Abstract
Purpose of Review
In this narrative review, we aim to summarize recent insights into the complex interplay between environmental and genetic factors affecting the etiology, development, and progression of chronic migraine (CM).
Recent Findings
Environmental factors such as stress, sleep dysfunction, fasting, hormonal changes, weather patterns, dietary compounds, and sensory stimuli are critical triggers that can contribute to the evolution of episodic migraine into CM. These triggers are particularly influential in genetically predisposed individuals. Concurrently, genome-wide association studies (GWAS) have revealed over 100 genetic loci linked to migraine, emphasizing a significant genetic basis for migraine susceptibility.
Summary
In CM, environmental and genetic factors are of equal importance and contribute to the pathophysiology of the condition. Understanding the bidirectional interactions between these elements is crucial for advancing therapeutic approaches and preventive strategies. This balanced perspective encourages continued research into the complex gene-environment nexus to improve our understanding and management of CM.
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Introduction
Migraine, which affects an estimated one billion individuals worldwide, is a complex disorder characterized by intense recurring headaches. These episodes are often accompanied by multiple symptoms such as nausea, vomiting, and extreme sensitivity to light and sound. Chronic migraine (CM), a particularly debilitating subtype of migraine, is defined as the presence of headaches for 15 days or more per month, with at least 8 days meeting the specific criteria for migraine. Depending on their severity and frequency, the headaches can substantially impair the quality of life and productivity of patients, making CM a major public health concern [1].
The etiology of CM involves a complex interplay between genetic and environmental factors. The genetic influences are substantial with heritability estimates ranging from 50 to 80%. Recent studies have identified more than 100 genetic loci associated with migraine that affect nerve transmission, inflammation, and pain perception [2]. Furthermore, the advent of genome-wide association studies (GWAS) has been instrumental in elucidating the polygenic nature of migraine [3••]. Environmental factors also play critical roles, particularly in genetically predisposed populations. These factors not only precipitate migraine episodes but also contribute to migraine chronification [4].
In this review, we aim to provide an up-to-date summary of the genetic variants and environmental exposures with potential roles in CM pathogenesis. Elucidating the genetic and environmental underpinnings of CM may provide biological insights into the development of targeted therapeutics and personalized prevention strategies for this disabling disorder.
Environmental Factors in CM
A myriad of environmental exposures have been implicated as triggers capable of precipitating acute migraine episodes, especially among genetically vulnerable individuals, based on their polymorphic risk profile. Common triggers include but are not limited to stress, sleep dysfunction, fasting, hormonal changes, weather patterns, odors, dietary compounds, and sensory stimuli [4]. Exposure to a combination of these triggers may also contribute to migraine chronification in patients prone to progressive sensitization. In this section, we review external and lifestyle-related factors (Table 1) linked to either provoking individual migraine attacks or gradually lowering the migraine activation threshold.
Stress
Migraine can activate the autonomic nervous system, particularly the hypothalamic–pituitary–adrenal (HPA) axis, when stress experienced exceeds an individual’s coping capacity. This stress response includes the release of cortisol and other stress hormones, potentially triggering or exacerbating migraine [5]. Furthermore, emotional disorders such as anxiety and depression are closely linked to the occurrence of migraine. These emotional states may enhance pain perception by affecting the pain-processing mechanisms in the brain. Conversely, migraine can also lead to changes in a patient’s emotional state, especially in those with CM. These emotional responses, potentially stemming from the pain itself or the effect of headaches on daily life, form a vicious cycle that further intensifies the pain [6].
Patients with CM often face higher stress due to frequent, prolonged headaches, potentially overactivating their HPA axis and leading to abnormal cortisol levels. In contrast, patients with episodic migraine (EM) have fewer headache episodes and less HPA axis disturbance. Fluctuations in the levels of neurotransmitters, particularly serotonin and norepinephrine, which are key to pain and emotion regulation, are more pronounced in CM, possibly because of frequent headache episodes and a high risk of depression or anxiety [7]. Specific brain regions such as the amygdala and prefrontal cortex also play major roles. The amygdala, which is involved in emotion processing, also functions in the emotionalization of pain [8]. The enhanced connectivity between the amygdala and visual processing areas in patients with CM, which has been implicated in pain and emotional response, may account for their increased pain sensitivity and emotional distress. This alteration in brain connectivity could be either a developing trait of CM, potentially acting as a risk factor, or an adaptive response mechanism of the brain to extended pain and stress, indicative of neural plasticity in response to continuous pain stimuli in CM [9•]. Some regions of the prefrontal cortex are also crucial for directing attention to pain and emotional responses [10].
Considering these factors, the current review emphasizes the importance of psychotherapy in migraine treatment strategies, particularly cognitive behavioral therapy (CBT) and stress management techniques, which have proven effective in reducing migraine attacks [11].
Sleep Disturbances
Individuals with migraine are more prone to sleep problems, such as insomnia and poor sleep quality, than the general population. Insufficient sleep can trigger migraine attacks, and prolonged poor sleep quality may lower the pain threshold, thereby exacerbating the migraine symptoms [12]. Further studies have revealed that sleep disturbances associated with migraine may be linked to the hypothalamus [13]. The posterior hypothalamus, pivotal in managing various physiological functions such as pain perception and sleep regulation, plays a key role in migraine pathophysiology, and its activity is regulated by pituitary adenylate cyclase-activating peptide (PACAP). PACAP, existing in forms such as PACAP-38 and PACAP-27, influences migraine development through its action on PAC1 receptors, which are closely linked to migraine attacks. It has been observed that PACAP can sensitize trigeminal neurons, an effect that can be inhibited by PAC1 antagonists. During migraine attacks, the concentration of PACAP-38 reportedly increases. The posterior hypothalamus, integral to the circadian rhythm entrainment, is associated with intrinsically photosensitive retinal ganglion cells (ipRGCs) via the retinohypothalamic tract (RHT). In this pathway, PACAP is crucial to modulating the transmission of light signals from the retina to the hypothalamus, thereby playing a vital role in the regulation of the sleep–wake cycle [14••].
Specific sleep stages are also associated with migraine. The maximum episodes of migraine attacks often occur early in the morning or late at night, which may be related to the rapid eye movement (REM) sleep stage. Serotonin levels also decrease throughout the body during REM sleep, which potentially explains the relationship between REM sleep and migraine [15]. Lack of sleep can sensitize the trigeminal pain pathway, thereby triggering migraine attacks. Untreated sleep disorders, such as obstructive sleep apnea (OSA), may also contribute to the progression of migraine by affecting hypoxia and oxidative stress pathways, further sensitizing the trigeminal nociceptors [16]. However, additional research is essential to better understand and define the association of sleep stages with CM.
While there is still debate over whether improving sleep quality can reduce the frequency of migraine, some clinical studies have confirmed the positive effect of managing sleep disorders on headache outcomes, including the use of suvorexant, an orexin antagonist [17], and implementation of behavioral sleep intervention programs [18].
Fasting and Meal Skipping
Delaying or missing meals are among the most frequently cited but underrecognized dietary contributors to migraine attacks. Nearly 40% of individuals with CM identify fasting or hunger as an attack trigger in surveys [19]. The mechanisms by which fasting promotes migraine episodes likely involve cerebral vasodilation, cortisol release, and hypoglycemia, all of which can enhance cortical excitability and sensitize meningeal trigeminal pain fibers [20]. Maintaining regular eating schedules has demonstrated some efficacy in reducing headache frequency, plausibly by stabilizing the serum glucose levels and preventing hypoglycemic states linked to cortical spreading depression (CSD) susceptibility [21]. However, additional research is essential to better understand and define its association with CM.
Weather Changes
Studies have indicated that the effect of weather on migraine remains contentious. Numerous patients with migraine have reported that specific weather conditions can trigger headaches. Over half of the patients suffering from migraine consider weather to be a trigger factor [22], especially when the atmospheric pressure drops by more than 5 hectopascals (hPa) [23]. The proposed mechanism involves changes in the intracranial pressure or the release of inflammatory mediators during storm fronts, which may promote vasodilation and activate meningeal nociceptors. Migraine attacks and the associated disabilities often peak during the transitional periods of spring and autumn [23].
Humidity and rainfall are also thought to affect migraine occurrence, but the association remains unclear. Some small-scale studies have suggested that cloudy and thundery weather conditions may trigger migraine, although these conclusions require cautious interpretation [24]. Large-scale studies, such as those conducted by Zebenholzer et al. did not confirm a significant correlation between weather conditions and migraine episodes [25]. High temperature has been identified as a major trigger of migraine and is possibly related to increased body temperature [26]. Some small-scale studies indicate that the preventative adjustment of behavioral habits based on predicted weather changes can alleviate weather-induced attacks in specific patients [27]. However, additional research is essential to better understand and define the association of high temperature with CM.
Hormones
Migraine presents with significant sex disparities in incidence rates, pathogenic mechanisms, and clinical manifestations. Female individuals exhibit a higher lifetime prevalence, especially during their reproductive years [28]. Estrogen has been linked to CM occurrence; it enhances pain sensitivity by increasing CSD sensitivity and disrupting neuronal vascular function, particularly in the central trigeminovascular system. It acts through estrogen receptor β (ERβ), affecting the central nervous system and leading to neurogenic inflammation and central sensitization. The binding of estrogen to the receptor increases calcium concentration in neurons, lowering the nociceptive neurotransmission threshold and contributing to central sensitization and cortical hyperexcitability [29]. This process is further amplified by enhanced N-methyl-D-aspartate (NMDA) receptor activity on glutamatergic neurons. Changes in the estrogen level also affect the levels of neurotransmitters such as CGRP and serotonin, potentially contributing to the progression of CM [30]. Prolonged-cycle oral contraceptive use can stabilize hormone levels and reduce symptomatic migraine episodes [31]. Overall, sex-dependent differences are likely the result of an interplay between genetics and hormones.
Clinically, migraine manifests differently in female individuals, often as unilateral headaches with photosensitivity and without nausea or vomiting [32]. They also frequently report nonspecific symptoms, such as neck stiffness, leading to potential misdiagnosis. Owing to physiological differences, the male and female individuals may respond differently to certain medications, with women being more sensitive to 5-HT1B/1D receptor agonists [28]. The transgender population experiences unique migraine patterns owing to hormonal changes and shifts in gender identity [33]. Sex-related differences also influence migraine treatment strategies, which is possibly related to the hormonal regulation of neurotransmitter signaling pathways. Oral contraceptives alleviate menstruation-related migraine attacks [34].
The biological basis of the increased susceptibility of females to migraine includes the distribution of estrogen receptors in the central structures related to pain processing, which affects pain management [35]. Nitric oxide synthase plays a role in migraine pathology, with a more concentrated distribution in the spinal neurons of female rats, and estrogen promotes increased nitric oxide synthesis in migraine models [36]. Variations in osteopontin gene polymorphisms related to calcium metabolism have been linked to an increased susceptibility to migraine in females. The neuropeptide PACAP plays a major role in migraine onset, and genetic polymorphisms in females are notably related to higher susceptibility [36].
Sex-related differences are also evident in the peak incidence of migraine. Before puberty, male and female individuals exhibited similar incidence rates. However, postmenstrual women are more prone to migraine, related to hormonal secretions and endometrial shedding. Pregnancy and menopause are high-risk periods due to drastic hormonal fluctuations, whereas males achieve a delayed peak, which is associated with increased androgen levels and decreased estrogen levels at puberty [28].
Dietary Compounds
Recent studies have identified a significant correlation between specific foods and beverages and the occurrence of migraine. Tyramine, a biogenic amine present in foods such as aged cheese, red wine, and fermented products, has been implicated in the onset of migraine. It is metabolized to dopamine, which promotes vasodilation and contributes to migraine pathogenesis; dopamine may also affect serotonin release [37]. Research indicates that abnormalities in tyrosine metabolism may play a role in the transformation of migraine without an aura into CM [38].
Nitrates and nitrites found in processed meat are also considered potential triggers of migraine. These compounds can be converted to nitric oxide (NO) in the body, causing vasodilation, which may lead to changes in cerebral blood flow and trigger headaches. Furthermore, nitrates and nitrites may induce migraine by stimulating the neural system in the brain [39].
Caffeine has a paradoxical relationship with migraine, serving as both a common treatment and, in cases of excess intake or withdrawal, a reported trigger. Adenosine levels in the blood increase during migraine attacks, and caffeine, which blocks adenosine receptors, inhibits the effects of adenosine. However, the specific mechanisms by which caffeine controls pain and induces headaches remain unclear [40].
Monosodium glutamate (MSG) intake has been linked to migraine induction in sensitive individuals and plays a major role in its pathophysiology [41]. Alcohol can stimulate meningeal nociceptors in the trigeminal ganglion and cause vasodilation and dehydration, potentially contributing to alcohol-induced migraine [42]. Foods rich in flavonoids, such as chocolate, wine, and tea, are also recognized triggers in some patients. This may be because of flavonoid-enhancing vanilloid receptors in the neurogenic inflammatory pathways associated with migraine [43].
Studies using the dietary inflammatory index (DII) as an assessment tool have found that higher DII scores are significantly correlated with an increased risk of severe headaches or migraine [44••]. Research shows that diets with a low glycemic index; low fat, ketogenic diets; and Dietary Approaches to Stop Hypertension (DASH) can help reduce the frequency and severity of CM [42].
Sensory Stimuli
External sensory stimuli, especially bright or flickering light, loud noise, and strong odor, can immediately trigger acute migraines in the majority of patients with CM [45], causing inconvenience in their daily lives. Odor sensitivity (olfactory hypersensitivity) is also common among patients with migraine. Odors such as those of perfumes, vehicle exhaust, cigarette smoke, cleaning agents, and other volatile chemicals can quickly induce headaches in patients with CM [46]. Studies have suggested that patients with severe migraine are more prone to odor-induced attacks and are more likely to experience insomnia, depression, fatigue, and sensory hypersensitivity [47]. Flickering light sources can also easily trigger migraine attacks in patients with CM, and specific patterns and colors may evoke discomfort, especially black-and-white stripes and high color contrasts [48]. Noise in the environment is one of the risk factors for migraine onset. Intense sounds or specific auditory stimuli (such as ambulance sirens or railway-level crossing bells) can easily trigger migraine attacks in patients with CM. Exposure to such sounds during an attack exacerbates the pain level. To avoid sound-induced pain, patients often adopt avoidance strategies, attempting to stay away from specific sources of sound that may trigger headaches. These strategies limit their daily activity range [49].
Overall, photosensitivity, odor sensitivity, and sound sensitivity reflect interictal dysregulation in sensory processing, lowering the migraine activation threshold, and potentially restricting daily activities [50]. Treatments targeting the regulation of trigeminal excitability and central amplification have been shown to reduce the sensitivity of patients with migraine to odor, light, and sound [45]. However, optimizing the sensory environment to avoid strong triggers has also been proven effective in reducing the frequency and severity of migraine attacks [50]. Additional research is essential to better understand and define the association of sensory stimuli with CM.
Genetic Factors in CM
Extensive research has explored the association between genes and migraine, with large-scale GWAS uncovering numerous genetic variants [3••, 51•]. Genetic research has also underscored the shared genetic factors between migraine and major comorbidities such as depression and high blood pressure [2]. Although genetic predisposition is believed to play a role, specific genetic markers associated with migraine chronification have not been fully identified. The transition from episodic migraine to CM typically occurs gradually and involves multiple risk factors.
An early comprehensive study [52•] on single-nucleotide polymorphisms in patients with CM and the subsequent whole-genome sequencing in another large cohort [53] revealed no distinct genetic differences between chronic and episodic migraine cases. The lack of specific rare variants or higher polygenic risk scores suggests that environmental factors, rather than genetic factors, play a more pronounced role in the progression of migraine from an episodic to chronic form.
Recent studies comparing chronic and episodic migraines have identified some genetic variants that may contribute to migraine chronification (Table 2). Additionally, several influential genes have been widely discussed in the literature as being involved in CM therapy. In this section, we summarize recent research on how genetic factors may contribute to CM.
Transient Receptor Potential Family
In CM research, transient receptor potential (TRP) ion channels, especially TRPV1 and TRPM8, are recognized as pivotal in transforming episodic migraine to CM [54,55,56]. These channels are integral in converting noxious stimuli into pain signals and are associated with CGRP, a key mediator of migraine development. Genetic variations in TRPV1, such as the 1911A > G variant, have been linked to CM and implicated in the sensitization of pain receptors [57]. TRPV1 activation results in increased CGRP release, which exacerbates migraine symptoms and prolongs meningeal nerve activation [58]. TRPM8, which is responsive to cold stimuli, also plays a role in migraine pain perception, with individuals carrying the rs10166942 T allele showing an increased risk of CM [56]. Moreover, TRPA1’s interaction with NMDARs and mu-opioid receptors underscores its significance in the modulation of pain signals [59]. Variants such as TRPV1 rs222741 and TRPM8 rs7577262 are associated with increased anxiety in certain migraine populations, indicating the role of TRP channels in migraine-related comorbidities [60].
Human Leukocyte Antigen Class I
Human leukocyte antigen (HLA) class I molecules are crucial components of the immune system and are primarily involved in the presentation of peptides to T cells [61]. Previous studies have suggested that migraines have genetic similarities with inflammatory diseases [62]. In a case–control study, Huang et al. found that genetic variations in HLA class I molecules positively correlated with the incidence of clinic-based migraine. In addition, the HLA-B*58:01 and HLA-C*03:02 alleles were significantly associated with CM. Drug molecules may affect the immune responses related to migraine, which could lead to the aggravation or chronification of headaches, particularly when painkillers or medications are overused [63].
Dopamine Beta-Hydroxylase
Dopamine beta-hydroxylase (DBH) converts dopamine to norepinephrine, which is important for neurotransmitter synthesis and plays a pivotal role in the pathophysiology of migraine [64]. Previous studies have indicated that the DBH rs7239728 and rs6271 polymorphisms increase the risk of migraine, and DBH rs2097629 increases the risk of migraine with aura [65,66,67]. According to a recent validation study, the DBH 19-bp insertion/deletion polymorphism may not be associated with migraine susceptibility but is linked to medication overuse in patients with CM. Prefrontal cortex hypofunction may be counteracted by lower dopaminergic activity in patients with CM carrying the I allele (increased DBH activity and reduced dopamine levels), thus shielding them from the risk of medication overuse [68].
Catechol-O-Methyltransferase
Catechol-O-methyltransferase (COMT) has been studied for its potential contribution to migraine. A study focused on assessing the significance of COMT polymorphisms in migraine suggested that the L allele of COMT is overrepresented in patients with migraine, particularly those with a family history of migraine, indicating the potential pharmacological importance of COMT polymorphisms in migraine [69]. In contrast, a study on the association of five single nucleotide polymorphisms (SNPs) in COMT with migraine in Western Japan found no significant differences between the patients with migraine and controls [70]. Thus, COMT’s specific link to CM remains uncertain and requires further research.
Calcitonin Gene-Related Peptide
Calcitonin gene-related peptide (CGRP) exists as αCGRP (CALCA) and βCGRP (CALCB) in the human body and plays a crucial role in pain transmission in the trigeminovascular system, making it a significant factor in migraine pathophysiology [71]. CGRP receptor antagonists are effective as a therapeutic strategy for migraine treatment [72,73,74]. Although GWAS have identified new loci in CALCA/CALCB, the relationship between CGRP gene variants and migraine chronification has not been fully established [71]. Epigenetic modifications of CALCA are associated with various migraine clinical features and can be potential targets for migraine therapy [75]. Moreover, inhibition of HDAC6 expression, which affects CGRP pathways, represents another promising treatment avenue [76].
Histone Deacetylase Inhibitors
Histone deacetylases (HDACs) have emerged as potential targets for the treatment of chronic pain syndromes such as CM [77]. HDACs play a crucial role in modulating neuroinflammatory responses. Studies have shown that HDAC inhibitors can effectively reduce neuroinflammation [78], and they have been implicated in modifying epigenetic changes in genes associated with chronic pain conditions [79]. Research using rat models has highlighted the effectiveness of HDAC inhibitors in treating medication overuse headache (MOH), a common complication of migraine management. These inhibitors have been found to counteract the overexpression of genes encoding CGRP and its receptor subunit RAMP1 in the trigeminal ganglion [80]. Additionally, HDAC6 inhibitors have shown promise in reversing structural neural disruptions and mitigating the symptoms of CM, including CSD [81]. A recent GWAS also identified a genetic variant of HDAC9 (rs1178326) associated with insomnia in patients with migraine, although its relevance to CM remains to be established [82].
Efficacy of Therapy
Although the association between genetic polymorphisms and CM remains debatable, numerous studies have discussed the effects of genetic variability on drug efficacy in patients with CM. In particular, the MAOA uVNTR polymorphism showed a strong correlation with triptan response. In addition, the CYP1A2*1F variant is associated with triptan overuse and response in certain patient groups [83, 84]. Further research on the efficacy of onabotulinumtoxinA highlights the role of genetic variations in the treatment response. Polymorphisms in the CALCA rs3781719 and TRPV1 rs222749 genes have been identified as potential markers for predicting the response to onabotulinumtoxinA in female patients with CM [85]. These genetic insights pave the way for personalized treatment approaches for CM.
Comorbidities
Numerous comorbidities have been identified as risk factors for the development of CM [86], and researchers have explored whether there is a correlation between genetic polymorphisms in migraine and these comorbidities. In a study, 14 SNPs were found to be associated with insomnia and CM [82]. Among the candidate genes, SLC38A10, which acts as a glutamate transporter, has been studied for its potential relationship with migraine onset. This gene can affect neuronal viability by protecting against glutamate toxicity and oxidative stress, which are assumed to contribute to migraine and insomnia onset [87, 88].
GWAS conducted in European populations have shown a genetic correlation between migraine and depression. The genetic profiles of patients who suffer from both depression and migraine are more closely aligned with those of patients with depression alone [89]. Ashina et al. utilized a validated questionnaire (PHQ-9 score ≥ 15) to analyze patients transitioning from episodic migraine to CM. They suggested that depression is associated with an increased risk of progression to CM and that this risk escalates with the severity of depression [90]. In a study involving Chinese population, the intergenic SNP rs9356570 was associated with CM and depression [91]. However, the underlying pathophysiological mechanisms require further investigation.
Cognitive dysfunction is a major issue in patients with migraine, with many reports of subjective cognitive decline (SCD). Clinical and neuroscientific studies have found that migraine episodes often coincide with reduced cognitive performance [92]. Depression and limited sleep during workdays have been linked to SCD in adult individuals with migraine [93]. Genetic research has identified two specific SNPs, rs17111293 in LOC107984361 and rs17111293 in ARHGAP29, which are associated with SCD and CM [94]. The dysregulation of the ARHGAP29 gene is implicated in a range of cognitive and neurological disorders, including migraine without aura [95]. The potentially shared genetic underpinnings between CM and SCD, particularly the genes influencing neuronal development, present a compelling area for future exploration.
Suicide, migraine, and mental illnesses have been linked by a strong bidirectional association, most likely due to shared neuropathic mechanisms. To understand the potential genetic links to suicidal risk in patients with CM with affective temperamental dysregulation, a focused study explored the association between specific gene variants (MAO-A3, CYP1A2*1F, and GNB3) and suicidal tendencies. This study found a correlation among high levels of affective dysregulation, increased hopelessness, and suicide risk. However, there was no direct association between the studied genetic variants and an increased risk of suicide. This outcome indicates that the risk of suicide in patients with CM is likely due to a multifaceted combination of genetic and environmental factors [96].
Epigenetics of Migraine Chronification
Recent research has focused on the role of epigenetic mechanisms in the chronification of migraine by exploring how changes in DNA methylation and gene expression can influence migraine susceptibility and its evolution from an episodic to chronic form [97, 98•, 99]. Studies have identified specific genes, such as SH2D5 and NPTX2, that are involved in regulating synaptic plasticity and may play a role in migraine chronification, although the findings have been inconclusive [98•, 99]. The exact biological mechanisms and effects of environmental factors, inflammation, and brain plasticity on these epigenetic changes are not yet fully understood [100].
This gene-environment interaction indicates the complexity of migraine as a chronic condition. The exact biological mechanisms underlying these epigenetic influences remain as areas of active investigation. However, considering epigenetics as a bridge between genetic and environmental factors is important for understanding the pathophysiology of migraine and developing effective treatment strategies.
Conclusions
In conclusion, both genetic predisposition and environmental influences contribute significantly to the pathogenesis of CM (Fig. 1). GWAS have identified numerous genetic variants associated with migraine; however, the specific factors driving the transition from an episodic to chronic form extend beyond genetics alone. Environmental triggers such as stress, sleep disturbances, and dietary factors are crucial in this process. Moreover, key genetic variants and the involvement of genes emphasize the genetic complexity of CM. Additionally, epigenetic mechanisms reveal how environmental factors affect gene expression, thereby influencing migraine susceptibility and chronification. This review highlights the need for a holistic approach to understand and manage CM. Advancements in this field promise more personalized and effective treatments, potentially easing the burden of CM in patients globally.
Environmental and genetic factors contributing to chronic migraine. This diagram illustrates the association between environmental and genetic factors influencing the development of chronic migraine. A question mark has been placed next to genetic factors with a low level of evidence or a degree of uncertainty regarding their direct association with chronic migraine
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This work was partially supported by the Ministry of Science and Technology of Taiwan (grant number MOST 110–2314-B-016–036-MY2) and the Tri-Service General Hospital, Taiwan (grant numbers TSGH-D-113108 and TSGH-D112097).
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Po-Kuan Yeh, Yu-Chin An, and Fu-Chi Yang wrote the main manuscript text and Yu-Chin An and Kuo-Sheng Hung prepared Fig. 1. All authors reviewed the manuscript.
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Yeh, PK., An, YC., Hung, KS. et al. Influences of Genetic and Environmental Factors on Chronic Migraine: A Narrative Review. Curr Pain Headache Rep 28, 169–180 (2024). https://doi.org/10.1007/s11916-024-01228-4
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DOI: https://doi.org/10.1007/s11916-024-01228-4