ABSTRACT Despite the increasing use of transcranial magnetic stimulation (TMS) in both research and clinical practice, the field nonetheless lacks a theoretical framework to predict the impact of TMS on circuits. In this application, we propose to test the over-arching hypothesis that brain responses to TMS are governed by both the network control properties of the stimulation site and the functional context of the network during stimulation. Recent advances in network control theory have provided quantitative diagnostics of network controllability, which collectively define how external input (e.g., TMS) to network nodes (e.g., brain regions) can move the entire system. In Aim 1, we will test the hypothesis that TMS targeted to regions of high network control will produce greater brain responses than TMS targeted to regions of low network control. Specifically, we will recruit healthy young adults (n=40) and use ultra-high resolution diffusion imaging to identify control points that are topologically situated to drive network reconfiguration. We will use cutting-edge interleaved TMS/fMRI to test the hypothesis that individually-targeted TMS at control points will produce greater network segregation, consisting of fronto-parietal network activation, DMN de-activation, and reduced connectivity between the two. In Aim 2, we will examine the impact of the functional context of TMS. We predict that TMS simulation during conditions of high working memory (WM) load will result in greater network segregation responses than in conditions of lower load. In Aims 3 & 4, we will examine the degree to which individually targeted stimulation during WM task performance augments behavioral WM performance following repetitive TMS. We predict that the behavioral impact of neuromodulation on WM performance will scale with observed increases in network segregation versus baseline in both our sample of healthy young adults as well as age-matched patients with ADHD who have documented executive deficits (n=35). This proposal leverages our group's unique expertise in advanced TMS/fMRI, network science, and multi-modal imaging. Together, this research will elucidate basic mechanisms of neuromodulation that will accelerate translation of these therapies to clinical practice and more definitive links between brain functional modules and brain functioning.

PROJECT NARRATIVE Transcranial magnetic stimulation (TMS) is a powerful tool for non-invasively modulating brain circuits. Yet, critically, the field lacks a mechanistic framework to predict the effects of TMS on brain and behavior. In this application, we propose to test the hypothesis that brain responses to TMS are governed both by the network properties of the stimulation site and by the cognitive context, as measured by patterns of functional activation during stimulation. We expect that augmenting TMS effects through these two mechanisms will enhance the impact of TMS in both healthy adults and those with executive impairment. Revealing mechanisms of TMS response has the potential to accelerate personalized neuromodulatory treatments for executive dysfunction, as well as to enhance understanding of how functional brain modules contribute to specific cognitive functions.