Effect of cTBS on Startle and TMS-evoked BOLD

The right dorsolateral prefrontal cortex (dlPFC) is increasingly being targeted with transcranial magnetic stimulation (TMS) to reduce anxiety expression in anxiety disorders, depression, and posttraumatic stress disorder (PTSD). However, we lack the basic evidence to determine critical details regarding the optimal stimulation parameters including the dose, target, and protocol. In addition, there is little mechanistic evidence for why any particular right dlPFC target/dose/protocol should be effective for a given set of patients. Indeed, there is little consensus as to whether such mechanistic evidence should generalize across disorders. Accordingly, there is a critical need to understand the mechanisms of action underlying neuromodulatory right dlPFC TMS protocols, yet there is not a standardized protocol to yield such evidence. Without a reliable approach to approach to generate such information, it will be difficult or impossible to develop and optimize novel TMS treatments for disorders like PTSD and anxiety. The objective of the current project is to develop a protocol using interleaved TMS/fMRI that can assess the effect of neuromodulatory (potentially therapeutic) TMS protocols on neural and behavioral measures related to anxiety expression. Our central hypothesis is that inhibition of the right dlPFC via cTBS will also inhibit activity throughout its downstream targets, resulting in reduced anxiety, connectivity, and TMS-evoked responses among these downstream circuits during threat. Accordingly, our approach will be to measure anxious arousal, resting state functional connectivity, and TMS evoked BOLD responses before and immediately after 600 pulses of cTBS or sham stimulation in 100 high anxious individuals using a within-subjects crossover design. For anxious arousal, our primary outcome will be anxiety potentiated startle (APS) recorded with electromyography during the neutral, predictable, and unpredictable (NPU) threat paradigm administered in the lab before and after the scanning session. For the interleaved TMS/fMRI runs, our primary outcome will be TMS-evoked BOLD responses in these same downstream regions. This study is innovative because it is the first to combine these technologies to study the effect of neuromodulatory TMS on threat-related TMS-evoked BOLD responses. This project is significant because it will provide future researchers with an systematic approach for evaluating the effectiveness of neuromodulatory TMS protocols on several neural and behavioral indices of anxiety expression. It will also yield direct evidence that cTBS modulate brain activity associated with anxiety expression and regulation.