Cerebellar iTBS in Patients With Disorders of Consciousness

Study Overview
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Brief Summary
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Previous studies showed the excitatory effect of cerebellar transcranial magnetic stimulation(TMS) on motor cortex.Investigator evaluate the effects of bilateral cerebellar TMS on Coma Recovery Scale-Revised (CRS-R) scores in patients with disorders of consciousness(DOC) in a randomized, double-blinded, sham-controlled, crossover experimental design.

Detailed Description
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Patients with disorders of consciousness(DOC) resulting from severe brain injury greatly burden caregivers, health care facilities, and society. However, there is no definitively effective treatment for patients with DOC. Previous studies showed the excitatory effect of cerebellar transcranial magnetic stimulation(TMS) on motor cortex through the dentato-rubro-thalamic tract. Investigators aim to validate the effect of 5 consecutive sessions of intermittent theta-burst stimulation(iTBS) of bilateral cerebellar on level of consciousness of patients in vegetative state(VS)/unresponsive awakening state(UWS)or minimally conscious (MCS) state in a randomized, double-blinded, sham-controlled, crossover study. TMS is a non-invasive and safe neural regulatory approach that is widely used in depression, schizophrenia, stroke, and Parkinson's disease.

Official Title
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MRI-navigated Cerebellar Intermittent Theta-Burst Stimulation（iTBS）in Patients With Disorders of Consciousness

Conditions
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Disorder of Consciousness, Vegetative State, Minimally Conscious State

Intervention / Treatment
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* Device: iTBS stimulation
* Device: sham stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: VS/UWS or MCS according to diagnostic criteria Age ≥18 years Written informed consent obtained Exclusion Criteria: Patients in coma Brain injury <1week Presence of metallic hardware in close contact to the discharging coil（such as cochlear implants, or an Internal Pulse Generator or medication pumps） Patients with high risks according to standard questionnaire to screen transcranial magnetic stimulation(TMS) candidates

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: Crossover Assignment
Interventional Model Description: A randomized double-blinded, sham-controlled, crossover study design is used to investigate the effects of bilateral cerebellar iTBS on patients with prolonged DOC in a VS/UWS or in a MCS state. We prospectively recruit 44 patients in VS/UWS or MCS state. Each patient will receive bilateral cerebellar iTBS and sham stimulation in random order, one session per day for 5 consecutive days, separated by a 5-day washout. TMS is performed by personalized neuro-navigation to target the cerebellar dentate nucleus. The primary research outcome is whether bilateral cerebellar iTBS, as compared to sham stimulation, will improve consciousness (as measured by changes in CRS-R total scores) in VS/UWS and MCS patients. Secondary research outcome is evaluated by Electroencephalogram(EEG), CRS-R subscore, and Glasgow Outcome Scale-Extended(GOSE) score at 3 and 6 months of enrollment.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: iTBS stimulation<br>Participants receive iTBS stimulation of bilateral cerebellar one session per day for 5 consecutive days. | Device: iTBS stimulation<br>* standard iTBS burst pattern:3 pulses at 50-Hz repeated at a rate of 5-Hz; 20 trains of 10 bursts given with 8-s intervals. 600 pulses on both side of cerebellar with an interval of 5 minutes.<br>|
| Sham Comparator: sham stimulation<br>Participants receive sham stimulation of bilateral cerebellar one session per day for 5 consecutive days. | Device: sham stimulation<br>* Participants receive a sound stimulation with the same pattern with iTBS stimulation,but without magnetic field<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CRS-R Total Scores | Whether bilateral cerebellar iTBS would improve consciousness in enrolled patients. CRS-R total score is used to measure level of consciousness of disorder.The coma recovery scale-revised(CRS-R) consists of six subscales addressing auditory, visual, motor, verbal, communication, and arousal functions.The lowest item on each subscale represents reflexive activity and the highest item represents cognitively mediated behavior. Maximum scores of each subscale are summed to obtain the total score (from 0 to 23).The score for each subscale is based on the presence or absence of a specific behavioral response to a sensory stimulus (higher scores are better). | Baseline and directly after 5 sessions of iTBS and sham stimulation（5 days） | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CRS-R Subscale Scores | The coma recovery scale-revised(CRS-R) consists of six subscales addressing auditory, visual, motor, verbal, communication, and arousal functions.The lowest item on each subscale represents reflexive activity and the highest item represents cognitively mediated behavior. The score for each subscale is based on the presence or absence of a specific behavioral response to a sensory stimulus (higher scores are better). | Baseline and directly after 5 sessions of iTBS and sham stimulation（5 days） | 
| Change of Influence on EEG | EEG will be monitored on the first and fifth sessions of both iTBS and sham stimulation, from 20 minutes before the start of stimulation until 30 minutes after the end of stimulation. | Baseline and after 5 sessions of iTBS and sham stimulation（5 days） | 
| Influence of time since insult on the results | Glasgow Outcome Scale-Extended(GOSE) score will be assessed at 3 and 6 months of enrollment. | Participants will be followed for the duration of 0.5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TMS, cerebellar, iTBS, DOC, MCS, VS