Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 https://doi.org/10.1186/s10194-020-01111-8 The Journal of Headache and Pain REVIEW ARTICLE Open Access From transformation to chronification of migraine: pathophysiological and clinical aspects M. Torres-Ferrús1*, F. Ursitti2, A. Alpuente-Ruiz1, F. Brunello3, D. Chiappino4, T. de Vries5, S. Di Marco6, S. Ferlisi6, L. Guerritore4, N. Gonzalez-Garcia7, A. Gonzalez-Martinez8, D. Khutorov9, M. Kritsilis10, A. Kyrou11, T. Makeeva12, A. Minguez-Olaondo13,14,15, L. Pilati6, A. Serrien16, O. Tsurkalenko17, D. Van den Abbeele18, W. S. van Hoogstraten19, C. Lampl20 and On behalf of School of Advanced Studies of European Headache Federation (EHF-SAS) Abstract Chronic migraine is a neurological disorder characterized by 15 or more headache days per month of which at least 8 days show typical migraine features. The process that describes the development from episodic migraine into chronic migraine is commonly referred to as migraine transformation or chronification. Ample studies have attempted to identify factors associated with migraine transformation from different perspectives. Understanding CM as a pathological brain state with trigeminovascular participation where biological changes occur, we have completed a comprehensive review on the clinical, epidemiological, genetic, molecular, structural, functional, physiological and preclinical evidence available. Keywords: Chronic migraine, Transformation, Pathophysiology, Risk factors, Genetics, Biomarker, Neurophysiology, Neuroimaging, Animal models Background month of which at least 8 days per month show typical Migraine is a neurological disorder characterized by at- migraine features, for at least 3 months. In 1982, Mathew tacks of throbbing headache and neurological symptoms et al. reported a series of patients with a clear-cut past his- such as nausea, vomiting, hypersensitivity to environmen- tory of distinct attacks of migraine whose headaches tal stimuli and mood changes. The development and evolved over the years into a daily or near daily problem course of migraine differs from patient to patient, where a [3]. He was the first who proposed the term “transformed subset of patients experience an increase in frequency over migraine”. a period of months or years [1]. This process may lead to Migraine transformation or chronification clinically a chronic form of migraine that, according to the Inter- represents a more or less consistent increase in migraine national Classification of Headache Disorders (ICHD-3) frequency until, in most of the cases, it develops into a [2], is called chronic migraine (CM). This form of mi- constant migraineur state with very frequent, disabling graine is characterized by 15 or more headache days per headache with associated symptoms, increased use of acute medication, high medical care and reduced quality * Correspondence: marttorr@vhebron.net of life. Headache interferes with life, work and results in 1 Headache and Craniofacial Pain Unit, Neurology Department, Hospital a high burden of the disease. Universitari Vall d’Hebron, Headache and Neurological Pain Research Group, The estimated prevalence of CM worldwide ranges Vall d’Hebron Research Institute (VHIR), Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain widely between 0.9% to 5% [4]. CM prevalence is three Full list of author information is available at the end of the article times more common in women than men (18.9% vs. © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 2 of 12 9.8%) and presents two peaks between ages of 18–29 Burden of Migraine Study (IBMS) [15] both EM and and 40–49 years-old [5, 6]. The development from EM CM are more common among women and young adults. to CM is estimated to occur in approximately 2.5% of Surprisingly, a recent study found that the typical risk the patients with EM per year, while only a limited pro- factors (demographics, headache features, and comor- portion with CM revert back to EM [5, 7]. bidities) predicted the chronification in men less Underlying this process, central and peripheral neuro- accurately. This implies that prognostic factors of chron- logical functional and even structural changes are occur- ification might not be as well understood in men than in ring. Many studies tried to identify factors associated women [16]. Similar sex correlations also seem to exist with migraine transformation utilizing different in the adolescent population, since the incidence of approaches. To establish the clinical risk factors for chronic daily headache and frequent migraine is higher chronification and the structural or functional neuro- in girls than in boys [17, 18]. logical changes that occur in patients who evolve to CM A pattern of increasing CM prevalence with age from studies should include large migraine cohort studies with 18 to 50 year-old has been observed for both males and long-term follow-up. Due to the evident complexity of females [6]. Regarding race, although both CM and EM these studies, the majority of studies have tried to ad- respondents were more likely to be Caucasian, a larger dress this question with retrospective approaches or by proportion of CM patients was Caucasian [9, 19, 20]. comparing cohorts of EM and CM patients. Less well characterized is the relation between lower A better understanding of these underlying patho- education status and CM. The majority of studies have physiological changes in light of the accompanying clin- found that patients with CM have lower levels of educa- ical developments, could possibly help us to discover tion compared to EM [5, 19, 21]. However, the AMPP new disease markers, or even future treatment targets. and IBMS studies found no significant difference with Subsequently, the objective of this review is to present regard to level of education [9, 15]. Furthermore, CM the current knowledge on clinical and pathophysiological patients were less likely to be employed full time, and signatures of CM in an attempt to unify the two differ- more likely to be occupationally disabled [9, 15, 19]. In ent perspectives. the same study differences regarding marital status have also been reported, although the majority of both groups Clinical characteristics were married and there were not any group with a con- The development into CM does not occur in all patients clusive higher risk [9]. Relating to these characteristics with EM [8]. Therefore, identifying risk factors associ- in adolescents with CM, high prevalence of chronic daily ated with migraine transformation/chronification may headache (CDH), a diagnosis partially including CM pa- provide crucial information in understanding the under- tients, has been shown to be associated with lower lying mechanisms [7]. Epidemiologic studies have de- household economic status and acute family financial scribed clinical factors that are more common in CM distress [17]. On the other hand, the Frequent Headache patients compared to EM patients [9, 10]. Although it Epidemiology study could not confirm any correlation has been described a statistically relevant association be- between onset of CDH and age, sex, marital status, edu- tween CM and demographic, lifestyles, comorbidities or cational level, and race [22]. Although numerous studies other migraine features [5], the underlying pathophysio- have found that CM patients tend to have lower levels of logical mechanisms remain to be elucidated. education than EM patients, no definitive conclusion Clinical risk factors for migraine transformation can can be drawn due to replication issues. be divided into non-modifiable and modifiable risk fac- tors. Non-modifiable risk factors mainly include sociode- Lifestyle mographic features. Modifiable factors, which can The identification of modifiable risk factors may provide provide targets for intervention, include lifestyle factors, targets for future interventions in order to avoid chroni- headache features and comorbidities [7, 9]. fication. Among these are caffeine misuse, body weight gain, and sleep disorders [7]. Demographic factors It has been shown that inappropriate high caffeine con- The most important non-modifiable risk factors for de- sumption increase the risk of progression into CM [23]. In veloping CM include age, sex, race, socioeconomic and fact, subjects with CDH were more likely to have been educational status [11]. high caffeine consumers before the onset of CDH [23]. Women tend to have a greater risk for chronification Comprehensive studies have investigated the associ- than men, even when adjusting the data for medication ation between migraine and obesity. Some population use and headache frequency [12, 13]. Additionally, ac- studies show a strong positive association between obes- cording to the American Migraine Prevalence and Pre- ity and headache frequency in obese women [24, 25]. vention (AMPP) Study [14] and the International Moreover, a recent meta-analysis of available Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 3 of 12 observational studies suggests an increased risk of having of employment status, can exacerbate symptoms and chronic migraine in obese and pre-obese patients com- headache frequency, increasing the risk of chronification pared with normal weight subjects [26]. This association [33]. Also, posttraumatic stress disorder [34] and certain seems to also exist between body weight and other non- personality profiles, particularly obsessive-compulsive, migraine headaches which questions whether there is a dependent, avoidant, and passive-aggressive are of prog- direct causal link between body weight and CM. nostic significance [35]. Poor sleep quality and sleep disorders are considered Chronic pain disorders, including fibromyalgia, back risk factors for migraine transformation. The Chronic Mi- pain, and neck pain, are more common in people with graine Epidemiology and Outcomes (CaMEO) study CM than EM [36]. Non-cephalic pain may be used to showed that CM patients more frequently reported sleep identify people with EM at risk of the onset of CM and apnea or were more likely to be at “high risk” for sleep people with CM at risk of persistent CM [36]. apnea than EM patients [27]. CM patients showed poorer Finally, cardiovascular disorders including heart sleep quality compared to EM patients with higher rates disease/angina, stroke and cardiovascular risk factors in- of sleep disturbance, snoring, shortness of breath, somno- cluding high blood pressure and high cholesterol oc- lence and sleep adequacy [27]. The relationship between curred with greater frequency in CM than EM patients obstructive sleep apnea and migraine progression are not [9, 20]. clearly understood but some physiological changes as fluc- tuations in intracranial and arterial pressure during snor- Headache features and treatment ing, hypoxia, hypercapnia, fragmentation of sleep and Headache frequency is one of the most important risk increased muscle activation during awakening during factor for progression from EM into CM [8]. The risk in- apnea may underlie this relationship [28]. creases with increase of headache frequency in a non- For the evidence set out before, lifestyle most likely linear fashion, where a minimum of 3 headaches per plays a role in migraine chronification. Consequently, month was associated with an elevated risk for new- dietary measures to minimize caffeine consumption and onset of chronic headache [22]. Although the threshold weight gain, exercise and sleep regulation strategies for CM has been set at 15 headache days/month, a clin- should be considered for prevention of migraine ical study [10], showed that patients suffering from 10 or transformation. more headache days per month showed less clinical dif- ferences with CM patients than those with lower fre- Comorbidities quencies suggesting that chronification is already Patients with CM significantly more often reported co- notable in patients with high frequency EM. morbidities than patients with EM such as psychiatric One of the most interesting headache features in CM disorders, head and neck injuries, cardiovascular disease, patients is cutaneous allodynia. This reflects the percep- metabolic syndrome, asthma, sleep apnea and other pain tion of pain in response to non-noxious stimuli and may syndromes [5, 7, 29]. If untreated, these comorbidities be considered a clinical marker for central sensitization can increase the risk for migraine chronification and [37]. Cutaneous allodynia affects 63% of migraineurs in migraine-related disability, leading to a decrease in the the population and is associated with frequency, severity, quality of life and adversely affect the treatment out- disability, and associated symptoms of migraine [38]. In comes [28, 30, 31]. a prospective study [39] allodynia was an independent In the CaMEO study furthermore it was shown that predictor for increase in number of migraine days and all comorbidity classes were associated with a statistically migraine chronification. This also has therapeutic impli- significant risk of progression to CM. However, the cations. Migraine patients who describe the presence of group of subjects with the most comorbidities were ap- allodynia during their attacks, should be treated within proximately 5 times more likely to progress to CM than 30 min from attack onset with triptans [40]. subjects of the fewest comorbidities class [32]. Other well-known and established risk factors for mi- Psychiatric comorbidity is particularly relevant in the graine transformation is medications disuse that includes group of patients with CM. CM is more common in medications overuse and ineffective treatment of mi- women with severe depressive disorders [28, 31], and graine attacks. Symptomatic medication overuse is be- has been shown to be strongly associated with moderate lieved to play a major role in progression from EM to and severe depression [29]. These associations are also CM. Acute medication overuse is defined as intake of highly relevant in the larger picture, as the effects of de- analgesics on 10–15 days per month. It can cause pression, anxiety and obesity are additive [5]. rebound-drug-induced headache, therefore transforming A variety of psychological and personality traits are self-limited headaches, and particularly migraine, into also discussed as risk factors of migraine progression. chronic headache [41]. The counter-proof of this con- Major life changes, such as divorce, marriage, or change cept is that withdrawal from the overused medication Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 4 of 12 leads to lower headache frequency and less disability have been described to play a role in migraine pathophysi- [42]. Among overused drugs, opioids and barbiturates ology [49, 50]. Oxidative stress is a subject increasing in are associated with dose-dependent increased risk of popularity regarding its relation to the pathophysiology of new-onset CM, while triptans induce migraine progres- migraine. However, a study that investigated 10 polymor- sion only in those with high frequency at baseline, but phisms in 8 oxidative stress-related genes in a small popu- not overall. Nonsteroidal anti-inflammatory drugs lation of CM patients did not detect a relationship with (NSAIDs) protect against migraine progression unless CM [51]. However, as migraine is considered a complex individuals have 10 or more headache days per month disease with multifactorial inheritance, Genome-Wide As- [26]. The most effective way to prevent medication over- sociation Study (GWAS) seems a more appropriate ap- use headache is to identify patients at risk and to edu- proach to study migraine genetic background. To date, 4 cate them about the use of acute medication. The risk is GWAS studies [52–55] and 3 meta-analyzes [56, 57] have higher in patients with frequent headaches, use of opi- been performed in EM patients leading to the identifica- oids and tranquilizers and comorbid anxiety and depres- tion of 44 single nucleotide polymorphisms (SNPs) on 38 sion [41]. distinct genomic loci associated with migraine, mainly in- On the other side, ineffective treatment, and the con- volved in vascular and neural function [58]. Although the sequent insufficient acute pain relief, can also lead to number of SNPs identified as associated with EM has central sensitization, which can further lower the thresh- steadily increased, our knowledge of CM genetics remains old of migraine attacks and promote chronification. In- considerably poor. Studies on the genetic association of adequate acute treatment efficacy was also associated several SNP tests failed to provide significant genetic risk with an increased risk of new-onset CM [43]. Patients factors for the development of CM. The first comprehen- using NSAIDs and simple analgesics were less likely to sive study on genetic association in CM and high- be in the high treatment efficacy categories than patients frequency migraine, tested 144 SNPs from 48 genes in who used triptans [43]. Moreover, acute treatment is less 1019 patients with CM or high-frequency migraine, with- effective in patients with CM than in patients with EM, out finding significant associations [52]. Since CM is a patients with more severe attacks, allodynia, comorbid complex disease with a probable poligenic background, depression and medication overuse headache [44]. For more genetic variants are likely to contribute to the sus- this reason, rapid and complete treatment of the mi- ceptibility of the disease, suggesting that a large number of graine attack is a crucial intervention to prevent mi- patients and controls are needed to achieve sufficient graine transformation. power to detect a genetic association. In recent years it seems increasingly clear that epigen- Genetics and epigenetics etic processes play an important role in a wide variety of Genetic factors seem to be a component in determining multifactorial diseases, including migraine. Although to the risk of developing EM with and without aura [45]. date, there are not specific studies in CM patients, there However, the role of a genetic influence on the progres- is some evidence that neuronal activity occurring during sion of EM into CM remains to be elucidated [46]. The cortical spreading depression, may cause epigenetic number of studies that specifically assess genetics in CM changes involved in neuronal plasticity, neuroprotection is very low and the relevance of their findings has to be [59] and regulation of basal synaptic activity [60]. It is interpreted with caution. therefore conceivable that increased neuronal activity in According to the scarce studies published on the pos- patients with high frequency migraine may alter the sible genetic link to migraine chronification, three groups cerebral epigenome, thereby promoting subsequent at- of genes have been proposed: genes potentially linked to tacks of migraine and creating a cycle in which the epi- migraine or pain progression, genes potentially linked to genetic programming of genes and pathways underlying addiction and analgesic overuse, and other genes involved excitability are altered towards a more sensitive baseline in neuronal hyperexcitability or oxidative stress [47]. [61]. Some of the SNPs associated with migraine in- Catechol-O-methyltransferase (COMT) polymorphisms volved genes related to epigenetic processes, as well as could be implicated in the predisposition to chronic pain epigenetic regulation of the Calcitonin Gene-Related conditions [48]. Previous reports indicate that COMT Peptide (CGRP) gene. This evidence have given import- polymorphisms are associated with susceptibility to EM ance to the role of epigenetic processes in the patho- [48], but no specific studies in CM have been conducted. physiology and chronicity of migraine [62, 63]. A variety of potential candidate genes in drug addiction have been shown to possibly play a role in migraine Molecular research and biomarkers chronification, especially in patients with analgesic over- Biomarkers are defined as physical signs or laboratory use [47]. It is remarkable that some of these genes in- measurements associated with a biological process with volved in serotonergic and dopaminergic pathways, also a diagnostic or prognostic utility [64]. Molecular Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 5 of 12 biomarker levels can be measured in body fluids. Thus, factor alpha (TNF-α), can act as mediators of inflamma- on the one hand diagnostic biomarkers signal a patho- tory processes linked to persistence and progression of genic process and are linked to disease risk and on the migraine [79]. Inflammatory mediators may decrease the other hand severity and therapeutic biomarkers indicate threshold for the onset of a migraine attack and may a treatment response and may predict the efficacy of an also contribute to central sensitization as in the case of intervention [65]. other pro-inflammatory cytokines [80–82]. Moreover, Even though several studies have been done to find increased serum leptin was detected in CM patients biomarkers in migraine [66], currently, there are no ac- [83]. Leptin levels are correlated with body mass index cepted biological markers for the diagnosis of migraine. and TNF-α and IL-6 [75, 81]. Furthermore, serum total The well-known marker CGRP is abundant in the body adiponectin and high molecular weight adiponectin and has a wide distribution throughout the central and levels were higher in CM [84], and were also elevated in peripheral nervous systems [67]. It is known that CGRP both EM and CM interictal periods [84, 85]. Further evi- plays an important role in the pathophysiology of mi- dence for the importance of adipokines in CM stems graine [68]. CGRP is a neuropeptide widely expressed in from the fact that CM seems to occur with higher inci- trigeminovascular system as well as numerous central dence in obese people, with the risk of EM to CM pro- nervous system sites associated with pain processing and gression being three or five times greater than in normal migraine symptoms [68]. Furthermore, It plays a key role weight subjects [86]. Levels of the proinflammatory cyto- in the development of peripheral sensitization and kine TNF-α have been found to be increased in cerebro- enhanced abnormal pain sensitivity through a central spinal fluid (CSF) in treatment-resistant CM patients pronociceptive role [69]. Elevated interictal CGRP levels [87], while levels of somatostatin and glial cell line- have been proposed as a possible diagnostic biomarker derived neurotrophic factor (GDNF) were decreased in for CM [70, 71]. Moreover, not all studies show a con- the CSF of patients with CM [88]. sistent increase in interictal serum CGRP levels in CM Another possible biomarker for CM is glutamate. Glu- patients compared to EM patients or healthy controls tamate levels in the CSF are higher in patients with CM [72]. Nonetheless, it has been shown that serum CGRP compared to controls [89], and glutamate levels mea- levels are associated with the response to treatment with sured in saliva have been found to be significantly in- Onabotulinumtoxin type A [73], which leads to a con- creased in CM patients compared to patients with EM troversial discussion of a potential valuable biomarker [90]. Moreover, prophylactic treatment using topiramate, for predicting treatment efficacy. Although the instability amitriptyline, flunarizine or propranolol reduced plasma and short-life of the peptide and the variable detection glutamate levels along with a reduction in the number of methods complicates reliable and feasible measurement headache days per month, with no differences among [68]. Even though CGRP may also contribute to the de- the types of prophylaxis [91]. Therefore, glutamate could velopment of peripheral and central sensitization [74, serve as a potential biomarker for CM. 75], further research is necessary to confirm the poten- Some other studies for migraine biomarkers include tial of CGRP as biomarker in CM [66]. serotonin, S100β, neurokinin A and substance P. How- A second neuropeptide that is proposed as a bio- ever, most of these studies focus on EM and results marker for CM is Vasoactive Intestinal Peptide (VIP). seem to be inconsistent [92–96]. Just like CGRP, VIP is released in the trigeminovascular Migraine-specific biomarkers are needed not only for system. Interictal serum levels of VIP have been found the improvement of therapeutic approaches, but also for to be significantly increased in CM patients compared to the development of new and personalized treatments. healthy controls [73, 76] and, even though VIP serum Multiple potential biomarkers for CM have been investi- levels seemed to be elevated compared to EM patients, gated so far, but further controlled clinical trials are still this was not significant [76]. Furthermore, serum levels needed to investigate both their diagnostic and thera- of VIP have been correlated with cranial autonomic peutic value. parasympathetic symptoms in patients with CM [77]. Responders to Onabotulinum toxin type A had signifi- Neurophysiology cantly higher VIP levels than non-responders. However, Neuronal activity in migraine has been widely character- these results showed poor specificity [73]. In contrast to ized through electrophysiological studies, which assess CGRP and VIP, another neuropeptide the “Pituitary Ad- the brain spontaneous activity and evaluate its response enylate Cyclase-activating Peptide (PACAP), that is also to different stimuli [97]. Between them, evoked poten- released in the trigeminovascular system, was not altered tials to different sensory modalities (in particular som- during the interictal phase in CM patients [78]. atosensory and visual), transcranial magnetic stimulation It is known that some adipokines (such as leptin and and magnetoencephalography studies have shown the adiponectin), interleukin 6 (IL-6) and tumor necrosis most relevant findings [98]. Notwithstanding, the Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 6 of 12 pathophysiology of migraine still remains not fully patients: both habituates normally but with an initial understood. Data from different studies are often diffi- sensitization response. Sensory sensitization may be ex- cult to compare because of methodological differences, plained by connections between the thalamus and cortex patient’s heterogeneity and different points of evaluation intensified in CM compared to EM between attacks thought the cycle of the migraine attack. [109]. These data support the fact that thalamocortical Neurophysiological studies have investigated the cor- dysfunction might be associated with a progressive ex- tical excitability state in migraine, so-called migraine tension of an acute electrophysiological alteration up to cortical “dysexcitability” [99]. Different pathophysio- a basal modification of neuronal activity. logical mechanisms might coexist in migraine, possibly In CM patients, rTMS applied to the primary motor being either expression of increased cortical responsivity cortex showed inhibitory responses resembling that ob- or compensatory mechanisms seeking to stabilize the served in EM patients with high attack frequency evalu- cortical excitability level [100]. ated interictally, and in patients in the ictal state, what Experimental data form EM patients have shown that may also be an expression of reduced inhibitory homeo- electrophysiological features of the migraineur’s brain static responses [100]. fluctuates in relation with the cyclical recurrence of the Differences between episodic and CM may not be migraine attack. Habituation is defined as a decremental principally confined to the number of headache days per response to repeated stimulations. Electrophysiological month, but instead reflect a more profound patho- techniques in EM revealed interictal deficient habitu- physiological distinction [110]. Taken together, neuro- ation of any kind of sensory responses (except for olfac- physiological data can be considered as robust evidence tory stimulation) attributed to abnormal thalamo- for the cycling functional brain alterations as a promin- cortical interactions that normalizes during the migraine ent features of migraine pathophysiology, but mecha- attack [101]. Studies with repetitive transcranial mag- nisms underlying progression are still unknown and netic stimulation (rTMS) have also reported interictal whether the diffuse excitability change of CM brain is paradoxical cortical responses in reaction to both de- the cause or the consequence of migraine chronification pressing or enhancing rTMS stimulation that changes process is not elucidated yet [109]. up to the bending point of an attack when cortical responsivity behaves differently [102]. Animal models Compared to EM, CM patients have lower pain CM is classified as a single entity, so, specific animal thresholds as measured on quantitative thermal and models that mimic CM features have been developed to mechanical sensory test [103]. Studies using blink reflex test preventative medications and investigate patho- showed a remote effect of C fiber activation by capsaicin physiological mechanisms of migraine transformation. that suggests impaired diffuse noxious inhibitory control, Currently, there are several methods to induce headpain that selectively inhibits action of nociceptive neurons lo- in animals but, because of the complexity of migraine, cated in the nucleus of the descending trigeminal tract there is no unique animal model that replicates all com- by remote noxious stimuli, in CM but not in EM [104]. ponents of CM, and current models focus on reprodu- But one of the most reproducible underlying features in cing single phenotypic or endophenotypic features. It is CM is an increased cortical excitability that has been possible to model CM using repeated stimuli that acti- demonstrated by different study methods. Magnetic vis- vates trigeminal nociceptors representing the episodic ual evoked responses in CM patients demonstrate lower nature of migraine attacks. This includes epidural appli- phosphene thresholds, decreased cortical inhibition [105, cation of an inflammatory soup and intravenous infusion 106] and persistent ictal-like excitability pattern of the of glyceryl trinitrate (GTN) [111]. Transgenic animal visual cortex between migraine attacks which may impli- models of CSD induction had not been completely vali- cate central inhibitory dysfunction [107]. The response dated for CM study. As mentioned before, one of the pattern of the visual cortex in patients with CM is simi- main features of migraine chronification is the lar to that found during a migraine attack in patients sensitization of the trigeminothalamic pathways. Allody- with EM, both normal with regard to habituation and nia is a common symptom of migraine that has been abnormal regarding amplitude of the evoked response correlated with central and peripherical sensitization, after a low number of stimuli [107]. But habituation def- increased migraine frequency ant thus, chronification icit reappears in CM patients who remitted to EM, sug- [112]. Due to its clinical translation in humans, trigemi- gesting that visual cortical excitability reflect the clinical nal mechanical sensitivity measurement in animals using status of migraine [108]. Similarly, it has been showed von Frey hair stimulation in facial or paws is considered that response pattern of the somatosensory cortex to re- one of the best strategies to determine pain sensitization, peated somatosensory evoked potentials in CM patients although nociceptive-related behavioral changes can be is similar to that found during a migraine attack in EM used [111]. Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 7 of 12 Current animal models to study CM includes a mouse expression of a CGRP receptor could be used in the fu- model involving the repeated intraperitoneal administra- ture to test the hypothesis of chronic CGRP-induced tion of GTN resulting in acute hyperalgesia, and a neurogenic neuroinflammation [129]. Furthermore, the chronic basal hyperalgesia reduced by topiramate, but central sensitization phenomenon underlines connectiv- not sumatriptan that persists after the cessation on GTN ity changes through synaptic plasticity. Actually, a rat [113]. Another model is based on repeated application model based on repeated stimulations with inflammatory of inflammatory soup onto the dura mater that induces soup has showed that central sensitization correlates to allodynia and increase of nociceptive-related behavior an increase of the synaptic efficiency through NR2B- that reduces after zolmitriptan administration [114]. pTyr expression. This protein has been already related A GTN model has been used to identify genes and to the regulation of the synaptic plasticity in the central biological processes impacted by chronification com- sensitization in this CM rat model [130]. pared to controls. Differential gene expression in trigem- Preclinical research with animal models has provided inal ganglion and nucleus accumbens in response to valuable information about the mechanism of action on NTG treatment has been demonstrated, including genes preventive treatments. Treatments that have proved effi- linked to glutamatergic and dopaminergic synapses and cacy in migraine patients, have been shown to prevent rhythmic process among others that could be involved mechanical hyperalgesia in animal models [113, 131]. For in CM pathophysiology [115]. example, botulinum toxin could act peripherally inhibiting CM animal models have shown increased CGRP gene the release of a variety of neurotransmitters which are expression in rodents pain processing areas such as tri- known to be key signaling molecules in CM including geminal nucleus caudalis [116, 117]. GTN induced CGRP [132, 133], so animal pre-treatment with botulinum model showed that animal behavioral changes in pain toxin can prevent mechanical sensitization inhibiting perception correlated with an increased gene expression mechanical nociception in peripheral trigeminovascular of CGRP in the medulla-pons region, cervical spinal neurons [134]. For example, the mechanism of action of cord and trigeminal ganglia [118], while it has not been noninvasive vagus nerve stimulation for migraine treat- demonstrated after acute GTN administration [119], ment have also been investigated in the inflammatory supporting CGRP contribution in central sensitization. soup model showing a decrease in periorbital sensitivity The BBB permeability during migraine attacks has after de vagal stimulation [135]. been widely discussed, and there is data that supports In summary, only a few CM models are available today [120, 121] and contradicts BBB disruption [122, 123] in that can mimicmigraine features observed in accordance EM but little is known about BBB permeability in CM with clinical findings. However, as these animal models patients. One study used the inflammatory soup rat for long-term activation of the trigeminovascular system model of trigeminal allodynia, to determine the impact can only show unique phenotypical features of CM, like of repeated dural inflammatory stimulation on BBB per- allodynia or photophobia so, it is important to stress that meability. and demonstrated a significant increase in these are not a model of the migraine spectrum. Ideally, BBB permeability and astrocyte and microglial activation specific models should be able to show the broad in the trigeminal nucleus caudalis during the chronic spectrum of symptoms developed by migraine patients. phase after repeated infusion [124]. These findings could be in line with inflammatory pain states producing sig- Neuroimaging nificant changes in the BBB permeability but need fur- Migraine is thought to conform a disease spectrum with ther confirmation [125]. symptoms gradually evolving from the episodic to In animals, chemical activation and sensitization of chronic forms that is characterized by several neuro- meningeal sensory neurons can lead to activation and physiological changes. Increasingly more studies suggest sensitization of central trigeminal neurons that receive that these changes may be evaluated using neuroimaging convergent input from the dura and skin [126]. Continu- techniques, which try to understand central underlying ous stimulation of trigeminal neurons during repeated pathophysiological mechanisms [136, 137]. Changes migraine attacks lead to changes in activity of intracellu- shown by these studies may reflect chronic pain suscep- lar signalling molecules that are relevant to pain and in- tibility or be a consequence of recurrent migraine at- crease expression of inflammatory cytokines in the tacks [138, 139]. trigeminovascular system, thereby promoting the chroni- Structural differences measured on magnetic reson- fication process [127]. Using inflammatory models the ance imaging (MRI) have been found between migraine findings indicate that inflammatory pathways and over- patients and normal healthy controls [140]. Some neuro- expression of CGRP in nociceptive neurons, could par- imaging studies performed in EM patients have shown ticipate in the generation of pain hypersensitivity [128]. structural differences correlated with headache fre- Transgenic mice sensitized to CGRP through elevated quency, that could be understood as indirect markers of Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 8 of 12 migraine chronification. Patients with a high frequency A promising way to explore the underlying anatomy of migraine attacks have thicker somatosensory cortex, and pathophysiology regarding the chronification of mi- anterior cingulate cortex and the inferior temporal gyrus graine is functional MRI. Functional MRI is an import- compared with patients with a low frequency of attacks ant tool to study both brain structure and brain function [141]. The frequency of migraine attacks was also corre- in one single technique [150]. Recent studies point to a lated with cortical thickness in the left middle frontal key role for the brainstem and hippocampus in the first gyrus and in the left central sulcus [142]. phase of a migraine attack [151]. The limbic system, on Studies performed specifically in CM patients have the other hand, seems to have an important role in pain shown volumetric changes in amygdala, putamen, hippo- networks in CM [140]. campus and brainstem areas [138, 143]. The volume of The amygdala (part of the limbic system) has a hippocampus and amygdala seems to change with head- uniquely increased connectivity with several parts of the ache frequency. The hippocampus is thought to be in- brain in patients with CM. This finding has not been volved in a maladaptive stress response, while the replicated in patients with EM, suggesting an important amygdala plays a central role in emotions, fear condi- limbic pain network dysfunction specifically in migraine tioning, processing of prolonged nociceptive inputs, and but not seen in other chronic pain syndromes [152]. The development of sensitization. Compared to healthy con- hypothalamus shows stronger activation in the CM pa- trols grey matter volume of the amygdala and putamen tient than in EM patients in response to painful trigemi- is increased in CM patients [138]. Another study also nal stimulation but also during a migraine attack [153]. shows an increasing in volume of the hippocampus and The posterior part of the hypothalamus seems to be in- left amygdala that positively correlates with frequency volved in the acute pain stage, while the anterior part followed by a decrease when the headache becomes seems to be involved in the attack generation and preic- chronic [144]. Patients with smaller hippocampus may tal phase and also migraine frequency, suggesting that it have a higher vulnerability to stress, stress related disor- plays an important role in chronification [153]. This is ders and persistent pain [144]. supported by the fact that there is an increased connect- Taken together, these structural differences seem con- ivity between the anterior hypothalamus and spinal tri- sistent enough that a model can be performed to accur- geminal nucleus in the CM compared to the episodic ately differentiate between chronic, episodic and healthy group [154]. A study that have compared EM and CM controls [145]. patients using resting state technique, points to stronger Structural differences have also been found in the peri- connectivity in the pain matrix of CM patients that aqueductal gray (PAG) of CM patients. PAG is a struc- might play a role in migraine chronification [155]. ture that plays an important role in the modulation of At this stage, there is still a far way to go until we find nociceptive stimuli from the trigeminal nucleus and it is a neuroimaging marker for CM. Although, the results considered a key structure of migraine. The volume of from neuroimaging studies in CM provide light to which periaqueductal gray matter is increased in EM patients structures or networks could be involved in the chronifi- in comparison to healthy controls but decreases again in cation process. CM patients [110]. It has also been demonstrated the presence of iron accumulation in the PAG as well as in Conclusions the red nucleus in CM patients compared to EM pa- CM patients show differences compared to EM patients tients. This accumulation can be due to recurrent at- and controls. EM patients with clinical factors associated tacks with secondary damage since biomarkers of to chronification may be on a higher risk for transform- endothelial dysfunction endothelial and blood brain bar- ation, so it is important to screen for clinical risk factors rier (BBB) molecular disruption are also elevated in this as well as educate and treat modifiable factors in order group. This could lead to progressive dysfunction and to prevent transformation. Although studies using differ- chronification, but this stays speculative since iron accu- ent approaches have demonstrated functional and struc- mulation increases with age, while migraine decreases tural differences between CM and EM patients, key with age [146]. structures and networks involved in the chronification Another common structural finding in migraine patients phenomena, and the pathophysiology of migraine trans- are white matter lesions (WML) [147]. The presence of formation are not fully understood. The changes shown WML has been related to disease duration and the attack may reflect migraine transformation susceptibility or be frequency [148] but there are no specific studies that evaluate a consequence of recurrent migraine attacks. Taking this the evolution of WML during transformation from episodic into account, the findings in this review do seem to to CM. Studies using diffusion tensor imaging (DTI) did not point towards general changes in excitability of the cen- find differences between chronic and EM patients due to tral and peripheral nervous system. For example, in- microstructural white matter changes [149]. creased levels of glutamate in the CSF, central Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 9 of 12 sensitization, altered habituation to sensory stimuli, im- Neurology, Medical center “New Medical Technologies”, Voronezh, Russia. 13 paired cortical inhibition and furthermore when investi- Department of Neurology, Universitary Hospital of Donostia, San Sebastian, Spain. 14Department of Neurology, Clínica Universidad de Navarra, Pamplona, gating magnetic visually evoked responses, and even Spain. 15Department of Neurology, Hospital Quironsalud Donostia, San predicting the state of chronification based on structural Sebastian, Spain. 16Department of Neurology, University Hospitals Leuven, imaging, are all compatible with a hypothesis of central Leuven, Belgium. 17Department of Neurology and Neurosurgery, State Institution “Dnipropetrovsk medical akademy MOH Ukraine”, Dnipro, Ukraine. and peripheral altered excitability being pivotal changes 18 Department of Neurology, Ghent University Hospital, Ghent, Belgium. happening in CM. Whether this would be part of the 19 Department of Neuroscience, Erasmus University Medical Centre, cause for, or a consequence of chronification remains to Rotterdam, The Netherlands. 20Headache Medical Center Linz, Ordensklinikum Linz Barmherzige Schwestern, Linz, Austria. be elucidated. Received: 30 January 2020 Accepted: 15 April 2020 Abbreviations AMPP: American Migraine Prevalence And Prevention; BBB: Blood Brain Barrier; CDH: Chronic Daily Headache; CGRP: Calcitonin Gene-Related Peptide; COMT: Catechol-O-Methyltransferase; CSF: Cerebrospinal Fluid; CM: Chronic References Migraine; EM: Episodic Migraine; GTN: Glyceryl Trinitrate; GWAS: Genome- 1. Bigal ME, Lipton RB (2008) Clinical course in migraine: conceptualizing Wide Association Study; IBMS: International Burden Of Migraine Study; ICHD- migraine transformation. Neurology 71(11):848–855 3: International Classification Of Headache Disorders; IL-6: Interleukin 6; 2. Headache Classification Committee of the International Headache Society MRI: Magnetic Resonance Imaging; NSAIDs: Nonsteroidal Anti-Inflammatory (2018) The international classification of headache disorders, 3rd edition. Drugs; PACAP: Pituitary Adenylate Cyclase-Activating Peptide; Cephalalgia 38(1):1–211 rTMS: Repetitive Transcranial Magnetic Stimulation; SNPs: Single Nucleotide 3. Mathew NT, Stubits E, Nigam MP (1982) Transformation of episodic Polymorphisms; TNF-α: Tumor Necrosis Factor Alpha; VIP: Vasoactive migraine into daily headache: analysis of factors. Headache 22(2):66–68 Intestinal Peptide 4. Natoli JL, Manack A, Dean B, Butler Q, Turkel CC, Stovner L et al (2010) Global prevalence of chronic migraine: a systematic review. Cephalalgia Acknowledgements 30(5):599–609 We thank Patricia Pozo-Rosich for useful comments on the manuscript. 5. Katsarava Z, Buse DC, Manack AN, Lipton RB (2012) Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep Authors’ contributions 16(1):86–92 CL, WSvH, MTF and FU made substantial contributions to the conception, 6. Buse DC, Manack AN, Fanning KM, Serrano D, Reed ML, Turkel CC et al desing and revised the work. The rest of authors have drafted the work. All (2012) Chronic migraine prevalence, disability, and Sociodemographic authors approved the submitted version. factors: results from the American Migraine Prevalence and Prevention study. Headache 52(10):1456–1470 Funding 7. Buse DC, Greisman JD, Baigi K, Lipton RB (2019) Migraine progression: a Not applicable. systematic review. Headache 59(3):306–338 8. Bigal ME, Lipton RB (2011) Migraine chronification. Curr Neurol Neurosci Availability of data and materials Rep 11(2):139–148 Not applicable. 9. Buse DC, Manack A, Serrano D, Turkel C, Lipton RB (2010) Sociodemographic and comorbidity profiles of chronic migraine and Ethics approval and consent to participate episodic migraine sufferers. J Neurol Neurosurg Psychiatry 81(4):428–432 Not applicable. 10. Torres-Ferrús M, Quintana M, Fernandez-Morales J, Alvarez-Sabin J, Pozo- Rosich P (2017) When does chronic migraine strike? A clinical comparison Consent for publication of migraine according to the headache days suffered per month. Not applicable. Cephalalgia 37(2):104–113 11. May A, Schulte LH (2016) Chronic migraine: risk factors, mechanisms and Competing interests treatment. Nat Rev Neurol 12(8):455–464 The authors declare that they have no competing interests regarding this 12. Finocchi C, Strada L (2014) Sex-related differences in migraine. Neurol Sci review. 35(Suppl 1):207–213 13. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M (2001) Prevalence Author details and burden of migraine in the United States: data from the American 1 Headache and Craniofacial Pain Unit, Neurology Department, Hospital migraine study II. Headache 41(7):646–657 Universitari Vall d’Hebron, Headache and Neurological Pain Research Group, 14. Stewart WF, Lipton RB, Dowson AJ, Sawyer J (2001) Development and Vall d’Hebron Research Institute (VHIR), Departament de Medicina, Universitat testing of the Migraine Disability Assessment (MIDAS) Questionnaire to Autònoma de Barcelona, Barcelona, Spain. 2Headache Center, Child assess headache-related disability. Neurology 56(suppl 1):S20 LP–S20S28 Neurology Unit, Bambino Gesu’ Children’s Hospital, Rome, Italy. 3Juvenile 15. Blumenfeld AM, Varon SF, Wilcox TK, Buse DC, Kawata AK, Manack A, Headache Centre, Department of Woman’s and Child’s Health, University Goadsby PJ, Lipton RB et al (2011) Disability, HRQoL and resource use Hospital of Padua, Padua, Italy. 4Department of Internal medicine, among chronic and episodic migraineurs: results from the international Sant’Andrea Hospital, University of Rome, Sapienza, Italy. 5Division of Vascular burden of migraine study (IBMS). Cephalalgia 31(3):301–315 Medicine and Pharmacology, Department of Internal Medicine, Erasmus 16. Scher AI, Wang S-J, Katsarava Z, Buse DC, Fanning KM, Adams AM et al University Medical Center, Rotterdam, The Netherlands. 6Department of (2019) Epidemiology of migraine in men: results from the chronic migraine Biomedicine Neuroscience and Advanced Diagnostics, Policlinico Paolo epidemiology and outcomes (CaMEO) study. Cephalalgia 39(2):296–305 Giaccone Hospital, University of Palermo, Palermo, Italy. 7Headache and 17. Lu S-R, Fuh J-L, Wang S-J, Juang K-D, Chen S-P, Liao Y-C et al (2013) Craniofacial Pain Unit, Neurology Department, Hospital Universitario Clínico Incidence and risk factors of chronic daily headache in young adolescents: a San Carlos, Madrid, Spain. 8Neurology Department, Hospital Universitario de school cohort study. Pediatrics 132(1):e9–e16 La Princesa & Instituto de Investigación Sanitaria de La Princesa, Universidad 18. Torres-Ferrus M, Vila-Sala C, Quintana M, Ajanovic S, Gallardo VJ, Gomez JB Autónoma de Madrid (UAM), Madrid, Spain. 9Department of Clinical et al (2018) Headache, comorbidities and lifestyle in an adolescent Neurology and Sleep Medicine, The Nikiforov Russian Center of Emergency population (The TEENs Study). Cephalalgia 39:91–99 [Epub ahead of print] and Radiation Medicine of EMERCOM of Russia, Saint-Petersburg, Russia. 19. Adams AM, Serrano D, Buse DC, Reed ML, Marske V, Fanning KM et al 10 Grevena General Hospital, Grevena, Greece. 11University Hospital of (2014) The impact of chronic migraine: the chronic migraine epidemiology Psychiatry and Psychotherapy, University of Bern, Switzerland University and outcomes (CaMEO) study methods and baseline results. Cephalalgia Hospital of Psychiatry, Bern, Switzerland. 12Headache Unit, Department of 0(0):1–16 Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 10 of 12 20. Payne KA, Varon SF, Kawata AK, Yeomans K, Wilcox TK, Manack A et al 46. Bigal ME, Serrano D, Reed M, Lipton RB (2008) Chronic migraine in the (2011) The International Burden of Migraine Study ( IBMS ): Study design , population: burden, diagnosis, and satisfaction with treatment. Neurology methodology , and baseline cohort characteristics. Cephalalgia 31(10):1116– 71(8):559–566 1130 47. Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering 21. Ferrari A, Leone S, Vergoni AV, Bertolini A, Sances G, Coccia CPR et al (2007) the genes. Nat Rev Genet 6(7):521–532 Similarities and differences between chronic migraine and episodic 48. Tammimäki A, Männistö PT (2012) Catechol-O-methyltransferase gene migraine. Headache 47(1):65–72 polymorphism and chronic human pain. Pharmacogenet Genomics 22(9): 22. Scher I, Stewart W, Ricci A, Lipton R (2003) Factors associated with the 673–691 onset and remission of chronic daily headache in a population-based study. 49. Hamel E, Currents H (2007) Serotonin and migraine: biology and clinical Pain 106(1–2):81–89 implications. Cephalalgia 27(11):1293–1300 23. Scher AI, Stewart WF, Lipton RB (2004) Caffeine as a risk factor for chronic 50. Akerman S, Goadsby PJ (2007) Dopamine and migraine: biology and clinical daily headache: a population-based study. Neurology 63(11):2022–2027 implications. Cephalalgia 27(11):1308–1314 24. Bigal ME, Lipton RB (2008) Obesity and chronic daily headache. Curr Pain 51. Gentile G, Negro A, D’Alonzo L, Aimati L, Simmaco M, Martelletti P et al Headache Rep 12(1):56–61 (2015) Lack of association between oxidative stress-related gene 25. Santos IS, Goulart AC, Passos VM, del Carmen Molina M, Lotufo PA, polymorphisms and chronic migraine in an Italian population. Expert Rev Bensenor IM (2015) Obesity, abdominal obesity and migraine: a cross- Neurother 15(2):215–225 sectional analysis of ELSA-Brasil baseline data. Cephalalgia 35(5):426–436 52. Louter MA, Fernandez-Morales J, de Vries B, Winsvold B, Anttila V, 26. Ornello R, Ripa P, Pistoia F, Degan D, Tiseo C, Carolei A et al (2015) Migraine Fernandez-Cadenas I et al (2015) Candidate-gene association study and body mass index categories: a systematic review and meta-analysis of searching for genetic factors involved in migraine chronification. observational studies. J Headache Pain 16:27 Cephalalgia 35(6):500–507 27. Buse DC, Rains JC, Pavlovic JM, Fanning KM, Reed ML, Manack Adams A 53. Anttila V, Steafansson H, Kallela M, Todt U et al (2010) Genome-wide et al (2019) Sleep disorders among people with migraine: results from the association study of migraine implicates a common susceptibility variant on chronic migraine epidemiology and outcomes (CaMEO) study. Headache 8q22.1. Nat Genet 42(10):869–873 59(1):32–45 54. Freilinger T, Anttila V, de Vries B, Malik R, Kallela M, Terwindt GM et al (2012) 28. Bigal ME, Lipton RB (2009) What predicts the change from episodic to Genome-wide association analysis identifies susceptibility loci for migraine chronic migraine? Curr Opin Neurol 22(3):269–276 without aura. Nat Genet 44(7):777–782 29. Buse D, Silberstein S, Manack A, Papapetropoulos S, Lipton R (2013) 55. Chasman DI, Schurks M, Anttila V, de Vries B, Schminke U, Launer LJ Psychiatric comorbidities of episodic and chronic migraine. J Neurol 260(8): et al (2011) Genome-wide association study reveals three susceptibility 1960–1969 loci for common migraine in the general population. Nat Genet 43(7): 30. Dodick DW (2009) Review of comorbidities and risk factors for the 695–698 development of migraine complications (infarct and chronic migraine). 56. Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G et al Cephalalgia 29(Suppl 3):7–14 (2013) Genome-wide meta-analysis identifies new susceptibility loci for 31. Negro A, D’Alonzo L, Martelletti P (2010) Chronic migraine: comorbidities, migraine. Nat Genet 45(8):912–917 risk factors, and rehabilitation. Intern Emerg Med 5(Suppl 1):S13–S19 57. Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH et al (2016) Meta- 32. Lipton RB, Fanning KM, Buse DC, Martin VT, Hohaia LB, Adams AM et al analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. (2019) Migraine progression in subgroups of migraine based on Nat Genet 48(8):856–866 comorbidities: results of the CaMEO study. Neurology 93(24):e2224–e2236 58. Sutherland HG, Griffiths LR (2017) Genetics of migraine: insights into the 33. Scher AI, Stewart WF, Buse D, Krantz DS, Lipton RB (2008) Major life changes molecular basis of migraine disorders. Headache 57(4):537–569 before and after the onset of chronic daily headache: a population-based 59. Vila-Pueyo M, Fernandez-Castillo N, Cormand B, Pozo-Rosich P, Macaya A study. Cephalalgia 28(8):868–876 (2014) Epigenetic changes in a rat model of migraine with aura. J Headache 34. Peterlin BL, Tietjen G, Meng S, Lidicker J, Bigal M (2008) Post-traumatic stress Pain 15(Suppl1):A6 disorder in episodic and chronic migraine. Headache 48(4):517–522 60. Nelson ED, Monteggia LM (2011) Epigenetics in the mature mammalian 35. Kayhan F, Ilik F (2016) Prevalence of personality disorders in patients with brain: effects on behavior and synaptic transmission. Neurobiol Learn Mem chronic migraine. Compr Psychiatry 68:60–64 96(1):53–60 36. Plesh O, Adams SH, Gansky SA (2012) Self-reported comorbid pains in 61. Eising E, Datson NA, van den Maagdenberg AM, Ferrari MD (2013) severe headaches or migraines in a US national sample. Headache 52(6): Epigenetic mechanisms in migraine: a promising avenue? BMC Med 11(1): 946–956 26 37. Burstein R (2001) Deconstructing migraine headache into peripheral and 62. Terlizzi R, Bacalini MG, Pirazzini C, Giannini G, Pierangeli G, Garagnani P et al central sensitization. Pain 89(2–3):107–110 (2018) Epigenetic DNA methylation changes in episodic and chronic 38. Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML et al (2008) migraine. Neurol Sci 39(Suppl 1):67–68 Cutaneous allodynia in the migraine population. Ann Neurol 63(2):148–158 63. Park K-Y, Fletcher JR, Raddant AC, Russo AF (2011) Epigenetic regulation of 39. Louter MA, Bosker JE, Van Oosterhout WPJ, Van Zwet EW, Zitman FG, Ferrari the calcitonin gene-related peptide gene in trigeminal glia. Cephalalgia MD et al (2013) Cutaneous allodynia as a predictor of migraine 31(5):614–624 chronification. Brain 136(11):3489–3496 64. Loder E, Rizzoli P (2006) Biomarkers in migraine: their promise, problems, 40. Lampl C, Huber G, Haas S, Rittberger E, Diener HC (2008) Difference in and practical applications. Headache 46(7):1046–1058 triptan effect in patients with migraine and early allodynia. Cephalalgia 65. Phillips KA, Van Bebber S, Issa AM (2006) Diagnostics and biomarker 28(10):1031–1038 development: priming the pipeline. Nat Rev Drug Discov 5(6):463–469 41. Ferrari A, Baraldi C, Sternieri E (2015) Medication overuse and chronic 66. Riesco N, Cernuda-Morollon E, Pascual J (2017) Neuropeptides as a marker migraine: a critical review according to clinical pharmacology. Expert Opin for chronic headache. Curr Pain Headache Rep 21(4):18 Drug Metab Toxicol 11(7):1127–1144 67. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, 42. Kristoffersen ES, Grande RB, Aaseth K, Russell MB, Lundqvist C (2018) Akerman S (2017) Pathophysiology of migraine: a disorder of sensory Medication-overuse headache detoxification reduces headache disability - processing. Physiol Rev 97(2):553–622 the Akershus study of chronic headache. Eur J Neurol 25(9):1140–1147 68. Edvinsson L, Haanes KA, Warfvinge K, Krause DN (2018) CGRP as the target 43. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC (2015) of new migraine therapies - successful translation from bench to clinic. Nat Ineffective acute treatment of episodic migraine is associated with new- Rev Neurol 14(6):338–350 onset chronic migraine. Neurology 84(7):688–695 69. Iyengar S, Ossipov MH, Johnson KW (2017) The role of calcitonin gene- 44. Lipton RB, Munjal S, Buse DC, Fanning KM, Bennett A, Reed ML (2016) related peptide in peripheral and central pain mechanisms including Predicting inadequate response to acute migraine medication: results from migraine. Pain 158(4):543–559 the American migraine prevalence. Headache 56(10):1635–1648 70. Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, 45. Russell MB, Olesen J (1995) Increased familial risk and evidence of genetic Pascual J (2013) Interictal increase of CGRP levels in peripheral blood as a factor in migraine. BMJ 311(7004):541–544 biomarker for chronic migraine. Neurology 81:1191–1196 Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 11 of 12 71. Edvinsson L (2019) Role of CGRP in migraine. Handb Exp Pharmacol 255: 94. Ren C, Liu J, Zhou J, Liang H, Wang Y, Sun Y et al (2018) Low levels of 121–130 serum serotonin and amino acids identified in migraine patients. Biochem 72. Lee MJ, Lee S-Y, Cho S, Kang E-S, Chung C-S (2018) Feasibility of serum Biophys Res Commun 496(2):267–273 CGRP measurement as a biomarker of chronic migraine: a critical 95. Leira R, Castillo J, Martinez F, Castro A, Lema M, Noya M (1991) Platelets and reappraisal. J Headache Pain 19(1):53 migraine. Correlation between biochemical markers of platelet aggregation 73. Cernuda-Morollón E, Martínez-Camblor P, Ramón C, Larrosa D, Serrano- and serotonin. Neurologia 6(1):10–12 Pertierra E, Pascual J (2014) CGRP and VIP levels as predictors of efficacy of 96. Sarchielli P, Pini LA, Zanchin G, Alberti A, Maggioni F, Rossi C et al (2006) Onabotulinumtoxin type a in chronic migraine. Headache 54(6):987–995 Clinical-biochemical correlates of migraine attacks in rizatriptan responders 74. Noseda R, Burstein R (2013) Migraine pathophysiology: anatomy of the and non-responders. Cephalalgia 26(3):257–265 trigeminovascular pathway and associated neurological symptoms, CSD, 97. Magis D, Ambrosini A, Bendtsen L, Ertas M, Kaube H, Schoenen J (2007) sensitization and modulation of pain. Pain 154(Suppl):S44–S53 Evaluation and proposal for optimalization of neurophysiological tests in 75. Kawasaki Y, Zhang L, Cheng J-K, Ji R-R (2008) Cytokine mechanisms of migraine: part 1--electrophysiological tests. Cephalalgia 27(12):1323–1338 central sensitization: distinct and overlapping role of interleukin-1beta, 98. Magis D, Vigano A, Sava S, d’Elia TS, Schoenen J, Coppola G (2013) interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and Pearls and pitfalls: electrophysiology for primary headaches. Cephalalgia neuronal activity in the superficial spinal cord. J Neurosci 28(20):5189–5194 33(8):526–539 76. Cernuda-Morollon E, Martinez-Camblor P, Alvarez R, Larrosa D, Ramon C, 99. Magis D, Lisicki M, Coppola G (2016) Highlights in migraine Pascual J (2015) Increased VIP levels in peripheral blood outside migraine electrophysiology: are controversies just reflecting disease heterogeneity? attacks as a potential biomarker of cranial parasympathetic activation in Curr Opin Neurol 29(3):320–330 chronic migraine. Cephalalgia 35(4):310–316 100. Cosentino G, Fierro B, Brighina F (2014) From different neurophysiological 77. Riesco N, Cernuda-Morollon E, Martinez-Camblor P, Perez-Alvarez AI, Verano methods to conflicting pathophysiological views in migraine: a critical L, Garcia-Cabo C et al (2017) Relationship between serum levels of VIP, but review of literature. Clin Neurophysiol 125(9):1721–1730 not of CGRP, and cranial autonomic parasympathetic symptoms: a study in 101. Coppola G, Di Lorenzo C, Schoenen J, Pierelli F (2013) Habituation and chronic migraine patients. Cephalalgia 37(9):823–827 sensitization in primary headaches. J Headache Pain 14(1):65 78. Cernuda-Morollon E, Riesco N, Martinez-Camblor P, Serrano-Pertierra E, Garcia- 102. Coppola G (2015) Neural plasticity and migraine. J Headache Pain 16(Suppl Cabo C, Pascual J (2016) No change in Interictal PACAP levels in peripheral 1):A26 blood in women with chronic migraine. Headache 56(9):1448–1454 103. Kitaj MB, Klink M (2005) Pain thresholds in daily transformed migraine versus 79. Novack V, Fuchs L, Lantsberg L, Kama S, Lahoud U, Horev A et al (2011) episodic migraine headache patients. Headache 45(8):992–998 Changes in headache frequency in premenopausal obese women with 104. de Tommaso M, Sardaro M, Pecoraro C, Di Fruscolo O, Serpino C, Lamberti migraine after bariatric surgery: a case series. Cephalalgia 31(13):1336–1342 P et al (2007) Effects of the remote C fibres stimulation induced by 80. Ji R-R, Nackley A, Huh Y, Terrando N, Maixner W (2018) Neuroinflammation capsaicin on the blink reflex in chronic migraine. Cephalalgia 27(8):881–890 and central sensitization in chronic and widespread pain. Anesthesiology 105. Aurora SK, Barrodale P, Chronicle EP, Mulleners WM (2005) Cortical 129(2):343–366 inhibition is reduced in chronic and episodic migraine and demonstrates a 81. Gomez-Ambrosi J, Salvador J, Paramo JA, Orbe J, de Irala J, Diez-Caballero A spectrum of illness. Headache 45(5):546–552 et al (2002) Involvement of leptin in the association between percentage of 106. Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A (2007) Brainstem body fat and cardiovascular risk factors. Clin Biochem 35(4):315–320 dysfunction in chronic migraine as evidenced by neurophysiological and 82. Rodriguez A, Ezquerro S, Mendez-Gimenez L, Becerril S, Fruhbeck G (2015) positron emission tomography studies. Headache 47(7):996–997 Revisiting the adipocyte: a model for integration of cytokine signaling in 107. Chen W-T, Wang S-J, Fuh J-L, Lin C-P, Ko Y-C, Lin Y-Y (2011) Persistent ictal- the regulation of energy metabolism. Am J Physiol Endocrinol Metab like visual cortical excitability in chronic migraine. Pain 152(2):254–258 309(8):E691–E714 108. Chen W-T, Wang S-J, Fuh J-L, Ko Y-C, Lee Y-C, Hamalainen MS et al (2012) 83. Dominguez C, Vieites-Prado A, Perez-Mato M, Sobrino T, Rodriguez-Osorio Visual cortex excitability and plasticity associated with remission from X, Lopez A et al (2018) Role of adipocytokines in the pathophysiology of chronic to episodic migraine. Cephalalgia 32(7):537–543 migraine: a cross-sectional study. Cephalalgia 38(5):904–911 109. Coppola G, Iacovelli E, Bracaglia M, Serrao M, Di Lorenzo C, Pierelli F (2013) 84. Peterlin BL, Alexander G, Tabby D, Reichenberger E (2008) Oligomerization Electrophysiological correlates of episodic migraine chronification: evidence state-dependent elevations of adiponectin in chronic daily headache. for thalamic involvement. J Headache Pain 14:76 Neurology 70(20):1905–1911 110. Saper JR (2015) Are chronic and episodic migraine distinct 85. Rubino E, Vacca A, Govone F, Gai A, Boschi S, Zucca M et al (2017) neurophysiological entities? More research is needed. Pain Med 16:1246 Investigating the role of adipokines in chronic migraine. Cephalalgia 37(11): 111. Chou TM, Chen SP (2018) Animal Models of Chronic Migraine. Curr Pain 1067–1073 Headache Rep 22(6):467 86. Minguez-Olaondo A, Irimia P, Fruhbeck G (2017) Obesity and the nervous 112. Bigal ME, Ashina S, Burstein R, Reed ML, Buse D, Serrano D et al (2008) system: more questions. Lancet 16:773 Prevalence and characteristics of allodynia in headache sufferers: a 87. Rozen T, Swidan SZ (2007) Elevation of CSF tumor necrosis factor alpha population study. Neurology 70(17):1525–1533 levels in new daily persistent headache and treatment refractory chronic 113. Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A (2014) migraine. Headache 47(7):1050–1055 Characterization of a novel model of chronic migraine. Pain 155(2):269–274 88. Sarchielli P, Alberti A, Candeliere A, Floridi A, Capocchi G, Calabresi P (2006) 114. Melo-Carrillo A, Lopez-Avila A (2013) A chronic animal model of migraine, Glial cell line-derived neurotrophic factor and somatostatin levels in induced by repeated meningeal nociception, characterized by a behavioral cerebrospinal fluid of patients affected by chronic migraine and and pharmacological approach. Cephalalgia 33(13):1096–1105 fibromyalgia. Cephalalgia 26(4):409–415 115. Jeong H, Moye LS, Southey BR, Hernandez AG, Pradhan AA, Rodriguez-zas 89. Peres MFP, Zukerman E, Senne Soares CA, Alonso EO, Santos BFC, Faulhaber SL (2018) Gene network Dysregulation in the trigeminal ganglia and MHW (2004) Cerebrospinal fluid glutamate levels in chronic migraine. nucleus Accumbens of a model of chronic migraine-associated Cephalalgia 24(9):735–739 Hyperalgesia. Front Syst Neurosci 12(December):1–19 90. Nam JH, Lee HS, Kim J, Kim J, Chu MK (2018) Salivary glutamate is elevated 116. Liang X, Wang S, Qin G, Xie J, Tan G, Zhou J et al (2017) Tyrosine in individuals with chronic migraine. Cephalalgia 38(8):1485–1492 phosphorylation of NR2B contributes to chronic migraines via increased 91. Ferrari A, Spaccapelo L, Pinetti D, Tacchi R, Bertolini A (2009) Effective expression of CGRP in rats. Biomed Res Int 2017:7203458 prophylactic treatments of migraine lower plasma glutamate levels. 117. Stucky NL, Gregory E, Winter MK, He Y-Y, Hamilton ES, McCarson KE et al Cephalalgia 29(4):423–429 (2011) Sex differences in behavior and expression of CGRP-related genes in 92. Papandreou O, Soldatou A, Tsitsika A, Kariyannis C, Papandreou T, Zachariadi A a rodent model of chronic migraine. Headache 51(5):674–692 et al (2005) Serum S100beta protein in children with acute recurrent headache: 118. Greco R, Tassorelli C, Sandrini G, Di Bella P, Buscone S, Nappi G (2008) Role a potentially useful marker for migraine. Headache 45(10):1313–1316 of calcitonin gene-related peptide and substance P in different models of 93. Jang M-U, Park J-W, Kho H-S, Chung S-C, Chung J-W (2011) Plasma and pain. Cephalalgia 28(2):114–126 saliva levels of nerve growth factor and neuropeptides in chronic migraine 119. Greco R, Demartini C, Zanaboni AM, Tassorelli C (2018) Chronic and patients. Oral Dis 17(2):187–193 intermittent administration of systemic nitroglycerin in the rat induces an Torres-Ferrús et al. The Journal of Headache and Pain (2020) 21:42 Page 12 of 12 increase in the gene expression of CGRP in central areas: potential 144. Liu H-Y, Chou K-H, Lee P-L, Fuh J-L, Niddam DM, Lai K-L et al (2017) contribution to pain processing. J Headache Pain 19(1):51 Hippocampus and amygdala volume in relation to migraine frequency and 120. Dreier JP, Jurkat-Rott K, Petzold GC, Tomkins O, Klingebiel R, Kopp UA et al prognosis. Cephalalgia 37(14):1329–1336 (2005) Opening of the blood-brain barrier preceding cortical edema in a 145. Schwedt TJ, Chong CD, Wu T, Gaw N, Fu Y, Li J (2015) Accurate severe attack of FHM type II. Neurology 64(12):2145–2147 classification of chronic migraine via brain magnetic resonance imaging. 121. Leira R, Sobrino T, Rodríguez-Yáñez M, Blanco M, Arias S, Castillo J (2007) Headache 55(6):762–777 MMP-9 Immunoreactivity in acute migraine. Headache 47(5):698–702 146. Dominguez C, Lopez A, Ramos-Cabrer P, Vieites-Prado A, Perez-Mato M, 122. Amin FM, Hougaard A, Cramer SP, Christensen CE, Wolfram F, Larsson HBW Villalba C et al (2019) Iron deposition in periaqueductal gray matter as a et al (2017) Intact blood−brain barrier during spontaneous attacks of potential biomarker for chronic migraine. Neurology 92(10):e1076–e1085 migraine without aura: a 3T DCE-MRI study. Eur J Neurol 24(9):1116–1124 147. Mc K, Ma VB, Pa H, Jt B. Migraine as a risk factor for deep brain lesions and 123. Hougaard A, Amin FM, Christensen CE, Younis S, Wolfram F, Cramer SP et al cardiovascular disease. 2007;295(4):976–980 (2017) Increased brainstem perfusion, but no blood-brain barrier disruption, 148. Toghae M, Rahimian E, Abdollahi M, Shoar S, Naderan M (2015) The during attacks of migraine with aura. Brain 140(6):1633–1642 prevalence of magnetic resonance imaging Hyperintensity in migraine 124. Fried NT, Maxwell CR, Elliott MB, Oshinsky ML (2018) Region-specific patients and its association with migraine headache characteristics and disruption of the blood-brain barrier following repeated inflammatory dural cardiovascular risk factors. Oman Med J 30(3):203–207 stimulation in a rat model of chronic trigeminal allodynia. Cephalalgia 38(4): 149. Neeb L, Bastian K, Villringer K, Gits HC, Israel H, Reuter U et al (2015) No 674–689 microstructural white matter alterations in chronic and episodic 125. DosSantos MF, Holanda-Afonso RC, Lima RL, DaSilva AF, Moura-Neto V migraineurs: a case-control diffusion tensor magnetic resonance imaging (2014) The role of the blood–brain barrier in the development and study. Headache 55(2):241–251 treatment of migraine and other pain disorders. Front Cell Neurosci 8:1–14 150. Chong CD, Schwedt TJ, Hougaard A (2019) Brain functional connectivity in 126. Burstein R, Yamamura H, Malick A, Strassman AM (1998) Chemical headache disorders: a narrative review of MRI investigations. J Cereb Blood stimulation of the intracranial Dura induces enhanced responses to facial Flow Metab 39(4):650–669 stimulation in brain stem trigeminal neurons. J Neurophysiol 79(2):964–982 151. Schulte LH, May A (2016) The migraine generator revisited: continuous 127. Edvinsson L, Haanes KA, Warfvinge K (2019) Does inflammation have a role scanning of the migraine cycle over 30 days and three spontaneous attacks. in migraine? Nat Rev Neurol 15(8):483–490 Brain 139(Pt 7):1987–1993 128. Kristiansen KA, Edvinsson L (2010) Neurogenic inflammation: a study of rat 152. Hadjikhani N, Ward N, Boshyan J, Napadow V, Maeda Y, Truini A et al (2013) trigeminal ganglion. J Headache Pain 11(6):485–495 2010/10/08 The missing link: enhanced functional connectivity between amygdala and 129. Russo AF, Kuburas A, Kaiser EA, Raddant AC, Recober A (2009) A potential visceroceptive cortex in migraine. Cephalalgia 33(15):1264–1268 preclinical migraine model: CGRP-sensitized mice. Mol Cell Pharmacol 1(5): 153. Schulte LH, Allers A, May A (2017) Hypothalamus as a mediator of chronic 264–270 migraine: evidence from high-resolution fMRI. Neurology 88(21):2011–2016 130. Wang X-Y, Zhou H-R, Wang S, Liu C-Y, Qin G-C, Fu Q-Q et al (2018) NR2B- 154. Lerebours F, Boulanouar K, Barege M, Denuelle M, Bonneville F, Payoux P Tyr phosphorylation regulates synaptic plasticity in central sensitization in a et al (2019) Functional connectivity of hypothalamus in chronic migraine chronic migraine rat model. J Headache Pain 19(1):102 with medication overuse. Cephalalgia 39(7):892–899 131. Tipton AF, Tarash I, McGuire B, Charles A, Pradhan AA (2016) The effects of 155. Lee MJ, Park B-Y, Cho S, Kim ST, Park H, Chung C-S (2019) Increased acute and preventive migraine therapies in a mouse model of chronic connectivity of pain matrix in chronic migraine: a resting-state functional migraine. Cephalalgia 36(11):1048–1056 MRI study. J Headache Pain 20(1):29 132. Sprenger T, Viana M, Tassorelli C (2018) Current prophylactic medications for migraine and their potential mechanisms of action. Neurotherapeutics 15:1–11 Publisher’s Note 133. Edvinsson J, Warfvinge K, Edvinsson L (2015) Modulation of inflammatory Springer Nature remains neutral with regard to jurisdictional claims in mediators in the trigeminal ganglion by botulinum neurotoxin type a: an published maps and institutional affiliations. organ culture study. J Headache Pain 16:555 134. Burstein R, Zhang X, Levy D, Aoki KR, Brin MF (2014) Selective inhibition of meningeal nociceptors by botulinum neurotoxin type a: therapeutic implications for migraine and other pains. Cephalalgia 34(11):853–869 135. Oshinsky ML, Murphy AL, Hekierski HJ, Cooper M, Simon BJ (2014) Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain 155(5):1037–1042 136. Eller-Smith OC, Nicol AL, Christianson JA (2018) Potential mechanisms underlying centralized pain and emerging therapeutic interventions. Front Cell Neurosci 12:35 137. Aurora SK, Brin MF (2017) Chronic migraine: an update on physiology, imaging, and the mechanism of action of two available pharmacologic therapies. Headache 57(1):109–125 138. Neeb L, Bastian K, Villringer K, Israel H, Reuter U, Fiebach JB (2017) Structural gray matter alterations in chronic migraine: implications for a progressive disease? Headache 57(3):400–416 139. Lee MJ, Chu MK, Choi H, Choi HA, Lee C, Chung C-S (2017) Longitudinal changes in cerebral blood flow velocities in different clinical courses of migraine. Cephalalgia 37(10):927–937 140. Russo A, Silvestro M, Tedeschi G, Tessitore A (2017) Physiopathology of migraine: what have we learned from functional imaging? Curr Neurol Neurosci Rep 17(12):95 141. Maleki N, Becerra L, Brawn J, Bigal M, Burstein R, Borsook D (2012) Concurrent functional and structural cortical alterations in migraine. Cephalalgia 32(8):607–620 142. Magon S, May A, Stankewitz A, Goadsby PJ, Schankin C, Ashina M et al (2019) Cortical abnormalities in episodic migraine: a multi-center 3T MRI study. Cephalalgia 39(5):665–673 143. Chen Z, Chen X, Liu M, Liu S, Ma L, Yu S (2017) Volume expansion of periaqueductal gray in episodic migraine: a pilot MRI structural imaging study. J Headache Pain 18(1):83