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.