Ladret, H. J.; Lupori, L.; Sieni, L.; Stroukov, E.; Kanamori, T.; Ulrich, S.; Schneider, E.; Deuring, G.; Bruhl, A. B.; Keller, G. B.

Electroconvulsive therapy (ECT) is a highly effective treatment for several psychiatric disorders, though its biological mechanisms remain unclear. Its therapeutic action has traditionally been attributed to the generalized seizure ECT induces. However, this view is challenged by the recent finding that electroconvulsive stimulation (ECS) can trigger a cortical spreading depression (CSD). Because CSD triggers massive intracellular molecular changes, we hypothesized that it could be a key mediator of ECT's therapeutic, plasticity-inducing effects. We observed similar neuronal oscillations following ECS in mice and patients undergoing ECT. We show that CSD drives increased expression of the immediate early gene Fos, a key marker of neuronal plasticity, and is associated with factors that predict positive ECT therapeutic outcome. Our results suggest that the therapeutic efficacy of ECT may be mediated by CSD. This challenges the seizure-centric model and implies that CSD, a currently unmonitored neurophysiological event, may serve as a more relevant biomarker for predicting and optimizing therapeutic outcomes of ECT.