The goal of this clinical trial is to learn if a new type of brain stimulation called theta-burst patterned temporal interference stimulation (tTIs) works to improve awareness in people with disorders of consciousness (DoC). The main questions it aims to answer are: 1. Does tTIs help people with disorders of consciousness show more signs of awareness? 2. Does tTIs improve the brain's ability to process information and connect different brain areas? Is tTIs safe and easy for people with disorders of consciousness to tolerate? Researchers will compare a group receiving active tTIs to a group receiving a "sham" stimulation (a look-alike stimulation that delivers no real current) to see if the real stimulation works better. Participants will:Receive either active tTIs or sham stimulation twice a day for 5 consecutive days (total of 10 sessions). Undergo brain activity tests (EEG) and physical exams to check their level of awareness before and after the 5 days of treatment. Have their progress followed by researchers through phone calls at 1, 3, and 6 months after the treatment ends.
1. Study Overview and Mechanism This study is a multicenter, randomized, double-blind, sham-controlled clinical trial designed to evaluate the efficacy of theta-burst patterned temporal interference stimulation (tTIs) in patients with disorders of consciousness (DoC). The intervention targets the centromedian-parafascicular nuclei complex (CM-pf) of the thalamus, a critical hub for maintaining and modulating consciousness. By utilizing high-frequency carrier waves (\>1 kHz), tTIs creates a low-frequency interference field at the deep target without directly activating the superficial cortex, thereby improving spatial selectivity and patient comfort. 2. Intervention Protocol (Revised 5-Day Course) Participants will be randomly assigned to either the tTIs-active group or the tTIs-control group (1:1 ratio). (1) Active Group: Participants will receive tTIs with a 100 Hz pulse burst repeated at a 5 Hz (theta) rhythm. Stimulation will be administered for 30 minutes per session, twice daily, for 5 consecutive days (totaling 10 sessions). The current intensity is set at 2 mA per channel (total 4 mA). (2) Control (Sham) Group: Participants will receive sham stimulation using the same device setup, but the current will be set to 0 mA after a brief initial ramp-up to simulate the sensation. 3\. Assessment and Monitoring Individualized MRI-based navigation will be used for precise targeting of the CM-pf complex. Awareness levels will be assessed using the Coma Recovery Scale-Revised (CRS-R) at baseline and within 24 hours after the completion of the 5-day intervention. Neurophysiological changes will be monitored via high-density EEG (ABCD typing), TMS-EEG (Perturbational Complexity Index, PCI), and Event-Related Potentials (MMN and P3a). 4\. Follow-up and Safety Safety and tolerability will be monitored throughout the treatment. Long-term behavioral changes will be followed via telephone at 1, 3, and 6 months post-intervention to record CRS-R score variations Note on Study Duration: The attached protocol (PDF) is the currently institutional-approved version specifying a 10-day course. However, an ethics amendment is currently being processed to optimize the intervention to a 5-day course (10 sessions total) as reflected in this registration. All study procedures will follow the updated 5-day plan once the formal amendment letter is issued.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
136
The intervention targets the CM-pf complex using two pairs of high-frequency electrodes. Carrier frequency f1 = 2 kHz and f2 = 2.1 kHz to generate a 100 Hz interference. The stimulation is delivered in theta-burst patterns (3-pulse bursts at 100 Hz, repeated at 5 Hz). Sessions last 30 minutes, administered twice daily for 5 consecutive days (totaling 10 sessions). Current intensity is 2 mA per channel.
The sham group uses the same device and electrode configuration as the active group. The device delivers 0 mA current after a 30-second ramp-up to mimic skin sensation. Sessions last 30 minutes, administered twice daily for 5 consecutive days (totaling 10 sessions).
Zhujiang Hospital of Southern Medical University
Guangzhou, Guangdong, China
RECRUITINGChange in Coma Recovery Scale-Revised (CRS-R) Total Score
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.
Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.
Change from Baseline Resting-State EEG
Based on the assumption that specific cortical oscillations indicate varying levels of thalamocortical integrity that has defined four dynamic regimes that build on the mesocircuit model, each detectable with EEG and corresponding to a thalamo cortical state that indicates progressive circuit recovery.These EEG types are labeled A-D (hence, ABCD model) .Later types (C, D) denote more progressive recovery (i.e., are "better") than earlier types, (A, B), which correspond to a quiescent thalamic state.
Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.
Change from Baseline TMS-EEG
Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) is an effective way to measure cortical activity..In this study, PCIst, a derivative version of PCI, PCIst was chosen as an alternative, which estimates the complexity of TMS perturbations by signal decomposition and recurrence quantification analysis (RQA).
Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.
Change from Baseline in Mismatch Negativity (MMN) Amplitude
MMN is an event-related potential (ERP) reflecting the brain's automatic processing of auditory information. The amplitude is measured in microvolts (μV). According to clinical standards, a more negative MMN amplitude (e.g., from -0.5 μV to -1.5 μV ) indicates better pre-attentive sensory processing.
Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.
Change from Baseline in P3a Amplitude
P3a is an ERP reflecting the brain's automatic bottom-up orienting response to novel stimuli. The amplitude is measured in microvolts (μV). A higher positive amplitude indicates more efficient automatic attention-switching and improved cognitive processing.
Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.
Long-term Changes in Coma Recovery Scale-Revised (CRS-R) Total Score
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.
Time frame: Baseline, and at 1 month, 3 months, and 6 months after the completion of the 5-day intervention.
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