Effectiveness of tTIs for Improving Consciousness in Patients With DoC

Effectiveness of Theta-Burst Patterned Temporal Interference Stimulation for Improving Awareness in Patients With Disorders of Consciousness: A Multicenter Randomized Double-Blind Controlled Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Disorders of Consciousness; Minimally Conscious State; Vegetative State
• Intervention / Treatment: Device: Theta-burst Patterned Temporal Interference Stimulation (tTIs); Device: Sham Temporal Interference Stimulation

Detailed Description

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
• Enrollment (Estimated): 136
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chengwei Xu; Phone Number: 86+13450457096; Email: xuchweii@163.com
• Study Contact Backup: Name: Shiying Zhuang; Phone Number: 86+13505085958; Email: 13505085958@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510280
      • Recruiting
      • ZhuJiang Hospital of Southern Medical University
      • Contact: Chengwei Xu; Phone Number: 86+13450457096; Email: xuchweii@163.com
      • Contact: Shiying Zhuang; Phone Number: 86+13505085958; Email: 13505085958@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: 18 to 70 years old.
• Condition: Patients diagnosed with Disorders of Consciousness (DoC), including Vegetative State (VS)/Unresponsive Wakefulness Syndrome (UWS) or Minimally Conscious State (MCS) according to international guidelines.
• Duration: Disease course ≤ 1 year.Medical History: No history of neuro-psychiatric disorders prior to the brain injury.
• Handedness: Right-handed.Safety: No contraindications for tTIs, EEG, or MRI.
• Medication: Not currently using sedative drugs or medications that interfere with brain stimulation, such as Na2+ or Ca2+ channel blockers, or NMDA receptor antagonists.

Exclusion Criteria:

• Concurrent Trials: Participation in other non-invasive or invasive neuromodulation trials.
• Epilepsy: Uncontrolled epilepsy, defined as a seizure within 4 weeks prior to enrollment.
• Implants: Presence of metal implants in the skull, brain pacemakers, or implanted brain devices (e.g., spinal cord stimulator).
• Structural Issues: Skull defects at the site of stimulation that prevent the implementation of tTIs.
• Systemic Implants: Presence of systemic metal implants, such as cardiac pacemakers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: tTIs-Active Group; 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).	Device: Theta-burst Patterned Temporal Interference Stimulation (tTIs); 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.; Other Names: Respiratory-burst tTIs; TBS-tTIs; Non-invasive Deep Brain Stimulation
Sham Comparator: tTIs-Control Group; 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).	Device: Sham Temporal Interference Stimulation; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.

Secondary Outcome Measures

Outcome Measure	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.	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.

Collaborators and Investigators

• Sponsor: Zhujiang Hospital
• Investigators: Study Chair: Qiuyou Xie, Zhujiang Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Helpful Links

• Department of Rehabilitation Medicine, Zhujiang Hospital of Southern Medical University.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): May 31, 2028

Study Registration Dates

• First Submitted: March 18, 2026
• First Submitted That Met QC Criteria: April 13, 2026
• First Posted (Actual): April 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 20, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Thalamic Stimulation; Coma Recovery Scale-Revised (CRS-R); Temporal Interference Stimulation (tTIs); Theta-burst Patterned Stimulation; Deep Brain Stimulation (Non-invasive); Centromedian-parafascicular Nuclei (CM-pf); Perturbational Complexity Index (PCI)
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurobehavioral Manifestations; Neurocognitive Disorders; Brain Damage, Chronic; Unconsciousness; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Consciousness Disorders; Persistent Vegetative State
• Other Study ID Numbers: L20260312

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No