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Background Magnetic stimulation of the facial nerve has been tested in preclinical studies as a new, non-invasive emergency treatment of ischemic stroke that acts by increasing cerebral blood flow (CBF). The objective of the studies reported herein was to identify minimal stimulation parameters that increase CBF in large animals and then test those stimulation parameters in healthy volunteers for safety, tolerability, and effectiveness at increasing CBF. This translational research is necessary preparation for clinical studies in ischemic stroke patients. Methods Initial experiments in anesthetized Yorkshire pigs were undertaken in order to identify the lowest stimulus power and duration that increase CBF. A full 3 × 3 factorial design was used to evaluate magnetic stimulation of the facial nerve at various stimulation powers (1.3, 1.6, and 1.9 Tesla field strength at coil surface) and for various durations (2, 3.5, and 5 min). CBF was measured with contrast MRI perfusion imaging and the internal carotid arteries were assessed with MR angiography. Magnetic facial nerve stimulation with parameters identified in the pig study was then applied to 35 healthy volunteers. Safety was assessed with adverse event reports and by medical examination. Tolerability was defined as each volunteer’s ability to withstand at least 2 min of stimulation. Volunteers could determine the maximum power of stimulation they received during a ramp-up period. Results In pigs, unilateral facial nerve stimulation increased CBF by as much as 77% over pre-stimulation baseline when administered across a range of 1.3–1.9 Tesla power and for 2- to 5-min duration. No clear dose–response relationship could be observed across this range, but lower powers and durations than these were markedly less effective. The effect of a single stimulation lasted 90 min. A second stimulation delivered 100 min after the first stimulation sustained the increased CBF without evidence of tachyphylaxis. In human, bilateral facial nerve stimulation caused only non-serious adverse events that were limited to the 2-min stimulation period. Tolerability was greatly improved by gentle encouragement from the study staff, which enabled most volunteers to tolerate 1.6–1.8 Tesla of stimulation power. CBF measures taken approximately 10 min after stimulation demonstrated on average a 32 ± 6% increase in CBF, with ≥ 25% increases in CBF occurring in 10 of the 31 volunteers who had adequate CBF measurements. Conclusions The minimal effective stimulation parameters defined by increased CBF, as identified in the pig study, translated into safe, tolerable, and effective stimulation of healthy volunteers. These results support the future development and evaluation of non-invasive facial nerve stimulation for the emergency treatment of ischemic stroke. Trial Registration retrospectively registered with clinicaltrials.gov NRV_P1_01_15 on June 6, 2017

Stimulation of the autonomic parasympathetic fibers of the facial nerve system (hereafter simply \"facial nerve\") rapidly dilates the cerebral arteries and increases cerebral blood flow whether that stimulation is delivered at the facial nerve trunk or at distal points such as the sphenopalatine ganglion. Facial nerve stimulation thus could be used as an emergency treatment of conditions of brain ischemia such as ischemic stroke. A rich history of scientific research has examined this property of the facial nerve, and various means of activating the facial nerve can be employed including noninvasive means. Herein, we review the anatomical and physiological research behind facial nerve stimulation and the facial nerve stimulation devices that are in development for the treatment of ischemic stroke.

Haemoglobin is released into the CNS during the breakdown of red blood cells after intracranial bleeding. Extracellular free haemoglobin is directly neurotoxic. Haemoglobin scavenging mechanisms clear haemoglobin and reduce toxicity; these mechanisms include erythrophagocytosis, haptoglobin binding of haemoglobin, haemopexin binding of haem and haem oxygenase breakdown of haem. However, the capacity of these mechanisms is limited in the CNS, and they easily become overwhelmed. Targeting of haemoglobin toxicity and scavenging is, therefore, a rational therapeutic strategy. In this Review, we summarize the neurotoxic mechanisms of extracellular haemoglobin and the peculiarities of haemoglobin scavenging pathways in the brain. Evidence for a role of haemoglobin toxicity in neurological disorders is discussed, with a focus on subarachnoid haemorrhage and intracerebral haemorrhage, and emerging treatment strategies based on the molecular pathways involved are considered. By focusing on a fundamental biological commonality between diverse neurological conditions, we aim to encourage the application of knowledge of haemoglobin toxicity and scavenging across various conditions. We also hope that the principles highlighted will stimulate research to explore the potential of the pathways discussed. Finally, we present a consensus opinion on the research priorities that will help to bring about clinical benefits.

Background: Cerebral infarction involving the insula has been associated with decreased survival following stroke. We hypothesized that infarct volume may reduce this association. Methods: The subjects were acute stroke patients who had consented to 2-year follow-up after stroke as part of the Michigan Acute Stroke Care Overview and Treatment Surveillance System registry. One hundred and eleven subjects exhibited areas of acute ischemic infarction on neuroimaging studies, 25 of whom had infarction involving the insula. Cox proportional hazard ratios (HR) were calculated to determine the association between mortality and acute infarction involving the insula, infarct volume, and other factors known to affect survival after stroke. Results: In unadjusted analysis, subjects with insula infarction had a nonsignificant twofold increase in 1-year mortality (HR = 2.1, 95% CI 0.6–7.0; p = 0.25). When adjusted for infarct volume, however, the HR for insula infarction was reduced to the null value (HR = 1.0, 95% CI 0.2–4.1; p = 1.00), indicating that the effect of insula infarction was entirely confounded by infarct volume. Conclusions: Insula infarction was associated with a nonsignificant twofold increase in mortality after stroke; however, this association was completely eliminated after adjusting for infarct volume. Infarct volume thus should be considered in future studies of insula infarction and mortality.

The goals of this dissertation were to characterize the effects on locus coeruleus (LC) neurons of interleukin-1 (IL-1), and to examine the role of IL-l in the alteration of LC electrophysiological activity by microorganism immunostimulants. Many of the actions of IL-1 are mediated by corticotropin-releasing hormone (CRH). Thus, we first examined the effects of CRH on LC neurons. Our findings show that CRH excites LC units in a manner involving (1) the sympathetic nervous system and (2) CRH receptors in the lateral parabrachium. Furthermore, we present evidence that microinjected CRH inhibits LC neurons, and that endogenous CRH tonically suppresses LC spontaneous activity. Our initial experiments with IL-1 showed that 50pg IL-1 increased LC sensory-evoked responses (SER) within 5min of microinjection. This effect increased over time and was anatomically specific. IL-1 excitation was blocked by the IL-1 receptor antagonist (IRA). Also, a low dose (5pg) of IL-1 was found to inhibit LC spontaneous activity by activating endogenous CRH systems. Subsequently we examined the effect of endogenous IL-1 on LC units. We used various doses of lipopolysaccharide (LPS) administered directly into brain or intraperitoneally (i.p.). LPS injected into brain increased LC SER in an IRA-sensitive manner and exhibited anatomical specificity. I.p. LPS increased LC SER in a dose- and time-related fashion, and this was reversed by IRA microinfusion; also, the excitation caused by i.p. LPS was not observed in subdiaphragmatic vagotomized rats. Other i.p. immunostimulants increased LC SER, albeit at higher doses and with shorter timecourses. Peptidoglycan increased LC SER in a manner reversible with IRA microinfusion and preventable by subdiaphragmatic vagotomy. Poly(I):(C) increased LC SER, but despite the observation that poly(I):(C) did not alter LC activity in subdiaphragmatic vagotomized rats, IRA could not reverse this excitatory effect. These experiments indicate that brain IL-1, stimulated by some types of microorganism immunostimulants, acts on LC neurons in a primarily excitatory manner. The immunostimulant signals, whether or not they involve IL-1 bioactivity in the LC region, are conveyed to the brain via the subdiaphragmatic vagal nerve.