Intracranial directed connectivity links subregions of the prefrontal cortex to major depression

Research on the neural basis of major depressive disorder suggests that it is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neuronal systems lead to diminished emotion regulation and intrusive rumination. Subregions of the prefrontal cortex are thought to be sources of this disinhibition. However, due to limited opportunities for intracranial recordings from humans with major depression, this hypothesis has not been directly tested. Here, we use intracranial recordings from the dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortices from patients with major depression to measure daily fluctuations in self-reported depression symptom severity. Results indicate that directed connectivity within the delta frequency band, which has been linked to cortical inhibition, transiently increases intensity during negative mood. Symptom severity also shifts as connectivity patterns within the left and right prefrontal cortices become imbalanced. Our findings support the overarching hypothesis that depression worsens with prefrontal disinhibition and functional imbalance between hemispheres.