To evaluate levels of 3 tear-soluble neuropeptides in dry eye patients and to identify the correlations with clinical signs and symptoms.

A total of 16 dry eye patients and 12 healthy volunteers were enrolled. Dry eye disease (DED) diagnosis was based on the 2017 Report of the Tear Film & Ocular Surface Society International Dry Eye Workshop (TFOS DEWS II). First time of noninvasive breakup time (NIBUT-1st), mean time of noninvasive breakup time (NIBUT-avg), tear meniscus height (TMH), Schirmer test, corneal fluorescein staining (CFS) score and ocular surface disease index (OSDI) were recorded. Tear fluid samples were collected and enzyme-linked immunoassay (ELISA was performed to analyze levels of calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY) and substance P (SP), as well as the association among the 3 neuropeptides and clinical findings.

Compared to normal controls, levels of tear CGRP (p=.003) and SP (p=.002) were significantly decreased in dry eye patients yet not NPY concentrations. Levels of tear CGRP and SP showed an inverse correlation with CFS and OSDI, which positively correlated with NIBUT-1st, NIBUT-avg and Schirmer test values. Multiple linear regression analysis showed that Schirmer test values were related to tear CGRP concentration. Subgroup analysis showed lower tear CGRP concentration in DED patients with severe symptoms (OSDI ≥ 46).

Levels of tear CGRP and SP decreased in DED patients and showed meaningful correlations with clinical symptoms and signs, implying a potential relationship between tear neuropeptides and ocular neurosensory function.

Botulinum toxin type A (BTX-A) has been used in the prevention and treatment of chronic migraine, but the detailed mechanism was not clear completely.

The effects of BTX-A on nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and interleukin-1 beta (IL-1β) were explored in the trigeminal ganglion of migraine model rats.

Healthy adult male Sprague-Dawley (SD) rats were randomly divided into groups. Von Frey fiber filaments were used to detect the periorbital pain area of rats. The immunoblotting and Immunofluorescence were used to detect the expression of NLRP3 inflammasome and IL-1β in the trigeminal ganglia of rats.

The periorbital pain area of rats in the migraine model group was significantly lower than that of the Sham group, and the difference was statistically significant (p < 0.05). Compared with the Sham group, the expressions of NLRP3, pro-caspase-1, caspase-1 and mature IL-1β in the migraine model group were significantly increased, and the difference was statistically significant (p < 0.05). Compared with the IA control group, the expressions of NLRP3, pro-caspase-1, caspase-1 and mature IL-1β in 5 U/kg BTX and 10 U/kg BTX-A group were significantly reduced (p < 0.05).

BTX-A inhibits the synthesis of NLRP3 inflammasome and mature IL-1β in the trigeminal ganglion from rat migraine models. Its inhibitory effect on the inflammation of the primary nociceptive neurons of the trigeminal nerve may be one of its important mechanisms for the prevention of migraine.

The neuropeptides calcitonin gene-related peptide (CGRP) and substance P are important mediators of neurogenic inflammation when they are released from activated primary nociceptive afferents. It is long evident that neuropeptides play an important role in migraine pathophysiology, but the significance of neurogenic inflammation is still debated.

In an approved hemisected rodent head preparation, we measured CGRP release from the cranial dura mater in parallel with substance P release using animals pre-treated with anti-CGRP antibodies or control solutions.

Apart from the known decrease in CGRP release following antibody treatment, we found a significant inverse correlation of basal and stimulated CGRP versus substance P release across all experiments. The results are discussed in connection with our previously published data.

An increase in CGRP release seems to inhibit substance P release in meningeal structures possibly decreasing substance P-dependent plasma extravasation, which argues against a significant role of neurogenic inflammation in migraine.

Increasing epidemiological evidence has reported that various factors are associated with migraine risk and subtypes. Nevertheless, definitive conclusions regarding whether the putative modifiable risk factors are causally related to the pathogenesis of migraine have not been drawn.

Using single-nucleotide polymorphisms as instrumental variables, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of 38 modifiable factors, including dietary nutrients, lifestyle factors, cardiometabolic diseases, and associated traits, as well as reproductive characteristics and sex hormones, on the risk of migraine, migraine with aura (MA), and migraine without aura (MO). Subsequently, meta-analyses were performed to combine causal estimates from two independent genome-wide association studies.

In the combined findings with multiple test correction, genetically predicted higher alcohol intake frequency (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.12-1.40), lifetime smoking index (OR: 1.24; 95% CI: 1.08-1.42), insomnia (OR: 1.20; 95% CI: 1.17-1.24), long sleep duration (OR: 1.26; 95% CI: 1.07-1.50), and hypertension (OR: 1.76; 95% CI: 1.47-2.11) were causally linked to migraine incidence. Subgroup analyses revealed higher carbohydrate and sugar intake, alcohol consumption frequency, lifetime smoking index, insomnia, and hypertension causally increased susceptibility to MA, while later age at first birth (AFB) had a protective effect on MA risk. Meanwhile, the MR findings revealed a detrimental association between alcohol intake frequency, insomnia, hypertension, and early AFB and MO incidence.

Overall, our study demonstrated various causal risk factors for migraine and its subtypes risk, providing insights into its pathogenesis and potential prevention strategies. Further research is needed to validate these findings and explore their clinical implications and underlying mechanisms.

ObjectiveTo determine whether serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) concentrations differ between adults with migraine and healthy controls.MethodsThis single-center, cross-sectional study was conducted from September 2020 to June 2022. Adults diagnosed with migraine and healthy controls were enrolled. Serum GFAP and NfL concentrations were quantified using an ultra-sensitive single-molecule array platform. Analyses were adjusted for potential confounders, including age, sex, body mass index and smoking status.ResultsWe assessed serum samples from 603 participants with migraine and 154 controls. Serum GFAP concentrations were 6.8% higher in the overall migraine group compared to controls (95% confidence interval = 0.4-13.5%; P = 0.036). Conversely, serum NfL concentrations did not differ between participants with migraine and controls (difference: -1.4%; 95% confidence interval = -7.9 to 5.6%; p = 0.68). Neither serum GFAP, nor NfL concentrations varied according to migraine subtype or headache status at the time of blood sampling.ConclusionsOur findings demonstrate a modest yet statistically significant increase in serum GFAP among adults with migraine, independent of migraine subtype, whereas serum NfL levels were comparable to those of controls. Further research is needed to clarify the neurobiological mechanisms underlying elevated serum GFAP in migraine.

Toll-like receptors (TLRs) play critical roles in pain modulation and immune responses. Polyinosinic-polycytidylic acid (Poly-IC), a TLR3-specific ligand, has shown promise in exerting neuroprotective effects, as it mitigates inflammation in several diseases. Considering that sterile neurogenic inflammation is involved in the pathogenesis of migraine, we explored the impact of Poly-IC on episodic migraine treatment and the potential mechanisms involved.

Episodic migraine was induced in male rats via a single intraperitoneal injection of nitroglycerin. Poly-IC (with or without a TLR3 inhibitor) treatment was performed before migraine induction. Pain was assessed according to the mechanical sensitivity threshold, head-directed grooming, and the Rat Grimace Scale. The expression of TLR3 and its downstream molecule TRIF was subsequently examined, after which calcitonin gene-related peptide (CGRP), c-fos, and proinflammatory cytokine expression was assessed. Moreover, TRIF expression in primary cultured neurons was knocked down by shRNA in vitro to further explore the mechanisms by which Poly-IC mediates migraine-like inflammation.

Poly-IC treatment significantly upregulated TLR3/TRIF expression, reduced the production of CGRP, c-fos, and inflammatory cytokines, and alleviated allodynia in an animal model of migraine. Moreover, TRIF knockdown blunted the anti-inflammatory effects of Poly-IC treatment in primary cultured neurons.

Poly-IC exerts therapeutic effects against neurogenic inflammation via the TLR3/TRIF signaling pathway in an episodic migraine model.

Recent research has sparked increasing interest in the role of neuroinflammation in the pathogenesis of migraine. We hypothesize that perilesional edema, an imaging marker of inflammation caused by an immune response in the brain parenchyma surrounding calcified neurocysticercosis (NCC), may influence migraine pathophysiology. This study was designed to explore the potential impact of perilesional edema on migraine severity and treatment response.

Cranial imaging of patients with primary headache may sometimes reveal calcified lesions indicative of calcified NCC. These lesions were once considered incidental and harmless findings. However, recent studies have shown that such calcifications are more frequently associated with headaches. Some research suggests that patients with calcified brain lesions experience more frequent and severe migraine compared to those without these lesions, though the pathophysiology underlying this association remains unclear.

This single-center, prospective cohort study was conducted at King George Medical University, India, from September 2022 to September 2024. A total of 80 patients with migraine with calcified NCC were enrolled. Cranial magnetic resonance imaging with contrast was used to detect perilesional edema. Patients were divided into two groups based on the presence (Group A) or absence (Group B) of perilesional edema. Both groups were assessed for migraine frequency, severity, and disability using standard scales. They were treated with standard migraine therapy and followed up for 3 months. Statistical analysis was performed to compare migraine characteristics, treatment responses, and disability between the two groups.

Perilesional edema was observed in six of the 80 patients (7.5%). At presentation, Group A (those with perilesional edema) experienced more frequent migraine, with a mean (standard deviation [SD]) of 22.5 (4.4) days/month, compared to Group B (those without perilesional edema), which averaged 8.2 (2.7) days/month. The headaches in Group A were also more severe, as indicated by higher median visual analog scale scores (median [interquartile range, IQR] in Group A of 10.0 [8.5-10.0] and 7 [7.0-8.0] in Group B, p < 0.001). Disability scores were significantly higher in Group A, with higher median scores on the Migraine Disability Assessment Scale (median [IQR] score in Group A of 43 [40.5-48.5] and 21.5 [17.0-26.3] in Group B, p < 0.001) and six-item Headache Impact Test (median [IQR] score in Group A of 66 [64.25-71.23] and 57 [54.8-62.0] in Group B, p < 0.001) scales. Although both groups showed improvement over 3 months of treatment, Group A continued to experience greater migraine severity. In Group A, the mean (SD) headache frequency was 22.5 (4.4) at presentation, 14.0 (1.6) at 30 days, 10.7 (1.6) at 60 days, and 9.2 (2.0) at 90 days (p < 0.001). Similarly, in Group B, headache frequency decreased over time, with a mean (SD) of 8.2 (2.7) at presentation, 3.8 (1.7) at 30 days, 2.3 (1.0) at 60 days, and 1.9 (1.0) at 90 days (p < 0.001). After 30 days, there was a significant reduction in the use of abortive medications, with more patients in Group B (56/74 [76%]) showing a favorable response compared to Group A (2/6 [33%]; p = 0.046; odds ratio 0.16, 95% confidence interval 0.03-0.95).

Our study found that among patients with migraine with calcified NCC, those with perilesional edema experienced more severe and harder-to-treat migraine compared to those without perilesional edema. These findings suggest that perilesional edema may influence the underlying mechanisms of migraine, leading to more severe migraine episodes.

To evaluate factors associated with new-onset migraine (NOM) after transcatheter atrial septal defect (ASD) closure and predictors of unremitting NOM. The pathogenic role of migraine biomarkers such as calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) were also assessed.

New-onset migraine has been observed after transcatheter ASD closure. Neuropeptides like CGRP and NPY stored both in the brain and heart are implicated in migraine pathophysiology. The potential role of those migraine biomarkers in NOM, as well as the risk factors and long-term outcomes of NOM, remain largely unknown.

We enrolled patients without previous migraine who underwent successful transcatheter ASD closure between 2001 and 2013. The parameters of transthoracic echocardiography, and plasma CGRP and NPY levels measured by enzyme-linked immunosorbent assay, were collected prospectively before and after ASD closure, and compared between patients with NOM and those without. Predictors of NOM were assessed. Telephone interviews were performed in 2022 to assess migraine status. Clinical and procedural characteristics were compared between patients with unremitting migraine and those with transient migraine that remitted within 1 year.

Of the 212 patients (median age, 21 years; 75.9% female), 43 (20.3%) had NOM. Potential predictors of NOM included a young age (adjusted odds ratio [aOR] 0.98, 95% confidence interval [CI] 0.96-0.99; p = 0.040), large ASD size (aOR 1.07, 95% CI 1.01-1.14; p = 0.022), and transient residual shunting after closure (aOR 2.78, 95% CI 1.05-7.36; p = 0.039). Post-closure plasma CGRP levels, but not NPY levels, were significantly higher than pre-closure levels (47.9 vs. 38.0 pg/mL, p = 0.023) among patients with NOM. Of the 27 patients with migraine who reported their migraine status at a median 14-year follow-up, 13 (48.1%) had unremitting migraine. Patients with unremitting migraine were more likely to have a smaller device-to-ASD size ratio (1.21 vs. 1.33, p = 0.039) and a larger pulmonary flow-to-systemic flow ratio (2.9 vs. 2.3, p = 0.012) than those with transient migraine.

Calcitonin gene-related peptide may play a pathogenic role in NOM after transcatheter ASD closure. A young age, large ASD size, and transient residual shunting potentially predict migraine occurrence after ASD closure. NOM not reaching remission for years may result from a significant shunt before closure.

Migraine is a prevalent neurological disorder characterized by recurrent headaches with autonomic and neurological symptoms, significantly impacting quality of life globally. Its pathogenesis involves genetic, neurological, inflammatory, and metabolic factors, with insulin resistance and metabolic dysfunction increasingly recognized as important contributors. Historically, it has been known that certain foods can trigger migraine attacks, which led for many years to the recommendation of elimination diets-now understood to primarily target histamine-rich foods. Over the past two decades, attention has shifted toward underlying metabolic disturbances, leading to the development of dietary approaches specifically aimed at addressing these dysfunctions.

A scoping literature review was conducted using PubMed and Embase to evaluate the relationships among migraine, insulin-related mechanisms, neurogenic inflammation, and dietary interventions. Initial searches focused on "MIGRAINE AND (neurogenic inflammation)" (2019-15 April 2025), followed by expanded searches from 1950 onward using terms such as "MIGRAINE AND (insulin, insulin resistance, hyperinsulinism)", and "MIGRAINE AND (diet, dietary, nutrition, nutritional)". A specific search also targeted "(INSULIN OR insulin resistance OR hyperinsulinism) AND (neurogenic inflammation)". Abstracts were screened, full texts were retrieved, and duplicates or irrelevant publications were excluded. No filters were applied by article type or language. Systematic reviews and meta-analyses were prioritized when available.

Migraine pathogenesis involves trigeminovascular system activation, neurogenic inflammation mediated by CGRP and PACAP, immune dysregulation, mast cell activation, and cortical spreading depression (CSD). Emerging evidence highlights significant associations between migraine, insulin resistance, and hyperinsulinism. Hyperinsulinism contributes to migraine through TRPV1 sensitization, increased CGRP release, oxidative stress, mitochondrial dysfunction, and systemic inflammation. Metabolic dysfunction, including obesity and insulin resistance, exacerbates migraine severity and frequency. Dietary interventions, particularly anti-inflammatory, Mediterranean, and ketogenic diets, show promise in reducing migraine frequency and severity through mechanisms involving reduced inflammation, oxidative stress, improved mitochondrial function, and glucose metabolism stabilization.

The interplay between insulin resistance, metabolic dysfunction, and neuroinflammation is crucial in migraine pathophysiology. Targeted dietary interventions, including ketogenic and Mediterranean diets, demonstrate significant potential in managing migraines, emphasizing the need for personalized nutritional strategies to optimize therapeutic outcomes.

Migraine is a common primary and often disabling neurological disorder, whose pathophysiology is still debated. It does not appear to be an isolated event of head pain but the consequence of recurrent disruption of healthy homeostasis in some brain functions. We propose a new theoretical model, focused on the existence of a "high-risk area" for migraine attacks, which can represent a potential target of non-pharmacologic treatment and prevention. We suggest that migraine arises from the combined effects of three primary factors, namely depressive or unstable mood, unrestful sleep and sympathetic-parasympathetic imbalance with parasympathetic prevalence, alongside with their temporal variability, potentially through dysfunction of homeostatic hypothalamic networks in susceptible individuals. Moreover, these three primary factors contribute to a state of low brain energy, that contains the high-risk area and represents the condition in which migraine attacks rise up. Wearable devices, self-administered questionnaires and clinical tools (i.e., polysomnography, pupillary light reflex, plasma catecholamines dosage) may be used to monitor autonomic nervous system function, mood and sleep and demonstrate the existence of the high-risk area. This will be helpful for patients to understand when they are about to enter in the high-risk area, in order to implement strategies to prevent migraine attacks. This approach would provide a significant advantage in terms of prevention and early treatment.

Protease activated receptor 2 (PAR2) is a G-protein coupled receptor expressed in meningeal neurons, fibroblasts and mast cells that may be targeted to treat migraine. MEDI0618, a fully humanized PAR2 monoclonal antibody, engineered to enhance FcRn-dependent recycling and currently in clinical development, was evaluated in human and rodent in vitro assays, in multiple murine in vivo migraine models and in a model of post-traumatic headache. MEDI0618 bound specifically and with high affinity to cells expressing human PAR2 (hPAR2) and prevented matriptase-induced increase in cytosolic calcium. Similarly, MEDI0618 prevented matriptase-induced calcium in primary fibroblasts and microvascular endothelial cells from human dura mater. MEDI0618 had no effect on hPAR1 receptors. Single-cell calcium imaging of acutely dissociated mouse trigeminal ganglion neurons confirmed expression and functionality of mouse PAR2. Studies in vivo used evoked cutaneous allodynia as a surrogate of headache-like pain and, in some experiments, rearing as a measure of non-evoked headache pain. MEDI0618 was administered subcutaneously to C57BL6/J female mice prior to induction of migraine-like pain with (i) systemic nitroglycerin or compound 48/80 (mast cell degranulator); or (ii) with supradural compound 48/80 or an inflammatory mediator (IM) cocktail. To assess possible efficacy against CGRP receptor (CGRP-R)-independent pain, MEDI0618 was also evaluated in the IM model in animals pretreated with systemic olcegepant (CGRP-R antagonist). Migraine-like pain was also induced by inhalational umbellulone, a TRPA1 agonist, in animals primed with restraint stress in the presence or absence of MEDI0618 as well as in a model of post-traumatic headache pain induced by a mild traumatic brain injury. MEDI0618 prevented cutaneous allodynia elicited by systemic nitroglycerin, compound 48/80 and from supradural compound 48/80 and IM. Systemic olcegepant completely blocked periorbital cutaneous allodynia induced by supradural CGRP but failed to reduce IM-induced cutaneous allodynia. In contrast, MEDI0618 fully prevented IM-induced cutaneous allodynia, regardless of pretreatment with olcegepant. Umbellulone elicited cutaneous allodynia only in restraint stress-primed animals, which was prevented by MEDI0618. MEDI0618 prevented the decrease in rearing behaviour elicited by compound 48/80. However, MEDI0618 did not prevent mild traumatic brain injury-related post-traumatic headache measures. These data indicate that MEDI0618 is a potent and selective inhibitor of PAR2 that is effective in human and rodent in vitro cell systems. Further, blockade of PAR2 with MEDI0618 was effective in all preclinical migraine models studied but not in a model of post-traumatic headache. MEDI0618 may represent a novel therapy for migraine prevention with activity against CGRP-dependent and independent attacks.

Recent studies suggest a link between gut microbiota and neurological diseases, implicating the microbiome's role in neurological health. However, the specific alterations in the microbiome associated with migraine remain underexplored. This study aims to systematically review the existing literature to determine whether migraine patients are associated with changes in gut microbiota composition.

A systematic review was conducted in accordance with the PRISMA statement. We included original empirical studies investigating the microbiome in migraine patients. Data extracted included study design, participant demographics, microbiome differences at various taxonomic levels, and measures of microbial diversity (alpha and beta diversity). The search and selection process involved four independent reviewers who assessed abstracts and full texts to ensure eligibility. The gut microbiota was evaluated using relative abundance and diversity indices.

Six studies, encompassing various regions including China, Korea, and Italy, were included in the analysis. The results indicated significant differences in gut microbiota between migraine patients and controls. Key findings include a reduction in Faecalibacterium, a genus known for its anti-inflammatory properties, in migraine patients, including those with chronic migraine. Conversely, Veillonella exhibited elevated abundance compared to controls. Other taxa, such as Prevotella and Parabacteroides, showed variable associations with migraine across different studies, suggesting a dysbiotic gut environment in migraine patients.

This review highlights that migraines are associated with specific alterations in gut microbiota, including decreased microbial diversity and changes in the abundance of key taxa. These findings suggest that gut microbiota dysbiosis may play a role in migraine pathophysiology. Further research is needed to explore the potential causal relationships and therapeutic implications, particularly targeting the microbiome in migraine management.

To evaluate the efficacy of 2 drug combinations on tinnitus severity and associated stress, depression, sleep, and anxiety.

A randomized, double-blind, placebo-controlled clinical trial conducted between 2019 and 2023 for an 8-week duration.

Single institution tertiary care center.

The study recruited adult patients with moderate to severe tinnitus for 6 months or more. In total, 81 patients were assessed for eligibility, 78 were enrolled and randomized, and 67 were included in the per-protocol analysis. Patients were randomized into 3 groups (1:1:1). Group NT received nortriptyline-topiramate, group VP received verapamil-paroxetine, and group P received placebo.

A total of 19 patients in group NT, 22 in group VP, and 26 patients in group P were included in the per-protocol analysis. In group NT, the Tinnitus Functional Index (TFI) score decreased from 58.4 ± 13.9 (baseline) to 46.3 ± 17.5 (end-of-trial) (P < .001). Similarly, in group VP, the TFI score decreased from 54.6 ± 17.5 to 42.2 ± 16.1 (P = .004). However, group P did not demonstrate any significant decrease in the TFI score from 51.2 ± 18.6 to 45.2 ± 20.1 (P = .086). The between-arm analysis did not yield any statistical significance decrease in the TFI score (analysis of variance, P = .265).

Both combinations of drugs were promising in improving tinnitus severity. However, larger-scale trials with longer follow-up periods are warranted to validate our findings between groups.

Soluble urokinase plasminogen activator receptor (suPAR) has garnered attention as a potential blood-based biomarker for low-grade chronic inflammation. However, its specific association with migraine, including its subtypes, remains to be elucidated. We sought to examine the association of plasma suPAR levels with migraine and its subtypes. In this single-centre, cross-sectional study, plasma was collected at a single time point in adults with migraine and sex-matched healthy controls from October 2020 to June 2022. The quantification of plasma suPAR levels was performed in a blinded fashion using a validated enzyme-linked immunosorbent assay. Plasma suPAR levels were compared between participants with migraine (including subgroups) and healthy controls. Plasma samples were analysed from 634 eligible participants with migraine [mean (SD) age, 44.0 (12.2) years; 568 (89.6%) females] and 154 healthy controls [mean (SD), 41.3 (11.8%) years; 132 (86%) females]. Plasma suPAR levels were 6.7% higher (95% CI: 0.1-13.6%; P = 0.045, adjusted for age, sex, body mass index and smoking) in participants with migraine with aura, when compared with healthy controls. Further analysis revealed no difference in plasma suPAR levels between the overall migraine group and healthy controls (3.7%; 95% CI: -0.7-8.2%; P = 0.097), as well as between participants with migraine without aura and healthy controls (2.5%; 95% CI: -2.9-8.3%; P = 0.81). Similarly, plasma suPAR levels did not differ across participants with episodic migraine, chronic migraine and healthy controls. Finally, we found no difference when comparing participants with migraine at time of blood sampling with participants with non-migraine headache (1.0%; 95% CI: -5.7-8.2; P > 0.99), participants without headache (1.2%; 95% CI: -4.2-7.0%; P > 0.99) or healthy controls (4.5%; 95% CI: -1.9-11.3%; P = 0.39). Elevated plasma suPAR levels in migraine with aura indicate the presence of low-grade chronic inflammation. Future research should explore the role of suPAR in the neurobiologic underpinnings of migraine with aura.

Melatonin has a therapeutic effect on migraine, but the mechanisms underlying its antimigraine effect have not been elucidated. This study therefore investigated for the first time the receptor-mediated mechanisms of action of melatonin in nitroglycerin (NTG)- induced migraine-like hyperalgesic conditions in rats. Melatonin, nonselective MT1/MT2 antagonist luzindole, selective MT2 antagonist DH97 or potent MT3 antagonist prazosin, alone or in various combinations, were administered to NTG-induced migraine rats and ex-vivo meningeal preparations. Basal and drug-treated pain behaviors were assessed with the von-Frey test. CGRP levels in the trigeminal ganglia, trigeminal nucleus caudalis (TNC) and ex-vivo superfusate medium, as well as c-fos level in the TNC, were measured by ELISA. Meningeal mast cells were stained with toluidine-blue and examined histologically for their activation and count. Melatonin mitigated mechanical hyperalgesia, and c-fos and CGRP expression in the TNC, CGRP expression in trigeminal ganglia, CGRP release from meningeal afferents, all of which were induced by NTG, and also suppressed NTG-stimulated meningeal mast cell activation. The effects of melatonin were abolished in the presence of luzindole and DH97, respectively. However, prazosin did not reverse the effects of melatonin except for mechanical hyperalgesia. Luzindole and DH97 in combinations with prazosin also canceled the effects of melatonin, respectively, other than CGRP expression in the TNC. Melatonin exerts its anti-hyperalgesic effects through modulation of trigeminal expression and meningeal release of CGRP, and meningeal mast cell activation in experimental migraine-like conditions. The effects of melatonin are mainly mediated by MT2 receptors, without excluding a possible role for MT1.

To evaluate the characteristics of hematological parameters and peripheral inflammatory markers (PIMs) in migraine, including chronic migraine (CM) and episodic migraine (EM), and to explore their underlying mechanisms.

A total of 88 subjects were enrolled, 58 with migraine (28 with CM and 30 with EM) and 30 healthy controls. All subjects were matched for age, gender, and body mass index, and peripheral blood was collected. Hematological parameters and PIMs were compared between migraineurs and healthy controls. The patients underwent hematological laboratory testing and calculated the PIMs. PIMs included neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio (LMR), neutrophil/monocyte ratio, platelet/lymphocyte ratio, and platelet/monocyte ratio (PMR) ratio.

Monocyte counts in migraine patients were significantly lower compared with healthy controls, while LMR and PMR were significantly higher. Statistically significant differences were observed in monocyte counts, LMR, and PMR among the three groups of CM, EM, and HC patients. Post hoc Bonferroni t-test showed that monocyte counts were significantly lower in the EM group compared with the HC group, while LMR and PMR were significantly higher. Comparison between the EM and CM groups showed that LMR was significantly higher in the EM group. Differences in monocyte counts, LMR, and PMR between the CM and HC groups were not statistically significant. Receiver operating characteristic curve analysis indicated that the area under the curve (AUC) for the diagnosing migraine using the combination of Mon, LMR, and PMR was 0.707, and the AUC for the diagnosis of EM was 0.758. The AUC value of PMR for diagnosing CM was 0.669, while the AUC for the combination of LMR and platelet/lymphocyte ratio in distinguishing CM and EM was 0.705.

Our findings indicate that migraine and its subtypes exhibit abnormalities in monocyte counts and PIMs, which possess diagnostic predictive value for differentiating migraine and its subtypes. This suggests that systemic inflammation may play a role in the pathogenesis of migraine.

Migraine, a prevalent neurovascular disorder, affects millions globally and is associated with significant morbidity. Emerging evidence suggests a crucial role of the gut microbiota and adipose tissue in the modulation of migraine pathophysiology, particularly through mechanisms involving neuroinflammation and metabolic regulation.

A narrative review of the literature from 2000 to 2024 was conducted using the PubMed database. Studies addressing the relationships between microbiota, adipose tissue, and migraine-including dietary interventions and their impact-were analyzed.

The findings highlight a bidirectional gut-brain axis, with gut microbiota influencing neuroinflammation via metabolites such as short-chain fatty acids (SCFAs). Obesity exacerbates migraine severity through chronic inflammation and the dysregulation of adipocytokines like leptin and adiponectin. Dietary patterns, such as low glycemic index diets and Mediterranean diets, and the use of prebiotics, probiotics, and postbiotics show potential in migraine management.

This review underscores the need for integrative approaches targeting the microbiota-gut-brain axis and adipose tissue in migraine therapy. Future studies should explore longitudinal effects and personalized interventions to optimize outcomes.

To evaluate the effects of Ligustrazine (Lig) on nitroglycerin-induced migraine and explore the mechanism through the mitochondria-inflammation pathway.

Rats were divided into control, model, Lig(50 mg/kg) + Erastin, Lig(100 mg/kg), Lig(50 mg/kg), and Zolmitriptan groups. Nitroglycerin (NTG) was administered through injection to trigger a migraine. The following parameters were measured: mechanical pain threshold, mitochondrial morphology, levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), Adenosine triphosphate (ATP), and Nitric oxide (NO). The neuronal nitric oxide synthase (nNOS), transient receptor potential A1 (TRPA1), interleukin 1 beta (IL-1β), nuclear factor-kappaB (NF-κB), and calcitonin gene-related peptide (CGRP) were detected by Western blotting and immunohistochemistry.

Compared with the model group, the Lig(100 mg/kg) and Lig(50 mg/kg) groups increased mechanical pain threshold as well as improved abnormal mitochondrial morphology. Moreover, compared with the model group, the Lig(100 mg/kg) and Lig(50 mg/kg) groups demonstrated reduced levels of ROS, and NO, and increased MMP, and ATP. Lig(100 mg/kg) and Lig(50 mg/kg) groups reduced inflammation and oxidative stress by inhibiting certain gene expressions. When Erastin was injected, the effectiveness of Lig decreased, indicating that Lig's therapeutic effect was related to the extent of mPTP opening.

The mitochondria-inflammation pathway plays a critical role in regulating migraine. Lig exerts anti-migraine effects primarily by modulating the mitochondria-inflammation pathway providing a novel perspective on migraine research that is beneficial for its clinical application.

Epidemiological studies on the association between migraine and Alzheimer's disease (AD) risk have yielded inconsistent conclusions. We aimed to characterize the phenotypic and genetic relationships between migraine and AD.

To investigate the association between migraine and the risk of AD by analyzing data from a large sample of 404,318 individuals who were initially free from all-cause dementia or cognitive impairment, utilizing the UK Biobank dataset. We employed Cox regression modeling and propensity score matching techniques to examine the relationship between migraine and subsequent occurrences of AD. Additionally, the study utilized Mendelian randomization (MR) analysis to identify the genetic relationship between migraine and the risk of AD.

Migraine patients had a significantly increased risk of developing AD, compared to non-migraine patients (adjusted hazard ratio (HR) = 2.34, 95% confidence interval (CI) = 2.01-0.74, P < 0.001). Moreover, the propensity scores matching analyses found that migraine patients had a significantly higher risk of developing AD compared to non-migraine patients (HR = 1.85, 95%CI = 1,68-2.05, P < 0.001). Additionally, the MR suggested that significant causal effects of migraine on AD risks were observed [odds ratio (OR) = 2.315; 95% confidence interval (CI) = 1.029-5.234; P = 0.002]. Moreover, no evidence supported the causal effects of AD on migraine (OR = 1.000; 95%CI = 0.999-1.006; P = 0.971).

The present study concludes that migraine patients, compared to a matched control group, exhibit an increased risk of developing AD. Moreover, migraine patients exhibit an increased predisposition of genetic susceptibility to AD. These findings hold significant clinical value for early intervention and treatment of migraines to reduce the risk of AD.

Since neurogenic inflammation and hemoconcentration have a prominent role in the pathophysiology of migraine, evaluation of hemogram parameters and indices showing inflammation can yield important information. In this study, we have investigated blood cell counts and ratios, systemic inflammation index (SII), systemic inflammation response index (SIRI) and red cell index (RCI) in the painless periods between pain attacks in patients with episodic migraine without aura.

Hemogram data of both 309 patients diagnosed with migraine without aura related to pain-free periods and 199 healthy individuals were retrospectively retrieved from hospital records. Data related to erythrocyte, leukocyte, lymphocyte, platelet, monocyte, eosinophil counts; hemoglobin, hematocrit, mean corpuscular volume, red blood cell distribution width (RDW), mean platelet volume (MPV), neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio (MLR), and neutrophil/monocyte ratio, SII, SIRI and RCI values were scanned to reveal intergroup differences in terms of these parameters.

A comparison of laboratory parameters revealed that certain indices differed significantly between the migraine and control groups. MLR (p = 0.005) and RDW (p < 0.001) values were significantly lower, while platelet (p = 0.016), MPV (p < 0.001) and hematocrit (p = 0.014) were significantly higher in the migraine patient group compared to the control group. There was no significant difference between the two groups regarding other parameters.

Higher hematocrit, platelet, mean platelet volume and lower monocyte/lymphocyte ratio values in this study support that hemoconcentration and chronic inflammation persist even in the absence of pain attacks in migraine patients without aura.

Oxidative stress and neuroinflammation play critical roles in the pathogenesis of migraine, a neurovascular disease. Cryptoxanthin is a carotenoid known for its potent antioxidant and anti-inflammatory properties. However, the specific association between serum cryptoxanthin levels and migraine remains unclear. This study aims to evaluate the correlation between migraine and serum cryptoxanthin levels.

For this cross-sectional analysis, information was gathered from individuals ≥20 years who took part in the National Health and Nutrition Examination Survey from 2001 to 2004. Details information was collected on migraines, serum cryptoxanthin levels and various crucial factors. Multivariable logistic regression and restricted cubic spline regression analyses were performed to investigate the relationship between serum cryptoxanthin and the occurrence of migraines.

The study included 8,645 participants, of whom 20.00%(1734/8645) experienced migraine. There was a nonlinear relationship (p < 0.001) between serum cryptoxanthin levels and migraine, which was depicted as an L-shaped curve. The occurrence rate of individuals with serum cryptoxanthin levels below 26.64 nmol/dL experiencing migraine was 0.976 (95% CI: 0.965∼0.987, p<0.001).

In adults among the United States, increased levels of serum cryptoxanthin were associated with decreased risk of migriane with a turning point at around 26.64 nmol/dL in American adults. Further studys are needed to confirm our findings.

Chronic migraine is a common central nervous system disorder characterized by recurrent, pulsating headaches. However, the extent and mechanisms of hypothalamic involvement in disease progression have not been thoroughly investigated. Herein, we created a chronic migraine mouse model using repeated intraperitoneal injections of nitroglycerin. We performed transcriptomic sequencing on the hypothalamus of mice with chronic migraine and control mice under normal physiological conditions, followed by differential gene set enrichment and functional analysis of the data. Additionally, we examined the intrinsic connection between chronic migraine and sleep disorders using transcriptomic sequencing data from sleep-deprived mice available in public databases. We identified 39 differentially expressed genes (DEGs) in the hypothalamus of a mouse model of chronic migraine. Functional analysis of DEGs revealed enrichment primarily in signaling transduction, immune-inflammatory responses, and the cellular microenvironment. A comparison of the transcriptomic data of sleep-deprived mice revealed two commonly expressed DEGs. Our findings indicate that the hypothalamic DEGs are primarily enriched in the PI3K/AKT/mTOR pathway and associated with the NF-κB/NLRP3/IL-1 β pathway activation to maintain the central sensitization of the chronic migraine. Chronic migraine-induced gene expression changes in the hypothalamus may help better understand the underlying mechanisms and identify therapeutic targets.

In recent decades, cranial and cervical vascular disorders have become major global health concerns, significantly impacting patients, families, and societies. Headache is a prevalent symptom of these vascular diseases and can often be the initial, primary, or sole manifestation. The intricate relationship between headaches and cranial/cervical vascular disorders poses a diagnostic and therapeutic challenge, with the underlying mechanisms remaining largely elusive. Understanding this association is crucial for the early diagnosis, prevention, and intervention of such conditions. This review aims to provide a comprehensive overview of the clinical features and potential pathogenesis of headaches attributed to cranial and cervical vascular disorders and provide a reference for disease management and a basis for potential pathological mechanisms.

Chronic migraine (CM) patients with medication overuse headache (MOH) were recently shown to be associated with leaky gut and inflammation. We aimed to investigate gut microbiota profiles of CM patients with MOH, and their correlations with inflammatory serum parameters, migraine food triggers, and comorbid anxiety and depression.

The study included women participants (32 CM patients with NSAID overuse headache, and 16 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, presence of irritable bowel syndrome symptoms, and HADS-D and HADS-A scores were recorded. Serum samples were collected to measure circulating LPS, HMGB1, HIF-1α, and IL-6. The gut microbiota profiles of the patients were evaluated using fecal samples.

Serum LPS, HMGB1, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the healthy controls. HADS-A and HADS-D scores were considerably higher in the CM + MOH group compared to the healthy controls. In the microbiota analysis, alpha and beta diversities were similar between the two groups. The class Clostridia, the order Eubacteriales, and the genus Ruminococcus were less abundant in the CM + NSAID overuse headache group compared to the control group. At the genus level Desulfovibrio, Gemmiger, and Dialister and at the species level, Clostridium fessum, Blautia luti, Dorea longicatena, Eubacterium coprostanoligenes, and Gemmiger formicilis were more abundant in the CM + NSAID overuse headache group compared to the control group. Desulfovibrio, Gemmiger, Dialister, Ethanoligenens harbinense, Eubacterium coprostanoligenes, Dorea longicatena, and Thermoclostridium stercorarium showed positive correlations and Clostridia bacteria showed negative correlations with migraine food triggers. Positive correlations were found between LPS and Hapalosiphonaceae, HMGB1 and Melghirimyces, HIF1-α and Rouxeilla and Blautia luti, IL-6 and Melghirimyces and Ruminococcus.

In CM patients with MOH, we have revealed the presence of dysbiosis towards an inflammatory state, and positive correlations were shown between altered gut microbiota and inflammatory serum parameters and migraine food triggers.

The importance of obesity as a factor that increases the probability of migraine episodes is increasingly acknowledged. Thus, this study aimed to explore the potential correlation between central obesity and migraine, emphasizing the waist-to-height ratio (WHtR) as a key measure in assessing this relationship.

This cross-sectional analysis included 13,344 individuals who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999-2004. To investigate the association associations between WHtR and migraine, we utilized refined multivariate logistic regression models, smoothing curve fitting methods, subpopulation analysis, and interactive testing.

Of the 13,344 participants, 2,764 (20.72%) had migraines. A significant positive correlation was observed between the WHtR and migraine incidence in both the partially adjusted model (3.08 [95% CI: 1.92-4.94]) and the crude model (1.95 [95% CI: 1.23-3.08]). The participants in the highest quartile of the WHtR had a 13% greater incidence of migraine than those in the lowest quartile [1.13(0.99,1.28)]. The interaction analysis revealed a statistically significant difference (p<0.01) in this relationship among the subgroups. Notably, the correlation between WHtR and migraine risk was not significant and negative in patients ≥60 years, indicating that obesity has a mitigating role in preventing migraine in this elderly population.

The incidence of migraine increased concomitantly with increased WHtR. However, central obesity has a protective effect against migraine occurrence in individuals ≥60 years. Thus, our findings underscore the importance of WHtR in migraine prevention and management strategies and highlight its potential as a critical biomarker for mitigating migraine incidence.

This study aimed to examine the association between Carbohydrate Quality Index (CQI) and headache severity, disability and duration among women with migraine.

In this cross-sectional study, 266 women (aged 18-45 years) were enrolled using a 147-item food frequency questionnaire (FFQ). CQI was defined by four criteria: fiber intake, dietary glycemic index (DGI), whole grains/total grains ratio and solid carbohydrates/total carbohydrates ratio. Anthropometric measurements, visual analogue scale (VAS), migraine disability assessment (MIDAS), and headache duration were assessed for all participants.

Participants with a high adherence to CQI had lower odds of moderate pain (OR = 0.45; 95% CI = 0.21-0.94; P = 0.03) and severe pain (OR = 0.39; 95% CI = 0.18-0.82; P = 0.01) compared to those with a low adherence to CQI. After controlling for potential confounders, individuals with the greatest adherence to CQI showed a 78% reduced prevalence in severe pains and a 63% decreased occurrence in moderate pains compared to those with the lowest adherence (OR = 0.22; 95% CI = 0.09-0.55; P = 0.01 and OR = 0.37; 95% CI = 0.16-0.84; P = 0.01, respectively). Moreover, Subjects with higher adherence to CQI had lower odds of headache duration (OR = 0.54; 95% CI= 0.31-0.96; P = 0.03). The significant association remained (P < 0.05) even after confounding variables (OR = 0.59; 95 % CI = 0.35-1.002; P = 0.05). Despite adjusting for confounding valuables, there was no significant association between the CQI and MIDAS scores (P > 0.05).

Higher adherence to CQI was associated with lower severity and duration in patients with migraine. Further studies are needed to confirm these results.

Our aim was to survey astrocyte and microglial activation across four brain regions in a mouse model of chronic migraine.

Chronic migraine is a leading cause of disability, with higher rates in females. The role of central nervous system neurons and glia in migraine pathophysiology is not fully elucidated. Preclinical studies have shown abnormal glial activation in the trigeminal nucleus caudalis of male rodents. No current reports have investigated glial activation in both sexes in other important brain regions involved with the nociceptive and emotional processing of pain.

The mouse nitroglycerin model of migraine was used, and nitroglycerin (10 mg/kg) or vehicle was administered every other day for 9 days. Prior to injections on days 1, 5, and 9, cephalic allodynia was determined by periorbital von Frey hair testing. Immunofluorescent staining of astrocyte marker, glial fibrillary protein (GFAP), and microglial marker, ionized calcium binding adaptor molecule 1 (Iba1), in male and female trigeminal nucleus caudalis, periaqueductal gray, somatosensory cortex, and nucleus accumbens was completed.

Behavioral testing demonstrated increased cephalic allodynia in nitroglycerin- versus vehicle-treated mice. An increase in the percent area covered by GFAP+ cells in the trigeminal nucleus caudalis and nucleus accumbens, but not the periaqueductal gray or somatosensory cortex, was observed in response to nitroglycerin. No significant differences were observed for Iba1 staining across brain regions. We did not detect significant sex differences in GFAP or Iba1 quantification.

Immunohistochemical analysis suggests that, at the time point tested, immunoreactivity of GFAP+ astrocytes, but not Iba1+ microglia, changes in response to chronic migraine-associated pain. Additionally, there do not appear to be significant differences between males and females in GFAP+ or Iba1+ cells across the four brain regions analyzed.

Microglia is the primary source of inflammatory factors during migraine attacks. This study aims to investigate the role of microglia related genes (MRGs) in migraine attacks.

The RNA sequencing results of migraineurs and the panglaodb database were used to obtain differentially expressed genes (DEGs) in migraine related to microglia. A migraine rat model was established for validating and localizing of the MRGs, and subsequent screening for target genes was conducted. A shRNA was designed to interference the expression of target genes and administered into the trigeminal ganglion (TG) of rats. Pain sensitivity in rats was evaluated via the hot water tail-flick (HWTF) and formalin-induced pain (FIP) experiments. ELISA was used to quantify the levels of inflammatory cytokines and CGRP. WB and immunofluorescence assays were applied to detect the activation of microglia.

A total of five DEGs in migraine related to microglia were obtained from RNA sequencing and panglaodb database. Animal experiments showed that these genes expression were heightened in the TG and medulla oblongata (MO) of migraine rats. The gene S100A8 co-localized with microglia in both TG and MO. The HWTF and FIP experiments demonstrated that interference with S100A8 alleviated the sense of pain in migraine rats. Moreover, the levels of TNFα, IL-1β, IL-6, and CGRP in the TG and MO of rats in the model rats were increased, and the expression of microglia markers IBA-1, M1 polarization markers CD86 and iNOS was upregulated. Significantly, interference with S100A8 reversed these indicators.

Interference with S100A8 in microglia increased the pain threshold during migraine attacks, and inhibited neuroinflammation and microglia activation.

Migraine is a ubiquitous neurological disorder that affects approximately 1 billion people worldwide. Migraine is the second leading cause of illness in people of all ages worldwide. Uncertainty in migraine diagnosis leads to unnecessary testing and increases the treatment costs. To date, the pathogenesis of migraine is not fully understood, but it is generally believed that migraine involves the trigeminal nerve and its axonal projections to intracranial blood vessels. Pain signals from the trigeminal neurovascular system are transmitted to the brain, resulting in migraines. As an important component of complementary and alternative medicine, traditional Chinese medicine (TCM) has shown significant efficacy in the treatment of migraine, and has attracted increasing attention worldwide. This review is based on the pathophysiology of migraines in modern medicine. To explore the comprehensive treatment of migraine using TCM, acupuncture, and various other TCM treatments.

miR-155 is involved in the generation and maintenance of inflammation and pain, endothelial function and immune system homeostasis, all functions that are relevant for migraine. The present study aims to assess the levels of miR-155 in migraine subtypes (episodic and chronic) in comparison to age- and sex-matched healthy controls.

This is a cross-sectional, controlled, study involving three study groups: I) episodic migraine (n = 52, EM), II) chronic migraine with medication overuse (n = 44, CM-MO), and III) healthy controls (n = 32, HCs). We assessed the interictal gene expression levels of miR-155, IL-1β, TNF-α, and IL-10 in peripheral blood monocytes using rtPCR. The monocytic differentiation toward the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes was assessed in circulating monocytes with flow cytometry analysis and cell sorting.

miR-155 gene expression was higher in CM-MO group (2.68 ± 2.47 Relative Quantification - RQ) when compared to EM group (1.46 ± 0.85 RQ, p = 0.006) and HCs (0.44 ± 0.18 RQ, p = 0.001). In addition, miR-155 gene expression was higher in EM group when compared to HCs (p = 0.001). A multivariate analysis confirmed the difference between EM and CM-MO groups after correction for age, sex, smoking habit, preventive treatment, aura, presence of psychiatric or other pain conditions. We found higher gene expression of IL-1β, TNF-α, and lower gene expression of IL-10 in migraine participants when compared to HCs (p = 0.001 for all comparisons). TNF-α and IL-10 genes alterations were more prominent in CM-MO when compared to EM participants (p = 0.001). miR-155 positively correlated with IL-1β (p = 0.001) and TNF-α (p = 0.001) expression levels. Finally, in people with CM-MO, we described an up-regulated percentage of events in both M1 and M2 monocytic profiles.

Our study shows for the first time a specific profile of activation of miR-155 gene expression levels in monocytes of selected migraine subpopulations, more pronounced in subjects with CM-MO. Interestingly, mir-155 expression correlated with markers of activation of the inflammatory and immune systems. The CM-MO subpopulation showed a peculiar increase of both pro-inflammatory and anti-inflammatory monocytes which worths further investigation.

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Gastroesophageal reflux disease (GERD) and migraine are public health concerns worldwide. No observational study has conclusively elucidated the causal relationship between these two conditions. We employed Mendelian randomization (MR) methods to explore the potential causal links between GERD and migraine.

Genome-wide association studies were subjected to MR to infer the causality between GERD and migraine. Bidirectional two-sample MR was performed to establish causal relationships. Multivariable MR analysis was conducted to adjust potential confounding factors, and mediation MR analysis was utilized to assess the role of depression between GERD and migraine as a mediator. We primarily utilized the inverse variance weighted method (IVW) and sensitivity analysis methods, including MR-Egger, weighted median, and leave-one-out methods. We assessed heterogeneity and pleiotropy to ensure the reliability of the results.

Bidirectional two-sample MR revealed a positive causal effect of GERD on migraine (IVW: OR = 1.49, 95% CI: 1.34-1.66, p = 3.70E-13). Migraine did not increase the risk of GERD (IVW: OR = 1.07, 95% CI: 0.98-1.17, p = 0.1139). Multivariable MR indicated that the positive causal effect of GERD on migraine remained after adjustment for factors, such as smoking, alcohol consumption, obesity, type 2 diabetes, and depression. Mediation MR revealed that depression mediated 28.72% of GERD's effect on migraine. MR analysis was supported by all sensitivity analyses and was replicated and validated in another independent dataset on migraine.

Our findings elucidate the positive causal effect of GERD on migraine and underscores the mediating role of depression in increasing the risk of migraine due to GERD. Effective control of GERD, particularly interventions targeting depression, may aid in preventing the occurrence of migraine. Future research should delve deeper into the specific pathophysiological mechanisms through which GERD affects migraine risk, facilitating the development of more effective drug targets or disease management strategies.

Associations between migraine and retinal vascular occlusion have been reported, but there is no large-scale and comprehensive study. Therefore, we aimed to determine risks of retinal vascular occlusion in patients with migraine. Using the Taiwan National Health Insurance Research Database from 2009 to 2020, we enrolled 628,760 patients with migraine and 628,760 matched individuals without migraine. Study outcomes were diagnoses of retinal vascular occlusion, including retinal artery occlusion (RAO) and retinal vein occlusion (RVO). Adjusted hazard ratio (aHR) of retinal vascular occlusion related to migraine was estimated. The cumulative incidences of subsequent retinal vascular occlusion, RAO, and RVO were significantly higher in migraine patients compared with controls (0.31% vs. 0.21%; 0.09% vs. 0.05%; 0.22% vs. 0.17%; all p < 0.001). The hazards of retinal vascular occlusion, RAO, and RVO were significantly greater in the migraine group (aHR, 1.69 [95% CI, 1.57, 1.83], 2.13 [95% CI, 1.84, 2.48] and 1.53 [95% CI, 1.40, 1.68], respectively). Risks of retinal vascular occlusion were significantly higher in migraine both with aura (MA) and without aura (MO) (aHR, 1.77 [95% CI, 1.58, 1.98], and 1.92 [95% CI, 1.64, 2.25]). Among patients with migraine, nonsteroidal anti-inflammatory drugs, propranolol, and flunarizine significantly reduce their risks of retinal vascular occlusion (aHR, 0.19 [95% CI, 0.16, 0.22], 0.73 [95% CI, 0.62, 0.86], 0.84 [95% CI, 0.76, 0.93]). Migraine, MA and MO are independently associated with higher risks of retinal vascular occlusion, RAO, and RVO.

A growing body of evidence underscores a significant association between neurological disorders, particularly migraines, and the gut microbiota. However, a research gap persists in understanding the cause-and-effect dynamics between these elements. Therefore, we employed robust methodologies aimed at thoroughly exploring the causal relationship between the gut microbiome and migraines.

Employing bidirectional Two Sample Mendelian Randomization (TSMR) analysis, we investigated the causal association between the composition of the gut microbiota and migraines. Data summarizing the relationship between gut microbiota and migraines were extracted from one or more genome-wide association studies. The TSMR analysis employed five methods to assess the correlation between the gut microbiota and migraines, with the inverse variance-weighted method serving as the primary approach for analyzing causal links. Sensitivity analyses were applied to address horizontal pleiotropy and heterogeneity. Simultaneously, a meta-analysis was performed to strengthen the robustness of the findings. Additionally, a reverse TSMR was carried out to explore potential occurrences of reverse causal relationships.

The ongoing TSMR analysis identified a collection of 14 bacterial taxa connected to migraines. Among these, 8 taxa exhibited a protective effect, while 5 taxa had a detrimental impact, and 1 taxon maintained a neutral relationship. The reverse Mendelian randomization analysis highlighted stable outcomes for only one bacterial taxonomic group.

The study confirms a causal relationship between the gut microbiota and migraines, offering a new perspective for migraine research. Strategically targeting specific bacterial taxa with dysregulation may be effective in both preventing and treating migraines, thus opening new avenues for therapeutic strategies.

Migraine is a debilitating neurological disorder characterized by recurring episodes of throbbing headaches that are frequently accompanied by sensory disturbances, nausea, and sensitivity to light and sound [...].

Migraine is a global public health concern, affecting both social and individual well-being. Calcitonin gene-related peptide (CGRP), a crucial neuropeptide, holds important research value in understanding migraine pathogenesis. CGRP receptor antagonists and monoclonal antibodies that target CGRP or its receptors have shown efficacy in reducing migraine frequency and severity, presenting a promising therapeutic approach. This study aimed to conduct a comprehensive bibliometric analysis to analyze the current state, research trends, and future directions of CGRP in migraine.

Bibliometric tools including CiteSpace, VOSviewer, etc., were utilized to extract and summarize publications related to CGRP in migraine from the Web of Science Core Collection Database (WOSCC) between 2004 and 2023, as of December 31, 2023. The analysis focused on trends in annual publications, leading countries/regions and institutions, prominent journals and references, influential authors, and high-frequency keywords in the field.

A total of 1,821 articles and reviews involving 5,180 authors from 1,315 organizations across 64 countries were included in the study. These publications were distributed across 362 journals and accumulated 56,999 citations by December 31, 2023. An increasing trend was observed in annual publications on CGRP in migraine. The United States emerged as the leading nation in both publications and citations, with academic Peter Goadsby contributing the highest number of publications. The University of Copenhagen stood out as the institution with the most publications, and Cephalalgia emerged as the most influential journal. The most cited paper identified was "Calcitonin gene-related peptide receptor antagonist BIBN4096BS for the acute treatment of migraine" by Jes Olesen, published in the New Engl Med. Keyword frequency analysis revealed prevalent terms such as "migraine," "CGRP," and "episodic migraine," along with emerging topics represented by keywords including "trial," "monoclonal antibodies," "preventive treatment," and "safety."

CGRP is pivotal in migraine pathogenesis, and there is a robust research foundation exploring its role. The US leads in research output on CGRP in migraine. Investigating the mechanism of CGRP and its receptor in migraine remains a key area of interest, particularly focusing on signaling pathways. Future research should target identifying critical therapeutic targets in CGRP antagonist pathways for migraine treatment.

Migraine is a common and debilitating neurological disorder characterized by the recurrent attack of pulsating headaches typically localized on one side of the head associated with other disabling symptoms, such as nausea, increased sensitivity to light, sound and smell and mood changes. Various clinical factors, including the excessive use of migraine medication, inadequate acute treatment and stressful events, can contribute to the worsening of the condition, which may evolve to chronic migraine, that is, a headache present on >15 days/month for at least 3 months. Chronic migraine is frequently associated with various comorbidities, including anxiety and mood disorders, particularly depression, which complicate the prognosis, response to treatment and overall clinical outcomes. Emerging research indicates a connection between alterations in the composition of the gut microbiota and mental health conditions, particularly anxiety and depression, which are considered disorders of the gut-brain axis. This underscores the potential of modulating the gut microbiota as a new avenue for managing these conditions. In this context, it is interesting to investigate whether migraine, particularly in its chronic form, exhibits a dysbiosis profile similar to that observed in individuals with anxiety and depression. This could pave the way for interventions aimed at modulating the gut microbiota for treating difficult-to-manage migraines.

The observational studies investigated the impact of migraine on Alzheimer's Disease (AD). However, these findings were limited by confounding factors and reverse causation, leading to contradictory results.

We utilized Univariable Mendelian Randomization (UVMR) to explore the link between migraine (13,971 cases/470,627 controls) and AD risk (Bellenguez et al., 39,106 cases/46,828 controls; FinnGen, 111,471 cases/111,471 controls). Meta-analysis was performed for comprehensive synthesis. Employing Multivariable Mendelian Randomization (MVMR), we created models incorporating migraine and 35 potential AD risk factors, examining migraine's independent impact on AD onset risk under considering these factors.

The meta-analysis of inverse variance weighted MR results, combining data from Bellenguez et al. (odds ratio (OR) [95% confidence interval (CI)]: 1.5717 [1.1868-2.0814], p = 0.0016) and FinnGen (OR [95% CI]: 1.2904 [0.5419-3.0730], p = 0.5646), provided evidence for a causal relationship between genetically predicted migraine and the heightened risk of AD occurrence (OR [95% CI]: 1.54 [1.18, 2.00], p < 0.01). After adjusting for Diastolic blood pressure (OR [95% CI]: 1.4120 [0.8487-2.3493], p = 0.1840) and Tumor necrosis factor alpha (OR [95% CI]: 1.2411 [0.8352-1.8443], p = 0.2852), no discernible association was detected between migraine and the risk of AD.

This study offers compelling evidence indicating a significant correlation between genetically predicted migraine and an elevated risk of AD.

Migraine is a common and disabling primary headache disorder and inflammation is a proposed factor in the complex ethiology of the disease. Gasdermin D (GSDMD) is a membrane pore-forming protein acting through the caspase system. End result is cell death caused by leakage of intracellular components to extracellular space which also results in inflammation. Stemming from this knowledge, the potential role of GSDMD in migraine was investigated in this prospective study. This prospective study was conducted between September 2022 to April 2023. 47 patients with migraine were designated as the patient group, whereas 47 healthy volunteers were designated as the control group. Serum GSDMD levels of both groups were compared, with an additional comparison between migraine patients during symptom-free and attack periods. Migraine related characteristics of the patients were also included in the study. Median GSDMD levels of the patient and control group did not reveal a significant difference. Nausea, vomiting and severity of headache were found to be correlated with GSDMD levels in migraine patients. Patients with nausea revealed a higher GSDMD level compared to patients without nausea during both symptom-free and attack periods (p = 0.021 and p = 0.01, respectively). Nausea was correlated to higher GSDMD levels in the patient population during symptom-free period (p = 0.030). The severity of pain was positively correlated with GSDMD levels during the attack period (p < 0.001). Gasdermin family and GSDMD in particular are promising prospects for therapy in a wide spectrum of disorders. Gasdermin proteins are candidates to be the focus for future studies both related to pathogenesis and drug therapy in migraine and varying inflammatory-driven clinical pictures.