Electroconvulsive therapy (ECT) is a fast-acting, highly effective, and safe treatment for medication-resistant depression. Historically, the clinical benefits of ECT have been attributed to generating a controlled seizure
however, the underlying neurobiology is understudied and unresolved. Using optical neuroimaging of neural activity and hemodynamics in a mouse model of ECT, we demonstrated that a second brain event follows seizure: cortical spreading depolarization (CSD). We found that ECT pulse parameters and electrode configuration directly shaped the wave dynamics of seizure and subsequent CSD. To translate these findings to human patients, we used non-invasive diffuse optical monitoring of cerebral blood flow and oxygenation during routine ECT treatments. We observed that human brains reliably generate hyperemic waves after ECT seizure which are highly consistent with CSD. These results challenge a long-held assumption that seizure is the primary outcome of ECT and point to new opportunities for optimizing ECT stimulation parameters and treatment outcomes.