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

Participants received individualized accelerated intermittent theta burst stimulation (aiTBS) synchronized to a specific phase of ongoing frontal theta oscillations measured using EEG.

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.

Participants received the same individualized aiTBS protocol without phase-locked synchronization to ongoing frontal theta oscillations.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.