Non-invasive neuromodulation mechanisms and dose/response metrics

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Project Summary / Abstract In an exciting era of growth in the use of non-invasive brain stimulation, new methods and applications are being disseminated widely with an increasing number of FDA approvals and equipment designed to probe or modulate the brain in fascinating new ways. The problem with this growing enthusiasm is that there are too few studies that have evaluated how tools such as transcranial magnetic stimulation (TMS) induce functional activation throughout a human brain, especially outside of the motor system. Neuromodulation made possible by administering trains of repetitive TMS (rTMS) is even more poorly understood since it requires capturing dynamic changes in the brain that are at the root of proposed changes in function. We have developed a protocol for assaying circuit communication by single pulse TMS delivered while recording functional MRI to follow brain wide effects of TMS to various prefrontal cortex targets. We are beginning to measure this circuit- specific communication flow before and after neuromodulatory rTMS to the same circuit to quantify changes in dynamics resulting from these acute brain interventions. With the proposed research, we plan to optimize targeting of two brain networks with TMS: inferior frontal gyrus to amygdala and lateral prefrontal to subgenual anterior cingulate cortex. By individualizing targeting from each person's functional MRI mapping, we believe that we can optimize our ability to affect the brain and ultimately better understand variability in behavioral response to TMS. A key set of proposed metrics for establishing a firmer understanding of TMS effects on the brain will be two different hypothesized dose/response relationships: 1) Circuit activation will increase as a function of absolute stimulation level and 2) Circuit communication will be modulated as a function of the cumulative number of rTMS pulses delivered during neuromodulatory brain stimulation. 3) Finally, to increase our chances of capturing a stratified sample of circuit integrity in the targeted pathways that are thought to be disrupted in affective disorders, a sub-sample of the recruited participants (who will otherwise be healthy) will be recently diagnosed with major depressive disorder. Significance: Our comprehensive assay of brain response to TMS will include TMS probe responses as well as resting fMRI recorded before, during, and after application of neuromodulatory TMS. This strategy will yield a significant step forward in understanding how non-invasive brain stimulation affects human brain functioning that can be a methodological and theoretical base for tool development and novel brain-based therapeutics.