This review (2021) argues that the changes in the anterior cingulate cortex (AAC) are the key to ketamine’s antidepressant effects. The subgenual and dorsal zones of the AAC are identified as most important in the ability to feel pleasure again.
“The subdivisions of the anterior cingulate cortex (ACC) – including subgenual, perigenual and dorsal zones – are implicated in the etiology, pathogenesis and treatment of major depression. We review an emerging body of evidence which suggests that changes in ACC activity are critically important in mediating the antidepressant effects of ketamine, the prototypical member of an emerging class of rapidly acting antidepressants. Infusions of ketamine induce acute (over minutes) and post-acute (over hours to days) modulations in subgenual and perigenual activity, and importantly, these changes can correlate with antidepressant efficacy. The subgenual and dorsal zones of the ACC have been specifically implicated in ketamine’s anti-anhedonic effects. We emphasize the synergistic relationship between neuroimaging studies in humans and brain manipulations in animals to understand the causal relationship between changes in brain activity and therapeutic efficacy. We conclude with circuit-based perspectives on ketamine’s action: first, related to ACC function in a central network mediating affective pain, and second, related to its role as the anterior node of the default mode network.“
Authors: Laith Alexander, Luke A. Jelen, Mitul A. Mehta & Allan H. Young
Correspondence: [email protected]
The anterior cingulate cortex is divided into three subdivisions, each consisting of multiple cytoarchitectonic Brodmann Areas (BAs), and is associated with major depression. Ketamine is the prototypical agent of a new ‘glutamate -based’ class of antidepressants; it attenuates depression symptoms within four hours and gradually builds to a maximum 24-72 hours later. Its mechanism of action is poorly understood at the molecular, cellular and circuit level.
NMDAR blockade can cause a glutamate surge acutely, followed by mTOR -mediated neuroplastic changes over several hours to days. However, ketamine’s antidepressant effects may also be mediated by AMPARs. Ketamine has a broad action on several neurotransmitter systems, including the glutamatergic transmission, the monoaminergic, cholinergic and opioid systems. It also modulates activity within the subgenual anterior cingulate cortex over acute and post-acute time courses. The sgACC is a heterogenous brain region that encompasses several BAs including BA24 and BA25 caudally. It is associated with increased activity in people with major depression.
The sgACC is likely to be important in the regulation of mood, and changes in activity within the sgACC may have effects on both positive and negative mood.
Macaque sgACC has reward-sensitive ventral region and punishment-sensitive dorsal region, which may explain heterogeneous responses to antidepressants. The acute effects of ketamine on the sgACC occur within minutes, with the post-acute effects occurring over hours. The decrease in BOLD signal in sgACC /24,32 correlated with dissociative symptoms, but the functional importance of this correlation is not clear. The activity of the dorsolateral prefrontal cortex increased in parallel with the activity of the superior frontal gyrus.
In this study, lamotrigine partially attenuated the inhibition of sgACC/24,32 by blocking glutamate release, but it also had additional effects on hyperpolarization-activated and cyclic nucleotide -gated (HCN) -mediated Ih-currents, which likely contribute to its effects. Studies using H215O PET and arterial spin labelling techniques to measure regional cerebral blood flow (rCBF) in healthy volunteers have shown acute increases in sgACC blood flow associated with ketamine infusions. There are three important differences between rCBF studies and BOLD -fMRI studies, including the time it takes to acquire the scan, the temporal resolution of the scan, and the type of administration used. This may account for the increased rather than decreased signal changes in sgACC and pgACC.
Studies in healthy volunteers are valuable in understanding the effects of ketamine on brain activity because they highlight sensitive brain regions and neural circuits, and can be used to test specific neuropsychopharmacological models using receptor blockers. Several studies have identified changes in sgACC activity associated with ketamine, some of which show correlation with antidepressant efficacy. Over longer time courses, antidepressant treatment with ketamine is associated with improvements in symptoms of anhedonia and the reduction of aberrant sgACC over-activity to rewarding incentives.
A study in people with major depression found an acute increase in sgACC activity following a continuous ketamine infusion without a bolus dose. Ketamine administration induces a brisk, transient physiological response including increased heart rate and blood pressure. The acute lowering of sgACC activity might reflect a compensatory mechanism to maintain homeostasis by increasing vagal tone in response to increases in heart rate and/or blood pressure. Studies in rodents and non-human primates have shown that the acute decrease in sgACC BOLD activity over minutes following a ketamine bolus could be a vascular artefact, or could be explained by the attenuation of the effect by risperidone, a D2, 1, and 5HT2A-antagonist.
Animal studies are invaluable for studying the ACC, as its subregions project to both higher order cortical areas and several important subcortical areas. These studies are particularly important when discussing the sgACC, as its manipulations have opposite effects in non-human primates. Ketamine alters the functional connectivity of the sgACC/24, 25, 32 regions to the dlPFC in macaques, marmosets, and humans, and prevents the deficits in anticipatory arousal to reward induced by pharmacological over-activation of the sgACC/25 region.
Ketamine rapidly modulates the putative functional analogue to sgACC/25 in rodents, increasing extracellular levels of glutamate within 40 minutes. Acute infusions of ketamine into IL evoke sustained antidepressant-like and anxiolytic-like effects, but acute inhibition of EAAT2 on astrocytes within IL does not. Ketamine modulates glutamate levels acutely in IL, which may explain the antidepressant-like effects of ketamine on rodent assays. However, the functional similarity between IL and BA32 may complicate the interpretation of rodent data.
Several studies have shown changes in sgA CC activity following ketamine infusion, but whether pgACC (BA24, 32) undergoes such rapid changes is unclear. Using resting-state fMRI, Scheidegger and colleagues found no difference in functional connectivity between the pgACC and the putamen 25 minutes after ketamine infusion in healthy volunteers. However, early studies employing H 215O PET showed changes in rCBF in the pgACC during ketamine infusions.
Activity modulations within pgACC occur over post-acute time courses of several hours to days, and include changes in glutamate:glutamine ratios, DMN connectivity, and BOLD-fMRI responses to negative pictures.
In people with major depression, ketamine infusions reduced functional connectivity of the pgACC/24,32 region with the right caudate and other prefrontal regions, and this connection persisted up to three weeks after infusion, despite improvements in HAM-D scores having returned to baseline.
Ketamine has opposite effects on sgACC and pgACC to putamen fronto-striatal connectivity in healthy volunteers compared to people with depression. This could contribute to the sustained anti-anhedonic action of ketamine.
Ketamine’s action over a time course of several hours or longer may be associated with neuroplastic changes in the pgACC, sgACC and other cingulate/limbic regions, a suggestion corroborated by preclinical work in animals. Ketamine increases levels of synaptic proteins in the prelimbic cortex and induces synapse formation 24 hours after intraperitoneal injection. Ketamine also prevents stress-associated decreases in synaptic spine density selectively in PL but not in IL several days after administration.
Ketamine’s action on the PL-DRN-amygdala circuit may be important in its antidepressant action. Anterior cingulate activity changes may be used to distinguish ketamine responders and non responders. If functional changes in the sgACC and pgACC are important in mediating the antidepressant effects of ketamine, then pre-treatment activity in these regions could predict successful response to ketamine.
A number of studies have looked at the relationship between neuroimaging biomarkers and ketamine response, and they have found that sgACC and pgACC activity may be involved. Vasavada et al. investigated whether fractional anisotropy (FA) in important fronto-limbic fiber tracts could be used to predict the efficacy of ketamine, and found that larger FA was associated with a better antidepressant response. Ketamine has shown promise in alleviating symptoms of anhedonia in people with bipolar disorder, and activity modulations within sgACC, dACC and adjacent dmPFC have most robustly been associated with this action.
Ketamine increased activity in the dACC/32 and dmPFC post-ketamine infusion, which was associated with decreased anhedonia. The sgACC was also found to be involved in mediating the anti anhedonic effects of ketamine. Ketamine has been demonstrated to ameliorate anhedonic-like behaviors in marmosets by altering the responsiveness of sgACC/25 to increases in extracellular glutamate induced by DHK. This effect was mediated by changes in activity in a downstream network of brain regions including dACC/24,32.
Ketamine induces negative symptoms of schizophrenia in healthy volunteers, including anhedonia and lassitude. These higher doses correlate with changes in NMDAR occupancy in dACC/24,32 and dmPFC, and increased connectivity between dACC/32 and dlPFC.
Ketamine’s effects on emotional pain networks in the anterior cingulate cortex could represent an important way in which ketamine reduces the ‘mental anguish’ associated with depression.
Ketamine’s opioid-mediated action may be an indirect effect, and naltrexone blocks ketamine’s sustained antidepressant effects in people with treatment-resistant depression. Ketamine’s rapid antidepressant response is also dependent on opioid receptor activation.
Dynorphins, endogenous agonists of KORs, are thought to lower mood and promote self-harming behavior, and may mediate the excessive emotional pain associated with depression. Ketamine induces KOR internalization in HEK293 cell lines and blocks dynorphins’ effects to stimulate activity within the lateral habenula, a region critical in mediating the antidepressant effects of ketamine. Ketamine’s rapid effects on depression ratings may be due to a direct action on sgACC/24,25, which sits directly above the cribriform plate. This would block a key node in the higher -order emotional pain circuit, and induce plastic changes in dlPFC over longer time courses. Ketamine’s action has been demonstrated in animal models of chronic pain by using the ACC to mediate the action of ketamine.
A single subanesthetic dose of ketamine alleviated mechanical allodynia in CFA-treated rodents, but the effect persisted for 5 days. This suggests that ketamine’s affective analgesic effect lasts significantly beyond its somatic analgesic effect. Ketamine’s affective analgesic effect could be due to its action on ACC opioid receptors, but further work is needed to understand the causal role of ACC subregions and opioid receptors in mediating ketamine’s antidepressant effect.
The DMN is a network of brain regions involved in internally directed, self-referential processes. Abnormalities in the DMN include excessive functional connectivity between components of the DMN itself and excessive functional connectivity between the sgACC and the DMN. Ketamine’s effectiveness depends in part on reducing connectivity between regions implicated in the DMN and modulating how these regions respond to emotional stimuli. This may be because ketamine breaks a pathological ruminative circuit of activity within which the ACC is locked. Greicius and colleagues showed that people with depression have greater functional connectivity between the DMN and sgACC /25, which is predicted by high levels of rumination. Successful treatment of major depression reduces sgACC -DMN connectivity, both in the case of SSRIs and transcranial magnetic stimulation.
Ketamine reduces connectivity between the sgACC and the DMN in healthy volunteers, and increases connectivity between the sgACC and the dmPFC in people with depression. This increased connectivity is associated with a greater antidepressant effect at 24 hours following ketamine treatment. A future study could test the connection between sgACC and DMN during active rumination and ketamine treatment. The high density of KORs within sgACC /25 are consistent with this hypothesis.
The anterior cingulate interacts with several other brain regions implicated in ketamine’s antidepressant response, including the lateral habenula, which mediates ketamine’s rapid antidepressant-like effect in the forced swim test and the effects of chronic pain on depression-like behaviors. Ketamine’s modulation of ACC connectivity to the ventral striatum could have feedforward effects on cognitive and motor cortico-striatal circuits, potentially leading to changes in cognition and motor function in directions which could differ from its effects in healthy controls.
In addition to neuronal atrophy, the hippocampus shows decreased levels of BDNF and VEGF expression in major depression. This pathway has been implicated in the pathogenesis of schizophrenia and depression. Carreno et al. demonstrated that projections from the ventral hippocampus to the IL are both necessary and sufficient for the sustained antidepressant-like effects of ketamine. Ketamine may also increase BDNF release in the ventral hippocampus leading to TrkB phosphorylation and plasticity within the ventral hippocampal -IL pathway.
Ketamine may act on several regions in the brain, including the hippocampal-ACC pathway, the cingulate-striatal loop, and the striatum. These regions may play a role in ketamine’s antidepressant effects. Ketamine’s effects on the anterior cingulate cortex are replicated in healthy controls and people with major depression, and vary in directionality across studies. These differences could be due to different time courses over which ketamine’s action was studied, different neuroimaging paradigms, different symptom domains being measured, and cross-species differences.
Ketamine’s antidepressant effect over acute and post-acute time courses is mediated by modulation of sgACC/25 activity and pgACC/24,32 activity. Ketamine also has delayed effects within pgACC, with neuroplastic and synaptogenic effects taking place over several hours or longer. Ketamine’s effects to reverse over-activity in the sgACC are correlated with anhedonia improvement in people with major depression and bipolar disorder. More work is needed to parcellate the role of different ACC subregions in anhedonia and its responsiveness to certain antidepressants. Ketamine may be particularly effective in inhibiting pathological, negative affect laden rumination mediated by excessive connectivity within the DMN.
Future investigations must continue to characterize ketamine’s effects on the anterior cingulate in people with major depression, as well as the neural correlates of ketamine’s effects on specific symptom clusters. Ketamine has much still to teach us about the underlying neurobiology of mood disorders. It is likely that its unique effects are due to a direct action within the ACC itself, or through effects on other brain regions which subsequently modulate ACC activity.
Ketamine treatment and global brain connectivity in major depression. Preclinical studies, especially in non-human primates, are crucial in establishing causality, and clinical studies must carefully stratify patient cohorts and understand the specific symptom clusters that ketamine is treating.
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A double-blind, placebo-controlled, randomized, longitudinal resting fMRI study examined the effects of ketamine on prefrontal cortex-related circuits in treatment-resistant depression.
Fuchikami, M., Thomas, A., Liu, R., Wohleb, E.S., Land, B.B., DiLeone, R.J., Aghajanian, G.K., and Duman, R.S. (2015) reported that optogenetic stimulation of infralimbic PFC reproduces ketamine’s rapid and sustained antidepressant actions.
Infralimbic GLT-1 blockade in rats evokes rapid antidepressant -like effects and changes connectivi ty of functional brain networks, including the thalamus, in healthy women and in patients with major depressive disorder.
A concurrent 11 C -raclopride positron emission tomography and functional magnetic resonance imaging investigation of major depression found that the ventromedial prefrontal cortex plays a multifaceted role in emotion, decision making, social cognition, and psychopathology. Ketamine-dependent neuronal activation in healthy volunteers, PET with H215O demonstration of ketamine actions in CNS dynamically, Janssen-Cilag’s Spravato 28 mg nasal spray summary of product characterists, and a randomised clinical trial in psychotic disorders are all mentioned in the article. Ketamine: A tale of two enantiomers, Joyce, M.K.P., Barbas, H., Kaiser, R.H., Andrews-Hanna, J.R., Wager, T.D., and Pizzagalli, D.A. (2018). Cortical connections position primate Area 25 as a keystone for interoception, emotion, and memory.
Ketamine modulates hippocampal neurochemistry and functional connectivity in healthy volunteers and treatment-resistant bipolar depression. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine treatment are also studied.
Ketamine and Beyond: Investigations into Ketamine’s Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities.
A variety of research studies have shown that deep brain stimulation can help treat depression, including the formation of new synapses in the subcallosal cingulate gyrus and the reversal of behavioral and synaptic deficits caused by chronic stress exposure. Ketamine induces large-scale persistent network reconfiguration in anesthetized monkeys: relevance to mood disorders. Maltbie, E., Gopinath, K., Urushino, N., Kempf, D., and Howell, L. (2016).
Ketamine treatment of major depressive disorder is associated with an amino acid neurotransmitter response similar to that seen in patients treated with deep brain stimulation.
Treatment-refractory depression with intranasal ketamine may be due to NMDA receptor actions in the pain circuitry representing mental anguis h.
A default mode network of brain function is believed to underlie depression and is involved in the regulation of threat and reward-elicited responses. A connectomic approach for subcallosal cingulate deep brain stimulation is being used to target the region for treatment-resistant depression. Anterior Cingulate Cortical Activity and Functional Connectivity with the Amygdala Predict Rapid Antidepressant Response to Ketamine.
Ketamine administration reduces amygdalohippocampal reactivity to emotional stimulation in rats. Serafini, G., Adavastro, G., Canepa, G., De Berardis, D., Valchera, A., Pom pili, M., Nasrallah, H., and Amore, M. (2018). Ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression: a 123I-CNS-1261 SPET study. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: a relationship to ketamine-induced psychopathology. Ketamine has no effect on cortical glutamate and glutamine in healthy volunteers, and there are many different models for the pathophysiology of major depressive disorder.
Ketamine has been shown to be effective in the treatment of depression, but its effects are attenuated by opioid receptor antagonism.
Ketamine modulates subgenual cingulate connectivity with the memory-related neural circuit to rapidly relieve depression. Yang, C., Shirayama, Y., Zhang, J., Ren, Q., Yao, W., Ma, M., Dong, C., and Hashimoto, K. (2015).
Transient effects of multi-infusion ketamine augmentation on treatment-resistant depressive symptoms in patients with treatment -resistant bipolar depression.