PROJECT SUMMARY – UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH Cognitive control requires the brain to dynamically allocate limited resources to manipulate internal representations as a function of behavioral demands, a process referred to as output-gating. Output-gating comprises two intertwined cognitive processes: the selection of relevant information and the suppression of irrelevant information. These two cognitive processes have been correlated with oscillatory neuronal network activity in two distinct frequency bands and network locations: theta oscillations (4-7 Hz) in prefrontal cortex (PFC) for selection and alpha oscillations (8-12 Hz) in posterior parietal cortex for suppression. However, the causal role of these oscillations and their interactions in output-gating has yet to be established. To address this gap, this proposal examines the causal role of theta and alpha oscillations in output-gating across multiple scales with individualized brain stimulation paradigms to provide a mechanistic delineation of how these oscillations support behavior, coordinate network activity, and regulate neuronal spiking activity. The objective of AIM 1 is to demonstrate the causal role of theta and alpha oscillations in selection and suppression, respectively. To accomplish this, theta and alpha frequency rhythmic transcranial magnetic stimulation is applied in healthy participants to frontal and parietal sites with simultaneous electroencephalography (EEG) during a working memory task with a retrospective cue that drives output-gating. The hypothesis of AIM 1 is that frontal theta activity coordinates the selection of relevant information, while parietal alpha activity coordinates the suppression of irrelevant information. The objective of AIM 2 is to spatially resolve the theta and alpha network dynamics that support selection and suppression, respectively. To achieve this objective, direct cortical stimulation combined with invasive EEG will be used in epilepsy patients with implanted electrodes for clinical purposes. The hypothesis of AIM 2 is that connectivity between frontal and parietal regions establishes oscillatory dynamics critical for selection and suppression. The objective of AIM 3 is to determine how oscillatory network dynamics regulate neuronal spiking activity. This is examined by applying theta and alpha frequency rhythmic optogenetic stimulation to frontal and parietal sites in the ferret with simultaneous electrophysiology recordings during an attentional task that modulates theta and alpha oscillations. The hypothesis of AIM 3 is that theta oscillations increase spiking and alpha oscillations decrease spiking activity. The proposed work is significant since it will provide a multi-scale mechanistic understanding of how theta and alpha oscillations coordinate output-gating. The proposed aims are innovative since they employ synergistic causal perturbations through targeted brain stimulation paradigms with concurrent electr...