Impact of Timing, Targeting, and Brain State on rTMS of Human and Non-Human Primates

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Non-invasive methods for stimulating the human brain show great promise for safe, effective treatments of psychiatric and motor disorders, and are in widespread use for basic research on human behavior and cognition. One such method, transcranial magnetic stimulation (TMS), is the application of time-varying magnetic fields above the scalp that induce transient electrical fields in the brain. TMS clearly stimulates the brain and affects behavior, but we do not know why it works; its effects on neural activity within brain regions and networks are not understood at a biological level. This project seeks to determine the neural basis of effects caused by TMS as applied in sequences of pulses, known as repetitive TMS (rTMS), a technique approved by the FDA for depression. Leveraging our expertise in application of TMS methodology during concurrent single neuron recording techniques in non-human primates and imaging and scalp potential techniques in humans (fMRI and EEG), we aim to resolve three interlocking problems in the design and application of rTMS: timing, spatial targeting, and interactions with brain state. In all studies, neuronal responses to rTMS will be quantified in human and non-human primates as they perform a visual motion task that allows systematic manipulation of brain activity and cognitive state. In both species, we will focus on a specific motion-selective brain area, MT, and the circuits that connect with it. First, we will determine the effects of timing on the pulse sequences delivered during rTMS. We will systematically trade off frequency with number of pulses delivered as human and non-human primates perform the task and brain activity and behavioral performance are monitored. Definitive dose-response relationships for rTMS temporal parameters will be established for both species. Second, we will assess simple but principled methods for spatial targeting of distributed networks. Based on imaging of white-matter connectivity and computational models of rTMS-induced neural activation, we will examine how location and orientation of the TMS coil differentially recruits two major pathways that emanate from it, the dorsal and ventral streams of the visual system. Third, we will tackle the fundamental question of how rTMS interacts with endogenous activity in the brain. By manipulating task demands, we will systematically control brain state and quantify how this alters the influence of rTMS on neural activity and cognitive performance. Taken together, this project will yield a multi-scale data set that links results from non- human primates to humans through experiments that should generalize well to the study of other cerebral cortical circuits. The results will help to advance rTMS from a method that relies on trial-and-error testing toward one that is founded on clear biological principles.