Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive brain stimulation technique capable of modulating activity in the targeted brain region and its connected brain circuits beyond the duration of the stimulation itself. rTMS is utilized in neuroscience research to investigate brain function during human cognition and behavior, and to understand brain pathophysiology in neuropsychiatric diseases. Clinically, rTMS protocols have diagnostic and therapeutic utility across a wide spectrum of disease states, and four rTMS devices are cleared by the Food and Drug Administration (FDA) for treatment of medication-resistant depression. However, the variability of the neuromodulatory effects of rTMS and its sources are ill-defined. This knowledge gap represents a fundamental limitation for both, the interpretation of rTMS results and the design of studies. For example, it is challenging to calculate or assess the sample size for a study, and one cannot optimize rTMS parameters for an individual without knowing whether individual differences in rTMS response are reproducible. In addition, one cannot assume that rTMS protocols tested in motor cortex will produce similar neuromodulatory effects when administered to other brain regions. In this proposal we will use MRI-guided rTMS in combination with EMG, EEG and behavioral measures to characterize the variability of rTMS effects in primary motor cortex (M1) and in dorsolateral prefrontal cortex (DLPFC). In a cohort of 60 subjects, we will evaluate the inter-subject and intra-subject test-retest reliability of the modulatory effects of the most widely used rTMS protocols applied to M1. We will compare the impact of different rTMS protocols on corticospinal excitability (measured via motor-evoked potentials), cortical excitability (measured via simultaneous TMS-EEG), and motor performance (using a sequential finger tapping task). Each subject will undergo a total of 10 TMS-EMG-EEG-behavior sessions, evaluating repeated sessions of excitatory and inhibitory protocols. In a separate cohort of 60 subjects, we will evaluate the transfer of rTMS effects across brain regions by applying 10 Hz rTMS and iTBS to both M1 and DLPFC. Each subject will undergo a total of 10 TMS-EEG-behavior sessions contrasting stimulation protocols across regions (M1 versus DLPFC). All subjects will undergo extensive baseline assessment, including detailed exam, neuropsychological measures, structural and resting-state functional-connectivity MRI, computational modeling, laboratory and genetic testing, and EEG to identify predictors of inter-subject variability in response to rTMS. All data will be placed in a secure repository and made publicly accessible to other investigators. This study will define the reproducibility of the neuromodulatory effects of rTMS, quantifying the intrinsic variability of the method within and across individuals, across levels of analysis (neurophysiologic and behavioral) and brain regions (M1 versus DLPFC). These results will serve as a foundation to guide the planning, development and interpretation of all future studies utilizing rTMS to modulate brain function.
Repetitive Transcranial Magnetic Stimulation (rTMS) is a noninvasive brain stimulation method increasingly being used in basic, translational, and clinical research, as well as for therapeutic applications in a variety of neurologic and psychiatric diseases. However, a critical impediment to greater utility and efficacy is a lack of knowledge of the reproducibility of the neuromodulatory effects of rTMS. We aim to address this knowledge gap with a series of experiments combining rTMS with electromyography, electroencephalography, and behavioral tasks to characterize the magnitude and reliability of rTMS effects across sessions, cortical sites, and subjects. This information is critical for calculation of sample size in studies, interpretation of results, and optimization of stimulation protocols.
