Individualized (fMRI-guided) TMS Intervention for Post-Traumatic Stress Disorder (PTSD)

This double-blind, randomized, sham-controlled clinical trial will investigate engagement and modulation of amygdala-related brain circuitry using individualized resting-state functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) in adults with posttraumatic stress disorder (PTSD). Following screening, participants will undergo a baseline MRI session that includes structural, diffusion, and resting-state imaging. Resting-state functional connectivity will be used to identify an individualized cortical stimulation target within the ventrolateral prefrontal cortex (vlPFC) that is positively connected with the basolateral amygdala. Before the 6-week intervention, participants will undergo a TMS/fMRI session to evaluate whether stimulation of the individualized target engages the amygdala. Single-pulse TMS will be delivered to three sites: the individualized amygdala-connected target, an individualized cortical control target with minimal functional connectivity to the amygdala, and a vertex control site. Amygdala blood oxygen level-dependent (BOLD) responses during TMS will be measured to assess target engagement and determine whether amygdala responses differ across stimulation sites. Participants will then be randomized in a 1:1 ratio to receive active or sham intermittent theta burst stimulation (iTBS) delivered to the individualized amygdala-connected target every weekday for 6 weeks (30 sessions). Sham procedures will be designed to resemble active stimulation without delivering the intended magnetic stimulation to the targeted brain circuit. Psychophysiological assessments will be conducted before, during, and after the intervention to evaluate fear learning, extinction, and extinction retention. During these tasks, physiological responses to fear-related stimuli will be measured. Following the 6-week intervention, participants will undergo a second TMS/fMRI session using the same stimulation targets and procedures as the pre-intervention session. Changes in amygdala responses from pre- to post-intervention will be compared between the active and sham groups to evaluate modulation of the targeted brain circuit. Clinical assessments, questionnaires, and cognitive testing will also be conducted throughout the study. Participants will complete remote follow-up assessments at 1, 6, and 12 months after their last TMS intervention session. After the 1-month follow-up, participants assigned to sham will be unblinded and may be offered an optional open-label active TMS intervention if they continue to have clinically significant PTSD symptoms and meet study eligibility criteria.