Project Summary: Motor evoked potentials (MEPs) elicited via non-invasive electrical stimulation of the human brain are the foundational basis for investigating the neural circuits that link cortical output to the spinal cord and muscles. Transcranial magnetic stimulation (TMS) methods have allowed the study of the organization and plasticity of motor control systems by monitoring MEPs in awake human subjects, with insights leading to myriad clinical applications for assessing and treating motor dysfunction. In stark contrast to MEPs from peripheral skeletal muscle, there is no comparable, objective measure of central neural influences on the smooth muscles of the gastrointestinal tract. This fundamental barrier has hindered progress in neurogastroenterology by limiting the ability to study the organization and plasticity of cortical influences on the neural control of the GI system in awake human subjects. To overcome this barrier, we have recently developed a direct electrophysiological readout of a neural circuit linking the cortex to the stomach that we call gastric evoked potentials (GEPs). GEPs are generated by coupling TMS with cutaneous electrogastrography (EGG), which provides a continual electrophysiological readout of gastric smooth muscle activity. Our pilot studies demonstrated distinct GEP signals resulting from TMS stimulation of the primary motor cortex (M1) in human subjects. Analogous to the fundamental role TMS-elicited MEPs have had in guiding the exploration of the neural control of movement, TMS-elicited GEPs will guide the exploration of the neural control of GI movement (i.e. `gut motility'). In this project, we seek to determine and standardize how best to record GEPs, to optimize the TMS parameters and conditions necessary to evoke GEPs, and to identify the location of cortical sites that most readily generate GEPs (`GEP hotspots') (Aim 1). We then will assess whether various modes of repetitive TMS (rTMS) neuromodulation (inhibitory 1Hz or stimulatory 10Hz) targeted to GEP hotspots shape gastric motor responses (Aim 2). This preliminary clinical research will develop GEPs as a non-invasive, direct measure of the neural circuit linking the cerebral cortex to the control of the stomach, with similar reliability and reproducibility to methods used to elicit MEPs. Our work will guide the development of TMS as a tool for mechanistic studies of gastric physiology in human subjects and brain- based methods to manipulate stomach function. This line of work could lead to clinical trials of TMS neuromodulation, directed to cortical sites identified as inducing maximal GEP responses, to treat gastric motility disturbances that arise in a variety of clinical contexts.