Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions

Neurochemical Diversity of Afferent Neurons That Transduce Sensory Signals From Dog Ventricular Myocardium

While much is known about the influence of ventricular afferent neurons on cardiovascular function in the dog, identification of the neurochemicals transmitting cardiac afferent signals to central neurons is lacking. Accordingly, we identified ventricular afferent neurons in canine dorsal root ganglia (DRG) and nodose ganglia by retrograde labeling after injecting horseradish peroxidase (HRP) into the anterior right and left ventricles. Primary antibodies from three host species were used in immunohistochemical experiments to simultaneously evaluate afferent somata for the presence of HRP and markers for two neurotransmitters. Only a small percentage (2%) of afferent somata were labeled with HRP. About half of the HRP-identified ventricular afferent neurons in T3 DRG also stained for substance P (SP), calcitonin gene-related peptide (CGRP), or neuronal nitric oxide synthase (nNOS), either alone or with two markers colocalized. Ventricular afferent neurons and the general population of T3 DRG neurons showed the same labeling profiles; CGRP (alone or colocalized with SP) being the most common (30-40% of ventricular afferent somata in T3 DRG). About 30% of the ventricular afferent neurons in T2 DRG displayed CGRP immunoreactivity and binding of the putative nociceptive marker IB4. Ventricular afferent neurons of the nodose ganglia were distinct from those in the DRG by having smaller size and lacking immunoreactivity for SP, CGRP, and nNOS. These findings suggest that ventricular sensory information is transferred to the central nervous system by relatively small populations of vagal and spinal afferent neurons and that spinal afferents use a variety of neurotransmitters

Neuromodulation Targets Intrinsic Cardiac Neurons to Attenuate Neuronally Mediated Atrial Arrhythmias

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T 1-T 3, 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ~4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential

Video-Based Facial Weakness Analysis.

OBJECTIVE: Facial weakness is a common sign of neurological diseases such as Bell\u27s palsy and stroke. However, recognizing facial weakness still remains as a challenge, because it requires experience and neurological training. METHODS: We propose a framework for facial weakness detection, which models the temporal dynamics of both shape and appearance-based features of each target frame through a bi-directional long short-term memory network (Bi-LSTM). The system is evaluated on a in-the-wild video dataset that is verified by three board-certified neurologists. In addition, three emergency medical services (EMS) personnel and three upper level residents rated the dataset. We compare the evaluation of the proposed algorithm with other comparison methods as well as the human raters. RESULTS: Experimental evaluation demonstrates that: (1) the proposed algorithm achieves the accuracy, sensitivity, and specificity of 94.3%, 91.4%, and 95.7%, which outperforms other comparison methods and achieves the equal performance to paramedics; (2) the framework can provide visualizable and interpretable results that increases model transparency and interpretability; (3) a prototype is implemented as a proof-of-concept showcase to show the feasibility of an inexpensive solution for facial weakness detection. CONCLUSION: The experiment results suggest that the proposed framework can identify facial weakness effectively. SIGNIFICANCE: We provide a proof-of-concept study, showing that such technology could be used by non-neurologists to more readily identify facial weakness in the field, leading to increasing coverage and earlier treatment

Brain arteriovenous malformations: A review of natural history, pathobiology, and interventions

Brain arteriovenous malformations (AVMs) are anomalous direct shunts between cerebral arteries and veins that convalesce into a vascular nidus. The treatment strategies for AVMs are challenging and variable. Intracranial hemorrhage and seizures comprise the most common presentations of AVMs. However, incidental AVMs are being diagnosed with increasing frequency due to widespread use of noninvasive neuroimaging. The balance between the estimated cumulative lifetime hemorrhage risk vs the risk of intervention is often the major determinant for treatment. Current management options include surgical resection, embolization, stereotactic radiosurgery (SRS), and observation. Complete nidal obliteration is the goal of AVM intervention. The risks and benefits of interventions vary and can be used in a combinatorial fashion. Resection of the AVM nidus affords high rates of immediate obliteration, but it is invasive and carries a moderate risk of neurologic morbidity. AVM embolization is minimally invasive, but cure can only be achieved in a minority of lesions. SRS is also minimally invasive and has little immediate morbidity, but AVM obliteration occurs in a delayed fashion, so the patient remains at risk of hemorrhage during the latency period. Whether obliteration can be achieved in unruptured AVMs with a lower risk of stroke or death compared with the natural history of AVMs remains controversial. Over the past 5 years, multicenter prospective and retrospective studies describing AVM natural history and treatment outcomes have been published. This review provides a contemporary and comprehensive discussion of the natural history, pathobiology, and interventions for brain AVMs

Vagus Nerve Stimulation Mitigates Intrinsic Cardiac Neuronal Remodeling and Cardiac Hypertrophy Induced by Chronic Pressure Overload in Guinea Pig

Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15–20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P \u3c 0.004), as well as systolic (114%, P \u3c 0.04) and diastolic (49%, P \u3c 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P \u3c 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling

Cigarette Smoking History and Functional Outcomes After Spontaneous Intracerebral Hemorrhage

Background and Purpose- Although cigarette use may be a risk for intracerebral hemorrhage (ICH), animal models suggest that nicotine has a potential neuroprotective effect. The aim of this multicenter study is to determine the effect of smoking history on outcome in ICH patients. Methods- We analyzed prospectively collected data from the Ethnic/Racial Variations of Intracerebral Hemorrhage study and included patients with smoking status data in the analysis. Patients were dichotomized into nonsmokers versus ever-smokers, and the latter group was further categorized as former (>30 days before ICH) or current (≤30 days before ICH) smokers. The primary outcome was 90-day modified Rankin Scale score shift analysis. Secondary outcomes were in-hospital mortality and mortality, Barthel Index, and self-reported health status measures at 90 days. Results- The overall study cohort comprised 1509 nonsmokers and 1423 ever-smokers (841 former, 577 current, 5 unknown). No difference in primary outcome was observed between nonsmokers versus ever-smokers (adjusted odds ratio [aOR], 1.041; 95% CI, 0.904-1.199; P=0.577). No differences in primary outcome were observed between former (aOR, 0.932; 95% CI, 0.791-1.178; P=0.399) or current smokers (aOR, 1.178; 95% CI, 0.970-1.431; P=0.098) versus nonsmokers. Subgroup analyses by race/ethnicity demonstrated no differences in primary outcome when former and current smokers were compared with nonsmokers. Former, but not current, smokers had a lower in-hospital mortality rate (aOR, 0.695; 95% CI, 0.500-0.968; P=0.031), which was only observed in Hispanics (aOR, 0.533; 95% CI, 0.309-0.921; P=0.024). Differences in self-reported health status measures were only observed in whites. Conclusions- Cigarette smoking history does not seem to provide a beneficial effect on 90-day functional outcome in patients with ICH

Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction

This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P \u3c 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P \u3c 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P \u3c 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P \u3c 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P \u3c 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions