Abnormal synaptic Ca(2+) homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice.

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 CaV 2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV 2.1 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 Ca(2+)-indicator yellow cameleon to investigate synaptic morphology and [Ca(2+)]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 CaV 2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. RESULTS: FHM1 mutations elevate neuronal [Ca(2+)]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV 2.1 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 [Ca(2+)]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca(2+)]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 Ca(2+) homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs.

Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations.

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 Ca(V)2.1 voltage-gated Ca(2+) channels render the brain more vulnerable to ischemic stroke. Compared with wild-type mice, 2 FHM1 mutant mouse strains developed earlier onset of anoxic depolarization and more frequent peri-infarct depolarizations associated with rapid expansion 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.

Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice.

Familial hemiplegic migraine type 1, a monogenic migraine variant with aura, is linked to gain-of-function mutations in the CACNA1A gene encoding Ca(V)2.1 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.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression.

Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.

CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis.

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+ elevations during spreading depolarizations in the mutants implicated a defect in extracellular K+ 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.

Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury.

BACKGROUND AND PURPOSE: Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the alpha(1) subunit of sGC (sGCalpha(1)(-/-)) with that in wild-type mice. METHODS: Blood pressure, cerebrovascular anatomy, and vasoreactivity of pressurized carotid arteries were compared in both mouse genotypes. Cerebral blood flow was measured before and during middle cerebral artery occlusion and reperfusion. We then assessed neurological deficit and infarct volume after 1 hour of occlusion and 23 hours of reperfusion and after 24 hours of occlusion. RESULTS: Blood pressure and cerebrovascular anatomy were similar between genotypes. We found that vasodilation of carotid arteries in response to acetylcholine or sodium nitroprusside was diminished in sGCalpha(1)(-/-) compared with wild-type mice. Cerebral blood flow deficits did not differ between the genotypes during occlusion, but during reperfusion, cerebral blood flow was 45% less in sGCalpha(1)(-/-) mice. Infarct volumes and neurological deficits were similar after 24 hours of occlusion in both genotypes. After 1 hour of ischemia and 23 hours of reperfusion, infarct volumes were 2-fold larger and neurological deficits were worse in sGCalpha(1)(-/-) than in the wild-type mice. CONCLUSIONS: sGCalpha(1) deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, suggesting that cGMP generated by sGCalpha(1)beta(1) is protective in ischemic stroke.

An oral administration of cilostazol before focal ischemia reduces the infarct volume with delayed cerebral blood flow increase in rats.

We studied the acute brain protection provided by an antiplatelet agent, cilostazol, in rat experimental focal ischemia model. We administered 30 mg/kg of cilostazol or vehicle orally 2 hours before transient middle cerebral artery (MCA) occlusion (MCAO) by the intraluminal thread method. We measured the absolute cerebral blood flow (CBF) 2 hours after cilostazol administration, the regional CBF (rCBF) of MCA territory during MCAO, and neurologic deficits and the infarct volume at 22 hours after reperfusion. We found that cilostazol did not increase absolute CBF just before MCAO. rCBF in the MCA territory was reduced to the same degree in both groups up to 60 minutes post-MCAO. A significant increase of rCBF was observed in cilostazol-treated rats at 90 minutes and maintained until reperfusion compared with the controls (P = .031 and P = .047). The average neurologic score and the infarct volume, determined by 2,3,5-triphenyltetrazolium chloride monohydrate staining, were significantly lower in cilostazol-treated rats (P = .010). The single oral administration of cilostazol before transient ischemia in healthy adult rats induced a delayed penumbral CBF increase and resulted in a significant reduction of stroke damage.

Efficacy of a direct puncture approach for anterior circulation aneurysms using a newly developed guiding catheter - especially for geriatric patients.

BACKGROUND: Endovascular surgery is being increasingly used as an alternative to craniotomy clipping surgery, especially for aged patients and complicated cases. However, tortuous atherosclerotic arteries sometimes interfere with advancement of catheters so that direct puncture may be necessary. Short guiding catheters for use with this approach have been newly developed, as discussed in this article. METHODS: One hundred twenty three anterior circulation aneurysms in 121 patients were consecutively treated by endovascular coil embolization, of which 42 (34%) were older than 70 years. RESULTS: With 21 aneurysms, coil embolization via the transfemoral approach failed, but all could be successfully treated with the direct puncture approach with minor complications such as 1 transient ischemic attack and 1 nonsymptomatic minor leakage. In the aged patients, the direct puncture approach with short guiding catheter resulted in complete obliteration of aneurysms in 20 (71%) of 28 with follow-up angiography. CONCLUSION: Direct puncture using newly developed short guiding catheters is an alternative to femoral approaches for patients with anterior circulation aneurysm with tortuous arteries and obvious atherosclerotic change at bifurcations of the common carotid artery.

Requisite ischemia for spreading depolarization occurrence after subarachnoid hemorrhage in rodents.

Spontaneous spreading depolarizations are frequent after various forms of human brain injury such as ischemic or hemorrhagic stroke and trauma, and worsen the outcome. We have recently shown that supply-demand mismatch transients trigger spreading depolarizations in ischemic stroke. Here, we examined the mechanisms triggering recurrent spreading depolarization events for many days after subarachnoid hemorrhage. Despite large volumes of subarachnoid hemorrhage induced by cisternal injection of fresh arterial blood in rodents, electrophysiological recordings did not detect a single spreading depolarization for up to 72 h after subarachnoid hemorrhage. Cortical susceptibility to spreading depolarization, measured by direct electrical stimulation or topical KCl application, was suppressed after subarachnoid hemorrhage. Focal cerebral ischemia experimentally induced after subarachnoid hemorrhage revealed a biphasic change in the propensity to develop peri-infarct spreading depolarizations. Frequency of peri-infarct spreading depolarizations decreased at 12 h, increased at 72 h and normalized at 7 days after subarachnoid hemorrhage compared with sham controls. However, ischemic tissue and neurological outcomes were significantly worse after subarachnoid hemorrhage even when peri-infarct spreading depolarization frequency was reduced. Laser speckle flowmetry implicated cerebrovascular hemodynamic mechanisms worsening the outcome. Altogether, our data suggest that cerebral ischemia is required for spreading depolarizations to be triggered after subarachnoid hemorrhage, which then creates a vicious cycle leading to the delayed cerebral ischemia syndrome.

Chronic cerebral venous hypertension model in rats.

Although cerebral venous hypertension is known as an important determinant factor for clinical manifestation and outcome in patients with dural arteriovenous malformation (AVM), the pathophysiology of that condition is not well understood. We have created a chronic rat model by cervical arteriovenous fistularization with jugular vein occlusion and examined effect of cerebral venous hypertension on cerebral blood flow regulation. This model may be suitable for investigating mechanisms of cerebrovascular alteration after venous hypertension.

Cortical spreading depression impairs oxygen delivery and metabolism in mice.

Cortical spreading depression (CSD) is associated with severe hypoperfusion in mice. Using minimally invasive multimodal optical imaging, we show that severe flow reductions during and after spreading depression are associated with a steep decline in cerebral metabolic rate of oxygen. Concurrent severe hemoglobin desaturation suggests that the oxygen metabolism becomes at least in part supply limited, and the decrease in cortical blood volume implicates vasoconstriction as the mechanism. In support of oxygen supply-demand mismatch, cortical nicotinamide adenine dinucleotide (NADH) fluorescence increases during spreading depression for at least 5 minutes, particularly away from parenchymal arterioles. However, modeling of tissue oxygen delivery shows that cerebral metabolic rate of oxygen drops more than predicted by a purely supply-limited model, raising the possibility of a concurrent reduction in oxygen demand during spreading depression. Importantly, a subsequent spreading depression triggered within 15 minutes evokes a monophasic flow increase superimposed on the oligemic baseline, which markedly differs from the response to the preceding spreading depression triggered in naive cortex. Altogether, these data suggest that CSD is associated with long-lasting oxygen supply-demand mismatch linked to severe vasoconstriction in mice.

Anterior-wall aneurysm of the internal carotid artery successfully treated solely by stenting: With special reference to etiology.

In this case, a ruptured anterior wall aneurysm of the internal carotid artery disappeared on angiography immediately after stent placement. We focus on the underlying nature of the lesion and this possible alternative treatment.

Neurocysticercosis: assessing where the infection was acquired from.

Histopathological specimen of a neurocysticercosis patient, who had been living in several endemic countries, was retrospectively analyzed for assessing the origin of the infection. Mitochondrial DNA analysis strongly suggested that the patient became infected with the parasite in Nepal at least 10 years before the onset of the disease.