Journal of Headache and Pain最新文献

Background: Migraine, a complex neurovascular disorder, is closely associated with neuroinflammation and immune dysregulation. However, the high heterogeneity of immune cell populations means that the specific cellular immune mechanisms driving migraine susceptibility remain unclear.

Methods: We integrated single-cell expression quantitative trait locus (sc-eQTL) data by applying single-cell Mendelian randomization (Mendelian randomization applied at single-cell resolution, scMR) and colocalization analyses to systematically explore immune-mediated regulatory mechanisms underlying migraine and to identify potential therapeutic targets.

Results: We assessed the causal effects of 9,117 unique sc-eQTLs on migraine across 14 immune cell types. Four genes (PRDM11, VIM, FGFRL1, C6orf25) were identified as high-priority targets. Colocalization analysis revealed a high probability (posterior probability PP.H4 > 0.90) that these genes share causal variants with migraine genome-wide association study (GWAS) signals. Single-cell RNA sequencing (scRNA-seq) analyses revealed differential expression patterns of these genes across cell types and migraine-related states. Safety assessments based on phenome-wide association studies (PheWAS) showed a low risk of off-target effects in multiple body systems, thus supporting their safety as therapeutic targets. Mapping these targets to a database of known drugs identified three repurposable drug candidates (one approved and two investigational) with therapeutic potential for migraine.

Conclusions: This study establishes an extensible multi-omics analytical framework, providing novel insights into the immunogenetic basis of migraine. Furthermore, it successfully identified repurposable candidate drugs targeting key pathogenic genes, offering new perspectives for developing novel immunomodulatory therapeutic strategies for migraine.

Background: Migraine is prevalent among women of childbearing age and is associated with increased long-term cardiovascular and cerebrovascular risk. Pregnancy, a hypercoagulable state, may potentiate these risks. This study aimed to quantify the association between migraine or pregnancy-related headaches and cerebrovascular and cardiovascular events during pregnancy and the postpartum period.

Methods: We conducted a PRISMA-compliant systematic review and meta-analysis of observational studies comparing pregnant women with and without migraine or pregnancy-related headaches. PubMed, Scopus, and Web of Science were searched through May 8, 2025. Adjusted odds ratios (ORs) were pooled using random-effects models.

Results: Twelve studies encompassing 94,195,776 pregnancies met the inclusion criteria. Migraine was associated with markedly increased odds of all strokes and transient ischemic attacks (OR 10.45; 95% CI 4.27-25.57) and ischemic stroke (OR 7.14; 95% CI 2.51-20.31). Hemorrhagic stroke risk was elevated but not statistically significant overall (OR 2.25; 95% CI 0.99-5.18), while subarachnoid hemorrhage showed a 69% increased odds. Regarding cardiovascular events: myocardial infarction risk increased by 96%, peripartum cardiomyopathy odds were 2.68-fold (95% CI 1.73-4.14), and spontaneous coronary artery dissection odds were 9.21-fold higher (95% CI 3.72-22.82). All included studies were rated as "good" quality by the Newcastle-Ottawa Scale.

Conclusions: Migraine and pregnancy-related headaches are independent risk factors for a broad spectrum of cerebrovascular and cardiovascular events during pregnancy and the puerperium. These findings highlight the need for heightened clinical surveillance, targeted cardiovascular risk counselling, and multidisciplinary management strategies for this population.

Background: Migraine is recognized as a global public health issue. It is more prevalent among women; therefore, studies focusing solely on migraine in men are scarce. We aimed to investigate the relationship between social factors and migraine or severe headache in men, based on a Chinese national population study and the National Health and Nutrition Examination Survey (NHANES).

Method: In 2009, we conducted a population-based survey on headaches, for which 5,041 unrelated individuals were randomly selected and visited in all regions of China. A secondary analysis was performed on the data pertaining to men. Data retrieved from the NHANES between 1999 and 2004 were analyzed alongside the same social factors. Logistic regression was used to analyze the factors affecting men. We compared the predictive performance of six machine learning models: XGBoost, Random Forest, Decision Tree, Logistic Regression, Support Vector Machine, and K-Nearest Neighbors.

Results: Of 2,496 male Chinese participants, 236 (9.5%) were diagnosed with migraine or severe headache. According to the NHANES data, 714 (16.6%) of 4,303 male participants reported migraine or severe headache. Logistic regression of the two studies consistently revealed a positive association between obesity and migraine or severe headache (Chinese participants: odds ratio [OR] = 2.017, p = 0.020; NHANES sample: OR = 1.256, p = 0.038) as well as a negative correlation between increased income and the same condition. Occupation was related to migraine or severe headache in the Chinese population, and races were associated with headaches in the NHANES data. The five-fold cross-validation results demonstrated that the logistic regression model was the most stable and generalizable classifier. The SHAP analysis clarifies that significant differences existed in the contribution of individual factors to migraine or severe headache between the two studies.

Conclusion: Obesity and high income were found to be associated with migraine or severe headache in men. Given the discrepancies observed between the two studies, further exploration of these factors across different countries may be warranted.

Background: Recent studies have indicated that mitochondrial dysfunction contributed to migraine development, yet the links between dietary intake of mitochondria-related nutrients and migraine risk haven't been explored in prospective cohort studies.

Methods: Data from 202,656 UK Biobank participants were used to explore associations between dietary intake of mitochondria-related nutrients, including magnesium, riboflavin (vitamin B2), thiamine (vitamin B1), niacin (vitamin B3), vitamin B6, vitamin B12, and folate (vitamin B9), with migraine risk. For analysis, Cox proportional hazards models, subgroup analyses, sensitivity analyses, and restricted cubic spline plots were used.

Results: After a median follow-up of 13.25 years, 1844 (0.9%) participants developed migraines. Those with migraines had substantially lower intakes of mitochondrial-related nutrients. In multivariable Cox regression, each 1SD increase in niacin intake was linked to a 3% migraine risk reduction (HR: 0.97; 95% CI: 0.94-0.99; p = 0.010*), as was each 1SD increase in vitamin B12 intake showed a 4% risk reduction (HR: 0.96; 95% CI: 0.93-0.99; p = 0.040*). Subgroup analyses showed no interactions between nutrient intakes and gender or age. Sensitivity analyses confirmed the stability of these associations. Significant nonlinear and negative associations between magnesium, niacin, and vitamin B12 with migraine were observed.

Conclusions: Higher dietary intake of mitochondrial-related nutrients was associated with a reduced risk of migraine, with niacin and vitamin B12 showing the most stable protective effects. Our study suggests that adjusting dietary intake of mitochondria-related nutrients may offer a promising strategy for the prevention and management of migraine.

Orofacial pain encompasses a diverse group of disorders that pose a significant clinical challenge, often progressing from acute to chronic conditions due to a disconnect between clinical diagnosis and underlying pathophysiology. This review provides a synthesis of the mechanisms driving this transition and evaluates emerging therapeutic strategies that target them. First, we dissect the pathophysiological mechanisms of acute pain, including peripheral sensitization and transient central sensitization; and then detail how these processes can become maladaptive, leading to chronic pain states sustained by a combination of persistent nociceptive input, neuropathic alterations, and nociplastic changes involving dysfunctional descending modulation and central network reorganization. Building on this mechanistic framework, we critically appraise novel therapeutic approaches, including targeted pharmacotherapies such as selective ion channel and endocannabinoid system modulators, alongside non-pharmacotherapeutic interventions that encompass neuromodulation techniques designed to regulate central neural plasticity and psychologically grounded therapies. By integrating molecular evidence with clinical presentations, this review offers a framework for advancing towards a more precise, mechanism-based management of orofacial pain.

Background: Propagation of spreading depolarization (SD), a wave of transient cellular depolarization, over the cerebral cortex drives migraine aura symptoms. Growing evidence suggests that hippocampus, brain region involved in regulation of mood and cognition, also contributes to pathogenesis of migraine. Hippocampus has highly inhomogeneous functional anatomy with strong dorsoventral difference in functional and network properties. We hypothesized that cerebral dysfunction induced by SD also varies within the hippocampus and studied characteristics and effects of SD in the dorsal and ventral hippocampus of awake animals. Given high susceptibility of the hippocampus to seizures, we focused on excitatory effects of SD.

Methods: Unilateral SD was induced by a pinprick of the dorsal hippocampus in freely behaving rats. In electrophysiological experiments, local field potentials were recorded bilaterally in different sites along the dorsoventral axis of the hippocampus; propagation patterns, electrographic manifestations and excitatory effects of SD were evaluated. In separate experiments, effect of hippocampal SD on behavior was assessed.

Results: SD waveforms varied depending on local cytoarchitecture of hippocampal zones (CA, dentate gyrus and fiber-rich areas), irrespectively of their dorsoventral level. In the dentate gyrus, unusual double-wave SDs were recorded. Reaching ventral hippocampus, unilateral SD triggered a bilateral seizure-like discharge recruited both ipsilateral (affected by SD) and contralateral (unaffected by SD) sides. The post-SD activation of the ventral hippocampus had striking behavioral manifestation - a bout of wet dog shakes.

Conclusions: This is the first experimental evidence that SD can trigger seizure-like activity in particular regions of awake non-epileptic brain. We suggest that the phenomenon may be relevant to mechanisms of migraine-aura triggered seizures (migralepsy).

Purpose: The pathogenesis of migraine remains incompletely understood, with traditional theories oscillating between purely vascular or strictly neuronal concepts. However, emerging evidence points to a more integrated "vessel-to-neuron" mechanism. This debate paper explores the role of intracranial vasculature in initiating migraine pain, offering a unifying concept that reconciles these traditionally divergent views.

Findings: Neurosurgical findings confirm that stimulating or mechanically distending intracranial arteries can elicit migraine-like pain, suggesting that these vessels might serve as substrates for migraine pathogenesis. Activation of the trigeminovascular system and subsequent release of migraine-inducing neuropeptides lead to neurogenic inflammation within the meninges, promoting both vasodilation and the sensitization of meningeal nociceptors. Interestingly, all identified molecular migraine triggers potently dilate the intracranial vasculature, converging on potassium efflux from vascular smooth muscle cells. This efflux likely modifies local chemical gradients, thereby depolarizing trigeminal afferents and driving the cascade of ascending nociceptive signaling. Therapeutic interventions further reinforce the causal role of vascular contributions to migraine pathogenesis. Blocking vasodilatory neuropeptides or constricting extracerebral arteries effectively prevents and terminates migraine attacks, underscoring the importance of peripheral mechanisms. More than mere vasodilation, this hypothesis posits that chemical agents, including potassium released by vascular smooth muscle cells, might precipitate migraine onset. The resulting mechano-chemical stimulus might activate perivascular nociceptors and ascending trigeminal pain signaling, ultimately culminating in generation of a migraine attack.