Vagal Nerve Stimulation to Reduce Inflammation and Hyperadrenergia

Study Overview
=================
Brief Summary
-----------------
The purpose of this research device study is to learn more about the autonomic nervous system. This system uses nerves to send information from the brain to the rest of the body by electrical signaling and has two divisions, the sympathetic and the parasympathetic branches. It has been thought that electrical stimulation devices could be used to restore balance to the nervous system. Because most of the imbalance seems to happen due to too much sympathetic activity, the investigator plans to focus on the parasympathetic branch. Specifically, the investigator hopes to restore balance by targeting the vagus nerve, which is the main communicator of the parasympathetic branch. The study will examine whether the investigator can decrease sympathetic activity and chronic inflammation by increasing parasympathetic activity. This is a device study that will examine the use of non-invasive vagal nerve stimulation to attenuate inflammatory stress and sympathetic hyperactivity in persons with Spinal Cord Injury and Non-Disabled Controls.

Official Title
-----------------
A Study of Safety and Autonomic Responses to Non-Invasive Vagal Stimulation in Persons With Spinal Cord Injury and Non-Disabled Controls Both With and Without Inflammatory Stress

Conditions
-----------------
Spinal Cord Injury

Intervention / Treatment
-----------------
* Device: InTENsity MicroCombo


Participation Criteria
=================
Eligibility Criteria
-----------------
Group 1 & 2: Inclusion Criteria: Age 18-65 Willingness to participate in the study Exclusion Criteria: Use of an active electrical implant, such as a cardiac pacemaker or cochlear implant Use of a hearing aid in the left ear Use of an implanted insulin or morphine (pain) pump Self-reported history of syncope from known or unknown origins Self-reported history of cardiovascular disease or dysfunction (e.g., cardiovascular disease, arrhythmia, congestive heart failure, or stroke) Group 3: Inclusion Criteria: Age 18-65 Overweight, with a BMI ≥ 27 Presence of chronic inflammation, with C-reactive protein values > 3 mg/l Willingness to participate in the study Exclusion Criteria: Use of an active electrical implant, such as a cardiac pacemaker or cochlear implant Use of a hearing aid in the left ear Use of an implanted insulin or morphine (pain) pump Self-reported history of syncope from known or unknown origins Self-reported history of cardiovascular disease or dysfunction (e.g., cardiovascular disease, arrhythmia, congestive heart failure, or stroke) Use of statin drugs Group 4: Inclusion Criteria: Age 18-65 ≥ 1-year post-injury Bladder management by clean intermittent catheterization Spinal cord injury resulting in Paraplegia level T1 to T6 and motor-complete (AIS A or B) impairment. Injury level and impairment will be confirmed by an ASIA exam conducted less than 2 years before study entry. If longer than 2 years, we will have a certified rater repeat the exam. Participant report of symptoms related to autonomic dysreflexia during episodes of full bladder or voiding, including elevated BP, mild headache, paresthesia, chills, nasal congestion, flushing of the skin, or diaphoresis. Willingness to participate in the study. Exclusion Criteria: Currently hospitalized American Spinal Injury Association (AIS) C-E Currently using an insulin, morphine (pain), or intrathecal pump Use of an active electrical implant, such as a cardiac pacemaker or cochlear implant Use of a hearing aid in the left ear Self-reported history of syncope from known or unknown origins Self-reported history of cardiovascular disease or dysfunction (e.g., cardiovascular disease, arrhythmia, congestive heart failure, or stroke)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Low Hertz<br>Participants will receive 10 hertz stimulation to the left auricular branch of the vagus nerve, delivered in one 15 minute session. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Experimental: Group 1: High Hertz<br>Participants will receive 30 hertz stimulation to the left auricular branch of the vagus nerve, delivered in one 15 minute session. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Sham Comparator: Group 1: Control<br>Participants will receive 30 hertz stimulation to a non-vagally innervated region of the left ear, delivered in one 15 minute session. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Experimental: Group 2: Pre-stressor<br>Participants will receive 10 or 30 hertz stimulation to the left auricular branch of the vagus nerve, delivered in one 15 minute session prior to receiving experimental sympathetic induction. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Experimental: Group 2: Post-stressor<br>Participants will receive 10 or 30 hertz stimulation to the left auricular branch of the vagus nerve, delivered in one 15 minute session after experimental sympathetic induction. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Placebo Comparator: Group 2: Control<br>Participants will receive 10 or 30 hertz stimulation to a non-vagally innervated region of the left ear, delivered in one 15 minute session prior to receiving experimental sympathetic induction. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Experimental: Group 3: 30 Hz<br>Participants will receive 10 or 30 hertz stimulation to the left auricular branch of the vagus nerve, delivered in one 15 minute session. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Experimental: Group 4: 30 Hz<br>Participants will receive 10 or 30 hertz stimulation to the left auricular branch of the vagus nerve, delivered in one 15 minute session. Participants will also receive stimulation on a subsequent session prior to urodynamic testing. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|
| Experimental: Group 1: Response<br>Participants will receive 10-30 hertz stimulation to the left auricular branch of the vagus nerve, delivered over the course of 1 hour. Device: InTENsity MicroCombo | Device: InTENsity MicroCombo<br>* An electrotherapy device.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in parasympathetic activity after vagal nerve stimulation by Heart Rate Variability | Measured by the normal-to-normal QRS complexes of the PQRST waveform of the electrocardiogram (ECG) | Baseline to 90 minutes post-vagal nerve stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Group 1 & 4: Change in acute heart rate response to vagal nerve stimulation | Measured by numerical heart rate in beats per minute | Baseline to 90 minutes post-vagal nerve stimulation | 
| Group 1 & 4: Change in acute blood pressure response to vagal nerve stimulation | Measured by diastolic and systolic blood pressure (mm/Hg) | Baseline to 90 minutes post-vagal nerve stimulation | 
| Group 1: Change in parasympathetic activity after vagal nerve stimulation by Vagus Somatosensory Evoked Potentials | Measured by far field potentials from the brain stem | Baseline to 90 minutes post-vagal nerve stimulation | 
| Group 2 & 4: Change in acute physiological stress response by a change in peripheral cortisol | Measured by cortisol levels in plasma | Baseline to 90 minutes post-experimental stimulus | 
| Group 2 & 4: Change in acute physiological stress response by a change in peripheral catecholamines | Measured by catecholamine levels in plasma | Baseline to 90 minutes post-experimental stimulus | 
| Group 2 & 4: Change in acute physiological stress response by a change in heart rate | Measured by numerical heart rate in beats per minute | Baseline to 90 minutes post-experimental stimulus | 
| Group 2 & 4: Change in acute physiological stress response by a change in blood pressure | Measured by diastolic and systolic blood pressure (mm/Hg) | Baseline to 90 minutes post-experimental stimulus | 
| Group 3 & 4: Change in inflammatory biomarkers after vagal nerve stimulation | Measured by cytokine levels in plasma | Baseline to 90 minutes post-vagal nerve stimulation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hyperadrenergia, Inflammatory stress