Pathophysiology of Migraine.

OBJECTIVE: This article provides an overview of the current understanding of migraine pathophysiology through insights gained from the extended symptom spectrum of migraine, neuroanatomy, migraine neurochemistry, and therapeutics. LATEST DEVELOPMENTS: Recent advances in human migraine research, including human experimental migraine models and functional neuroimaging, have provided novel insights into migraine attack initiation, neurochemistry, neuroanatomy, and therapeutic substrates. It has become clear that migraine is a neural disorder, in which a wide range of brain areas and neurochemical systems are implicated, producing a heterogeneous clinical phenotype. Many of these neural pathways are monoaminergic and peptidergic, such as those involving calcitonin gene-related peptide and pituitary adenylate cyclase-activating polypeptide. We are currently witnessing an exciting era in which specific drugs targeting these pathways have shown promise in treating migraine, including some studies suggesting efficacy before headache has even started. ESSENTIAL POINTS: Migraine is a brain disorder involving both headache and altered sensory, limbic, and homeostatic processing. A complex interplay between neurotransmitter systems, physiologic systems, and pain processing likely occurs. Targeting various therapeutic substrates within these networks provides an exciting avenue for future migraine therapeutics.

Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations.

Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Molecular Mechanisms of Migraine: Nitric Oxide Synthase and Neuropeptides.

Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology and therapeutics, much remains to be learned about the mechanisms at play in this complex neurovascular condition. Additionally, there remains a relative paucity of specific and targeted therapies available. Many sufferers remain underserved by currently available broad action preventive strategies, which are also complicated by poor tolerance and adverse effects. The development of preclinical migraine models in the laboratory, and the advances in human experimental migraine provocation, have led to the identification of key molecules likely involved in the molecular circuity of migraine, and have provided novel therapeutic targets. Importantly, the identification that vasoconstriction is neither necessary nor required for headache abortion has changed the landscape of migraine treatment and has broadened the therapy targets for patients with vascular risk factors or vascular disease. These targets include nitric oxide synthase (NOS) and several neuropeptides that are involved in migraine. The ability of NO donors and infusion of some of these peptides into humans to trigger typical migraine-like attacks has supported the development of targeted therapies against these molecules. Some of these, such as those targeting calcitonin gene-related peptide (CGRP), have already reached clinical practice and are displaying a positive outcome in migraineurs for the better by offering targeted efficacy without significant adverse effects. Others, such as those targeting pituitary adenylate cyclase activating polypeptide (PACAP), are showing promise and are likely to enter phase 3 clinical trials in the near future. Understanding these nitrergic and peptidergic mechanisms in migraine and their interactions is likely to lead to further therapeutic strategies for migraine in the future.

Neuroimaging in the pre-ictal or premonitory phase of migraine: a narrative review.

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

Abnormal Glutamatergic and Serotonergic Connectivity in Visual Snow Syndrome and Migraine with Aura.

OBJECTIVE: Neuropharmacological changes in visual snow syndrome (VSS) are poorly understood. We aimed to use receptor target maps combined with resting functional magnetic resonance imaging (fMRI) data to identify which neurotransmitters might modulate brain circuits involved in VSS. METHODS: We used Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT) to estimate and compare the molecular-enriched functional networks related to 5 neurotransmitter systems of patients with VSS (n = 24), healthy controls (HCs; n = 24), and migraine patients ([MIG], n = 25, 15 of whom had migraine with aura [MwA]). For REACT we used receptor density templates for the transporters of noradrenaline, dopamine, and serotonin, GABA-A and NMDA receptors, as well as 5HT1B and 5HT2A receptors, and estimated the subject-specific voxel-wise maps of functional connectivity (FC). We then performed voxel-wise comparisons of these maps among HCs, MIG, and VSS. RESULTS: Patients with VSS had reduced FC in glutamatergic networks localized in the anterior cingulate cortex (ACC) compared to HCs and patients with migraine, and reduced FC in serotoninergic networks localized in the insula, temporal pole, and orbitofrontal cortex compared to controls, similar to patients with migraine with aura. Patients with VSS also showed reduced FC in 5HT2A -enriched networks, largely localized in occipito-temporo-parietal association cortices. As revealed by subgroup analyses, these changes were independent of, and analogous to, those found in patients with migraine with aura. INTERPRETATION: Our results show that glutamate and serotonin are involved in brain connectivity alterations in areas of the visual, salience, and limbic systems in VSS. Importantly, altered serotonergic connectivity is independent of migraine in VSS, and simultaneously comparable to that of migraine with aura, highlighting a shared biology between the disorders. ANN NEUROL 2023;94:873-884.

Regional cerebral perfusion during the premonitory phase of triggered migraine: A double-blind randomized placebo-controlled functional imaging study using pseudo-continuous arterial spin labeling.

OBJECTIVE: To identify changes in regional cerebral blood flow (CBF) associated with premonitory symptoms (PS) of nitroglycerin (NTG)-triggered migraine attacks. BACKGROUND: PS could provide insights into attack initiation and alterations in neuronal function prior to headache onset. METHODS: We undertook a functional imaging study using a double-blind placebo-controlled randomized approach in patients with migraine who spontaneously experienced PS, and in whom PS and migraine-like headache could be induced by administration of NTG. All study visits took place in a dedicated clinical research facility housing a monitoring area with clinical beds next to a 3Tesla magnetic resonance imaging scanner. Fifty-three patients with migraine were enrolled; imaging on at least one triggered visit was obtained from 25 patients, with 21 patients completing the entire imaging protocol including a placebo visit. Whole brain CBF maps were acquired using 3D pseudo-continuous arterial spin labeling (3D pCASL). RESULTS: The primary outcome was that patients with migraine not taking preventive treatment (n = 12) displayed significant increases in CBF in anterior cingulate cortex, caudate, midbrain, lentiform, amygdala and hippocampus (p < 0.05 family-wise error-corrected) during NTG-induced PS. A separate region of interest analysis revealed significant CBF increases in the region of the hypothalamus (p = 0.006, effect size 0.77). Post hoc analyses revealed significant reductions in CBF over the occipital cortices in participants with a history of migraine with underlying aura (n = 14). CONCLUSIONS: We identified significant regional CBF changes associated with NTG-induced PS, consistent with other investigations and with novel findings, withstanding statistical comparison against placebo. These findings were not present in patients who continually took preventive medication. Additional findings were identified only in participants who experience migraine with aura. Understanding this biological and treatment-related heterogeneity is vital to evaluating functional imaging outcomes in migraine research.

Revisiting dose-finding of monoclonal antibodies in migraine.

Migraine is a debilitating disorder, and while the introduction of monoclonal antibodies (mAbs) has led to efficacious and tolerable responses, a substantial number of patients are so-called "non-responders". We introduce reasons for this insufficient response, including insufficient blockade of Calcitonin Gene-Related Peptide (CGRP) or its receptor. We present a clinical case, i.e. a female migraine patient who mistakenly administered supratherapeutic (three-fold higher) doses of erenumab leading to more efficacious clinical responses without any side-effects. This example illustrates that the initial dosages might have been too low, resulting in a remaining undesired increased effect of CGRP. While a capsaicin forearm model has repeatedly been used to evaluate the pharmacokinetic-pharmacodynamic relationship of mAbs, we provide directions to revisit or reconsider dose-finding and dose-ranging of these drugs. These directions include (i) refinement and application of a capsaicin forehead model (instead of a forearm model) to study trigeminovascular activity and improve dosing, and (ii) reconsideration of trial populations. Indeed, the dose-finding studies were mainly performed in relatively young and normal-weight males, while most phase III/IV trials are marked by a high female-to-male ratio, mainly consisting of overweight to obese females. Considering these aspects in future trials could optimize healthcare for a larger proportion of migraine patients.

Evaluating migraine with typical aura with neuroimaging.

Objective: To provide an up-to-date narrative literature review of imaging in migraine with typical aura, as a means to understand better migraine subtypes and aura biology. Background: Characterizing subtypes of migraine with typical aura and appreciating possible biological differences between migraine with and without aura, are important to understanding the neurobiology of aura and trying to advance personalized therapeutics in this area through imaging biomarkers. One means of doing this over recent years has been the use of increasingly advanced neuroimaging techniques. Methods: We conducted a literature review of neuroimaging studies in migraine with aura, using a PubMed search for terms 'imaging migraine', 'aura imaging', 'migraine with aura imaging', 'migraine functional imaging' and 'migraine structural imaging'. We collated the findings of the main studies, excluding small case reports and series with n < 6, and have summarized these and their implications for better understanding of aura mechanisms. Results: Aura is likely mediated by widespread brain dysfunction in areas involving, but not limited to, visual cortex, somatosensory and insular cortex, and thalamus. Higher brain excitability in response to sensory stimulation and altered resting-state functional connectivity in migraine sufferers with aura could have a genetic component. Pure visual aura compared to visual aura with other sensory or speech symptoms as well, may involve different functional reorganization of brain networks and additional mitochondrial dysfunction mediating more aura symptoms. Conclusion: There is a suggestion of at least some distinct neurobiological differences between migraine with and without aura, despite the shared phenotypic similarity in headache and other migraine-associated symptoms. It is clear from the vast majority of aura phenotypes being visual that there is a particular predisposition of the occipital cortex to aura mechanisms. Why this is the case, along with the relationships between cortical spreading depression and headache, and the reasons why aura does not consistently present in affected individuals, are all important research questions for the future.

New Oral Drugs for Migraine.

Migraine is a common and disabling neurological disorder, with several manifestations, of which pain is just one. Despite its worldwide prevalence, there remains a paucity of targeted and effective treatments for the condition, leaving many of those affected underserved by available treatments. Work over the last 30+ years has recently led to the emergence of the first targeted acute and preventive treatments in our practice since the triptan era in the early 1990s, which are changing the landscape of migraine treatment. These include the monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. Evolving work on novel therapeutic targets, as well as continuing to exploit drugs used in other disorders that may also have a therapeutic effect in migraine, is likely to lead to more and more treatments being able to be offered to migraineurs. Future work involves the development of agents that lack vasoconstrictive effects, such as lasmiditan, do not contribute to medication overuse, such as the gepants, and do not interact with other drugs that may be used for the disorder, as well as agents that can act both acutely and preventively, thereby utilising the quantum between acute and preventive drug effects which has been demonstrated with different migraine drugs before. Here we discuss the evolution of oral migraine treatments over the last 5 years, including those that have gained regulatory approval and reached clinical practice, those in development and potential other targets for the future.

Cranial autonomic symptoms: prevalence, phenotype and laterality in migraine and two potentially new symptoms.

BACKGROUND: Whilst cranial autonomic symptoms (CAS) are typically associated with trigeminal autonomic cephalalgias (TAC's), they have also been reported in migraine. Identification and understanding of these symptoms in migraine is important to ensure timely diagnosis and effective management. METHODS: Migraineurs seen in a tertiary headache service between 2014 and 2018 (n = 340): cohort one, and a separate cohort of headache patients seen between 2014-May 2021 reporting voice change, or throat swelling, or both, as CAS were selected (n = 64): cohort two. We performed a service evaluation of our records regarding age, sex, diagnosis, headache and CAS frequency and laterality as acquired from the first consultation, during which a detailed headache history is taken by a headache trained physician. RESULTS: Cohort 1: Mean age 43 (range 14-94, SD 15). The most common diagnosis was chronic migraine (78%). Median monthly headache frequency was 26 days (IQR 15-75). At least one CAS was reported in 74%, with a median of two (IQR 0-3). The most common were nasal congestion (32%), lacrimation (31%) and aural fullness (25%). Most patients reported their most common headache as unilateral (80%) and with it strictly unilateral CAS (64%). There was a positive association between headache and CAS laterality (χ21 = 20.7, P < 0.001), with a positive correlation between baseline headache frequency and number of CAS reported (r = 0.11, P = 0.047). Cohort two: mean age 49 (range 23-83, SD 14). Diagnoses were chronic migraine (50%), chronic cluster headache (11%), undifferentiated continuous lateralised headache (9%), SUNCT/SUNA (8%), hemicrania continua (8%), episodic migraine (8%), episodic cluster headache (3%) and trigeminal neuropathies (3%). Most (89%) described trigeminal distribution pain; 25% involving all three divisions. Throat swelling was reported by 54, voice change by 17, and both by 7. The most common CAS reported were lacrimation (n = 47), facial swelling (n = 45) and rhinorrhoea (n = 37). There was significant agreement between the co-reporting of throat swelling (χ21 = 7.59, P = 0.013) and voice change (χ21 = 6.49, P = 0.02) with aural fullness. CONCLUSIONS: CAS are common in migraine, are associated with increasing headache frequency and tend to lateralise with headache. Voice change and throat swelling should be recognized as possible parasympathetically-mediated CAS. They may be co-associated and associated with aural fullness, suggesting a broadly somatotopic endophenotype.

Migraine: beyond pain.

Most people who see, treat or experience migraine will be aware that its clinical manifestations exceed the symptom of head pain. However, available acute treatments so far have targeted migraine symptoms only in the context of the pain phase of an attack. The associated disability clearly involves more than just these symptoms, and the phenotype can include additional painless features, including alterations in mood, cognition and homeostasis and sensory sensitivities. Recognising these symptoms, understanding their neurobiological basis and systematically recording them prospectively in clinical therapeutic trials are likely to offer valuable pathophysiological and therapeutic insights into this complex brain disorder, ultimately helping to improve the quality of lives of sufferers. We aim to explore the multifaceted disorder that is migraine, with a particular focus on the non-painful non-aura symptoms.

Localised increase in regional cerebral perfusion in patients with visual snow syndrome: a pseudo-continuous arterial spin labelling study.

OBJECTIVES: We aimed to investigate changes in regional cerebral blood flow (rCBF) using arterial spin labelling (ASL) in patients with visual snow syndrome (VSS), in order to understand more about the underlying neurobiology of the condition, which remains mostly unknown. METHODS: We performed an MRI study in which whole-brain maps of rCBF were obtained using pseudo-continuous ASL. Twenty-four patients with VSS and an equal number of gender and age-matched healthy volunteers took part in the study. All subjects were examined with both a visual paradigm consisting of a visual-snow like stimulus, simulating key features of the snow, and a blank screen at rest, randomly presented. RESULTS: Patients with VSS had higher rCBF than controls over an extensive brain network, including the bilateral cuneus, precuneus, supplementary motor cortex, premotor cortex and posterior cingulate cortex, as well as the left primary auditory cortex, fusiform gyrus and cerebellum. These areas were largely analogous comparing patients either at rest, or when looking at a 'snow-like' visual stimulus. This widespread, similar pattern of perfusion differences in either condition suggests a neurophysiological signature of visual snow. Furthermore, right insula rCBF was increased in VSS subjects compared with controls during visual stimulation, reflecting a greater task-related change and suggesting a difference in interoceptive processing with constant perception of altered visual input. CONCLUSION: The data suggest VSS patients have marked differences in brain processing of visual stimuli, validating its neurobiological basis.

Emerging drugs for the prevention of migraine.

INTRODUCTION: Migraine is a common and disabling neurological disorder. A greater understanding of the pathophysiological mechanisms underlying migraine has led to the availability of specific new drugs targeting calcitonin gene-related peptide (CGRP). The success of the CGRP inhibitors validates research efforts into migraine-specific therapies. AREAS COVERED: There are additional promising therapeutic targets that will be covered in this paper, focusing on the pain phase. They include pituitary adenylate cyclase-activating polypeptide (PACAP), the orexinergic system, the nitric oxide signaling pathway specifically neuronal nitric oxide synthase inhibitors (nNOSi), and metabotropic glutamate receptor 5 (mGluR5). EXPERT OPINION: Based on currently available research; the targets discussed in this paper are all on equal footing with each other in terms of their potential as effective novel migraine therapies. There is a need for more clinical trials to pinpoint which of these potential drug targets will be effective for migraine preventio.

Migraine Is More Than Just Headache: Is the Link to Chronic Fatigue and Mood Disorders Simply Due to Shared Biological Systems?

Migraine is a symptomatically heterogeneous condition, of which headache is just one manifestation. Migraine is a disorder of altered sensory thresholding, with hypersensitivity among sufferers to sensory input. Advances in functional neuroimaging have highlighted that several brain areas are involved even prior to pain onset. Clinically, patients can experience symptoms hours to days prior to migraine pain, which can warn of impending headache. These symptoms can include mood and cognitive change, fatigue, and neck discomfort. Some epidemiological studies have suggested that migraine is associated in a bidirectional fashion with other disorders, such as mood disorders and chronic fatigue, as well as with other pain conditions such as fibromyalgia. This review will focus on the literature surrounding alterations in fatigue, mood, and cognition in particular, in association with migraine, and the suggested links to disorders such as chronic fatigue syndrome and depression. We hypothesize that migraine should be considered a neural disorder of brain function, in which alterations in aminergic networks integrating the limbic system with the sensory and homeostatic systems occur early and persist after headache resolution and perhaps interictally. The associations with some of these other disorders may allude to the inherent sensory sensitivity of the migraine brain and shared neurobiology and neurotransmitter systems rather than true co-morbidity.

The migraine postdrome: Spontaneous and triggered phenotypes.

BACKGROUND: Non-painful symptoms in migraine following headache resolution can last up to days. Studying the postdrome is important to appreciate the morbidity associated with migraine. METHODS: Fifty-three subjects (n = 53) with migraine were studied in an experimental setting, collecting historical phenotypic information on the postdrome in their spontaneous attacks, and also associated with nitroglycerin-triggered attacks, while being observed prospectively. In a separate headache clinic-based cohort of migraineurs (n = 42), who were age and sex-matched to the experimental group, the same phenotypic data were extracted from their clinic records. Spontaneous and nitroglycerin-triggered attack phenotypes, and experimental and clinical cohort phenotypes were compared using agreement analysis. RESULTS: In the experimental group, 100% had a postdrome with their triggered attack, while 98% reported a postdrome in their spontaneous attacks. In the clinical group, 79% had reported a postdrome. In the experimental group, there was good agreement between spontaneous and nitroglycerin-triggered tiredness, hunger, mood change, sensory sensitivities and vertigo and with similarity in premonitory and postdrome phenotypes experienced in the same individual. CONCLUSIONS: The migraine postdrome is common and symptomatically similar to the premonitory phase. The nitroglycerin model and migraine abortive agents can be used to study the postdrome experimentally. Systematic questioning of symptoms, as well as collateral histories from direct observers of migraine attacks, are likely to enhance symptomatic capture of the migraine postdrome, and aid understanding of attack mediation, abortion and neurobiology.

Are some patient-perceived migraine triggers simply early manifestations of the attack?

OBJECTIVE: To study the agreement between self-reported trigger factors and early premonitory symptoms amongst a group of migraineurs in both spontaneous and pharmacologically provoked attacks. METHODS: Fifty-three subjects with migraine with and without aura, with ≤ 22 headache days/month, with spontaneous premonitory symptoms associated with migraine attacks were recruited nationally. A detailed history was taken by a study investigator to confirm diagnosis and extended phenotyping was performed to identify patient-reported triggers for migraine attacks, premonitory symptom phenotype and headache characteristics, using a standardised physician-administered questionnaire. The same subjects were exposed to a 0.5 mcg/kg/min nitroglycerin infusion over 20 min, to determine if similar migraine symptoms could be triggered. The triggered attacks were phenotyped in the same way as spontaneous ones. Percentage agreement and Cohen's kappa measure of agreement were used to identify concordance between patient-reported triggers and the corresponding spontaneous and triggered premonitory symptoms. Percentage agreement of > 60% and/or a kappa value > 0.3 with P < 0.05 were considered significant. RESULTS: There was statistically significant agreement between perception of light as a migraine trigger and spontaneous premonitory photophobia; perception of sound as a trigger and triggered premonitory phonophobia; skipping meals as a trigger and spontaneous premonitory food cravings; and food triggers and spontaneous premonitory food cravings. There was good agreement between stress and premonitory triggered mood change. CONCLUSIONS: At least some patient-reported triggers, such as light, sound, foods and skipping meals, may represent early brain manifestations of the premonitory phase of the migraine attack.

Therapeutic targeting of nitroglycerin-mediated trigeminovascular neuronal hypersensitivity predicts clinical outcomes of migraine abortives.

ABSTRACT: Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Furthermore, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a calcitonin gene-related peptide receptor antagonist, gepant (olcegepant), a 5-HT1F receptor agonist, ditan (LY344864), and an NK1 receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine and as a screen to dissect potentially efficacious migraine therapeutic targets.

Alterations in Functional Connectivity During Different Phases of the Triggered Migraine Attack.

OBJECTIVE: To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack. BACKGROUND: Migraine is a symptomatically heterogeneous disorder. Understanding the possible changes in brain function and, therefore, neurobiology during different phases of the migraine attack is important in developing disease biomarkers and advancing therapeutics. DESIGN: Randomized, double-blind, placebo-controlled, multi-visit experimental study. METHODS: Subjects aged 18-50 years with migraine with and without aura (≤22 headache days per month) were recruited from across the UK using advertising, from both population and hospital clinic samples (n = 53). Consented subjects were randomized to a 0.5 µg/kg/min nitroglycerin infusion or to placebo over 20 minutes across different study visits, during the period February 2015-July 2017.* All subjects were exposed to a nitroglycerin infusion at least on 1 occasion at screening.** For those subjects who consented to participate in imaging visits (n = 25), structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependant contrast (rsBOLD) time series, using a multiecho EPI sequence, were conducted over 30-40 minutes at baseline and rsBOLD during premonitory symptoms and migraine headache on a 3T General Electric MR750 MRI scanner. For the placebo visit, the imaging was conducted at the same times following infusion in the absence of symptoms. RESULTS: Montreal Neurological Institute (MNI) coordinates were used to characterize identified brain areas of connectivity change. Using repeated measures ANOVA models with time (visit number) and trigger substance (nitroglycerin/placebo) as factors, significant positive functional coupling was found between the thalami bilaterally and the right precuneus and cuneus regions during the nitroglycerin-triggered premonitory phase (T = 3.23, peak connectivity change at [-6, -68, 40] for left thalamus, P = 0.012 and [-4, -68, 40] for right thalamus, P = 0.019). The nitroglycerin-triggered premonitory phase was associated with a change in the direction of connectivity from positive to negative between the pons and the limbic lobe (T = 3.47, peak connectivity change at [2, 8, 50], P < 0.001). The headache phase of the nitroglycerin-triggered migraine attack was associated with ongoing negative functional coupling between the pons and the cingulate and frontal cortices, and positive functional coupling between the pons and the cerebellar tonsils and medulla (T = 3.47, peak connectivity change at [-8, -52, -58], P = 0.007). CONCLUSIONS: Understanding the functional reorganization between subcortical and cortical brain areas in different phases of the migraine attack provides novel insights into the abnormal sensory processing and integration during migraine, as well as functional correlation with clinical symptoms displayed during each phase. [*Correction added on July 22, 2020 after first online publication: This sentence was revised from, "Consented subjects had a 0.5 µg/kg/min nitroglycerin infusion…".] [**Correction added on July 22, 2020 after first online publication: This sentence was revised from, "… at least on 1 occasion at screening."].

Imaging the Premonitory Phase of Migraine.

Migraine is a common and disabling brain disorder with a broad and heterogeneous phenotype, involving both pain and painless symptoms. Over recent years, more clinical and research attention has been focused toward the premonitory phase of the migraine attack, which can start up to days before the onset of head pain. This early phase can involve symptomatology, such as cognitive and mood change, yawning, thirst and urinary frequency and sensory sensitivities, such as photophobia and phonophobia. In some patients, these symptoms can warn of an impending headache and therefore offer novel neurobiological insights and therapeutic potential. As well as characterization of the phenotype of this phase, recent studies have attempted to image this early phase using functional neuroimaging and tried to understand how the symptoms are mediated, how a migraine attack may be initiated, and how nociception may follow thereafter. This review will summarize the recent and evolving findings in this field and hypothesize a mechanism of subcortical and diencephalic brain activation during the start of the attack, including that of basal ganglia, hypothalamus, and thalamus prior to headache, which causes a top-down effect on brainstem structures involved in trigeminovascular nociception, leading ultimately to headache.

Patent foramen ovale.

Patent foramen ovale (PFO) is the most common anatomical cause of an interatrial shunt. It is usually asymptomatic but may cause paradoxical embolism, manifesting as stroke, myocardial infarction or visceral/peripheral ischaemia. PFO is a risk factor for stroke and may be associated with migraine with aura. New evidence suggests PFO closure reduces the risk of recurrent ischaemic stroke in a highly selected population of stroke survivors: those aged 60 years or younger with a cryptogenic stroke syndrome, a large right-to-left shunt, an atrial septal aneurysm and no evidence of atrial fibrillation. They benefit from percutaneous PFO closure in addition to antiplatelet therapy, rather than antiplatelet therapy alone. Current evidence does not support PFO closure in the treatment of migraine.