The effect of right dlPFC cTBS on acute measures of anxiety, functional connectivity, and TMS-evoked BOLD responses

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). There seems to be clear mechanistic evidence that right dlPFC downregulation of amygdala activity should reduce fear and anxiety. Despite this mechanistic evidence, the primary approaches to treat anxiety with neuromodulation involve right dlPFC inhibition. 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. Concurrent TMS/fMRI offers a unique translational perspective for understanding psychopathology. By experimentally stimulating a region of the brain and then directly measuring the activity evoked by this stimulation, it is possible to causally determine the downstream targets of this region, facilitating the development of 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. As a proof of concept, we will determine the effect of continuous theta burst stimulation (cTBS) to the right dlPFC on TMS-evoked fMRI responses in anxious subjects. Our central hypothesis is that cTBS of the right dlPFC will drive down activity throughout its downstream targets, resulting in reduced anxiety and greater TMS-evoked deactivations in these downstream circuits. Accordingly, our approach will be to measure anxious arousal and TMS-evoked BOLD responses before and immediately after 1800 pulses of cTBS, or sham stimulation in 140 high anxious individuals using a within-subjects crossover design. Our primary outcome will be TMS-evoked BOLD responses in a network of downstream targets involved in emotion expression (i.e. amygdala, BNST, sgACC). Aim 1 will be to examine the effects of right dlPFC cTBS vs. sham on anxious arousal. Aim 2 will be to examine the effects of right dlPFC cTBS vs. sham on TMS-evoked BOLD responses. Our exploratory aim will be to determine the links between anxiety phenotype, anxious arousal, and TMS-evoked BOLD responses. Our study team features Dr. Desmond Oathes, who is a pioneer in the field of TMS/fMRI, Dr. Lily Brown, who is the head of the Center for the Treatment and Study of Anxiety, and is led by Dr. Nicholas Balderston, who is (to our knowledge) the only researcher who has successfully combined threat of shock with interleaved TMS/fMRI. 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 a 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 can modulate brain activity associated with anxiety. Project Number: 1R01MH138375-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: nicholas balderston (+1 co-PI) | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $762,440 | Activity Code: R01 | Study Section: Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section[NPAS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11222995