Familial hemiplegic migraine in Indian children-a tertiary center experience.

Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.

The right amygdala and migraine: Analyzing volume reduction and its relationship with symptom severity.

This study aimed to explore the relationship between gray matter volume changes and various clinical parameters in patients with migraine, focusing on symptom severity, quality of life, and states of depression and anxiety. Using a case-control design, we examined 33 patients with migraine, with or without aura, and 27 age-matched healthy subjects. We used magnetic resonance imaging to assess the volumes of 140 bilateral brain regions. Clinical evaluations included the Migraine Disability Assessment, the Migraine Specific Quality of Life Questionnaire, the Center for Epidemiologic Studies Depression scale, Spielberger's State and Trait Anxiety scales, and the Japanese version of the Montreal Cognitive Assessment. We compared the scores of these measures between migraine patients and healthy controls to examine the interplay between brain structure and clinical symptoms. Significant volumetric differences were observed in the pallidum and amygdala between migraine patients and healthy individuals. The reduction in the right amygdala volume correlated significantly with migraine severity as measured by the Migraine Disability Assessment. Path analysis revealed a model where Migraine Disability Assessment scores were influenced by Migraine Specific Quality of Life Questionnaire outcomes, which were further affected by depression, anxiety, and a low right pallidum volume. Our findings suggest that the chronicity and severity of migraine headaches specifically affect the right amygdala. Our path model suggests a complex relationship whereby migraine disability is strongly influenced by quality of life, which is, in turn, affected by psychological states, such as anxiety and depression.

Investigations of the migraine-provoking effect of levcromakalim in patients with migraine with aura.

BACKGROUND/HYPOTHESIS: Experimental provocation studies have yielded important insights in migraine pathophysiology. Levcromakalim has been previously shown to induce migraine-like attacks with and without aura. In this study, we aim to further explore the migraine aura-inducing potential of levcromakalim. METHODS: In a double-blind, randomized, placebo-controlled cross-over study, 27 adult participants with migraine with aura received intravenous infusions of levcromakalim and saline. Headache, aura and associated symptoms were evaluated for 24 hours following administration of the study drug. The primary endpoint was occurrence of migraine-like attacks with or without aura in the 24-hour observation period. RESULTS: Thirteen participants developed migraine-like attacks on the active day only (P = 0.0098), and four participants developed aura on the active day only (P = 0.68). The median time to onset of migraine-like headache was three hours, and the median time to onset of aura was 27.5 minutes. CONCLUSION/INTERPRETATION: Our findings affirm the potent migraine-inducing effect of levcromakalim. We observed a lower induction-rate of migraine aura than previously reported. Further studies are warranted to identify predictors of migraine aura following levcromakalim. CLINICALTRIALS.GOV IDENTIFIER: NCT04905654.

Brainstem depolarization-induced lethal apnea associated with gain-of-function SCN1AL263V is prevented by sodium channel blockade.

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations.

Effect of anti-CGRP-targeted therapy on migraine aura: Results of an observational case series study.

INTRODUCTION: Limited clinical evidence is available regarding the potential effectiveness of anti-CGRP monoclonal antibodies for the preventive treatment of migraine with aura. AIM OF THE STUDY: This observational study involved a series of migraine patients affected by either migraine with or without aura, who were investigated for any changes in their frequencies and their migraine aura attack characteristics observed during treatment with anti-CGRP Mabs over a 1-year period. PATIENTS AND METHODS: Twelve migraine patients were included, seven of whom were treated with erenumab, 2 with fremanezumab, and 3 with galcanezumab. Clinical data were collected at baseline, which were defined as 3 months prior to the initiation of treatment, and thereafter at each trimester, over the 1-year treatment period. The parameters included the number of headache and migraine days/month, the frequency of aura episodes, the number of days with acute drug intakes/month, and the scores from the migraine disability status scale (MIDAS), and the Headache Impact Test 6 (HIT-6). RESULTS: Anti-CGRP Mbs antibodies induced significant decreases in mean headache and migraine without aura days per month, the number of days with medication intake, as well as MIDAS and HIT-6 scores (p < 0.0001). In contrast, the anti-CGRP Mab treatment did not appear to impact the frequency of migraine with aura attacks but seemed to reduce both the intensity and the duration of headache phases of migraine aura. Furthermore, some migraine patients referred to having aura attacks without headache over the course of the treatment period. CONCLUSIONS: Based on the above findings, we hypothesize that anti-CGRP Mabs did not influence neuronal and vascular events related to cortical spreading depression (CSD) which is considered the pathophysiological substrate of aura. Conversely, these antibodies are able to counteract, via their peripheral mechanisms of action, the sensitization of the trigemino-vascular pathway which is triggered by CSD. This aforementioned might explain why in our patients, migraine aura attacks remained unchanged in their frequencies, but the headache phases were either reduced or absent.

Migraine with brainstem aura.

Migraine with brainstem aura has been long described but remains poorly understood. Previously known as "basilar" or "basilar artery" migraine, it is an uncommon subtype of migraine with aura, one seen primarily in children, adolescents, and younger adults. The condition is characterized by migraine headache accompanied by several neurological symptoms conventionally assigned to dysfunction of brainstem structures. Initially felt to be vascular in origin, partly due to prevailing concepts of migraine pathophysiology at the time, most now believe the aura symptoms of migraine with brainstem aura are secondary to neural circuitry dysfunction. The differential diagnosis is reasonably broad, and most patients warrant investigation to exclude conditions bearing high degrees of morbidity and mortality. Neuroimaging, specifically brain MRI without contrast, is recommended for migraine with brainstem aura. Depending on the clinical presentation certain cases may require consideration of contrasted or vascular imaging, EEG, or lumbar puncture with cerebrospinal fluid analysis. Migraine prophylaxis should involve lifestyle adjustments and preventive medical therapies shown to be effective in clinical trials of migraine, following evidence-based guidelines. The acute pharmacological management of attacks of migraine with brainstem aura remains a matter of controversy. The prognosis is generally favorable. Future refinements in the diagnostic criteria might possibly enhance diagnostic specificity and improved clinical research.

Hemiplegic migraine.

Hemiplegic migraine (HM) is a rare subtype of migraine with aura in which the aura phase includes transient motor weakness. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-3). The most important diagnostic tools remain a patient interview, neurological examination during attacks, and exclusion of other disorders, such as epilepsy, stroke, encephalitis and secondary headache syndromes. Hemiplegic migraine can occur either familial or sporadic. Three genes, CACNA1A, ATP1A2, and SCN1A have been identified. Taken together, mutations in these three genes predict increased neurotransmitter and potassium ion levels at the synaptic cleft, which facilitates cortical spreading depolarization, the phenomenon underlying the migraine aura. The presence of several symptoms, including extensive weakness and brainstem manifestations increase the likelihood of finding a monogenic cause. While the diagnosis can be confirmed by genetic testing, it cannot be excluded if one of the known (F)HM genes is not implicated. Most patients with hemiplegic migraine without a mutation in CACNA1A, ATP1A2, or SCN1A display a mild phenotype that is more akin to that of common (nonhemiplegic) migraine. Additional diagnostics such as brain imaging, cerebrospinal fluid analysis or an electroencephalography are mainly performed to exclude other causes of focal neurologic symptoms associated with hemiparesis and headache. Due to the rarity of the disorder, current treatment recommendations are based on small, unblinded studies and empirical data.

Migrainous infarction.

Migrainous infarction is defined as a migraine attack occurring as migraine with aura, typical of the patient's previous attacks, except that one or more aura symptoms persist for >60min, and neuroimaging demonstrates ischemic infarct in the relevant area. To better understand migrainous infarction, one must disentangle the complex interactions between migraine and stroke. In this chapter, we first discuss the migraine-stroke association in sections including "Increased Risks of Stroke and Subclinical Infarcts in Patients With Migraine," "Migrainous Headache Cooccurring or Triggered by Ischemic Stroke," "Stroke Progression in Patients With Migraine," and "Clinic Conditions Associated With Higher Risks of Both Migraine and Stroke." As an extreme example of migraine-stroke association, the annual incidence of migrainous infarction was reported to be 0.80/100,000/year, with the incidence in females nearly twofold that of male patients. Patients diagnosed with migrainous infarction are typically younger (average age 29-39 in case series), have fewer traditional vascular risk factors, and have more favorable prognosis compared to strokes from traditional risk factors. Thorough evaluation is recommended to rule out other etiologies of stroke. Patients diagnosed with migrainous infarction should receive antiplatelet therapy and migraine preventive therapy to avoid future events. Vasoactive medications, including triptans and ergots, should be avoided.

Retinal migraine.

Retinal migraine is usually characterized by attacks of fully reversible monocular visual loss associated with migraine headache. Retinal migraine is most common in women of child-bearing age who have a history of migraine with aura. In the typical attack, monocular visual features consist of partial or complete visual loss lasting less than 1h. Although the current diagnostic criteria for retinal migraine require fully reversible visual loss, our findings suggest that irreversible visual loss is part of the retinal migraine spectrum. Nearly half of reported cases with recurrent transient monocular visual loss subsequently experienced permanent monocular visual loss.

Persistent aura, visual snow, and other visual symptoms.

In neurology practice, it is common to encounter a variety of visual complaints. Historically, in the absence of known ocular pathology, epilepsy, or insult to the central nervous system, positive symptoms were assumed to be migrainous in origin. This assumption was sometimes made even in the absence of a history of migraine. In the past decade, there has been considerable effort to better delineate and study nonmigrainous visual phenomena, with the most extensive focus on a newly defined syndrome, visual snow syndrome (VSS). The heightened awareness of visual snow as a symptom and syndrome has greatly enhanced the understanding of this visual phenomenon; however, in the last few years, there has been an almost pendulous swing in clinic, with patients now being given the diagnosis of VSS for any dots or flickering they may have in their vision. To avoid clinical misdiagnosis, it is critical that we expand our understanding not just of VSS but also of underlying pathologies that may present similarly. This chapter will review classical migraine aura, persistent migraine aura, visual snow and a number of positive and negative visual complaints that are on the differential when seeing patients with suspected aura or visual snow. This is followed by an in-depth discussion on the current understanding of the presenting symptoms, pathophysiology, evaluation and management of VSS. We also outline secondary causes of visual snow.

Astrocytic Na+, K+ ATPases in physiology and pathophysiology.

The Na+, K+ ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na+, K+ ATPases, the review focuses on the role of the astrocytic Na+, K+ pumps in extracellular K+ and glutamate homeostasis, intracellular Na+ and Ca2+ homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na+, K+ ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2). On the other hand, the α2 Na+, K+ ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na+, K+ ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na+, K+ ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration.

Visual migraine aura iconography: A multicentre, cross-sectional study of individuals with migraine with aura.

INTRODUCTION: Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms. OBJECTIVES: To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback. METHODS: We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey. RESULTS: Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant. CONCLUSION: Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes.

Characteristics of acute ischemic stroke and unusual aura in patients with migraine with aura.

BACKGROUND: Sometimes migraine aura changes from attack to attack, raising the question of whether the change is heralding an ischemic stroke or an unusual aura. Differentiating unusual migraine aura from the onset of an acute ischemic stroke in patients with migraine with aura (MwA) can be challenging. OBJECTIVE: The aim of this cohort study was to assess clinical characteristics that help distinguish between MwA and minor stroke in patients with a previous history of MwA who presented with suspicion of stroke. METHODS: We interviewed patients with MwA and ischemic stroke (MwA + IS) and patients with MwA and unusual aura, but without ischemic stroke (MwA - IS) from a tertiary hospital using a structured questionnaire. We assessed how symptoms of ischemic stroke or unusual aura differed from usual, that is, the typical aura in each patient. Stroke or exclusion of stroke was verified by multimodal magnetic resonance imaging. RESULTS: Seventeen patients with MwA + IS and twelve patients with MwA - IS were included. New focal neurological symptoms (13/17 [76%] vs. 3/12 [25%]), change of the first symptom (10/17 [59%] vs. 1/12 [8%]), and absence of headache (6/15 [40%] vs. 2/10 [20%]) were more often reported during ischemic stroke. The physical examination was normal in 8/17 (47%) MwA + IS and in 6/12 (50%) MwA - IS patients. In 5/17 (29%) patients with MwA + IS, there were unequivocal physical signs suggestive of stroke such as persistent visual loss, ataxia, or paresis. CONCLUSION: There are clues from the history that might help identify stroke in patients with MwA with changed aura symptoms. These might be particularly useful in patients presenting without physical findings suggestive of stroke.

Signatures of migraine aura in high-density-EEG.

OBJECTIVE: Cortical spreading depolarization is highly conserved among the species. It is easily detectable in direct cortical surface recordings and has been recorded in the cortex of humans with severe neurological disease. It is considered the pathophysiological correlate of human migraine aura, but direct electrophysiological evidence is still missing. As signatures of cortical spreading depolarization have been recognized in scalp EEG, we investigated typical spontaneous migraine aura, using full band high-density EEG (HD-EEG). METHODS: In this prospective study, patients with migraine with aura were investigated during spontaneous migraine aura and interictally. Time compressed HD-EEG were analyzed for the presence of cortical spreading depolarization characterized by (a) slow potential changes below 0.05 Hz, (b) suppression of faster activity from 0.5 Hz - 45 Hz (c) spreading of these changes to neighboring regions during the aura phase. Further, topographical changes in alpha-power spectral density (8-14 Hz) during aura were analyzed. RESULTS: In total, 26 HD-EEGs were recorded in patients with migraine with aura, thereof 10 HD-EEGs during aura. Eight HD-EEGs were recorded in the same subject. During aura, no slow potentials were recorded, but alpha-power was significantly decreased in parieto-occipito-temporal location on the hemisphere contralateral to visual aura, lasting into the headache phase. Interictal alpha-power in patients with migraine with aura did not differ significantly from age- and sex-matched healthy controls. CONCLUSIONS: Unequivocal signatures of spreading depolarization were not recorded with EEG on the intact scalp in migraine. The decrease in alpha-power contralateral to predominant visual symptoms is consistent with focal depression of spontaneous brain activity as a consequence of cortical spreading depolarization but is not specific thereof. SIGNIFICANCE: Cortical spreading depolarization is relevant in migraine, other paroxysmal neurological disorders and neurointensive care.

Clinical features of migraine with aura: a REFORM study.

BACKGROUND: About one-third of persons with migraine experience transient neurologic symptoms, referred to as aura. Despite its widespread prevalence, comprehensive clinical descriptions of migraine with aura remain sparse. Therefore, we aimed to provide an in-depth phenotypic analysis of aura symptoms and characteristics in a cross-sectional study of a large sample of adults diagnosed with migraine with aura. METHODS: Data were extracted from the baseline characteristics of participants in the Registry for Migraine (REFORM) study - a single-center, prospective, longitudinal cohort study. Participants were adults diagnosed with migraine aura, reporting ≥ 4 monthly migraine days in the preceding 3 months. Trained personnel conducted in-person semi-structured interviews, capturing details on the nature, duration, localization, and progression of individual aura symptoms. RESULTS: Of the 227 enrolled participants with migraine with aura, the mean age was 41.1 years, with a predominant female representation (n = 205 [90.3%]). Visual aura was present in 215 (94.7%) participants, somatosensory aura in 81 (35.7%), and speech and/or language aura in 31 (13.7%). A single type of aura was observed in 148 (65.2%) participants, whilst 79 (34.8%) reported multiple aura types. Most participants (n = 220 [96.9%]) described their aura symptoms as positive or gradually spreading. Headache in relation to aura was noted by 218 (96.0%) participants, with 177 (80.8%) stating that the onset of aura symptoms preceded the onset of headache. CONCLUSIONS: This study offers a detailed clinical depiction of persons with migraine with aura, who were predominantly enrolled from a tertiary care unit. The findings highlight potential gaps in the available literature on migraine with aura and should bolster clinicians' acumen in diagnosing migraine with aura in clinical settings.

Causal association between systemic lupus erythematosus and the risk of migraine: A Mendelian randomization study.

BACKGROUND: Numerous studies have found that patients with systemic lupus erythematosus (SLE) often have comorbid headache, especially migraine. However, the causal relationship between genetically determined SLE and migraine risk remains unclear. Therefore, we conducted a Mendelian randomization (MR) study to explore this causal association. METHODS: Genome-wide association studies (GWAS) provided the instrumental variables. We selected summary data from GWAS of SLE as exposure (5201 SLE patients and 9066 controls). Both outcome GWAS data were from the Finnish Gene GWAS, including migraine with aura, migraine with aura and triptan purchases, and migraine without aura. The main MR approach was inverse-variance weighted. Pleiotropy and heterogeneity were detected using the MR pleiotropy residual sum and outlier, MR-Egger intercept test, leave-one-out analysis, and Cochran's Q test. RESULTS: There was a significant association between genetically predicted SLE susceptibility and increased risk of migraine with aura [odds ratio (OR) = 1.05, 95% confidence interval (CI) = 1.02-1.08, p = .001]. The result was consistent when the outcome was migraine with aura and triptan purchases [OR = 1.05, 95% CI = 1.02-1.08, p = .001]. However, we found no association between SLE and migraine without aura. Our MR study showed no pleiotropy or heterogeneity. CONCLUSIONS: Our study indicates that genetic susceptibility to SLE increases the incidence of migraine with aura but not migraine without aura. It is necessary for the routine evaluation and early recognition of migraine in patients with SLE in clinical settings.

Grey matter structure within the visual networks in migraine with aura: multivariate and univariate analyses.

BACKGROUND: The visual cortex is involved in the generation of migraine aura. Voxel-based multivariate analyses applied to this region may provide complementary information about aura mechanisms relative to the commonly used mass-univariate analyses. METHODS: Structural images constrained within the functional resting-state visual networks were obtained in migraine patients with (n = 50) and without (n = 50) visual aura and healthy controls (n = 50). The masked images entered a multivariate analysis in which Gaussian process classification was used to generate pairwise models. Generalizability was assessed by five-fold cross-validation and non-parametric permutation tests were used to estimate significance levels. A univariate voxel-based morphometry analysis was also performed. RESULTS: A multivariate pattern of grey matter voxels within the ventral medial visual network contained significant information related to the diagnosis of migraine with visual aura (aura vs. healthy controls: classification accuracy = 78%, p < 0.001; area under the curve = 0.84, p < 0.001; migraine with aura vs. without aura: classification accuracy = 71%, p < 0.001; area under the curve = 0.73, p < 0.003). Furthermore, patients with visual aura exhibited increased grey matter volume in the medial occipital cortex compared to the two other groups. CONCLUSIONS: Migraine with visual aura is characterized by multivariate and univariate patterns of grey matter changes within the medial occipital cortex that have discriminative power and may reflect pathological mechanisms.

Different vulnerability of fast and slow cortical oscillations to suppressive effect of spreading depolarization: state-dependent features potentially relevant to pathogenesis of migraine aura.

BACKGROUND: Spreading depolarization (SD), underlying mechanism of migraine aura and potential activator of pain pathways, is known to elicit transient local silencing cortical activity. Sweeping across the cortex, the electrocorticographic depression is supposed to underlie spreading negative symptoms of migraine aura. Main information about the suppressive effect of SD on cortical oscillations was obtained in anesthetized animals while ictal recordings in conscious patients failed to detect EEG depression during migraine aura. Here, we investigate the suppressive effect of SD on spontaneous cortical activity in awake animals and examine whether the anesthesia modifies the SD effect. METHODS: Spectral and spatiotemporal characteristics of spontaneous cortical activity following a single unilateral SD elicited by amygdala pinprick were analyzed in awake freely behaving rats and after induction of urethane anesthesia. RESULTS: In wakefulness, SD transiently suppressed cortical oscillations in all frequency bands except delta. Slow delta activity did not decline its power during SD and even increased it afterwards; high-frequency gamma oscillations showed the strongest and longest depression under awake conditions. Unexpectedly, gamma power reduced not only during SD invasion the recording cortical sites but also when SD occupied distant subcortical/cortical areas. Contralateral cortex not invaded by SD also showed transient depression of gamma activity in awake animals. Introduction of general anesthesia modified the pattern of SD-induced depression: SD evoked the strongest cessation of slow delta activity, milder suppression of fast oscillations and no distant changes in gamma activity. CONCLUSION: Slow and fast cortical oscillations differ in their vulnerability to SD influence, especially in wakefulness. In the conscious brain, SD produces stronger and spatially broader depression of fast cortical oscillations than slow ones. The frequency-specific effects of SD on cortical activity of awake brain may underlie some previously unexplained clinical features of migraine aura.