Insights on the cellular mechanisms of intracranial electrical stimulation using optical imaging in preclinical models.

Intracranial electrical stimulation is increasingly used to treat neurological and psychiatric conditions. However, the underlying therapeutic mechanisms at the cellular and circuit levels remain poorly understood. Exciting progress in the development of genetically encoded neural activity indicators enables artifact-free, high-spatiotemporal-resolution optical analysis of the impact of intracranial stimulation on membrane potentials, cytosolic calcium, and neurotransmitter and neuromodulator dynamics. Using these optical imaging tools in vivo, in the mammalian brain, preclinical studies probed the effect of intracranial stimulation on individual neurons and population network dynamics across timescales ranging from milliseconds to minutes or more. These studies have revealed complex, stimulation parameter-dependent effects across cell types and provided experimental support for various therapeutic mechanisms. We discuss these studies in the context of clinical observations and highlight the exciting potential of optical imaging in advancing the mechanistic understanding of clinical electrical stimulation in epilepsy and other neurological and psychiatric orders.