Project Summary/Abstract Patients suffering from schizophrenia and related disorders experience cognitive disruptions associated with poor functional outcomes. It is therefore critical to achieve the long-term goal of developing efficacious and mechanistically informed treatments to improve cognition in this population. Targeted cognitive training (TCT) has shown promise for improving cognition in patients with schizophrenia, but individual differences in behavioral and neural target engagement limit the efficiency and sustainability of this treatment. TCT enhances prefrontal oscillatory gamma that coincides with improved cognition in patients with schizophrenia. Similar increases in prefrontal gamma and cognitive performance in schizophrenia have been demonstrated using transcranial direct current stimulation (tDCS). The current study will determine whether cognitive enhancement in schizophrenia can be achieved more efficiently by combining tDCS that enhances neural oscillatory rhythms with TCT that harnesses gamma oscillatory plasticity in prefronto-temporal systems. Using an experimental medicine framework, this study will test the central hypothesis that TCT+tDCS will—via the mechanism of increased prefrontal oscillatory gamma—accelerate and sustain the behavioral effects of cognitive training over TCT+Sham. This study will pursue 3 specific aims: 1) Determine whether TCT+tDCS more rapidly improves cognition compared to TCT+Sham; 2) examine the relationship between change in cognition and change in prefrontal oscillatory gamma following TCT+tDCS; and 3) determine whether cognitive and functional benefits following TCT+tDCS are sustained after a 3-month follow-up. An exploratory aim will examine cross-frequency coupling (CFC) between theta and gamma oscillatory signals and determine whether changes in CFC corresponds to improved cognition. To carry out these aims, patients with schizophrenia will be randomized to undergo either 20 hours of TCT+tDCS or TCT+Sham. Participants will be assessed on measures of cognition, symptoms, and functioning at baseline, after 10 hours of training, after 20 of training, and at a 3-month follow- up. To measure changes in oscillatory gamma, participants will undergo task/resting EEG at baseline, after 10 hours, and after 20 hours. The approach is innovative as it investigates the combined effects of a behavioral intervention and neuromodulation, uses an experimental medicine framework to probe neural target engagement, and relies on novel computational and neural analyses. The proposed research is significant because it will establish prefrontal gamma as a treatment target in schizophrenia, and lay the groundwork for personalized treatments that could be deployed in a clinical setting. The outlined proposal will also facilitate the candidate’s training goals: 1) Administration of tDCS; 2) Administration and analysis of EEG; 3) learning computational psychiatry methods. Completion of these goals will establish th...