PROJECT SUMMARY – Pulvinar Neuro LLC, TOWNSEND The causal role of circuit activity dynamics in depression remains poorly understood due to the lack of tools for non-invasive, targeted circuit modulation. Today’s non-invasive brain stimulation approaches apply generic stimulation waveforms without targeting individual activity signatures and without dynamically adapting stimulation to ongoing fluctuations in brain activity. To address this gap, the long-term goal of Pulvinar Neuro is to develop, evaluate, and commercialize targeted closed-loop transcranial alternating current stimulation (tACS) technology, which measures brain activity with EEG and dynamically applies weak rhythmic electric fields to modulate network oscillations. In the previous Phase 1 SBIR, Pulvinar Neuro developed XCSITE 100Pro, a closed-loop tACS device that was successfully tested for feasibility in healthy human participants, and XCSITE 200, a cloud-based platform for remote stimulation. The overall goal of this application is to develop and evaluate the XCSITE 300 platform that will integrate closed-loop capabilities with cloud-based stimulation and study management. The rationale for this project is that such a solution will drive the next generation of circuit-based research in psychiatry and that closed-loop tACS has the potential to become a safe and effective treatment for depression given the initial positive findings of open-loop tACS for the treatment of depression and the substantial unmet market need. Three specific aims will be pursued to accomplish this goal. (1) Integrate and bench test closed-loop tACS technology with cloud-based infrastructure, (2) Test XCSITE 300 for in-lab use in a pilot double-blind single-site study for the treatment of depression (XCSITE 300 Clinic), and (3) Adapt device form factor and user interface for at-home use (XCSITE 300 Home) and establish feasibility in a pilot study in people with depression. At completion of the proposed work, feasibility and preliminary efficacy of closed-loop tACS will be established and closed-loop tACS for use in a clinic and for at-home use by patients will be ready for pivotal studies for the treatment of depression. The work in this application is innovative given the lack of available cloud-enabled (“smart”) closed-loop tACS devices for probing circuit dynamics and for evaluation of clinical efficacy in rigorous double-blind trials. The proposed work is significant since closed-loop tACS will enable the investigation of the causal role of specific circuit dynamics in humans and the development of novel treatments for depression which are urgently needed.