CONsciousness Transcranial Electric STimulation

Study Overview
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Brief Summary
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The aim of this study is to investigate the effect of transcranial Alternating Current Stimulation (tACS) at theta frequency and the the effect of transcranial Direct Current Stimulation (tDCS) on the conscious state of non-communicating patients. tACS and tDCS are non-invasive stimulation techniques that are used to induce brain oscillations at certain frequency or to increase the brain activity in applied region. Limited treatments are available to improve consciousness in severely brain injured patients. Transcranial Direct Current stimulation (tDCS) is one of the few therapeutics that showed evidence of efficacy to increase level of consciousness and functional communication in some Minimally Conscious State (MCS) patients, and in some Vegetative State (VS) patients. However the optimal intensity of electrical current stimulation remains unknown and transcranial Alternative Current Stimulation (tACS), with the ability to stimulate cortex at specific frequencies and to manipulate phase-synchrony between regions is a promising techniques to improve patients' consciousness. In this study, the investigators will use prefrontal tDCS and theta tACS to improve patients consciousness level.

Detailed Description
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This study is constituted of two independent sub-studies investigating two types of stimulation (tDCS and tACS) with the same cross-over design Study design The study design is composed of two experimental sessions, one active stimulation and one sham comparator. Sessions will be randomized in a double-blind randomized crossover design (neither the participant nor the experimenter knows which session includes which stimulation type), with at least 2 days of interval between them. In these sessions, the patients' state of consciousness participants will first be determined using the dedicated Coma Recovery Scale - Revised (Giacino, Neurology 2002) (CRS-R) scale before stimulation. Resting state brain activity EEG and cognitive auditory paradigm (local-global paradigm, Bekinschtein, PNAS 2009) will also be recorded before stimulation. Twenty minutes stimulation will then be performed (see below). CRS-R, resting state EEG and local-global paradigm will be repeated after stimulation. Outcome measures will be the same in the two studies. The primary outcome will be the change of CRS-R between before and after stimulation. Secondary outcomes will be the neurophysiological correlates of consciousness in resting state EEG and during the local global paradigm. tACS stimulation During tACS sessions, 6 Hz stimulation (1000 μA) will be applied simultaneously over the left prefrontal dorso-lateral cortex (F3 of the 10-20 international scalp EEG system) and the left parietal cortex (P3) using an 8-channels stimulator (Starstim NE, Neuroelectrics, Barcelona, Spain) with small round sponge electrodes (25 cm2 surface, maximal current density of 0.06 μA/cm2), controlled via Bluetooth. In the in-phase condition, the phase difference between the two stimulation sites will be 0° which will entrain synchronization between sites. In the sham condition, the stimulation will start with a current intensity of 1000 μA lasting for 30 seconds. Afterwards, the intensity will progressively decrease over 20 seconds until cessation. Each stimulation session will take 20 minutes and the positions of stimulation electrodes and the duration of the stimulation will be kept identical for all conditions. tDCS stimulation During tDCS session, 2000 μA stimulation will be applied over the left prefrontal dorso-lateral cortex (F3 of the 10-20 international scalp EEG system) (Starstim NE, Neuroelectrics, Barcelona, Spain) with small round sponge electrodes (25 cm2 surface, maximal current density of 0.06 μA/cm2), controlled via Bluetooth. In the sham condition, the stimulation will start with a current intensity of 2000 μA lasting for 30 seconds. Afterwards, the intensity will progressively decrease over 20 seconds until cessation. Each stimulation session will take 20 minutes and the positions of stimulation electrodes and the duration of the stimulation will be kept identical for all conditions.

Official Title
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Effect of Transcranial Electrical Stimulation on the Consciousness of Non-communicating Patients.

Conditions
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Disorder of Consciousness

Intervention / Treatment
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* Device: In-phase 6 Hz prefronto-parietal tACS
* Device: Sham prefronto-parietal tACS
* Device: 2 mA left prefrontal tDCS
* Device: Sham left prefrontal tDCS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 80 years Non communicative patients with disorder of consciousness diagnosed by CRS-R (VS, MCS, exitMCS) Patients with stable clinical examination (even in intensive care) Brain injury confirmed by cerebral imaging (MRI or TDM) French social security affiliation Signed and informed consent by the patient or by a legal representant Exclusion Criteria: Status epilepticus or uncontrolled epilepsy Severely neurodegenerative illnesses (Alzheimer disease, Lewy Body Dementia) Electrical stimulation contraindication (metallic intra-cranial implants, pacemaker or implantable cardioverter-defibrillator, cranial prosthesis) Pregnant, parturient or breastfeeding women- Patients underage

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Crossover Assignment
Interventional Model Description: This study is composed of two independent sub-studies, one exploring the effects of tACS and the other the effects of tDCS, with different participants assigned to the two sub-studies. There will be 2 arms in tACS group and 2 arms in tDCS group. Among each sub-study, all participants will participate in all arms (hence the cross-over design).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: In-phase 6 Hz prefronto-parietal tACS<br>6 Hz stimulation (1000 μA) with transcranial Alternative Current Stimulation (tACS) will be applied simultaneously over the left prefrontal dorso-lateral cortex (F3 of the 10-20 international scalp EEG system) and the left parietal cortex (P3 of the 10-20 international scalp EEG system, with a return electrode in Cz) for 20 minutes. The phase difference between the two stimulation sites will be 0°. | Device: In-phase 6 Hz prefronto-parietal tACS<br>* tACS is a non-invasive stimulation technique that works by delivering a weak sinusoidally oscillating electrical current to the surface of the skull to entrain oscillations in the brain.<br>|
| Sham Comparator: Sham prefronto-parietal tACS<br>The same stimulation as in in-phase transcranial Alternative Current Stimulation tACS (6 Hz F3 and P3 stimulation with 0° phase difference) will start with a current intensity of 1000 μA lasting for 30 seconds. Afterwards, the intensity will progressively decrease over 20 seconds until cessation. The whole session duration is 20 minutes. | Device: Sham prefronto-parietal tACS<br>* tACS is a non-invasive stimulation technique that works by delivering a weak sinusoidally oscillating electrical current to the surface of the skull to entrain oscillations in the brain.<br>|
| Experimental: 2 mA left prefrontal tDCS<br>2000 μA anodal transcranial Direct Current Stimulation (tDCS) will be applied over the left prefrontal dorso-lateral cortex (F3 of the 10-20 international scalp EEG system with a right supraorbital return electrode (Fp2 of the 10-20 international scalp EEG system) during 20 minutes. | Device: 2 mA left prefrontal tDCS<br>* tDCS is a form of neuromodulation method where very low levels of constant current are delivered to specifically targeted areas of the brain<br>|
| Sham Comparator: Sham left prefrontal tDCS<br>The same stimulation as active transcranial Direct Current Stimulation (tDCS) (anodal F3 and return in Fp2) will start at 2 mA intensity for 30 seconds. Afterwards, the intensity will progressively decrease over 20 seconds until cessation. The whole session duration is 20 minutes. | Device: Sham left prefrontal tDCS<br>* tDCS is a form of neuromodulation method where very low levels of constant current are delivered to specifically targeted areas of the brain<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| State of consciousness | Change of the Coma Recovery Scale-Revised scores (CRS-R, Giacino et al. Neurology 2002 and Kalmar et al., Neuropsychol Rehabil 2005) between before and after stimulation (CRS-R post stimulation - CRS-R before stimulation). The CRS-R score is a qualitative and quantitative scales ranking predefined behaviors elicited by the patients in the following six subscales, auditory function, visual function, motor function, verbal and oromotor function, communication and wakefulness, the sum of which give a total score ranging from 0 to 23. Higher values of the scale mean a better state of consciousness. This change in state of consciousness will be compared between active stimulation and sham stimulation | Two time points: immediately before (baseline) and immediately after stimulation (post-stimulation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evoked response potential during local-global paradigm | Change of the ERPS recorded during the local global auditory paradigm (Bekinschtein et al., PNAS 2009) | Two time points: immediately before (baseline) and immediately after stimulation (post-stimulation) | 
| Resting state EEG | Change from baseline of the multivariate automatic classification of conscious state from EEG (Sitt et al., Brain et al. 2014) | Two time points: immediately before (baseline) and immediately after stimulation (post-stimulation) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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State of consciousness, tACS, tDCS, Global neuronal workspace, Brain injury