TY - JOUR
T1 - Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals
AU - Alexander, Laith
AU - Hawkins, Peter C.T.
AU - Evans, Jennifer W.
AU - Mehta, Mitul A.
AU - Zarate, Carlos A.
N1 - Funding Information:
The research was carried out at the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC). Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) (ZIAMH002857; NCT00088699; 04-M-0222); a NIHR Academic Clinical Fellowship award (ACF-2022-17-016) to LA; a NARSAD Independent Investigator to CAZ; and a Brain & Behavior Mood Disorders Research Award to CAZ. MAM is employed by King’s College London and his grant funding for the past 3 years is Takeda, Johnson & Johnson, Lundbeck, Wellcome Trust (212952/Z/18/Z; 200102/Z/15/Z), MRC (MR/R005931/1; MR/R005885/1; MR/S003444/1), NIHR (CRF-2016-10023). For the purposes of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Accepted Author Manuscript version arising from this submission.
Funding Information:
The research was carried out at the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre (BRC). Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) (ZIAMH002857; NCT00088699; 04-M-0222); a NIHR Academic Clinical Fellowship award (ACF-2022-17-016) to LA; a NARSAD Independent Investigator to CAZ; and a Brain & Behavior Mood Disorders Research Award to CAZ. MAM is employed by King’s College London and his grant funding for the past 3 years is Takeda, Johnson & Johnson, Lundbeck, Wellcome Trust (212952/Z/18/Z; 200102/Z/15/Z), MRC (MR/R005931/1; MR/R005885/1; MR/S003444/1), NIHR (CRF-2016-10023). For the purposes of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Accepted Author Manuscript version arising from this submission.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine’s effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine’s antidepressant and anti-anhedonic action.
AB - Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine’s effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine’s antidepressant and anti-anhedonic action.
UR - http://www.scopus.com/inward/record.url?scp=85178238085&partnerID=8YFLogxK
U2 - 10.1038/s41398-023-02674-1
DO - 10.1038/s41398-023-02674-1
M3 - Article
C2 - 38040678
AN - SCOPUS:85178238085
SN - 2158-3188
VL - 13
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 371
ER -
