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

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.

The extracted text presents a narrative, integrative review rather than a report of a new experimental study. It does not describe a formal systematic search strategy, inclusion/exclusion criteria, or pre-registered methods; instead, the paper collates and synthesises findings from multiple human neuroimaging modalities and preclinical experimental approaches. Evidence sources brought together include: human BOLD-fMRI studies (task-based and resting-state), H2 15 O PET and arterial spin labelling studies measuring regional cerebral blood flow (rCBF), magnetic resonance spectroscopy (MRS) measuring glutamate and glutamine, magnetoencephalography (MEG), 18F-FDG PET metabolic measures, and diffusion MRI measures of white matter integrity. On the preclinical side, the review integrates rodent and non-human primate experiments employing pharmacological manipulations (local infusions, systemic dosing), receptor blockers, optogenetics, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and PET/fMRI in awake animals. The authors frame analyses around two time scales of ketamine action—acute (within minutes, during or immediately after infusion) and post-acute (hours to days)—and around anatomical subdivisions of the ACC (sgACC, pgACC, dACC). Where available, they report associations between imaging changes and clinical outcomes (depression scores, suicidal ideation, anhedonia scales) and note studies that probe causal mechanisms in animals. The extracted text does not report quantitative meta-analytic methods, pooled effect sizes, or risk-of-bias assessments, consistent with a qualitative review approach.

Across human neuroimaging studies, ketamine produces both rapid and delayed changes in ACC activity and connectivity, but the direction and timing of these effects vary by modality, dosing regimen and population. In healthy volunteers, minute-by-minute BOLD-fMRI during a ketamine bolus showed deactivation in sgACC (BA24/32/25) beginning within minutes and persisting for several minutes; this acute decrease correlated with dissociative symptoms on the CADSS in one study. By contrast, PET and arterial spin labelling studies with coarser temporal resolution often report acute increases in rCBF in ACC regions during infusions. The divergence between BOLD and rCBF findings may reflect differences in temporal resolution, bolus versus slow-infusion protocols, and spatial resolution that conflates sgACC subregions. In people with major depression, post-acute changes (hours to days) in sgACC and pgACC activity/connectivity are more consistently linked to clinical benefit. Examples include correlations between reduced sgACC 18F-FDG uptake and reductions in suicidal ideation at around 230 minutes, reduced sgACC–insula connectivity at similar timepoints, and relationships between altered sg/pgACC–striatal connectivity and improvements in anhedonia measured days after infusion. Some studies report that baseline sg/pgACC measures predict response: MEG markers of sg/pgACC disengagement during cognitive tasks, elevated baseline sgACC metabolism, and structural white matter integrity (fractional anisotropy in the cingulum bundle and forceps minor) have each been associated with better antidepressant responses to ketamine. The pgACC shows equivocal acute findings across studies (MRS and fMRI results are mixed), but more consistent post-acute modulations emerge 24–48 hours after infusion. For example, increases in pgACC glutamate:glutamine ratios at 24 hours have been tied to changes in default mode network connectivity, and reductions in pgACC connectivity to frontal regions or expansions of global connectivity have been observed across 24–48 hours and up to days after repeated infusions. In rodents, the prelimbic cortex (putative pgACC homologue) demonstrates mTOR activation, increased synaptic proteins within 2–6 hours, and synaptogenesis by 24 hours after ketamine; functional manipulations of prelimbic–dorsal raphe nucleus projections modulate ketamine’s prophylactic effects on stress resilience. dACC and caudal sgACC/25 have been implicated in ketamine’s anti-anhedonic effects. Human PET and fMRI studies found that decreased anhedonia correlated with increased dACC/dmPFC activity and with reversal of sgACC/25 hyper-responsivity to positive incentives. Marmoset work showed that ketamine prevents reward-related anticipatory deficits induced by sgACC/25 over-activation and that ketamine alters sgACC glutamate handling and downstream dACC/dmPFC activity. Conversely, in healthy volunteers higher ketamine doses can induce transient negative symptoms and reduce rCBF in dACC/dmPFC, underlining dose- and state-dependent effects. Circuit-level findings highlight the ACC’s interactions with the lateral habenula, striatum and hippocampus. Preclinical evidence shows lateral habenula NMDAR antagonism mediates rapid antidepressant-like effects and that ACC projections converge with habenula and striatal circuits implicated in reward and punishment signalling. Alterations in ACC–striatal connectivity after ketamine appear circuit- and diagnosis-specific, with opposing directionality between healthy controls and depressed patients in some studies. Finally, the opioid system has emerged as a potential mediator: small clinical trials reported that pre-treatment with naltrexone blocked ketamine’s sustained antidepressant and antisuicidal effects, and rodent studies indicate opioid receptor involvement; these findings are preliminary and require replication.

Alexander and colleagues interpret the assembled evidence to position the ACC—subgenual, perigenual and dorsal subdivisions—as a key cortical locus for ketamine’s antidepressant action. They emphasise that ketamine induces both rapid, focal changes detectable during infusions (notably in sgACC) and delayed, plasticity-related changes over hours-to-days (notably in pgACC and its connectivity). The authors argue that ACC modulations are functionally important because they correlate with symptom improvements (including antidepressant response, reductions in suicidal ideation, and amelioration of anhedonia) and because causal manipulations in animals implicate ACC subregions in ketamine-like behavioural effects. The review situates these findings within two inter-related circuit hypotheses. One posits that ketamine reduces activity in a medial 'emotional pain' network anchored on caudal sgACC/25, thereby alleviating affective pain and potentially suicidal ideation. The other proposes that ketamine disrupts pathological engagement of the anterior node of the default mode network (pgACC/mPFC) with the sgACC, thereby breaking ruminative, self-referential processing. Both perspectives are supported to varying degrees by human imaging and animal circuit-manipulation studies, and the ACC’s dense reciprocal connections with lateral habenula, striatum and hippocampus provide plausible routes for ketamine’s rapid versus sustained effects. Key limitations and uncertainties acknowledged by the authors include heterogeneity in findings across imaging modalities, dosing regimens, bolus versus infusion protocols, species differences between rodents, non-human primates and humans, variability in symptom domains measured, and the predominance of healthy volunteer studies for some acute imaging findings. The authors note that some ACC changes observed during infusion may reflect physiological or vascular confounds (for example, autonomic changes or proximity to major arteries) and that PET versus BOLD discrepancies complicate interpretation of acute effects. For future work, the review calls for more longitudinal neuroimaging in people with major depression to characterise the full temporal profile of ACC changes, experiments that link neural signatures to specific symptom clusters rather than global depression scores, systematic comparisons of ketamine enantiomers and metabolites, further causal translational studies in non-human primates, and careful patient stratification. They also highlight the need to clarify the opioid system’s role, given preliminary clinical and preclinical evidence that opioid receptor activity may be necessary for some sustained antidepressant effects. Finally, the authors caution that ACC modulation is not unique to ketamine—ACC changes occur with other antidepressant treatments—so determining which aspects of ACC modulation are ketamine-specific versus shared across therapies remains an open question.