Transcutaneous vagus nerve stimulation in cerebral ischemia


Principal Investigator: Ilknur Ay
Abstract: DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the therapeutic potential of transcutaneous vagus nerve stimulation (tVNS) in acute cerebral ischemia. Electrical stimulation of the afferent vagal fibers in the neck has been shown to activate the brainstem vagal centers, induce anti-excitotoxic and anti-inflammatory mechanisms, and increase cerebral blood flow (CBF). Stimulation of the cervical vagus nerve using surgically implanted electrodes (cVNS) is an FDA-approved treatment in some epilepsy and depression patients. Recent studies demonstrated that cVNS provides substantial protection against tissue injury and motor function loss in animal models of ischemic stroke as well. cVNS, when initiated up to 2.5 hours after ischemia, reduces infarct volume by approximately 50% in a variety of rat models of focal cerebral ischemia and in animals with comorbid conditions. The mechanism of protection is not clear yet, but initial findings suggest that it is CBF independent. Even though the findings of ischemia studies are quite encouraging, cVNS is not applicable to acute stroke cases in humans due to invasive nature of the stimulation. In this application, we propose two different tVNS approaches to circumvent the problem of surgical intervention: (1) to stimulate the cervical vagus nerve through the intact skin using a recently available technology and (2) to stimulate the auricular branch of the vagus nerve that supplies a dermatome in external ear using needle electrodes. Both cervical and auricular tVNS have been safely and successfully used in patients with hiccups and pain, respectively. Our specific aims are: (1) determine the efficacy of tVNS techniques in focal ischemia, (2) describe the optimal time window of tVNS treatment, (3) study whether concomitant application of tVNS and tPA is safe and effective in cerebral ischemia. We will determine the effects of cervical tVNS and ear tVNS on infarct size (as assessed by vital stain) and motor function (as assessed by behavioral tests and grip strength measurements). To determine their safety, we will monitor physiological parameters (e.g., arterial blood pressure, heart rate, heart rate variability, and respiration rate) during an immediately after stimulation and will follow-up animals up to 1 week after the treatment. In an additional group of animals, to verify the activation of brainstem vagal centers, we will perform c Fos immunohistochemistry after tVNS. After determining the safety and efficacy of neck tVNS and ear tVNS in specific aim 1, we will continue our studies with the safest and most efficacious tVNS. To determine the time window of tVNS after ischemia, we initiate tVNS 3 hours or more after ischemia and determine its effect on infarct size. We also propose to determine the interaction between tPA and tVNS. We will examine the effect of tPA - tVNS co-administration on risk of hemorrhage. We also will investigate the effect of tVNS on tPA's time window and efficacy using multi-modal MR imaging with molecular thrombus imaging. The proposed studies will provide the proof of principle that tVNS improves stroke outcome. If successful, the findings of these exploratory studies will be used in near future translational studies designed to optimize tVNS treatment for acute ischemic stroke in humans.
Funding Period: 2012-09-30 - 2014-07-31
more information: NIH RePORT

Detail Information

Research Grants31

  1. Novel NMDA Antagonists to Treat Stroke
    Bhaumik B Patel; Fiscal Year: 2013
    ..Moreover, the studies will help us identify new molecular targets for future, more specific therapies for acute ischemic stroke. ..
  2. Remote Ischemic Conditioning:Translating Endogenous Neuroprotection in Embolic St
    David C Hess; Fiscal Year: 2013
  3. Spatial and Temporal Scales of Motor Sequence Learning
    SCOTT THOMAS GRAFTON; Fiscal Year: 2013
    ..The collaborative effort can be expected to significantly advance our knowledge about mechanisms that support motor cortex plasticity. ..
  4. NF Center: from animal models to therapeutics
    Luis F Parada; Fiscal Year: 2013
    ..Together, the proposed program of research promises to contribute to a better understanding of NF1-associated tumorigenesis at the molecular, cellular, and systems levels. ..
  5. Hypothermia in Acute Stroke with Thrombolysis Imaging Evaluation of Revasculariza
  6. Genetics of Parkonsonism
    Jeffery Marvin Vance; Fiscal Year: 2013
  7. US-China Collaborative Research on Stroke Imaging
    Jinyuan Zhou; Fiscal Year: 2013
    ..If the hypotheses are proven correct, we expect to have an additional marker that can be used for diagnosis and prognosis of stroke patients in the clinic. ..
  8. COBRE: The Delaware Center for Neuroscience Research
    Melissa A Harrington; Fiscal Year: 2013
    ..Second, the Center will support a group of junior women faculty to become R01-funded investigators and advance to senior levels both academically and scientifically. ..
  9. The Discovering Healthcare Innovations to Address Disparties in Stroke (DIADS) pr
    Stephen Sidney; Fiscal Year: 2013
  10. Hormonal Signals that Regulate Ovarian Diffrentiation
    Kelly E Mayo; Fiscal Year: 2013
    ..It is our expectation that the basic research projects presented in this P01 program proposal will have considerable impact, ultimately leading to improvements in human reproductive health. ..
  11. Mechanisms and Markers of Prostate Cancer Metastases
    ROBERT LOUIS VESSELLA; Fiscal Year: 2013
    ..It also conducts pre-clinical xenograft studies and provides statistical support to the overall P01 program. Core B is the Administrative Core which provides overall administrative support to the investigators. ..
  12. Neuronal Regeneration of Stroked Brain with Perlecan Domain V
    GREGORY JAYE BIX; Fiscal Year: 2013
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..
  14. Intranasal deferoxamine to treat stroke in young and older, male and female rats
    SAMUEL SCOTT PANTER; Fiscal Year: 2013
    ..In phase 2, older male and female rats will be dosed utilizing the same regimens as phase 1. ..
  15. Histone deacetylases - therapeutic targets for functional restoration after strok
    SEAN PADRAIG MURPHY; Fiscal Year: 2013
    ..Selected drugs will be tested to reveal what functional benefits they confer on the recovery of mice from stroke injury. ..
  16. Cell Characterization and Imaging for Regenerative Therapies in Ischemic Diseases
    PHILLIP CHUNG MING YANG; Fiscal Year: 2013
    ..We intend to correlate these subsets with clinical endpoints in our PAD and CAD research protocols, to determine what cell subsets may be most critical for any observed benefit. ..
  17. A Gene therapeutic approach to stable suppression of HIV-1 replication
    MICHAEL R FARZAN; Fiscal Year: 2013
    ..These studies will establish principles and protocols directly applicable to subsequent human clinical trials. ..
  18. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  19. Cyclooxygenase-2 Regulation of Blood-Brain Barrier Opening in Ischemic Stroke
    ..This will help to reduce the burdens of this neurological disease. ..
    David M Pollock; Fiscal Year: 2013
    ..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
    Berislav V Zlokovic; Fiscal Year: 2013
  22. Specialized Programs of Translational Research in Acute Stroke at the Partners
    Steven M Greenberg; Fiscal Year: 2013
    ..If our study is successful, we can potentially expand use of lytics to a stroke patient population for whom little acute intervention is currently offered. ..
  23. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  24. Recombinant annexin A2 plus tPA for combination stroke therapy
    Xiaoying Wang; Fiscal Year: 2013
    ..We believe our proposal should be directly relevant for PA-07-233, "Multidisciplinary Translational Research in Critical Care" (R01). ..