EAGER: A novel, non- invasive approach to reliably alter cortical excitability using high frequency (kHz) transcranial magnetic perturbation.

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The past two decades have witnessed an exponential increase in the use of non-invasive brain stimulation (NIBS) methods. The two most commonly used methods, transcranial electrical stimulation (tES) and transcranial magnetic stimulation (TMS), provide tools to manipulate activity in targeted brain regions, and this give cognitive neuroscientists a method to test functional hypotheses. Despite this potential, there are substantial concerns about the reliability and robustness of the physiological and behavioral changes resulting from these NIBS methods, especially when used to induce modulatory perturbations in the state of neural excitability. The purpose of this project is to create a new and more robust method for modulatory NIBS in human participants. The method, referred to as kilohertz transcranial magnetic perturbation (kTMP), will open a new experimental electromagnetic subspace for perturbing brain function. This method will open several new opportunities for cortical stimulation: larger electrical fields, more precise timing, better spatial control, and both a greater range and a more precise delivery of stimulation frequency. This novel magnetic stimulation holds promise to produce meaningful focal physiological changes, for several reasons. First, subthreshold kilohertz (kHz) electrical stimulation has been shown to alter motor-evoked responses with an effect size similar to that of direct current electric fields. Second, suprathreshold kHz frequency electric fields robustly block nerve conduction in a reversible manner. Third, suprathreshold experiments have shown that kHz tES can mimic low frequency electric fields in the motor cortex of the mouse, presumably due to frequency intermodulation. This project will employ subthreshold electric fields, albeit at much higher amplitude than those presently available with tES and with the frequency specificity not possible with extant TMS methods. kTMP offers a hybrid subthreshold approach that will exploit strong midrange electric field amplitudes with frequency specificity, including frequency intermodulation effects, offering a new approach to perturb brain function. The initial empirical evaluation of kTMP will focus on modulating human motor cortex excitability, the "gold standard" approach for evaluating NIBS methods. Importantly, by substantially expanding the range of electric field induction, it should be possible to obtain dose-dependent functions, something that has proven elusive with other subthreshold NIBS methods. Once these benchmark tests are met, kTMP should be readily adopted for basic cognitive neuroscience research, providing a robust tool to perturb and modulate targeted cortical regions as a means to test functional hypotheses in physiological and behavioral studies. In the long term, kTMP has promise to be employed in the treatment of psychiatric and neurological disorders.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.