Migraine is a major cause of disability and efficacious interventions are needed. In this mechanistic study, we investigate the combined, and potentially synergistic, effects of a multimodal intervention combining Mindfulness-Based Stress Reduction (MBSR) and transcutaneous auricular Vagal Nerve Stimulation (taVNS) for migraine.

We utilize a modified double-blinded, placebo-controlled, 2 × 2 factorial randomized longitudinal design to assess the effects of an 8-week MBSR intervention with concomitant Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) taVNS on migraine pathophysiology primary outcomes. We will enroll 150 patients with migraine (4-20 headache days/month). After a run-in month of daily diaries, we expect to randomly assign N = 96 participants to one of four treatment groups: (1) MBSR+RAVANS taVNS, (2) MBSR+Sham taVNS, (3) Nature Education Control (NEC) + RAVANS taVNS, or (4) NEC + Sham taVNS. Before and after intervention, participants have three in-person assessments (a 7 T MRI scan, an autonomic/sensory testing (AST) visit, and a 3 T PET-MRI scan). The primary outcomes for this study assess (1) central sensitization (brainstem/cortical response to trigeminal sensory afference), (2) autonomic dysfunction (High Frequency-Heart Rate Variability (HF-HRV) response to stressors), and (3) neuroinflammation (PET[11C]PBR28 signal).

Funded by NIH (P01AT009965), registered (NCT03592329). Final longitudinal outcomes will be collected by May 2025.

This mechanistic study is designed to investigate both independent and synergistic neurobiological effects of MBSR and RAVANS taVNS interventions on three distinct pathophysiological mechanisms of migraine. This research will elucidate the mechanistic and potentially synergistic effects of behavioral interventions (e.g., mindfulness) and device-based treatments (e.g., taVNS) for migraine.

Increasing endocannabinoids (endoCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), through inhibition of the degrading hydrolase enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively, has been proposed as approach to alleviate migraine pain. Notwithstanding, the impact of AEA and 2-AG on neuronal firing of meningeal afferents, which is relevant to the genesis of migraine pain, remains elusive.

The impact of AEA and 2-AG on meningeal nerve afferent firing was examined through electrophysiological evaluation upon application of 50 mM KCl with or without DMSO, exogenous AEA (10 µM), or 2-AG (10 µM) to separate groups of C57BL/6J mouse hemiskull preparations. At the end of each experiment, capsaicin (1 µM), an agonist of TRPV1 channels, was tested, as a positive control of presumably nociceptive firing. Advanced clustering and spectral analysis on the electrophysiological data allowed differentiating spiking patterns with respect to their temporal and neurochemical profiles. Activity-based protein profiling and liquid chromatography with tandem mass spectrometry was used to assess endogenous FAAH and MAGL activity and determine endogenous levels of AEA and 2-AG in mouse meninges.

Local application of endoCBs decreased KCl-induced firing of meningeal nerve afferents, which was most profound for AEA. AEA first produced a short, mild activation in firing, which was followed by a long-lasting reduction. Instead, 2-AG directly led to a short-lasting reduction in firing. Cluster analysis revealed that the transient activation by AEA involved fibers with small-amplitude spikes fired at rates of 1-2 Hz, whereas the persistently suppressed fibers consisted of high-amplitude spikes fired at rates exceeding 10 Hz. Only AEA inhibited subsequent capsaicininduced firing in the afferents long after AEA application, suggesting a broader mode of action for AEA than 2-AG. The more profound inhibitory effects of AEA are consistent with the observed higher activity of FAAH over MAGL and lower level of endogenous AEA than 2-AG in mouse meninges.

Our study revealed a stronger anti-nociceptive action of AEA than of 2-AG, as measured by meningeal afferent firing in mouse hemiskulls. This difference can be exploited for relieving migraine pain by primarily increasing the tone of AEA through inhibition of FAAH outside the central nervous system.

In many countries, patients with headache disorders such as migraine remain under-recognized and under-diagnosed. Patients affected by these disorders are often unaware of the seriousness of their conditions, as headaches are neither fatal nor contagious. In many cases, patients with migraine are often misdiagnosed as regular headaches.

In this article, we present a study on migraine, covering known triggers, different phases, classification of migraine into different types based on clinical studies, and the use of various machine learning algorithms such as logistic regression (LR), support vector machine (SVM), random forest (RF), and artificial neural network (ANN) to learn and classify different migraine types. This study will only consider using these methods for diagnostic purposes. Models based on these algorithms are then trained using the dataset, which includes a compilation of the types of migraine experienced by various patients. These models are then used to classify the types of migraines, and the results are analyzed.

The results of the machine learning models trained on the dataset are verified for their performance. The results are further evaluated by selective sampling and tuning, and improved performance is observed. The precision and accuracy obtained by the support vector machine and artificial neural network are 91% compared to logistic regression (90%) and random forest (87%). These models are run with the dataset without optimal tuning across the entire dataset for different migraine types; which is further improved with selective sampling and optimal tuning. These results indicate that the discussed models are relatively good and can be used with high precision and accuracy for diagnosing different types of migraine.

Our study presents a realistic assessment of promising models that are dependable in aiding physicians. The study shows the performance of various models based on the classification metrics computed for each model. It is evident from the results that the artificial neural network (ANN) performs better, irrespective of the sampling techniques used. With these machine learning models, types of migraines can be classified with high accuracy and reliability, enabling physicians to make timely clinical diagnoses of patients.

The exact mechanisms that trigger the activation of the trigeminovascular system in migraine remain unclear. The involvement of calcitonin gene-related peptide (CGRP) in migraine is well-documented, and treatments aimed at blocking CGRP activity have proven successful in reducing migraine attacks for some patients. However, around one third of individuals do not respond to these therapies, which are also limited by factors like cost, side effects, and contraindications. There is growing evidence suggesting that glutamate, an excitatory neurotransmitter, plays a crucial role in the onset and maintenance of migraine pain, partially by enhancing CGRP release. Increased glutamate levels have been linked to both peripheral and central sensitization, potentially contributing to the development and persistence of chronic migraine. The relationship between CGRP and glutamate is complex, with glutamate possibly acting as an upstream trigger for CGRP release. This review examines the interplay between CGRP and glutamate, and their involvement in both peripheral and central sensitization. It also explores the therapeutic potential of targeting either glutamate or CGRP, aiming to address both peripheral and central migraine mechanisms. Finally, the role of triggers in migraine initiation at the peripheral level is discussed, offering insights into potential preventive strategies.

The relationship between adipose-muscle distribution and its effect on migraine remains unclear. This study examines the association between muscle mass and migraine prevalence and evaluates potential mediation by systemic inflammatory biomarkers.

Using a cross-sectional design, we analyzed data from 10,400 participants in the National Health and Nutrition Examination Survey (NHANES) (1999-2004). The association between appendicular lean mass normalized to body mass index (ALM/BMI) and migraine prevalence was evaluated through weighted logistic regression and subgroup analyses. Mediation analyses were conducted to examine the potential mediating roles of inflammatory markers, including C-reactive protein (CRP), white blood cell count (WBC), and neutrophils, in the relationship between ALM/BMI and migraine prevalence. Genetic causality was investigated via two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) data.

20% of total participants reported migraines. A higher ALM/BMI ratio was inversely associated with migraine after full adjustment (OR = 0.243; 95% CI: 0.122-0.487, p < 0.001). Vigorous activity reduced migraine susceptibility by 24% (OR = 0.760; 95% CI: 0.663-0.872, p < 0.001). CRP, WBC and neutrophils mediated 2.0% (p = 0.024), 3.1% (p = 0.011), and 2.8% (p = 0.019) of the ALM/BMI-migraine association, respectively. The inverse-variance weighted approach (IVW) in MR analysis indicated that higher basal metabolic rate (BMR) reduced migraine risk (OR = 0.996, 95% CI: 0.992-0.998, p = 0.004) and headache risk (OR = 0.998, 95% CI: 0.997-1.000, p = 0.018). Fat-free mass also exhibited protective effects on migraines (OR = 0.997, 95% CI: 0.994-1.000, p = 0.045).

Increased muscle mass is associated with reduced migraine risk, partially mediated by attenuating systemic inflammation. These findings provide us with an approach of health management to prevent migraines.

It is controversial to what extent afterimages, as distinct visual phenomena, are altered in patients with migraine and whether they have a specific role in migraine pathophysiology.

The aim of this cross-sectional study was to investigate the duration of afterimages in patients with migraine, migraine with aura (MwA), and migraine without aura (MwoA), compared to healthy controls (HCs).

Adults with migraine, MwA, and MwoA, diagnosed according to The International Classification of Headache Disorders, third edition criteria and HCs without relevant headache history were included. Initially, factors affecting the experimental setting of testing afterimage latency were determined. Then, afterimage duration was measured in the two study groups (MwA and MwoA) and the HC group. Patient characteristics, intraocular pressure, and relevant comorbid conditions, as well as scales on depressive symptoms (nine-item Patient Health Questionnaire) and headache-specific psychosocial impairment (six-item Headache Impact Test) were recorded. Lastly, the role of different stimulus colors, as well as habituation effects after repeated stimulation, were investigated.

The main study included 174 participants (40 with MwA, 53 with MwoA, and 81 HCs). The duration of the afterimage in patients with MwA was significantly longer than in HCs, at a mean (standard error of the mean [SEM]) of 12.6 (2.6) versus 5.5 ( 0.3) s (p = 0.035), while there was no significant difference between patients with MwoA (mean [SEM] 7.7 [1.6] s; p = 0.510) and HCs. There was also no significant effect of stimulus color on afterimage latency (mean [SEM] red: 8.9 [1.2] s and black: 8.4 [1.2] s).

We found significantly longer afterimage duration in patients with MwA compared to both HCs and patients with MwoA. Furthermore, partially selective stimulation of retinal rods and cones by different stimulus colors had no effect on afterimage duration suggesting a relevant subcortical and/or cortical modulation in migraine aura with increased excitability.

Although there are numerous complementary treatments for migraine, comparisons among themselves are relatively rare. This study aimed to investigate and compare the effectiveness of wet cupping therapy (WCT) and acupuncture applications in treating migraine patients.

This was a randomized controlled clinical trial conducted between 01.03.2022 and 01.10.2023 in the Traditional and Complementary Medicine Center of a tertiary hospital. Patients diagnosed with migraine were included in the study and randomized into three arms. The WCT group received cupping 3 times, once a month. The acupuncture group received 10 sessions of acupuncture once a week. The waiting list was assigned as the control group. VAS and MIDAS scales were applied to all groups at the beginning and the end of the treatment, and the results were compared.

All three groups were similar regarding age and sex. Migraine Disability Assessment Scale (MIDAS) and Visual Analogue Scale (VAS) pain scores decreased significantly in both treatment groups after the applications, while they remained similar for the same period in the control group. Additionally, the post-treatment values of MIDAS and VAS in both the WCT and acupuncture groups were significantly lower compared to controls, while they were similar when compared in between.

Both of these applications were found to be similarly effective in improving disability status and pain intensity in patients with migraine.

Migraine, a condition stemming from neurological and vascular irregularities with inflammation involvement, was investigated in a case-control study focusing on the Chinese Han population.

The research analyzed specific genetic variations-TNF-α -308 G/A, TNF-α -857 C/T, TNF-α -238G/A, IL1B-3953 C/T, and IL1RN -2018T/C SNPs-within 212 migraine patients and 210 healthy controls. Utilizing SNaPshot technology, scientists genotyped these markers related to TNF-α and IL-1 genes.

Findings revealed a significant association between the IL1B-3953 C/T SNP and migraine susceptibility, particularly noting its link with a familial history of the disorder. The presence of the C allele at this location was more prevalent in migraine sufferers. Multivariate analysis reinforced this connection, indicating the C allele under a dominant model as an independent risk factor for migraine (OR = 2.315, 95%CI: 1.053-5.090, P = 0.037). Additionally, the study observed a sex-specific difference regarding the TNF-α -857 C/T SNP among migraine patients.

Overall, this investigation contributes to understanding the genetic underpinnings of migraine in the Han Chinese population, highlighting the IL1B-3953 C/T SNP as a potential biomarker for migraine susceptibility.

Previous studies have linked migraine to weather conditions, but variations in the factors examined and inconsistent focus have complicated comparisons. This underscores the need for a more comprehensive and clearer analysis.

Studies published before December 2024 on the association between weather and migraine were searched from PubMed, Embase, Web of Science, and Cochrane. Meta-analyses based on effect sizes were performed using Review Manager version 5.4.1.

A total of 31 studies were included in the meta-analyses. It revealed a significant association between migraine attack and weather changes reported as a trigger factor (RD = 0.47, 95% CI = 0.40-0.54). Additionally, specific weather factors, such as temperature (OR = 1.15, 95% CI = 1.02-1.29) and ambient pressure (OR = 1.07, 95% CI = 1.01-1.15), were significantly associated with migraine attacks, while humidity (OR = 1.04, 95% CI = 0.97-1.11) did not show a significant association. Moreover, increased levels of air pollutants, including PM10 (OR = 1.07, 95% CI = 1.03-1.11), PM2.5 (OR = 1.04, 95% CI = 1.01-1.06), NO2 (OR = 1.08, 95% CI = 1.03-1.14), CO (OR = 1.08, 95% CI = 1.01-1.16), and O3 (OR = 1.12, 95% CI = 1.03-1.21), were significantly associated with an increased risk of migraine clinical visits, whereas SO2 (OR = 1.02, 95% CI = 1.00-1.04) was not.

This meta-analysis revealed that weather changes are significant trigger factors for migraine, with temperature and ambient pressure playing notable roles in this association. Additionally, increased levels of air pollutants are linked to a higher risk of migraine attacks. These findings could lead to new interventions for patients who are weather-sensitive and offer fresh perspectives for future research into the pathogenesis of migraine.

Sleep disturbances are common in patients with chronic migraine, yet the clinical predictors of sleep quality in this population remain unclear. This study aimed to explore the relationship between sleep quality and clinical, psychological, and lifestyle factors in chronic migraine.

This retrospective observational study included patients with chronic migraine at a tertiary medical center in Taiwan. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Clinical variables included monthly headache days, pain severity, and migraine-related disability. Multiple regression analyses were used to identify predictors of sleep quality.

Among the 56 participants (85.7% women, mean age 42.7 ± 13.3 years), 46 (82.1%) reported poor sleep quality (PSQI ≥ 6). In unadjusted analyses, higher pain severity (β = 0.94, p = 0.010), anxiety (β = 0.22, p < 0.001), and depressive symptoms (β = 0.19, p < 0.001) were significantly associated with poorer sleep quality. Adjusted analyses revealed that anxiety (β = 0.20, p = 0.001) and depressive symptoms (β = 0.17, p = 0.002) were significant predictors of poor sleep quality in their respective models, after adjusting for demographic and clinical variables. Participants with poor sleep quality had significantly higher anxiety (19.59 ± 13.28 vs. 9.50 ± 6.42, p = 0.001) and depression scores (20.59 ± 14.45 vs. 12.40 ± 7.69, p = 0.018) than those with good sleep quality.

Anxiety and depression are strongly associated with poor sleep quality in chronic migraine patients. Addressing psychological comorbidities is essential to improve sleep quality, highlighting the need for an integrated treatment approach.

This study aimed to identify cerebral radiomic features related to migraine diagnosis and subtyping into migraine with aura (MwA) and migraine without aura (MwoA) and to develop predictive models based on these markers.

We retrospectively analyzed MR imaging from 88 migraine patients (32 MwA and 56 MwoA) and 49 healthy control subjects (HCs). Features representing the gray matter morphometry and diffusion properties were extracted from participants via histogram analysis. These features were put through an all-relevant feature selection procedure within cross-validation loops to identify features with significant discriminative power for migraine diagnosis and subtyping. Based on the selected features, the predictive ability of the random forest models constructed from the previous sample was tested in an independent sample of 30 patients (10 MwA) and 17 HCs.

No overall differences in total brain volume or gray matter volume were revealed between patients and HCs, or between MwA and MwoA (all P values > 0.05). Six features significantly differed between patients and HCs for migraine diagnosis, and four features distinguished MwA from MwoA for subtyping (all P values < 0.001). Four features were significantly correlated with headache severity score (all P values < 0.01). Based on these relevant features, the random forest models achieved accuracies of 80.9% in distinguishing patients from HCs and 76.7% in differentiating MwA from MwoA in the testing cohort.

Our findings suggest cerebral radiomic alterations in migraine patients may potentially serve as a biomarker to assist in migraine diagnosis and subtyping, contributing to personalized treatment strategy.

Not applicable.

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

Clinical observations have shown that transcutaneous occipital nerve stimulation (tONS) is effective in treating migraine. However, the underlying mechanisms are poorly understood. This study employs a rodent model to investigate the therapeutic effects of tONS on migraine-related pain and to explore potential mechanisms.

The SD rats were used to establish the migraine model by repeated epidural infusions of inflammatory soup (IS). Modified bilateral electrodes were attached noninvasively for tONS treatments. Periorbital mechanical thresholds were assessed using von-Frey filaments, and other pain-related nociceptive behaviors were analyzed through video recordings. The expressions of c-Fos, synaptophysin (Syp) and calcitonin gene-related peptide (CGRP) in the trigeminal nucleus caudalis (TNC) and/or periaqueductal gray (PAG) area were measured by immunofluorescence and western blotting analyses. The excitatory synaptic transmission in the PAG was detected by whole-cell patch-clamp recording among migraine rats.

The reduction in periorbital mechanical thresholds induced by repeated IS infusions was partially reversed by tONS treatments in migraine rats. Other pain-related behaviors, including exploration, rest, and unilateral grooming, consistently improved following tONS treatment. The TNC and PAG area were activated after IS modeling, and the CGRP expressions in the PAG significantly decreased after tONS treatments. tONS could inhibit the enhanced excitatory synaptic transmission in the PAG of migraine rats.

Our findings suggest that tONS has therapeutic potential in treating migraine, with the PAG excitability and CGRP expression playing a role in its mechanisms of action. tONS may represent a promising non-invasive neuromodulation approach for the management of migraine in the future.

Background/Objectives: Pediatric migraine is a prevalent neurological disorder that significantly impacts children's quality of life, academic performance, and social interactions. Unlike migraines in adults, pediatric migraines often present differently and involve unique underlying mechanisms, making diagnosis and treatment more complex. Methods: This review discusses the clinical phases of pediatric migraine, key trigger factors, sex- and age-related differences, and the role of childhood maltreatment in migraine development. We also discuss episodic syndromes such as cyclic vomiting syndrome, abdominal migraine, benign paroxysmal vertigo, and benign paroxysmal torticollis, along with comorbidities such as psychiatric disorders, sleep disturbances, and epilepsy. Results: The underlying pathophysiological mechanisms for pediatric migraines, including genetic predispositions, neuroinflammation, and gut microbiota dysbiosis, are summarized. Current therapeutic strategies, including conventional and emerging pharmacological treatments, nutraceuticals, and non-pharmacological approaches, are evaluated. Non-pharmacological strategies, particularly evidence-based lifestyle interventions such as stress management, diet, hydration, sleep, exercise, screen time moderation, and cognitive behavioral therapy, are highlighted as key components of migraine prevention and management. The long-term prognosis and follow-up of pediatric migraine patients are reviewed, emphasizing the importance of early diagnosis, and tailored multidisciplinary care to prevent chronic progression. Conclusions: Future research should focus on novel therapeutic targets and integrating gut-brain axis modulation, with a need for longitudinal studies to better understand the long-term course of pediatric migraine.

Topological indices, derived from molecular graphs, provide valuable numerical descriptors for the comprehensive analysis of pharmaceuticals. These indices are pivotal in the physicochemical characterization and predictive assessment of various drugs. In this study, we calculate several degree-based topological indices for a range of migraine treatment medications, including aspirin, caffeine, eletriptan, ergotamine, sumatriptan, rizatriptan, verapamil, diclofenac, frovatriptan, and droperidol. The process involves several steps: data collection on the molecular structures of migraine drugs and their corresponding biological activities, followed by the calculation of descriptors that represent key features of molecules. Calculating the values of these descriptors, we use vertex degree, edge division, and the counting degree technique. We employ curvilinear regression models, including linear, quadratic, and cubic regressions, to analyze each topological indicator. This research emphasizes the application of curvilinear regression techniques and performs extensive testing using these models to enhance the understanding of drug properties. The Weighted Aggregated Sum Product Assessment (WASPAS) method is applied to evaluate and rank these drugs based on various topological indices attributes, integrating both the weighted sum model and the weighted product model to provide a comprehensive assessment.

Migraine is a disabling neurological disorder with a complex neurobiology. It appears as a cyclic disorder of sensory processing, affecting multiple systems beyond nociception. Overlapping mechanisms, including dysfunctional processing of sensory input from brain structures are involved in the generation of attacks.

This review provides a comprehensive synthesis on migraine neurobiology, which was additionally informed by search of research databases (PubMed, ClinicalTrials.gov). Findings from the most recent literature are integrated in a pathophysiological framework. By combining mechanistic insights and clinical trial data, this review highlights the trajectory of precision medicine in migraine treatment, offering a perspective on the near future of targeted and individualized therapeutic strategies.

Recent advances in migraine neurobiology offer potential solutions to longstanding challenges. While targeted CGRP therapies have shown promise by addressing specific mechanisms, the pathophysiology of migraine suggests that combination therapies targeting multiple pathways could be beneficial in migraine prevention. The growing diversity of treatment options presents challenges in therapy selection, underscoring the need for predictive biomarkers. These innovations can optimize treatment strategies and improve patient outcomes. As the field progresses, personalized, multimodal approaches are poised to become the standard of care, significantly advancing precision medicine in this area.

Designing new verified methods for the determination of pharmaceutical compounds in their specified formulation without prior separation and with high sensitivity taking in consideration analytical performance and simplicity has become a major concern of pharmaceutical quality control units. In the present work, a new simple and eco-friendly spectrofluorimetric method was developed and validated for the determination of Naproxen (NAP) and Domperidone (DOM) in their binary mixture, pharmaceutical formulation in addition to human plasma without prior separation. The proposed method is based on measuring the second derivative fluorescence intensity for NAP at 345 nm and for DOM at 292 after excitation at 235 nm without any interference from each other. All the variables affecting fluorescence intensity were studied and optimized. The proposed method showed excellent sensitivity with limit of detection (LOD) 12.286 ng/mL and 3.240 ng/mL for NAP and DOM respectively. In compliance with the ICH requirements, the optimized method was validated and was successfully utilized for the determination of both drugs in their pharmaceutical formulation and human plasma. Finally, the greenness of the proposed method was assessed using different assessment tools.

Limited data are available describing the frequency, severity, and consistency of prodromal symptoms followed by headache. This analysis of the PRODROME trial screening period characterized prodromal symptoms in people with migraine, including the most common symptoms and their severity, and the frequency and consistency with which prodromal symptoms were followed by headache.

PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial conducted in the United States that enrolled adults with 2-8 migraine attacks per month who stated they could identify prodromal symptoms that were reliably followed by a headache. The trial included a 60-day screening period designed to test the predictive validity of "qualifying prodrome events" before the onset of headache. Participants used an eDiary to report qualifying prodrome events, defined as prodromal symptoms whereby the participant was confident a headache would follow within 1-6 hours. This analysis evaluated common prodromal symptoms and their severity, time from prodrome onset to headache onset, and the percentage of participants who identified prodromal symptoms that were followed by a headache ≥75% of the time over the 60-day screening period.

A total of 920 participants entered eDiary data, with a mean of 5.2 qualifying prodrome events during the 60-day screening period. A total of 4,802 qualifying prodrome events were recorded. The most common prodromal symptoms identified were sensitivity to light (57.2%; 2,748/4,802), fatigue (50.1%; 2,408/4,802), neck pain (41.9%; 2,013/4,802), sensitivity to sound (33.9%; 1,630/4,802), either difficulty thinking or concentrating (30.0%; 1,442/4,802), and dizziness (27.8%; 1,333/4,802). Of all qualifying prodrome events reported, 81.5% (3,913/4,802) were followed by headache of any intensity within 1-6 hours. For each participant, a mean of 84.4% of their qualifying prodrome events were followed by a headache within 1-6 hours, with 76.9% of participants identifying qualifying prodrome events that were followed by headache within 1-6 hours ≥75% of the time.

Participants were able to identify migraine attacks in which prodromal symptoms were reliably followed by a headache within 1-6 hours. These findings suggest the potential for initiating treatment during the prodrome to prevent headache.

ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; First patient enrolled: August 21, 2020. clinicaltrials.gov/study/NCT04492020.

Migraine is one of the most prevalent and disabling neurological diseases, significantly affecting quality of life and productivity, as well as contributing to substantial societal costs. Recent innovations, including calcitonin gene-related peptide (CGRP) pathway inhibitors and onabotulinumtoxinA, have transformed migraine prevention by offering high efficacy and excellent tolerability, thus improving adherence. Clinical trials and real-world studies show that significant reductions in migraine frequency and, in some cases, complete migraine freedom is achievable. In this Position Statement, we advocate for raising the standards of migraine prevention by setting ambitious treatment goals aimed at optimal outcomes, such as migraine freedom or very low number of days with migraine or moderate/severe headache. We emphasize the importance of addressing residual migraine burden, highlighting that achieving a ≥50% reduction in monthly migraine days, although often considered a successful response, may not fully restore quality of life. Relying solely on percentage-based improvements can obscure the persisting impact of residual burden. This Position Statement does not want to change the standards for clinical trials but aims primarily at real-world clinical practice and proposes a shift from percentage-based measures of success to absolute goals while on treatment. We outline a framework that categorizes outcomes into four tiers: migraine freedom (no days with migraine or moderate-to-severe headache), optimal control (less than four days with migraine or moderate-to-severe headache), modest control (four to six days with migraine or moderate-to-severe headache) and insufficient control (more than days with migraine or moderate-to-severe headache). Focusing on residual burden while on treatment aims to further improve patient quality of life and drive innovation in preventive therapies and non-pharmacological approaches. By advocating for higher standards, this Position Statement, is not aimed primarily to drive reimbursement policies for migraine preventive treatments, but seeks to inspire clinicians, researchers and policymakers to prioritize ambitious goals in migraine prevention, ultimately enhancing patient outcomes and reducing the broader societal and economic impact of this debilitating condition.

In about half of migraine patients, anti-calcitonin gene-related peptide monoclonal antibodies reduce monthly migraine days by >50%. In these patients, this class of drugs may change cortical functions by decreasing nociceptive afferent barrage. This prospective study investigated functional connectivity changes in treatment responders after three-month treatment with galcanezumab.

Resting-state functional magnetic resonance imaging data were acquired for patients with high-frequency episodic or chronic migraine (N = 36) before and after treatment. Of these, 19 patients were classified as treatment responders (≥50% reduction in monthly migraine days) and 17 were considered non-responders (<50% reduction). Functional connectivity across cortical regions was assessed using a region-of-interest (ROI)-to-ROI analysis approach.

At baseline, there were no significant differences between treatment responders and treatment non-responders. In the treatment responder group, reduced functional connectivity was observed after treatment between regions of the primary somatosensory and motor cortices, insula, and several occipital and temporo-occipital areas (within the visual network). In contrast, no such changes were seen in the non-responder group.

These findings suggest that even a relatively short period of reduced nociceptive signals may be sufficient to initiate a cortical recovery process in which its resting hyperexcitable mode shifts to a less excitable state.

A key unanswered question in migraine neurobiology concerns the mechanisms that make the brain of migraineurs susceptible to cortical spreading depression (CSD, a spreading depolarization that underlies migraine aura and may trigger the migraine pain mechanisms). Important insights into this question can be obtained by studying the mechanisms of facilitation of CSD initiation in genetic mouse models of the disease. These models, all generated from families with hereditary migraine, allow the investigation of the functional consequences of disease-causing mutations at the molecular, cellular, synaptic and neural circuit levels. In this review, after describing the available genetic mouse models of migraine, which all share increased susceptibility to experimentally induced CSD, we will discuss the functional alterations in their cerebral cortex and the mechanisms underlying the facilitation of CSD initiation in their cortex, as well as the insights that these mechanisms may give into the mechanisms of initiation of spontaneous CSDs in migraine.

Recent studies have shown that migraine significantly increases the incidence of anxiety and is positively correlated with the severity and frequency of migraine. The relationship between migraine and anxiety has attracted extensive attention. This study focused on the association between migraine and anxiety, aiming to predict potential future research trends.

A bibliometric analysis was conducted using publications from the Core Collection of Web of Science. We utilized CiteSpace.5.8.R3 and VOSviewer 1.6.17 to evaluate the value of articles over the past 10 years.

The number of publications has increased significantly over the past 10 years. The cooperative network analysis shows that the United States is the most collaborative country. Additionally, Harvard University is the institution and Richard B. Lipton the individual with the highest number of studies on migraine. The analysis of keyword outbreaks indicates that the strong citation burst words are closely related to sex differences, activation, allodynia, and preventive treatment, which represent emerging new research areas and potential hotspots for future research.

An overall upward trend in the research of migraine and anxiety was observed. Sex differences, functional magnetic resonance imaging (fMRI), activation, allodynia, and preventive treatment are predicted to be hotspots in the future.

Migraine with aura (MwA) is a common and severely disabling neurological disorder, characterised by transient yet recurrent visual disturbances, including scintillating scotomas, flickering photopsias, and complex geometric patterns. These episodic visual phenomena significantly compromise daily functioning, productivity, and overall quality of life. Despite extensive research, the underlying pathophysiological mechanisms remain only partially understood. Cortical spreading depression (CSD), a propagating wave of neuronal and glial depolarisation, has been identified as a central process in MwA. This phenomenon is triggered by ion channel dysfunction, leading to elevated intracellular calcium levels and excessive glutamate release, which contribute to widespread cortical hyperexcitability. Genetic studies, particularly involving the CACNA gene family, further implicate dysregulation of calcium channels in the pathogenesis of MwA. Recent advances in neuroimaging, particularly functional magnetic resonance imaging (fMRI), have provided critical insights into the neurophysiology of MwA. These results support the central role of CSD as a basic mechanism behind MwA and imply that cortical dysfunction endures beyond brief episodes, possibly due to chronic neuronal dysregulation or hyperexcitability. The visual cortex of MwA patients exhibits activation patterns in comparison to other neuroimaging studies, supporting the possibility that it is a disease-specific biomarker. Its distinctive sensory and cognitive characteristics are influenced by a complex interplay of cortical, vascular, and genetic factors, demonstrating the multifactorial nature of MwA. We now know much more about the pathophysiology of MwA thanks to the combination of molecular and genetic research with sophisticated neuroimaging techniques like arterial spin labelling (ASL) and fMRI. This review aims to synthesize current knowledge and analyse molecular and neurophysiological targets, providing a foundation for developing targeted therapies to modulate cortical excitability, restore neural network stability, and alleviate the burden of migraine with aura. The most important and impactful research in our field has been the focus of this review, which highlights important developments and their contributions to the knowledge and treatment of migraine with aura.

Exploration of the potential of serotonergic psychedelic drugs, such as psilocybin and LSD, as potential treatments for headache disorders. This review addresses the need for well-informed physician guidelines and discusses mechanisms, safety, and efficacy of these treatments. Further research, including the consideration of combination with psychotherapy, is needed.

Psychedelics demonstrate promising outcomes as treatments for headache disorders. Recent findings indicated that some patients who underwent brief periods of treatment with psychedelics experienced a reduction in headache attack frequency, severity, or duration. When prescription medications are ineffective at treating headache disorders, or are habit-forming, patients often turn to alternative options. There is anecdotal evidence that psychedelic drugs like LSD and psilocybin can effectively treat and prevent pain in patients with headache disorders, such as migraine or cluster headache. It is vital that physicians treating patients who self-treat with psychedelics be well-informed about the mechanisms and their effects to best advise their patients and coordinate their care well. This is a review assessing the literature on the mechanisms, safety, and efficacy of psychedelic drugs as a headache management intervention. We believe there is evidence that may support further investigation into the clinical use of psychedelic medications to treat cluster headache and migraine, including the consideration of use in conjunction with other interventions like cognitive behavioral therapy or acceptance and commitment training.

The combination of the tricyclic antidepressant amitriptyline hydrochloride (AMH) and the non-selective beta-adrenergic blocker propranolol hydrochloride (PPH) is used for migraine prophylaxis. Higher doses of AMH trigger cardiac arrhythmias, anxiety, tachycardia, convulsions, hyperglycemia and anticholinergic side effects. The combined dosage formulation of AMH and PPH leads to drug-drug interactions; causes sedation, xerostomia, dysuria, insomnia and bradycardia; and results in patient non-compliance. The quantification of AMH and PPN becomes essential, especially for combination formulations, in addition to regular quality control to avoid clinical issues. Considering these facts into account, the reverse-phase -high-performance liquid chromatography (RP-HPLC) method was developed in accordance with International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Q2(R1) guidelines for the simultaneous determination of AMH and PPH. The HPLC separation was performed on an HPLC system (Shimadzu, Japan, Prominence I series 2030C) using a Shimadzu Shim-Pack GIST C18 column (100 mm × 4.6 mm, 5 μ), which was equipped with an ultraviolet detector at the isosbestic point 238 nm. The mixture of acetonitrile and orthophosphoric acid (pH 3.5) in a ratio of 35:65 v/v with a flow rate of 0.75 mL/min was used as the mobile phase. The regression coefficients of AMH (r2 > 0.998) and PPH (r2 > 0.999) show good linearity between peak areas and drug concentration ranges. The limits of detection (AMH = 0.67 μg/mL, PPH = 0.67 μg/mL) and limits of quantification (AMH = 2.04 μg/mL, PPH = 2.05 μg/mL) demonstrated the higher detection sensitivity of the proposed method.

Inter-individual variability in symptoms and the dynamic nature of brain pathophysiology present significant challenges in constructing a robust diagnostic model for migraine. In this study, we aimed to integrate different types of magnetic resonance imaging (MRI), providing structural and functional information, and develop a robust machine learning model that classifies migraine patients from healthy controls by testing multiple combinations of hyperparameters to ensure stability across different migraine phases and longitudinally repeated data. Specifically, we constructed a diagnostic model to classify patients with episodic migraine from healthy controls, and validated its performance across ictal and interictal phases, as well as in a longitudinal setting. We obtained T1-weighted and resting-state functional MRI data from 50 patients with episodic migraine and 50 age- and sex-matched healthy controls, with follow-up data collected after one year. Morphological features, including cortical thickness, curvature, and sulcal depth, and functional connectivity features, such as low-dimensional representation of functional connectivity (gradient), degree centrality, and betweenness centrality, were utilized. We employed a regularization-based feature selection method combined with a random forest classifier to construct a diagnostic model. By testing the models with varying feature combinations, penalty terms, and spatial granularities within a strict cross-validation framework, we found that the combination of curvature, sulcal depth, cortical thickness, and functional gradient achieved a robust classification performance. The model performance was assessed using the test dataset and achieved 87% accuracy and 0.94 area under the curve (AUC) at distinguishing migraine patients from healthy controls, with 85%, 0.97 and 84%, 0.93 during the interictal and ictal/peri-ictal phases, respectively. When validated using follow-up data, which was not included during model training, the model achieved 91%, 94%, 89% accuracies and 0.96, 0.94, 0.98 AUC for the total, interictal, and ictal/peri-ictal phases, respectively, confirming its robustness. Feature importance and clinical association analyses exhibited that the somatomotor, limbic, and default mode regions could be reliable markers of migraine. Our findings, which demonstrate a robust diagnostic performance using multimodal MRI features and a machine-learning framework, may offer a valuable approach for clinical diagnosis across diverse cohorts and help alleviate the decision-making burden for clinicians.

The literature on clinical psychophysiology highlights the possibility of using Heart Rate Variability (HRV) as an index of psychophysical balance and resilience to stress. This study investigates the differences in stress reactivity and subsequent recovery between a group of migraineurs and healthy controls.

Socio-demographic (i.e., sex, age, profession, marital status, and level of education) and psychophysiological (HR and HRV) measures of a group of thirty subjects with migraine (26 migraineurs without aura (86.7%), 2 migraineurs with aura (6.7%), and 2 migraineurs with and without aura (6.7%)) and from thirty healthy control subjects were collected. In particular, HRV was analyzed through frequency-domain parameters, including Low-Frequency (LF; 0.04-0.15 Hz) and High-Frequency (HF; 0.15-0.4 Hz) bands as well as LF/HF ratio during a Psychophysiological Stress Profile (PSP) structured in seven phases: (1) Baseline, (2) Objective stressor 1 (Stroop Test), (3) Rest 1, (4) Objective stressor 2 (Mental Arithmetic Task), (5) Rest 2, (6) Subjective stressor (recount a significant life event), and (7) Rest 3. The LF, HF, and LF/HF ratio values were transformed into a logarithmic scale (i.e., log-LF, log-HF, and log LF/HF ratio). Additionally, LF and HF were converted into normalized units (0-100) (i.e., LF% and HF%) which, in turn, were used to obtain reactivity and recovery to stress through delta values (Δ) calculation.

Subjects with migraine reported greater ΔLF% levels of reactivity and recovery to subjective stressor, demonstrating a prevalence of sympathetic activity while recounting a personal life event. At the same time, a lowering of the same values was found in the subjects of the group control.

Our results underline the importance of conducting a psychophysiological assessment in patients with headaches because reduced stress management skills could influence the clinical manifestations of the disease, considering stress as one of the most common triggers for migraine patients.

This study aims to investigate Auditory Evoked Brainstem Responses (ABR) and Distortion Product Otoacoustic Emission (DPOAE) suppression in migraine patients with and without phonophobia.

Thirty-two migraine patients with normal hearing and 30 healthy individuals were included in the study. Migraine characteristics and phonophobia status of migraine patients were noted. The patients were divided into two groups according to their phonophobia status. All participants underwent ABR, DPOAE and DPOAE suppression.

Migraine patients had less DPOAE suppression (1481 and 2222 hz) and shorter ABR wave latencies compared to the control group (p < 0.05). Twelve (37.5%) of the migraine patients did not have phonophobia, and 20 (62.5%) had phonophobia. Phonophobia was not found to affect DPOAE suppression (p > 0.05). However, ABR wave I and V latencies in migraine patients with phonophobia were shorter than in healthy individuals (p < 0.05).

There are changes in the auditory evoked brainstem responses and medial olivocochlear efferent system of migraine patients. While phonophobia in migraine patients does not affect the medial olivocochlear efferent system, it may affect auditory evoked brainstem responses.

There is evidence that iron metabolism may play a role in the underlying pathophysiological mechanism of migraine. Studies using R 2 ∗ (=1/ T 2 ∗ ) relaxometry, a common MRI-based iron mapping technique, have reported increased R 2 ∗ values in various brain structures of migraineurs, indicating iron accumulation compared to healthy controls.

To investigate whether there are short-term changes in R 2 ∗ during a migraine attack.

26-year-old male patient diagnosed with episodic migraine with aura according to ICHD-3 criteria.

3 T, 64-channel head coil, for quantification of R 2 ∗ relaxation a multi-echo gradient echo (GRE) sequence with TE = 4.92, 9.84, 14.7, 19.6, 24.6 and 29.51 ms, TR = 35 ms, flip angle = 15°, and 0.9 × 0.9 × 0.9 mm3 isotropic resolution was used.

Quantitative MRI, including R 2 ∗ relaxometry and diffusion tensor imaging (DTI), was acquired from a migraine patient on 21 consecutive days, including migraine-free days and days with a migraine attack.

Statistical analysis was performed using R, the Shapiro-Wilk test, the t-test and Mann Whitney U test, analysis of variance (ANOVA) or Kruskal-Wallis test, depending on the distribution of the data. p-value <0.05 was considered significant.

Significant difference in R 2 ∗ was found between the left and right hemispheres during a migraine attack. An increase in R 2 ∗ was observed in the left hemisphere, whereas in the right hemisphere R 2 ∗ was found to decrease. In the left cerebral white matter, R 2 ∗ increased by 1.8% (p = 0.021), in the right cerebral white matter, R 2 ∗ anisotropy decreased by 17% (p = 0.011) during a migraine attack.

Our study showed a decrease and increase in iron content during the migraine cycle. Furthermore, during a migraine attack, white matter iron content increased, accompanied by a decrease in anisotropic tissue components, suggesting additional changes in vascular components.

Background: Mucosal contact between the turbinates and septum is implicated as a cause of headache and migraine. The prevalence of mucosal contact is reported to be as low as 4%. However, the inclusion criteria in that study were restrictive, and no data on the superior turbinate were reported. We sought to determine the prevalence of mucosal contact on nasal endoscopy and its association with migraine. Methods: A cohort study of 355 subjects was conducted. All patients underwent nasal endoscopy and were queried as to migraine history. The prevalence of mucosal contact in the migraine cohort was compared to that in the non-migraine cohort, and the prevalence of migraine in the contact cohort was compared to that in the non-contact group. The frequency of mucosal contact at each turbinate involved was noted. Results: The overall prevalence of mucosal contact was 49.3% (175/355). The superior turbinate was most frequently involved (34.9%: 124/355), followed by the inferior turbinate (14.6%; 52/355), the middle turbinate (14.1%: 50/355), and multiple turbinate involvement (13.5%; 48/355). Migraine history was elicited in 31.8% of subjects (113/355); 52% (91/175) of patients with mucosal contact reported migraine history; 65.3% (81/124) with superior turbinate contact, 50% (25/50) with middle turbinate contact, and 21.1% (12/52) with inferior turbinate contact; 80.5% (91/113) of patients with migraine demonstrated mucosal contact; 71.7% (81/113) with superior turbinate contact, 22.1% (25/113) with middle turbinate contact, and 10.6% (12/113) with inferior turbinate contact. Multivariate analysis demonstrated that superior and middle turbinate contact were associated with migraine (P < .001 and P = .034, respectively), but inferior turbinate contact was not (P = .272). Conclusion: Mucosal contact is much more prevalent than previously reported and is associated with migraine, especially at the superior turbinate level.

Calcium ions play a key role in the physiological processes of the central nervous system. The intracellular calcium signal, in nerve cells, is part of the neurotransmission mechanism. They are responsible for stabilizing membrane potential and controlling the excitability of neurons. Calcium ions are a universal second messenger that participates in depolarizing signal transduction and contributes to synaptic activity. These ions take an active part in the mechanisms related to memory and learning. As a result of depolarization of the plasma membrane or stimulation of receptors, there is an extracellular influx of calcium ions into the cytosol or mobilization of these cations inside the cell, which increases the concentration of these ions in neurons. The influx of calcium ions into neurons occurs via plasma membrane receptors and voltage-dependent ion channels. Calcium channels play a key role in the functioning of the nervous system, regulating, among others, neuronal depolarization and neurotransmitter release. Channelopathies are groups of diseases resulting from mutations in genes encoding ion channel subunits, observed including the pathophysiology of neurological diseases such as migraine. A disturbed ability of neurons to maintain an appropriate level of calcium ions is also observed in such neurodegenerative processes as Alzheimer's disease, Parkinson's disease, Huntington's disease, and epilepsy. This review focuses on the involvement of calcium ions in physiological and pathological processes of the central nervous system. We also consider the use of calcium ions as a target for pharmacotherapy in the future.

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

Trigeminal neuropathic pain (TNP), migraine, and cluster headache (CH) profoundly impact the quality of life and present significant clinical challenges due to their complex neurobiological underpinnings. This review delves into the pivotal role of the hypothalamus in the pathophysiology of these facial pain syndromes, highlighting its distinctive functions and potential as a primary target for research, diagnosis, and therapy. While the involvement of the hypothalamus in migraine and CH has been increasingly supported by imaging and clinical studies, the precise mechanisms of its role remain under active investigation. The role of the hypothalamus in TNP, in contrast, is less explored and represents a critical gap in our understanding. The hypothalamus's involvement varies significantly across these conditions, orchestrating a unique interplay of neural circuits and neurotransmitter systems that underlie the distinct characteristics of each pain type. We have explored advanced neuromodulation techniques, such as deep brain stimulation (DBS) and optogenetics, which show promise in targeting hypothalamic dysfunction to alleviate pain symptoms. Furthermore, we discuss the neuroplastic changes within the hypothalamus that contribute to the chronicity of these pains and the implications of these findings for developing targeted therapies. By offering a comprehensive examination of the hypothalamus's roles, this paper aims to bridge existing knowledge gaps and propel forward the understanding and management of facial neuralgias, underscoring the hypothalamus's critical position in future neurological research.

Background/Objectives: Research on calcitonin-gene-related peptide (CGRP) in adult migraine is extensive, but its role in childhood migraine remains unclear. This study aimed to evaluate serum CGRP levels in children experiencing migraine and tension-type headache (TTH) during interictal periods, comparing these levels to age-matched healthy controls. Methods: A total of 66 migraine patients, 59 with TTH, and 53 controls were recruited and stratified by headache onset age: under 7, 7-12, and over 12 years. CGRP levels were quantified using enzyme-linked immunosorbent assay (ELISA). Results: The migraine patients showed significantly higher serum CGRP levels than both the TTH patients and the controls (p < 0.001), with no significant difference between the latter two groups. Among the migraine patients, those without aura (MO) exhibited higher CGRP levels than those with aura (MA). The CGRP levels were lower in the. MA patients whose headaches began between ages 7 and 12 compared to the subjects with MO, while no significant differences were found in the patients whose headaches began after age 12. Conclusions: These findings suggest that elevated serum CGRP is indicative of pediatric migraine, with variations based on migraine type and age of onset. The difference in CGRP in preadolescent migraineurs with and without aura suggest that CGRP levels may vary depending on age and on migraine type.

Migraine is a highly prevalent and disabling pain disorder that affects >1 billion people worldwide. One central hypothesis points to the cranial meninges as a key site underlying migraine headache genesis through complex interplay between meningeal sensory nerves, blood vessels, and adjacent immune cells. How these interactions might generate migraine headaches remains incompletely understood and a subject of much debate. In this review we discuss clinical and preclinical evidence supporting the concept that meningeal sterile inflammation, involving neurovascular and neuroimmune interactions, underlies migraine headache genesis. We examine downstream signaling pathways implicated in the development of migraine pain in response to exogenous events such as infusing migraine-triggering chemical substances. We further discuss cortex-to-meninges signaling pathways that could underlie migraine pain in response to endogenous events, such as cortical spreading depolarization (CSD), and explore future directions for the field.

Background: Migraine prevalence has been estimated to be as high as 25% during reproductive years. Despite this, and the known significantly lower odds of acute stroke being correctly diagnosed among women versus men, little is known about the migraine-stroke connection in this vulnerable population. Our study seeks to provide a consolidated examination of cerebrovascular and obstetric complications of migraines in pregnant women and to evaluate the role of concurrent comorbidities. Methods: We utilized the 2016-2020 Healthcare Cost and Utilization Project's National Inpatient Sample with the International Classification of Diseases, 10th Revision diagnostic codes to compare pregnant patients with migraines with those without migraines. Multivariable logistic regression was used to examine the incidence of subtypes of stroke while controlling for confounding variables. Results: Overall, 19,825,525 pregnant patients were evaluated; 219,175 (1.1%) had a concomitant diagnosis of migraine. Pregnant patients with migraines were more likely to suffer ischemic (0.1% versus 0.0%) or hemorrhagic stroke (0.3% versus 0.1%). On multivariate analysis, acute ischemic stroke was most strongly associated with migraine with aura (odds ratio [OR], 23.26; 95% confidence interval [CI], 18.46-29.31), followed by migraine without aura (OR, 8.15; 95% CI, 4.79-13.88). Conclusions: Pregnant women with migraine are at a significantly increased risk for both ischemic and hemorrhagic stroke. Pregnant women with migraines should be cautioned that they may be at an increased risk of stroke, particularly if they are experiencing an aura, and encouraged to contact their medical providers to rule out neurological complications.

The pathophysiology of migraine remains poorly understood. Like most migraine preventive therapies, patent foramen ovale (PFO) closure was never intended for the treatment of migraine. After closure of PFO for other reasons, migraine symptom reduction/elimination was noted in some patients. Subsequent small trials failed to prove its benefit. There is significant evidence suggesting a platelet-mediated mechanism linking migraines to PFO. The GORE RELIEF Clinical Study is a randomized, blinded, placebo- and sham-controlled trial, currently enrolling. The study design is meant to optimize patient selection using thienopyridine responsiveness as an inclusion criterion.

Environmental contaminants may play a significant role in the development of migraine. Perchlorate, nitrate, and thiocyanate were selected for this study due to their known impact on thyroid function, which is closely linked to neurological processes. Disruptions in thyroid function have been associated with various neurological disorders, including migraines. However, there is currently no evidence linking exposure to these specific chemicals to migraine. The study aims to evaluate the association between urinary concentrations of perchlorate, nitrate, and thiocyanate with the prevalence of severe headache or migraine in U.S. adults.

A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2004. Utilizing electrospray tandem mass spectrometry in conjunction with ion chromatography, urinary concentrations of perchlorate, nitrate, and thiocyanate urine were measured. Multiple logistic regression models were employed to evaluate the linear correlation between perchlorate, nitrate, and thiocyanate exposure and severe headache or migraine. The non-linear relationship is described analytically using a fitted smoothing curve and a two-piecewise regression model. Subgroup analyses were used to further clarify the stability of this relationship across different populations.

There were 1,446 participants in this population-based study, ranging in age from 20 to 85. After adjusting for potential confounding variables, the multiple logistic regression findings demonstrated that thiocyanate was significantly positively associated with the prevalence of migraine (odds ratio [OR] = 1.18; [1.06, 1.30]; p < 0.001). There was consistency in this connection across different subgroups (p for interaction >0.05). Furthermore, there was a non-linear correlation between urinary thiocyanate and migraine. Using a fitted smoothing curve and a two-piecewise regression model, it was found that the correlation between urinary thiocyanate and migraine was U-shaped (p for Log-likelihood ratio = 0.002). According to the findings of the multiple regression analysis, there was no significant correlation between urinary perchlorate and nitrate and migraine (both p > 0.05).

We should limit our exposure to thiocyanate by keeping it within a reasonable range, as indicated by the U-shaped correlation between urinary thiocyanate and migraine.

The trigeminal sensory system consists of the trigeminal nerve, the trigeminal ganglion, and the trigeminal sensory nuclei (the mesencephalic nucleus, the principal nucleus, the spinal trigeminal nucleus, and several smaller nuclei). Various sensory signals carried by the trigeminal nerve from the orofacial area travel into the trigeminal sensory system, where they are processed into integrated sensory information that is relayed to higher sensory brain areas. Thus, knowledge of the trigeminal sensory system is essential for comprehending orofacial pain. This review elucidates the individual nuclei that comprise the trigeminal sensory system and their synaptic transmission. Additionally, it discusses four types of orofacial pain and their relationship to the system. Consequently, this review aims to enhance the understanding of the mechanisms underlying orofacial pain.

Migraine is a prevalent neurological disorder, particularly among individuals aged 20-50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies.

Cortical spreading depression (CSD) is an electrophysiologic pathological state in which a wave of depolarization in the cerebral cortex is followed by the suppression of spontaneous neuronal activity. This transient spread of neuronal depolarization on the surface of the cortex is the hallmark of CSD. Numerous investigations have demonstrated that transmembrane ion transport, astrocytic ion clearing and fatigue, glucose metabolism, the presence of certain genetic markers, point mutations, and the expression of the enzyme responsible for the production of various arachidonic acid derivatives that participate in the inflammatory response, namely, cyclooxygenase (COX), all influence CSD. Here, we explore the associations between CSD occurrence in the cortex and various factors, including how CSD is related to migraines, how the glucose state affects CSD, the effect of TBI and its relationship with CSD and glucose metabolism, how different markers can be measured to determine the severity of CSD, and possible connections to oligemia, orexin, and leptin.