Spreading depolarization, not seizure activity, drives immediate early gene expression in mouse cortex after electroconvulsive stimulation

Electroconvulsive therapy (ECT) is a highly effective treatment for several psychiatric disorders, though its biological mechanisms remain unclear. ECT's therapeutic action has traditionally been attributed to the generalized seizure it induces. However, this view is challenged by the recent finding that electroconvulsive stimulation (ECS) can trigger a spreading depolarization (SD) in cortex. Because SD drives massive molecular changes, including expression of the plasticity-related immediate early gene Fos, we hypothesized that SD could be a key mediator of ECT's plasticity-inducing effects. We recorded the neuronal response to ECS in mouse dorsal cortex and observed similar activity to that of patients undergoing ECT. SD, rather than the seizure activity, accounted for increased Fos expression in mouse dorsal cortex. SD was also associated with EEG features that predict positive treatment outcome of ECT in patients. Our results suggest that the therapeutic efficacy of ECT may be mediated by SD and imply that a currently unmonitored neurophysiological event may serve as a relevant biomarker to predict and optimize ECT outcomes.