Role In Migraine Research Articles

Current Evidence on Potential Uses of MicroRNA Biomarkers for Migraine: From Diagnosis to Treatment.

Migraine is a disabling and recurrent neurological disorder characterized by headache attacks that are often accompanied by sensory and motor disturbances. The value and importance of reliable biomarkers in migraine have been long recognized and a diverse range of biomarkers from biological samples to electrophysiological patterns and brain imaging has been proposed. There is still no consensus on specific biomarker(s) for migraine. Ideally, not a single but a battery of biomarkers would provide a multidisciplinary way to understand and treat migraine better. Translational research has witnessed an escalating number of studies on microRNAs (miRNAs) during the last decade. Identification of the first miRNA occurred in 1993, and currently more than 2000 human miRNAs have been recognized. miRNAs are a group of endogenous small non-coding molecules that play a key role in post-transcriptional gene processes and hence are involved in health and disease. miRNAs have already been found to be involved in the onset and progression of several human disorders including chronic pain conditions; however, there have been far fewer studies in migraine and other headaches. Current evidence does suggest that miRNAs play a role in migraine and its relief and hence these molecules are proposed as potential migraine biomarkers. This review updates the current evidence for the role of miRNAs in migraine; including their potential as biomarkers, with a role in understanding of its pathogenesis, the population at risk, diagnosis, patient stratification, chronification risk factors, response to treatments, and miRNA-based therapeutic options. Limitations exist and further research is required to completely unwrap the potential of miRNAs in migraine research and practice.

Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review.

Calcitonin-gene-related peptide (CGRP), a neuropeptide broadly distributed in neuronal and non-neuronal regions throughout the body, plays a fundamental role in migraine and cluster headache (CH) pathophysiology. CGRP functional blockade alleviates neurogenic inflammation and reduces pain pathway sensitization. Two types of CGRP function-blocking modalities, monoclonal antibodies (MAbs), and small molecules (gepants), have been designed to target the CGRP ligands and CGRP receptors. In this narrative review, we summarized the latest clinical trials on gepants and CGRP function-blocking MAbs for migraine and CH prevention. At the time of writing, newer gepants are currently under Federal Drug Administration (FDA) review for migraine management, but there is no study yet on the usage of gepants for CH. Erenumab, fremanezumab, and galcanezumab have been approved by the FDA for migraine prevention while eptinezumab is under FDA review. CGRP MAbs are as effective as and more tolerable than conventional migraine preventives. For CH prevention, galcanezumab has shown some promising findings and was recently approved for use in episodic cluster prevention. CGRP function-blocking therapy not only demonstrates high efficacy and superior safety profile, but also improves headache frequency and quality of life. Convenient monthly dosing for the MAbs can further improve medication adherence, hence better headache control. With CGRP function-blocking therapy showing efficacy even in individuals who failed other preventives, it has become an exciting new therapeutic option in the field of migraine and CH.

Does inflammation have a role in migraine?

Migraine is a prevalent disorder, affecting 15.1% of the world's population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develop chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, we review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. We propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. We present evidence from preclinical research that supports this view and discuss the implications for migraine therapy.

CSD-Induced Arterial Dilatation and Plasma Protein Extravasation Are Unaffected by Fremanezumab: Implications for CGRP's Role in Migraine with Aura.

Cortical spreading depression (CSD) is a wave of neuronal depolarization thought to underlie migraine aura. Calcitonin gene-related peptide (CGRP) is a potent vasodilator involved in migraine pathophysiology. Evidence for functional connectivity between CSD and CGRP has triggered scientific interest in the possibility that CGRP antagonism may disrupt vascular responses to CSD and the ensuing plasma protein extravasation (PPE). Using imaging tools that allow us to generate continuous, live, high-resolution views of spatial and temporal changes that affect arteries and veins in the dura and pia, we determined the extent to which CGRP contributes to the induction of arterial dilatation or PPE by CSD in female rats, and how these events are affected by the anti-CGRP monoclonal antibody (anti-CGRP-mAb) fremanezumab. We found that the CSD-induced brief dilatation and prolonged constriction of pial arteries, prolonged dilatation of dural arteries and PPE are all unaffected by fremanezumab, whereas the brief constriction and prolonged dilatation of pial veins are affected. In comparison, although CGRP infusion gave rise to the expected dilatation of dural arteries, which was effectively blocked by fremanezumab, it did not induce dilatation in pial arteries, pial veins, or dural veins. It also failed to induce PPE. Regardless of whether the nociceptors become active before or after the induction of arterial dilatation or PPE by CSD, the inability of fremanezumab to prevent them suggests that these events are not mediated by CGRP, a conclusion with important implications for our understanding of the mechanism of action of anti-CGRP-mAbs in migraine prevention.SIGNIFICANCE STATEMENT The current study identifies fundamental differences between two commonly used models of migraine, CSD induction and systemic CGRP infusion. It raises the possibility that conclusions drawn from one model may not be true or relevant to the other. It sharpens the need to accept the view that there is more than one truth to migraine pathophysiology and that it is unlikely that one theory will explain all types of migraine headache or the mechanisms of action of drugs that prevent it. Regarding the latter, it is concluded that not all vascular responses in the meninges are born alike and, consequently, that drugs that prevent vascular dilatation through different molecular pathways may have different therapeutic outcomes in different types of migraine.

CGRP and the Trigeminal System in Migraine.

ObjectiveThe goal of this narrative review is to provide an overview of migraine pathophysiology, with an emphasis on the role of calcitonin gene‐related peptide (CGRP) within the context of the trigeminovascular system.BackgroundMigraine is a prevalent and disabling neurological disease that is characterized in part by intense, throbbing, and unilateral headaches. Despite recent advances in understanding its pathophysiology, migraine still represents an unmet medical need, as it is often underrecognized and undertreated. Although CGRP has been known to play a pivotal role in migraine for the last 2 decades, this has now received more interest spurred by the early clinical successes of drugs that block CGRP signaling in the trigeminovascular system.DesignThis narrative review presents an update on the role of CGRP within the trigeminovascular system. PubMed searches were used to find recent (ie, 2016 to November 2018) published articles presenting new study results. Review articles are also included not as primary references but to bring these to the attention of the reader. Original research is referenced in describing the core of the narrative, and review articles are used to support ancillary points.ResultsThe trigeminal ganglion neurons provide the connection between the periphery, stemming from the interface between the primary afferent fibers of the trigeminal ganglion and the meningeal vasculature and the central terminals in the trigeminal nucleus caudalis. The neuropeptide CGRP is abundant in trigeminal ganglion neurons, and is released from the peripheral nerve and central nerve terminals as well as being secreted within the trigeminal ganglion. Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization, and can drive central sensitization of the second‐order neurons. A shift in central sensitization from activity‐dependent to activity‐independent central sensitization may indicate a mechanism driving the progression of episodic migraine to chronic migraine. The pathophysiology of cluster headache is much more obscure than that of migraine, but emerging evidence suggests that it may also involve hypersensitivity of the trigeminovascular system. Ongoing clinical studies with therapies targeted at CGRP will provide additional, valuable insights into the pathophysiology of this disorder.ConclusionsCGRP plays an essential role in the pathophysiology of migraine. Treatments that interfere with the functioning of CGRP in the peripheral trigeminal system are effective against migraine. Blocking sensitization of the trigeminal nerve by attenuating CGRP activity in the periphery may be sufficient to block a migraine attack. Additionally, the potential exists that this therapeutic strategy may also alleviate cluster headache as well.

Clinical characteristics of migraine in patients with calcified neurocysticercosis.

Patients with neurocysticercosis (NCC) may have an increased frequency of migraine. We studied the characteristics of migraine attacks in patients with calcified NCC on brain imaging. Of 350 migraine patients who visited our outpatient department from January 2016 through June 2018, 166 had undergone brain imaging. Seventy-two patients with migraines had calcified NCC. The migraine attacks of the patients with calcification (MiC) were compared with those of 94 patients without calcification (MiNC). Side-locked headaches were seen in 48.6% of the MiC patients. Aura preceding the migraine attack was more common in the MiC group than in the MiNC group (22.22% vs 7.4%; p=0.001). The MiC group had fewer headache episodes per month (5 vs 6; p<0.0001) with fewer common associated features (62.5% vs 84.1%; p=0.006). They also required fewer drugs for secondary prophylaxis (2 vs 3; p=0.002). Some of the clinical characteristics of migraine attacks are sufficiently different in patients with and without NCC. This may suggest some influence of NCC in the pathophysiology of migraine to account for alterations in the clinical manifestations of the disease. Whether this difference could be inferred as NCC having a causative role in migraine needs further research.

Effect of TRPA1 activator allyl isothiocyanate (AITC) on rat dural and pial arteries.

Transient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo. The genuine closed-cranial window technique in rats was used to examine changes in dural and pial artery diameter and mean arterial blood pressure (MABP) after intracarotid infusion of AITC. Blockade experiments were performed by intravenous infusion of olcegepant, HC-030031, sumatriptan or capsazepine immediately after infusion of AITC, in four different groups of rats. AITC caused a significant dilation of dural arteries, which was inhibited by HC-030031, olcegepant and sumatriptan, but not by capsazepine. In pial arteries AITC caused a significant dilation, which was not inhibited by any of the pre-treatments, suggesting a poor penetration of the blood-brain barrier or autoregulation due to dimethyl sulfoxide (DMSO) mediated decrease in MABP during HC-030031 infusion. AITC did not cause a significant change in MABP. AITC causes dilation of dural arteries via a mechanism dependent on CGRP and TRPA1 that is sensitive to sumatriptan. AITC causes a small but significant dilation of pial arteries.

Therapeutic role of melatonin in migraine prophylaxis: A systematic review.

BackgroundMelatonin is the “clock factor” generated from pineal gland dominating regular circadian rhythm in humans. Migraine is one of the most severe and debilitating primary headache disorders. Thus far, many diseases have been found to associate with melatonin, including the migraine. Therefore, melatonin's therapeutic potential for migraine is drawing attention.ObjectivesThe aim of this study is to offer a systematic review of extant data of melatonin in migraine prophylaxis and to provide clinical implications and specific recommendations for future studies.Data sources and study methodsA systematic research was conducted in September 2018 by using PubMed and Google Scholar databases to search for science literature published after 1988.ResultsIn all, 7 eligible articles were identified, including 4 randomized controlled studies and 3 observational studies. Due to high heterogeneities and limited number of studies, meta-analysis was not feasible, and only systematic review was performed. The results show that present evidence cannot claim melatonin's effectiveness according to the conflicting outcomes; however, the two negative outcomes of melatonin not different from placebo and melatonin inferior to amitriptyline are possible under-powering because of methodological, pharmacological, and therapeutic shortcomings. Observational studies also support melatonin's efficacy in migraine. As a result, melatonin is very likely to benefit migraine in prophylaxis and may have a similar effectiveness to other main preventive medications. Immediate-release melatonin 3 mg was established as effective, melatonin receptor agonist (Agomelatine) 25 mg and prolonged-release melatonin 4 mg were observed efficacious in observational studies. Melatonin displayed ineffective in the 2-month trial; thus, 3 months or more may be an enough duration for migraine therapy. Despite melatonin being generally safe, emerging literature is illustrating that a few severe adverse effects can be caused by melatonin, for example, liver injuries, reproductive system dysfunctions, and detrimental immunostimulation.ConclusionsMelatonin is very likely to be a promising alternative for migraine prophylaxis. Current literature examining melatonin's efficacy in migraine prevention is growing, but still limited. Future studies of perfect design in methodology, pharmacology, and therapeutics are needed to achieve a deeper awareness of melatonin's role in migraine as well as more studies to explore the safety issues of melatonin medicine.

Introducing Genes With Significant Role in Migraine: An Interactomic Approach.

Introduction:Migraine is a severe kind of headache with the chance hereditary of 50%. Molecular studies can promote understanding of migraine pathophysiology. One of which is bioinformatics approach that could provide additional information related to the identified biomarkers.Methods:In this research, migraine genes are studies in terms of interaction pattern to introduce important individuals. Through STRING database Plug-in in Cytoscape, candidate genes for migraine were retrieved and analyzed by related applications. Based on centrality and action types (expression, activation, and inhibition) genes were screened.Results:Numbers of 33 central genes including seven hub-bottlenecks were identified which 70% of central genes were involved in expression action with each other. Activation was dominate action relative to inhibition between the central genes.Conclusion:The finding indicates that insulin is the most important gene relative to migraine. It seems regulation of metabolism play critical role in control of migraine.

Efficacy of CoQ10 as supplementation for migraine: A meta-analysis.

Migraine ranks among the most frequent neurological disorders globally. Co-enzyme Q10 (CoQ10) is a nutritional agent that might play a preventative role in migraine. This meta-analysis aimed to investigate the effects of CoQ10 as a supplemental agent in migraine. Web of Science, PubMed, and Cochrane Library were searched for potential articles that assessed the effects of CoQ10 on migraine. Data were extracted by two independent reviewers and analyzed with Revman 5.2 software (The Nordic Cochrane Centre, Copenhagen, Denmark). We included five studies with 346 patients (120 pediatric and 226 adult subjects) in the meta-analysis. CoQ10 was comparable with placebo with respect to migraine attacks/month (P=0.08) and migraine severity/day (P=0.08). However, CoQ10 was more effective than placebo in reducing migraine days/month (P<0.00001) and migraine duration (P=0.009). This is the first study to demonstrate the effects of CoQ10 supplementation on migraine. The results support the use of CoQ10 as a potent therapeutic agent with respect to migraine duration and migraine days/month. Nonetheless, more studies are needed to support the conclusions.

Recurrent Headache Increases Blood-Brain Barrier Permeability and VEGF Expression in Rats

Background: The blood-brain barrier (BBB) is an important anatomical structure of the central nervous system (CNS) that limits the penetration of a variety of substances from the blood into the parenchyma. Dysfunction of the BBB is involved in various CNS disorders, including stroke, inflammation, and pain. However, the evidence concerning its role in migraine is insufficient. Objective: This study will investigate whether recurrent headache increases BBB permeability and vascular endothelial growth factor (VEGF) expression in a rat model. Study Design: This study used an experimental design. Setting: The research took place in the Laboratory Research Center at The First Affiliated Hospital of Chongqing Medical University. Methods: Eighty male Sprague-Dawley rats were randomly divided into 3 groups: inflammatory soup (IS), control (PBS), and treatment (IS+Sumatriptan) groups. Recurrent headache was induced by episodic IS stimulation: 20 µL of IS were pumped into the dura 3 times per week in rats. The control group was administered 20 µL of PBS. The rats in the treatment group were simultaneously treated with sumatriptan (300 ug/kg, intraperitoneal) at the same time that IS was applied to the dura. Mechanical nociceptive thresholds were examined by electronic von Frey filaments with rigid tips. BBB permeability changes were measured with Evans blue (EB). The expression of VEGF was measured by double labeling and Western blotting. Results: After 4 IS applications, the mechanical nociceptive thresholds significantly decreased. In addition, the mechanical hypersensitivity persisted for 4 hours after 9 applications. Only after 9 applications did the BBB permeability increase, as demonstrated by the EB tracer. The BBB disruption was accompanied by an elevation in VEGF expression. Sumatriptan treatment significantly reduced the mechanical hypersensitivity induced by IS stimulations and decreased the BBB disruption and VEGF expression. Limitations: Potential mechanisms that underlie the relationship between BBB and VEGF were not examined in this study. Conclusions: The present study showed that repeated IS stimulations induced long-lasting allodynia, increased BBB permeability, and upregulated VEGF expression, all of which could be attenuated by early sumatriptan treatment. Key words: Migraine, inflammatory soup, blood-brain barrier, vascular endothelial growth factor, sumatriptan

From LBR-101 to Fremanezumab for Migraine.

Calcitonin gene-related peptide (CGRP) is a neuropeptide of importance in migraine pathogenesis. Its central role in migraine was proven pharmacologically by the development of CGRP receptor antagonists. Monoclonal antibodies targeting CGRP or its receptor are effective in the preventive treatment of episodic and chronic migraine and are considered potential breakthroughs in their treatment. Fremanezumab (previously known as TEV-48125, LBR-101, or RN-307) is a humanized IgG2a monoclonal antibody that binds to CGRP. The development of this antibody validated the role of CGRP in chronic migraine and the drug has been recently approved in the US by the FDA, while it continues to be reviewed by other regulatory agencies. Herein we provide an in-depth review of its development. We start by summarizing its in vitro and in vivo pharmacology, and the phase I studies. We then review the late-stage clinical development, with a focus on its efficacy, safety, similarities, and uniqueness relative to other CGRP antibodies. We close by discussing lessons learned on the mechanisms of migraine and areas for future development and exploration.

The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects.

Calcitonin gene-related peptide (CGRP) is a highly potent vasoactive peptide released from sensory nerves, which is now proposed to have protective effects in several cardiovascular diseases. The major α-form is produced from alternate splicing and processing of the calcitonin gene. The CGRP receptor is a complex composed of calcitonin like receptor (CLR) and a single transmembrane protein, RAMP1. CGRP is a potent vasodilator and proposed to have protective effects in several cardiovascular diseases. CGRP has a proven role in migraine and selective antagonists and antibodies are now reaching the clinic for treatment of migraine. These clinical trials with antagonists and antibodies indicate that CGRP does not play an obvious role in the physiological control of human blood pressure. This review discusses the vasodilator and hypotensive effects of CGRP and the role of CGRP in mediating cardioprotective effects in various cardiovascular models and disorders. In models of hypertension, CGRP protects against the onset and progression of hypertensive states by potentially counteracting against the pro-hypertensive systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic system. With regards to its cardioprotective effects in conditions such as heart failure and ischaemia, CGRP-containing nerves innervate throughout cardiac tissue and the vasculature, where evidence shows this peptide alleviates various aspects of their pathophysiology, including cardiac hypertrophy, reperfusion injury, cardiac inflammation, and apoptosis. Hence, CGRP has been suggested as a cardioprotective, endogenous mediator released under stress to help preserve cardiovascular function. With the recent developments of various CGRP-targeted pharmacotherapies, in the form of CGRP antibodies/antagonists as well as a CGRP analog, this review provides a summary and a discussion of the most recent basic science and clinical findings, initiating a discussion on the future of CGRP as a novel target in various cardiovascular diseases.

The Role of Migraine in Hearing and Balance Symptoms

The Role of Migraine in Hearing and Balance Symptoms

Using NEURON for Reaction-Diffusion Modeling of Extracellular Dynamics.

Development of credible clinically-relevant brain simulations has been slowed due to a focus on electrophysiology in computational neuroscience, neglecting the multiscale whole-tissue modeling approach used for simulation in most other organ systems. We have now begun to extend the NEURON simulation platform in this direction by adding extracellular modeling. The extracellular medium of neural tissue is an active medium of neuromodulators, ions, inflammatory cells, oxygen, NO and other gases, with additional physiological, pharmacological and pathological agents. These extracellular agents influence, and are influenced by, cellular electrophysiology, and cellular chemophysiology—the complex internal cellular milieu of second-messenger signaling and cascades. NEURON's extracellular reaction-diffusion is supported by an intuitive Python-based where/who/what command sequence, derived from that used for intracellular reaction diffusion, to support coarse-grained macroscopic extracellular models. This simulation specification separates the expression of the conceptual model and parameters from the underlying numerical methods. In the volume-averaging approach used, the macroscopic model of tissue is characterized by free volume fraction—the proportion of space in which species are able to diffuse, and tortuosity—the average increase in path length due to obstacles. These tissue characteristics can be defined within particular spatial regions, enabling the modeler to account for regional differences, due either to intrinsic organization, particularly gray vs. white matter, or to pathology such as edema. We illustrate simulation development using spreading depression, a pathological phenomenon thought to play roles in migraine, epilepsy and stroke. Simulation results were verified against analytic results and against the extracellular portion of the simulation run under FiPy. The creation of this NEURON interface provides a pathway for interoperability that can be used to automatically export this class of models into complex intracellular/extracellular simulations and future cross-simulator standardization.

Neurogenic inflammation and its role in migraine.

The etiology of migraine pain involves sensitized meningeal afferents that densely innervate the dural vasculature. These afferents, with their cell bodies located in the trigeminal ganglion, project to the nucleus caudalis, which in turn transmits signals to higher brain centers. Factors such as chronic stress, diet, hormonal fluctuations, or events like cortical spreading depression can generate a state of "sterile inflammation" in the intracranial meninges resulting in the sensitization and activation of trigeminal meningeal nociceptors. This sterile inflammatory phenotype also referred to as neurogenic inflammation is characterized by the release of neuropeptides (such as substance P, calcitonin gene related peptide) from the trigeminal innervation. This release leads to vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Although neurogenic inflammation has been observed and extensively studied in peripheral tissues, its role has been primarily investigated in the genesis and maintenance of migraine pain. While some aspects of neurogenic inflammation has been disregarded in the occurrence of migraine pain, targeted analysis of factors have opened up the possibilities of a dialogue between the neurons and immune cells in driving such a sterile neuroinflammatory state in migraine pathophysiology.

CGRP Receptor Signalling Pathways.

Calcitonin gene-related peptide (CGRP) is a promiscuous peptide, similar to many other members of the calcitonin family of peptides. The potential of CGRP to act on many different receptors with differing affinities and efficacies makes deciphering the signalling from the CGRP receptor a challenging task for researchers.Although it is not a typical G protein-coupled receptor (GPCR), in that it is composed not just of a GPCR, the CGRP receptor activates many of the same signalling pathways common for other GPCRs. This includes the family of G proteins and a variety of protein kinases and transcription factors. It is now also clear that in addition to the initiation of cell-surface signalling, GPCRs, including the CGRP receptor, also activate distinct signalling pathways as the receptor is trafficking along the endocytic conduit.Given CGRP's characteristic of activating multiple GPCRs, we will first consider the complex of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) as the CGRP receptor. We will discuss the discovery of the CGRP receptor components, the molecular mechanisms controlling its internalization and post-endocytic trafficking (recycling and degradation) and the diverse signalling cascades that are elicited by this receptor in model cell lines. We will then discuss CGRP-mediated signalling pathways in primary cells pertinent to migraine including neurons, glial cells and vascular smooth muscle cells.Investigation of all the CGRP- and CGRP receptor-mediated signalling cascades is vital if we are to fully understand CGRP's role in migraine and will no doubt unearth new targets for the treatment of migraine and other CGRP-driven diseases.

Executive function and its clinical correlates among migraineurs

Background: The studies conducted in the field of migraine and its effect on various cognitive functions revealed contradicting results mainly due to the incorporation of patients from varied socioeconomic status, clinical conditions, and the methodology adopted to the study. Methods: The participants of the study consist of 130 migraineurs, selected from the outpatient department of neurology from reputed tertiary centers at Chennai, South India, and controls were picked up from the community. Patients were selected on the basis of clinical examination and screening. The instruments used are Migraine Severity Scale, Headache impact test, hospital anxiety and depression scale (HADS), Wisconsin Card Sorting Test, Trail Making Test, and Controlled Oral word Association Test. Results: The study found that migraine group to have deficits in some aspects of problem-solving and concept formation competencies in comparison with healthy individuals and also found strong and weak correlation with various clinical variables such as its severity, duration, and headache impact indicating the role of migraine on cognitive functioning. Conclusion: The condition of migraine does lead to mild-to-moderate levels of impairment in various frontal lobe-involved cognitive functions such as attention, planning, and problem-solving even in a high-profile samples having higher levels of education and occupation. The relation between the migraine and impairment in cognitive functions are further cemented by the strong correlation found between various clinical factors such as its severity, duration, and its impact. Findings from such a study will also pave new ways and means to incorporate the implementation of a holistic approach in the treatment and management of migraine, and thereby to enhance the quality of life of these patients.

Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors.

Calcitonin gene-related peptide (CGRP), the most abundant neuropeptide in primary afferent sensory neurons, is strongly implicated in the pathophysiology of migraine headache, but its role in migraine is still equivocal. As a new approach to migraine treatment, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs) were developed to reduce the availability of CGRP, and were found effective in reducing the frequency of chronic and episodic migraine. We recently tested the effect of fremanezumab (TEV-48125), a CGRP-mAb, on the activity of second-order trigeminovascular dorsal horn neurons that receive peripheral input from the cranial dura, and found a selective inhibition of high-threshold but not wide-dynamic range class of neurons. To investigate the basis for this selective inhibitory effect, and further explore the mechanism of action of CGRP-mAbs, we tested the effect of fremanezumab on the cortical spreading depression-evoked activation of mechanosensitive primary afferent meningeal nociceptors that innervate the cranial dura, using single-unit recording in the trigeminal ganglion of anesthetized male rats. Fremanezumab pretreatment selectively inhibited the responsiveness of Aδ neurons, but not C-fiber neurons, as reflected in a decrease in the percentage of neurons that showed activation by cortical spreading depression. These findings identify Aδ meningeal nociceptors as a likely site of action of fremanezumab in the prevention of headache. The selectivity in its peripheral inhibitory action may partly account for fremanezumab's selective inhibition of high-threshold, as a result of a predominant A-δ input to high-threshold neurons, but not wide dynamic-range dorsal horn neurons, and why it may not be effective in all migraine patients.SIGNIFICANCE STATEMENT Recently, we reported that humanized CGRP monoclonal antibodies (CGRP-mAbs) prevent activation and sensitization of high-threshold (HT) but not wide-dynamic range trigeminovascular neurons by cortical spreading depression (CSD). In the current paper, we report that CGRP-mAbs prevent the activation of Aδ but not C-type meningeal nociceptors by CSD. This is the first identification of an anti-migraine drug that appears to be selective for Aδ-fibers (peripherally) and HT neurons (centrally). As the main CGRP-mAb site of action appears to be situated outside the brain, we conclude that the initiation of the headache phase of migraine depends on activation of meningeal nociceptors, and that for selected patients, activation of the Aδ-HT pain pathway may be sufficient for the generation of headache perception.

The role of migraine headache severity, associated features and interactions with overweight/obesity in inhibitory control

ABSTRACTAim of the Study: While migraine and obesity are related and both conditions are associated with reduced executive functioning, no study has examined whether obesity exacerbates executive dysfunction in migraine. This cross-sectional study examined whether overweight/obesity moderated associations of migraine severity and associated features with inhibitory control, one aspect of executive function.Materials and Methods: Women (n = 124) aged 18–50 years old with overweight/obesity body mass index (BMI) = 35.1 ± 6.4 kg/m2 and migraine completed a 28-day smartphone-based headache diary assessing migraine headache severity (attack frequency, pain intensity) and frequency of associated features (aura, photophobia, phonophobia, nausea). They then completed computerized measures of inhibitory control during an interictal (headache-free) period.Results: Participants with higher migraine attack frequency performed worse on the Flanker test (accuracy and reaction time; p < .05). Migraine attack frequency and pain intensity interacted with BMI to predict slower Stroop and/or Flanker Reaction Time (RT; p < .05). More frequent photophobia, phonophobia and aura were independently related to slower RT on the Stroop and/or Flanker tests (p < .05), and BMI moderated the relationship between the occurrence of aura and Stroop RT (p = .03).Conclusions: Associations of migraine severity and presence of associated features with inhibitory control varied by BMI in overweight/obese women with migraine. These findings warrant consideration of weight status in clarifying the role of migraine in executive functioning.