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Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular [K.sup.+] elevations during spreading depolarizations in the mutants implicated a defect in extracellular [K.sup.+] clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL., Introduction Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic small vessel disease, characterized by frequent migraine attacks with aura, progressive white matter degeneration, and [...]

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the [[alpha].sub.1A] subunit of [Ca.sub.v]2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura., Introduction Spreading depression (SD) is characterized by an intense depolarization of neuronal and glial membranes that propagates in brain tissue at a rate of approximately 3 mm/min (1), (2). Evoked [...]

Objective: To determine whether transgenic mouse models of migraine exhibit upper gastrointestinal dysmotility comparable to those observed in migraine patients. Background: There is considerable evidence supporting the comorbidity of gastrointestinal dysmotility and migraine. Gastrointestinal motility, however, has never been investigated in transgenic mouse models of migraine. Methods: Three transgenic mouse strains that express pathogenic gene mutations linked to monogenic migraine‐relevant phenotypes were studied: CADASIL (Notch3‐Tg88), FASP (CSNK1D‐T44A), and FHM1 (CACNA1A‐S218L). Upper gastrointestinal motility was quantified by measuring gastric emptying and small intestinal transit in mutant and control animals. Gastrointestinal motility was measured at baseline and after pretreatment with 10 mg/kg nitroglycerin (NTG). Results: No significant differences were observed for gastric emptying or small intestinal transit at baseline for any of the 3 transgenic strains when compared to appropriate controls or after pretreatment with NTG when compared to vehicle. Conclusions: We detected no evidence of upper gastrointestinal dysmotility in mice that express mutations in genes linked to monogenic migraine‐relevant phenotypes. Future studies seeking to understand why humans with migraine experience delayed gastric emptying may benefit from pursuing other modifiers of gastrointestinal motility, such as epigenetic or microbiome‐related factors. [ABSTRACT FROM AUTHOR]

Migraine and stroke are among the most prevalent and disabling neurological diseases. Epidemiologic studies showed that there is an association between migraine and stroke. Migraineurs, especially those with aura, are more likely to develop subclinical infarct‐like lesions in the brain and are at risk for cryptogenic or cardioembolic stroke. Migrainous headache can be found at the onset of acute ischemic stroke in some patients, and in rare instances, an infarction can be directly attributed to a prolonged migraine aura, ie, migrainous infarction. Importantly, recent studies suggest that in the event of cerebral artery occlusion, even a history of migraine is sufficient to accelerate infarct progression and worsen outcomes. The mechanisms underlying the migraine‐stroke connection are multifactorial, with genetic predisposition, aura‐related electrophysiological mechanisms (cortical spreading depolarization), and cerebral microembolism being the most convincing ones at this point. Here, we provide a comprehensive overview on recent imaging studies that have helped us better understand the complex association between migraine and stroke. [ABSTRACT FROM AUTHOR]

Migraine is a common chronic neurological disease that disproportionately affects women. Migraine has significant negative effects on physical, emotional, and social aspects of health, and can be costly for patients, employers, and society as a whole. Growing evidence supports the roles of sex and gender in migraine risk, pathophysiology, presentation, diagnosis, treatment, and management. However, sex and gender differences in migraine have received limited attention, which can impede advancements in migraine detection, treatment, care, and education. The Society for Women's Health Research convened an interdisciplinary expert panel of researchers, clinicians, and advocates for a roundtable meeting to review the current research on sex and gender differences in migraine. This review summarizes discussions from the roundtable and prioritizes areas of need that warrant further attention in migraine research, care, and education. Examining sex and gender differences in migraine and addressing knowledge gaps will decrease the health and economic burden of migraine for both women and men. [ABSTRACT FROM AUTHOR]

Spreading depolarization is a wave of neuronal and glial depolarization. Within minutes after spreading depolarization, the neuronal hemichannel pannexin 1 (PANX1) opens and forms a pore complex with the ligand-gated cation channel P2X7, allowing the release of excitatory neurotransmitters to sustain spreading depolarization and activate neuroinflammation. Here, we explore the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility with important consequences for neuroinflammation and trigeminovascular activation. We found that genetic loss of function or ablation of the P2x7 gene inhibits spreading depolarization. Moreover, pharmacological suppression of the P2X7-PANX1 pore complex inhibits spreading depolarization in mice carrying the human familial hemiplegic migraine type 1 R192Q missense mutation as well as in wild-type mice and rats. Pore inhibitors elevate the electrical threshold for spreading depolarization, and reduce spreading depolarization frequency and amplitude. Pore inhibitors also suppress downstream consequences of spreading depolarization such as upregulation of interleukin-1 beta, inducible nitric oxide synthase and cyclooxygenase-2 in the cortex after spreading depolarization. In addition, they inhibit surrogates for trigeminovascular activation, including expression of calcitonin gene-related peptide in the trigeminal ganglion and c-Fos in the trigeminal nucleus caudalis. Our results are consistent with the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility and its downstream consequences, of potential relevance to its signature disorders such as migraine. [ABSTRACT FROM AUTHOR]

Objective Migraine is among the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear. Methods We employed in vivo multiphoton microscopy of the genetically encoded Ca2+-indicator yellow cameleon to investigate synaptic morphology and [Ca2+]i in FHM1 mice. To study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings, we investigated the effect of the CaV2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. Results FHM1 mutations elevate neuronal [Ca2+]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV2.1 gating modifier in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly of the mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca2+]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca2+]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains. Interpretation Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca2+ homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs. Ann Neurol 2015;78:193-210 [ABSTRACT FROM AUTHOR]

To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing the FHM type 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the α1A subunit of neuronal CaV2.1 channels. We determined stimulus intensity-response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo. We also studied learning and memory using contextual fear-conditioning, Morris water maze, and novel object recognition tests. Hippocampal field potentials were significantly enhanced in R192Q mice compared with wild-type controls. Stimulus intensity-response curves were shifted to the left and displayed larger maxima in the mutants. LTP was augmented by twofold in R192Q mice, whereas LTD was unchanged compared with wild-type mice. R192Q mice showed significant spatial memory deficits in contextual fear-conditioning and Morris water maze tests compared with wild-type controls. Novel object recognition was not impaired in R192Q mice; however, mice carrying the more severe S218L CACNA1A mutation showed marked deficits in this test, suggesting a genotype-phenotype relationship. Thus, whereas FHM1 gain-of-function mutations enhance hippocampal excitatory transmission and LTP, learning and memory are paradoxically impaired, providing a possible explanation for cognitive changes detected in FHM. Data suggest that abnormally enhanced plasticity can be as detrimental to efficient learning as reduced plasticity and highlight how genetically enhanced neuronal excitability may impact cognitive function. [ABSTRACT FROM AUTHOR]

Stress is a putative migraine trigger, but the pathogenic mechanisms involved are unknown. Stress and stress hormones increase neuronal excitability by enhancing glutamatergic neurotransmission, but inhibitory effects have also been reported. We hypothesise that an acute rise in stress hormones, such as corticosteroids which are released after stress, increase neuronal excitability and thereby may increase susceptibility to cortical spreading depression (CSD), the mechanism underlying the migraine aura. Here we investigated effects of acute restraint stress and of the stress hormone corticosterone on CSD susceptibility as surrogate migraine marker, in a transgenic mouse model of familial hemiplegic migraine type 1 (FHM1), which displays increased glutamatergic cortical neurotransmission and increased propensity for CSD. We found that 20-min and 3-h restraint stress did not influence CSD susceptibility in mutant or wild-type mice, despite elevated levels of plasma corticosterone. By contrast, subcutaneous administration of 20 mg/kg corticosterone increased CSD frequency exclusively in mutant mice, while corticosterone plasma levels were similarly elevated in mutants and wild types. The effect of corticosterone on CSD frequency was normalised by pre-administration of the glucocorticoid receptor (GR) antagonist mifepristone. These findings suggest that corticosteroid-induced GR activation can enhance susceptibility to CSD in genetically susceptible individuals, and may predispose to attacks of migraine. Although corticosterone levels rise also during acute stress, the latter likely triggers a spatiotemporally more complex biological response with multiple positive and negative modulators which may not be adequately modeled by exogenous administration of corticosterone alone. [ABSTRACT FROM AUTHOR]

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties. [ABSTRACT FROM AUTHOR]

Background--Migraine is an independent risk factor for stroke. Mechanisms underlying this association are unclear. Familial hemiplegic migraine (FHM), a migraine subtype that also carries an increased stroke risk, is a useful model for common migraine phenotypes because of shared aura and headache features, trigger factors, and underlying glutamatergic mechanisms. Methods and Results--Here, we show that FHM type 1 (FHM1) mutations in CaV2.1 voltage-gated Ca2+ channels render the brain more vulnerable to ischemic stroke. Compared with wild-type mice, 2 FHM 1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations associated with rapid expausion of infarct core on diffusion-weighted magnetic resonance imaging and larger perfusion deficits on laser speckle flowmetry. Cerebral blood flow required for tissue survival was higher in the mutants, leading to infarction with milder ischemia. As a result, mutants developed larger infarcts and worse neurological outcomes after stroke, which were selectively attenuated by a glutamate receptor antagonist. Conclusions--We propose that enhanced susceptibility to ischemic depolarizations akin to spreading depression predisposes migraineurs to infarction during mild ischemic events, thereby increasing the stroke risk. [ABSTRACT FROM AUTHOR]

Familial hemiplegic migraine type 1, a monogenic migraine variant with aura, is linked to gain-of-function mutations in the CACNA1A gene encoding CaV2.1 channels. The S218L mutation causes severe channel dysfunction, and paroxysmal migraine attacks can be accompanied by seizures, coma, and hemiplegia; patients expressing the R192Q mutation exhibit hemiplegia only. Familial hemiplegic migraine knock-in mice expressing the S218L or R192Q mutation are highly susceptible to cortical spreading depression, the electrophysiological surrogate for migraine aura, and develop severe and prolonged motor deficits after spreading depression. The S218L mutants also develop coma and seizures and sometimes die. To investigate underlying mechanisms for these symptoms, we used multielectrode electrophysiological recordings, diffusion-weighted magnetic resonance imaging, and c-fos immunohistochemistry to trace spreading depression propagation into subcortical structures. We showed that unlike the wild type, cortical spreading depression readily propagated into subcortical structures in both familial hemiplegic migraine type 1 mutants. Whereas the facilitated subcortical spread appeared limited to the striatum in R192Q, hippocampal and thalamic spread was detected in the S218L mutants with an allele-dosage effect. Both strains exhibited increased susceptibility to subcortical spreading depression and reverberating spreading depression waves. Altogether, these data show that spreading depression propagates between cortex, basal ganglia, diencephalon, and hippocampus in genetically susceptible brains, which could explain the prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura. [ABSTRACT FROM AUTHOR]

Objective Patent foramen ovale and pulmonary arteriovenous shunts are associated with serious complications such as cerebral emboli, stroke, and migraine with aura. The pathophysiological mechanisms that link these conditions are unknown. We aimed to establish a mechanism linking microembolization to migraine aura in an experimental animal model. Methods We introduced particulate or air microemboli into the carotid circulation in mice to determine whether transient microvascular occlusion, insufficient to cause infarcts, triggered cortical spreading depression (CSD), a propagating slow depolarization that underlies migraine aura. Results Air microemboli reliably triggered CSD without causing infarction. Polystyrene microspheres (10μm) or cholesterol crystals (<70μm) triggered CSD in 16 of 28 mice, with 60% of the mice (40% of those with CSD) showing no infarcts or inflammation on detailed histological analysis of serial brain sections. No evidence of injury was detected on magnetic resonance imaging examination (9.4T; T2 weighted) in 14 of 15 selected animals. The occurrence of CSD appeared to be related to the magnitude and duration of flow reduction, with a triggering mechanism that depended on decreased brain perfusion but not sustained tissue damage. Interpretation In a mouse model, microemboli triggered CSD, often without causing microinfarction. Paradoxical embolization then may link cardiac and extracardiac right-to-left shunts to migraine aura. If translatable to humans, a subset of migraine auras may belong to a spectrum of hypoperfusion disorders along with transient ischemic attacks and silent infarcts. ANN NEUROL 2010;67:221-229 [ABSTRACT FROM AUTHOR]

Familial hemiplegic migraine type 1 (FHM1), a severe migraine with aura variant, is caused by mutations in the CACNA1A gene. Mutant mice carrying the FHM1 R192Q mutation exhibit increased propensity for cortical spreading depression (CSD), a propagating wave of neuroglial depolarization implicated in migraine aura. The CSD phenotype is stronger in female R192Q mutants and diminishes after ovariectomy. Here, we show that orchiectomy reciprocally increases CSD susceptibility in R192Q mutant mice. Chronic testosterone replacement restores CSD susceptibility by an androgen receptor-dependent mechanism. Hence, androgens modulate genetically-enhanced CSD susceptibility and may provide a novel prophylactic target for migraine. Ann Neurol 2009;66:564-568 [ABSTRACT FROM AUTHOR]

We aimed to test the feasibility of detecting gliosis in living brains when the blood-brain barrier (BBB) is disrupted. We designed a novel magnetic resonance (MR) probe that contains superparamagnetic iron oxide nanoparticles (SPION, a T2 susceptibility contrast agent) linked to a short DNA sequence complementary to the cerebral mRNA of glial fibrillary acidic protein (GFAP) found in glia and astrocytes. As a control, we also used a sequence complementary to the mRNA of β-actin. Our objectives are to demonstrate that this new probe, SPION-gfap, could be delivered to the brain when administered by eyedrop solution to the conjunctival sac. We induced BBB leakage by puncture wound, global cerebral ischemia, and cortical spreading depression in C57BL6 mice; 1 day after probe delivery we acquired T2* MR images and R2* (R2*=1/T2*) maps using a transcription MRI technique in live mice. We found that the SPION-gfap probe reported foci with elevated signal in subtraction R2* maps and that these foci matched areas identified as having extensive glial network (gliosis) in postmortem immunohistochemistry. Similarly, animals administered the control probe exhibited foci of R2* elevation that matched β-actin-expressing endothelia in the vascular wall. We conclude that our modular MR probe, delivered in an eyedrop solution, effectively reports gliosis associated with acute neurological disorders in living animals. As BBB leakage is often observed in acute neurological disorders, this study also served to validate noninvasive delivery of MR probes to the brains of live animals after acute neurological disorders. [ABSTRACT FROM AUTHOR]