UltraSONIC Vagus Nerve Stimulation: Investigation U-VNS Effects on Physiological, Emotional and Cognitive Biomarkers
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 3
- 主要终点
- Continuous Glucose Monitoring (CGM)-derived glycaemic variability
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participant is willing and able to give informed consent for participation in the study
- •Not currently taking any medications (except the contraceptive pill)
- •Aged 18 or over
- •Good general health
- •Able and willing to remove any piercings in the left ear
- •Able to abstain from exercise and fast from food for 12 hours before the second and third visit
排除标准
- •Current or past diagnosis of a major neurological, neurosurgical, or psychiatric disorder (including self-reported depression)
- •Inability to complete informed consent process
- •Personal history of cardiac arrhythmia
- •High blood pressure (>140 mmHg systolic and/or >90 mmHg diastolic)
- •Other significant medical condition (including cardiological disorders; specific details to be reviewed by the CI prior to inclusion)
- •Use of medication or recreational drugs that affect the nervous system in the past 3 months
- •Medication intake (such as beta-blockers, glucocorticoids, antidepressants, anti-inflammatory drugs) in the last 7 days - contraceptive medication in women is allowed
- •Currently pregnant or breastfeeding
- •Allergy to aquasonic gel or any of its components (propylene glycol, glycerin, isothiazolinones)
- •Participation in a research study in the last 3 months involving invasive procedures or an inconvenience allowance (required for all UoN FMHS UREC-approved studies)
- •BMI < 18 kg/m² or > 30 kg/m²
- •Excessive consumption of alcohol (>2 alcoholic beverages/day) or tobacco (>5 cigarettes/day)
- •Previous experience with stress tests
- •Known infection in the last 8 weeks
结局指标
主要结局
Continuous Glucose Monitoring (CGM)-derived glycaemic variability
时间窗: Baseline to 20-25 days. Measurements taken every 5 minutes continuously through a GCM device. Measurements taken in mg/dL
Glucose Level measured in mg/dL extracted derived from Continuous Glucose Monitoring (CGM)
时间窗: Baseline to 20-25 days with Baseline to 20-25 days. Measurements taken every 5 minutes continuously through a GCM device. Measurements taken in mg/dLin between
EEG Power in Alpha Band (8-12Hz)
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
EEG Power in Theta Band (4-7Hz)
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
EEG Power in Beta Band (13-30Hz)
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
EEG Power in Gamma Band (31-45Hz)
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
EEG-derived Event-Related Potential (ERP) amplitude
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
EEG-derived Time-locked spectral power changes
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
ECG-derived Heart Rate (HR)
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
ECG-derived QT interval
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
ECG-RR Interval (inter-beat Interval)
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
ECG-derived Heart Rate Variability (HRV)
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
ECG-derived PR Interval
时间窗: Baseline to 20-25 days, measured before, during, and after stimulation
次要结局
- Fitbit smartwatch-derived Heart Rate (HR) during sleep(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device with PPG)
- Fitbit smartwatch-derived Daily Heart Rate Variability (HRV)(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device with PPG)
- Fitbit smartwatch-derived resting Heart Rate (HR)(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device with PPG)
- Fitbit smartwatch-derived daily step count(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device)
- Fitbit smartwatch-derived daily ratio of Sedentary (no activity) vs active time(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device)
- Fitbit smartwatch-derived Total sleep duration (hours per day)(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device)
- Fitbit smartwatch-derived daily percentage of sleep stages (including light, deep and REM sleep)(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device.)
- Fitbit smartwatch-derived daily sleep efficiency measured as daily ratio of total sleep time to time in bed(Baseline to 20-25 days. Measurements taken continuously through a Fitbit device)
- Continuous Skin conductance (electrodermal activity) levels measured via GSR sensors (kOhms)(Baseline to 20-25 days, measured before, during, and after stimulation)
- Respiration Rate measured as percentage of chest expansion (%) through a wearable chest sensor(Baseline to 20-25 days, measured before, during, and after stimulation)
- Vagus Nerve electrical activity (µV) variability recorded through a bipolar electrode placed on the cymba conchae of the right ear.(Baseline to 20-25 days, measured before, during, and after stimulation)
- Event-related Vagus Nerve amplitude changes recorded through a bipolar electrode placed on the cymba conchae of the right ear(Baseline to 20-25 days, measured before, during, and after stimulation)
- Total score on the Oxford-Liverpool Inventory of Feelings and Experiences questionnaire. Higher scores indicate higher levels of schizotypal traits.(Baseline, questionnaire done once before the first visit)
- Total score on the Autism-Spectrum Quotient (AQ) questionnaire. Higher scores indicate greater or higher presence of autistic traits.(Baseline, questionnaire done once before the first visit)
- Total score on the Multidimensional Assessment of Interoceptive Awareness (MAIA) questionnaire. Higher scores indicate greater interoceptive awareness.(Baseline, questionnaire done once before the first visit)
- Total score on the State-Trait Anxiety Inventory - Trait subscale (long form). Higher scores indicate greater trait anxiety.(Baseline, questionnaire done once before the first visit)
- Total score on the State-Trait Anxiety Inventory - Trait subscale (short form). Higher scores indicate greater state anxiety.(Baseline to 20-25 days, questionnaire done before the first visit, one hour before stimulation and one hour after stimulation)
- Total score on the Beck Depression Inventory (range 0-63). Higher scores indicate more severe depressive symptoms(24 hours after stimulation)
- Total score on the Beck Anxiety Inventory (BAI) (range 0-63). Higher scores indicate more severe anxiety symptoms.(24 hours after stimulation)
- Structured questionnaire assessing adverse effects of ultrasonic Vagus nerve stimulation (VNS).(24 hours after stimulation)
- Average Reaction time (ms) measured from a Stroop Cognitive task(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Continuous Body temperature measured using a thermistor (°C)(Baseline to 20-25 days, measured before, during, and after stimulation)
- Average Reaction time (ms) measured from a Semantic Memory Cognitive task(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Average Reaction time (ms) measured from an Emotional Bias Cognitive task.(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Average Reaction time (ms) measured from a symbol-to-symbol matching Cognitive task.(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Average Reaction time (ms) measured from an Object-in-place Working memory Cognitive task(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Overall task accuracy (%) measured from an Emotional Bias Cognitive task.(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Overall task accuracy (%) measured from a symbol-to-symbol matching Cognitive task(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Overall task accuracy (%) measured from an Object-in-place Working memory Cognitive task.(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Overall task accuracy (%) measured from a Stroop Cognitive task.(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)
- Overall task accuracy (%) measured from a Semantic Memory Cognitive task(Baseline to 20-25 days, measured immediately before, during, and immediately after stimulation)