Effects of passive smoking on cortical spreading depolarization in male and female mice.

BACKGROUND: Patients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura. FINDINGS: Fifty C57BL/6 mice (25 males and 25 females) were exposed for one hour to cigarette smoke or room air. Subsequently, potassium chloride (KCl) was administered under isoflurane anesthesia to induce CSD, and the CSD threshold, frequency of induction, and propagation velocity were determined. The threshold to induce CSD (median [interquartile range (IQR)]) was significantly lower in female mice (adjusted p = 0.01) in the smoking group (0.05 [0.05, 0.088]) than in the sham group (0.125 [0.1, 0.15]); however, there was no significant difference in the male mice (adjusted p = 0.77). CSD frequency or propagation velocity did not differ significantly between the two groups for either sex. CONCLUSIONS: Female mice in the smoking group showed lower CSD threshold compared to the sham group, suggesting a potential sex-specific difference in the effect of smoking on the pathogenesis of CSD and migraine with aura. This finding may contribute to the understanding of migraine pathophysiology in association with passive smoking and sex difference.

Meningeal brain borders and migraine headache genesis.

Migraine is a highly prevalent and disabling pain disorder that affects >1 billion people worldwide. One central hypothesis points to the cranial meninges as a key site underlying migraine headache genesis through complex interplay between meningeal sensory nerves, blood vessels, and adjacent immune cells. How these interactions might generate migraine headaches remains incompletely understood and a subject of much debate. In this review we discuss clinical and preclinical evidence supporting the concept that meningeal sterile inflammation, involving neurovascular and neuroimmune interactions, underlies migraine headache genesis. We examine downstream signaling pathways implicated in the development of migraine pain in response to exogenous events such as infusing migraine-triggering chemical substances. We further discuss cortex-to-meninges signaling pathways that could underlie migraine pain in response to endogenous events, such as cortical spreading depolarization (CSD), and explore future directions for the field.

[Transient neurological deficits in a patient with chronic subdural hematoma].

A 62-year-old, right-handed man was diagnosed with asymptomatic bilateral chronic subdural hematomas and underwent hematoma removal on the left side only. At 1 month after surgery, he was admitted to our hospital because he began to have one or two attacks/day of apraxia of speech and dysesthesia of the right hand with a duration of approximately 5 |min. The left hematoma had not re-expanded, but fluid-attenuated inversion resonance imaging showed hyperintense lesions in the sulci adjacent to the hematoma. Moreover, single-photon emission computed tomography revealed low-uptake lesions in the left cerebrum adjacent to the hematoma. Electroencephalogram showed no abnormalities, and CT angiography showed a slight deviation of the left middle cerebral arteries due to the hematoma. The attacks disappeared within 10 days, although the volume of the hematoma was unchanged. It was suggested that his transient neurological deficits were caused by cerebral ischemia related to chronic subdural hematoma.

[Epileptic seizure and migraine attack: A revisit from the "Borderland of Epilepsy" to clinical implementation of infraslow activity/DC shifts in scalp EEG].

Migraine attacks, especially ones with aura, have symptoms similar to epileptic seizures, and the two may sometimes be difficult to differentiate clinically. However, the characteristic minute-by-minute symptom development and progress within 60 |min is useful for diagnosis. Although the details of its pathophysiology remain unsolved, cortical spreading depolarization (CSD) is one of the main pathogenetic factors. In epilepsy, clinical data have shown that ictal DC shifts could reflect impaired homeostasis of extracellular potassium by astrocyte dysfunction. Ictal DC shifts were found to be difficult to detect by scalp EEG, but can be clinically recorded from the seizure focus using wide-band EEG method. The similarity between DC shifts and CSD has been gaining attention from the neurophysiology point of view. The clinical implementation of infraslow activity/DC shifts analysis of scalp EEG is expected to elucidate further the pathophysiology of migraine, which may lie in the borderland of epilepsy.

Alice in Wonderland Syndrome (AIWS): prevalence and characteristics in adults with migraine.

OBJECTIVE: Alice in Wonderland Syndrome (AIWS) is a sensory disorder characterized by a distorted somatosensory and/or visual perception. Additionally, distortion of time perception and symptoms of derealization/depersonalization may occur. AIWS is frequently associated with migraine. However, its prevalence, and clinical characteristics remain poorly understood. Here, we investigated the prevalence and features of AIWS in individuals with migraine. We hypothesized AIWS is more frequent in migraine patients with aura than in those without aura. METHODS: This was a prospective cross-sectional cohort study, conducted at a tertiary headache center. Participants with migraine filled out questionnaires, providing details on demographics, headache, AIWS characteristics and the occurrence of transient visual phenomena such as fragmented vision. RESULTS: Of 808 migraine patients, 133 individuals (16.5%, mean age 44.4 ± 13.3 years, 87% women) reported AIWS symptoms throughout their lives. Micro- and/or telopsia (72.9%) were most frequent, followed by micro- and/or macrosomatognosia (49.6%), and macro- and/or pelopsia (38.3%), lasting on average half an hour. AIWS symptoms occurred in association with headache in 65.1% of individuals, and 53.7% had their first AIWS episode at the age of 18 years or earlier. Migraine patients with aura were more likely to report AIWS symptoms than those without aura (19.5% vs. 14.1%, p = 0.04). Participants with AIWS reported a higher incidence of 17 out of the 22 investigated visual phenomena. CONCLUSION: AIWS symptoms appear to be a common lifetime phenomenon in migraine patients. The correlation and clinical parallels between AIWS and migraine aura could indicate shared underlying pathomechanisms.

Galanin diminishes cortical spreading depolarization across rodents - A candidate for treatment?

Galanin (Gal) is a neuropeptide with the potential to ameliorate cortical spreading depolarization (CSD), an electrophysiological phenomenon occurring after brain injury or in migraine aura. Gal is expressed in all cortical neurons both in rat and in mouse cortices. Here we investigated whether the effect of Gal on CSD previously described in the rat is conserved in the mouse cortex. In rats, the topical application of Gal to the cortex for 1 h did not induce any change in CSD amplitudes, propagation velocity, or threshold of elicitation. Rather, topical application of Gal for 3 h was necessary to obtain a significant decrease in these CSD parameters and to develop a remarkable increase in the KCl threshold to elicit a CSD in rat cortex. In contrast, the topical application of Gal on cortical surface for 1 h in mice was sufficient to significantly attenuate CSD amplitudes and increase threshold. A thinner cortex, a faster diffusion or different affinity/expression of receptors for Gal are possible reasons to explain this difference in the time course between rats and mice. Our data are relevant to postulate Gal as a potential target for inhibition of CSD under pathological situations such as stroke or ischemia. SIGNIFICANCE STATEMENT: The neuropeptide Galanin (Gal) is expressed in all neurons throughout the cerebral cortex, both in rats and mice, and is able to reduce or even inhibit Cortical Spreading Depolarization, thus, Gal has the potential to control neuronal excitability that may identify Gal as a target in drug development against CSD.

Transient Receptor Potential Ankyrin 1-dependent Activation of Extracellular Signal-regulated Kinase 2 in the Cerebral Cortices Contributes to Cortical Spreading Depolarization.

Extracellular signal-regulated kinase (ERK) are serine/threonine-selective proteins and ERK1/2 can be phosphorylated in peripheral and central brain regions after cortical spreading depolarization (CSD) and calcitonin gene-related peptide; However, it remains unclear about whether and how ERK activity modulates CSD that correlates to migraine aura. Here, we determined the role of ERK in regulating CSD and explored the underlying mechanism involving transient receptor potential ankyrin 1 (TRPA1), a stress-sensing cation channel. CSD was recorded using intrinsic optical imaging in mouse brain slices, and electrophysiology in rats. Phosphorylated ERK (pERK1/2) and interleukin-1ß (IL-1ß) protein levels were detected using Western blot or enzyme-linked immunosorbent assay, respectively. IL-1ß mRNA level was detected using qPCR. The results showed that an ERK inhibitor, SCH77298, markedly prolonged CSD latency and reduced propagation rate in mouse brain slices. Corresponding to this, CSD induction increased levels of cytosolic pERK1/2 in ipsilateral cerebral cortices of rats, the elevation of which correlated to the level of IL-1ß mRNA. Mechanistic analysis showed that pre-treatment of an anti-TRPA1 antibody reduced the cytosolic pERK2 level but not pERK1 following CSD in cerebral cortices of rats and this level of pERK2 correlated with that of cerebral cortical IL-1ß protein. Furthermore, an ERK activator, AES16-2M, but not its scrambled control, reversed the prolonged CSD latency by a TRPA1 inhibitor, HC-030031, in mouse brain slices. These data revealed a crucial role of ERK activity in regulating CSD, and elevation of pERK and IL-1ß production induced by CSD is predominantly TRPA1 channel-dependent, thereby contributing to migraine pathogenesis.

Spontaneous and optogenetically induced cortical spreading depolarization in familial hemiplegic migraine type 1 mutant mice.

Mechanisms underlying the migraine aura are incompletely understood, which to large extent is related to a lack of models in which cortical spreading depolarization (CSD), the correlate of the aura, occurs spontaneously. Here, we investigated electrophysiological and behavioural CSD features in freely behaving mice expressing mutant CaV2.1 Ca2+ channels, either with the milder R192Q or the severer S218L missense mutation in the α1 subunit, known to cause familial hemiplegic migraine type 1 (FHM1) in patients. Very rarely, spontaneous CSDs were observed in mutant but never in wildtype mice. In homozygous Cacna1aR192Q mice exclusively single-wave CSDs were observed whereas heterozygous Cacna1aS218L mice displayed multiple-wave events, seemingly in line with the more severe clinical phenotype associated with the S218L mutation. Spontaneous CSDs were associated with body stretching, one-directional slow head turning, and rotating movement of the body. Spontaneous CSD events were compared with those induced in a controlled manner using minimally invasive optogenetics. Also in the optogenetic experiments single-wave CSDs were observed in Cacna1aR192Q and Cacna1aS218L mice (whereas the latter also showed multiple-wave events) with movements similar to those observed with spontaneous events. Compared to wildtype mice, FHM1 mutant mice exhibited a reduced threshold and an increased propagation speed for optogenetically induced CSD with a more profound CSD-associated dysfunction, as indicated by a prolonged suppression of transcallosal evoked potentials and a reduction of unilateral forepaw grip performance. When induced during sleep, the optogenetic CSD threshold was particularly lowered, which may explain why spontaneous CSD events predominantly occurred during sleep. In conclusion, our data show that key neurophysiological and behavioural features of optogenetically induced CSDs mimic those of rare spontaneous events in FHM1 R192Q and S218L mutant mice with differences in severity in line with FHM1 clinical phenotypes seen with these mutations.

Migraine headache and aura induced by hypoxia.

Migraine, a common neurological disorder, impacts over a billion individuals globally. Its complex aetiology involves various signalling cascades. Hypoxia causes headaches such as high-altitude headache and acute mountain sickness which share phenotypical similarities with migraine. Epidemiological data indicate an increased prevalence of migraine with and without aura in high-altitude populations. Experimental studies have further shown that hypoxia can induce migraine attacks. This review summarizes evidence linking hypoxia to migraine, delves into potential pathophysiological mechanisms and highlights research gaps.

Bibliometric Analysis of Research on Migraine-Stroke Association from 2013 to 2023.

Background: Both migraine and stroke heavily burden individuals, health systems, and society. The migraine-stroke association is of concern and has been studied widely. Our objective is to explore and overview the current research status and emerging trends. Materials and Methods: Studies on migraine-stroke association from January 2013 to May 2023 were retrieved and screened from the Web of Science Core Collection (WOSCC) database. Records fulfilling the selection criteria were downloaded and imported into CiteSpace for data mining and visualization. Results: A total of 862 papers on migraine-stroke association were included. Annual publications grew slowly. The United States and European countries dominated research in this area. Harvard University published the largest number of articles, while the University of London was most active with other institutions. Ayata Cenk contributed the most articles, while KURTH T and NEUROLOGY were co-cited most. Research hotspots included migraine with aura, ischemic stroke, patent foramen ovale, cortical spreading depolarization, meta-analysis, cross-sectional study, and risk factors. Pathophysiology and small vessel disease represented research frontiers and emerging trends. Conclusion: Our study scientifically outlines the migraine-stroke association over the past decade, presenting useful information.

Vagus Nerve Stimulation in Ischemic Stroke.

PURPOSE OF REVIEW: Vagus nerve stimulation (VNS) has emerged as a potential therapeutic approach for neurological and psychiatric disorders. In recent years, there has been increasing interest in VNS for treating ischemic stroke. This review discusses the evidence supporting VNS as a treatment option for ischemic stroke and elucidates its underlying mechanisms. RECENT FINDINGS: Preclinical studies investigating VNS in stroke models have shown reduced infarct volumes and improved neurological deficits. Additionally, VNS has been found to reduce reperfusion injury. VNS may promote neuroprotection by reducing inflammation, enhancing cerebral blood flow, and modulating the release of neurotransmitters. Additionally, VNS may stimulate neuroplasticity, thereby facilitating post-stroke recovery. The Food and Drug Administration has approved invasive VNS (iVNS) combined with rehabilitation for ischemic stroke patients with moderate to severe upper limb deficits. However, iVNS is not feasible in acute stroke due to its time-sensitive nature. Non-invasive VNS (nVNS) may be an alternative approach for treating ischemic stroke. While the evidence from preclinical studies and clinical trials of nVNS is promising, the mechanisms through which VNS exerts its beneficial effects on ischemic stroke are still being elucidated. Therefore, further research is needed to better understand the efficacy and underlying mechanisms of nVNS in ischemic stroke. Moreover, large-scale randomized clinical trials are necessary to determine the optimal nVNS protocols, assess its long-term effects on stroke recovery and outcomes, and identify the potential benefits of combining nVNS with other rehabilitation strategies.

A Case of Reversible Posterior Leukoencephalopathy Syndrome (PRES) With a History of Migraine and Onset With Initial Visual Aura and Migraine-Like Headache, With a Significant Response to Lasmiditan: A Case Report.

Posterior reversible encephalopathy syndrome (PRES) is a neurological disease that presents with various neurological symptoms and is often accompanied by elevated blood pressure at onset. Neuroimaging, especially magnetic resonance imaging (MRI), often shows a characteristic parieto-occipital pattern with a symmetrical distribution of changes, reflecting vasogenic edema. Hypertension and endothelial cell damage are the most common causes of PRES. An association between migraine and endothelial cell damage has been suggested, but the relationship between migraine and PRES is unknown. Reports on PRES triggered by migraines are scarce. We report a case of PRES in a 59-year-old woman with migraine without aura. At the onset, the patient experienced a first-ever visual aura and a migraine-like headache. In this case, it was also difficult to distinguish between PRES headache and headache caused by a pre-existing migraine; however, lasmiditan, an acute migraine treatment without vasoconstrictive properties, was remarkably effective for headaches.

Cortical spreading depolarization is a potential target for rat brain excitability modulation by Galanin.

The inhibitory neuropeptide Galanin (Gal) has been shown to mediate anticonvulsion and neuroprotection. Here we investigated whether Gal affects cortical spreading depolarization (CSD). CSD is considered the pathophysiological neuronal mechanism of migraine aura, and a neuronal mechanism aggravating brain damage upon afflictions of the brain. Immunohistochemistry localized Gal and the Gal receptors 1-3 (GalR1-3) in native rat cortex and evaluated microglial morphology after exposure to Gal. In anesthetized rats, Gal was applied alone and together with the GalR antagonists M40, M871, or SNAP 37889 locally to the exposed cortex. The spontaneous electrocorticogram and CSDs evoked by remote KCl pressure microinjection were measured. In rat cortex, Gal was present in all neurons of all cortical layers, but not in astrocytes, microglia and vessels. GalR2 and GalR3 were expressed throughout all neurons, whereas GalR1 was preponderantly located at neurons in layers IV and V, but only in about half of the neurons. In susceptible rats, topical application of Gal on cortex decreased CSD amplitude, slowed CSD propagation velocity, and increased the threshold for KCl to ignite CSD. In some rats, washout of previously applied Gal induced periods of epileptiform patterns in the electrocorticogram. Blockade of GalR2 by M871 robustly prevented all Gal effects on CSD, whereas blockade of GalR1 or GalR3 was less effective. Although microglia did not express GalRs, topical application of Gal changed microglial morphology indicating microglial activation. This effect of Gal on microglia was prevented by blocking neuronal GalR2. In conclusion, Gal has the potential to ameliorate CSD thus reducing pathophysiological neuronal events caused by or associated with CSD.

Migraine Aura-Catch Me If You Can with EEG and MRI-A Narrative Review.

Roughly one-third of migraine patients suffer from migraine with aura, characterized by transient focal neurological symptoms or signs such as visual disturbance, sensory abnormalities, speech problems, or paresis in association with the headache attack. Migraine with aura is associated with an increased risk for stroke, epilepsy, and with anxiety disorder. Diagnosis of migraine with aura sometimes requires exclusion of secondary causes if neurological deficits present for the first time or are atypical. It was the aim of this review to summarize EEG an MRI findings during migraine aura in the context of pathophysiological concepts. This is a narrative review based on a systematic literature search. During visual auras, EEG showed no consistent abnormalities related to aura, although transient focal slowing in occipital regions has been observed in quantitative studies. In contrast, in familial hemiplegic migraine (FHM) and migraine with brain stem aura, significant EEG abnormalities have been described consistently, including slowing over the affected hemisphere or bilaterally or suppression of EEG activity. Epileptiform potentials in FHM are most likely attributable to associated epilepsy. The initial perfusion change during migraine aura is probably a short lasting hyperperfusion. Subsequently, perfusion MRI has consistently demonstrated cerebral hypoperfusion usually not restricted to one vascular territory, sometimes associated with vasoconstriction of peripheral arteries, particularly in pediatric patients, and rebound hyperperfusion in later phases. An emerging potential MRI signature of migraine aura is the appearance of dilated veins in susceptibility-weighted imaging, which may point towards the cortical regions related to aura symptoms ("index vein"). Conclusions: Cortical spreading depression (CSD) cannot be directly visualized but there are probable consequences thereof that can be captured Non-invasive detection of CSD is probably very challenging in migraine. Future perspectives will be elaborated based on the studies summarized.

Calcitonin gene-related peptide causes migraine aura.

BACKGROUND: Although the involvement of calcitonin gene-related peptide (CGRP) in migraines is well-established, its specific role in investigating the aura phase, which often precedes the headache, remains largely unexplored. This study aims to instigate CGRP's potential in triggering aura, thus establishing its role in the early stages of migraine. METHODS: In this open-label, non-randomized, single-arm trial, 34 participants with migraine with aura received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min on a single experimental day. Participants were required to be free of headache and report no use of acute medications 24 h before infusion start. The primary endpoint was the incidence of migraine aura during the 12-hour observational period after the start of infusion. RESULTS: Thirteen (38%) of 34 participants developed migraine aura after CGRP infusion. In addition, 24 (71%) of 34 participants developed migraine headache following CGRP infusion. CONCLUSIONS: Our findings suggest that CGRP could play an important role in the early phases of a migraine attack, including during the aura phase. These insights offer a new perspective on the pathogenesis of migraines with aura. They underscore the need for additional research to further explore the role of CGRP in these initial stages of a migraine attack, and potentially inform future development of therapeutic interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04592952.

The Role of Glial Cells in Different Phases of Migraine: Lessons from Preclinical Studies.

Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine.

Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury.

Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.

Near-death experiences are associated with rapid eye movement (REM) sleep intrusions in migraine patients, independent of migraine aura.

BACKGROUND AND PURPOSE: Migraine aura, near-death experiences (NDEs), and rapid eye movement (REM) sleep intrusions might share common mechanisms. Here, we investigated the prevalence of NDEs and REM sleep intrusions in people with migraine. We hypothesized that NDEs and REM sleep intrusions are more prevalent in migraine patients with aura than in those without. METHODS: We conducted a prospective cross-sectional cohort study at a tertiary headache center, based on a prespecified sample size (n = 808). Migraine patients completed a series of questionnaires, including questions about demographic and headache characteristics, the 16-item Greyson NDE scale, four questions about REM sleep intrusions, and the Depression, Anxiety, and Stress Scale 21 (DASS-21). RESULTS: Of 808 migraine patients (mean age 44.4 ± 13.3 years, 87.0% women), 353 (43.7%) had a current or previous history of migraine aura. Prevalence of NDE was 2.7% and not different in patients with and without aura (2.8% vs. 2.6%; p > 0.999). REM sleep intrusions were reported by 5.4% of participants and in a similar proportion of patients with and without aura (6.3% vs. 4.9%; p = 0.43). However, participants with REM sleep intrusions had had an NDE more often than participants without REM sleep intrusions (n = 5/44, 11.4% vs. n = 17/754, 2.2%; p = 0.005). Higher DASS-21 scores were associated with REM sleep intrusions (p < 0.001). CONCLUSIONS: In this tertiary center cohort study, the prevalence of NDE and REM sleep intrusions was not influenced by migraine aura status. However, we identified an association between NDE and REM sleep intrusions, which corroborates the notion that they might share pathophysiological mechanisms.

Meningeal P2X7 Signaling Mediates Migraine-Related Intracranial Mechanical Hypersensitivity.

Cortical spreading depolarization (CSD) is a key pathophysiological event that underlies visual and sensory auras in migraine. CSD is also thought to drive the headache phase in migraine by promoting the activation and mechanical sensitization of trigeminal primary afferent nociceptive neurons that innervate the cranial meninges. The factors underlying meningeal nociception in the wake of CSD remain poorly understood but potentially involve the parenchymal release of algesic mediators and damage-associated molecular patterns, particularly ATP. Here, we explored the role of ATP-P2X purinergic receptor signaling in mediating CSD-evoked meningeal afferent activation and mechanical sensitization. Male rats were subjected to a single CSD episode. In vivo, extracellular single-unit recording was used to measure meningeal afferent ongoing activity changes. Quantitative mechanical stimuli using a servomotor force-controlled stimulator assessed changes in the afferent's mechanosensitivity. Manipulation of meningeal P2X receptors was achieved via local administration of pharmacological agents. Broad-spectrum P2X receptor inhibition, selective blockade of the P2X7 receptor, and its related Pannexin 1 channel suppressed CSD-evoked afferent mechanical sensitization but did not affect the accompanying afferent activation response. Surprisingly, inhibition of the pronociceptive P2X2/3 receptor did not affect the activation or sensitization of meningeal afferents post-CSD. P2X7 signaling underlying afferent mechanosensitization was localized to the meninges and did not affect CSD susceptibility. We propose that meningeal P2X7 and Pannexin 1 signaling, potentially in meningeal macrophages or neutrophils, mediates the mechanical sensitization of meningeal afferents, which contributes to migraine pain by exacerbating the headache during normally innocuous physical activities.SIGNIFICANCE STATEMENT Activation and sensitization of meningeal afferents play a key role in migraine headache, but the underlying mechanisms remain unclear. Here, using a rat model of migraine with aura involving cortical spreading depolarization (CSD), we demonstrate that meningeal purinergic P2X7 signaling and its related Pannexin 1 pore, but not nociceptive P2X2/3 receptors, mediate prolonged meningeal afferent sensitization. Additionally, we show that meningeal P2X signaling does not contribute to the increased afferent ongoing activity in the wake of CSD. Our finding points to meningeal P2X7 signaling as a critical mechanism underlying meningeal nociception in migraine, the presence of distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for effective migraine therapy.

A model of neurovascular coupling and its application to cortical spreading depolarization.

Cortical spreading depolarization (CSD) is a neuropathological condition involving propagating waves of neuronal silence, and is related to multiple diseases, such as migraine aura, traumatic brain injury (TBI), stroke, and cardiac arrest, as well as poor outcome of patients. While CSDs of different severity share similar roots on the ion exchange level, they can lead to different vascular responses (namely spreading hyperemia and spreading ischemia). In this paper, we propose a mathematical model relating neuronal activities to predict vascular changes as measured with near-infrared spectroscopy (NIRS) and fMRI recordings, and apply it to the extreme case of CSD, where sustained near-complete neuronal depolarization is seen. We utilize three serially connected models (namely, ion exchange, neurovascular coupling, and hemodynamic model) which are described by differential equations. Propagating waves of ion concentrations, as well as the associated vasodynamics and hemodynamics, are simulated by solving these equations. Our proposed model predicts vasodynamics and hemodynamics that agree both qualitatively and quantitatively with experimental literature. Mathematical modeling and simulation offer a powerful tool to help understand the underlying mechanisms of CSD and help interpret the data. In addition, it helps develop novel monitoring techniques prior to data collection. Our simulated results strongly suggest that fMRI is unable to reliably distinguish between spreading hyperemia and spreading ischemia, while NIRS signals are substantially distinct in the two cases.