The overarching goal of this work is to improve treatments of medication-resistant neuropsychiatric diseases with repetitive transcranial stimulation (rTMS) by tailoring the target to an individual's brain networks. We are indeed in critical need of these individualized treatments for mental health disorders, which affect nearly 50% of Americans during our lifetimes, and brain stimulation treatments, including rTMS represent innovative approaches for these patients. To alleviate depression, rTMS attempts to target a region of the prefrontal cortex generally located within the central executive network (CEN), which drives decision making, cognitive control, and is critically impaired in depression. However, rTMS is delivered without targeting an individual's CEN, and as such may inadvertently deliver stimulation outside the CEN. This application is motivated by recent developments in the field, including a large-scale whole-brain connectivity database derived from invasive recordings and the demonstration that rTMS in depressed patients induces brain changes that predict clinical improvement. In this proposal, we combine non- invasive TMS studies in healthy subjects and depressed patients with invasive direct stimulation studies from surgical patients. We test the hypothesis that the CEN connectivity is weakened in depression and can be maximally modulated by individualizing localization. The project consists of three aims: (1) investigate the excitability, connectivity, and neuronal properties within the CEN using direct brain recordings in surgical patients with epilepsy; (2) derive accurate TMS tools to measure CEN connectivity non-invasively in healthy and depressed populations; and (3) in a depressed population characterize inter-individual variability within the CEN and prospectively test if localization with TMS at the individual level more effectively modulates this brain network. This approach, which can be generalized to any brain region and disorder, utilizes a large database of direct brain recordings to map a brain network at an unparalleled level of detail, develops a link to direct brain recordings in order to yield validated non-invasive brain measures, and applies these insights to individually localize the network and improve targeted brain stimulation. Scientific outcomes include: (1) the first causal, functional map of the human CEN from direct brain recordings; (2) novel non-invasive brain measures of connectivity grounded in electrophysiology; (3) causal brain signatures of depression in the CEN; (4) a methodology to target an individual's CEN in the clinic; and (5) improved modulation of the CEN using this methodology. In summary, a successful outcome of the proposed work would yield an algorithm and guidelines for personalized TMS targeting based on fully validated brain signatures in depression. RELEVANCE (See instructions): Brain stimulation for depression targets the central executive network (CEN), involved in decision ...