Salience Network Informed rTMS for 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.

• Active MRI-Guided intermittent theta burst stimulation (iTBS) (Device), also known as MagVenture TMS Therapy System: 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.
• Sham MRI-Guided intermittent theta burst stimulation (iTBS) (Device), 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.

Primary outcomes

• Change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Total Severity Score [Baseline and immediately following completion of treatment (approximately Week 4-6)]: 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.
• Change in Anterior Insula Resting-State Functional Connectivity [Baseline and immediately following completion of treatment (approximately Week 4-6)]: 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.

Secondary outcomes

• Change in Brain Activation During the Anticipation Task [Baseline and immediately following completion of treatment (approximately Week 4-6)]: 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.
• Change in Heart Rate Variability [Baseline and immediately following completion of treatment (approximately Week 4-6)]: 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.
• Differential Change in CAPS-5 PTSD Symptom Cluster Severity [Baseline and immediately following completion of treatment (approximately Week 4-6)]: 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.

Other outcomes

• Change in Patient Health Questionnaire-9 (PHQ-9) Total Score [Baseline, post-treatment (Week 4, up to Week 6), and 4-week and 8-week post-treatment follow-ups.]: 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.
• Change in Generalized Anxiety Disorder-7 (GAD-7) Total Score [Baseline, post-treatment (Week 4, up to Week 6), and 4-week and 8-week post-treatment follow-ups]: 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.
• Change in PTSD Checklist for DSM-5 (PCL-5) Total Score [Baseline, post-treatment (Week 4, up to Week 6), and 4-week and 8-week post-treatment follow-ups]: 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.

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Veteran status
* Current diagnosis of posttraumatic stress disorder (PTSD), as determined by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
* Able to provide informed consent
* Able to speak, read, and write English
* Willing and able to complete 20 intermittent theta burst stimulation (iTBS) treatment sessions, scheduled 5 days per week for 4 weeks, with completion permitted within up to 6 weeks when needed
* Willing and able to complete magnetic resonance imaging (MRI) assessments before and after the iTBS treatment course

Exclusion Criteria:

* History of a neurological disorder associated with cognitive dysfunction, such as dementia or mild cognitive impairment
* History of traumatic brain injury associated with an estimated loss of consciousness greater than 30 minutes
* Current acute suicidal ideation or recent psychiatric hospitalization when, in the judgment of the study clinician or treating psychiatrist, the condition would interfere with safe study participation
* Current psychotic disorder or bipolar disorder/mania
* Current severe alcohol or substance use disorder; Mild or moderate alcohol or substance use disorder is not exclusionary
* Pregnancy; less than 3 months postpartum; or less than 3 months since cessation of breastfeeding
* Contraindication to magnetic resonance imaging (MRI) or transcranial magnetic stimulation (TMS), including MRI/TMS-incompatible implanted metallic or electronic devices, retained metallic foreign bodies, or other implants determined to be unsafe following MRI/TMS safety review
* History of neurosurgery when incompatible with safe MRI or TMS participation
* Claustrophobia that would prevent completion of MRI
* Inability to lie still in the MRI scanner for approximately 60 minutes
* Vision impairment that cannot be adequately corrected for completion of study procedures
* Initiation of a new psychiatric medication within 4 weeks before enrollment or anticipated inability to maintain a stable medication regimen during study participation

• Daniel M Stout, PhD, Principal investigator, VA San Diego Healthcare System, San Diego, CA