Delta power during sleep is modulated by EEG-gated auricular vagal afferent nerve stimulation (EAVANS)

Vagus nerve stimulation (VNS) has many clinical applications under development. In particular, there is a large interest in transcutaneous auricular VNS (taVNS) because it is non-invasive and provides easy access to neuromodulation. The present study proposes a novel approach for electroencephalography (EEG)-gated taVNS, with the ultimate goal of enhancing therapeutic outcomes, including for the treatment of delirium. Delirium arises from an altered state of consciousness and is the most common neuropsychiatric disorder observed in hospitalized patients, especially the elderly. Delirium has been linked to specific disturbances in EEG rhythms. Here, we propose an EEG-gated auricular vagal afferent nerve stimulation (EAVANS) approach to deliver stimulation targeting a specific instantaneous phase of the EEG Delta rhythm to modulate arousal and downstream reduction of neuroinflammation, two of the contributing factors to delirium. We hypothesize that treatment with EAVANS will modulate Delta power, which has been linked with delirium. As dominant Delta power is also a typical feature of non-rapid eye movement (NREM) sleep, we applied a prototype of an EAVANS device on healthy volunteers during sleep to establish preliminary validation. We successfully employed our closed-loop approach to target vagal afference during the rising Delta phase in the range [-π/2 0] radians. We found a significant reduction in Delta wave power for stimulation during the rising Delta phase compared to 1) absence of stimulation, 2) active stimulation during the descending Delta phase, and 3) active stimulation targeting non-vagal territory (i.e. greater auricular nerve) during the rising Delta phase. Further validation of our EEG-gated taVNS approach in the peri-operative period will be needed. As there is presently a lack of effective treatments for delirium, our non-pharmacological and non-invasive approach, if validated, could be easily deployed in clinical settings.Clinical Relevance— Given the serious health consequences and costs associated with delirium, and the absence of effective non-pharmacological treatments, the proposed neuromodulatory approach may be a promising option for reducing delirium and other disorders of consciousness. Our EAVANS prototype system has been tested on healthy volunteers during a NREM sleep state and will require further validation in different patient populations to optimize the proposed technology and gather more evidence to support its clinical utility. This novel non-pharmacological and non-invasive closed-loop neuromodulatory device could be used peri-operatively and in inpatient hospital settings to treat patients at risk of developing delirium. For instance, in a pre-operative setting, this technology may provide an effective preventative "pre-habilitation" approach for patients at high risk of developing delirium. Post-operatively, our technology may help manage patients with delirium more effectively.