¹The Hong Kong Polytechnic University, Rehabilitation Sciences, Hong Kong, China, ²School of Medicine, Tongji University, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Shanghai, China, ³The Hong Kong Polytechnic University, Mental Health Research Center (MHRC), Hong Kong, China

Background: Stanford Neuromodulation Therapy (SNT) has achieved rapid remission in treatment-resistant depression through an accelerated, high-dose iTBS schedule. While this implies a cumulative induction of synaptic plasticity, the acute neurophysiological mechanisms of a single session (1800 pulses)—the fundamental building block of this effect—remain elusive. Investigating the “silent” left DLPFC is challenging; however, concurrent TMS-EEG provides a direct, in situ readout of cortical reactivity, bypassing peripheral pathways. Thus, this technique is uniquely positioned to unveil the dynamic evolution of Transcranial Evoked Potentials (TEPs) induced by high-dose iTBS.

Aims & Objectives: The present study utilizes TMS-EEG to characterize the specific acute neurophysiological modulation of the left DLPFC induced by a single high-dose iTBS session in healthy volunteers.

Method: Twenty-two healthy, right-handed males (aged 20–30) completed this randomized, sham-controlled, crossover study (one-week washout). Targeting of the left DLPFC (MNI: -38, 44, 26) used neuronavigation to ensure spatial consistency. Concurrent 64-channel TMS-EEG was recorded pre- and post-intervention (100 pulses at 100% RMT; jittered ISI). White noise masked coil clicks. The active intervention was a single high-dose iTBS session (1800 pulses; 50Hz triplets at 5Hz, 70% RMT), while the sham condition utilized the placebo side of the same A/P coil to replicate sensory cues without cortical stimulation. EEG data were preprocessed using the TESA pipeline. TEP amplitudes were extracted from a left frontal ROI (F1, F3, FC1, FC3) for N40 (40–45ms), P60 (50–70ms), N100 (95–135ms), and P200 (160–240ms). Paired t-tests assessed pre-to-post changes within conditions.

Results: Paired t-tests in the active group revealed a significant modulation of the early N40 amplitude (t₍₂₁₎ = 2.26, p = .035), indicating an acute alteration in GABA-A mediated cortical inhibition. Regarding temporal dynamics, the active intervention induced significant delays in peak latencies for both P60 (t₍₂₁₎ = -2.36, p = .028) and N100 (t₍₂₁₎ = -2.39, p = .026). Crucially, no significant pre-to-post changes were observed in the sham group for any TEP amplitudes or latencies (all p > .05). This dissociation confirms that the observed neurophysiological modulations were specific to the high-dose iTBS intervention rather than sensory confounds or placebo effects.

Discussion & Conclusions: This study provides the sham-controlled evidence that a single high-dose iTBS session induces specific neurophysiological modulation in the left DLPFC. The selective enhancement of N40 amplitude likely reflects a homeostatic upregulation of GABA-A mediated inhibition (i.e., homeostatic plasticity) triggered to counterbalance the massive excitatory drive of the high-dose protocol. These findings suggest that the rapid efficacy of SNT may stem from engaging these powerful compensatory mechanisms, thereby rapidly resetting the cortical Excitation/Inhibition (E/I) balance in depression-implicated circuits.