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Introduction: Migraine, a prevalent headache disorder with unclear mechanisms and limited treatments, may be influenced by dyslipidemia and genetic factors. Statins and emerging lipid-modifying agents show potential but lack evidence for migraine management. Mendelian Randomization analysis offers insights into causal relationships and therapeutic targets. This study aims to explore genetically predicted lipid traits, drug targets, and their association with migraine risk. Method: We conducted Mendelian randomization (MR) analyses utilizing genetic variants associated with lipid traits and variants in genes encoding the protein targets of various classes of lipid-lowering drugs. The specific drug classes investigated included HMGCR, PCSK9, NPC1L1, ABCG5/ABCG8, LDLR, LPL, ANGPTL3, APOB, CETP, and APOC3. To determine the effects on migraine risk, we meta-analyzed MR estimates for regional variants using data from two large sample sets. The genetic variants were weighted based on their associations with specific lipid traits, such as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Apolipoprotein A1, and Apolipoprotein B. To obtain association weights, we utilized data from lipid genetics consortia. For lipid-modifying drug targets that exhibited suggestive significance, we further employed expression quantitative trait locus (eQTL) data. Additionally, we performed colocalization analysis to assess genetic confounding. Result: The use of genetic proxies for HMGCR inhibition demonstrated a significant association with a decreased risk of migraine in the FinnGen dataset (OR = 0.64, 95% CI: 0.46–0.88, p = 0.0006) and a nearly significant association in the Choquet dataset (OR = 0.78, 95% CI: 0.60–1.01, p = 0.06). When pooling the estimates, the overall effect size showed a reduced risk of migraine (OR = 0.73, 95% CI: 0.60–0.89, p = 0.0016). Similarly, genetic mimicry of LPL enhancement was associated with a lower risk of migraine in the FinnGen dataset (OR = 0.82, 95% CI: 0.69–0.96, p = 0.01) and the Choquet dataset (OR = 0.91, 95% CI: 0.83–0.99, p = 0.03). Pooling the estimates showed a consistent effect size (OR = 0.89, 95% CI: 0.83–0.96, p = 0.002). Sensitivity analyses yielded no statistically significant evidence of bias arising from pleiotropy or genetic confounding. Conclusion: In the study, it was observed that among the 10 lipid-lowering drug targets investigated, LPL and HMGCR showed significant associations with migraine risk. These findings indicate that LPL and HMGCR have the potential to serve as candidate drug targets for the treatment or prevention of migraines. [ABSTRACT FROM AUTHOR]

Background: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. Methods: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. Results: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. Conclusions: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine. [ABSTRACT FROM AUTHOR]

Background: The premonitory phase, or prodrome, of migraine, provides valuable opportunities to study attack initiation and for treating the attack before headache starts. Much that has been learned about this phase in recent times has come from the outcomes of functional imaging studies. This review will summarise these studies to date and use their results to provide some feasible insights into migraine neurobiology. Main body: The ability to scan repeatedly a patient without radiation and with non-invasive imaging modalities, as well as the recognition that human experimental migraine provocation compounds, such as nitroglycerin (NTG) and pituitary adenylate cyclase activating polypeptide (PACAP), can trigger typical premonitory symptoms (PS) and migraine-like headache in patients with migraine, have allowed feasible and reproducible imaging of the premonitory phase using NTG. Some studies have used serial scanning of patients with migraine to image the migraine cycle, including the 'pre-ictal' phase, defined by timing to headache onset rather than symptom phenotype. Direct observation and functional neuroimaging of triggered PS have also revealed compatible neural substrates for PS in the absence of headache. Various imaging methods including resting state functional MRI (rsfMRI), arterial spin labelling (ASL), positron emission tomography (PET) and diffusion tensor imaging (DTI) have been used. The results of imaging the spontaneous and triggered premonitory phase have been largely consistent and support a theory of central migraine attack initiation involving brain areas such as the hypothalamus, midbrain and limbic system. Early dysfunctional pain, sensory, limbic and homeostatic processing via monoaminergic and peptidergic neurotransmission likely manifests in the heterogeneous PS phenotype. Conclusion: Advances in human migraine research, including the use of functional imaging techniques lacking radiation or radio-isotope exposure, have led to an exciting opportunity to study the premonitory phase using repeated measures imaging designs. These studies have provided novel insights into attack initiation, migraine neurochemistry and therapeutic targets. Emerging migraine-specific therapies, such as those targeting calcitonin gene-related peptide (CGRP), are showing promise acutely when taken during premonitory phase to reduce symptoms and prevent subsequent headache. Therapeutic research in this area using PS for headache onset prediction and early treatment is likely to grow in the future. [ABSTRACT FROM AUTHOR]

Background: Depression, the most frequent and harmful mental disorder, has been associated with specific somatic diseases as the leading cause of death. The purposes of this prospective study were to predict incident chronic diseases based on baseline depressive symptoms and to test sex-dependent effects. Methods: In a representative German community sample of over 12 000 participants, baseline depressive symptoms (assessed using the Patient Health Questionnaire-9) were tested as a predictor of new onset of cardiovascular disease (CVD), chronic obstructive lung disease, diabetes, cancer, and migraine at 5-year follow-up. To study disease incidence, we created subsamples for each chronic disease by excluding participants who already had the respective disease at baseline. Potential confounders were included in logistic regression models and sex-specific analyses were performed. Results: Controlling for demographic characteristics and loneliness, in men and women, baseline depressive symptoms were predictive of CVD, chronic obstructive lung disease, diabetes, and migraine, but not of cancer. When we additionally adjusted for metabolic and lifestyle risk factors, there was an 8% increase of chronic obstructive lung disease and migraine per point of depressive symptoms. There was a trend for CVD (4%; p = 0.053). Sex-sensitive analyses revealed trends for the relevance of depressive symptoms for CVD in men (p = 0.065), and for diabetes in women (p = 0.077). Conclusions: These findings underscore the need to implement screening for depression in the treatment of major somatic illnesses. At the same time, depressed patients should be screened for metabolic and lifestyle risk factors and for somatic diseases and offered lifestyle interventions. [ABSTRACT FROM AUTHOR]

Objective: To describe differences in clinical and demographic characteristics between patients with episodic migraine (EM) or chronic migraine (CM) and determine the effect of migraine subtype on patient‐reported outcome measures (PROM). Background: Prior studies have characterized migraine in the general population. While this provides a basis for our understanding of migraine, we have less insight into the characteristics, comorbidities, and outcomes of migraine patients who present to subspecialty headache clinics. These patients represent a subset of the population that bears the greatest burden of migraine disability and are more representative of migraine patients who seek medical care. Valuable insights can be gained from a better understanding of CM and EM in this population. Methods: We conducted a retrospective observational cohort study of patients with CM or EM seen in the Cleveland Clinic Headache Center between January 2012 and June 2017. Demographics, clinical characteristics, and patient‐reported outcome measures (3‐Level European Quality of Life 5‐Dimension [EQ‐5D‐3L], Headache Impact Test‐6 [HIT‐6], Patient Health Questionnaire‐9 [PHQ‐9]) were compared between groups. Results: Eleven thousand thirty‐seven patients who had 29,032 visits were included. More CM patients reported being on disability 517/3652 (14.2%) than EM patients 249/4881 (5.1%) and had significantly worse mean HIT‐6 (67.3 ± 7.4 vs. 63.1 ± 7.4, p < 0.001) and median [interquartile range] EQ‐5D‐3L (0.77 [0.44–0.82] vs. 0.83 [0.77–1.00], p < 0.001), and PHQ‐9 (10 [6–16] vs. 5 [2–10], p < 0.001). Conclusions: There are multiple differences in demographic characteristics and comorbid conditions between patients with CM and EM. After adjustment for these factors, CM patients had higher PHQ‐9 scores, lower quality of life scores, greater disability, and greater work restrictions/unemployment. [ABSTRACT FROM AUTHOR]

Objective: To assess the association between hypermobility spectrum disorders/hypermobile type Ehlers Danlos Syndrome (HSD/hEDS) and migraine in a national sample of adolescents in Israel. Background: The association between HSD/hEDS and migraine is unclear, even more so in pediatric populations. Methods: This population‐based, cross‐sectional study included 1,627,345 Israeli adolescents (945,519/1,626,407 [58%] males; mean age 17 ± 0.5 years) who were medically assessed before mandatory military service during 1998–2020. Diagnoses of migraine with at least one attack per month (active migraine) and HSD/hEDS were confirmed by certified specialists. The prevalences of active migraine in adolescents with and without HSD/hEDS were computed and the association between HSD/hEDS and active migraine was examined. Results: Active migraine was significantly more prevalent in adolescents with HSD/hEDS (307/4686 [6.5%]) compared to those without HSD/hEDS (51,931/1,621,721 [3.2%]) (OR = 2.16, 95% CI 1.90–2.45). The association between HSD/hEDS and active migraine persisted in a multivariable analysis (OR = 2.08, 95% CI 1.85–2.34) and in several sensitivity analyses. Conclusions: We found a significant association between HSD/hEDS and active migraine in both male and female adolescents. Clinical awareness of the association can promote early diagnosis and treatment of migraine. Further research is required to identify appropriate pharmacologic and nonpharmacologic migraine treatment strategies for individuals with HSD/hEDS. [ABSTRACT FROM AUTHOR]

Migraine is a common and complex neurological disease potentially caused by a polygenic interaction of multiple gene variants. Many genes associated with migraine are involved in pathways controlling the synaptic function and neurotransmitters release. However, the molecular mechanisms underpinning migraine need to be further explored. Recent studies raised the possibility that migraine may arise from the effect of regulatory non-coding variants. In this study, we explored the effect of candidate non-coding variants potentially associated with migraine and predicted to lie within regulatory elements: VAMP2_rs1150, SNAP25_rs2327264, and STX1A_rs6951030. The involvement of these genes, which are constituents of the SNARE complex involved in membrane fusion and neurotransmitter release, underscores their significance in migraine pathogenesis. Our reporter gene assays confirmed the impact of at least two of these non-coding variants. VAMP2 and SNAP25 risk alleles were associated with a decrease and increase in gene expression, respectively, while STX1A risk allele showed a tendency to reduce luciferase activity in neuronal-like cells. Therefore, the VAMP2_rs1150 and SNAP25_rs2327264 non-coding variants affect gene expression, which may have implications in migraine susceptibility. Based on previous in silico analysis, it is plausible that these variants influence the binding of regulators, such as transcription factors and micro-RNAs. Still, further studies exploring these mechanisms would be important to shed light on the association between SNAREs dysregulation and migraine susceptibility. [ABSTRACT FROM AUTHOR]

This study examined the longitudinal relationship of anxiety, depression, and perseverative cognition with headache frequency, severity, and disability among non-clinical students in two waves. The interval between the two self-reported measurements was one month for Sample 1 (n = 426) and one week for Sample 2 (n = 92). The results showed that anxiety and repetitive negative thinking predicted the onset of migraine after one month. Depression was related to higher headache parameters after one month. Among probable migraine sufferers, repetitive negative thinking predicted higher headache impact after one month. Contrarily, metacognitions related to repetitive negative thinking indicated both positive and negative prospective relations to headache a month later, according to initial migraine status. [ABSTRACT FROM AUTHOR]

Background: Although studies have identified a high prevalence of migraine among employees in the banking sector, the symptoms of migraine, related disability and occupational risk factors are not well understood. Aims: To determine migraine prevalence, symptoms and disability among bank employees in Guizhou province in China and to examine occupational risk factors associated with migraine positivity and symptoms. Methods: In a cross-sectional survey, two-stage probability sampling was used to select bank employees in Guizhou province, China. From May to October 2022, uniformly trained interviewers conducted face-to-face interviews using the HARDSHIP questionnaire. Logistic regression was used to examine factors associated with migraine positivity and symptoms. Results: Of 1,985 contactable eligible subjects, 1,929 (male 45.4%, female 54.6%) completed the survey. The one-year prevalence of migraine was 27.2% (95% CI 25.2–29.2%). Of migraine-positive individuals, 11.2% had a monthly frequency ≥ 15 days, 11.8% had an attack duration > 72 h, and 14.9% had severe pain intensity. The median of days lost from work, housework and social activities due to migraine during a three-month period was 4, 3 and 2 days, respectively, with more than half (52.8%) patients reporting Grade III or IV disability. In multivariable analyses, positions in data analysis (OR = 1.8 [95% CI 1.2–2.8], p < 0.01) and information technology (OR = 3.8 [95% CI 1.7–8.3], p < 0.01) were occupational risk factors for migraine positivity. It was also found that professional positions were predictive of migraine attacks ≥ 15 days per month, administrative positions were predictive of duration > 72 h and severe pain intensity of migraine attacks, and working in remote branches was predictive of duration > 72 h. Conclusions: Migraine is prevalent among employees in the banking sector in Guizhou province in China, with a large proportion of sufferers carrying a high burden of symptoms and disability. The practical implication of this study is that the risk factors identified here could be translated to the focus of workplace monitoring and interventions to manage and prevent migraine. [ABSTRACT FROM AUTHOR]

The article discusses Hormonal contraceptives, such as the hormonal intrauterine device (IUD), can help perimenopausal women manage symptoms and improve their quality of life. These contraceptives not only prevent unwanted pregnancies but also provide noncontraceptive benefits like treating abnormal uterine bleeding, relieving vasomotor symptoms and menstrual migraines, protecting against bone loss and endometrial issues, and reducing the risk of musculoskeletal issues and mood disorders.

Background: Periodontal disease may drive a systemic inflammatory response that triggers migraine; however, the association between periodontal disease and migraine has rarely been investigated in a community‐based setting. Methods: This cross‐sectional study included 66,109 participants aged 30 to 70 years from Taiwan Biobank (TWB). A structured questionnaire was administered to participants, who were also subjected to whole‐genome single nucleotide polymorphism genotyping using the customized Axiom–TWB array. To identify subjects with periodontal disease and migraine, the computerized linkage of data obtained from TWB and the National Health Insurance Research Database was performed. Participants were evaluated for their genetic predisposition to migraine using a polygenic risk score. We examined and estimated the magnitude of associations between periodontal disease and migraine. Results: In this study, 4618 (4618/66,109; 7%) participants with migraine and 61,491 (61,491/66,109; 83%) participants without migraine were included. Participants with migraine exhibited a higher prevalence of periodontal disease than participants without migraine (4324/4618; 94% vs. 56,036/61,491; 91%). A significant positive association was observed between periodontal disease and migraine, with an adjusted odds ratio (ORadj) of 1.40 (95% confidence interval [CI] = 1.24–1.59; p < 0.001). The association remained consistent even after excluding participants with other comorbidities (ORadj = 1.34; 95% CI = 1.16–1.55; p < 0.001). Moreover, the positive association between periodontal disease and migraine remained significant across the subgroups of age, sex, other comorbidities, and classified polygenic risk scores of migraine, with the ORadj ranging from 1.26 to 1.78. Conclusions: A significant positive association was observed between periodontal disease and migraine. Future studies need to explore the biological mechanisms of how periodontal disease might affect migraine. [ABSTRACT FROM AUTHOR]

Background: Migraine is a prevalent disorder with significant socioeconomic impact. The impairment of metabolic homeostasis in migraine warrants further investigation. Changes in serum levels of Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15) are characteristic of some metabolic and mitochondrial diseases. This study aimed to assess whether the presence of migraine affects serum levels of FGF-21 and GDF-15, and taking metabolic disorders into account as potential confounding factors. Methods: We collected serum samples from 221 migraine patients (153 episodic migraineurs and 68 chronic migraineurs) and 124 healthy controls. The serum concentrations of FGF-21 and GDF-15 were measured using an enzyme-linked immunosorbent assay (ELISA) based approach. Clinical variables, including monthly headache days, peak headache pain intensity, the 6-item Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS), were also addressed. The associations between the clinical variables of migraine patients and serum levels of FGF-21 and GDF-15 were studied. Results: In the multiple regression that corrected for age, we found that the serum levels of FGF-21 and GDF-15 were significantly higher in migraine sufferers than in healthy controls. A significant elevation in serum concentration of FGF-21, but not GDF-15, was observed in patients with chronic migraine (CM) compared to those with episodic migraine (EM). Regarding migraine-related disability, higher scores on the HIT-6 and MIDAS were associated with higher levels of FGF-21 and GDF-15. For the receiver operating characteristic (ROC) analysis, the diagnosis of migraine using GDF-15 showed that the area under the ROC curve (AUC) was 0.801 and the AUC of chronic migraine was 0.880. Conclusion: Serum GDF-15 and FGF-21 levels are increased in patients with migraine and associated with the severity of migraine-related disability. [ABSTRACT FROM AUTHOR]

Introduction: Headache is a common symptom in patients with Coronavirus-19 infection (COVID-19). In this research, we aim to assess the frequency, characteristics, and response to treatment of headache in patients with COVID-19 and its correlation with psychosocial features in Turkey. Methods: To describe the clinical features of headache in COVID-19 positive individuals. Patients were evaluated and followed up with faceto- face visits in a tertiary hospital during the pandemic period. Results: One hundred and seventeen of 150 patients (78%) had a headache diagnosed before and during the pandemic, 62 of 150 (41.3%) had a new type of headache. No significant differences were observed in terms of demographics, Beck Depression Score, Beck Anxiety Score, and quality of life scales (QOLS) between patients with and without headache (p>0.05). The most common triggering factor for headache was stress and fatigue in 59% (n=69), while the second most common (32.4%, n=38) was COVID-19 infection. 46.5% of the patients reported that the severity and frequency of their current headaches increased after the COVID-19 infection. Among new-onset headaches, the social functionality and pain score subgroups of the QOLS form were significantly lower in housewives and unemployed patients compared to the working group (p=0.018; p=0.039 respectively). Twelve of 117 patients had a mild to moderate, throbbing headache in the temporoparietal region, which did not fulfill the International Classification of Headache Disorders diagnosis criteria, but showed as a common feature among COVID-19 patients. Nineteen of 62 patients (30.9%) had a newly diagnosed migraine syndrome. Conclusion: The diagnosis incidence of migraine in patients with COVID-19 disease being more than other headaches types may suggest the existence of a common pathway in possible immune mechanisms. [ABSTRACT FROM AUTHOR]

Objective: In this prospective cohort study, characteristics of perimenstrual and non‐perimenstrual migraine attacks in women were compared with migraine attacks in men. Background: Women report longer migraine attacks and more accompanying symptoms than men in cross‐sectional questionnaire studies, but this has not been confirmed in longitudinal studies. Supposed differences could result from different characteristics specific to perimenstrual migraine attacks, or of attacks in women in general. Methods: This cohort study was performed among patients with migraine who were treated at the Leiden Headache Clinic. We assessed differences in migraine attack characteristics between men and women who were prospectively followed by a previously validated electronic headache diary. The primary outcome was "attack" duration. Differences between perimenstrual (Days −2 to +3 of the menstrual cycle) and non‐perimenstrual attacks in women versus attacks in men were corrected for age, chronic migraine, and medication overuse headache. Results: A total of 1347 women and 284 men were included, reflecting the preponderance of women in migraine prevalence. Crude median (first and third quartile [Q1−Q3]) attack duration in men was 32.1 [17.7–53.6] h, compared to 36.7 [21.9–62.4] h for non‐perimenstrual migraine attacks and 44.4 [17.9–79.0] h for perimenstrual migraine attacks in women. After correction for confounding, perimenstrual migraine attacks were 1.62 (95% confidence interval [CI] 1.47–1.79; p < 0.001) and non‐perimenstrual 1.15 (95% CI 1.05–1.25; p = 0.003) times longer compared to migraine attacks in men. The mean relapse percentage in men was 9.2%, compared to 12.6% for non‐perimenstrual migraine attacks, and 15.7% for perimenstrual migraine attacks. Relapse risk was greater for perimenstrual (odds ratio [OR] 2.39, 95% CI 1.93–2.95; p < 0.001), but not for non‐perimenstrual (OR 1.18, 95% CI 0.97–1.45; p = 0.060) attacks. Migraine attacks in women were more often accompanied by photophobia, phonophobia, and nausea, but less often aura. Conclusion: Compared to attacks in men, both perimenstrual and non‐perimenstrual migraine attacks are of longer duration and are more often accompanied by associated symptoms. A sex‐specific approach to migraine treatment and research is needed. [ABSTRACT FROM AUTHOR]

Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes code for proteins expressed in neurons, glial cells, or vessels, all of which increase susceptibility to cortical spreading depression. The study of monogenic migraines has shown that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified numerous susceptibility variants that each result in only a small increase in overall migraine risk. The more than 180 known variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also highlighted the importance of shared genetic factors between migraine and its major co-morbidities, including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes. [ABSTRACT FROM AUTHOR]

Background: Migraine is a disabling neurological disorder with the pathophysiology yet to be understood. The microstructural alteration in brain white matter (WM) has been suggested to be related to migraine in recent studies, but these evidence are observational essentially and cannot infer a causal relationship. The present study aims to reveal the causal relationship between migraine and microstructural WM using genetic data and Mendelian randomization (MR). Methods: We collected the Genome-wide association study (GWAS) summary statistics of migraine (48,975 cases / 550,381 controls) and 360 WM imaging-derived phenotypes (IDPs) (31,356 samples) that were used to measure microstructural WM. Based on instrumental variables (IVs) selected from the GWAS summary statistics, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between migraine and microstructural WM. In forward MR analysis, we inferred the causal effect of microstructural WM on migraine by reporting the odds ratio (OR) that quantified the risk change of migraine for per 1 standard deviation (SD) increase of IDPs. In reverse MR analysis, we inferred the causal effect of migraine on microstructural WM by reporting the β value that represented SDs of changes in IDPs were caused by migraine. Results: Three WM IDPs showed significant causal associations (p < 3.29 × 10− 4, Bonferroni correction) with migraine and were proved to be reliable via sensitivity analysis. The mode of anisotropy (MO) of left inferior fronto-occipital fasciculus (OR = 1.76, p = 6.46 × 10− 5) and orientation dispersion index (OD) of right posterior thalamic radiation (OR = 0.78, p = 1.86 × 10− 4) exerted significant causal effects on migraine. Migraine exerted a significant causal effect on the OD of left superior cerebellar peduncle (β = − 0.09, p = 2.78 × 10− 4). Conclusions: Our findings provided genetic evidence for the causal relationships between migraine and microstructural WM, bringing new insights into brain structure for the development and experience of migraine. [ABSTRACT FROM AUTHOR]

Objective: To investigate the links between adolescent migraine and comorbid and co‐occurring conditions using a large, nationally representative longitudinal study. Background: Comorbidities and co‐occurring conditions play an important role in the clinical treatment of individuals with migraine. Research in this area has focused largely on the adult population using cross‐sectional data, but less is known about adolescents and how conditions may co‐occur over time from a broader developmental perspective. The goals of this manuscript were to empirically evaluate the associations between adolescent migraine and several linked conditions and explore the relative timings of onset of these conditions from adolescence to adulthood. Methods: Data came from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a school‐based study of the health‐related behaviors and conditions of adolescents. The present study examined data from Wave 1 (W1, study years: 1994–1995), Wave 4 (W4, study years: 2008–2009), and Wave 5 (W5, study years: 2016–2018). Analyses and visual plots were used to evaluate potential links between parent‐reported adolescent migraine status (PR‐AdMig) at W1 and 15 medical conditions identified based on self‐reported medical diagnoses (SR‐MDs) at W4 and W5. Based on prior literature in adults, we identified 11 conditions predicted to be associated with PR‐AdMig and four conditions predicted not to be associated with PR‐AdMig. The analyses were exploratory and post hoc. Results: The total sample size pooling over all analyses was n = 13,786, but the wave‐specific sample sizes differed due to missing data (W4 analyses, n = 12,692; W5 analyses, n = 10,340); 7243/13,786 (unweighted: 52.5%; weighted: 50.5%) of participants were female, 7640/13,786 (unweighted: 55.4%; weighted: 68.6%) were White, and 1580/13,786 (unweighted: 11.5%; weighted: 12.0%) had PR‐AdMig. The average ages were 15.8 years at W1, 28.7 years at W4, and 37.8 years at W5. Findings showed that PR‐AdMig was associated with anxiety/panic disorder (W4: PR‐AdMig vs. Control weighted %: 17.1% vs. 12.6%, unadjusted odds ratio [OR] = 1.43, 95% confidence interval [CI] 1.18–1.74, p = 0.0003; W5: 31.6% vs. 22.4%, OR = 1.60, 95% CI 1.28–2.02, p < 0.0001), asthma/chronic bronchitis/emphysema (W4: 20.0% vs. 14.7%, OR = 1.45, 95% CI 1.20–1.76, p < 0.001; W5: 21.0% vs. 14.6%, OR = 1.55, 95% CI 1.25–1.94, p < 0.001), attention deficit hyperactivity disorder (W4: 8.3% vs. 5.4%, OR = 1.58, 95% CI 1.18–2.10, p = 0.002), depression (W4: 23.7% vs. 15.4%, OR = 1.71, 95% CI 1.43–2.04, p < 0.0001; W5: 33.8% vs. 25.1%, OR = 1.53, 95% CI 1.22–1.90, p < 0.001), epilepsy/seizure disorder (W4: 2.2% vs. 1.2%, OR = 1.84, 95% CI 1.23–2.76, p = 0.004), migraine (W4: 38.8% vs. 11.9%, OR = 4.7, 95% CI 4.1–5.5, p < 0.001), post‐traumatic stress disorder (W4: 4.1% vs. 2.8%, OR = 1.45, 95% CI 1.01–2.08, p = 0.042; W5: 11.3% vs. 7.1%, OR = 1.67, 95% CI 1.27–2.20, p < 0.001), and sleep apnea (W5: 11.0% vs. 7.6%, OR = 1.51, 95% CI 1.15–1.98, p = 0.003). Among theoretically unlinked conditions, only hepatitis C at W4 was shown to have a relationship with adolescent onset migraine (0.7% vs. 0.2%, OR = 3.63, 95% CI 1.32–10.0, p = 0.013). Visual plots suggested that the retrospective, self‐report timing of onset of specific subsets of co‐occurring conditions tended to group together over time. Conclusions: Consistent with the existing headache literature, results showed that adolescent migraine was associated with other medical and psychological conditions and visual plots suggested that there may be developmental patterns in the occurrence of migraine with other related conditions. [ABSTRACT FROM AUTHOR]

Objectives: Determine the prevalence of possible bruxism in the adult population of Campinas, Brazil, and investigate its association with health behaviors, health status, and multimorbidity. Methods: A population‐based cross‐sectional study was conducted with data from the 2014/2015 Campinas Health Survey. The sample was composed of 1986 adults (≥20 years of age). The data were collected with the aid of a pre‐coded questionnaire, and the dependent variable was self‐reported bruxism (possible bruxism). The prevalence of possible bruxism was estimated according to the independent variables (health‐related behaviors, morbidities, demographic and socioeconomic characteristics). A hierarchical model was employed using stepwise backward regression in two stages. Principal component analysis was also performed to identify multimorbidity patterns. Results: The prevalence of possible bruxism was 13.6%. Associations were found with the consumption of alcoholic beverages, sleep quality, and the number of chronic diseases/health problems. Bruxism was more associated with multimorbidity pattern 2, which was composed of asthma, rhinitis, sinusitis, dizziness/vertigo, migraine/headache, emotional/mental problem, back pain, and allergy. Conclusion: The present findings justify the planning of actions directed at reducing the consumption of alcoholic beverages and can help guide the health actions of the multidisciplinary team, prioritizing a reduction in the harm caused by the simultaneous presence of health problems associated with possible bruxism. [ABSTRACT FROM AUTHOR]

Aims: Migraine is one of the most common neurological diseases and the second cause of disability worldwide. Various trigger factors have been reported in different populations. The current study was designed to extract the main trigger factors using factor analysis, and compare the chronic and episodic patient scores for every extracted pattern. Methods: In this cross‐sectional study, 300 migrainous women (25–55 years old) participated. A constructed 46‐item Likert questionnaire was developed to assess the primary triggers. The validity of the designed questionnaire was assessed by Content Validity Ratio and Content Validity Index coefficients. The test–retest method was employed to assess reliability. The exploratory factor analysis was performed to extract patterns of correlation among 46 triggers. Each participant was given a score for every extracted pattern. The mean scores of chronic and episodic patients were compared using the Mann–Whitney test. Results: The mean body mass index of participants was 28.17 ± 5.44 kg/m2. Most participants (90.7%) had migraine without aura. Four factors were extracted using factor analysis that explained 22.37% of the total variance: (1) environmental and behavioural factors; (2) condiments; (3) nitrite, tyramine and caffeine; and (4) fats. None of these factors explained the difference between chronic and episodic migrainous women. Conclusions: The current study suggests that environmental and behavioural factors, relative to dietary triggers, play an essential role in causing migraine in women and more than dietary triggers. The most important triggers did not differ between episodic and chronic migrainous women. [ABSTRACT FROM AUTHOR]

Objective: This study explored the bidirectional relationship between fibromyalgia and migraine among probands with either of the two disorders and their unaffected siblings. Background: Evidence suggests a bidirectional association between fibromyalgia and migraine in individuals and in twins. However, whether a bidirectional association between fibromyalgia and migraine also occurs among siblings remains unknown. Methods: Using the Taiwan National Health Insurance Research Database, we examined the data of 2677 probands with fibromyalgia, 2780 unaffected siblings, and 11,120 matched controls to assess the risk of migraine. In contrast, 1830 probands with migraine, 1936 unaffected siblings, and 7744 matched controls to assess the risk of fibromyalgia. Results: Logistic regression analyses demonstrated that patients with fibromyalgia (odds ratio [OR]: 3.69; 95% confidence interval [CI]: 2.87–4.74) and unaffected siblings (OR: 1.51; 95% CI: 1.08–2.10) were more likely to develop migraine than the controls during the follow‐up period. Moreover, patients with migraine and unaffected siblings had a 4.86‐fold (95% CI: 3.86–6.09) and 1.59‐fold (95% CI: 1.18–2.12) increased risk of fibromyalgia than the controls. Conclusion: The bidirectional association between fibromyalgia and migraine among probands and unaffected siblings suggests a familial coaggregation of these two conditions. Additional studies are required to investigate the genetic and environmental etiologies for this coaggregation. [ABSTRACT FROM AUTHOR]

Objective: To assess whether alcohol intake is associated with the onset of migraine attacks up to 2 days after consumption in individuals with episodic migraine (EM). Background: Although alcohol has long been suspected to be a common migraine trigger, studies have been inconclusive in proving this association. Methods: This was an observational prospective cohort study among individuals with migraine who registered to use a digital health platform for headache. Eligible individuals were aged ≥18 years with EM who consumed alcohol and had tracked their headache symptoms and alcohol intake for ≥90 days. People who did not drink any alcohol were excluded. The association of alcohol intake ("Yes/No") and of the number of alcoholic beverages in the 2 days preceding a migraine attack was assessed accounting for the presence of migraine on day‐2 and its interaction with alcohol intake on day‐2, and further adjusted for sex, age, and average weekly alcohol intake. Results: Data on 487 individuals reporting 5913 migraine attacks and a total of 40,165 diary days were included in the analysis. Presence of migraine on day‐2 and its interaction with alcohol intake on day‐2 were not significant and removed from the model. At the population level, alcohol intake on day‐2 was associated with a lower probability of migraine attack (OR [95% CI] = 0.75 [0.68, 0.82]; event rate 1006/4679, 21.5%), while the effect of alcohol intake on day‐1 was not significant (OR [95% CI] = 1.01 [0.91, 1.11]; event rate 1163/4679, 24.9%) after adjusting for sex, age, and average weekly alcohol intake. Similar results were obtained with the number of beverages as exposure. Conclusions: In this English‐speaking cohort of individuals with EM who identified themselves as mostly low‐dose alcohol consumers, there was no significant effect on the probability of a migraine attack in the 24 h following consumption, and a slightly lower likelihood of a migraine attack from 24 to 48 h following use. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between self‐reported triggers and the occurrence of migraine attacks using a smartphone application. Background: One of several issues around the study of migraine attack triggers is that limited available evidence supports whether self‐reported triggers can induce a headache on a particular subject. Methods: This is an observational longitudinal cohort study of individuals with migraine registered to track their headaches prospectively using a smartphone application. For 90 days, participants entered daily data about triggers (potential triggers and premonitory symptoms) that may be associated with attack risk, as well as migraine symptoms. The statistical significance of univariate associations between each trigger and migraine recurrent events was determined for each individual. Statistically identified triggers were then compared to self‐reported triggers. Results: In 328 individuals (290/328 [88.4%] female; mean [standard deviation] 4.2 [1.5] migraine attacks/month) the mean (standard deviation) number of triggers moderately or highly endorsed per individual was 28.0 (7.7) in individuals presented with up to 38 possible triggers. Of these, an average (standard deviation) of 2.2 (2.1) triggers per individual were statistically associated with increased risk of attacks. Even the most commonly endorsed triggers (sleep quality, stress, tiredness/fatigue, sleep duration, dehydration, neck pain, missed meals, eyestrain, mean barometric pressure, and anxiety) were statistically associated in fewer than one third of individuals suspecting each, with the exception of neck pain (117/302 [38.7%]). Conclusions: Individuals with episodic migraine believe that many triggers contribute to their attacks; however, few of these withstand statistical testing at the individual level. Improved personal knowledge of potential triggers and premonitory symptoms may help individuals adopt behavioral changes to mitigate attack risk. [ABSTRACT FROM AUTHOR]

Air pollution, the most prevalent form of pollution worldwide, is associated with a wide range of neurological disorders, including neurodegenerative conditions, stroke, autism, depression, and developmental delay. There is accumulating evidence on the association between air pollution and headache disorders, especially migraine. Many classical and non-classical air pollutants have been associated with headache, including particulate matter, nitrogen dioxide, sulfur dioxide, ozone, carbon monoxide, as well as polycyclic aromatic hydrocarbons and volatile organic compounds. There has also been research on the impact of biomass fuels on health-related symptoms, including headache, which form an important source of air pollution in our country. The exact mechanisms underlying headache pathophysiology vis-à-vis air pollution are not precisely defined but include triggering of neuroinflammation and activation of the transient receptor potential ankyrin 1 (TRPA1)-associated pathways. Evidence from different regions of the world indicates a significant association between headache incidence and prevalence, and occurrence of air pollution. Despite growing data, research on adverse effects of air pollution on headache disorders remains limited, and appropriate outcome measures are not holistically defined in these studies. Due to the rapid advancement of the scourge of air pollution, there is a pressing need to expand the arena of research, specifically focused on pathological mechanisms, impact on health and quality-of-life parameters, as well as broader global ramifications. [ABSTRACT FROM AUTHOR]

Background: The onset and duration of spontaneous migraine attacks are most often difficult to predict which, in turn, makes it challenging to study the neurobiologic underpinnings of the disease in a controlled experimental setting. To address this challenge, human provocation studies can be used to identify signaling molecules (e.g. calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide) that, upon intravenous or oral administration, induce migraine attacks in people with migraine and mild or no headache in healthy volunteers. This approach has proven to be valid for decades and plays an integral role in mapping signaling pathways underlying migraine pathogenesis and identification of novel drug targets. However, the question arises as to whether the pathogenic mechanisms of provoked and spontaneous migraine attacks differ. In this paper, we provide an opinionated discussion on the similarities and differences between provoked and spontaneous attacks based on the current understanding of migraine pathogenesis. Methods: The PubMed database was searched in July 2022 for original research articles on human provocation studies that included participants with migraine. The reference lists of originally identified articles were also searched and we selected those we judged relevant. Discussion: People with migraine describe that provoked attacks resemble their spontaneous attacks and can be treated with their usual rescue medication. From a neurobiologic standpoint, provoked and spontaneous migraine attacks appear to be similar, except for the source of migraine-inducing substances (exogenous vs. endogenous source). In addition, provoked attacks can likely not be used to study the events that precede the release of migraine-inducing signaling molecules from sensory afferents and/or parasympathetic efferents during spontaneous attacks. [ABSTRACT FROM AUTHOR]

Aims: To investigate the potential contributions of diastolic and systolic blood pressure (BP) and the circadian rhythm of BP to chronic migraine evolution. Methods: This cross-sectional study included four groups of patients selected based on migraine frequency (high frequency ≥ 10 days per month and low frequency < 10) and on the presence of hypertension. Among-group and pairwise comparisons were carried out to investigate potential neurophysiologic differences in the cerebral vessel reactivity to a nitroglycerin test, in autonomic balance (tilting test), and BP circadian rhythm. Results: A more marked decrease in cerebral blood flow velocity was observed in hypertensive high-frequency migraineurs compared to all other groups (P = .037). Moreover, a smaller decrease in vagal tone was recorded in the orthostatic position in hypertensive subjects, whether they were high- (P = .032) or low-frequency migraineurs (P = .014), with a consistently higher vagal to sympathetic tone ratio (P = .033). Finally, in nonhypertensive subjects, a higher but not significant prevalence of systolic nondippers was detected in high-frequency migraineurs (67%) compared to low-frequency subjects (25%; P = .099). Conclusion: These findings suggest that hypertension may contribute to the chronic evolution of headache with mechanisms shared with migraine; ie, vascular tone alteration and autonomic dysregulation. [ABSTRACT FROM AUTHOR]

Headaches and migraine are a common neurological complaint post SARS-CoV2 (COVID-19) infection, with research published in Cepalalgia; an international journal of headache, indicates approximately a fifth of people experience post COVID-19 persistent migraine symptoms lasting for weeks or months after testing negative to the virus. 1 For persistent Post COVID migraine sufferers, however, headaches can be catastrophic and debilitating. Knowledge is emerging about the pathophysiology of post-COVID headache, however based on early migraine clinical observations, providing nutritional support to the trigeminovascular system and meningeal nociceptors may provide mitochondrial support. [ABSTRACT FROM AUTHOR]

Migraine and chronic migraine are caused by a combination of modifiable and non-modifiable genetic, social, behavioral and environmental risk factors. Further research of possible modifiable risk factors for this headache disorder is merited, given its role as one of the leading causes of years lived with disability per year. The first aim of this online cross-sectional study was to investigate the psychosocial risk factors that predicted chronic migraine and severe migraine-related disability in 507 Irish and UK participants, focusing specifically on childhood maltreatment, attachment and tendency to dissociate, or experience depressed mood and/or anxiety. Additionally, this study aimed to examine variables that mediated the relationships between these psychosocial risk factors and migraine chronicity or severe migraine-related disability. Adjusted binary logistic regression revealed that shutdown dissociation (Odds Ratio [OR] 4.57, 95% Confidence Interval [CI] 2.66–7.85) and severe physical abuse (OR 4.30, 95% CI 1.44–12.83 had significant odds of predicting migraine chronicity, while depression (OR 3.28, 95% CI 1.86–5.77) significantly predicted severe migraine-related disability. Mediation analyses indicated that shutdown dissociation mediated the relationship between seven predictor variables and both chronicity and severe disability including possible predisposing factors emotional abuse, physical neglect, avoidant attachment and anxious attachment. These findings suggest that early life stressors (such as childhood trauma and avoidant attachment style), shutdown dissociation and depression may impact on migraine trajectory. To investigate whether these psychosocial factors are risk factors for migraine chronicity or disability, prospective research should be conducted in this area to account for fluctuations in migraine chronicity over time. [ABSTRACT FROM AUTHOR]

Perimenopause is linked to increased migraine (Mg), especially menstrual Mg (MMg), influenced by hormonal changes. Compared to nonmenstrual attacks, menstrual attacks are more disabling and less responsive to treatment. Women with perimenstrual estrogen withdrawal have been linked to Mg during menstruation, whereas Mg during perimenopause has been linked to unpredictable fluctuations in estrogen levels. It has been widely established that female sex hormones play a role in Mg, but how it occurs remains unclear. This narrative review was identified using Medline and PubMed searches between 1946 and 2021. Search terms included "headache," "migraine," "menstrual migraine," "menstruation," "menopause," "perimenopause," "estrogen," and "progesterone." This article focuses on the candidate genes and female hormones that play a role in MMg. More study is necessary to understand better the environmental components that play a critical role in disease development. Currently, there is insufficient clinical evidence to support the function of menstrual Mg. The specific research facts examined MMg unique candidate genes and female hormonal factors that support their association and found MMg etiologic processes for generating an early diagnostic marker. [ABSTRACT FROM AUTHOR]

Objective: This study explored the risk of migraine in children, adolescents, and young adults with attention deficit hyperactivity disorder (ADHD) and its association with ADHD medications. Background: The prevalence of migraine peaks between the ages of 35 and 39 years. Recent studies have reported a positive association between ADHD and migraine. Methods: This longitudinal case‐cohort study was conducted using data from the Taiwan National Health Insurance Database. Between 2001 and 2009, we enrolled 81,441 participants with ADHD and a 1:1‐matched control cohort for age, sex, and physical and psychiatric comorbidities. All participants had no diagnosis of migraine before enrollment and were followed up to the end of 2011. We examined the risk of newly diagnosed migraine among patients with ADHD and matched controls after adjusting for demographics and physical/psychiatric comorbidities. Results: Patients with ADHD had a higher incidence of migraine than those in the control group (462/81441 [0.6%] vs. 212/81441 [0.3%] patients, p < 0.001). After adjusting for potential confounders, the hazard ratio (HR) was 1.92 (95% CI, 1.64–2.34) for migraine in patients with ADHD versus controls. The subgroup analyses stratified by age showed the HRs were 2.01 (95% CI, 1.63–2.49), 1.94 (95% CI, 1.35–2.79), and 1.31 (95% CI, 0.58–2.98) for children (<12 years old), adolescents (12–17), and young adults (18–29), respectively, versus controls. When stratified by sex, the HR was 1.97 (95% CI, 1.58–2.46) for men and 1.94 (95% CI, 1.44–2.62) for women versus controls. The cumulative daily dose of ADHD medications was not associated with the risk of migraine. Conclusion: Children and adolescents with ADHD were associated with an increased risk of migraine compared with matched controls. The increased risk was not observed in young adults with ADHD. Further studies are required to examine the mechanisms between migraine and ADHD. [ABSTRACT FROM AUTHOR]

Background: Adverse childhood experiences (ACEs) are cross‐sectionally associated with headache, including migraine, in pediatric populations. Objective: The objective of this study was to determine whether ACEs are prospectively associated with incident health‐professional diagnosed migraine and prevalence of non‐migraine frequent headache in adolescence, either directly or indirectly through symptoms of depression and anxiety. Methods: We used data from the National Longitudinal Survey of Children and Youth, a Canadian cohort study that followed children aged 0/1 at baseline, and the person most knowledgeable about them (PMK) until the child reached adolescence. The PMK reported on 14 ACEs (e.g., parental death) when the child was 4/5 and 6/7 years, and symptoms of depression and anxiety in late childhood (age 8/9 years), using a validated tool. Migraine (primary outcome) was ascertained via PMK report of a health‐professional diagnosis, and non‐migraine frequent headache (>1 time per week) was adolescent self‐report, both measured at age 14/15. We estimated direct and indirect effects (IEs) on the log‐odds scale through symptoms of depression and anxiety (mediator). We adjusted for sex, parental migraine, and economic deprivation. The analytic sample sizes were: n = 2058 (migraine) and n = 1730 (frequent headache). Results: There were nunweighted = 71 respondents with migraine (3.4%, 71/2058) and nunweighted = 204 with non‐migraine frequent headache (11.8%, 204/1730). Most respondents experienced no ACEs (weighted percentage = 55.7), followed by 1 ACE (weighted percentage = 34.7) and greater than or equal to two ACEs (weighted percentage = 9.6), respectively. There were direct associations between experiencing one (odds ratio [OR] = 1.71, 95% confidence interval [CI]: 1.01–2.87) and equal to or greater than two (OR = 2.33, 95% CI: 1.13–4.80) ACEs and migraine, but not for non‐migraine frequent headache. There were no indirect relationships through symptoms of depression and anxiety for migraine (1 ACE: OR = 1.06, 95% CI: 0.99–1.13 and ≥2 ACEs: OR = 1.11, 95% CI: 0.98–1.28) or non‐migraine frequent headache (1 ACE: OR = 0.99, 95% CI: 0.95–1.03 and ≥2 ACEs: OR = 0.98, 95% CI: 0.90–1.07). Conclusions: ACEs may confer an increased risk of migraine onset in adolescence. The association was not explained by symptoms of depression and anxiety in late childhood. [ABSTRACT FROM AUTHOR]

Background: This study set out to determine the prevalence and possible risk factors of headache and/or migraine in U.S. children, as well as the prevalence of complementary medicine use in this population. Methods: This is a secondary analysis of data from the 2017 U.S. National Health Interview Survey. Sociodemographic and clinical characteristics were compared between individuals with and without headaches. A backward stepwise procedure with a logistic regression statistic was used to test for potential predictors. Results: Six percent of children reported headaches and/or migraine within the past 12 months. Headaches were predicted by older age, female sex, non-Hispanic white ethnicity, and living in the southern United States. Inability to afford balanced meals and feeling sad or depressed in the past 6 months were also associated with higher odds of headache. A total of 19.2% of children with headaches reported using mind-body medicine, compared with 12.2% of children without headaches. Most frequently used therapy was yoga (57.2%), followed by spiritual meditation (31.1%) and mindfulness meditation (24.0%). The prevalence of visits to a complementary medicine practitioner or healer was 12.5%. Most frequently seen practitioners were chiropractors (62.1%), followed by naturopaths (21.2%), homeopaths (14.1%), and traditional healers (2.5%). Conclusions: The common use of complementary medicine among children suffering from headaches is worth noting. Understanding the motivation for using complementary medicine, as well as the choice of different forms of such therapy, may shed further light on the health-seeking behavior of this population. [ABSTRACT FROM AUTHOR]

Objective Migraine is recognized as a disease with unknown etiology and various pathophysiologic pathways which are not fully understood. Due to the relation between dairy intake and various chronic conditions in children and also the paucity of data on the probable role of dairy intake on pediatrics' odds of having migraine, this study was designed. Materials & Methods The present study was a population-based case-control design that was accomplished in a tertiary headache clinic.290 child (aged from7 to 14 years old) was included in this study. A definite diagnosis of migraine was performed by a neurologist; concerning the 2018 international classification of headache disorder 3 (ICHD3) criteria. Also, demographic and anthropometric characteristics were obtained. In addition, the usual dietary intake of participants was evaluated using a validated semi-quantitative food frequency questionnaire (FFQ). Results Those children in the case group significantly had higher age and BMI means (P.value:0.000). In the second regression model, odds of migraine were 48% (OR: 0.52; 95%CI:0.27-1.00) diminished in the second tertile and 53% (OR:0.47;95%CI:0.24-0.92) in the third tertile of low-fat dairy intake (P-trend:0.03). In the fully adjusted model, the achieved migraine ORs were as followings:0.48 (95% CI:0.240.95) in the second tertile and 0.46 (95% CI:0.21-0.96) in the third tertile (P-trend:0.04), respectively. Children with more high-fat dairy intake also consumed higher amounts of energy, pastries, simple sugar, unhealthy snacks, and hydrogenated oil (P<0.05). Conclusion This study results proposed that a greater amount of lowfat dairy intake may attenuate the odds of having migraine attacks in pediatrics and adolescents who might be at risk of headache, which can be attributed to the micronutrient and also to the bioactive content of these dietary components. [ABSTRACT FROM AUTHOR]

Background: The purpose of this narrative review is to examine the literature investigating a causal relationship between stress and migraine and evaluate its implications for managing migraine. Methods: PubMed, PsycINFO and CINAHL were searched from 1988 to August 2021, identifying 2223 records evaluating the relationship between stress and migraine. Records were systematically screened. All potentially relevant records were thematically categorized into six mechanistic groups. Within each group the most recent reports providing new insights were cited. Results: First, studies have demonstrated an association of uncertain causality between high stress loads from stressful life events, daily hassles or other sources, and the incidence of new-onset migraine. Second, major stressful life events seem to precede the transformation from episodic to chronic migraine. Third, there is some evidence for changes in levels of stress as a risk factor for migraine attacks. Research also suggests there may be a reversed causality or that stress-trigger patterns are too individually heterogeneous for any generalized causality. Fourth, migraine symptom burden seems to increase in a setting of stress, partially driven by psychiatric comorbidity. Fifth, stress may induce sensitization and altered cortical excitability, partially explaining attack triggering, development of chronic migraine, and increased symptom burden including interictal symptom burden such as allodynia, photophobia or anxiety. Finally, behavioral interventions and forecasting models including stress variables seem to be useful in managing migraine. Conclusion: The exact causal relationships in which stress causes incidence, chronification, migraine attacks, or increased burden of migraine remains unclear. Several individuals benefit from stress-oriented therapies, and such therapies should be offered as an adjuvant to conventional treatment and to those with a preference. Further understanding the relationship between stress, migraine and effective therapeutic options is likely to be improved by characterizing individual patterns of stress and migraine, and may in turn improve therapeutics. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) and migraine are both more common among women than men. Women's reproductive years are associated with increased susceptibility to recurrence of both conditions, suggesting a potential role of sex hormones in aetiology. We examined associations between comorbid migraine and clinical features of MDD in women, including relationships with lifetime reproductive events such as childbirth. Lifetime clinical characteristics and reproductive events in a well-characterised sample of 222 UK women with recurrent MDD, with (n = 98) and without (n = 124) migraine were compared. Women had all been recruited as part of a UK-based ongoing programme of research into the genetic and non-genetic determinants of mood disorders. Multivariate analysis showed a specific association between the lifetime presence of migraine and postpartum depression (PPD) within 6 weeks of delivery (OR = 2.555; 95% CI: 1.037–6.295, p = 0.041). This association did not extend to a broader definition of PPD with onset up to 6 months postpartum. All other factors included in the analysis were not significantly associated with the presence of migraine: family history of depression, younger age at depression onset, history of suicide attempt and severe premenstrual syndrome symptoms. The finding that women with MDD and comorbid migraine may be particularly sensitive to hormonal changes early in the postpartum period leads to aetiological hypotheses and suggests this group may be useful for future studies attempting to characterise PPD and MDD phenotypes. The refinement of such phenotypes has implications for individualising risk and treatment and for future biological and genetic studies. [ABSTRACT FROM AUTHOR]

Background: Obesity confers adverse effects to every system in the body including the central nervous system. Obesity is associated with both migraine and idiopathic intracranial hypertension (IIH). The mechanisms underlying the association between obesity and these headache diseases remain unclear. Methods: We conducted a narrative review of the evidence in both humans and rodents, for the putative mechanisms underlying the link between obesity, migraine and IIH. Results: Truncal adiposity, a key feature of obesity, is associated with increased migraine morbidity and disability through increased headache severity, frequency and more severe cutaneous allodynia. Obesity may also increase intracranial pressure and could contribute to headache morbidity in migraine and be causative in IIH headache. Weight loss can improve both migraine and IIH headache. Preclinical research highlights that obesity increases the sensitivity of the trigeminovascular system to noxious stimuli including inflammatory stimuli, but the underlying molecular mechanisms remain unelucidated. Conclusions: This review highlights that at the epidemiological and clinical level, obesity increases morbidity in migraine and IIH headache, where weight loss can improve headache morbidity. However, further research is required to understand the molecular underpinnings of obesity related headache in order to generate novel treatments. [ABSTRACT FROM AUTHOR]

Background: Migraine is a common neurological disease with extremely debilitating, but fully reversible symptoms. Women suffer from migraine more often than men. It was assumed that fluctuation of oestrogen level during menstrual cycle is one of many factors responsible for more frequent migraine attacks. The second-to-fourth digit ratio (2D:4D) is considered as an indicator of prenatal sex steroids. Balance of prenatal androgens (testosterone) and oestrogen has been studied in numerous diseases that are affected by hormones. However, the relationship between migraine and the sex steroids balance in prenatal development is still unexplained. The aim of this paper is to provide an evidence of relationship between prenatal oestrogen and testosterone exposure following 2D:4D digit ratio, and migraine prevalence in adults. Methods: We examined a group of 151 adults (33 males, 118 females) with migraine and a control group of 111 adults (45 males, 66 females). 2D:4D digit ratio of both hands was measured using sliding Vernier calliper. Results: Significant differences were found in the right hand. Female migraineurs had lower value of 2D:4D ratio than the control group and the right 2D:4D was lower than left 2D:4D (Δ2D:4D), suggesting prenatal testosterone dominance. The opposite relationship was observed in males. Male migraineurs had higher value of 2D:4D ratio and Δ2D:4D was greater than the control group, suggesting prenatal oestrogen dominance. Conclusions: Our results suggest that depending on sex, different proportion of prenatal sex steroids might be a risk factor of migraine in adults. Women with migraine were presumably exposed in prenatal life to higher testosterone levels relative to oestrogen, while men with migraine were probably exposed in prenatal life to higher levels of oestrogen relative to testosterone. [ABSTRACT FROM AUTHOR]

Background: Asthma and migraine are the most common chronic conditions. Few studies have concurrently evaluated the bidirectional association between asthma and migraine in pedaitric patients. Objective: We aimed to identify the relationship between these conditions. Methods: This retrospective study was carried out in a tertiary center. School-age patients diagnosed with migraine were included in the study by evaluating electronic patient files who complain with headache. These patients were diagnosed with asthma by a pediatric allergist. Results: Of 5242 patients whose medical records were accessed. The number of patients with asthma who were referred to the pediatric neurology department for headache during the study period was 1427 (913 girls/514 boys). Two hundred and thirty-six (15.5%) patients were diagnosed with migraine. At the same period, 3815 (2193 girls/1622 boys) patients without asthma presented to the pediatric neurology department for the evaluation of headache. Of those, 207 (5.4%) patients were diagnosed with migraine. The frequency of migraine was significantly higher in patients with asthma than those without asthma (OR = 1.84 (95% CI 1.62-2.05), P <0.001). Conclusion: The risk of migraine is significantly increased in school age children with asthma. This study is very important in that it is one of the largest pediatric studies performed so far in our country. [ABSTRACT FROM AUTHOR]

Objective Previous studies have demonstrated that emotional stress, changes in lifestyle habits and infections can worsen the clinical course of migraine. We hypothesize that changes in habits and medical care during coronavirus disease 2019 (COVID-19) lockdown might have worsened the clinical course of migraine. Design Retrospective survey study collecting online responses from migraine patients followed-up by neurologists at three tertiary hospitals between June and July 2020. Methods We used a web-based survey that included demographic data, clinical variables related with any headache (frequency) and migraine (subjective worsening, frequency, and intensity), lockdown, and symptoms of post-traumatic stress. Results The response rate of the survey was 239/324 (73.8%). The final analysis included 222 subjects. Among them, 201/222 (90.5%) were women, aged 42.5 ± 12.0 (mean±SD). Subjective improvement of migraine during lockdown was reported in 31/222 participants (14.0%), while worsening in 105/222 (47.3%) and was associated with changes in migraine triggers such as stress related to going outdoors and intake of specific foods or drinks. Intensity of attacks increased in 67/222 patients (30.2%), and it was associated with the subjective worsening, female sex, recent insomnia, and use of acute medication during a headache. An increase in monthly days with any headache was observed in 105/222 patients (47.3%) and was related to symptoms of post-traumatic stress, older age and living with five or more people. Conclusions Approximately half the migraine patients reported worsening of their usual pain during the lockdown. Worse clinical course in migraine patients was related to changes in triggers and the emotional impact of the lockdown. [ABSTRACT FROM AUTHOR]

In some settings, it may be difficult to differentiate between a confounder and a mediator. For instance, the observed association of self-reported childhood psychological abuse (CPA) with onset of chronic obstructive pulmonary disease (COPD) and migraine may be confounded by current mood/psychological state (e.g., the subjective evaluation of one's own affective state), as well as mediated by an individual's psychopathological symptoms. In this study, we propose the "independence hypothesis," which could prove meaningful to explore in data that lack prospective or objective indices of CPA. We used cross-sectional data from wave VI (2007-2008) of the Tromsø Study, Norway (N = 12,981). The associations between CPA and COPD and migraine were assessed with Poisson regression models. CPA was associated with a 46% increased risk of COPD (relative risk [RR] = 1.46, 95% confidence interval [CI]: [1.02, 1.90]) and a 28% increased risk of migraine in adulthood (RR = 1.28, 95% CI: [1.04, 1.53]), independent of age, sex, parental history of psychiatric problems/asthma/dementia, smoking, respondent's mood/psychological state, and mental health. These findings suggest that the association between retrospectively reported CPA and COPD and migraine is not driven entirely by respondent's mood/psychological state and mental health. Assessing the independent effect of self-reported CPA on COPD and migraine in retrospective studies may prove more meaningful than exploring the mediating role of mental health. Here, we provide the analytical rationale for assessing the independent effect in settings where it is difficult to differentiate between a confounder and a mediator. Moreover, we provide a theoretical rationale for assessing the independent effect of retrospectively reported childhood adversity on health and well-being. [ABSTRACT FROM AUTHOR]

Background: Headache is one of the most common symptoms after concussion, and mild traumatic brain injury (mTBI) is a risk factor for chronic migraine (CM). However, there remains a paucity of data regarding the impact of mTBI on migraine-related symptoms and clinical course. Methods: Of 2161 migraine patients who participated in the American Registry for Migraine Research between February 2016 and March 2020, 1098 completed questions assessing history of TBI (50.8%). Forty-four patients reported a history of moderate to severe TBI, 413 patients reported a history of mTBI. Patients' demographics, headache symptoms and triggers, history of physical abuse, allodynia symptoms (ASC-12), migraine disability (MIDAS), depression (PHQ-2), and anxiety (GAD-7) were compared between migraine groups with (n = 413) and without (n = 641) a history of mTBI. Either the chi-square-test or Fisher's exact test, as appropriate, was used for the analyses of categorical variables. The Mann-Whitney test was used for the analyses of continuous variables. Logistic regression models were used to compare variables of interest while adjusting for age, gender, and CM. Results: A significantly higher proportion of patients with mTBI had CM (74.3% [307/413] vs. 65.8% [422/641], P = 0.004), had never been married or were divorced (36.6% [147/402] vs. 29.4% [187/636], P = 0.007), self-reported a history of physical abuse (24.3% [84/345] vs. 14.3% [70/491], P < 0.001), had mild to severe anxiety (50.5% [205/406] vs. 41.0% [258/630], P = 0.003), had headache-related vertigo (23.0% [95/413] vs. 15.9% [102/640], P = 0.009), and difficulty finding words (43.0% [174/405] vs. 32.9% [208/633], P < 0.001) in more than half their attacks, and headaches triggered by lack of sleep (39.4% [155/393] vs. 32.6% [198/607], P = 0.018) and reading (6.6% [26/393] vs. 3.0% [18/607], P = 0.016), compared to patients without mTBI. Patients with mTBI had significantly greater ASC-12 scores (median [interquartile range]; 5 [1–9] vs. 4 [1–7], P < 0.001), MIDAS scores (42 [18–85] vs. 34.5 [15–72], P = 0.034), and PHQ-2 scores (1 [0–2] vs. 1 [0–2], P = 0.012). Conclusion: Patients with a history of mTBI are more likely to have a self-reported a history of physical abuse, vertigo, and allodynia during headache attacks, headaches triggered by lack of sleep and reading, greater headache burden and headache disability, and symptoms of anxiety and depression. This study suggests that a history of mTBI is associated with the phenotype, burden, clinical course, and associated comorbid diseases in patients with migraine, and highlights the importance of inquiring about a lifetime history of mTBI in patients being evaluated for migraine. [ABSTRACT FROM AUTHOR]

Background: Migraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach. Methods: We leveraged available summary statistics from genome-wide association studies (GWAS) of 1,504 phenotypes and self-reported migraine and inferred pair-wise causal relationships using the latent causal variable (LCV) method. Results: We identify 18 potential causal relationships between self-reported migraine and other complex traits. Hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping. We observed that sources of abdominal pain and discomfort might influence a higher risk for migraine. Moreover, occupational and environmental factors such as working with paints, thinner or glues, and being exposed to diesel exhaust were causally associated with higher migraine risk. Psychiatric-related phenotypes, including stressful life events, increased migraine risk. In contrast, ever feeling unenthusiastic / disinterested for a whole week, a phenotype related to the psychological well-being of individuals, was a potential outcome of migraine. Conclusions: Overall, our results suggest a potential vascular component to migraine, highlighting the role of vasoconstriction and platelet clumping. Stressful life events and occupational variables potentially influence a higher migraine risk. Additionally, a migraine could impact the psychological well-being of individuals. Our findings provide novel testable hypotheses for future studies that may inform the design of new interventions to prevent or reduce migraine risk and recurrence. [ABSTRACT FROM AUTHOR]

Background: Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients. Methods: Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS). Results: Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling. Conclusions: Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine. [ABSTRACT FROM AUTHOR]

Background and Objectives: Prior studies have established an association between a history of abuse and the development of migraine. This cross‐sectional observational study explored the relationship between self‐reported abuse history with migraine‐related sensory hypersensitivity symptoms. Methods: In total, 588 adult patients with migraine from the American Registry for Migraine Research completed questionnaires: Generalized Anxiety Disorder‐7, Patient Health Questionnaire‐2 for depression, Photosensitivity Assessment Questionnaire, Hyperacusis Questionnaire, and Allodynia Symptom Checklist. Using four binary screening questions, patients were asked to self‐report if they believed they had suffered emotional, physical, or sexual abuse in their lifetime. Differences in questionnaire scores between groups with and without a history of abuse were determined. Regression models adjusted for age, sex, and basic headache features analyzed the relationship between abuse history and sensory hypersensitivity symptoms. Moderation analysis explored the role of headache frequency in this relationship. Mediation analysis assessed the indirect (Mediated) effect (IE) of abuse on sensory hypersensitivity through depression or anxiety. Additional models analyzed relationships between sensory hypersensitivity symptoms and abuse subtypes or the number of abuse subtypes. Results: Of 588 participants, 222 (38%) reported a history of abuse. Patients with a history of abuse reported statistically significantly greater average headache frequency (7.6 vs. 4.7 days, p = 0.030). Patients with a history of abuse also reported higher average or median questionnaire scores: anxiety (7.6 vs. 4.7, p < 0.001, d = 0.56), depression (1.7 vs. 1.3, p = 0.009, d = 0.24), photophobia (0.54 vs. 0.44, p < 0.001, d = 0.32), hyperacusis (19.6 vs. 14.9, p < 0.001, d = 0.49), ictal allodynia (6.0 vs. 3.0, p < 0.001, d = 0.46), and interictal allodynia (1.0 vs. 0.0, p < 0.001, d = 0.30). After controlling for patient age, sex and years lived with headache, abuse maintained a significant association with every sensory hypersensitivity measure. Headache frequency significantly moderated the relationship between a history of abuse with increased ictal allodynia (p = 0.036). Anxiety significantly mediated the relationships between abuse with photophobia (IE = 0.03, 95% CI = 0.01–0.04), hyperacusis (IE = 1.51, 95% CI = 0.91–2.24), ictal allodynia (IE = 0.02, 95% CI = 0.01–0.04), and interictal allodynia (IE = 0.02, 95% CI = 0.01–0.06). Depression significantly mediated the relationship between abuse with photophobia (IE = 0.02, 95% CI = 0.01–0.03) and with hyperacusis (IE = 0.45, 95% CI = 0.11–0.88). The association between the individual subtypes of abuse and the number of subtypes of abuse with sensory hypersensitivity symptoms varied. Conclusion: A history of abuse is associated with greater migraine‐related sensory hypersensitivity symptoms. To reduce the impact of abuse on migraine symptoms, future studies should explore mechanistic connections between abuse and migraine‐associated symptoms. [ABSTRACT FROM AUTHOR]

Objective: To investigate between and within‐woman differences in the association between menstruation and migraine days. Background: Prior diary studies have shown that at the population level, aggregating across individuals, the odds of migraine increase during the perimenstrual window (from day −2 to day +3, where +1 is the first day of bleeding). These studies have been neither long nor large enough to assess the association between migraine and menses from an individual perspective. Consequently, existing research on menstrual‐related migraine has largely overlooked between and within‐woman variation that is critical for progressing clinical understanding and practice. Methods: Intensive longitudinal data for the current study were collected in a digital platform (N1‐Headache®) that tracks individual migraine‐related factors daily. Participants for the current study were actively menstruating adult (18+ years old) women who used the platform. Two variables were of primary interest, migraine day (no/yes) and menstrual status (inside or outside the 5‐day perimenstrual window). Results: The sample consisted of 203 women with a mean age of 35.6 (SD = 8.7) years. At baseline, the women reported an average of 30.6 (SD = 23.6) headache days over the last 3 months. Analyses were based on a total of 53,302 days (median of 150 per person), 18,520 of which were migraine days (median of 44 per person), and a total of 2,126 menstrual cycles (median of 7 per person). Results showed that the 5‐day perimenstrual window was associated with a 34% increase in odds of a migraine day compared to other days (OR = 1.34, 95% CI: 1.23–1.45, p < 0.0001). Importantly, there was between and within‐woman variability in the association between menses and migraine days (between‐woman variability: p = 0.002; within‐woman [between‐cycles] variability: p < 0.0001). Exploration of these individual differences demonstrated that relationship between menses and migraine days varied more within‐person across cycles than between women. Discussion: This study supports previous research and demonstrates that the odds of migraine days are elevated from day −2 to day +3 of the menstrual cycle. We also show that the effect of menses on migraine days varies more within‐woman than between‐women. This work provides an initial foundation for better understanding menstrual‐related migraine from the perspective of the individual patient. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have demonstrated magnesium supplements to be effective for prophylactic treatment of migraine. Dietary magnesium intake of many Americans is known to be below nutritional recommendations, but typical magnesium intake from dietary sources in adults with migraine has not previously been evaluated. Objective: This study aimed to quantify dietary and total (diet + supplement) magnesium consumption of adults with migraine or severe headache in the United States, and to investigate the relationship between magnesium consumption levels and prevalence of migraine or severe headache. Methods: This analysis included cross‐sectional data from 3626 participants, 20‐ to 50‐years old in the National Health and Nutrition Examination Survey between 2001 and 2004. Presence of migraine or severe headache in the past 3 months was determined by questionnaire. Individuals responding affirmatively were classified as having migraine, and individuals reporting not experiencing migraine or severe headache were classified as controls. Dietary magnesium intake was determined from a 24‐hour recall interview, supplemental magnesium intake was determined from the dietary supplements interview, and total magnesium intake was the sum of dietary and supplement intake. Results: Mean dietary consumption of magnesium was below the recommended dietary allowance (RDA) for both migraine (n = 905) and control groups (n = 2721). Attainment of the RDA through a combination of diet and supplements was associated with lower adjusted odds of migraine (odds ratio [OR] = 0.83, 95% confidence intervals [CIs] = 0.70, 0.99, p = 0.035). Magnesium consumption in the highest quartile (Q) was associated with lower odds of migraine than in the lowest Q for both dietary (OR = 0.76, 95% CI = 0.63, 0.92, p = 0.006) and total (OR = 0.78, 95% CI = 0.62, 0.99, p = 0.042) magnesium intake in adjusted models. Conclusion: These results suggest inadequate consumption of magnesium intake is associated with migraine in U.S. adults ages 20–50. Further prospective investigations are warranted to evaluate the role of dietary magnesium intake on migraine. [ABSTRACT FROM AUTHOR]

Migraine is a common clinical chronic neurovascular disease, which seriously affects the quality of life of patients. Studies have shown that patent foramen ovale (PFO) may be related to migraine, such as transient hypoxemia caused by patent foramen ovale related right - to - left shunt, or vasoactive substances passing through an unclosed oval foramen, avoiding lung tissue metabolism and directly entering the arterial system, and contradictory micro-embolism and other mechanisms may be related to migraines related to patent foramen ovale, especially migraine with aura. The closure of patent foramen ovale can benefit some migraine patients. This article intends to outline the relationship between patent foramen ovale and migraine, and its mechanism, prevention and treatment. [ABSTRACT FROM AUTHOR]

Objective: In this study, we explored the relationship between migraine and sport in a physically active population of students, analyzing the risk of migraine among sporty students. Background: The relationship between sport and migraine is controversial; moreover, several studies report on sport as a migraine trigger, but there is evidence that physical activity could have a relevant role in migraine prevention. Methods: A cross‐sectional survey was conducted using the validated ID‐migraine questionnaire including specific demo‐anthropometric (gender, age, weight, height) and sports variables on a potentially active student population of the University of Palermo. Evaluation in putative migraine subjects of clinical features and disability was explored through the administration of the Italian version of the Migraine Disability Assessment Scale. Statistical analyses were performed using univariate and logistic regression analyses. Results: Three hundred and ninety‐three out of 520 students (210 F, mean age: 23.5 ± 0.7 years; 183 M; mean age: 20.5 ± 0.7 years) participated in this study. Migraine screened positive in 102 subjects (26.0%) and its prevalence was significantly higher among females (P <.001). An increased risk of migraine was found in females, and a protective effect of sport on the risk of migraine among females, but not among males. Conclusions: The role of exercise in migraine is still unclear. This study supports a protective role of sport in migraine reporting a protective effect in females. Further studies are needed to deepen the association between sport and migraine. [ABSTRACT FROM AUTHOR]

An editorial is presented on the predicting the Future of Migraine Attack Prediction. Topics icnlude the empirical observation may lead to mechanistic hypotheses that can subsequently be tested, the prediction models for migraine are primarily based on external and internal events which are temporally associated with increased risk of an attack, and the triggers are events associated with an increased probability of an attack of a relatively brief period.