Discrete cortico-hippocampal circuit states underlie mood state transitions in depression

The hippocampus has long been implicated in depression, yet the underlying mechanisms remain incompletely understood. Leveraging precision functional mapping in densely sampled individuals and large cross-sectional cohorts, and validating key results in direct intracranial EEG recordings from the human brain, we show that hippocampal connectivity alternates between two discrete and opposing network states on the order of minutes: one dominated by default mode network (DMN) coupling and another by sensorimotor system (SM) coupling. This dynamic switching is a fundamental property of hippocampal function in both healthy brains and in major depressive disorder (MDD). In MDD, this equilibrium is disrupted, such that the DMN-dominant state is overrepresented. In densely sampled individuals, hippocampus-DMN coupling tracks symptom fluctuations over time and normalizes after electroconvulsive therapy (ECT), which drives switches in hippocampal connectivity away from the DMN-dominant state and toward the SM-dominant state, an effect that was closely linked to a positive treatment response. Direct intracranial recordings in patients with MDD identified analogous fluctuations in hippocampal-DMN theta synchrony, which tracks symptom fluctuations over hours and days. Together, these findings identify a dynamic cortico-hippocampal mechanism underlying depression and indicate that successful neuromodulation treatments such as ECT act in part by restoring a dynamic equilibrium in hippocampal network connectivity.