ID: 41070562
Title: Gut microbiota, probiotics, and migraine: a clinical review and meta-analysis.
Abstract: Migraine is a primary headache disorder affecting about 14% of the global population. The knowledge about migraine pathophysiology is increasing constantly; however, there are still many unknowns and uncertainties. Intestinal microbiota builds the gut environment together with metabolites and the immune system. Its connections with disorders outside the digestive system have been described, mainly neuropsychiatric diseases, due to the existence of the microbiota-gut-brain axis. Therefore, it is suggested that migraine is also correlated with changes in the microbiome. The review aimed to summarize the available literature related to the topic. We performed an electronic article search through the Embase Database and PubMed Database, and included 14 articles after analysis under the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. Subsequently, a meta-analysis of randomized controlled clinical trials summarizing probiotics' effect on migraine prevention was conducted based on the same guidelines and resulted in including 2 adequate trials. Microbiome alterations have been observed in migraine patients with an influence on clinical presentation. Preclinical studies suggested a direct connection between migraine and microbiome changes. The meta-analysis has shown the influence of probiotics on migraine frequency (p = 0.003; Hedges' g = 1.22; standard error (SE) = 0.41), and no impact on migraine severity (p = 0.069; Hedges' g = 1.10; SE = 0.61) and attacks' duration (p = 0.149; Hedges' g = 0.18; SE = 0.15). However, the former was close to the statistical significance. The following work demonstrates a correlation between migraine and microbiome, which has a putative positive impact on migraine management. Moreover, probiotic supplementation can alleviate migraine symptoms. However, the main limitation is the limited number of studies, together with high heterogeneity and limited methodological consistency in the meta-analysis.

ID: 41136816
Title: Effect and Safety of Phytosomal Curcumin Supplementation on Migraine Patients: A Randomized, Double-Blind and Placebo-Controlled Trial.
Abstract: To investigate the effect and safety of phytosomal curcumin supplementation on patients with migraine. In this randomized, double-blind and placebo-controlled trial, 70 patients suffered from migraine without aura were randomized into 2 groups to receive 250 mg/d of phytosomal curcumin (intervention group) or maltodextrin (placebo group) for 8 weeks, 35 cases per group. All patients in both groups received their standard treatment and common medications. The severity, duration, frequency of headaches, quality of life (QoL), mental status, headache impact, and sleep quality of patients were assessed before and after treatment. Adverse effects were also assessed. Sixty-five patients completed the trial (33 in the intervention group and 32 in the placebo group). Phytosomal curcumin supplementation significantly reduced severity, duration and frequency of migraine attacks, stress score, and headache impact, and improved QoL and sleep quality of patients in the intervention group, compared with the placebo group (P<0.05 or P<0.01). However, it had no significant effect on depression and anxiety scores in the intervention group, compared with the placebo group (P>0.05). No adverse effects had been reported in response to the intervention. Phytosomal curcumin as a safe supplement had a beneficial effect on migraine symptoms, stress level, as well as the sleep quality and QoL in patients with migraine. (Trial registration No. IRCT20201129049534N2).

ID: 41219695
Title: Associations between dietary intake of mitochondria-related nutrients with the risk of migraine: a prospective study of 202,656 participants.
Abstract: 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. 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. 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. 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.

ID: 41454664
Title: Targeting the microbiome in pediatric migraine: gastrointestinal manifestations and the therapeutic role of Bifidobacterium longum.
Abstract: Migraine is a disabling neurological disorder that often begins in childhood or adolescence and is frequently accompanied by gastrointestinal (GI) symptoms. However, the microbiota signatures and gut-brain interactions underlying pediatric migraine, particularly in the presence of GI disorder, remain poorly defined. This study aimed to explore the clinical and microbial features of pediatric migraine, as well as the therapeutic potential of probiotics.We prospectively enrolled 126 pediatric migraine patients (ages 6-19) with or without GI disorder and 50 age-matched healthy controls. Fecal microbiota was profiled using 16S rRNA sequencing. Patients with migraine were stratified based on Rome IV-defined GI disorders and evaluated for headache characteristics, PedMIDAS scores (disability assessment), plasma calcitonin gene related peptide (CGRP, thought as a key biomarker of migraine), cytokines, and fecal calprotectin. Probiotic effects were tested in both young (3-4 weeks) and adult capsaicin-induced migraine rat models, and an exploratory pilot study involving 23 pediatric migraine patients.Compared to controls, migraine patients exhibited distinct gut microbiota with reduced Bifidobacterium longum. and elevated Bacteroides. GI disorders were present in 46.8% of migraine patients and were associated with significantly higher rates of abdominal pain (50% vs. 13%, p <0.001), greater migraine-related disability (PedMIDAS: 60 ± 13.2 vs. 29 ± 7.0, p = 0.042), elevated fecal calprotectin, and enrichment of Streptococcus gallolyticus. In contrast, Faecalibacterium prausnitzii, positively correlated with B. longum, was linked to milder symptoms and shorter disease duration in migraine patients without GI disorder. In animal models, B. longum attenuated trigeminal activation in both young and adult rats. An exploratory pilot study showed B. longum supplementation led to reductions in headache days, intensity, and frequency. These findings reveal distinct gut microbial signatures in pediatric migraine, and identify B. longum as a promising microbiota-targeted therapeutic strategy. Our work highlights the therapeutic potential of modifying the gut-brain axis in childhood migraine.

ID: 41478596
Title: Effect of Flaxseed Supplementation on Headache Characteristics and Quality of Life in Patients with Migraine: A Randomized Controlled Trial.
Abstract: Migraine is a prevalent neurologic disorder that is linked to neuroinflammation. Flaxseed is a plant source of omega-3 (n‒3) fatty acids, which may display anti-inflammatory effects through conversion to long-chain ω-3 fatty acids with known anti-inflammatory potential. We examined the effect of flaxseed supplementation on headache characteristics and psychosocial well-being in patients with migraine. This randomized controlled trial was conducted on 68 patients with migraine. Participants consumed 20 g/d of either flaxseed powder (intervention) or roasted wheat powder (control) for 8 wk. Primary outcomes included: headache frequency, duration, and severity. Secondary outcomes were psychological states (depression, anxiety, and stress), quality of life, sleep quality, weight, and blood pressure. Data were analyzed using SPSS. At the end of the 8-wk intervention, the flaxseed group showed significant improvements in headache severity (‒5.0 ± 2.2 compared with ‒1.0 ± 1.9, P < 0.001), headache impact score (quality of life) (‒15.7 ± 11.0 compared with ‒2.3 ± 8.1, P < 0.001), and insomnia severity index (‒4.6 ± 6.5 compared with ‒1.6 ± 4.9, P = 0.029) compared with the control group. Changes in headache frequency or duration, as well as other measurements, were not significant between groups. Per-protocol and intention-to-treat analyses yielded identical results. Daily consumption of flaxseed for 8 wk may improve headache severity, sleep quality, and quality of life in patients with migraine. Further research is warranted to confirm these findings and explore underlying mechanisms.

ID: 41512309
Title: Association of parthenolide and salicin as a preventive treatment on a migraine model induced by dural inflammatory soup application.
Abstract: Parthenolide (PTL) and salicin (SA), the main active components in Feverfew (Tanacetum parthenium) and White Willow (Salix alba), respectively, have been traditionally used as a remedy for various types of pain, including headaches. Because PTL and SA have different mechanisms of action, we hypothesize that a combination of these drugs would result in an additive effect. We investigated the effects of local and/or systemic administration of PTL, SA, or their combination on cephalic mechanical hypersensitivity (MH) in acute and chronic model of migraine induced by dural application of inflammatory soup (IS) in rats of both sexes. We also studied the effect of combination of PTL and SA on the sensitization of the trigeminocervical complex (TCC) induced by IS application using immunohistochemical (calcitonin gene-related peptide [CGRP] expression) and electrophysiological approaches. When combining low doses of PTL (2.5 mg/kg) and SA (5 mg/kg), we found that single systemic administration of combination prevented acute cephalic MH only in females. However, when administered daily, the combination prevented both chronic ictal and interictal cephalic MH as well as the IS-induced increase in CGRP-immunoreactivity within the TCC, in both sexes. Notably, a single dural application of the combination also prevented acute sensitization of TCC wide dynamic range neurons. Combining PTL and SA have an antimigraine effect in both male and female rats. The combination exerts its preventive effect, at least in part, by blocking the afferent inputs from the dura during the induction phase, preventing thus the establishment of central sensitization.

ID: 41515121
Title: Associations Between Dietary Intakes of Omega-3 Fatty Acids, Blood Levels, and Pain Interference in People with Migraine: A Path Analysis of Randomized Trial Data.
Abstract: Background/Objectives: Increasing evidence supports the hypothesis that dietary intervention can improve pain among individuals with headaches, including migraine, a highly prevalent condition that can be disabling. Non-pharmacologic treatments for migraine are particularly attractive. In this secondary analysis of 182 participants enrolled in a randomized controlled trial of a dietary intervention designed to increase omega-3 (n-3) compared with a control diet, we examined the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both thought to decrease inflammatory processes. Methods: Path models with two time points (baseline and 16 weeks after randomization), were used to test the relationships between exposures of n-3 blood levels and self-reported dietary intake on outcomes of pain interference using the PROMIS pain interference scale and the Headache Impact Test (HIT-6). Model building was based on our published conceptual model. Results: Good fit was demonstrated for both models (EPA model: CFI = 0.984, RMSEA = 0.039, and SRMR = 0.045; DHA model: CFI = 0.981, RMSEA = 0.040, and SRMR = 0.040). Both EPA and DHA in the blood at 16 weeks were associated with lower levels of pain interference, but the effect for EPA was stronger (B = -0.56, p < 0.001 for EPA, and B = -0.43, p = 0.057 for DHA). Conclusions: Our findings are consistent with an indirect pathway linking diet to pain interference through blood levels of EPA and DHA in migraine.

ID: 41555115
Title: Evaluation of the antimigraine and anti-neuroinflammatory activity of purified constituents of Petasites hybridus L. in a migraine-like pain model in mice.
Abstract: Migraine is a prevalent neurovascular disorder strongly associated with neuroinflammation, altered neurotransmitter release, and sensory hypersensitivity. Extracts of Petasites hybridus (butterbur) rootstocks, standardized with eremophilane-type sesquiterpenoids (petasins), have clinically demonstrated efficacy in migraine. However, the pharmacological properties of purified petasins remain insufficiently explored. This study aimed to evaluate their antimigraine and anti-neuroinflammatory potential both in vivo and in vitro. Six sesquiterpenoids were isolated via centrifugal partition chromatography and preparative high-performance liquid chromatography. Male C57BL/6 J mice were subjected to a nitroglycerin model of migraine-like pain, followed by administration of the isolated sesquiterpenoids and mechanical hypersensitivity was evaluated via von Frey filaments. The sesquiterpenoid and neurotransmitter levels in the brain tissues were analyzed via LC‒MS/MS, and the cytokine levels were measured via ELISA. In LPS-stimulated BV-2 microglial cells, anti-inflammatory effects were assessed via Griess assay and a cytokine bead array, and cell viability was measured via MTT assay. Isopetasin significantly attenuated nitroglycerin‒induced mechanical allodynia in both the paw and periorbital regions. These effects may be associated with reduced brain levels of the chemokine CCL2, while LC‒MS/MS confirmed the central bioavailability of isopetasin. In vitro, sesquiterpenoids suppressed LPS‒induced nitric oxide and proinflammatory cytokine release, with isopetasin showing the broadest anti-inflammatory activity. Neurochemical profiling revealed modulation of glutamic acid and GABA associated with the excitatory/inhibitory balance. Purified petasins from butterbur rootstocks, particularly isopetasin, display significant antinociceptive and anti-inflammatory activity in preclinical migraine model. These findings support the importance of well-chemically defined butterbur constituents and provide a foundation for their further investigation as anti-neuroinflammatory agents.

ID: 41574142
Title: Efficacy and safety of magnesium prophylaxis in children with migraine without aura.
Abstract: Migraine is one of the prevalent types of primary headache disorders in children and significantly affects their quality of life. Although pharmacological prophylaxis is often necessary, conventional treatments are frequently limited by adverse effects and modest efficacy. Magnesium, a vital intracellular cation involved in numerous neuronal and vascular functions, has been proposed as a safer alternative. However, data on its use in pediatric migraine remain limited. To investigate the effectiveness and safety profile of magnesium oxide prophylaxis in children diagnosed with migraine without aura. This retrospective study included pediatric patients aged 7-18 years with a diagnosis of migraine without aura, treated exclusively with magnesium oxide at a dosage of 6-9 mg/kg/day or a fixed dose of 365 mg/day for four months. Headache frequency, migraine-related disability (assessed by PedMIDAS), and quality of life (measured by HIT-6) were evaluated before and after four months of prophylaxis. Following magnesium prophylaxis, a statistically significant reduction was observed in headache frequency, PedMIDAS scores, and HIT-6 scores (p<0.001 for all). Additionally, disability levels according to PedMIDAS grading improved significantly. No participants reported side effects during the study. Magnesium oxide appears to be a well-tolerated, safe, and potentially effective prophylactic option for children with migraine without aura. It was associated with a significant reduction in attack frequency, disability scores, and improved quality of life. Despite promising results, the absence of a control group and serum magnesium data are notable limitations. Further prospective, randomized controlled studies are required to confirm these findings and establish the most effective dosage, duration, and formulation of magnesium for pediatric use.

ID: 41615317
Title: [Non-drug therapies in the treatment of migraine].
Abstract: The treatment of migraine is complex, and non-pharmacological methods are useful and necessary complements or alternatives to pharmacotherapy. We reviewed techniques that can be recommended for the treatment of episodic and chronic migraine attacks and prevention, and described methods for which there is no evidence of effectiveness. The most important of the therapies that can be recommended for migraine prevention are the elimination of provoking factors, lifestyle modification and regular exercise, and some diets have also been suggested to be beneficial. Based on the available evidence, supplementing preventive treatment with acupuncture or psychological therapy reduces the frequency of headaches in episodic migraine, and some psychological techniques may also be recommended for chronic migraine or attack therapy. Among the nutritional supplements, the effectiveness of riboflavin, magnesium and Q10 have been clinically proven to be effective in the preventive treatment of migraine. Interventional and invasive neuromodulation techniques are not widespread due to specific equipment requirements and increased risk of complications, however, based on good tolerability, some non-invasive methods can be recommended in the treatment of chronic migraine attacks and prevention. A large proportion of patients try other complementary or alternative methods, the efficacy or ineffectiveness of which has not been clinically proven, and therefore cannot be recommended. A migrén kezelése összetett, a nem gyógyszeres lehetőségek a farmakoterápia hasz­nos és szükséges kiegészítői vagy al­ terna­ tívái. Közleményünkben áttekintjük az epi­ zodikus és krónikus migrén roham- és megelőző kezelésében ajánlható technikákat, továbbá ismertetjük azokat a módszereket is, amelyek hatékonyságára nem állnak rendelkezésre evidenciák. A migrénprevencióban ajánlható terápiák közül legfontosabb a provokáló tényezők kiiktatása, az életmódváltás és a rendszeres sport, emellett néhány diéta jótékony hatása is felmerült. A rendelkezésre álló bizonyítékok alapján a megelőző kezelés akupunktúrával vagy pszichológiai terápiával való kiegészítése csökkenti a fejfájásgyakoriságot epizodikus migrénben, néhány pszichológiai módszer krónikus migrénben vagy rohamterápiában is ajánlható. A táplálékkiegészítők közül a riboflavin, a magnézium és a Q10 hatékonyságát támasztja alá klinikai vizsgálat a migrénprevencióban. Az intervenciós és invazív neuromodulációs technikák a speciális felszereltségi igény és a szövődmények fokozott kockázata miatt nem elterjedtek, a jó tolerálhatóság alapján azonban néhány nem invazív módszer a krónikus roham- és megelőző kezelésében ajánlható. A betegek nagy része egyéb komplementer vagy alternatív módszert is kipróbál, melyek hatásosságát vagy hatástalanságát klinikai vizsgálat nem igazolja, ezért nem javasolhatók.

ID: 41618241
Title: Effectiveness of neuromodulation techniques for migraine prophylaxis: a systematic review and network meta-analysis of randomized controlled trials.
Abstract: BACKGROUND: Given limited efficacy and potential complications of pharmacological approaches, neuromodulation techniques are emerging as non-pharmacological alternatives for migraine prevention. The present study aimed to conduct a systematic review and network meta-analysis to compare the effectiveness of neurostimulation interventions for migraine prophylaxis. METHODS: The PubMed/MEDLINE, Cochrane, Web of Science, Embase, Clinicaltrials.gov, China National Knowledge Infrastructure, Chongqing VIP, Wanfang, Chinese Biomedical Literature Database, Chinese Clinical Trial Registry, and International Traditional Chinese Medicine Clinical Trial Registry databases were systematically searched up to February 7th, 2025 for randomized controlled trials (RCTs). Outcomes of interest were changes in monthly migraine days, response rate and changes in pain intensity. Network meta-analyses were based on a Bayesian framework. RESULTS: Forty RCTs (N = 4341; mean age = 38.7 years; % females = 81.2) were included in the network meta-analysis. Transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), percutaneous mastoid electrical stimulation (PMES), supraorbital transcutaneous stimulation (STS), and acupuncture were associated with significant improvements in migraine frequency, response rate and pain severity. Both invasive and non-invasive occipital nerve stimulation (ONS) demonstrated significantly higher response rates relative to sham controls. Among all the investigated interventions, tES (SUCRA = 82%; SMD = 0.9; 95% CrI = 0.32, 1) yielded the greatest reduction in monthly migraine days, transcutaneous ONS (tONS) (SUCRA = 90%; RR = 12; 95% CrI = 1.9, 389) exhibited the highest response rate, and PMES (SUCRA = 96%; SMD = 2.4; 95% CrI = 0.75, 3.4) yielded the most decreased pain intensity after intervention. CONCLUSIONS: The main findings of this study highlight the beneficial effect of tES and tONS in reducing migraine frequency and improving treatment response, respectively. Due to scanty evidence for certain interventions and network model limitations, caution is needed when interpreting the results. Future large-scale and well-conducted RCTs are required to strengthen the reliability and validity of the findings. TRIAL REGISTRATION: The study protocol was registered on the International Prospective Register of Systematic Reviews. Registration Number: CRD42025642688.

ID: 41627537
Title: Efficacy and Safety of Melatonin in Migraine Prophylaxis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Abstract: Migraine is a chronic, disabling brain disorder. Melatonin, a circadian regulator with anti-inflammatory and antinociceptive actions, has been proposed for migraine prevention. We evaluated the efficacy and safety of melatonin for prophylaxis. We systematically searched PubMed, Cochrane, Scopus, Embase, and Web of Science (September 29, 2024) for randomised controlled trials (RCTs) comparing melatonin with placebo or other active drugs. Outcomes were analysed as change from baseline to last follow-up using mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI). Nine RCTs (n = 788) were included. Versus placebo, melatonin reduced attack duration (MD -4.98 h; 95% CI -9.30 to -0.67; p = 0.02), headache days (MD -1.54 days; 95% CI -2.50 to -0.58; p < 0.01), headache severity (MD -2.08; 95% CI -2.91 to -1.26; p < 0.01), and analgesic use (MD -1.38; 95% CI -2.41 to -0.36; p < 0.01). Melatonin also increased the response rate (≥ 50% reduction in monthly headache frequency) (RR 1.38; 95% CI 1.11-1.70; p < 0.01) and improved sleep quality (PSQI: MD -1.64; 95% CI -2.85 to -0.42; p = 0.008) and disability (MIDAS: SMD - 4.07; 95% CI -5.45 to -2.69; p < 0.001). Compared with amitriptyline, melatonin was generally less effective for attack duration and severity, with no consistent advantage on analgesic use or response; however, melatonin showed a more favourable tolerability profile, including lower risk of sleepiness (RR 0.49; 95% CI 0.28-0.87; p = 0.01). Melatonin demonstrates benefits over placebo for reducing migraine burden and improving patient-reported outcomes, with a favourable safety profile. While amitriptyline remains more potent for several efficacy endpoints, melatonin represents a reasonable preventive option, particularly as an adjunct during titration of first-line agents. Further head-to-head trials with standardised dosing and longer follow-up are warranted.

ID: 41634602
Title: Association of diet quality, dietary acid load and antioxidant index with migraine severity, disability, and duration: a cross-sectional study.
Abstract: BACKGROUND: Migraine disproportionately affects women and may be modulated by dietary factors. This cross-sectional study investigated associations between diet quality (Alternative Healthy Eating Index, AHEI), dietary acid load (Net Endogenous Acid Production, NEAP), and dietary antioxidant capacity (Dietary Antioxidant Index, DAI) with migraine pain intensity, disability, and headache duration in Iranian women. METHODS: A total of 280 women aged 18–50 years with migraine (diagnosed per ICHD-3 criteria) were recruited from neurology clinics in Zanjan, Iran (August 2024–June 2025). Dietary intake was assessed using a validated 168-item food frequency questionnaire. AHEI, NEAP, and DAI scores were calculated and stratified into tertiles. Outcomes included pain intensity (Visual Analog Scale [VAS]: mild [1–3; reference], moderate [4–7], severe [8–10]), disability (Migraine Disability Assessment Scale [MIDAS]: none [0–5; reference], mild [6–10], moderate [11–20], severe [> 20]), and mean headache duration (hours). Multivariable-adjusted multinomial logistic regression (for VAS and MIDAS) and linear regression (for duration) were used to estimate odds ratios (ORs) and β coefficients with 95% confidence intervals (CIs), comparing the middle (T2) and highest (T3) tertiles versus the lowest (T1; reference), adjusted for age, BMI, physical activity, prophylactic medication use, and socioeconomic status. P-for-trend was calculated using tertile medians as continuous variables. RESULTS: Higher AHEI tertiles showed graded protective associations with severe pain (T3 OR 0.69, 95% CI 0.51–0.89, p = 0.010; P-for-trend = 0.009) and shorter headache duration (T3 β − 1.58, 95% CI − 2.75 to − 0.41, p = 0.009; P-for-trend = 0.008). Higher NEAP tertiles were linked to increased severe pain (T3 OR 1.38, 95% CI 1.08–1.66, p = 0.021; P-for-trend = 0.018), severe disability (T3 OR 1.29, 95% CI 1.02–1.56, p = 0.044; P-for-trend = 0.039), and longer duration (T3 β 1.28, 95% CI 0.25–2.31, p = 0.015; P-for-trend = 0.013). Higher DAI tertiles demonstrated the strongest graded reductions in moderate pain (T3 OR 0.59, 95% CI 0.41–0.83, p = 0.035; P-for-trend = 0.012), severe pain (T3 OR 0.47, 95% CI 0.33–0.74, p = 0.024; P-for-trend = 0.007), moderate disability (T3 OR 0.73, 95% CI 0.52–0.97, p = 0.048; P-for-trend = 0.031), severe disability (T3 OR 0.69, 95% CI 0.47–0.91, p = 0.038; P-for-trend = 0.022), and shorter duration (T3 β − 1.34, 95% CI − 2.33 to − 0.35, p = 0.008; P-for-trend = 0.006). CONCLUSIONS: Better diet quality and higher antioxidant capacity were associated with reduced migraine burden, while higher dietary acid load correlated with increased burden. These findings highlight potential graded associations and support the need for prospective studies to establish causality and evaluate dietary interventions in women with migraine.

ID: 41673123
Title: The metabolic consequences of evoked spreading depolarization in brain slices.
Abstract: Spreading depolarization is a wave of neuronal and glial depolarization that propagates through brain tissue, triggering neuropeptide release and altered blood flow. It has been observed in ischemic stroke, traumatic brain injury, subarachnoid haemorrhage, epilepsy, and migraine aura. Spreading depolarization imposes a high energetic demand, and recovery impaired under metabolic substrate deficiency. Despite its clinical relevance, metabolic responses remain poorly understood, limiting therapeutic progress. We investigated metabolic effects of spreading depolarisation using an ex vivo brain slice model, aiming to characterise changes in intracellular calcium signalling, mitochondrial function, and central carbon metabolism, and to assess the impact of glucose deprivation. We further tested whether coenzyme Q10 could improve recovery under metabolically compromised conditions. Spreading depolarization increased mitochondrial activity and shifted metabolism toward anaerobic respiration and glycolysis. Glucose deprivation impaired recovery, inducing mitochondrial dysfunction and accumulation intermediates indicative of tricarboxylic acid cycle stalling and disrupted central carbon metabolism. Supplementing glucose-deprived brain slices with coenzyme Q10 shortened spreading depolarization repolarization duration, indicating enhanced metabolic recovery. These findings demonstrate that spreading depolarization imposes a significant metabolic burden, particularly under glucose limitation, and that mitochondrial-targeted interventions such as coenzyme Q10 may enhance tissue resilience in neurological disorders.

ID: 41769676
Title: The effect of riboflavin on the mean attack frequency, severity, and duration of migraine headaches: A systematic review and dose-response meta-analysis of clinical trials.
Abstract: Due to the anti-inflammatory and antioxidant effects of riboflavin, this vitamin can be effective in improving migraine. However, due to conflicting results in previous studies, the present study aimed to determine the effectiveness of riboflavin in improving migraine in a systematic review and dose-response meta-analysis. Scopus, ISI Web of Science, and PubMed databases, as well as Google Scholar, were searched up to March 15, 2025 to find trials, published in the English language, that investigated the effect of riboflavin on migraine. Quality assessment of trial studies was done using the Cochrane Collaboration tool. STATA software was used to analyze the data. The present study included 12 trials with a total sample size 749. The dose-response meta-analysis revealed a significant linear relationship, showing that increasing riboflavin intake up to 400 mg/day was associated with greater reductions in migraine frequency and duration, without evidence of a threshold effect (P < 0.001). Riboflavin had a significant effect on frequency (weighted mean difference [WMD]: -1.39, 95%CI: -2.52 to -0.25; I 2 = 91.7%, P < 0.001) and duration of migraine (WMD: -1.36, 95% CI: -2.69 to -0.03; I 2 = 90.4%, P < 0.001) in comparison to the control. In terms of methodological approach, eight trials had a good and four had a fair quality. Riboflavin exhibits promising effects in reducing the frequency and duration of migraine. The limitations of the present study include the absence of a control group and the small sample size in some included studies.

ID: 41824241
Title: Pharmacokinetics and Pharmacodynamics, Efficacy and Safety of Fremanezumab in Children and Adolescents with Migraine.
Abstract: Migraine affects up to 11% of children and adolescents, leading to substantial disability through school absenteeism, cognitive impairment, and reduced quality of life. Traditionally, preventive treatment options for this population have been limited to the off-label use of nutraceuticals, antiseizure medications, calcium channel blockers, serotonin modulators, antidepressants, or beta-blockers, with limited efficacy and tolerability data. Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have transformed adult migraine prevention, and fremanezumab is the first in this class to receive regulatory approval for pediatric use. In August 2025, the US Food and Drug Administration approved fremanezumab for the preventive treatment of episodic migraine in patients aged 6-17 years weighing at least 45 kg, based on the pivotal phase three SPACE trial. This randomized, placebo-controlled study demonstrated significant reductions in monthly migraine and headache days, with nearly half of treated participants achieving a ≥50% response rate, and a safety profile consistent with adult data. In this review, we provide an integrated, pediatric-focused synthesis of the pharmacokinetic, pharmacodynamic, and regulatory evidence supporting fremanezumab use in children and adolescents. In particular, we contextualize population pharmacokinetic modeling and pediatric phase 1 data to explain the rationale for weight-based dosing, exposure matching with adults, and the selection of the dosing regimens used in clinical trials and regulatory labeling. Pharmacokinetic analyses indicate that fremanezumab follows a two-compartment model with first-order absorption and a terminal half-life of approximately 30 days in pediatric patients, similar to adults, with body weight as the primary determinant of exposure. Finally, we discuss unresolved issues related to long-term CGRP blockade during growth, including theoretical effects on vascular regulation, bone metabolism, and neurodevelopment. Overall, fremanezumab represents a novel, mechanism-based preventive option for older children and adolescents with episodic migraine, while highlighting the need for continued longitudinal studies to define its long-term safety and optimal role in pediatric migraine management.

ID: 41829891
Title: Migraine and the Gut-Brain Axis-The Role of Microbiome-Targeted Biotics.
Abstract: Background: Migraine is a highly prevalent and disabling primary headache disorder frequently accompanied by gastrointestinal symptoms and comorbid gastrointestinal diseases. Increasing evidence suggests that alterations in the gut microbiota and dysregulation of the microbiome-gut-brain axis may contribute to migraine pathophysiology through immune activation, oxidative stress, impaired intestinal barrier function, and neuroinflammatory signaling. Objectives: This narrative review aims to summarize current mechanistic and clinical evidence linking the gut-brain axis to migraine, with a particular focus on the potential roles of probiotics, prebiotics, and postbiotics as adjunctive strategies in migraine management. Methods: A narrative synthesis of experimental, translational, and clinical studies was performed, focusing on microbiome composition, gut barrier integrity, immune and oxidative pathways, and interventional trials evaluating probiotics, prebiotics, synbiotics, and microbiota-derived metabolites in adult and pediatric migraine populations. Results: Migraine has been associated with intestinal dysbiosis, increased gut permeability, and low-grade systemic inflammation. Probiotics, most commonly strains of Lactobacillus and Bifidobacterium, may modulate inflammatory cytokine profiles, enhance tight junction integrity, reduce oxidative stress, and influence neurotransmitter-related pathways along the gut-brain axis. Clinical trials evaluating probiotic supplementation report heterogeneous but promising signals, including reductions in migraine frequency, severity, disability scores, and analgesic use, particularly in chronic migraine and pediatric populations. Emerging evidence also supports a potential role for prebiotics (e.g., inulin-type fructans) and microbiota-derived metabolites such as short-chain fatty acids, although direct clinical data remain limited. Conclusions: Modulation of the microbiome-gut-brain axis represents a biologically plausible adjunct approach in migraine management. While probiotics, prebiotics, and postbiotics show potential benefits with favorable safety profiles, current evidence of their strain-, formulation-, and population-specific characteristics is lacking. Well-powered, placebo-controlled trials with standardized migraine endpoints and integrated microbiome and metabolomic analyses are needed to define responders, optimal interventions, and clinical relevance.

ID: 41872423
Title: Hypomagnesemia: A Clinical and Nutritional Update.
Abstract: PURPOSE OF REVIEW: Hypomagnesemia, defined as low serum/plasma magnesium concentration, is a highly prevalent yet underrecognized electrolyte disorder with extensive clinical, metabolic, and nutritional implications. This review provides an updated synthesis of magnesium physiology, dietary determinants, homeostatic regulation, diagnostic challenges, and therapeutic strategies, with particular emphasis on recent meta-analyses and large-scale epidemiological evidence linking hypomagnesemia to multisystem disease. RECENT FINDINGS: Accumulating evidence has shown consistent associations between low serum or dietary magnesium and increased risk of cardiometabolic disorders (hypertension, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular disease), neuropsychiatric conditions (migraine, depression, cognitive impairment, and dementia), osteoporosis, immune dysregulation, and adverse outcomes in hospitalized, critically ill, and chronic kidney disease patients. Mechanistic studies have clarified the roles of TRPM6/7 channels, tight junction claudins, and basolateral magnesium transporters in intestinal and renal magnesium handling, elucidating pathways underlying both inherited and acquired deficiencies. Research has also highlighted the contribution of modern dietary patterns, food processing, mineral-depleted drinking water, medication use (notably proton pump inhibitors, diuretics and chemotherapeutic agents), and gut microbiome alterations to widespread subclinical deficiency. Meta-analyses of RCTs indicate that magnesium supplementation confers modest but clinically relevant improvements in blood pressure, glycemic control, inflammatory markers, endothelial function, migraine frequency, and depressive symptoms, particularly in individuals with baseline hypomagnesemia. However, serum magnesium remains an insensitive biomarker of total body magnesium status, and consensus on optimal diagnostic thresholds and replacement strategies is lacking. Magnesium deficiency contributes to a wide spectrum of multisystem disorders, and is driven by dietary insufficiency, gastrointestinal and renal losses, medication use, chronic disease, and altered microbiome function. Meta-analytic evidence supports its role as a modifiable risk factor across cardiovascular, metabolic, neurological, skeletal, and immune disorders. Dietary modification, optimized supplementation, and correction of underlying causes of deficiency remain central to management. Future research should focus on improved diagnostic tools, personalized dosing approaches and long-term outcomes of magnesium repletion. Enhancing clinical awareness and integrating magnesium evaluation into routine care may reduce the growing burden of hypomagnesemia.

ID: 41908273
Title: Efficacy of Petasites hybridus in migraine prophylaxis: the first real-world study.
Abstract: Petasites hybridus is a plant from the Asteraceae family used in migraine prophylaxis. Petasins and isopetasins, one of its constituents, act through antinociceptive, anti-CGRP, anti-inflammatory mechanisms and on calcium channels. This study aimed to evaluate the therapeutic efficacy of Petasites hybridus in the prophylaxis of episodic migraine (EM) and chronic migraine (CM). This was a single-center, retrospective, observational, uncontrolled, descriptive, and real-world study with 120 consecutive patients with EM or CM treated with Petasites hybridus. One hundred and twenty patients (72 with EM and 48 with CM) were treated with Petasites hybridus, whose mean age was 35.4 ± 12.4 years, ranging from 18 to 60 years. Before treatment, the average frequency of headache for EM and CM was 6.0 ± 2.7 and 26.3 ± 5.1 days per month, respectively. After 12 weeks, there was a reduction in the number of days with headache, both in the EM and CM, respectively, to 2.6 ± 2.9 and 12.7 ± 8.6 (p < 0.0001). The reduction in headache attacks was greater than 50% in 59.2% of patients. There was a reduction in disability in both groups. Adverse events occurred in 28.3% of patients, including a bitter sensation in the mouth and/or eructation, lasting 6.4 ± 2.7 days and ranging from 2 to 14 days. Petasites hybridus was well tolerated and reduced the number of headache days per month by ≥50% in 60% of migraine patients within the first 12 weeks, providing a reduction in the degree of disability. Furthermore, Petasites hybridus (Petamig®) is free of pyrrolizidine alkaloids, making it appropriate and safe for prescription to patients.

ID: 42021338
Title: The effects of Mixodin supplementation on migraine headache characteristics, oxidative stress and inflammatory biomarkers in patients with migraine: a double-blind, placebo-controlled, randomized trial.
Abstract: BACKGROUND: Migraine is a prevalent neurological disorder closely linked to oxidative stress and neurogenic inflammation. Curcumin, gingerol, and piperine are natural compounds with well-established anti-inflammatory and antioxidant properties; however, clinical evidence on their combined effects in migraine remains limited. AIM: This study aimed to evaluate the effects of eight weeks of Mixodin supplementation on inflammatory and oxidative stress biomarkers, and clinical migraine characteristics, in patients with migraine. METHODS: This randomized, double-blind, placebo-controlled trial enrolled 60 patients with migraine, who were randomly assigned to receive two Mixodin capsules daily (each containing 300 mg curcumin, 7.5 mg gingerol, and 3.75 mg piperine) or placebo for eight weeks. Serum hs-CRP, NO, MDA, TOS, TAC, and SOD were measured before and after the intervention. Headache severity, frequency, and duration were recorded using VAS and a headache diary. RESULTS: Mixodin supplementation significantly reduced serum Hs-CRP (− 0.87 ± 0.19 vs. − 0.16 ± 0.09 mg/L; P = 0.001) and NO levels (− 5.53 ± 1.53 vs. + 3.51 ± 1.79 µmol/L; P = 0.042) compared with placebo. Additionally, eight weeks of Mixodin supplementation resulted in a trend toward increased SOD activity and TAC, and a trend toward decreased TOS; however, these changes did not reach statistical significance when compared with the control group (all P > 0.05). No significant change was observed in MDA levels. Mixodin supplementation significantly reduced headache severity (-1.93 ± 0.30vs. -0.36 ± 0.21; P = 0.001) compared with placebo, whereas frequency and duration did not differ significantly between groups (P = 0.737 and P = 0.873, respectively). CONCLUSION: Eight weeks of Mixodin supplementation significantly improved hs-CRP, NO levels, and headache severity among migraine patients, suggesting a promising role for this combination as an adjunctive therapeutic approach in migraine management. Further large-scale trials with longer follow-up are needed. TRIAL REGISTRATION: Iranian Registry of Clinical Trials ( www.irct.ir ) (ID: IRCT20241009063312N1).

ID: 42197013
Title: Myoinositol and Selenium (MYSE) Supplementation Is Associated with Favorable Changes in Thyroid Parameters and Migraine Outcomes in Patients with Migraine and Hashimoto's Thyroiditis: A Retrospective Cohort Study.
Abstract: Background/Objectives: Migraine and Hashimoto's thyroiditis (HT) are frequently comorbid, implying shared biological pathways. Selenium and myoinositol are involved in migraine pathophysiology, and their supplementation has been shown to improve thyroid function, particularly in individuals with HT. This study aimed to evaluate the impact of combined myoinositol and selenium (MYSE) supplementation on thyroid function and migraine outcomes in patients with migraine and HT. Methods: We conducted a retrospective study on a cohort of 163 adults with migraine comorbid with HT who received a 6-month MYSE supplementation. Thyroid parameters, namely thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3), and migraine features, namely monthly migraine days (MMDs), monthly migraine attacks (MMAs), and monthly symptomatic drug use (MSDs), were assessed at baseline and at follow-up. Because Shapiro-Wilk testing showed that all thyroid and migraine outcomes deviated significantly from normality, pre-post comparisons were evaluated with the Wilcoxon signed-rank test, between-group comparisons with the Mann-Whitney U test, and a three-tier non-parametric strategy (Aligned Rank Transform with ART-C contrasts, the Brunner-Langer non-parametric mixed model, and a trimmed-means between-within ANOVA) to analyze time × migraine × gender, adjusted for age and illness duration. Spearman rank correlations with percentile-bootstrap 95% confidence intervals were computed, and both robust MM-regression and rank-based Jaeckel regression were carried out. Another analysis stratified participants by baseline thyroid status: euthyroid vs. subclinical hypothyroidism (SCH). Results: After six months of MYSE supplementation, significant reductions were observed in TSH (median 3.60 → 2.80 mIU/L, Wilcoxon p < 0.001, rank-biserial r = -0.94), MMDs (14 → 11, p < 0.001, r = -0.99), and MSDs (14 → 11, p < 0.001, r = -0.99), while fT4 increased slightly (1.30 → 1.50 ng/dL, p < 0.001) and fT3 remained stable. For MMAs, a small effect was detected by the paired Wilcoxon test (p = 0.002) but the main effect of time did not survive adjustment in any of the three covariate-adjusted mixed models (ART p = 0.079; nparLD p = 0.55; WRS2 p = 0.084). Chronic migraine patients had higher baseline and follow-up headache burden but experienced greater reductions in MMDs. The percentage reduction in TSH was positively correlated with improvement in MMDs (Spearman ρ = 0.45, bootstrap 95% CI 0.31-0.57, p < 0.001) and was the only significant predictor in both robust MM-regression (β = 0.28, p < 0.001) and rank-based regression (β = 0.25, p < 0.001). The TSH-MMD association held within each thyroid-status stratum separately (ρ = 0.42 in euthyroid, ρ = 0.51 in SCH; p < 0.001 for both), indicating an individual-level signal rather than a between-group artefact. Conclusions: MYSE supplementation was associated with improved thyroid parameters and a meaningful reduction in migraine burden among patients with migraine and HT. The association between TSH reduction and headache improvement supports the hypothesis of an endocrine-metabolic contribution to migraine severity and warrants confirmation in prospective controlled trials. It also supports the clinical value of assessing and addressing thyroid function in this population.

ID: 42198398
Title: Back to the Roots: Safety and Tolerability of Standardised Ashwagandha (Withania somnifera) Root Extract in Healthy Adults-A Systematic Review of Biomarkers and Adverse Events.
Abstract: Background: Standardised Ashwagandha root extract (SARE), characterised by its content of bioactive withanolides, is widely used for its antioxidant and adaptogenic properties; however, recent case reports have raised safety concerns, primarily involving non-standardised or multi-ingredient formulations. This systematic review evaluated the safety and tolerability of SARE in healthy adults, with a focus on clinical biomarkers and adverse event reporting. Methods: Randomised trials were identified through searches of PubMed, Web of Science and Google Scholar, published from 2010 to April 2026. Studies administering single-ingredient, standardised root-only extracts to generally healthy populations were included. Risk of bias was assessed using the Cochrane RoB 2 tool. Results: Twenty-three studies with a total of 2317 participants met the inclusion criteria, with doses ranging from 125 to 600 mg/day and intervention durations from a single dose to 180 days. Across studies, hepatic, renal, haematological, endocrine, and cardiovascular biomarkers remained within normal clinical ranges, with no clinically meaningful adverse alterations reported. Reductions in cortisol were consistently observed, while increases in testosterone remained within physiological ranges. No serious adverse events attributable to SARE were reported. Mild adverse events, including gastrointestinal discomfort, headache, and transient drowsiness, were infrequently reported and occurred in both intervention and comparator groups. Conclusions: SARE was well tolerated in healthy adults at the studied doses and durations. However, limited long-term data (>180 days) and heterogeneity in study design and reporting warrant further large-scale, standardised trials to confirm safety across extended use and diverse populations. The review is registered in the PROSPERO database with ID CRD420261337116.

ID: 42301133
Title: Single-Nucleus RNA-Seq Reveals Neuroprotective Effects of Acupuncture in Chronic Migraine Through Modulation of Glial Subtypes.
Abstract: Chronic migraine (CM) is a debilitating neurological disorder with limited treatment options. Although acupuncture has demonstrated clinical efficacy in relieving CM symptoms, its cellular and molecular mechanisms remain poorly understood. This study aimed to delineate the cell-type-specific transcriptional landscape and intercellular communication network reshaped by acupuncture. A rat model of CM was induced by repeated administration of nitroglycerin. Acupuncture was applied at GB8 and GB34 points. Single-nucleus RNA sequencing (snRNA-seq) was performed on the TNC region to profile transcriptomic changes across different cell types. Differential expression analysis, functional enrichment, and pseudotime trajectory inference were performed, along with intercellular communication analysis using CellChat. Acupuncture alleviated pain-related behaviors and restored aberrant cell compositions in the TNC, especially among neurons, astrocytes, and microglia. It reversed the CM-induced upregulation of inflammatory and oxidative stress-related genes (e.g., Nfkbia, S100a8, S100a9, Penk). The imbalance between neuronal excitability and metabolism was rectified through the modulation of glutamatergic transmission and oxidative phosphorylation pathways. Microglial polarization shifted from pro-inflammatory (M1/M5) to reparative ones (M2/M4), while astrocytic subtypes rebalanced toward anti-inflammatory and metabolic repair states. CellChat analysis showed that acupuncture also remodeled neuron-glia communication disrupted by CM. This study sheds light on the cellular and molecular mechanisms by which acupuncture alleviates CM, providing novel insights into its effects on oxidative stress, inflammation, and neuronal function in the TNC. These findings have important implications for both basic science and clinical practice, supporting the potential of acupuncture as a non-invasive, adjunctive therapy for migraine treatment.

ID: 42314279
Title: Therapeutic evaluation of herbal poultice (Ḍimād) in the management of pain and disability of chronic migraine: A case report.
Abstract: Chronic migraine ('Shaqīqa-i-Muzmin) is a common and disabling neurological condition affecting 1-3% of the global population. Esteemed Unāni physicians documented the use of an herbal poultice (Ḍimād) for treating chronic migraine. This case report describes the clinical outcomes of a patient with chronic migraine treated with a herbal poultice (Ḍimād). A 45-year-old female presented to the Outpatient Department of Ilāj bi'l Tadbīr at Kashmir Tibbia College Hospital and Research Centre in Kashmir, India, with a 12-year history of chronic migraine. She experienced recurrent unilateral, throbbing headaches accompanied by nausea, photophobia, and phonophobia, occurring on approximately 18 days per month. Prior conventional treatments provided only temporary symptomatic relief. At baseline, her Visual Analogue Scale (VAS) score was 8/10, and her Migraine Disability Assessment Scale (MIDAS) score was 42, indicating severe disability. The patient received treatment with an Ḍimād composed of Euphorbia resinifera Berg. (Farfiyūn), Ferula foetida Regel (Hiltīt), and Ferula galbaniflua Boiss. (Jāwshīr), prepared in sugarcane vinegar. The formulation was applied once daily to the forehead and right frontotemporal region for 28 consecutive days. After treatment, headache frequency dropped from 18 to 4 days per month, the VAS score improved from 8 to 2, and the MIDAS score decreased from 42 to 10. Associated symptoms were significantly reduced. No adverse events occurred, treatment adherence was excellent, and clinical improvement persisted throughout the six-month follow-up period. This case suggests that Ḍimād may be a safe and potentially beneficial complementary therapeutic option for chronic migraine. Additional controlled studies are needed to validate its efficacy and safety.

ID: 42316353
Title: Branched-chain amino acid supplementation as a potential trigger for migraine without aura: a case report.
Abstract: Migraine is a common and disabling neurological disorder with a wide range of reported triggers, including dietary factors and nutritional supplements. Branched-chain amino acids (BCAAs) are frequently consumed to enhance athletic performance; however, their potential role in triggering migraine attacks remains largely unexplored. A 28-year-old White man developed a severe unilateral pulsatile headache associated with nausea, vomiting, and photophobia 2 hours after consuming a BCAA supplement following exercise. Neuroimaging and laboratory investigations were unremarkable, and the patient fulfilled the International Classification of Headache Disorders, 3rd edition (ICHD-3), criteria for migraine without aura. Symptoms resolved with acute treatment, and no further attacks occurred following discontinuation of BCAA supplementation and implementation of preventive and lifestyle measures during 6 months of follow-up. This case highlights BCAA supplementation as a potential trigger for migraine and discusses plausible neurobiological mechanisms relevant to migraine susceptibility. Further studies are needed to clarify this potential association.

ID: 42318710
Title: Treatment outcomes in new daily persistent headache in children and adolescents.
Abstract: BackgroundNew daily persistent headache (NDPH) is a primary headache disorder that often presents in adolescence. Presently, there is no effective treatment for NDPH and a paucity of clinical trials exploring therapeutic options. In this study, we explored the relative benefit of currently used treatments to help inform future trials and clinical decision-making.MethodsIn this retrospective chart review study, patients aged 5-17 years with abrupt onset continuous headache and headache duration of at least one month (constituting NDPH or probable NDPH) were identified based on responses to a Headache Questionnaire in child neurology clinic and confirmed with chart review. We included all treatments (transitional therapy, preventive supplement, preventive medication and preventive non-medication therapy) started during continuous headache until both break in continuous headache and sustained improvement in headache were achieved. For treatments tried by at least 10 patients and for the first treatment tried in each category, we calculated proportions of any documented benefit, including "Significant" (≥30% improvement lasting ≥4 weeks) and "Some improvement" (all other improvement) and proportions of negative outcome (those with worsened headaches or side effects warranting discontinuation), as well as median time to treatment. We used multivariable regression modeling to examine for factors associated with headache outcomes. Treatments may have overlapped.ResultsOf the 165 patients, the largest proportion of patients experienced benefit with the first transitional therapy (62/108; 57%), which was usually intravenous medications ± oral corticosteroids. The first supplement tried, usually riboflavin ± magnesium, offered benefit in (36/118; 31%), with few negative outcomes (3/118; 3%). The first prescription preventive tried, usually amitriptyline or topiramate, offered similar benefit (37/106; 35%) as the first supplement, but with more negative outcomes (25/106; 24%). Despite being tried after oral preventives, onabotulinumtoxinA injections offered benefit to the largest proportion of patients (14/20; 70%) without negative outcomes (0%). Overall, the time to first therapy was weeks to months into continuous headache: shortest for transitional therapies (median = 49 days, interquartile range = 17-92 days), and longest for non-medication therapies (median = 144 days, interquartile range = 61-381 days). Increased time to any first treatment was associated with decreased odds of headache improvement at one-year follow-up (odds ratio = 0.823, 95% confidence interval = 0.715-0.946, p = 0.006).ConclusionsChildren and adolescents with new onset continuous headache experience treatment delays which are associated with worse outcomes. Clinicians should consider use of transitional therapies in combination with preventive treatments as early as possible. Prospective natural history studies and trials are needed to improve treatment outcomes for pediatric patients with NDPH.

ID: 42333817
Title: Acupuncture Alleviates Neuroinflammation in Chronic Migraine by Modulating Lactobacillus and Its Metabolite Pathways.
Abstract: Chronic migraine (CM) is a highly prevalent and disabling neurological disorder lacking universally effective treatments. Acupuncture has shown significant clinical efficacy, yet its precise mechanisms remain unclear. This study aimed to evaluate the therapeutic effects and underlying mechanisms of acupuncture in CM, integrating gut microbiota and metabolomic analyses. Forty-two Sprague-Dawley rats were randomly assigned to seven groups: control (Con), CM model (Mod), acupuncture (Acu), model + probiotics (Mod + Pro), model + antibiotics (Mod + Anti), acupuncture + probiotics (Acu + Pro), and acupuncture + antibiotics (Acu + Anti). CM was induced via subcutaneous nitroglycerin injection. Acupuncture was performed for nine days at bilateral Shuaigu (GB8) and Yanglingquan (GB34) points (20 min/day). Probiotics were administered by oral gavage of a mixed Lactobacillus preparation for 9 days; antibiotics were given as an oral cocktail for 2 weeks premodeling. Pain sensitivity and central inflammation were assessed by behavioral tests and ELISA. Gut microbiota and metabolites were profiled using 16S rDNA sequencing and metabolomics. Acupuncture alleviated pain hypersensitivity and central inflammation, reversing CM-induced gut dysbiosis, with marked effects on Akkermansia muciniphila and Lactobacillus. Metabolomics identified multiple altered metabolites, with strong correlations between Limosilactobacillus and unclassified_Lactobacillaceae and cis-5-dodecenoic acid and dihydrolipoamide. Network analysis revealed Limosilactobacillus as a core node, suggesting modulation of gut-brain axis signaling via specific metabolic pathways. Exogenous Lactobacillus markedly alleviated hyperalgesia and inflammation in model rats, with further analgesic and anti-inflammatory potentiation when combined with acupuncture. Acupuncture may exert antimigraine effects by modulating the Lactobacillus-metabolite-inflammation axis, restoring gut homeostasis, and alleviating pain and neuroinflammation. Probiotic supplementation further supports the role of gut microbiota in mediating acupuncture's benefits, offering insight for mechanistic studies and clinical translation.

ID: 42340335
Title: Impaired bone status in high frequency episodic or chronic migraine women: A case-control study with blood and densitometric parameters.
Abstract: Background/AimMigraine and osteoporosis are highly prevalent in women and represent a substantial socio-health burden. We aimed to comprehensively assess bone status in women with frequent migraine.Patients and MethodsAdult women with high-frequency episodic migraine (HFEM) or chronic migraine (CM) were recruited and compared with age- and body mass index-matched female controls. Serum parameters of bone metabolism, including 25-hydroxyvitamin D (25[OH]D), calcium and parathyroid hormone (PTH), as well as bone turnover markers (procollagen type 1 N-terminal propeptide [P1NP] and C-terminal telopeptide of type I collagen [CTX]), were measured. Bone mineral density (BMD), T-scores and trabecular bone score (TBS) were assessed by dual-energy X-ray absorptiometry.ResultsA total of 108 women with CM/HFEM and 129 matched controls were included. Compared with controls, women with migraine had lower serum 25(OH)D and calcium levels (p ≤ 0.001) and higher adjusted CTX levels (p = 0.039). Densitometric assessment revealed significantly reduction in BMD at femoral neck (g/cm2 and T-score) and total hip (T-score) in the migraine group (p < 0.001). Lumbar TBS was also lower in CM/HFEM patients (p < 0.001). After multivariable adjustment, TBS remained independently associated with migraine status. These alterations remained in women with HFEM and in those younger than 50 years, and were associated with reduced physical activity and sun exposure.ConclusionsWomen with frequent migraine exhibit impaired bone health, characterized by alterations in bone mass and trabecular microarchitecture. TBS appears to be a sensitive marker of early skeletal involvement in this population. The presence of bone impairment in HFEM and in premenopausal women supports early assessment of bone status and reinforcement of lifestyle interventions, including adequate physical activity and sun exposure.

ID: 42356280
Title: Integrating Nutrition and Physical Activity into the EXEMIG/01 Interdisciplinary Model for Chronic and High-Frequency Migraine.
Abstract: Background: Migraine (MIG) management guidelines support a comprehensive approach combining medication, therapeutic patient education (TPE), behavioral strategies, lifestyle changes, diet, and physical activity (PA). Objective: To present an innovative interdisciplinary outpatient model for individuals with MIG, focusing on PA, sedentary behavior, eating habits (EH), metabolic health, temporomandibular disorders, and postural dysfunctions. Design: A randomized controlled trial will enroll 200 adults with MIG over two years. Inclusion criteria are chronic MIG (≥15 attacks/month for ≥3 months) or high-frequency episodic MIG (8-14 attacks/month), physical inactivity, and independent walking ability. Exclusion criteria include contraindications to PA and lack of informed consent. Participants will be randomized to standard care (SC) or an intervention group receiving TPE plus three months of supervised exercise (EXE). All participants will receive an informational brochure with nutritional tips (included in SC) and undergo: (1) neurological examination, (2) validated questionnaires, (3) kinesiological and postural assessment, and (4) gnathological evaluation. The primary outcome is change in monthly MIG frequency at 6 and 12 months; additional outcomes include disability, quality of life, and intensity of MIG, PA levels, sedentary behavior, medication use, EH, functional capabilities, postural parameters, and temporomandibular disorder-related variables. Results: Hypothetically, the intervention may reduce monthly MIG frequency by approximately 15-20% relative to baseline. Improvements may also occur in disability, quality of life, medication use, lifestyle behaviors, and psychological and cardiometabolic parameters. Conclusions: This trial will evaluate whether adding supervised EXE and TPE to SC may improve MIG outcomes compared with SC alone, supporting a comprehensive management strategy.

ID: 42367252
Title: Red Ear Syndrome: A Case Report and Review of Literature.
Abstract: Red ear syndrome (RES) is a rare disorder characterized by episodic erythema, warmth, and burning pain of the external ear. RES is frequently associated with migraine. We report the case of a 35-year-old male with a long-standing history of poorly controlled migraine who presented with recurrent bilateral auricular erythema and burning pain, predominantly affecting the left ear. Symptoms were triggered by migraine attacks, heat exposure, and ear manipulation and relieved by cooling measures. Clinical examination, laboratory investigations, and imaging were normal. RES was diagnosed after excluding infectious and inflammatory causes. Treatment with indomethacin and magnesium resulted in complete symptom resolution. RES should be considered in patients with recurrent auricular erythema and burning pain, particularly in those with migraine. Careful clinical assessment and systematic exclusion of alternative diagnoses are crucial for identifying RES and preventing inappropriate management.

ID: 42375040
Title: Association of Iron Deficiency Anemia with Migraine: A Case-Control Study.
Abstract: Migraine headache is a common primary headache disorder which is multifactorial in origin. On the other hand, iron deficiency anemia causes metabolic abnormalities in the brain which leads to a reduction in neuronal activities. The study was designed to determine the association between iron deficiency anemia and migraine. This was a case-control study which was conducted among patients attending at the outpatient department of Neurology of Mymensingh Medical College Hospital with migraine headache fulfilling the International Headache Society criteria and non-Migraine age and sex matched healthy individuals from November 2019 to April 2021. Total 155 migraine patients (case) and 155 non-migraine healthy individuals (control) were included in this study. After signing the informed written consent, the blood samples were collected for complete blood count and serum ferritin level. The study result showed that iron deficiency anemia was more common in migraine patients than non-migraine healthy individuals (p<0.001). In female patients, serum hemoglobin and ferritin level were significantly low in migraine (p<0.001 and p<0.001 respectably) but in male patients only serum ferritin level was significantly low (p=0.001). There is also an association between severity of migraine attack and iron deficiency anemia (p=0.042). The patients with severe headache had lower serum hemoglobin and ferritin level which were statistically significant (p=0.005 and p<0.01 respectably). The study observed an association between iron-deficiency anemia, serum hemoglobin and ferritin levels with migraine. Therefore, iron deficiency anemia may be investigated in migraine patients and iron supplements might be an effective treatment in patients with migraine.

ID: 42377084
Title: Efficacy of digital therapeutic sinCephalea for personalised nutrition versus control for migraine prevention: A 12-week open-label randomised clinical trial.
Abstract: BackgroundLow-glycaemic diet may alleviate migraine; however, individual blood glucose variability can affect efficacy. In this open-label randomised controlled trial in Germany, we assessed whether the digital therapeutic (DTx) sinCephalea, which delivers personalised low-glycaemic nutritional recommendations supported by intermittent continuous glucose monitoring (CGM), reduces migraine frequency compared with a design-matched control application.MethodsThis open-label trial in Germany assessed the DTx sinCephalea for migraine prevention. Adults aged 18-65 years with episodic migraine were randomised 1:1 (in addition to standard treatment) to the digital therapeutic (intervention) or a design-matched control application. Patients completed a daily headache and medication diary, and 4-weekly patient-reported outcome questionnaires. Adherence to nutritional recommendations was monitored. Primary endpoint (Week 12): change from baseline in monthly migraine days (every 4 weeks) for intervention versus control. Secondary endpoints: change from baseline in monthly migraine days in patients with ≥50% adherence to nutritional recommendations, 30% response rates, migraine- and headache-related impairment, quality-of-life, and acute medication use for intervention versus control. Adverse events were recorded.Results842 patients were randomised between July 2021 and August 2023 (full analysis set: intervention = 416; control = 419). There were significantly greater reductions in monthly migraine days at week 12 for intervention versus control (mean [SD] change: 1.7 [3.4] versus 1.2 [3.2] days; between-group difference estimate: -0.53 [95% CI -0.98 to -0.09]; p = 0.0195) with similar monthly migraine days reductions observed in adherent patients (p = 0.0062; adjusted α = 0.05). Response rate was 54.9% (185/337) in intervention versus 42.9% (168/392) in control (odds ratio: 1.63 [95% CI 1.21-2.19]; p = 0.0012; adjusted α = 0.0125). Migraine- and headache-related impairment were lower at week 12 for intervention versus control (p = 0.0247, adjusted α = 0.0167and p = 0.0001, adjusted α = 0.01, respectively). There was no significant difference in quality-of-life or acute medication use and no digital therapeutic-related adverse events.ConclusionPersonalised nutrition, supported by intermittent CGM, via the DTx sinCephalea, was efficacious for migraine prevention without DTx-related adverse events. This study provides evidence in support of the link between diet and migraine frequency and symptoms. Additionally, as this is a non-pharmacological treatment with no DTx-related side effects, it may be an attractive option for patients. DTx could also reduce the burden of migraine on healthcare systems by providing a scalable, remote, non-invasive and convenient treatment option.

ID: 42386646
Title: [Pharmacological characteristics and clinical outcomes of Rimegepant (Nurtec® ODT), an oral CGRP receptor antagonist for the acute treatment and prevention of migraine].
Abstract: Migraine is a highly prevalent neurological disorder and is associated with substantial mental, social, and disease burden. Current migraine management comprises acute and preventive treatments; however, conventional acute and preventive medications have been associated with challenges such as contraindications, a delayed onset of efficacy, and adverse drug reactions. Rimegepant is an orally available small molecule calcitonin gene-related peptide (CGRP) receptor antagonist uniquely approved for both acute and preventive treatments. Nonclinical studies have demonstrated its high affinity for the CGRP receptor without inducing vasoconstriction in coronary or intracranial arteries. Consistent with these findings, clinical studies have shown no signals suggestive of cardiovascular risk, indicating a low concern for vasoconstrictive effects as triptans. In Phase 1 studies in healthy Japanese adults, rimegepant showed rapid absorption, supporting a rapid onset of action in acute treatment, and relatively longer half-life (10 h), supporting sustained efficacy. From a preventive perspective, while existing CGRP monoclonal antibodies are administered as injectable formulations, rimegepant can be administered orally as an orally disintegrating (OD) tablet. Drug-drug interaction studies demonstrated co-administration of rimegepant with triptans is possible due to a lack of clinically meaningful blood pressure elevation or pharmacokinetic interactions. Multiple clinical trials have confirmed the efficacy and safety of rimegepant for acute treatment, and every other day (EOD) dosing significantly reduced monthly migraine days. In addition to its favorable safety profile, the flexible use of the same formulation for both acute and preventive treatments represents a clinically meaningful, new option in migraine treatment.

ID: 42392550
Title: Migraine relief: Solutions from natural bioactive products of Traditional Chinese medicine.
Abstract: Migraine is a chronic and refractory primary neurological disorder that is characterized by recurrent and pulsating headache accompanied by reversible neurological or systemic symptoms, such as visual aura, phonophobia, and gastrointestinal symptoms. Natural bioactive products derived from traditional Chinese medicine (TCM) are regarded as promising candidates for migraine owing to multi-target and pathway synergistic effects. This paper aims to systematically evaluate the therapeutic effects of natural bioactive products from TCM on migraine, elucidate the roles of neurons, microglia, and astrocytes in the pathogenesis of migraine, and propose novel therapies for migraine from TCM. The publications were summarized from 2015 to 2025 in the Google Scholar, PubMed, and Web of Science databases. The keywords used for the search were "migraine", "neurons", "microglia", "astrocytes", "natural products", and "TCM". The bibliometrics was used to analyze the research hotspots of literature on TCM and migraine over the past decade. The Global Burden of Disease Study (2023) and network pharmacology analysis were conducted on migraine. The abnormal communication between neurons and glial cells contributes to the pathological process of migraine, manifested as cortical spreading depression, neuroinflammation, and central sensitization. Correcting the vicious cycle of headache attacks to restore the disorder between neurons and glia cells is a promising strategy for migraine. TCM bioactive products, such as alkaloids, flavonoids, phenols, glycosides, etc., have been proven to relieve migraine by modulating the excitability of neurons, microglia activation, the increase in reactive astrocytes, and the abnormal cross-talk between neurons and glial cells. It is worth noting that the critical biological molecules targeted by natural bioactive products mainly include Nrf2, NF-κB, and HIF-1α signaling pathways, thereby suppressing inflammatory responses, reducing oxidative stress, ameliorating neurotransmitter disturbances, and restoring mitochondrial function in migraine. The roles of neurons and glial cells in migraine, as well as the therapeutic effects of TCM bioactive products on migraine, provide a scientific foundation for a better understanding of the pathological mechanism of migraine and are expected to promote the development of novel therapies for migraine from TCM.

ID: 42394926
Title: Efficacy, tolerability and barriers to the use of anti-CGRP medications among migraine patients in Egypt: real world experience.
Abstract: With the introduction of anti-CGRP therapies in Egypt in 2019, there is a growing need to evaluate their real-world use, including effectiveness, tolerability, barriers to access, and treatment adherence among migraine patients. This study aimed to describe the clinical outcomes, tolerability, and barriers to the use of anti-CGRP therapies in an Egyptian cohort. In this descriptive observational study, migraine patients who were prescribed anti-CGRP therapy were assessed using headache diaries, MIDAS, and HIT-6 at baseline, with follow-up at one and three months after treatment initiation. Patients were also evaluated for background headache and medication overuse headache pre- and post-treatment, the reasons for treatment discontinuation, and relapse rate after drug discontinuation (defined as loss of ≥50% of initial improvement). A total of 80 patients (62 chronic and 18 episodic migraine) received Erenumab, Galcanezumab, or Rimegepant. Overall, 54 patients (68%) showed a favorable ≥50% response, with clinically significant reduction in monthly migraine days, headache severity, duration, HIT-6 and MIDAS scores (p < 0.001), as well as prevalence of background headache and medication overuse. Tolerability was generally favorable and treatment discontinuation occurred in 35 patients, primarily due to either satisfactory improvement, lack of improvement or cost, and was associated with relapse in 42.1% of cases. This study provides real-world insights into the use of anti-CGRP therapies among migraine patients in Egypt, demonstrating consistent clinical improvement and good tolerability. It also highlights important challenges related to treatment access and adherence. Findings should be interpreted in the context of observational design of the study, and further controlled studies are warranted.

ID: 42396835
Title: Eggshell-like Intraosseous Cyst of the Ethmoid Perpendicular Plate: Imaging Clues and Endoscopic Management.
Abstract: Intraosseous cysts of the ethmoid perpendicular plate are rare and anatomically distinctive lesions. Because such lesions may clinically resemble septal deviation, inflammatory sinonasal disease, or other osseous septal masses, preoperative imaging recognition is essential. We describe a 36-year-old man with recurrent postnasal drip, headache, and snoring, in whom nasal endoscopy revealed a smooth superior septal bulge compressing the adjacent middle turbinate. Computed tomography showed a sharply marginated expansile cyst centered within the ethmoid perpendicular plate and surrounded by a thin eggshell-like osseous shell. Magnetic resonance imaging demonstrated a non-enhancing cystic lesion with low T1 and high T2 signal intensity, supporting a benign intraosseous process. Complete endoscopic excision of the cyst wall and its delicate bony shell was performed, together with correction of septal deviation and treatment of concomitant sinonasal inflammation. Histopathology confirmed a benign respiratory epithelium-lined intraosseous cyst with chronic inflammation. Postoperatively, the patient's symptoms improved, and endoscopic follow-up at 6 months showed good mucosal healing and no visible residual or recurrent lesion. This case emphasizes that an eggshell-like, non-enhancing cystic lesion centered in the ethmoid perpendicular plate represents a distinctive CT-MRI pattern that can guide accurate diagnosis, distinguish this entity from more common septal or sinonasal lesions, and facilitate complete endoscopic treatment.

ID: 42398658
Title: Xiongzhi Qufeng Zhitong Granule alleviates nitroglycerin-induced migraine-like nociception and central neuroinflammation by regulating the HMGB1 / TRPV1 / MAPK signaling axis.
Abstract: Chronic migraine (CM) represents a highly prevalent neuroinflammatory disorder with limited therapeutic options. Xiongzhi Qufeng Zhitong Granules (XZQF), a clinically used traditional Chinese medicine, displays promising anti-migraine potential with favorable safety profiles; however, its systematic efficacy and underlying mechanisms remain poorly defined. This study aimed to investigate the protective effects of XZQF on a CM model in rats triggered by nitroglycerin (NTG) injection, and to unveil the potential mechanisms focusing on HMGB1/TRPV1/MAPK signaling pathway. A CM rat model was first established, and the effects of XZQF on CM were evaluated integrating behavioral testing, enzyme-linked immunosorbent assay (ELISA), and histopathological staining analysis. Subsequently, anti-CM mechanism verification, including network pharmacological analysis, immunofluorescence, immunohistochemistry, and Western blotting, were employed to reveal the molecular mechanism of XZQF in regulating HMGB1/TRPV1/MAPK signaling axis to against CM. Both behavioral assays, ELISA test, and histopathological assessment demonstrated that XZQF significantly restored body weight and pain thresholds, reduced serum and brain levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), pain modulators (PGE2, 5-HT, β-EP), and vasoactive mediators (CGRP, VIP, NO, iNOS), while alleviating migraine-associated brain tissue damage. Network pharmacology identified core targets (STAT3, NFKB1, JUN, PTGS2, IL1B) and key bioactive components (ferulic acid, senkyunolides E/F, neocnidilide, methyleugenol), with enrichment in MAPK, PI3K-Akt, and cAMP signaling cascades. Immunofluorescence, immunohistochemistry, and Western blotting further validated that XZQF markedly suppressed the expression of CGRP, TRPV1, c-Fos, COX-2, and HMGB1, as well as the phosphorylation of MEK and MAPK. Collectively, these findings demonstrate that XZQF exerts robust analgesic, anti-inflammatory, and vasoregulatory effects against CM by blunting central neuroinflammation through the HMGB1/TRPV1/MAPK signaling axis. Our work establishes a mechanistic framework for understanding the anti-CM activity of XZQF and supports its further development as a therapeutic intervention for CM.

ID: 42402434
Title: The Amapola Test: description of a novel screening tool for visual alterations in primary care.
Abstract: To describe a novel screening tool for the detection of visual alterations in primary care. A prospective study was conducted in order to assess concordance and feasibility of the Amapola Test. In patients with a visual complaint, a primary care resident physician identified the visual symptom using the Amapola Test and the results were then compared with an expert history-taking conducted by an ophthalmologist. The Amapola Test was administered to 350 patients with visual disturbances. Of these, 321 patients identified the symptom on the visual charts. The test showed a high concordance rate, with a usability of 89.4% (95% CI: 86.2%-92.6%). The most frequently identified visual symptoms were blurred vision (109), isolated floaters (75), floaters combined with photopsia (23), and isolated photopsia (20). The most common diagnoses were posterior vitreous detachment (100), migraine visual aura (28), and exudative age-related macular degeneration (19). The Amapola Test allows for correct identification of visual symptoms. This study demonstrates a high level of concordance between patient-reported symptoms using the test and expert clinical history, and indicates potential application as a supportive tool in primary care. However, further studies in real-life settings are needed to demonstrate its usefulness and to evaluate its diagnostic performance. not applicable.

ID: 42403127
Title: Dry Eye Disease among Young Pakistanis: Association with Digital Screen Use.
Abstract: To evaluate the influence of digital screen use on dry eye disease (DED) and ocular health in the young Pakistani population. A cross-sectional study. Place and Duration of the Study: Department of Ophthalmology, Federal General Hospital and Shifa Foundation Community Health Centre, Islamabad, Pakistan, from July 2022 to June 2023. A total of 232 participants aged 13-25 years presenting for refraction were enrolled. Data on digital eye symptoms, type of digital devices used, and duration and pattern of screen exposure were collected. All participants underwent a detailed ocular examination, including tear film breakup time (TBUT) and Schirmer test. The association between digital screen use and DED was evaluated using the Mann-Whitney U test. The median age of the study population was 20 (6.75) years, with 49.1% male population. Digital device-related ocular complaints were reported by 74.2% of participants. Headache was the most common symptom (21.6%), followed by eye fatigue (20.3%). A significant positive correlation was observed between the Schirmer test and TBUT values (Spearman's ρ = 0.337, p <0.001).  Based on TBUT, DED showed significant associations with the type of digital device used, continuous usage pattern, and refractive errors.  According to the Schirmer test, a significant association was observed only between DED and refractive errors. Digital screen-related DED is highly prevalent among Pakistani youth, with two-thirds experiencing symptoms. Raising awareness, reducing screen time, and promoting eye examination can help prevent digital eye strain and reduce the burden of related eye diseases. Dry eye syndrome, Dry eye disease, Dry eyes, Keratoconjunctivitis sicca, Eyestrain, Visual fatigue, Screen time.

ID: 42403198
Title: Potential role of tirzepatide, a dual GLP-1 and GIP receptor agonist, for preventive treatment of migraine: A case series.
Abstract: Obesity is a known comorbidity of migraine that can increase attack frequency and severity and lead to disease chronification. Glucagon-like peptide-1 (GLP-1) receptor agonists and related medications have demonstrated benefits beyond glycemic control and weight management, with emerging evidence suggesting a potential role in pain modulation. Clinical observations have also suggested the role of GLP-1 based therapies for the treatment of idiopathic intracranial hypertension, but their role in migraine has not been established. Here, we report two cases of patients with migraine who experienced a reduction in migraine headache frequency following initiation of tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist. These cases suggest that GLP-1 receptor agonists and dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonists may have potential therapeutic relevance in migraine management. Notably, both patients experienced weight loss with treatment, which represents a significant confounding factor that limits conclusions about a direct migraine-specific effect. These cases should be interpreted as preliminary observations. Future studies evaluating migraine outcomes in patients treated with these medications are needed to better understand the underlying mechanism and explore their potential role as novel therapeutic pathways for migraine. With the expanding use of glucagon‐like peptide‐1 receptor agonists, there is growing interest in whether this class of medications may be effective in migraine management. In this case series, we discuss two patients with migraine who experienced a reduction in migraine frequency with initiation of tirzepatide. These observations suggest a potential signal that warrants further research to better understand whether this class of medications could be a future therapeutic option for migraine management.

ID: 42403307
Title: Thiamine deficiency in patients with chronic migraine: A case-control study.
Abstract: Thiamine deficiency is well recognized in several neurological disorders, and subclinical deficiency has been associated with nonspecific symptoms, including headache. However, thiamine deficiency is not currently recognized as a cause of headache in standard headache classifications. Chronic migraine (CM) is often accompanied by symptoms such as nausea, vomiting, and reduced appetite, which may influence nutritional intake and micronutrient status, including thiamine depletion. These factors raise the possibility of an interaction between migraine and thiamine status. Our objectives were to compare serum thiamine levels in patients with CM and matched healthy controls and to explore whether low thiamine levels are associated with CM and related clinical features. In this observational case-control study conducted at a tertiary care neurology center in Vadodara, India, between May 2024 and October 2025, 100 adults with CM diagnosed according to the International Classification of Headache Disorders, 3rd edition, and 100 healthy controls were enrolled. Controls were frequency matched for age and sex. Fasting serum thiamine levels were measured using enzyme-linked immunosorbent assay. Associations between thiamine levels and CM, including dose-response relationships, were evaluated using regression models adjusted for potential confounders. Mean serum thiamine levels were significantly lower in patients with CM than in controls (52.4 ± 22.5 vs. 83.8 ± 18.6 nmol/L, p < 0.001). Thiamine levels <30 nmol/L were independently associated with CM (adjusted odds ratio=4.9, 95% CI = 2.1-11.7, p < 0.001). In a continuous sensitivity analysis, each 10 nmol/L decrease in serum thiamine was associated with higher odds of CM (adjusted odds ratio = 5.3, 95% CI = 3.4-8.3, p < 0.001). Patients with low thiamine levels had longer disease duration (13.6 ± 6.2 vs. 10.4 ± 5.3, p < 0.010), more headache days per month (20.7 ± 5.0 vs. 18.0 ± 3.6, p < 0.020), and a higher frequency of symptoms such as fatigue (81% vs. 41%, p < 0.001), dizziness (69% vs. 40%, p < 0.001), disturbed sleep (84% vs. 41%, p < 0.001), and abdominal pain (75% vs. 41%, p 0.002). Low serum thiamine levels are significantly associated with CM and greater disease burden. These findings support a potential relationship between thiamine status and migraine-related factors, although causality cannot be established. Further research is required to clarify whether thiamine deficiency represents a consequence of CM or contributes to migraine-related biological mechanisms. The role of nutritional factors in migraine remains unclear, including whether thiamine (vitamin B1) plays a role. In this study, we compared blood levels of thiamine in 100 adults with chronic migraine to 100 adults of similar age and sex without migraine. We found that patients with chronic migraine had lower thiamine levels, and that lower thiamine was associated with a higher headache burden, suggesting a possible link between nutritional status and migraine.

ID: 42405602
Title: Rimegepant for migraine prevention in clinical practice: A multicenter study including patients with prior anti-CGRP monoclonal antibody failure (GEMA project).
Abstract: BackgroundRimegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist approved for both acute and preventive treatment of episodic migraine. Real-world data on its preventive use remain limited, particularly in patients with multiple prior preventive failures. This study evaluated the effectiveness and tolerability of rimegepant in routine clinical practice, focusing on a highly treatment-resistant population.MethodsWe conducted a prospective, multicenter real-world cohort study within the GEMA (GEpants in MigrAine) Project across nine tertiary Headache Units in Spain. Adults initiating rimegepant for migraine prevention were consecutively enrolled and followed for up to 6 months. The primary endpoint was the 3-month change in monthly headache days (MHD). Secondary endpoints included the change in monthly migraine days (MMD), response rates, predictors of response, and tolerability. Baseline characteristics, prior preventive failures, medication overuse, adverse events, and patient-reported outcomes (Headache Impact Test-6 (HIT-6), HADS, and Insomnia Severity Index) were recorded.ResultsIn total, 150 patients completed 3-month follow-up and 64 reached 6 months. The cohort was predominantly female (85.3%), with 70.7% episodic migraine, a median age of 48 years (interquartile range (IQR) = 39-57), and a median of 6 prior preventive failures (IQR = 4-8), reflecting high treatment resistance. At 3 months, median MHD decreased from 12 to 7.5 and MMD from 10 to 6 (p < 0.05), with significant improvement in HIT-6. Overall, 36% and 43% achieved ≥ 50% reduction in MHD and MMD, respectively (≥ 75%: 15% and 20%). Among patients with 6-month data, further reductions were observed (MHD, 6 days; MMD, 5 days), with ≥ 50% response rates increasing to 48% and 58%. Clinical responders showed greater improvements in anxiety and depressive symptoms. Medication overuse, chronic migraine, and prior exposure to anti-CGRP monoclonal antibodies and onabotulinumtoxinA were independent predictors of poorer outcomes, with response declining with increasing prior anti-CGRP exposure, although a relevant proportion still achieved meaningful benefit. Rimegepant was well tolerated, with predominantly mild adverse events (nausea 13%, constipation 8%) and low discontinuation (7% at 3 months), and with nausea being the most frequent cause.ConclusionsRimegepant showed meaningful preventive effectiveness and good tolerability in routine clinical practice, including in highly treatment-resistant patients with prior anti-CGRP monoclonal antibody exposure. The response was influenced by baseline disease burden and prior treatment exposure. These findings suggest that earlier use of rimegepant in the treatment course may be associated with greater clinical benefit.

ID: 42410539
Title: Efficacy of prefrontal-occipital transcranial direct current stimulation for refractory chronic migraine.
Abstract: Patients with chronic migraine (CM) frequently demonstrate resistance to conventional medical therapies, likely attributable to the multifactorial pathophysiology underlying their pain. Transcranial direct current stimulation (tDCS) has recently emerged as a promising non-invasive neuromodulation technique for migraine prophylaxis. In this study, we evaluate the efficacy of a tDCS protocol in treating CM patients, both with and without medication-overuse headache (MOH). Thirty patients diagnosed with chronic migraine (CM) underwent treatment with tDCS (2 mA, 20 min/session) targeting the anodal right dorsolateral prefrontal cortex (DLPFC) and cathodal occipital region for three days each week over two weeks, followed by once-weekly sessions for an additional six weeks. The tDCS demonstrated significant efficacy in pain reduction for CM patients, regardless of MOH comorbidity. After eight weeks, tDCS had significantly reduced severe migraine days (VAS score > 7), awakening migraine episodes, and mean headache intensity and duration. The maximum effects were observed for headache duration and the number of severe headache days. A reduction of more than 50% in the mean headache duration was achieved in 80% of participants. Similarly, 70% of patients demonstrated >50% decrease in severe headache days (VAS >7). Treatment was well-tolerated, with no serious adverse effects reported during the study period. TDCS appears to be an effective, well-tolerated, non-invasive treatment for CM patients, including cases with MOH. The significant reductions in headache duration, intensity, and frequency suggest that tDCS may be a valuable option for those resistant to standard medical therapies. Iranian Registry of Clinical Trials IRCT20140624018213N2. Registered 17 June 2026. Retrospectively registered.

ID: 42410711
Title: The Association of Headache and Physical Activity in Times of the COVID-19 Pandemic: A Prospective Cohort Study.
Abstract: Prospective studies of the risk of headache with low levels of physical activity are limited. Pandemic-related lifestyle changes and the potential headache risk associated with Coronavirus Disease (COVID-19) and SARS-CoV-2 vaccination may complicate this association. Our study aims to investigate the potential risk of new bothersome headache in relation to physical activity and explore the impact of COVID-19 and SARS-CoV-2 vaccines on this association. This prospective cohort study utilized questionnaires from the Norwegian Mother, Father, and Child Cohort Study (MoBa). Logistic regression analyses were conducted to estimate the adjusted odds ratio (aOR) for new-onset headache according to physical activity levels. Models were adjusted for gender, age, body mass index, education level, smoking, alcohol intake, anxiety/depression, and COVID-19 and SARS-CoV-2 vaccination prior to February 2022. The potential impact of COVID-19 disease was investigated in a stratified analysis. Both low level of physical activity and inactivity were significantly associated with new bothersome headache when compared to moderate to high activity levels (low activity: aOR 1.22, 95% CI 1.13 to 1.30; inactive: aOR 1.26, 95% CI 1.05 to 1.51). The corresponding adjusted absolute risk differences were 1.9% (95% CI 1.2 to 2.6) and 2.3% (95% CI 0.4 to 4.3), respectively. Findings persisted across COVID-19 status strata, without significant interactions. Our findings underscore the potential role of physical activity in mitigating new bothersome headache also for headache associated with COVID-19. Encouraging regular physical activity may serve as a preventive measure for headache in a pandemic setting.

ID: 42417072
Title: Differential thalamic GSH/Glu ratios Among primary headache subtypes and clinical implications: A cross-sectional magnetic resonance spectroscopy study.
Abstract: BackgroundGlutathione (GSH) and glutamate (Glu) have been individually implicated in migraine pathophysiology, but their ratio as a marker of oxidative-excitatory balance in the thalamus-a key pain-processing hub-remains unexplored. This study investigated thalamic GSH/Glu ratios across primary headache subtypes and evaluated their diagnostic utility.MethodsThis cross-sectional study included 131 participants: 36 healthy controls (HC), 17 migraine with aura (MwA), 46 migraine without aura (MwoA), and 32 tension-type headache (TTH). Single-voxel proton magnetic resonance spectroscopy was performed at 3T using a MEGA-PRESS sequence targeting bilateral thalami. Metabolite concentrations were quantified with LCModel and corrected for partial volume effects using an established tissue correction framework. Group differences were analyzed using ANOVA with Tukey HSD correction; diagnostic performance was assessed using ROC analysis with bootstrap resampling.ResultsThe GSH/Glu ratio differed significantly across groups (F = 9.41, p < 0.001, η2 = 0.183), confirmed by bootstrap validation. MwA (0.250 ± 0.038, p < 0.001, Cohen's d = 1.47) and MwoA (0.280 ± 0.052, p = 0.006, d = 0.79) showed significantly lower ratios than HC (0.320 ± 0.055), whereas TTH (0.318 ± 0.068) did not differ from HC. This reduction was driven by decreased GSH levels, with Glu concentrations unchanged across groups. Exploratory ROC analysis yielded apparent AUCs of 0.874 for GSH and 0.758 for the GSH/Glu ratio; these estimates require independent validation.ConclusionsMigraine is characterized by reduced thalamic GSH levels and decreased GSH/Glu ratios, reflecting diminished antioxidant buffering capacity against normal excitatory neurotransmission. This metabolic alteration distinguishes migraine from TTH, supporting distinct pathophysiological mechanisms.

ID: 42417898
Title: Safety and Efficacy of Perioperative Magnesium Sulfate Injection for Postoperative Pain Management and Opioid Sparing Effects in Surgeries of the Nervous System: A Systematic Review and Meta Analysis.
Abstract: Postoperative pain following spinal and neurological surgeries is often severe and can hinder recovery, mobilization, and increase risk of chronic pain. While opioids are the traditional standard for pain management, associated risks and the ongoing opioid crisis necessitate alternative therapies. Magnesium sulfate, an NMDA receptor antagonist and calcium channel blocker, has shown promise in reducing postoperative pain and opioid consumption. The present investigation utilized a systematic search for studies from PubMed, Embase, and Web of Science. Sources were eligible for inclusion in this review if published from 2010 to present, if patients received a spinal or neurological surgery regardless of patient age, country, race, and gender, and if the source was a randomized control trial, case report, or case series. Sources in non-English, without full-text access, and systematic reviews/meta-analyses were excluded, as well as studies focused on non-human subjects or studies with adjuvant therapies. Nine randomized controlled trials met our criteria. Pain scores (VAS/NRS) and opioid consumption were the primary outcomes. Meta-analysis was conducted using Cochrane Review Manager with fixed or random-effects models depending on heterogeneity. Magnesium sulfate significantly reduced pain scores at rest at multiple postoperative time points, including 0 h (MD=- 0.79; p = 0.004), 4 h (MD= -1.03, p < 0.00001), 24 h (MD= -0.78: p = 0.005), and 48 h (MD= -0.67: p = 0.0006). Opioid consumption was also significantly reduced at various intervals. No major adverse events were reported. Perioperative magnesium sulfate infusion is a safe and effective adjunct for reducing postoperative pain and opioid use in spinal surgery patients, with potential applications in neurological procedures pending further research.

ID: 42418101
Title: IL-17A, IL-17RA, and IL-22 as biomarkers in migraine: associations with disease activity and clinical features.
Abstract: Migraine is increasingly recognized as a neuroinflammatory disorder involving immune-mediated mechanisms. Th17-related cytokines, including interleukin-17 A (IL-17 A) and interleukin-22 (IL-22), together with the IL-17 receptor A (IL-17RA), may contribute to these processes; however, their clinical relevance remains incompletely understood. This study aimed to assess their levels in patients with migraine and to investigate their associations with clinical characteristics. Ninety-nine patients with migraine and 50 healthy controls were included. Serum IL-17 A, IL-17RA, and IL-22 levels were measured using the enzyme-linked immunosorbent assay (ELISA), and their relationships with clinical features were analyzed. Serum levels of IL-17 A, IL-17RA, and IL-22 were significantly higher in patients with migraine compared to healthy controls (p < 0.05 for all). IL-22 levels were positively correlated with attack frequency and inversely correlated with disease duration. A negative correlation was observed between IL-17 A levels and attack severity, whereas IL-17RA levels were positively correlated with attack severity. In multivariate analysis, IL-22 and IL-17RA emerged as independent factors associated with migraine. IL-17RA demonstrated the modest discriminatory performance in ROC analysis (AUC = 0.696, p < 0.001). Th17-related cytokines appear to play a role in migraine pathophysiology. IL-17RA, as a receptor involved in IL-17 A signaling, may serve as a potential independent biomarker, while IL-22 may reflect disease activity and early inflammatory responses. Not applicable.

ID: 42418214
Title: Safety and tolerability of transnasal evaporative cooling for the acute treatment of migraine in an at-home setting: A randomized, double-blind, sham-controlled, decentralized clinical trial.
Abstract: Transnasal evaporative cooling (TNEC) is thought to modulate activity in the sphenopalatine ganglion and maxillary division of the trigeminal nerve. The safety, tolerability, and potential for therapeutic benefits of TNEC in adults with migraine have not been assessed in a fully decentralized setting. Our objectives were to determine the safety and tolerability of a TNEC device in adults with migraine and generate hypotheses for testing in studies designed to assess efficacy. This prospective, double-blind, sham-controlled, randomized, decentralized clinical trial was conducted in the United States between November 2023 and June 2024. Eligible adults 18-65 years of age who self-reported migraine for ≥1 year were randomized to one of three active treatment groups (4, 6, or 10 L/min of dehumidified air) or to a sham control (2 L/min of ambient air delivered intermittently for ~10% of total time). Tolerability was measured by the percentage of participants who discontinued their treatment session due to discomfort. The assessment of TNEC treatment effects was hypothesis-generating; reported p-values are nominal. The trial was registered at clinicaltrials.gov (NCT06051604). Participants (N = 137) had a mean (SD) age of 39.4 (10.1) years, 79.6% (109/137) were female, and 85.4% (117/137) were White. The most common adverse events were rhinorrhea (2.2% [3/137]) and nasal irritation, ear pressure, runny nose, and sore throat (each 1.5% [2/137]). No participants (0% [0/128]) discontinued treatment early due to discomfort. At 2 h posttreatment, 57.6% ([19/33] 95% confidence interval [CI] = 39.2-74.5) of participants in the sham group had pain relief compared with 48.4% ([15/31] 95% CI = 30.2-66.9) of participants who received 4 L/min TNEC (p = 0.462), 61.8% ([21/34] 95% CI = 43.6-77.8) of those who received 6 L/min (p = 0.727), and 70.0% ([21/30] 95% CI = 50.6-85.3) who received 10 L/min (p = 0.306). The percentage of participants with pain freedom at 2 h posttreatment was higher in the TNEC 10 L/min group than in the sham group (33.3% [10/30] vs. 12.1% [4/33], p = 0.043). Treatment with TNEC was safe and feasible in a decentralized setting, and it was tolerable at high flow rates. Observed treatment effects in the acute treatment of migraine need to be confirmed in larger, adequately powered clinical trials. Many people with migraine do not respond to or cannot take the medications available for acute treatment. We studied a new device that treats migraine by delivering a gentle stream of dry, room‐temperature air into the nose (transnasal evaporative cooling). We found that the device appears to be safe, but more research is needed to determine if it is effective at relieving migraine pain and associated symptoms.