Phase-Locked Accelerated Intermittent Theta Burst Stimulation for Treatment-Resistant Depression

Development of Precision Medicine in the Field of iTBS on Patients With TRD Using Multimodal Functional Brain Imaging and Deep Learning

This study aims to investigate whether synchronizing accelerated intermittent theta burst stimulation (aiTBS) with an individual's ongoing brain activity improves treatment outcomes in adults with Treatment-Resistant Depression (TRD).

Participants were randomly assigned to one of two treatment groups:

1. Phase-locked aiTBS (PL-aiTBS): Magnetic stimulation was synchronized with a specific phase of ongoing brain activity measured using electroencephalography (EEG).
2. Random-phase aiTBS (RP-aiTBS): Participants received the same stimulation protocol without synchronization to a specific phase of brain activity.

Both groups received personalized stimulation based on their individual theta frequency. Treatment consisted of 10 sessions over three consecutive days, with three sessions on Day 1, three sessions on Day 2, and four sessions on Day 3 (3-3-4 schedule). Each session delivered 1,800 magnetic pulses, resulting in a total of 18,000 pulses per participant.

The primary objective was to compare changes in depressive symptoms between the two treatment groups. Depression severity was assessed using the 17-item Hamilton Depression Rating Scale (HAM-D) and the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (before the first stimulation session), mid-treatment (after the sixth session, Day 2), post-treatment (after the tenth session, Day 3), and follow-up (Day7).

Resting-state EEG recordings were collected before and after stimulation sessions to investigate treatment-related changes in neural oscillatory activity, phase-amplitude coupling, functional connectivity, and other neurophysiological measures, as well as their potential associations with improvements in depressive symptoms.

Study Overview

• Status: Completed
• Conditions: Treatment Resistant Depression (TRD)
• Intervention / Treatment: Device: Phase-Locked Accelerated Intermittent Theta Burst Stimulation; Device: Random-Phase Accelerated Intermittent Theta Burst Stimulation

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • Taipei City
    • Taipei, Taipei City, Taiwan, 112
      • Cheng Hsin General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults aged 18 to 70 years.
• Diagnosis of major depressive disorder (MDD).
• Inadequate response to at least two antidepressant trials of adequate dose and duration.
• A 17-item Hamilton Depression Rating Scale (HAM-D) score of 9 or higher.
• A Montgomery-Åsberg Depression Rating Scale (MADRS) score of 16 or higher.
• Willingness to participate in the study and provision of written informed consent.

Exclusion Criteria:

• Other psychiatric disorders or serious medical conditions.
• Psychotic disorders.
• Current illicit drug use or alcohol use disorder.
• Neurological or seizure disorders.
• Contraindications to transcranial magnetic stimulation (TMS), including cardiac pacemakers or metallic implants.
• Pregnancy or postpartum depression.
• Electroconvulsive therapy (ECT) within the previous 12 months.
• Unstable medical illness.
• Inability to comply with study procedures.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase-Locked Accelerated iTBS (PL-aiTBS); Participants received individualized accelerated intermittent theta burst stimulation (aiTBS) synchronized to a specific phase of ongoing frontal theta oscillations measured using EEG.	Device: Phase-Locked Accelerated Intermittent Theta Burst Stimulation; Stimulation was delivered to the left dorsolateral prefrontal cortex (DLPFC; F3) using an individualized theta-frequency-based iTBS protocol. Each participant received 10 sessions over three consecutive days (3-3-4 schedule), with 1,800 pulses per session (18,000 pulses total). Stimulation was synchronized to the trough of ongoing frontal theta oscillations using real-time EEG phase estimation.
Active Comparator: Random-Phase Accelerated iTBS (RP-aiTBS); Participants received the same individualized aiTBS protocol without phase-locked synchronization to ongoing frontal theta oscillations.	Device: Random-Phase Accelerated Intermittent Theta Burst Stimulation; Participants received the same individualized iTBS protocol targeting the left DLPFC (F3), consisting of 10 sessions over three consecutive days (3-3-4 schedule), with 1,800 pulses per session (18,000 pulses total). Stimulation was delivered without phase-locked synchronization to ongoing frontal theta oscillations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HAM-D Total Score	Depression severity was assessed using the 17-item Hamilton Depression Rating Scale (HAM-D), with total scores ranging from 0 to 52. Higher scores indicate greater depressive symptom severity. Changes in total scores from baseline were evaluated at each post-baseline assessment.	Baseline (Day 1), Mid-treatment (Day 2), Post-treatment (Day 3), and Follow-up (Day 7)
Change in MADRS Total Score	Depression severity was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), with total scores ranging from 0 to 60. Higher scores indicate greater depressive symptom severity. Changes in total scores from baseline were evaluated at each post-baseline assessment.	Baseline (Day 1), Mid-treatment (Day 2), Post-treatment (Day 3), and Follow-up (Day 7)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate Based on HAM-D	Treatment response was defined as a reduction of at least 50% in HAM-D total score relative to baseline. The response rate was calculated as the percentage of participants meeting this criterion at each assessment time point.	Mid-treatment (Day 2), Post-treatment (Day 3), and Follow-up (Day 7)
Response Rate Based on MADRS	Treatment response was defined as a reduction of at least 50% in MADRS total score relative to baseline. The response rate was calculated as the percentage of participants meeting this criterion at each assessment time point.	Mid-treatment (Day 2), Post-treatment (Day 3), and Follow-up (Day 7)
Remission Rate Based on HAM-D17	Remission was defined as a HAM-D17 total score of 7 or lower. The remission rate was calculated as the percentage of participants meeting this criterion at each assessment time point.	Mid-treatment (Day 2), Post-treatment (Day 3), and Follow-up (Day 7)
Remission Rate Based on MADRS	Remission was defined as a MADRS total score of 10 or lower. The remission rate was calculated as the percentage of participants meeting this criterion at each assessment time point.	Mid-treatment (Day 2), Post-treatment (Day 3), and Follow-up (Day 7)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Resting-State EEG Spectral Power	Resting-state electroencephalography (EEG) was recorded to assess changes in neural oscillatory activity following accelerated intermittent theta burst stimulation (aiTBS). Spectral power was quantified across conventional frequency bands, including delta, theta, alpha, beta, and gamma. Changes in spectral power from baseline were evaluated across treatment stages.	Before and after each of the 10 stimulation sessions over the 3-day treatment period (Days 1-3).
Change From Baseline in Resting-State EEG Phase-Amplitude Coupling	Resting-state EEG was analyzed to assess phase-amplitude coupling (PAC), reflecting the relationship between the phase of lower-frequency oscillations and the amplitude of higher-frequency activity. Changes in PAC strength from baseline were evaluated across treatment stages to characterize neurophysiological effects of aiTBS.	Before and after each of the 10 stimulation sessions over the 3-day treatment period (Days 1-3).
Resting-State EEG Functional Connectivity	Resting-state EEG functional connectivity was assessed using phase-based synchronization measures between brain regions. Changes in functional connectivity from baseline were evaluated across treatment stages to investigate stimulation-related alterations in neural synchronization.	Before and after each of the 10 stimulation sessions over the 3-day treatment period (Days 1-3).
Change From Baseline in Resting-State EEG Microstate Parameters	Resting-state EEG microstate analysis was used to characterize changes in the temporal dynamics of large-scale brain network activity. Microstate parameters included mean duration (ms), occurrence rate (events/s), time coverage (%), and transition probabilities between microstate classes. Changes in these parameters were evaluated across treatment sessions to investigate stimulation-related alterations in brain network dynamics.	Before and after each of the 10 stimulation sessions over the 3-day treatment period (Days 1-3).

Collaborators and Investigators

• Sponsor: Cheng-Hsin General Hospital
• Collaborators: National Yang Ming Chiao Tung University

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2024
• Primary Completion (Actual): April 15, 2026
• Study Completion (Actual): April 15, 2026

Study Registration Dates

• First Submitted: November 4, 2026
• First Submitted That Met QC Criteria: November 4, 2026
• First Posted (Actual): November 10, 2026

Study Record Updates

• Last Update Posted (Actual): November 10, 2026
• Last Update Submitted That Met QC Criteria: November 4, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Keywords: Major Depressive Disorder; Repetitive Transcranial Magnetic Stimulation; Treatment Resistant Depression (TRD); Accelerated Intermittent Theta Burst Stimulation; Phase-Locked Stimulation; EEG-Guided Neuromodulation
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant
• Other Study ID Numbers: (985)111A-63; (1126)113A-56 (Other Identifier: Cheng Hsin General Hospital Institutional Review Board)

Plan for Individual participant data (IPD)

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

IPD Plan Description

Individual participant data will not be shared publicly due to participant confidentiality and privacy considerations. No external IPD sharing is currently planned.

Drug and device information, study documents

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