Vagal Nerve Stimulation in Coma Patients

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• Persistent Vegetative State 70
• Consciousness Disorders 233

Keywords

• Vagus nerve stimulation
• vegetative state
• minimally conscious state
• akinetic mutism
• consciousness
• connectivity

Study arms

• Experimental
  All patients will undergo the same procedure

  Device: stimulation device

Interventions

• Devicestimulation device

  All patients included in the study will undergo baseline assessment of all measures before surgery (implantation of a vagus nerve stimulation device). A second baseline assessment will take place after surgery, before the beginning of the stimulation. Stimulation intensity will start at 0.25mA and increase progressively by 0.25mA each week until reaching 1mA. Then, intensity will be set at 1.5mA (recommended by manufacturer) and will stay to this level until the end of the trial. Experimenters will keep the right to modify these parameters depending on patients' reaction to the treatment.

Primary outcomes

1. Change over time of clinical scores on the Coma Recovery Scale - Revised

   The primary outcome will be the change over time of patients' clinical state. Investigators will employ a widely used scale: Coma Recovery Scale - Revised. Patients will be evaluated by the same trained doctor. Results will be analyzed using a within subject design, each patients will be his own control. Investigators predict a progressive improvement after the onset of treatment, compared to the two pre-stimulation evaluations.

   Time frame: First assessment one week before implantation second assessment 3 weeks after implantation, then once per week for a month starting one week after the beginning of stimulation; then once a month for 6 months.

Secondary outcomes

1. Evaluation of brain activity changes using EEG

   EEG will allow investigators to monitor brain activity at rest as well as in response to various sensory stimuli. Investigators will measure changes in evoked potentials, source of activity and frequency power known to be altered in coma patients. In addition EEG will offer the opportunity to record brain activity while the stimulating device is on.

   Time frame: First assessment one week before implantation second assessment 3 weeks after implantation, then once per week for a month starting one week after the beginning of stimulation, then once a month for 6 months.

2. MRI (anisotropy and fibers density) evaluation of anatomo-connectivity changes

   Investigators will use Diffusion Tensor Imaging (DTI) before and after VNS to evaluate anisotropy and anatomical connectivity between brain stem, thalamus and various cortical areas, especially regarding the thalamo-cortical loops. During the MRI exams the stimulation device will be turned off for safety reasons.

   Time frame: First assessment one week before implantation second assessment 3 weeks after implantation and then one, three and six months after the onset of stimulation.

3. fMRI evaluation of bold signal resting state activity and functional connectivity changes

   WInvestigators will perform resting state analysis of bold signal and functional connectivity to quantify reactivation of brain region after VNS and inter region communication, especially regarding the thalamo-cortical loops. During the fMRI exams the stimulation device will be turned off for safety reasons.

   Time frame: Firsts First assessment one week before implantation second assessment 3 weeks after implantation,, and then one, three and six months after the onset of stimulation.

4. PET scan evaluation of brain metabolism (Glucose consumption) changes

   Investigators will use the radioligand Fluorodesoxyglucose \[18F-FDG\] to assess brain consumption of glucose. This measure is complementary to the one provided by fMRI and has already been used in coma patients. Moreover, thanks to a hybrid MRI/PET scanner, investigators will perform the two exams simultaneously to correlate these two measures in real time.

   Time frame: One baseline assessment one week before stimulation and a second one after 3 months of stimulation.

5. Monitoring heart rate variability

   Investigators hypothesize that VNS will modulate several physiological parameters, among those Heart Rate Variability, a marker of the balance between sympathetic and parasympathetic activity. Investigators will measure changes of high frequencies / low frequencies ratio.

   Time frame: First assessment one week before implantation second assessment 3 weeks after implantation, then once per week for a month starting one week after the beginning of stimulation, then once a month for 6 months.

6. : Monitoring changes of serum free serotonin concentration

   Vagus nerve is known to stimulate raphe nuclei, the region of serotonin synthesis. Investigators hypothesize that VNS will increase serum free serotonin concentration. Investigators will measure it using high performance liquid chromatography, and report the changes of values of serotonin concentration.

   Time frame: First assessment one week before implantation second assessment 3 weeks after implantation, then once per week for a month starting one week after the beginning of stimulation, then once a month for 6 months.

7. Monitoring changes of thermal reaction to emotional stimuli

   Investigators will use regulation of facial temperature as an index of consciousness. When humans react to emotions, the temperature of their face changes. This regulation is dependent on consciousness state, and therefore should vary across time in this protocol. Investigators will measure changes in temperature (°Celsius) of patients' face throughout the task.

   Time frame: First assessment one week before implantation second assessment 3 weeks after implantation, then once per week for a month starting one week after the beginning of stimulation, then once a month for 6 months.