Network Localization of Functional Brain Changes Associated With Ketamine's Therapeutic Effects in Depression.

Background: Although numerous studies have attempted to identify the functional pathways that underlie the rapid antidepressant effects of ketamine, their findings have been inconsistent, limiting our understanding of the neural mechanisms involved.

Methods: In this study, we aimed to delineate a specific brain circuit by integrating diverse functional findings related to ketamine's efficacy in depression. We conducted a systematic review of multimodal neuroimaging studies that reported brain locations associated with ketamine's effects on depression. Using functional connectivity network mapping and a large-scale normative connectome database, we mapped these locations onto a ketamine functional brain network. We tested the robustness of this network by evaluating its stability under parameter perturbations and leave-one-contrast-out validation and assessed its specificity for depression relative to other mental disorders. We further identified a ketamine-specific brain circuit compared with an antidepressant functional brain network constructed using the same methodology.

Results: Our review included 18 multimodal neuroimaging studies with 440 individuals with depression and 174 healthy control individuals. The heterogeneous brain locations localized to a connected network primarily involving regions implicated in the default mode, ventral attention, and frontoparietal networks. This network demonstrated robustness to minor perturbations and validation and was specifically linked to depression. Compared with the antidepressant functional brain network, the ketamine-specific brain circuit predominantly encompassed brain regions such as the subgenual cingulate cortex and dorsolateral prefrontal cortex, which aligned with optimal brain stimulation sites for depression.

Conclusions: These findings help reconcile seemingly inconsistent neuroimaging results and provide new insights into the neuropathology of ketamine's therapeutic effects from a network perspective.