Project Summary. Schizophrenia is a severe mental illness with an estimated economic burden of more than $160 billion per year in the US alone. To mitigate this burden, a promising approach involves the discovery of novel treatment interventions targeting specific neuronal circuit dysfunction, especially early in the illness, thus ameliorating the course of the disorder. In recent work, we found that the oscillatory activity of the dorsolateral prefrontal cortex (DLPFC), assessed with Transcranial Magnetic Stimulation (TMS) and EEG, was markedly reduced in chronic schizophrenia (Ch-SCZ) patients. DLPFC oscillatory deficits are also present in early course (EC-SCZ) patients and are associated to their reduced working memory (WM) performance. But findings to date are limited by a correlational/cross-sectional design, leaving the potential causal role of DLPFC oscillatory deficits in SCZ cognitive dysfunction unclear. The overarching goal of this proposal is to establish whether, by acutely enhancing DLPFC oscillatory activity, we see a corresponding improvement in WM function in EC-SCZ patients. In addition to being used to assess cortical function, as in combination with EEG, TMS can be delivered in repetitive, high-frequency patterns (rTMS), to modulate brain activity, including prefrontal cortical oscillations. Theta Burst Stimulation (TBS) is a type of rTMS that induces more rapid effects on neural activity than conventional rTMS; continuous TBS (cTBS) and intermittent TBS (iTBS) can decrease and enhance cortical excitability, respectively. Recent studies have shown that iTBS of DLPFC can acutely enhance prefrontal excitability in healthy individuals. Yet, the immediate impact of TBS on DLPFC oscillatory activity in patients with SCZ remains unknown. The first broad Aim of this proposal is to use iTBS to acutely ameliorate deficits in DLPFC oscillatory activity in EC-SCZ patients. WM relies on a neural network in which DLPFC serves as a central hub. EEG studies have reported that SCZ patients have DLPFC oscillatory abnormalities during WM tasks, and we recently found that reduced DLPFC oscillatory activity predicts poorer WM performance in EC-SCZ patients. It therefore stands to reason that enhancing DLPFC oscillatory activity with TBS may benefit cognitive functioning. The second broad Aim of this proposal is to use iTBS to acutely ameliorate WM impairments in EC-SCZ patients. To achieve these goals, we will perform TMS/EEG assessments of DLPFC oscillatory parameters and evaluate WM ability before and after two TBS sessions (iTBS and sham TBS of DLPFC) in seventy-five EC-SCZ patients. The proposed study aims to provide initial evidence that TBS can acutely enhance DLPFC oscillatory activity, which in turn predicts better WM performance, in EC-SCZ patients. Building on these findings, future neuromodulation-based treatment interventions applying chronic doses of TBS may more persistently ameliorate/restore DLPFC oscillatory parameters and relat...