This study aims to investigate the immediate neurophysiological and autonomic effects of two noninvasive brain stimulation protocols-prolonged intermittent theta-burst stimulation (prolonged iTBS) and high-frequency repetitive transcranial magnetic stimulation (HF-rTMS)-in patients with posttraumatic stress disorder (PTSD) comorbid with major depressive disorder (MDD). Using a randomized, double-blind, sham-controlled crossover design, changes in prefrontal cortical activity measured by functional near-infrared spectroscopy (fNIRS) and autonomic nervous system function measured by heart rate variability (HRV) will be assessed before and immediately after a single stimulation session.
Adults aged 18 to 65 years.
Clinical diagnosis of posttraumatic stress disorder (PTSD) according to DSM-5 criteria, confirmed by a board-certified psychiatrist.
Presence of comorbid major depressive disorder with stable clinical condition.
PTSD symptom severity defined as: PTSD Checklist for DSM-5, Chinese version (C-PCL-5) total score ≥ 31.
Lifetime diagnosis of schizophrenia spectrum disorders, bipolar disorder, or pervasive developmental disorders.
Alcohol or substance use disorder (excluding caffeine and nicotine) within the past 6 months.
Ongoing trauma-focused psychotherapy during the study period.
Prior exposure to repetitive TMS treatment exceeding five sessions.
Crossover
Prolonged Intermittent Theta-Burst Stimulation (prolonged iTBS)
DeviceProlonged intermittent theta-burst stimulation is delivered using a Magstim Rapid2 stimulator with a figure-eight coil targeting the right dorsolateral prefrontal cortex (DLPFC), localized with the Beam F4 method. Stimulation is administered at 80% of individual motor threshold using an intermittent theta-burst pattern (2 seconds on, 8 seconds off), consisting of 3-pulse bursts at 50 Hz repeated at 5 Hz. A single session lasts approximately 9.5 minutes and delivers a total of 1,800 pulses.
High-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS)
DeviceHigh-frequency rTMS is delivered using a Magstim Rapid2 stimulator with a figure-eight coil targeting the right dorsolateral prefrontal cortex (DLPFC), localized with the Beam F4 method. Stimulation follows the DASH protocol at 120% of motor threshold and 10 Hz frequency, with 4-second stimulation trains (40 pulses per train) followed by an 11-second inter-train interval, for a total of 75 trains. The single-session duration is approximately 18.75 minutes, delivering 3,000 pulses.
Sham Transcranial Magnetic Stimulation
DeviceSham stimulation is delivered using a placebo coil identical in appearance and acoustic output to the active coil but without producing a magnetic field sufficient to induce cortical stimulation. Sham sessions match the corresponding active stimulation protocol in duration and procedure to maintain blinding.
Change in Prefrontal Cortical Activation
Change in prefrontal cortical activation, measured as differences in oxygenated hemoglobin (HbO₂) concentration using multi-channel functional near-infrared spectroscopy (fNIRS). Measurements are obtained at rest immediately before and immediately after each stimulation session to assess acute neurophysiological effects of prolonged intermittent theta-burst stimulation and high-frequency repetitive transcranial magnetic stimulation.
Change in Autonomic Nervous System Activity
Autonomic nervous system activity assessed by heart rate variability (HRV) derived from 5-minute resting-state electrocardiographic recordings. HRV parameters are analyzed to evaluate acute changes in autonomic regulation following active versus sham brain stimulation.
Incidence of Adverse Events
Frequency and type of adverse events, including local discomfort, headache, dizziness, autonomic symptoms, or other reported events, assessed using standardized safety checklists immediately after stimulation, during 24-hour follow-up, and at post-study visit.
Change in PTSD Symptom Severity
Change in posttraumatic stress disorder symptom severity measured by the PTSD Checklist for DSM-5, Chinese version (C-PCL-5), used to monitor symptom stability and safety during the crossover study. This instrument consists of 20 items, each scored from 0 to 4, resulting in a total score range of 0-80. A cut-off score between 31 and 33 is commonly used to indicate clinically significant symptoms, with higher scores reflecting greater symptom severity.
Change in Depressive Symptom Severity
Change in depressive symptom severity assessed using the Patient Health Questionnaire-9 (PHQ-9), primarily for safety monitoring and detection of symptom exacerbation during the study period. The 9-item PHQ-9 utilizes a 4-point Likert scale ranging from 0 (not at all) to 3 (nearly every day), with a total score range of 0-27. Scores are interpreted as mild (10-14), moderate (15-19), or severe (≥ 20) depressive symptoms.
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