Ketamine normalizes subgenual cingulate cortex hyper-activity in depression
Open accessAbstract
Mounting evidence supports the rapid antidepressant efficacy of the N-methyl-D-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven in part by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful antidepressant treatment. This study aimed to examine whether task-based sgACC activity was higher in patients with MDD compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol at baseline and following a 40 min infusion of ketamine (0.5 mg/kg). Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its antidepressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Ketamine infusion reduced FC between the sgACC and limbic regions (e.g., hippocampus).
“Specifically, ketamine infusion reduced (1) hyperactivation in the sgACC (BA25) to positive feedback [121], (2) FC between the pgACC and dACC [199], and (3) FC between the sgACC and limbic regions (e.g., hippocampus) [121].”
From Prefrontal cortex and depression (2022) · cites this paper as [121]
The Effects of ketamine section explicitly reports no significant change in hippocampus–sgACC connectivity before versus after ketamine (p > 0.05). The Discussion mentions reduced connectivity in a previous study of healthy men, but that is not the finding of this paper’s ketamine cohort. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAmong TRD patients, sgACC hyper-activation to positive feedback correlated with more anticipatory anhedonia (but not anxiety symptoms).
“Finally, among TRD patients, sgACC hyper-activation to positive feedback correlated with more anticipatory anhedonia (but not anxiety symptoms) [121].”
From Prefrontal cortex and depression (2022) · cites this paper as [121]
The Participants results report that sgACC activation to positive feedback correlated with worse anticipatory anhedonia, but not anxiety. However, the correlation was calculated across the full sample of depressed patients and healthy controls, not specifically among TRD patients. The Participants and procedures section does not establish treatment resistance as a criterion for that cohort. (LLM, conf=0.90)
Experimental — accuracy not yet measuredKetamine infusion reduced hyperactivation in the sgACC (BA25) to positive feedback.
“Specifically, ketamine infusion reduced (1) hyperactivation in the sgACC (BA25) to positive feedback [121], (2) FC between the pgACC and dACC [199], and (3) FC between the sgACC and limbic regions (e.g., hippocampus) [121].”
From Prefrontal cortex and depression (2022) · cites this paper as [121]
The Discussion reports that ketamine reduced sgACC activation to positive feedback in patients with MDD (Fig. 3). However, the BA25-specific analysis in “Subdivisions within sgACC” found only a trend toward reduced hyperactivity (p = 0.062), so the claim states that more specific result more firmly than the paper does. (LLM, conf=0.85)
Experimental — accuracy not yet measuredsgACC hyper-activation to positive (but not negative) incentives was normalized (decreased) by a single ketamine infusion.
“Importantly, sgACC hyper-activation to positive (but not negative) incentives was normalized (decreased) by a single ketamine infusion.”
From Prefrontal cortex and depression (2022) · cites this paper as [121]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A new depression scale designed to be sensitive to change
Montgomery, S. A., & Åsberg, M. (1979) · British Journal of Psychiatry · doi:10.1192/bjp.134.4.382 · Cited by 13,962 · see citing works
Jenkinson, M., Beckmann, C. F., Behrens, T. E. J., Woolrich, M. W., & Smith, S. M. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2011.09.015 · Cited by 11,314 · see citing works
AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages
Cox, R. W. (1996) · Computers and Biomedical Research · doi:10.1006/cbmr.1996.0014 · Cited by 10,913 · see citing works
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.11.1905 · Cited by 5,643 · see citing works
Deep Brain Stimulation for Treatment-Resistant Depression
Mayberg, H. S., Lozano, A. M., Voon, V., McNeely, H. E., Seminowicz, D., Hamani, C., Schwalb, J. M., & Kennedy, S. H. (2005) · Neuron · doi:10.1016/j.neuron.2005.02.014 · Cited by 4,059 · see citing works
Antidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856 · see citing works
Self-citationA randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · see citing works
Self-citationGrand challenges in global mental health
Collins, P. Y., Patel, V., Joestl, S. S., March, D., Insel, T. R., Daar, A. S., Bordin, I. A., Costello, E. J., Durkin, M., Fairburn, C., et al. (2011) · Nature · doi:10.1038/475027a · Cited by 2,043 · see citing works
Principles of Behavior. An Introduction to Behavior Theory
N., E., & Hull, C. L. (1943) · The Journal of Philosophy · doi:10.2307/2019960 · Cited by 1,731 · see citing works
Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., Iqbal, S., Pillemer, S., Foulkes, A., Shah, A., et al. (2013) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.13030392 · Cited by 1,205 · see citing works
Self-citationThe subgenual anterior cingulate cortex in mood disorders
Drevets, W. C., Savitz, J., & Trimble, M. (2008) · CNS Spectrums · doi:10.1017/s1092852900013754 · Cited by 1,109 · see citing works
Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder
Zhang, J., Wang, J., Wu, Q., Kuang, W., Huang, X., He, Y., & Gong, Q. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.05.018 · Cited by 951 · see citing works
Architectonic subdivision of the human orbital and medial prefrontal cortex
Öngür, D., Ferry, A. T., & Price, J. L. (2003) · Journal of Comparative Neurology · doi:10.1002/cne.10609 · Cited by 944 · see citing works
Murrough, J. W., Perez, A. M., Pillemer, S., Stern, J., Parides, M. K., aan het Rot, M., Collins, K. A., Mathew, S. J., Charney, D. S., & Iosifescu, D. V. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.06.022 · Cited by 786 · see citing works
Self-citationAnterior cingulate cortex: unique role in cognition and emotion
Stevens, F. L., Hurley, R. A., & Taber, K. H. (2011) · The Journal of Neuropsychiatry and Clinical Neurosciences · doi:10.1176/jnp.23.2.jnp121 · Cited by 779 · see citing works
MacQueen, G., & Frodl, T. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.80 · Cited by 665 · see citing works
The Neural Correlates of Anhedonia in Major Depressive Disorder
Keedwell, P. A., Andrew, C., Williams, S. C. R., Brammer, M. J., & Phillips, M. L. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.05.019 · Cited by 650 · see citing works
Differentiating BOLD and non-BOLD signals in fMRI time series using multi-echo EPI
Kundu, P., Inati, S., Evans, J. W., Luh, W., & Bandettini, P. A. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.12.028 · Cited by 604 · see citing works
Johansen-Berg, H., Gutman, D. A., Behrens, T. E. J., Matthews, P. M., Rushworth, M. F. S., Katz, E., Lozano, A. M., & Mayberg, H. S. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhm167 · Cited by 561 · see citing works
Integrated strategy for improving functional connectivity mapping using multiecho fMRI
Kundu, P., Brenowitz, N. D., Voon, V., Worbe, Y., Vértes, P. E., Inati, S. J., Saad, Z. S., Bandettini, P. A., & Bullmore, E. T. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301725110 · Cited by 399 · see citing works
High-speed imaging reveals neurophysiological links to behavior in an animal model of depression
Airan, R. D., Meltzer, L. A., Roy, M., Gong, Y., Chen, H., & Deisseroth, K. (2007) · Science · doi:10.1126/science.1144400 · Cited by 396 · see citing works
Ree, M. J., French, D. J., MacLeod, C., & Locke, V. (2008) · Behavioural and Cognitive Psychotherapy · doi:10.1017/s1352465808004232 · Cited by 379 · see citing works
Hamilton, J. P., Chen, G., Thomason, M. E., Schwartz, M., & Gotlib, I. H. (2010) · Molecular Psychiatry · doi:10.1038/mp.2010.46 · Cited by 329 · see citing works
Deakin, J. F. W., Lees, J., McKie, S., Hallak, J. E. C., Williams, S. R., & Dursun, S. M. (2008) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2007.37 · Cited by 311 · see citing works
Deep brain stimulation for treatment-resistant depression
Mayberg, H. S. (2008) · Journal of Affective Disorders · doi:10.1016/j.jad.2007.12.153 · Cited by 237 · see citing works
Relation Between Structural and Functional Connectivity in Major Depressive Disorder
de Kwaasteniet, B., Ruhe, E., Caan, M., Rive, M., Olabarriaga, S., Groefsema, M., Heesink, L., van Wingen, G., & Denys, D. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.12.024 · Cited by 229 · see citing works
Chan, R. C. K., Shi, Y., Lai, M.-K., Wang, Y.-N., Wang, Y., & Kring, A. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035352 · Cited by 201 · see citing works
Hofmann, S. G., & Bitran, S. (2006) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2006.12.003 · Cited by 179 · see citing works
Carlson, P. J., Diazgranados, N., Nugent, A. C., Ibrahim, L., Luckenbaugh, D. A., Brutsche, N., Herscovitch, P., Manji, H. K., Zarate, C. A., & Drevets, W. C. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.02.008 · Cited by 168 · see citing works
Medial frontal cortex activity and loss-related responses to errors
Taylor, S. F., Martis, B., Fitzgerald, K. D., Welsh, R. C., Abelson, J. L., Liberzon, I., Himle, J. A., & Gehring, W. J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4709-05.2006 · Cited by 160 · see citing works
A role for primate subgenual cingulate cortex in sustaining autonomic arousal
Rudebeck, P. H., Putnam, P. T., Daniels, T. E., Yang, T., Mitz, A. R., Rhodes, S. E. V., & Murray, E. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1317695111 · Cited by 160 · see citing works
Sambataro, F., Wolf, N. D., Pennuto, M., Vasic, N., & Wolf, R. C. (2014) · Psychological Medicine · doi:10.1017/s0033291713002596 · Cited by 149 · see citing works
Stern, E. R., Welsh, R. C., Fitzgerald, K. D., Gehring, W. J., Lister, J. J., Himle, J. A., Abelson, J. L., & Taylor, S. F. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.09.048 · Cited by 135 · see citing works
Self-citationABRAMS, K. Y., Yune, S. K., Kim, S. J., Jeon, H. J., Han, S. J., Hwang, J., Sung, Y. H., LEE, K. J., & Lyoo, I. K. (2004) · Psychiatry and Clinical Neurosciences · doi:10.1111/j.1440-1819.2004.01226.x · Cited by 120 · see citing works
Alexander, L., Gaskin, P. L. R., Sawiak, S. J., Fryer, T. D., Hong, Y. T., Cockcroft, G. J., Clarke, H. F., & Roberts, A. C. (2019) · Neuron · doi:10.1016/j.neuron.2018.11.021 · Cited by 120 · see citing works
Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate
Downey, D., Dutta, A., McKie, S., Dawson, G. R., Dourish, C. T., Craig, K., Smith, M. A., McCarthy, D. J., Harmer, C. J., Goodwin, G. M., et al. (2016) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2016.03.006 · Cited by 116 · see citing works
Monosov, I. E., & Hikosaka, O. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1801-12.2012 · Cited by 115 · see citing works
Mackey, S., & Petrides, M. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07465.x · Cited by 105 · see citing works
The dynamics of the stress neuromatrix
Sousa, N. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.196 · Cited by 105 · see citing works
How long to onset of antidepressant action
Tollefson, G. D., & Holman, S. (1994) · International Clinical Psychopharmacology · doi:10.1097/00004850-199400940-00003 · Cited by 63 · see citing works
Costi, S., Soleimani, L., Glasgow, A., Brallier, J., Spivack, J., Schwartz, J., Levitch, C. F., Richards, S., Hoch, M., Stade, E. C., et al. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0365-0 · Cited by 56 · see citing works
Self-citationWong, J. J., O’Daly, O., Mehta, M. A., Young, A. H., & Stone, J. M. (2016) · PeerJ · doi:10.7717/peerj.1710 · Cited by 39 · see citing works
Wallis, C. U., Cockcroft, G. J., Cardinal, R. N., Roberts, A. C., & Clarke, H. F. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz015 · Cited by 30 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [28]28. Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM. Fsl. Neuro- image. 2012;62:782-90.
Cited by
Sorted by citations
McIntyre, R. S., Rosenblat, J. D., Nemeroff, C. B., Sanacora, G., Murrough, J. W., Berk, M., Brietzke, E., Dodd, S., Gorwood, P., Ho, R., et al. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20081251 · Cited by 731 · see citing works
Self-citationPrefrontal cortex and depression
Pizzagalli, D. A., & Roberts, A. C. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-021-01101-7 · Cited by 644 · see citing works
Nogo, D., Jasrai, A. K., Kim, H., Nasri, F., Ceban, F., Lui, L. M. W., Rosenblat, J. D., Vinberg, M., Ho, R., & McIntyre, R. S. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06105-9 · Cited by 54 · see citing works
Siegel, J. S., Palanca, B. J. A., Ances, B. M., Kharasch, E. D., Schweiger, J. A., Yingling, M. D., Snyder, A. Z., Nicol, G. E., Lenze, E. J., & Farber, N. B. (2021) · Psychopharmacology · doi:10.1007/s00213-021-05762-6 · Cited by 50 · see citing works
Ketamine Normalizes the Structural Alterations of Inferior Frontal Gyrus in Depression
Dai, D., Lacadie, C. M., Holmes, S. E., Cool, R., Anticevic, A., Averill, C., Abdallah, C., & Esterlis, I. (2020) · Chronic Stress · doi:10.1177/2470547020980681 · Cited by 34 · see citing works
Intrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review
Demchenko, I., Tassone, V. K., Kennedy, S. H., Dunlop, K., & Bhat, V. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.864902 · Cited by 29 · see citing works
“(148) 42, 20 fMRI ROI in sgACC Computed between sgACC and HPC”
MethodNakamura, T., Tomita, M., Horikawa, N., Ishibashi, M., Uematsu, K., Hiraki, T., Abe, T., & Uchimura, N. (2021) · Neuropsychopharmacology Reports · doi:10.1002/npr2.12165 · Cited by 28 · see citing works
Alario, A. A., & Niciu, M. J. (2021) · Chronic Stress · doi:10.1177/24705470211014210 · Cited by 26 · see citing works
(2020) · Advances in Pharmacology · doi:10.1016/bs.apha.2020.04.003 · Cited by 18 · see citing works
Self-citationEffectiveness of intravenous ketamine in mood disorder patients with a history of neurostimulation
Rodrigues, N. B., Siegel, A., Lipsitz, O., Cha, D. S., Gill, H., Nasri, F., Simonson, K., Shekotikhina, M., Lee, Y., Subramaniapillai, M., et al. (2022) · CNS Spectrums · doi:10.1017/s1092852920002187 · Cited by 17 · see citing works
- Authors
- Morris, L. S., Costi, S., Tan, A., Stern, E. R., Charney, D. S., & Murrough, J. W.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- New York University (US)
- Corresponding author
- Murrough, James W.
- Venue
- Neuropsychopharmacology
- Published
- 2020-01-02
- Volume
- 45
- Issue
- 6
- Pages
- 975-981
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC7162851
- OpenAlex
- W2997603839
- Cited by
- 104
- References
- 43
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 18 · 2023: 17 · 2022: 13 · 2021: 24 · 2020: 10
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (L30 MH095136, R21MH109771, K23MH094707)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- ketamine, major depressive disorder, subgenual anterior cingulate cortex, antidepressant mechanism, NMDA receptor antagonists, anhedonia, anxiety, resting-state functional connectivity
- MeSH terms
- Depression, Major Depressive Disorder, Gyrus Cinguli, Humans, Ketamine, Magnetic Resonance Imaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
