rTMS and EEG in DOC Patients

Study Overview
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Brief Summary
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Background: Severe brain injury could cause chronic disorders of consciousness (DOC). Treating DOC patients to improve recovery remains very challenging. A few randomized controlled studies have been published in the recent years, focusing on non-invasive brain stimulation (NIBS) treatments to improve patients' neurobehavioural functioning. Among NIBS, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can modulate cortical excitability, enhance neural plasticity, and induce strong neuromodulatory effects that outlast the period of stimulation. It is thought to modulate cortical activity and could therefore be effective for treating DOC patients. Currently, there is no unified protocol for rTMS in DOC patients and studies vary in many aspects. In this study, the investigators aim to improve the functional recovery of DOC patients following severe brain injury using rTMS in two multi-center double-blind studies. Methods/design: The investigators will recruit 90 DOC patients. Patients will have three rTMS sessions that will be randomized within patients in a crossover design: (i) one real stimulation on the left dorsolateral prefrontal cortex (DLPFC); (ii) one real stimulation on the left angular cortex (AG) and (iii) one sham stimulation. Sessions will be separated by at least 5 days washout period. Each stimulation session will last 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold - RMT). The RMT, i.e., the minimum stimulus intensity that generated a motor evoked potential response of at least 50μV at rest for 5 out of 10 trials, will be calculated for the stimulation target using single-pulses on the right abductor pollicis brevis muscle. After an interval of one week, a parallel design study will begin. Ninety patients will be randomly divided in two experimental groups and one sham group (30 patients per group). Stimulation will be performed for 20 working days once a day with the same stimulation parameters as in the crossover study. Primary outcome will be determined as behavioral response to treatment as measured using the Coma Recovery Scale - Revised (CRS-R). Resting-state high-density EEG will be also recorded to investigate the neurophysiological correlates by rTMS. Discussion: This study will contribute to define the role of rTMS for the treatment of DOC patients and characterise the neural correlates of its action. In addition, the investigators will define the responders' profile based on patients' characteristics and functional impairments and develop biomarkers of responsiveness using machine learning to categorize EEG signals according to clinical responsiveness to the treatment.

Official Title
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Repetitive Transcranial Magnetic Stimulation and Electroencephalography in Patients With Disorders of Consciousness

Conditions
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Disorder of Consciousness

Intervention / Treatment
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* Device: Sham Stimulation for Crossover Study
* Device: DLPFC Stimulation for Crossover Study
* Device: AG Stimulation for Crossover Study
* Device: Sham Stimulation for Parallel Study
* Device: DLPFC Stimulation for Parallel Study
* Device: AG Stimulation for Parallel Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: over 18 years old > 28 days post-injury patients with DOC due to acquired brain lesions classified according to international guidelines as UWS or MCS with repeated behavioural assessments with the CRS-R stable vital parameters no previous neurological deficits anterior to the brain lesions no pregnancy no contraindication for rTMS or EEG (e.g., uncontrolled epilepsy, that is, seizure within 4 weeks prior to enrollment, metallic implant in the skull, pacemaker, craniotomy under the stimulated site, implanted brain device, sensitive skin) no sedative drugs and drugs thought to interfere with brain stimulation such as Na or Ca channel blockers (e.g., carbamazepine) or NMDA receptor antagonists (e.g., dextromethorphan) no drugs or substances which have strong potential of seizure induction (imipramine, amitriptyline, doxepin, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, phencyclidine, ketamine, gamma-hydroxybutyrate, alcohol, and theophylline). All etiologies (e.g., trauma, stroke, and anoxia) Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: We will perform a 3 arm crossover trial. Subsequently, we will perform a longer protocol using a 3 arm parallel design.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Sham Stimulation Group for Crossover Study (DLPFC + AG)<br>Sham stimulation will be delivered on the dorsolateral prefrontal cortex (DLPFC) and on the angular cortex (AG) using a sham coil in the crossover study. | Device: Sham Stimulation for Crossover Study<br>* Stimulation will be delivered on the dorsolateral prefrontal cortex (DLPFC) or the angular cortex (AG) using a sham coil for 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold ) in one session. A single session will be conducted.<br>|
| Active Comparator: DLPFC Stimulation Group for Crossover Study<br>Real stimulation will be delivered on the left dorsolateral prefrontal cortex (DLPFC) using a real coil in the crossover study. | Device: DLPFC Stimulation for Crossover Study<br>* Stimulation will be delivered on the left dorsolateral prefrontal cortex (DLPFC) using a real coil for 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold ) in one session. A single session will be conducted.<br>|
| Active Comparator: AG Stimulation Group for Crossover Study<br>Real stimulation will be delivered on the left angular cortex (AG) using a real coil in the crossover study. | Device: AG Stimulation for Crossover Study<br>* Stimulation will be delivered on the left angular cortex (AG) using a real coil for 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold ) in one session. A single session will be conducted.<br>|
| Sham Comparator: Sham Stimulation Group for Parallel Study (DLPFC + AG)<br>Sham stimulation will be delivered on the dorsolateral prefrontal cortex (DLPFC) or on the angular cortex (AG) using a sham coil in the parallel study. | Device: Sham Stimulation for Parallel Study<br>* Stimulation will be delivered on the dorsolateral prefrontal cortex (DLPFC) or the angular cortex (AG) using a sham coil for 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold ) in one session. Twenty sessions will be conducted.<br>|
| Active Comparator: DLPFC Stimulation Group for Parallel Study<br>Real stimulation will be delivered on the left dorsolateral prefrontal cortex (DLPFC) using a real coil in the parallel study. | Device: DLPFC Stimulation for Parallel Study<br>* Stimulation will be delivered on the left dorsolateral prefrontal cortex (DLPFC) using a real coil for 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold ) in one session. Twenty sessions will be conducted.<br>|
| Active Comparator: AG Stimulation Group for Parallel Study<br>Real stimulation will be delivered on the left angular cortex (AG) using a real coil in the parallel study. | Device: AG Stimulation for Parallel Study<br>* Stimulation will be delivered on the left angular cortex (AG) using a real coil for 20 minutes with a frequency of 20Hz (train duration: 4s; inter-train interval: 26s; 3200 pulses at 80% of the resting motor threshold ) in one session. Twenty sessions will be conducted.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline Coma Recovery Scale - Revised for Crossover Study | The Coma Recovery Scale - Revised is a non-invasive behavioural examination. It contains 23 items hierarchically presented and divided in 6 sub-scales (auditory, visual, motor, oro-motor/verbal, communication and arousal). The score is based on presence or absence of behaviours in response to sensory stimulations. The quantitative score can be calculated by adding the best observed response in each sub-scale. The diagnosis is obtained from the quality of observed behaviours (e.g., the ability of visual tracking means that the patient is minimally conscious). The total score ranges between 0 and 23. Higher scores mean a better outcome. | immediately after each rTMS session | 
| Change from Baseline Coma Recovery Scale - Revised for Parallel Study 1 | The Coma Recovery Scale - Revised is a non-invasive behavioural examination. It contains 23 items hierarchically presented and divided in 6 sub-scales (auditory, visual, motor, oro-motor/verbal, communication and arousal). The score is based on presence or absence of behaviours in response to sensory stimulations. The quantitative score can be calculated by adding the best observed response in each sub-scale. The diagnosis is obtained from the quality of observed behaviours (e.g., the ability of visual tracking means that the patient is minimally conscious). The total score ranges between 0 and 23. Higher scores mean a better outcome. | immediately after the last rTMS session | 
| Change from Baseline Coma Recovery Scale - Revised for Parallel Study 2 | The Coma Recovery Scale - Revised is a non-invasive behavioural examination. It contains 23 items hierarchically presented and divided in 6 sub-scales (auditory, visual, motor, oro-motor/verbal, communication and arousal). The score is based on presence or absence of behaviours in response to sensory stimulations. The quantitative score can be calculated by adding the best observed response in each sub-scale. The diagnosis is obtained from the quality of observed behaviours (e.g., the ability of visual tracking means that the patient is minimally conscious). The total score ranges between 0 and 23. Higher scores mean a better outcome. | 1 week after the last rTMS session | 
| Change from Baseline Coma Recovery Scale - Revised for Parallel Study 3 | The Coma Recovery Scale - Revised is a non-invasive behavioural examination. It contains 23 items hierarchically presented and divided in 6 sub-scales (auditory, visual, motor, oro-motor/verbal, communication and arousal). The score is based on presence or absence of behaviours in response to sensory stimulations. The quantitative score can be calculated by adding the best observed response in each sub-scale. The diagnosis is obtained from the quality of observed behaviours (e.g., the ability of visual tracking means that the patient is minimally conscious). The total score ranges between 0 and 23. Higher scores mean a better outcome. | 2 week after the last rTMS session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline Resting-State EEG for Crossover Study 1 | EEG will be collected using a high-density EEG. Fifteen minutes of resting state will be performed. Resting-state EEG complexity and connectivity analyses will be performed at the individual and group level. The investigators will compute spectral measures as well as cortical functional connectivity using median spectral connectivity and graph-theoretic topology metrics such as clustering coefficient, path length, modularity and participation coefficient. | during each rTMS session | 
| Change from Baseline Resting-State EEG for Crossover Study 2 | EEG will be collected using a high-density EEG. Fifteen minutes of resting state will be performed. Resting-state EEG complexity and connectivity analyses will be performed at the individual and group level. The investigators will compute spectral measures as well as cortical functional connectivity using median spectral connectivity and graph-theoretic topology metrics such as clustering coefficient, path length, modularity and participation coefficient. | immediately after each rTMS session | 
| Change from Baseline Resting-State EEG for Parallel Study 1 | EEG will be collected using a high-density EEG. Fifteen minutes of resting state will be performed. Resting-state EEG complexity and connectivity analyses will be performed at the individual and group level. The investigators will compute spectral measures as well as cortical functional connectivity using median spectral connectivity and graph-theoretic topology metrics such as clustering coefficient, path length, modularity and participation coefficient. | immediately after the last rTMS session | 
| Change from Baseline Resting-State EEG for Parallel Study 2 | EEG will be collected using a high-density EEG. Fifteen minutes of resting state will be performed. Resting-state EEG complexity and connectivity analyses will be performed at the individual and group level. The investigators will compute spectral measures as well as cortical functional connectivity using median spectral connectivity and graph-theoretic topology metrics such as clustering coefficient, path length, modularity and participation coefficient. | 1 week after the last rTMS session | 
| Change from Baseline Resting-State EEG for Parallel Study 3 | EEG will be collected using a high-density EEG. Fifteen minutes of resting state will be performed. Resting-state EEG complexity and connectivity analyses will be performed at the individual and group level. The investigators will compute spectral measures as well as cortical functional connectivity using median spectral connectivity and graph-theoretic topology metrics such as clustering coefficient, path length, modularity and participation coefficient. | 2 week after the last rTMS session | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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disorders of consciousness, transcranial magnetic stimulation