Parsing the Network Mechanisms of Electroconvulsive Therapy

ABSTRACT Electroconvulsive therapy is one of the oldest and most effective forms of neurostimulation, where electrical current is used to elicit brief, generalized seizures under general anesthesia. When electrodes are positioned to target fronto-temporal cortex, ECT is arguably the most effective treatment for severe major depression, with response rates and times superior to other available antidepressant therapies. Neuroimaging research has been pivotal in improving the field’s mechanistic understanding of ECT, with a growing number of MRI studies demonstrating hippocampal plasticity after ECT, in line with evidence of upregulated neurotrophic processes in the hippocampus in animal models. However, the precise roles of the hippocampus and other brain regions in antidepressant response to ECT remain unclear. Seizure physiology may also play a role in antidepressant response to ECT, as indicated by early PET/SPECT and EEG research, and corroborated by recent ECT-MRI studies. In this review, we discuss the evidence supporting neuroplasticity in the hippocampus and other brain regions during and after ECT, and their associations with antidepressant response. We also offer a mechanistic, circuit-level model which proposes that core mechanisms of antidepressant response to ECT involve thalamocortical and cerebellar networks that are active during seizure generalization and termination over repeated ECT sessions, and their interactions with corticolimbic circuits that are dysfunctional prior to treatment and targeted with the electrical stimulus.