Effectiveness of tTIs for Improving Consciousness in Patients With DoC

Official title

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

Overview

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.

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.

Interventions

• 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.
• 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).

Primary outcome measures

• Change in Coma Recovery Scale-Revised (CRS-R) Total Score [Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.]

Secondary outcome measures (5)

• Change from Baseline Resting-State EEG [Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.]
• Change from Baseline TMS-EEG [Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.]
• Change from Baseline in Mismatch Negativity (MMN) Amplitude [Time frame: Baseline and within 24 hours after the completion of the 5-day intervention.]
• Change from Baseline in P3a Amplitude [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 [Time frame: Baseline, and at 1 month, 3 months, and 6 months after the completion of the 5-day intervention.]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Zhujiang Hospital of Southern Medical University — Guangzhou

Publications

• 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. PMID 22466565
• 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. PMID 37872331
• 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. PMID 28575667

Identifiers

NCT: NCT07539740 · L20260312

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗