To Investigate the Change of Brain and Autonomic Function From Different Protocols of Repeated Transcranial Magnetic Stimulation Therapy for Patients With Post-traumatic Stress Disorder Comorbid Major Depressive Disorder

The Pathophysiological Mechanisms and Novel Treatments Linking Stress and Mental Health Conditions -To Investigate the Change of Brain and Autonomic Function From Different Protocols of Repeated Transcranial Magnetic Stimulation Therapy for Patients With Post-traumatic Stress Disorder Comorbid Major Depressive Disorder: a Randomized, Double-blind, Crossover Study

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.

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition frequently accompanied by depressive symptoms and autonomic dysregulation. Although pharmacotherapy and psychotherapy are standard treatments, many patients show limited response or experience significant side effects. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising noninvasive neuromodulatory intervention; however, the optimal stimulation protocol for PTSD remains unclear.

This randomized, double-blind, crossover study is designed to compare the immediate effects of prolonged iTBS and HF-rTMS applied to the right dorsolateral prefrontal cortex (DLPFC) on brain function and autonomic regulation in adults with PTSD comorbid with MDD. Each participant will receive one active stimulation session (either prolonged iTBS or HF-rTMS) and one sham stimulation session in a randomized order, separated by a 7-day washout period to minimize carryover effects.

Prefrontal cortical activation will be measured using multi-channel functional near-infrared spectroscopy (fNIRS), and autonomic nervous system activity will be assessed using heart rate variability (HRV) analysis derived from electrocardiographic recordings. The primary objective is to characterize protocol-specific neurophysiological response patterns and identify quantifiable biomarkers of brain stimulation response that may inform future personalized treatment strategies for PTSD with comorbid depression.

Inclusion Criteria:

1. Adults aged 18 to 65 years.
2. Clinical diagnosis of posttraumatic stress disorder (PTSD) according to DSM-5 criteria, confirmed by a board-certified psychiatrist.
3. Presence of comorbid major depressive disorder with stable clinical condition.
4. PTSD symptom severity defined as: PTSD Checklist for DSM-5, Chinese version (C-PCL-5) total score ≥ 31.
5. Depressive symptom severity defined as: Patient Health Questionnaire-9 (PHQ-9) total score ≥ 10.
6. Stable psychiatric medication regimen for at least 4 weeks prior to enrollment, or medication-free.
7. Ability to understand the study procedures and provide written informed consent.
8. Normal or corrected-to-normal vision and hearing.
9. Ability to comply with study procedures and visit schedule.

Exclusion Criteria:

1. Lifetime diagnosis of schizophrenia spectrum disorders, bipolar disorder, or pervasive developmental disorders.
2. Alcohol or substance use disorder (excluding caffeine and nicotine) within the past 6 months.
3. Ongoing trauma-focused psychotherapy during the study period.
4. Prior exposure to repetitive TMS treatment exceeding five sessions.
5. Current or recent (within the past year) suicidal ideation or behavior, defined as: PHQ-9 item 9 score ≥ 1, confirmed by clinical psychiatric evaluation.
6. Self-injurious behavior requiring medical attention within the past 3 months.
7. History of epilepsy, seizure disorder, or family history of epilepsy.
8. Significant neurological disorders, severe traumatic brain injury, or history of brain surgery.
9. Presence of implanted metallic or electronic medical devices (e.g., pacemakers, cochlear implants, neurostimulators).
10. Uncontrolled major medical illnesses or severe cardiovascular disease.
11. Pregnancy or breastfeeding.
12. Skin lesions or infections at the stimulation site.
13. Use of medications known to significantly lower seizure threshold (e.g., tricyclic antidepressants or certain analgesics).
14. Any condition deemed by the investigator to render the participant unsuitable for rTMS.