Personalized fMRI-Guided TMS Targeting the Threat Neurocircuitry in PTSD: A Randomized Clinical Trial

OBJECTIVE: Transcranial magnetic stimulation (TMS) has shown promise in reducing posttraumatic stress disorder (PTSD) symptoms, with varied clinical results. A mechanistic understanding is needed to personalize treatment and improve response rates. The threat neurocircuitry, specifically the right amygdala, has consistently been implicated in PTSD pathophysiology. This neuroscience-informed trial aimed to modulate the threat neurocircuitry using functional MRI (fMRI)-guided TMS to treat PTSD. METHODS: In a double-blind clinical trial, 50 adults with PTSD symptoms were randomized to 10 twice-daily sessions of either 1-Hz TMS or sham TMS. TMS was delivered to an fMRI-guided target within the right dorsolateral prefrontal cortex with the strongest functional connection to the right amygdala. The primary outcomes were right amygdala threat reactivity, assessed by fMRI, and skin conductance reactivity during trauma recall, measured pre- and post-TMS. The secondary outcomes were hyperarousal and total PTSD symptoms (based on the PTSD Checklist for DSM-5), measured pre- and post-TMS and at a follow-up assessment between 3 and 6 months after TMS. RESULTS: Active TMS significantly reduced right amygdala threat reactivity compared with sham TMS. No significant effect of TMS was observed on skin conductance reactivity. From pre- to post-TMS, significant reductions in hyperarousal and total PTSD symptoms were observed across groups, but no significant differences between groups were observed. From pre-TMS to follow-up, active TMS compared with sham TMS significantly reduced hyperarousal and total PTSD symptoms. Clinical findings were found to be robust in sensitivity analyses. CONCLUSIONS: This is the first clinical trial to demonstrate that personalized fMRI-guided TMS targeting the threat neurocircuitry reduces amygdala threat reactivity and improves long-term PTSD symptoms at follow-up. These findings suggest the potential for a personalized approach to neuromodulation in individuals with PTSD.