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      Vagus nerve stimulation reduces spreading depolarization burden and cortical infarct volume in a rat model of stroke

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          Abstract

          Cortical spreading depolarization (SD) waves negatively affect neuronal survival and outcome after ischemic stroke. We here aimed to investigate the effects of vagus nerve stimulation (VNS) on SDs in a rat model of focal ischemia. To this end, we delivered non-invasive VNS (nVNS) or invasive VNS (iVNS) during permanent middle cerebral artery occlusion (MCAO), and found that both interventions significantly reduced the frequency of SDs in the cortical peri-infarct area compared to sham VNS, without affecting relative blood flow changes, blood pressure, heart rate or breathing rate. In separate groups of rats subjected to transient MCAO, we found that cortical stroke volume was reduced 72 h after transient MCAO, whereas stroke volume in the basal ganglia remained unchanged. In rats treated with nVNS, motor outcome was improved 2 days after transient MCAO, but was similar to sham VNS animals 3 days after ischemia. We postulate that VNS may be a safe and efficient intervention to reduce the clinical burden of SD waves in stroke and other conditions.

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          Most cited references31

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          The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease.

          The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. Spreading depolarization is induced experimentally by various noxious conditions including chemicals such as potassium, glutamate, inhibitors of the sodium pump, status epilepticus, hypoxia, hypoglycemia and ischemia, but it can can also invade healthy, naive tissue. Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.
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            Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury.

            Cortical spreading depression (CSD) and depolarization waves are associated with dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells, increased energy metabolism and changes in cerebral blood flow (CBF). There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine, stroke, subarachnoid hemorrhage and traumatic brain injury. The implications of these findings are widespread and suggest that intrinsic brain mechanisms have the potential to worsen the outcome of cerebrovascular episodes or brain trauma. The consequences of these intrinsic mechanisms are intimately linked to the composition of the brain extracellular microenvironment and to the level of brain perfusion and in consequence brain energy supply. This paper summarizes the evidence provided by novel invasive techniques, which implicates CSD as a pathophysiological mechanism for this group of acute neurological disorders. The findings have implications for monitoring and treatment of patients with acute brain disorders in the intensive care unit. Drawing on the large body of experimental findings from animal studies of CSD obtained during decades we suggest treatment strategies, which may be used to prevent or attenuate secondary neuronal damage in acutely injured human brain cortex caused by depolarization waves.
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              Functional assessments in the rodent stroke model

              Stroke is a common cause of permanent disability accompanied by devastating impairments for which there is a pressing need for effective treatment. Motor, sensory and cognitive deficits are common following stroke, yet treatment is limited. Along with histological measures, functional outcome in animal models has provided valuable insight to the biological basis and potential rehabilitation efforts of experimental stroke. Developing and using tests that have the ability to identify behavioral deficits is essential to expanding the development of translational therapies. The present aim of this paper is to review many of the current behavioral tests that assess functional outcome after stoke in rodent models. While there is no perfect test, there are many assessments that are sensitive to detecting the array of impairments, from global to modality specific, after stroke.
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 July 2020
                2020
                : 15
                : 7
                : e0236444
                Affiliations
                [1 ] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
                [2 ] electroCore Inc., Basking Ridge, New Jersey, United States of America
                [3 ] Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
                [4 ] Division of Functional and Stereotactic Neurosurgery, Department of Neurosurgery, University Hospital Erlangen, Erlangen, Germany
                [5 ] Division of Vascular Neurology, Department of Neurology, University Hospital Bonn, Bonn, Germany
                University of Warwick, UNITED KINGDOM
                Author notes

                Competing Interests: The author BJS is a former employee with electroCore, Inc., currently consults for the company and own shares in the company. He is also an inventor of several of the company’s patents. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-4888-543X
                http://orcid.org/0000-0002-0145-8641
                Article
                PONE-D-20-09207
                10.1371/journal.pone.0236444
                7377493
                32702055
                77c65e6a-59c8-492b-8d6e-92cd055a00a1
                © 2020 Lindemann et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 March 2020
                : 6 July 2020
                Page count
                Figures: 5, Tables: 0, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: FOR2795
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100005224, Deutsches Zentrum für Neurodegenerative Erkrankungen;
                Award ID: DEMDAS
                Award Recipient :
                This work was supported by grants to GCP from the German Science Foundation DFG (FOR 2795/PE1193/6-1) and the DZNE (DEMDAS Intersite grant). The funder electroCore Inc. provided support in the form of materials (electrodes and stimulators) and salary for author BJS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Research and Analysis Methods
                Bioassays and Physiological Analysis
                Cardiovascular Analysis
                Cerebral Blood Flow Assay
                Medicine and Health Sciences
                Neurology
                Cerebrovascular Diseases
                Stroke
                Ischemic Stroke
                Medicine and Health Sciences
                Vascular Medicine
                Stroke
                Ischemic Stroke
                Medicine and Health Sciences
                Vascular Medicine
                Ischemia
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Functional Electrical Stimulation
                Medicine and Health Sciences
                Neurology
                Cerebrovascular Diseases
                Stroke
                Medicine and Health Sciences
                Vascular Medicine
                Stroke
                Medicine and Health Sciences
                Cardiology
                Heart Rate
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Membrane Potential
                Depolarization
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Membrane Potential
                Depolarization
                Engineering and Technology
                Equipment
                Optical Equipment
                Lasers
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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