Non-invasive Ultrasonic Auricular Vagus Nerve Stimulation

Overview

The Vagus nerve, one of 12 cranial nerves that connect the brain to the human body, controls specific involuntary functions such as breathing, heart rate, the digestive system and the immune system, and it is crucial to unlocking the relaxation response (parasympathetic nervous system). Vagus nerve stimulation (VNS) can be invasive or non-invasive, and both methods have been trialled in research studies. Some non-invasive VNS involves the use of a device which is placed on the skin, to send electrical impulses to the Vagus nerve. The device sends electrical impulses to some areas of the brain which changes brain activity and helps in treating certain disorders. Invasive methods utilise a surgically implanted Vagus nerve stimulator on the left Vagus nerve in the neck area. VNS is used in treatment of epilepsy and studies has shown to have a therapeutic effect on treatment resistant depression. Currently, research indicates that invasive VNS to treat anxiety yield mixed results, whilst other studies suggest that VNS with exposure-based therapies might enhance outcomes for anxiety patients. Stimulating the Vagus nerve comes with serious technical challenges. Most importantly, electric currents follow the path of least resistance. When running through biological tissues, such as skin, cartilage or bone, it is difficult to aim for the part of the body that needs to be stimulated. This means it isn't always easy to tell whether the Vagus nerve is indeed being stimulated and how much of the current is reaching the Vagus nerve. This problem can be overcome by ultrasound stimulation. Ultrasound stimulation employs high frequency sound waves to stimulate tissue. These soundwaves travel through the human body much more predictably than electric currents. As such, ultrasound stimulation of the Vagus nerve may be more effective than electrical stimulation. The ZenBud device is designed to apply ultrasound stimulation to part of the auricular branch of the Vagus nerve. Ultrasound stimulation allows for more targeted stimulation, increasing the chance of the stimulation reaching the Vagus nerve. The ZenBud device is safe for use in healthy adults and received CE marking. Before testing the therapeutic effect of the Zenbud on patients with symptoms it is important to identify physiological, cognition or emotional changes in health volunteers. Identifying these changes could lead to identifying possible future therapeutic uses for ultrasound-VNS (U-VNS).

The vagus nerve is the longest cranial nerve travelling from the medulla to the colon and is involved in the autonomic, cardiovascular, respiratory, gastrointestinal, immune and endocrine systems. The vagus nerves are part of the body's nervous system and control specific bodily functions such as mood, breathing and heart rate, the digestive system and immune system. These responses are involuntary and are not controlled consciously. The vagus nerve is one of twelve cranial nerves that connect the brain to the body. It runs from the brain stem into the gut and is part of the rest and digest system, crucial to unlocking the relaxation response of the parasympathetic nervous system. Vagus nerve stimulation (VNS) is established as a therapeutic treatment for epilepsy and has promise as a treatment in neuropsychiatric conditions such as drug-resistant depression and headaches. Stimulation of the vagus nerve can be conducted either invasively via a surgical implant or non-invasively (transcutaneous). Transcutaneous VNS can be delivered via the ear, stimulating the auricular branch of the vagus nerve, or at the neck, stimulating the cervical branch. Invasive VNS entails the implantation of a pulse generator device connected to electrodes placed around the cervical vagus nerve; implantation can lead to infection around the wound site, pain, and peri-incisional haematoma. Traditionally, VNS is electrical, which presents technical limitations since stimulating currents are conducted differently depending on the tissue, and controlling the focus and direction of the current is challenging as it diffuses. In tVNS it is impossible to determine with absolute certainty whether, and to what extent, the administered electric current reaches the vagus nerve. Ultrasound stimulation of the vagus nerve is an alternative to electrical stimulation through the employment of high-frequency sound waves, which stimulate the central nervous system. The ZenBud device uses ultrasound stimulation on the vagus nerve branch that runs through the ear region. Applying pulses rather than an electric current overcomes technical issues related to electrical conductivity. Ultrasound stimulation enables targeted activation, increasing the likelihood that the stimulation reaches its intended site. ZenBud devices are evidenced as safe to use among healthy adults and have received CE marking following assessments conducted at the University of Nottingham. Anatomical studies propose that direct stimulation of the vagus nerve fibres in the ear region can produce similar effects to invasive VNS and reduce somatic symptoms of mild to moderate depression and epilepsy, avoiding the need for surgery, which is a common feature of invasive VNS. The presence of tVNS has been associated with improvements in psychological wellbeing. Animal studies suggest that stimulation of the ear area and its vagus nerve fibres produces physiological changes such as decreased heart rate and arterial pressure. Studies have shown that VNS can be effective in treating epilepsy and depression, and there is evidence that it may be useful in pain management and autoimmune or inflammatory disorders; however, a greater understanding of its effects on the body is required. Research indicates that auricular vagus nerve stimulation can influence EEG and EMG activity in healthy individuals and suggests potential as a non-invasive treatment for various clinical conditions. The purpose of this study is to investigate the efficacy, safety and usability of the wearable headset and to identify changes in biomarkers due to the use of ultrasound VNS. Identifying physiological, cognitive or emotional changes could help determine potential future therapeutic uses for U-VNS. For this study, participants will attend multiple visits, with an upper limit of five. Participants will be randomly allocated to receive either U-VNS in the first appointment and sham in the second, or vice versa. Sham will consist of wearing the device without stimulation being delivered. At the first appointment, safety screening will be confirmed using the U-VNS safety questionnaire, and informed consent will be obtained. Participants will have heart rate and blood pressure recorded. Then, participants will insert a continuous glucose monitor (CGM, Dexcom) and be given a Fitbit smartwatch to wear for monitoring physiological signals, activity and sleep throughout the study. For the second appointment, participants will be asked to avoid exercise and fast from food for 12 hours prior to arrival. Physiological (heart rate and blood pressure), cognitive and emotional markers will be recorded. A pre-, during- and post stimulation ECG may be performed. EEG data may also be recorded before, during and after stimulation on the same day. Additional physiological markers such as body temperature, skin conductance (via GSR), or ear electrodes located on the cymba conchae through a bipolar electrode may also be recorded. Participants will complete questionnaires about emotional wellbeing and sleep, such as the STAI and a short Oxford-Liverpool Inventory of Feelings and Experiences (O-Life) and undergo cognitive assessments. These tasks will be completed using PsychoPy or a similar application and will focus on attention, emotion and memory. All tasks involve visual stimuli with responses recorded via keyboard or mouse, and each takes approximately 5-10 minutes to complete. These tasks provide a comprehensive assessment of cognitive and emotional functioning and are tailored to measure domains influenced by VNS. Following this, participants will receive the intervention using the ZenBud or sham device for up to 30 minutes. After 30 minutes, the device will automatically turn off. Participants will again complete the physiological, cognitive and emotional assessments 10 minutes after stimulation onset and after completion. The participants will also complete the effectiveness of blinding and adverse effects questionnaires. After a one-week washout period, participants will attend a third appointment. Participants will be asked about any eligibility changes and confirm continued consent. As in the second appointment, participants will fast and refrain from exercise for 12 hours before undergoing the alternate intervention (U-VNS or sham) for 30 minutes. The same assessments and questionnaires will be repeated. During the second and third visits, participants will use the ZenBud device for up to 30 minutes. If the participants received real U-VNS first, the participants will receive sham second, and vice versa. The device automatically turns off after 30 minutes. Apart from collecting demographics and medical history during the first visit, the second and third visits will include the same physical, cognitive and emotional assessments before, during and after U-VNS. Participants will wear a Fitbit throughout the study to monitor heart rate and sleep patterns