Symposium (Fast track) session 1b.01 - Applications of vagus nerve stimulation for brain health

Recent research has shown that stimulation of the auricular branch of the vagus (accessed through the ear) has shown improvements in learning and memory. A newer device stimulates a different branch of the vagus nerve noninvasively via the cervical branch of the nerve located in the neck. Clinically, research has found that noninvasive cervical transcutaneous vagal nerve stimulation (ctVNS) has been successfully used to treat various types of headache disorders. Our lab has recently been investigating this form of stimulation as a way to improve cognitive performance in healthy individuals. This presentation will cover the performance benefits we have found thus far in learning, attention, arousal, multi-tasking, fatigue mitigation, and mood. For instance, we have found that a single dose of ctVNS can sustain multi-tasking ability, reaction time, and mood during sleep deprivation stress. We have also found that participants receiving ctVNS learn to identify ground targets in aerial imagery faster and retain what they learned longer than those who received sham stimulation. The studies all use various populations of active-duty military participants in both highly controlled laboratory studies as well as field tests with operational units. These studies demonstrate that ctVNS has the potential to enhance cognitive performance in healthy individuals. More research is needed to replicate and expand these findings as well as to investigate the mechanisms causing the enhancements in performance.

The vagus nerve is the longest cranial nerve in the body, descending from the brainstem and extensively innervating the major visceral organs. The ascending sensory and descending motor fibers connecting the brain to the body are composed of a variety of fiber types, ranging from large myelinated A-fibers to small unmyelinated C-fibers. The mixed composition of the vagus nerve presents a challenge, and also an opportunity, for achieving fiber-specific neuromodulation to treat a variety of conditions. In this talk, I will present our work on using electrical vagus nerve stimulation (VNS) and optogenetic approaches for selective activation of specific vagus nerve fibers subsets for the neural regulation of inflammation. Specifically, I will cover how the selection of electrical stimulation parameters in cervical VNS can change serum cytokine production. I will also present how optogenetic photostimulation of cholinergic neurons in the brainstem dorsal motor nucleus reduces serum cytokines in the context of acute inflammation through a well-defined vagus nerve-to-spleen circuit. By using nerve cuff electrophysiology and optical imaging techniques, our lab has also shown that stimulation at the cervical level of the vagus nerve in genetically modified mice can be used to achieve selective activation of glutamatergic sensory afferents and cholinergic motor efferents within the vagus nerve. This talk will include prior published work on the circuit mechanisms for neuro-immune regulation, as well as recent unpublished work using leading-edge neuroscience tools to probe these circuits in the brain and the peripheral nervous system. 

Millions of Americans live with Alzheimer’s disease (AD) and routinely require common surgical interventions, such as orthopedic surgery. However, these potentially life-saving procedures often increase the risk for further cognitive complications, such as delirium, which in many cases associate with worse prognosis and even death. Currently, we do not have effective strategies to prevent postoperative neuroinflammation and treat delirium. Using an AD-like mouse model (CVN-AD) we established a translational paradigm to study delirium superimposed on dementia. Here we describe the effects of a minimally-invasive ultrasound guided percutaneous approach to stimulate the vagus nerve (termed pVNS) in CVN-AD mice after orthopedic surgery. A 30-minute stimulation at 10 Hz was performed in 12-months-old CVN-AD mice before subjecting them to tibial fracture and repair. Surgery induced a robust neuroinflammatory response in these mice, with evident morphological changes in microglia and astrocytes, as well as an acute deposition of Aβ plaques in the hippocampus compared to age-matched controls. pVNS after surgery rescued morphological changes in microglia and astrocytes, as well as effectively reduced Aβ plaques deposition in the hippocampus at 24 hours. Notably, pVNS altered the autophagy-lysosomal pathway by increasing TFEB and LAMP1 expression, which are key regulators of autophagy and lysosomal biogenesis. These changes were observed using Nanostring assay on hippocampal tissue combined with immunofluorescence staining. Overall, these data highlight a novel role for vagus nerve stimulation in regulating neuroimmune interactions and resolving inflammation in delirium superimposed on dementia.

Vagus nerve stimulation (VNS) is known to have anti-inflammatory properties such as reduced pro-inflammatory cytokine production and reduced gliosis both in the periphery and in the central nervous system, thereby providing a wide range of potential clinical indications for VNS. Chronic neuroinflammation is one of the mechanisms that contributes to cell damage in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.  While previous work has demonstrated great potential for VNS in neurodegenerative diseases, our lab set out to determine the ideal stimulation paradigm in an animal model of Parkinson's disease.  These parameters were chosen based on the hypothesis that stimulation frequency can differentially regulate inflammatory circuits and the extrapyramidal motor pathway. Our results indicate that higher stimulation frequencies provide greater benefits for motor function and neuronal health as measured by tyrosine hydroxylase expression in the substantia nigra and locus coeruleus, as well as reduced intrasomal α-synuclein accumulation in neurons of the substantia nigra. Studies are ongoing in the lab to assess neuroinflammation in these brain regions and levels of pro-inflammatory cytokines, acetylcholine, and norepinephrine levels in serum and in the central nervous system. These changes will indicate which pathways are activated by specific sets of VNS parameters, thereby helping to characterize each stimulation paradigm and determine which paradigm provides the greatest therapeutic potential for Parkinson’s disease.