Effect of Individualized Repetitive Transcranial Magnetic Stimulation (rTMS) in Patients With Disorder of Consciousness
Phase: NA
Conditions: Disorder of Consciousness, Transcranial Magnetic Stimulation
Sponsor: Qiuyou Xie

Version number: 8.0; Version date: 2021.11.1
Research unit: Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University;
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Effect of Individualized Repetitive Transcranial Magnetic Stimulation (rTMS)
in Patients With Disorder of Consciousness
Title
Effect of Individualized Repetitive Transcranial Magnetic Stimulation (rTMS) in
Patients With Disorder of Consciousness
Application
Department of Rehabilitation, Zhujiang Hospital, Southern Medical University
Purpose
Primary objectives: To examine whether individualized rTMS is more effective to
improve CRS-R scores in DoC patients than the rTMS-sham control.
Secondary objective : (1)To examine whether individualized rTMS is more effective
to improve relative spectral power of EEG in DoC patients than the rTMS-sham
control;
(2)To examine whether individualized rTMS is more effective to improve functional
connectivity of EEG in DoC patients than the rTMS-sham control;
(3)To evaluate the safety of rTMS in DoC patients.
Research
hypothesis
rTMS applied on the Individual-targeted selection area will improve DOC patients’
level of consciousness
Design
Exploratory single-center, cross-over, double-blind, randomized controlled trial
Sample size
This is a crossover pilot study. The CRS-R total score after two-stage treatments will
be considered as the primary efficacy outcome, while high-density EEG analysis
(relative spectral power and functional connectivity) will be the secondary outcome.
In this context[1], the sample size calculation will be based on an expected difference
between the treatment groups of 20%, setting a significance level of 0.05% and a
power of 80%. Considering patients’ compliance and approximately 20% dropout
rate during the study, the final sample size of 30 participants is needed. We consider
this is an achievable sample size and adequate to allow for the dropout rate while still
leaving a reasonable final sample.
Eligibility
Inclusion Criteria:
1) acquired brain injuries less than 1 year and more than 28 days in DOC;
2) no medical history of neuropsychiatric diseases;
3) no contraindications for rTMS or EEG, no sedatives in use or other drugs that
might interfere with brain stimulation, such as Na+ or Ca2+ channel blockers or
NMDA receptor antagonists;
4) stable state of disease and vital signs;
5) the families of the patients volunteered the patient to participate in the study and
provided signed informed consent;
6) the integrity of the individualized stimulation target cortex are verified by
MRI.Exclusion criteria:
Exclusion Criteria:

Version number: 8.0; Version date: 2021.11.1
Research unit: Department of Rehabilitation Medicine, Zhujiang Hospital, Southern Medical University;
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1) patients in other non-invasive or invasive neuroregulation trials;
2) motor evoked potential (MEP) in M1 region cannot be induced by TMS pulse;
3) uncontrolled epilepsy, seizure within 4 weeks before enrollment;
4) metallic implant in the skull, pacemaker, craniotomy under the stimulated site,
implanted brain device.
Major
interventions
10Hz rTMS
Evaluating
indicator
Primary outcome: The Coma Recovery Scale-Revised (CRS-R), a total of 23 points,
is widely used to define the level of consciousness and assess neurobehavioral
recovery of patients with DOC. It is based on six subscales that assess auditory (4
points), visual (5 points), motor (6 points), motor/speech (3 points), communication
(2 points), and arousal processes (3 points). Each item of CRS-R is in good
agreement with the diagnostic and differential diagnostic criteria of VS/UWS, MCS
and EMCS. The higher scores mean a better outcome.
Secondary outcome: EEG will be acquired from 66 channels with positions of the
International 10-20 System for 10 mins. The relative spectral power (RSP) and
functional connectivity (FC) of participants will be calculated by the selected
artifact-free EEG epochs at five frequency bands: δ (1-4 Hz), θ (4-8 Hz), α (8-13 Hz),
β (13-30 Hz), and γ (30-45 Hz). The investigators will compute off-line analysis to
calculate RSP and FC.
Statistical
method
Statistical hypothesis: Parametric hypothesis test
1. Group mean CRS-R scores before and after active/sham rTMS were analyzed by
ANOVA with a two-stage crossover design;
2. The relative spectrum power and coherence before and after active/sham rTMS
were analyzed by ANOVA with a two-stage crossover design;
3. If the overall means were unequal across each group, pairwise comparisons were
performed using the SNK-q test;
4. Select the channel of interest at the average level of the active/sham rTMS group,
extract the relative spectrum energies of each frequency band, and use the
paired-sample t-test to compare the differences between the relative spectrum
energies of the two groups;
5. Pairwise channel coherence was calculated along each channel at the mean
frequency band of active/sham rTMS group using the paired sample t-test to compare
the differences between the specific channel coherence of the two component pairs;
Non-parametric test was used if the normal distribution is not satisfied.
Effectiveness test: The efficiency test adopts the 2 test of paired R x C contingency
table data. If the sample size is <40 or T <1, the Fisher exact probability method of
four table data is used;

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#Table 1 Schematic timeline of the study
TIMEPOINT
Enrollment
Allocation
Post-allocation
Close-out
-t1
t0
t1
t2
t3
t4
t5
t6
Enrolment
×
Eligibility screen
×
Informed consent
×
Demographic information1)
×
Medical history2)
×
Vital signs3)
×
×
×
Randomization
×
Allocation
×
Interventions
Active rTMS
×
Washout
×
Sham rTMS
×
Washout
×
Assessments
CRS-R4)
×
×
×
×
EEG recording5)
×
×
×
×
Adverse events
×
×
×
×
×
×
1) Demographic information includes the patients date of birth, sex and race;
2) Medical history includes DoC resulting from brain injury and other clinically significant past and present
medical history;
3) Vital signs include blood pressure, pulse rate, respiration and body temperature;
4) CRS-R: Coma Recovery Scale-Revised;
5) EEG: Electroencephalogram.
Reference：
[1]
Steven-A Julious. Sample size of 12 per group rule of thumb for a pilot study[J]. Pharmaceutical Statistics,
2005, 4(4): 287-291.