Non-Invasive Vagus Nerve Stimulation in Subarachnoid Hemorrhage

About This Grant

Aneurysmal subarachnoid hemorrhage (SAH) carries high mortality in ~40% and poor outcomes in ~20% of all. About 30% of patients who initially survive the rupture develop early brain injury and delayed cerebral ischemia, both major causes of mortality, prolonged hospital stay, and disability. Microvascular dysfunction and vasospasm, inflammation, spreading depolarizations (SD), and seizures all contribute to poor outcomes. There is no established treatment after SAH except nimodipine and enhancing tissue perfusion via induced hypertension. Therefore, aneurysmal SAH management is an urgent unmet need. We here propose to develop non-invasive transcutaneous vagus nerve stimulation (nVNS) as a novel neuromodulatory intervention targeting SAH. Vagus nerve stimulation (VNS), a neuromodulation technique in clinical use for intractable epilepsy and depression, inhibits SDs and has anti-ischemic, anti-inflammatory, anti-hypertensive, and anti-epileptic properties. However, the need for highly invasive surgical implantation of electrodes around the vagus has so far limited its clinical applications. Recently, non-invasive VNS (nVNS) techniques with excellent safety and tolerability profiles have been developed and approved for clinical use. nVNS is a pleiotropic intervention on multiple targets relevant to SAH (Figure 1). We recently showed that nVNS improves outcomes in animals with ruptured aneurysms and SAH. Building upon these proof-of-concept data, our overarching aim in this translational proposal is to build a foundation for nVNS targeting SAH, better understand the mechanisms, and prepare this novel neuromodulatory therapy for clinical trials in SAH. Aim 1: We will test whether nVNS improves SAH outcomes in three complementary animal models of SAH: prechiasmatic blood injection, endovascular puncture, and skull-base elastase injection to induce aneurysms in the circle of Willis that rupture spontaneously. We will establish nVNS dose-response in both sexes, circadian stages, and aging animals on clinically relevant functional and tissue outcomes to define the therapeutic profile of nVNS in SAH. Aim 2: We will test whether nVNS improves biological substrates of SAH outcomes. We will examine optical resting-state functional connectivity, inflammation using myeloperoxidase MRI, blood-brain barrier integrity using dynamic contrast-enhanced MRI, cerebral blood flow autoregulation and cerebrovascular reserve using laser speckle flowmetry, and microcirculatory thrombi and neutrophil extracellular traps using histology. These will confirm target engagement and bolster our confidence in the therapeutic activity optimized in Aim 1. Aim 3: We will test whether nVNS efficacy in SAH is mediated via central or peripheral vagal pathways by ablating the vagus proximal or distal to the cervical nVNS site, lesioning the principal central vagal relay nucleus tractus solitarius, and pharmacologically manipulating the cholinergic anti-inflammatory pathway activated by nVNS. These experiments will identify the vagal projections and their downstream targets relevant to SAH.