Depression - Major Depressive Disorder, Posttraumatic Stress Disorder (PTSD)
Conditions
Keywords
PTSD, functional near-infrared spectroscopy, Heart Rate Variability; HRV, rTMS
Brief summary
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.
Detailed description
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.
Interventions
DEVICEProlonged Intermittent Theta-Burst Stimulation (prolonged iTBS)
Prolonged 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.
DEVICEHigh-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS)
High-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.
DEVICESham Transcranial Magnetic Stimulation
Sham 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.
Sponsors
Tri-Service General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Participants and outcome assessors will be blinded to treatment assignment. Active and sham stimulation will be delivered using coils identical in appearance and sound. The stimulation operator will not participate in clinical or physiological outcome assessments. Blinding codes will remain concealed until completion of data collection and database lock.
Intervention model description
This study uses a randomized, double-blind, sham-controlled, crossover design to examine the immediate neurophysiological effects of noninvasive brain stimulation in patients with posttraumatic stress disorder comorbid with major depressive disorder. Each participant receives both an active stimulation session (either prolonged intermittent theta-burst stimulation or high-frequency repetitive transcranial magnetic stimulation) and a sham stimulation session in a randomized sequence. A washout period of 7 days is implemented between sessions to minimize potential carryover effects. Blinding is maintained for participants and outcome assessors, while stimulation operators are not involved in outcome evaluation. Prefrontal cortical activity and autonomic nervous system responses are assessed immediately before and after each stimulation session.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Prefrontal Cortical Activation | Immediately before stimulation and immediately after each single stimulation session (active and sham), within each study period | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Autonomic Nervous System Activity | Immediately before stimulation and immediately after each single stimulation session (active and sham), within each study period | 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 | From the start of the first stimulation session through 7 days after the second stimulation session | 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 | Baseline, before the second stimulation session (Day 8), and 7 days after completion of the crossover phase | 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 | Baseline, before the second stimulation session (Day 8), and 7 days after completion of the crossover phase | 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. |
Countries
Taiwan
Contacts
CONTACTTao-Yi Chao, BS
PRINCIPAL_INVESTIGATORTien-Yu Chen, PhD, MD
Tri-Service General Hospital
Outcome results
None listed