Migraine Research Research Articles

Polygenic risk score: use in migraine research

BackgroundThe latest Genome-Wide Association Study identified 38 genetic variants associated with migraine. In this type of studies the significance level is very difficult to achieve (5 × 10− 8) due to multiple testing. Thus, the identified variants only explain a small fraction of the genetic risk. It is expected that hundreds of thousands of variants also confer an increased risk but do not reach significance levels. One way to capture this information is by constructing a Polygenic Risk Score. Polygenic Risk Score has been widely used with success in genetics studies within neuropsychiatric disorders. The use of polygenic scores is highly relevant as data from a large migraine Genome-Wide Association Study are now available, which will form an excellent basis for Polygenic Risk Score in migraine studies.ResultsPolygenic Risk Score has been used in studies of neuropsychiatric disorders to assess prediction of disease status in case-control studies, shared genetic correlation between co-morbid diseases, and shared genetic correlation between a disease and specific endophenotypes.ConclusionPolygenic Risk Score provides an opportunity to investigate the shared genetic risk between known and previously unestablished co-morbidities in migraine research, and may lead to better and personalized treatment of migraine if used as a clinical assistant when identifying responders to specific drugs. Polygenic Risk Score can be used to analyze the genetic relationship between different headache types and migraine endophenotypes. Finally, Polygenic Risk Score can be used to assess pharmacogenetic effects, and perhaps help to predict efficacy of the Calcitonin Gene-Related Peptide monoclonal antibodies that soon become available as migraine treatment.KeywordsMigraine genetics; Genome-Wide Association Studies; Polygenic Risk Score; pleiotropy; endophenotype.

Altered Permeability Of The Blood‐CSF Barrier In Chronic Migraine

BackgroundMolecular communication from blood circulation to brain is tightly regulated at multiple biological barriers, but is disrupted in a variety of diseases, disorders, and infections. Recent human and animal data in migraine research has shown conflicting results regarding barrier disruption. These contradictions require resolution because a leaky barrier will expose the brain to potentially harmful components with diverse deleterious effects on brain function.MethodsSince blood‐to‐CSF transfer studies have not yet been performed in migraineurs, we studied surrogate biomarkers of barrier disruption in blood and CSF from non‐headache suffering controls and chronic migraine sufferers.ResultsWhen compared to controls, study participants with chronic migraine had clear evidence of barrier leak based on their higher CSF—blood albumin ratio, CSF fibrinogen levels, and CSF levels of the pericyte biomarker, soluble platelet‐derived growth factor receptor β. To test if other blood components were leaking through this barrier, we examined how CSF and blood lipids relate to the CSF—blood albumin ratio. The CSF—blood ratios of trans palmitoleic acid, linoleic acid, and ceramide were higher in chronic migraine and these lipid ratios correlated significantly with the CSF—blood albumin index, consistent with their derivation, at least partly, from a leaking barrier.ConclusionWe conclude that individuals with chronic migraine have distinct disruption of central nervous system (CNS) barriers that allows leakage into the CNS of multiple blood components, including proteins and lipids, and which likely results from, and contributes to the pathophysiology of migraine. The blood‐brain barrier and molecules that leak into the CNS are potential treatment targets.Support or Funding InformationThe National Institutes of Health, R01 NS043295, Higgins Family TrustsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Determinants of Optogenetic Cortical Spreading Depolarizations.

Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies.

Increased functional connectivity between the right temporo-parietal junction and the temporal poles in migraine without aura

Rather than a localized alteration, increased visual reactivity in migraine patients seems to result from a complex interaction between several brain structures, mostly involving the ventral attention network. The hub of this network is the right temporo-parietal junction. In this report, complementing our previous findings, we describe the differences in seed-to-voxel resting-state functional connectivity seeded in the right temporo-parietal junction (right angular gyrus) between migraine patients and healthy controls. Resting-state functional MRIs of episodic migraine without aura patients in the interictal period ( n = 19) and matched healthy controls ( n = 19) were analysed. With the seed placed in the right temporo-parietal junction (right angular gyrus), seed-to-voxel connectivity was compared between groups. Electrophysiological, voxel-based morphometry (both groups) and specific region of interest (ROI)-to-ROI functional connectivity (migraine patients) data have already been published. Migraine patients showed a higher positive interaction between the right temporo-parietal junction and both temporal poles and a higher negative interaction between this same region and bilateral areas of the visual cortex. On the basis of our results, and because of their established properties as multisensory integration hubs, it is likely that the right temporo-parietal junction and both temporal poles are involved in the altered processing of sensory stimulus commonly observed in migraine patients. Therefore, more attention should be paid to these regions for migraine research in the future.

Novel PAC1 receptor antagonist inhibits nitroglycerin-induced migraine-like pain responses in mice

Migraine is a common neurovascular disorder with uncomplete understood pathogenetic mechanisms. Pain modulation is an important issue in migraine research field. Therefore, understanding the pathogenesis of migraine and developing new treatments based on pathophysiological mechanisms are major issues in neuropharmacology.

Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors and Migraine: Should Cochrane Close the Door?

The Cochrane Collaboration completed a review entitled “Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-norepinephrine Reuptake Inhibitors (SNRIs) for the Prevention of Migraine in Adults” in 2015. In the review, they acknowledge that poor-quality research and low levels of evidence make it difficult to draw definitive conclusions, but then state that “A randomised controlled trial comparing a SSRI or a SNRI versus another drug or another non-pharmacological intervention is not a priority in the migraine research pipeline and might not exert a significant impact on the overall evidence”. A detailed evaluation of 10 of the 11 papers analysed in the Cochrane Review reveals that 9 of them use the International Classification of Headache Disorders (ICHD) system to determine their study cohorts. Despite being the current globally accepted standard for classification, diagnosis and categorization of migraine, the ICHD criteria are based on an arbitrary symptom list and offer little, if any, insight into the possible mechanisms involved in the pathophysiology of a migraine. Using the ICHD system in scientific studies which investigate the prevention and treatment of migraines, including those analyzed by the 2015 Cochrane Review, therefore results in amorphous cohort selection for those studies. This directly impacts the clinical relevance of the results drawn from the research. We acknowledge, and are grateful for, the important and highly credible contribution that the Cochrane Collaboration brings to our body of scientific knowledge. We are, however, concerned that the conclusions drawn in this important review might negatively impact on clinician ability to help individual migraine patients, not through any fault of the Cochrane Collaboration review system, but due to a fundamental flaw in the classification of migraines.

Meta-Synthesis on Migraine Management.

Migraine is one of the top 10 most disabling conditions among adults worldwide. Most migraine research is quantitative and indicates concerns about medication adherence, stigma, and more. Qualitative studies might reveal an improved understanding of migraine patients' perspectives regarding migraine treatment. The aim of this study was to synthesize the qualitative research on migraine patients' perspectives regarding migraine treatment to (a) identify common patterns across various types of migraine treatment studies and (b) inform future research. A systematic search for qualitative studies in the HA (HA) literature was conducted in Medline (PubMed), PsycINFO, EMBASE, CINAHL, Web of Science, Joanna Briggs Institute EBP Database, and The Cochrane Library. Search terms (subject headings and keywords) were HA, HA disorders, migraine, qualitative studies, and qualitative research. Qualitative studies were systematically identified by using published qualitative search filters recommended by The InterTASC Information Specialists' Sub-Group (ISSG). The search was limited to English only, peer reviewed publications, and studies published between 1996 and 2016. For screening, additional inclusion criteria were (1) adult migraine patients; (2) must mention treatment in the title or study design of the abstract. Ten studies met the inclusion criteria. The Critical Appraisal Skills Program tool was applied to appraise study quality. Thematic analysis produced the codes and themes. Two authors read articles separately and individually created codes. Code lists were synthesized and themes emerged iteratively from the process. Study sample sizes ranged from 10 to 33 participants, with our findings representing 161 participants. Data were collected either using interviews or focus groups. The more common methodologies were grounded theory and phenomenology. Few (3) studies described the number of headache (HA) days for inclusion in the study. Eight out of 10 used International Classification of Headache Disorders (ICHD) criteria. Our synthesis produced five major themes. The first theme was "Migraine patients' difficulties with health care utilization," and it included issues surrounding the cost of migraine treatment (seeing providers and prescription medications). The second theme was "Migraine patients' perceived relationships with their providers," which included the role and relationship with the provider, as well as trust in the provider and the providers' knowledge in managing HAs. The third theme was "Thoughts about the various migraine treatments." It was based on patients' comments indicating an aversion to prescription medications, the use of non-pharmacological interventions for treatment, behavioral modification as a form of treatment, and the need for additional treatment options. The fourth and fifth themes were "Understanding diagnosis/triggers" and "Societal implications," respectively. The latter theme included feelings of not being taken seriously and issues surrounding quality of life. The metasynthesis revealed several key commonalities regarding patients' perspectives on migraine treatment and identified new areas for research using a qualitative approach. Researchers conducting qualitative research with patients experiencing migraines might consider using and reporting more of the inclusion and exclusion criteria commonly used in migraine research, for example, reporting whether the ICHD criteria were used and the number of HA days for patients to be in a study. Future studies might be done to determine how the role of allied health care providers, for example, pharmacists, physical therapists, and psychologists, might be expanded to help with migraine treatment and ultimately to improve patient outcomes.

Behavioral study of a rat model of migraine induced by CGRP

Migraine is a debilitating disorder characterized by recurrent headache arising from neurovascular dysfunction. Despite recent progress in migraine research, the exact mechanisms underpinning migraine are poorly understood. Furthermore, it is difficult to develop an animal model of migraine that resembles all symptoms of patients. In this study, we established a novel animal model of migraine induced by epidural injection of calcitonin gene-related peptide (CGRP), and examined climbing hutch behavior, facial-grooming behavior, body-grooming behavior, freezing behavior, resting behavior, and ipsilateral hindpaw facial grooming behavior of rats following CGRP injection. CGRP significantly reduced climbing hutch behavior, and face-grooming behavior, and increased immobile behavior. We also found that the P15 and P85 percentile range of behavioral data exhibited a high positive rate (83.3%) for establishing the model with less false positive rate. Our results verified that the rat model of migraine induced by CGRP featured many behaviors of migraine patients demonstrated during migraine attacks. Our findings suggest that this new model can be a useful tool for understanding the pathophysiology of migraine and studying novel therapeutic strategies for the treatment of migraine.

The Non-Inferiority Margins in Migraine Research (NIMM) Survey.

To survey experts in Headache Medicine on their opinions regarding appropriate non-inferiority margins for outcomes commonly used in migraine research. Members of the American Headache Society and the Canadian Headache Society were invited to participate in the Non-Inferiority Margins in Migraine Research (NIMM) survey. Adult and child neurologists with expertise in Headache Medicine were eligible to participate. The survey had a multiple choice format and comprised questions on respondent characteristics, eligibility, as well as expert opinion on non-inferiority margins for outcomes commonly used in trials of both prophylactic and acute interventions for migraine. Ninety-nine eligible respondents completed the survey. Most respondents were adult neurologists (84.9%) and 74% reported practicing in the USA. The following were the most commonly selected non-inferiority margins: (1) change in monthly migraine attacks comparing baseline to the treatment period: 1 attack (39.4% selecting), (2) change in monthly migraine days comparing baseline to the treatment period: 1 day (44.4%), (3) change in average migraine intensity on a 4-point scale comparing baseline to the treatment period: 1.0 (31.3%), (4) percentage of participants who are pain-free 2 hours after the intervention: 5% (41.4%), (5) percentage of participants who have a migraine recurrence within 48 hours of treatment: 5% (42.4%), and (6) percentage of participants with sustained pain freedom: 5% (42.4%). The results of the NIMM survey describe the opinions of a group of experts on appropriate non-inferiority margins for outcomes commonly used in migraine clinical trials. There was significant variability in responses and lack of consensus on the choice of non-inferiority margins. The survey did not incorporate the patient perspective and was not validated prior to distribution. Further work in this area is required in order to explore how to incorporate clinical considerations into the selection of non-inferiority margins for migraine research.

Minority Representation in Migraine Treatment Trials.

Minorities have historically been underrepresented in clinical research trials despite having comparatively poor health indicators. Recognizing the dual inequalities of increased disease burden and decreased research participation, the National Institute of Health (NIH) Revitalization Act of 1993 mandated the inclusion and reporting of women and minorities in NIH-funded research. While progress has been made in the subsequent decades, this underrepresentation of minorities in research trials persists and has been documented in multiple disciplines. However, the extent of adequate representation and reporting of minority inclusion in clinical trials for migraine remains unknown. In this systematic review and study, we review the literature examining the representation of women and minorities in migraine clinical research trials METHODS: First we searched PubMed for pertinent articles examining the inclusion of women and minorities in migraine clinical research trials. Second, we identified controlled-trials for migraine published since 2011 in major neurology, headache, and general medicine journals using the terms "migraine randomized controlled trial." We then reviewed the results manually and excluded pilot studies and those with fewer than 50 participants. We next determined (a) how frequently representation of minorities and women were reported in these major trials; (b) what factors correlated with reporting; and (c) whether women and minority inclusion comprised their ratios in the general population. We identified 128 relevant clinical trials, of which 36 met our inclusion criteria. All 36 trials (100%) reported gender frequency, and 25 of 36 (69.4%) reported ethnicity or race. Among all studies, women and Whites represented 84.2 and 82.9% of participants (mean), respectively. Studies conducted in the United States and funded by a private company were more likely to report race than studies conducted exclusively outside of the U.S. or with a public sponsor. No studies stratified efficacy or safety by ethnicity or gender. Men and non-Whites in the U.S. were statistically underrepresented. Most recent headache studies comply with the NIH mandate to include women and minorities in research trials, particularly U.S.-based and industry-funded studies. Whites are overrepresented compared to both the general population and the population of migraineurs. Future studies should strive to increase minority participation and investigate race-based differences in migraine expression, treatment response, and medication toxicity.

Scientometric Assessment of India’s Migraine Research Publications during 2006-15

The present study examines 579 Indian publications on “Migraine” research as covered in Scopus database during 2006-15, experiencing an annual growth rate of 17.37%, citation impact per paper of 8.32, international collaborative publication share of 9.80% and global publication share of 2.56%. The global publications share on “Migraine” came from several countries, of which the top 10 most productive countries accounted for 75.30% share of global publications output during 2006-15. A large number of Indian organizations and authors participated in Indian research on “Migraine” research during 2006-15, of which the top 15 organizations and 15 authors contributed 31.26% and 25.22% publications share and 70.50% and 23.50% citation share respectively of the Indian output and citations. Medicine, among subjects, contributed the largest publications (63.90%), followed by pharmacology, toxicology & pharmaceutics (34.72%), neurosciences (14.16%), biochemistry, genetics & molecular biology (13.64%) and chemistry (3.97%) during 2006-15. Indian publications on migraine research appeared in several journals, of which the top 15 journals contributed 32.64% share of the India’s output. The top 14 highly cited papers registered 53 to 1087 citations, and together contributed 2094 citations, leading to the average citation per paper of 149.57. Concludes that there is an urgent need to frame a national policy in this area, undertake more R&D and recognize migraine research as a public health problem and allocate more healthcare funds in this area. Key words: Migraine, Pain, Disease, Publications, India, Bibliometrics, Scientometrics.

Pathophysiological targets for non-pharmacological treatment of migraine.

Background Migraine is the most prevalent neurological disorder worldwide and ranked sixth among all diseases in years lived with disability. Overall preventive anti-migraine therapies have an effect in one patient out of two at the most, many of them being endowed with disabling adverse effects. No new disease-modifying drugs have come into clinical practice since the application to migraine of topiramate and botulinum toxin, the latter for its chronic form. There is thus clearly a need for more effective treatments that are devoid of, or have acceptable side effects. In recent years, scientific progress in migraine research has led to substantial changes in our understanding of the pathophysiology of migraine and paved the way for novel non-drug pathophysiological-targeted treatment strategies. Overview Several such non-drug therapies have been tested in migraine, such as oxidative phosphorylation enhancers, diets and non-invasive central or peripheral neurostimulation. All of them are promising for preventive migraine treatment and are quasi-devoid of side effects. Their advantage is that they can in theory be selected for individual patients according to their pathophysiological profile and they can (and probably should) be combined with the classical pharmacological armamentarium. Conclusion We will review here how knowledge of the functional anatomy and physiology of migraine mechanisms holds the key for more specific and effective non-pharmacological treatments.

Metabotropic glutamate receptor 5: a target for migraine therapy.

IntroductionMany patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine‐specific target, the mGlu5 receptor.MethodsWe studied the effect of mGlu5 blockade using ADX10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mGlu5 mechanism was tested with ADX10059 orally in a double‐blind placebo‐controlled, parallel group, clinical trial.ResultsThe negative allosteric mGlu5 modulator ADX10059 attenuated dural vasodilator responses to meningeal stimulation in a dose‐dependent manner, comparable to naratriptan, while the N‐methyl‐d‐aspartate receptor blocker MK‐801 had no effect. ADX10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mGlu5 and not mGlu1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment‐emergent event at 48%.InterpretationOur findings provide preclinical and clinical proof of concept establishing mGlu5 as a novel therapeutic target in the treatment of migraine. Although ADX10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy.

The Revolution in Migraine Genetics: From Aching Channels Disorders to a Next-Generation Medicine.

Channelopathies are a heterogeneous group of neurological disorders resulting from dysfunction of ion channels located in cell membranes and organelles. The clinical scenario is broad and symptoms such as generalized epilepsy (with or without fever), migraine (with or without aura), episodic ataxia and periodic muscle paralysis are some of the best known consequences of gain- or loss-of-function mutations in ion channels. We review the main clinical effects of ion channel mutations associated with a significant impact on migraine headache. Given the increasing and evolving use of genetic analysis in migraine research—greater emphasis is now placed on genetic markers of dysfunctional biological systems—we also show how novel information in rare monogenic forms of migraine might help to clarify the disease mechanisms in the general population of migraineurs. Next-generation sequencing (NGS) and more accurate and precise phenotyping strategies are expected to further increase understanding of migraine pathophysiology and genetics.

New migraine therapies promise prevention: A new generation of drugs could avert migraine attacks rather than merely relieve symptoms.

Migraine has been documented almost from the beginning of recorded history and was one of the first targets of pain relief therapies, though most were ineffective until the 20th century. Even today when effective drugs are available for treating attacks, there is no cure beyond the fact that in some people the condition diminishes or disappears with age. Migraine remains one of the world's most common afflictions with relatively little regional variation around a global average of 15% that is skewed three to one towards women. In the USA, the incidence of migraine or severe headache ranges from 26.1% within a 3‐month period among women aged 18–44 at the top end to 4.6% among men older than 75 at the bottom [1]. According to the non‐profit organization Migraine Research Foundation, this equates to 113 million lost workdays per year costing employers an estimated US$13 billion. Around 14 million people in the USA—or 4.5% of the population—suffer from chronic and severe headaches on an almost daily basis; treatment comes in at an estimated annual cost of US$50 billion on top of lost productivity (http://www.migraineresearchfoundation.org/frequently-asked-questions.html). With this background, it is hardly surprising that migraine has been a major focus of research and clinical development. Yet, and in common with other areas of pain relief, treatment of migraine has evolved almost in the dark without a firm understanding of the condition's underlying biology. Nevertheless, after many years of work, there is now considerable optimism that the field is on the verge of substantive progress, even though the fundamental mechanism remains elusive. “We are currently at an exciting time for migraine research and therapy with several novel therapies in the pipeline”, said Philip Holland, Head of Preclinical Research in the Headache Group at King's College, London. A new generation of …

Coffee But Not Anticipation of Coffee Alters the Outcome of Explosive Bench Pressing

When administering a drug, the degree of anticipation influences perceptual outcomes in migraine research (Slavenka Kam‐Hansen, 2014). Specifically, pain scores vary depending on the information given (percent anticipation). Little is known, however, to what extent anticipation affects physical performance. Often, coffee and caffeine research include a 50% anticipation in the form of experimental beverage or placebo. Few coffee studies, though, also include a true control such as water. The purpose of this study was to compare a highly‐caffeinated instant coffee (VIA) to both an identical decaffeinated placebo (DCF) and to water (WTR). This provides the typical 50% anticipation comparison and a 0% anticipation true control. We hypothesized that VIA would increase explosive performance compared to both DCF (50% anticipation) and to WTR (0% anticipation). Further, we hypothesized that DCF (50% anticipation) would increase performance and psychostimulant variables compared to WTR (0% anticipation). Ten resistance‐trained participants with varied levels of coffee habituation were tested at 50% of one‐repetition maximum (1RM) in the Smith bench press 60 minutes after ingesting 20 oz. (2 packets) VIA, DCF, or WTR. Force, bar velocity (VEL), power (POW), rate of force development (RFD) and time to peak power (TPP) were measured using the Smith bench press and a Ballistic Measurement System (BMS, Innervations, Inc., South Australia). Psychostimulant testing included Likert‐type (1–5 scale) ratings of alertness, focus and energy. After repeated measures analysis of variance and Newman‐Keuls post hoc testing, VEL and POW increased after consuming VIA versus DCF or WTR (mean ± SE: 1.15 ± 0.05 m/s vs. 0.99 ± 0.05 m/s and 1.01 ± 0.05 m/s; p=0.004 and p=0.005, respectively and 561.1 ± 109.4 W vs. 482.2 ± 92.4 W and 465.4 ± 84.7 W; p=0.009 and p=0.007 respectively). No performance differences were noted between DCF and WTR. Upon psychostimulant analysis, VIA increased alertness compared to DCF and WTR (4.22 ± 0.22 vs. 3.44 ± 0.29 and 2.94 ± 0.34; p=0.006 and p=0.0004 respectively). There was a trend for DCF to increase alertness versus WTR (3.44 ± 0.29 vs. 2.94 ± 0.34; p=0.06). Within the limitations of this design, we conclude that our hypothesis regarding VIA and physical performance was supported but the hypothesis involving anticipation of DCF largely was not. DCF had no effect on explosive physical performance but did tend to affect perception of alertness.

A Pain in the Brain

The article discusses migraine headaches, with a particular focus on the development of a drug designed to prevent migraines. The drug targets the neurotransmitter calcitonin gene-related peptide (CGRP) in the trigeminal nerve system, which researcher Peter Goadsby believes is the center of migraine activity. Details on the history of migraine research and treatment, including the drugs known as triptans and the suspected role of vasodilation in migraines, are presented. Transcranial magnetic stimulation (TMS) is also discussed.

Laser evoked potentials and central sensitization in migraine.

Migraine is a disabling disorder of neuro-vascular origin. An abnormal neuronal excitability, largely based on genetic nature, is a predisposing factor to attack onset. A reduced habituation to multimodal repetitive non nociceptive stimuli was observed in migraine. The pattern of reduced habituation to nociceptive stimuli may favor the increase of pain and the phenomena of central sensitization. Central sensitization is a phenomenon of pain processing, which may predispose to chronic pain. Allodynia occurring during migraine attack and persistent pericranial tenderness in migraine are symptoms of central sensitization[1, 2]. CO2 laser evoked potentials (LEPs) have been used in migraine research, proving very useful in demonstrating functional abnormalities of the central nociceptive system which might be linked to the pathophysiological mechanisms of this disease. Abnormalities of pain processing seem to characterize children with migraine. Reduced habituation and progressive amplification of cortical responses under laser stimuli indicate an overactive nociceptive system just at the onset of migraine, which may subtend symptoms of central sensitization as allodynia and pericranial tenderness. An abnormal pattern of habituation of the trigeminal nociceptive system is an endophenotypic marker of migraine[3], suggesting that the nociceptive system is prone to sensitization even before clinical appearance[4]. These aspects may guide therapeutic approach: in a recent work in which we explored the efficacy of botulinum toxin in the treatment of chronic migraine, we found a correlation of the clinical effect with an improvement of the LEPs habituation deficit. The modes of action of pharmacological or nonpharmacological interventions, such as neuromodulation methods, should therefore be reconsidered in terms of their ability to normalize the complex abnormalities of brain hyperresponsivity and the central sensitization phenomena.

Resting state brain activity in patients with migraine: a magnetoencephalography study.

BackgroundRecent advances in migraine research have shown that the cerebral cortex serves a primary role in the pathogenesis of migraine. Since aberrant brain activity in migraine can be noninvasively detected with magnetoencephalography (MEG), The object of this study was to investigate the resting state cortical activity differences between migraineurs and controls and its related clinical characteristics.MethodsTwenty-two subjects with an acute migraine and twenty-two age- and gender-matched controls were studied using MEG. MEG recordings were recorded 120 seconds during the headache attack. Analyze MEG signals from low (1–4 Hz) to high (200–1000 Hz)-frequency ranges.ResultsIn comparison with the controls, brain activity in migraine subjects was significantly different from that of the controls both in two frequency ranges (55–90 Hz, p < 0.001) and (90–200 Hz, p < 0.004). But the power value showed no significantly differences between control and migraines in all frequency ranges (p > 0.05). All the clinical characteristics had no significant correlation with aberrant brain activity.ConclusionsThe results demonstrated that migraine subjects in resting state had significantly aberrant ictal brain activity that can be measured with neuromagnetic imaging techniques. The findings may facilitate the development of new therapeutic strategies in migraine treatment via alterations in cortical excitability with TMS and other medications in the future.

From migraine genes to mechanisms.

Migraine is a common multifactorial episodic brain disorder with strong genetic basis. Monogenic subtypes include rare familial hemiplegic migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, familial advanced sleep-phase syndrome (FASPS), and retinal vasculopathy with cerebral leukodystrophy. Functional studies of disease-causing mutations in cellular and/or transgenic models revealed enhanced (glutamatergic) neurotransmission and abnormal vascular function as key migraine mechanisms. Common forms of migraine (both with and without an aura), instead, are thought to have a polygenic makeup. Genome-wide association studies have already identified over a dozen genes involved in neuronal and vascular mechanisms. Here, we review the current state of molecular genetic research in migraine, also with respect to functional and pathway analyses. We will also discuss how novel experimental approaches for the identification and functional characterization of migraine genes, such as next-generation sequencing, induced pluripotent stem cell, and optogenetic technologies will further our understanding of the molecular pathways involved in migraine pathogenesis.