Transcutaneous Auricular Vagal Nerve Stimulation for Post-coma Patients With Disorders of Consciousness

Study Overview
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Brief Summary
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Non-invasive brain stimulations techniques have recently shown promising results in patients with disorders of consciousness. Notably, a case reported improvement of level of consciousness using transcutaneous auricular vagal nerve stimulation in a patient in unresponsive wakefulness syndrome. Here we aim to assess the effects of transcutaneous auricular vagal nerve stimulation on post-coma patients with disorders of consciousness in a first randomized controlled trial. To measure these effects, behavioral (Coma recovery scale revised - CRS-R -primary outcome) and neuro-electrophysiological (electroencephalography - EEG - secondary outcome) data will be recorded in severely brain-injured patients with DOC.

Detailed Description
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Currently, therapeutic options for severely brain-injured patients with disorders of consciousness (DOC), including patients in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), are limited and still need to be improved to influence long-term outcomes. Non-invasive brain stimulations (NIBS) techniques have recently shown promising results in DOC. Transcutaneous auricular vagal nerve stimulation (taVNS-R, tVNS Technologies GmbH, Germany) seems to be a promising approach. In a recent case report, a patient in UWS improved to MCS using this therapeutic technique. To confirm this positive result, we propose a first randomized double-blind controlled trial. The patients will be randomized in the active stimulation group and will receive bilateral stimulations of the cymba conchae or in the sham stimulation group and will receive bilateral stimulations of the ear lobe. All stimulations will be performed for 45 minutes bilaterally for 5 consecutive days, between 7 and 90 days post-injury in severely brain-damaged patients with disorders of consciousness. The stimulation will start at 3 mA and will be decreased if signs of pain were observed (more than 4/9 according to the Nociceptive Coma Scale-Revised - NCS-R) until stimulation stays under pain threshold. Behavioral assessments will be performed using the Coma Recovery Scale-Revised before and after the first and last session by an investigator blinded to the treatment allocation. Fifteen minutes of high-density EEG will also be recorded directly before and after the first and last stimulation session. During this same period of time, electrocardiography (EKG) will be recorded to measure parasympathetic indirect signs of vagal stimulation. 3 months after the last stimulation session, an outcome follow-up will be done, using the Glasgow Outcome Scale Extended (GOS-E) and the Disability Rating scale (DRS).

Official Title
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Transcutaneous Auricular Vagal Nerve Stimulation for Post-coma Patients With Disorders of Consciousness: a Randomized Double-blind Controlled Trial

Conditions
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Consciousness Disorder, Minimally Conscious State, Vegetative State

Intervention / Treatment
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* Device: Active taVNS
* Device: sham taVNS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old State of consciousness: unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) as defined by CRS-R performed during the screening period. Cerebral damage of known etiology Time since injury between 7 and 90 days Intact skin at the ears Consent given by the substitute decision maker Exclusion Criteria: Anyone who is deemed medically unsuitable for this study as determined by a physician involved with the study (e.g. severe rythmic heart condition) Previous history of neurological disorders Documented pregnancy Active implant (i.e. pacemaker) Profound sedation such as one caused by general anaesthetics (e.g., propofol) or a combination of central acting sedatives (e.g., benzodiazepines, opioids)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active taVNS<br>Patients will receive 5 days of transcutaneous auricular vagal nerve stimulation (taVNS) bilaterally, at the cymba conchae, the active localization. It will be preceded and followed by a clinical assessment (Coma Recovery Scale- Revised) and a neurophysiological assessment (128/256 channels EEG and electrocardiograph) the first and last day of stimulation. | Device: Active taVNS<br>* Patients will receive transcutaneous auricular vagal nerve stimulation (taVNS) for 5 consecutive days, at the cymba conchae, bilaterally, during 45 minutes (alternating 30 s on and 30 s off periods). Current intensity: 3 mA or less according to the participant's pain threshold, width: 200-300 μsec.<br>|
| Placebo Comparator: Sham taVNS<br>Patients will receive 5 days of transcutaneous auricular vagal nerve stimulation (taVNS) bilaterally, at the ear lobe, the sham localization. It will be preceded and followed by a clinical assessment (Coma Recovery Scale- Revised) and a neurophysiological assessment (128/256 channels EEG and electrocardiograph) the first and last day of stimulation. | Device: sham taVNS<br>* Patients will receive transcutaneous auricular vagal nerve stimulation (taVNS) for 5 consecutive days, at the ear lobe, bilaterally, during 45 minutes (alternating 30 s on and 30 s off periods). Current intensity: 3 mA or less according to the participant's pain threshold, width: 200-300 μsec.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CRS-R total score and index score | Behavioral improvement measured by standardized scale. This scale is ranging from 0 to 23, highest score represents more signs of consciousness. The index score is ranging from 0 to 100. | Before the installation of the EEG equipment in the pre-stimulation period and 5 minutes after the post-stimulation resting state EEG (immediately after removing the equipment). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in EEG | Improvement in cerebral activity (i.e. power spectrum in the alpha and theta band and connectivity) as measured by EEG | 15 min before the stimulation period and 15 min after the stimulation period. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcutaneous electrical nerve stimulation, Neuromodulation, High-density EEG, Unresponsive wakefulness syndrome, Vagus nerve stimulation, Non-invasive brain stimulation, Vegetative state, Minimally Conscious state, Consciousness disorder