Effectiveness of tTIs for Improving Consciousness in Patients With DoC

• 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.
• 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.

• 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).

• 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.

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.