A Phase 2 interventional study of Active MRI-Guided intermittent theta burst stimulation (iTBS) and Sham MRI-Guided intermittent theta burst stimulation (iTBS) in Stress Disorders, Post-Traumatic, sponsored by VA Office of Research and Development. Not yet recruiting at 1 site in United States. Open to participants aged 18 Years to 60 Years. Per ClinicalTrials.gov, last updated 2026-10-21.
Sponsored by VA Office of Research and Development · Phase 2, Interventional, and Treatment
The proposed study will test whether magnetic resonance imaging (MRI)-guided transcranial magnetic stimulation (TMS) can reduce posttraumatic stress disorder (PTSD) symptoms in Veterans. TMS is a noninvasive treatment that uses magnetic pulses to change activity in specific areas of the brain. In this study, MRI will be used to personalize the location of TMS based on brain networks involved in detecting and responding to important or threatening information. Veterans with PTSD will be randomly assigned to receive either active or non-active control TMS over 20 sessions. The study will examine whether active TMS improves PTSD symptoms and changes the brain circuits targeted by treatment. If effective, this approach may help improve and personalize TMS treatment for Veterans with PTSD. This project supports the Department of Veterans Affairs mission of developing more effective, biologically informed treatments for Veterans with PTSD.
Posttraumatic stress disorder (PTSD) is a common and debilitating condition among Veterans. Although evidence-based psychological and pharmacological treatments are effective for many individuals, a substantial proportion of patients continue to experience clinically significant symptoms after treatment, underscoring the need for alternative interventions. PTSD is associated with alterations in brain circuits involved in threat detection, emotional regulation, cognitive control, and physiological arousal. One brain network implicated in these processes is the salience network, particularly the anterior insula, which contributes to detecting and responding to behaviorally important internal and external information.
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that uses magnetic pulses to influence activity in targeted brain regions. Previous studies suggest that rTMS targeting the dorsolateral prefrontal cortex (DLPFC) may reduce PTSD symptoms, but treatment effects vary substantially across individuals. One potential source of this variability is that standard anatomical stimulation locations may not consistently engage the same PTSD-relevant functional brain circuits across individuals. Functional magnetic resonance imaging (fMRI)-guided neuronavigation provides an approach for personalizing stimulation locations based on each individual's functional brain organization.
The purpose of this study is to determine whether personalized, neuronavigation-guided rTMS targeting a brain circuit associated with salience network function can improve PTSD symptoms and modulate PTSD-relevant neural circuitry in Veterans. Each participant's stimulation location within the right DLPFC will be personalized using resting-state fMRI based on the functional connectivity between the right DLPFC and right anterior insula, a key region of the salience network.
The study is a double-blind, randomized controlled trial that will enroll up to 82 Veterans with PTSD. Participants will be randomly assigned to receive either active rTMS or control (sham) stimulation. Treatment will consist of 20 stimulation sessions delivered over four weeks. Participants will complete MRI assessments before and after treatment to evaluate changes in salience network activity and functional connectivity.
The study will evaluate whether active rTMS, compared with control stimulation, produces improvements in PTSD symptoms and changes in neural and physiological measures associated with PTSD. In addition to clinical symptoms and fMRI measures, the study will assess autonomic nervous system function using measures including heart rate variability and skin conductance response. The overarching hypothesis is that personalized stimulation of a DLPFC location functionally connected with the anterior insula will modulate salience network circuitry and that these neural changes will be associated with improvement in PTSD symptoms.
This study is designed to clarify the neural mechanisms through which rTMS may affect PTSD symptoms and to determine whether individualized, fMRI-guided targeting can reliably engage PTSD-relevant brain circuitry. Findings may help inform the development of more precise and mechanistically informed neuromodulation treatments for Veterans with PTSD.
2,284 studies on the registry are indexed under Stress Disorders, Post-Traumatic; 557 are open to participants now.
This study's planned enrollment of 84 is above the median of 70 across 1,897 interventional studies indexed under Stress Disorders, Post-Traumatic.
Browse Stress Disorders, Post-Traumatic studies →VA Office of Research and Development is the lead sponsor of 1,767 studies on the registry; 394 are open to participants now.
Of its 209 completed or terminated interventional studies of FDA-regulated products, 183 (88%) have results posted.
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Participants randomized to this arm will receive 20 sessions of active intermittent theta burst stimulation (iTBS), scheduled 5 days per week for 4 weeks. When needed because of scheduling interruptions, the 20 sessions may be completed within up to 6 weeks. Treatment will be delivered to an individualized right dorsolateral prefrontal cortex target identified using MRI/fMRI-based functional connectivity.
Device: Active MRI-Guided intermittent theta burst stimulation (iTBS)
Participants randomized to this arm will receive 20 sessions of sham intermittent theta burst stimulation (iTBS), scheduled 5 days per week for 4 weeks. When needed because of scheduling interruptions, the 20 sessions may be completed within up to 6 weeks. The same individualized MRI/fMRI-guided treatment location and treatment schedule will be used as in the active arm.
Device: Sham MRI-Guided intermittent theta burst stimulation (iTBS)
Active intermittent theta burst stimulation (iTBS) will be delivered using the MagVenture TMS Therapy System. An individualized right dorsolateral prefrontal cortex treatment target will be identified using MRI/fMRI-based functional connectivity with the right anterior insula of the salience network. The Brainsight neuronavigation system will be used to localize the individualized target and guide TMS coil positioning. Each treatment session will consist of 600 pulses. Participants will receive 20 treatment sessions, scheduled 5 days per week for 4 weeks. When needed because of scheduling interruptions, the 20 sessions may be completed within up to 6 weeks.
Also known as: MagVenture TMS Therapy System
Sham intermittent theta burst stimulation (iTBS) will be delivered using the MagVenture TMS Therapy System. An individualized right dorsolateral prefrontal cortex treatment target will be identified using MRI/fMRI-based functional connectivity with the right anterior insula of the salience network. The Brainsight neuronavigation system will be used to localize the individualized target and guide TMS coil positioning. Sham stimulation will use the same treatment location, session structure, and treatment schedule as the active condition and is designed to mimic the treatment experience without delivering active therapeutic stimulation. Participants will receive 20 sham treatment sessions, scheduled 5 days per week for 4 weeks. When needed because of scheduling interruptions, the 20 sessions may be completed within up to 6 weeks.
Also known as: MagVenture TMS Therapy System
Change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Severity Score
The CAPS-5 is a clinician-administered interview used to assess PTSD symptoms according to DSM-5 criteria. Total PTSD symptom severity scores range from 0 to 80, with higher scores indicating greater PTSD symptom severity. The outcome is change in CAPS-5 total severity score from baseline to the post-treatment assessment.
Time frame: Baseline and immediately following completion of treatment (approximately Week 4-6)
Change in Anterior Insula Resting-State Functional Connectivity
Resting-state functional MRI will be used to assess functional connectivity of the anterior insula (aINS). The aINS seed will be defined using the region used for personalized TMS targeting. Functional connectivity is measured as the relationship between the aINS blood-oxygen-level-dependent (BOLD) time series and BOLD time series to the brain. Higher association means higher functional connectivity. The outcome is change in aINS resting-state functional connectivity from the pre-treatment to post-treatment MRI assessment.
Time frame: Baseline and immediately following completion of treatment (approximately Week 4-6)
Change in Brain Activation During the Anticipation Task
Task-based functional MRI will be used to assess blood-oxygen-level-dependent (BOLD) activation during the Anticipation task. Higher BOLD response indicates greater activation. The outcome is change in task-related BOLD activation from the pre-treatment to post-treatment MRI assessment.
Time frame: Baseline and immediately following completion of treatment (approximately Week 4-6)
Change in Heart Rate Variability
Photoplethysmography (PPG) will be used to derive inter-beat intervals for heart rate variability (HRV) analysis. HRV will be quantified as an index of beat-to-beat variation in cardiac activity. The outcome is change in HRV from the pre-treatment to post-treatment assessment.
Time frame: Baseline and immediately following completion of treatment (approximately Week 4-6)
Differential Change in CAPS-5 PTSD Symptom Cluster Severity
The CAPS-5 assesses PTSD symptoms across four DSM-5 symptom clusters: intrusion, avoidance, negative alterations in cognition and mood, and alterations in arousal and reactivity. Symptom severity within each cluster is calculated by summing the CAPS-5 severity ratings for symptoms within that cluster. High scores indicate greater symptom severity. Changes in symptom-cluster severity from baseline to post-treatment will be examined to determine whether treatment effects differ across PTSD symptom clusters.
Time frame: Baseline and immediately following completion of treatment (approximately Week 4-6)
Change in Patient Health Questionnaire-9 (PHQ-9) Total Score
The Patient Health Questionnaire-9 (PHQ-9) is a 9-item self-report measure of depressive symptom severity. Total scores range from 0 to 27, with higher scores indicating greater depressive symptom severity. Change in PHQ-9 total score will be assessed from baseline to post-treatment and at 4-week and 8-week post-treatment follow-up assessments.
Time frame: Baseline, post-treatment (Week 4, up to Week 6), and 4-week and 8-week post-treatment follow-ups.
Change in Generalized Anxiety Disorder-7 (GAD-7) Total Score
The Generalized Anxiety Disorder-7 (GAD-7) is a 7-item self-report measure of anxiety symptom severity. Total scores range from 0 to 21, with higher scores indicating greater anxiety symptom severity. Change in GAD-7 total score will be assessed from baseline to post-treatment and at 4-week and 8-week post-treatment follow-up assessments.
Time frame: Baseline, post-treatment (Week 4, up to Week 6), and 4-week and 8-week post-treatment follow-ups
Change in PTSD Checklist for DSM-5 (PCL-5) Total Score
The PTSD Checklist for DSM-5 (PCL-5) is a 20-item self-report measure of PTSD symptom severity. Total scores range from 0 to 80, with higher scores indicating greater PTSD symptom severity. Change in PCL-5 total score will be assessed from baseline to post-treatment and at 4-week and 8-week post-treatment follow-up assessments.
Time frame: Baseline, post-treatment (Week 4, up to Week 6), and 4-week and 8-week post-treatment follow-ups
Plan to share: Yes — Coded individual participant data underlying publications resulting from this study will be made available after removal of personal identifiers and in accordance with applicable VA requirements. Data sharing will be subject to appropriate privacy protections and any required data use agreements to prevent identification or re-identification of participants.
Time frame: Data will become available following publication of the primary study results and will remain available in accordance with applicable VA data-retention and data-sharing requirements.
Access criteria: Data will be made available to qualified investigators for scientifically appropriate research purposes following review and approval by the appropriate VA and institutional authorities. Access will require compliance with applicable VA privacy and security requirements and execution of any required data use agreement.
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