The anterior cingulate cortex as a key locus of ketamine’s antidepressant action

Introduction

Neuroimaging work has repeatedly linked activity within the anterior cingulate cortex (ACC) to the pathophysiology of major depression and to successful antidepressant treatments. The ACC is anatomically and functionally heterogeneous and is commonly subdivided into subgenual (sgACC), perigenual (pgACC) and dorsal (dACC) zones. Ketamine, a prototype glutamate-based rapid-acting antidepressant, produces clinical improvements within hours to days, but its molecular and circuit-level mechanisms remain incompletely understood. The balance of N-methyl-D-aspartate receptor (NMDAR) expression across cell types, ketamine-induced glutamate surges, downstream synaptogenic signalling (for example via mTOR), and actions on multiple neurotransmitter systems (including AMPAR, monoaminergic and opioid systems) are all implicated to varying degrees in its effects. Alexander and colleagues set out to review evidence connecting ketamine’s antidepressant effects to modulations of ACC activity. The review synthesises human neuroimaging findings (BOLD-fMRI, PET, arterial spin labelling, MRS, MEG), clinical correlational studies, and causal manipulations from animal models (rodents and non-human primates). Particular emphasis is placed on the temporal dynamics of ketamine’s action (acute changes over minutes versus post-acute changes over hours-to-days), the role of ACC subregions in specific symptom domains such as anhedonia and suicidal ideation, and circuit-level hypotheses linking the ACC to emotional pain and default mode network (DMN) dysfunction.