The clinical application of Deep Brain Stimulation (DBS) represents one of the most significant leaps in neuromodulation, yet the field remains constrained by a fundamental paradox: we are successfully deploying an intervention whose primary biophysical mechanisms remain a matter of intense academic debate. While it is clear that implanted electrodes can alleviate symptoms of psychiatric and neurological diseases, the black box nature of the interaction between electrical fields and neural tissue persists, For decades, the search for a definitive mechanistic framework has been stalled by electrical interference—where the stimulation pulse creates an artifact that drowns out the very neuronal signals we need to measure—and a persistent inability to record high-resolution membrane voltage in vivo during DBS. This project aims to break this technical impasse by shifting the paradigm from electrical to optical recording, utilizing cellular voltage fluorescence microscopy to bypass the artifact problem entirely. By integrating this advanced imaging with computational modeling in a mouse model of temporal lobe epilepsy, the research will provide an unprecedented view of how temporal lobe circuits react to DBS and provide the first direct in vivo evidence of how DBS modulates information transfer and network synchronization to enable therapeutic effects. This innovative and comprehensive approach will likely provide fundamental insights into the membrane voltage changes occurring with DBS, which will provide an unprecedented opportunity to build a data-driven mechanistic framework of DBS action with the ultimate goal of identifying more effective and targeted DBS protocols for human patients.
