidence interval: 1.09–1.52), and the minor allele of the rs2230515 variant in MERTK was associated with lower risk in the meta-analysis (odds ratio = 0.69, confidence interval: 0.52–0.92). Methylation analysis further revealed altered methylation status of MERTK. Moreover, changes in relative gene expression were found for several candidate genes: a decrease in the mRNA expression of DUSP10 (P < 0.001), CAPN2 (P < 0.001), UFL1 (P < 0.001) and LRP1 (P = 0.007) in blood, and a decrease of CAPN2 (P < 0.001) as well as an increase in the mRNA expression of FTCDNL1/FONG (P = 0.004) in fibroblasts in CH vs. controls. Only two genes; PLCE1 and WNT2, could not be validated in the biological tissue studied; WNT2, possibly due to limited power, while PLCE1 was not expressed in the available tissue. These results confirm the validity of seven candidate genes for cluster headache identified through GWAS. Furthermore, five of the candidate genes are abundantly expressed in both immune and blood cells, converge functionally on inflammatory signalling pathways and suggest a potential role for inflammasomes in cluster headache.
Headache disorders are among the most common neurological complaints worldwide, particularly among medical students who are exposed to high academic stress. This study aimed to assess the prevalence and clinical characteristics of headaches among medical students in Abidjan, Côte d’Ivoire. A descriptive cross-sectional study was conducted from February to May 2025 among 506 medical students at Félix Houphouët-Boigny University in Abidjan (response rate: 25.0
