PREVENT study: Promoting resilience via early neurostimulation after trauma

About This Grant

Project Summary The majority of Americans will experience a traumatic event during their lifetimes, but only a subset experience chronic negative psychiatric outcomes such as post-traumatic stress disorder (PTSD) and depression. Several cohort studies over the past 10 years have identified brain-based risk mechanisms early after trauma, which predict risk for chronic symptoms such as hyper-arousal, intrusive memories of the trauma, and negative affect. One of the most widely-replicated and theoretically-grounded such mechanisms involves early high amygdala responses to threat cues. Given the strength of current evidence, we propose that this is an actionable target for intervention early post-trauma, to prevent chronic impairing and distressing symptoms. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that can induce functional brain changes as potential intervention for neuropsychiatric disorders. Emerging findings along with our preliminary data suggest that the amygdala can be reached and dampened via stimulation of a functionally connected cortical prefrontal area. Here we propose that using TMS to dampen amygdala hyperreactivity will prevent a cascade of symptoms that could develop following trauma exposure. We propose to identify Emergency Department patients who have experienced a recent traumatic event (meets DSM-5 Criterion A), and who have high initial PTSD symptoms at 1 week post-trauma. In the R61 phase we will deliver a staged single-blind TMS intervention with a lead-in sham, followed by active treatments with increasing doses, measuring amygdala reactivity at each phase. R61 milestones involve: 1: Target engagement: Determination that active TMS versus sham decreases within-subject amygdala threat reactivity (decrease in reactivity to fearful faces). 2: Dose response: Determination that 4 vs 1 session of TMS decreases these same targets. 3: Safety and feasibility: Demonstrating feasibility of recruitment and retention (75% of participants are able to complete 75% of sessions), and no Serious Adverse Events (SAE) deemed related to the TMS intervention. If these are met, the R33 phase will involve a randomized double-blind sham-controlled trial, providing a double- blind replication of the immediate effects on the amygdala target and 1-month later, as well as longitudinal assessments of TMS effects on both PTSD and depression symptoms over 3 months post-trauma. The research environment at Emory University School of Medicine will provide excellent support for the successful completion of the proposed research, particularly with state-of-the-art neuroimaging facilities, a well-developed infrastructure for identifying participants at risk for chronic trauma-related symptoms through the Grady Trauma Project and Grady Healthcare System, and a strong community of experts in trauma and neuromodulation. If the hypotheses are confirmed, this study will lay the groundwork for future early intervention trials using non- invasive dampening of amygdala reactivity to prevent chronic trauma-related symptoms.