PROJECT SUMMARY/ABSTRACT Intentional and flexible behavior, often called ?cognitive control?, requires the maintenance and selection of perceptual, mnemonic, and response representations consistent with the broader context and higher-level goals. One of the most challenging problems in neuroscience is determining how voluntary, goal-directed behavior arises from the distributed activity of billions of neurons in the brain. To tackle this problem, one must understand the cognitive and neural mechanisms of working memory (WM), a fundamental ability underlying goal-directed behavior. The study of WM, however, has only minimally benefited from the revolution in neural dynamics that has been experienced in other fields. Discovery of WM neural dynamics is particularly important given that WM requires the interaction of multiple brain systems, notably the lateral PFC (lPFC) and posterior processing systems. Thus, a determination of the neural mechanisms underlying lPFC function, the most elaborated neocortical region in primates, and WM, remains a fundamental goal of neuroscience research. To achieve this goal, three different methods will be implemented in human subjects in this proposal during the performance of WM task ? ECoG, fMRI and TMS. This will provide a convergent approach that tests hypotheses regarding the spatio-temporal basis of WM and will be able to determine the causality of the electrophysiological and neuroimaging findings. Although not the prime focus of the proposal, the ECoG data will also provide a link to monkey neurophysiology and the neural drivers of the fMRI BOLD signal. Basic knowledge about WM and frontal lobe function can provide substantial insights into the nature of a large number of psychiatric and neurological disorders affecting PFC function such as schizophrenia, dementia, stroke and traumatic brain injury; as well as many other conditions such as attention-deficit disorder, substance addiction and normal aging, that are proposed to involve selective dysfunction of frontal brain systems. Moreover, cognitive and behavioral deficits from PFC damage are particularly challenging to treat. A greater understanding of frontal lobe function is necessary for developing effective therapeutic interventions.