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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:
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) 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| tTIs-Active Group | Experimental | Participants will receive active theta-burst patterned temporal interference stimulation (tTIs) targeting the centromedian-parafascicular nuclei complex (CM-pf). The stimulation consists of 3-pulse bursts at 100 Hz, repeated at a 5 Hz (theta) rhythm. Treatment will be administered for 30 minutes per session, twice daily, for 5 consecutive days (totaling 10 sessions). The current intensity is 2 mA per channel (total 4 mA). |
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| tTIs-Control Group | Sham Comparator | Participants will receive sham stimulation using the same device and electrode placement as the active group. The device will deliver 0 mA current after a brief initial ramp-up period to mimic the skin sensation. The procedure lasts 30 minutes per session, twice daily, for 5 consecutive days (totaling 10 sessions). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Theta-burst Patterned Temporal Interference Stimulation (tTIs) | Device | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Change 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. | Baseline and within 24 hours after the completion of the 5-day intervention. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Chengwei Xu | Contact | 86+13450457096 | xuchweii@163.com | |
| Shiying Zhuang | Contact | 86+13505085958 | 13505085958@163.com |
| Name | Affiliation | Role |
|---|---|---|
| Qiuyou Xie | Zhujiang Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Zhujiang Hospital of Southern Medical University | Recruiting | Guangzhou | Guangdong | 510280 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22466565 | Background | Yasuno T, Okamoto H, Nagai M, Kimura S, Yamamoto T, Nagano K, Furubayashi T, Yoshikawa Y, Yasui H, Katsumi H, Sakane T, Yamamoto A. In vitro study on the transport of zinc across intestinal epithelial cells using Caco-2 monolayers and isolated rat intestinal membranes. Biol Pharm Bull. 2012;35(4):588-93. doi: 10.1248/bpb.35.588. | |
| 37872331 |
| Label | URL |
|---|---|
| Department of Rehabilitation Medicine, Zhujiang Hospital of Southern Medical University. | View source |
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The raw neurophysiological data (EEG) collected in this study are classified as human genetic resources under national regulations. To ensure participant privacy and data security, the individual participant data (IPD) will not be shared with outside researchers.
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| ID | Term |
|---|---|
| D003244 | Consciousness Disorders |
| D018458 | Persistent Vegetative State |
| ID | Term |
|---|---|
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
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This is a multicenter, randomized, double-blind, sham-controlled parallel-group trial. Participants are randomly assigned to either the tTIs-active group or the tTIs-control group in a 1:1 ratio.
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| Sham Temporal Interference Stimulation | Device | 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). |
|
| 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). | 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. | 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. | 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. | Baseline, and at 1 month, 3 months, and 6 months after the completion of the 5-day intervention. |
| Wei H, Zhang L, Wang Z. Four antibiotics and copper interactive effects on the growth and physiological characteristics of Hydrilla verticillata (L.f.) Royle. Environ Sci Pollut Res Int. 2023 Nov;30(55):117531-117544. doi: 10.1007/s11356-023-30415-w. Epub 2023 Oct 23. |
| 28575667 | Background | Grossman N, Bono D, Dedic N, Kodandaramaiah SB, Rudenko A, Suk HJ, Cassara AM, Neufeld E, Kuster N, Tsai LH, Pascual-Leone A, Boyden ES. Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields. Cell. 2017 Jun 1;169(6):1029-1041.e16. doi: 10.1016/j.cell.2017.05.024. |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D001925 | Brain Damage, Chronic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D014474 | Unconsciousness |