Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans.
Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine's effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n = 25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated their own set of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns.


CONCLUSIONS
In this paper, we found that subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. The alterations in frontoparietal connectivity patterns we observe here may be important in generating the antidepressant response to ketamine.
Schools of Pharmacy and Psychology, The University of Auckland, Auckland 1142, New Zealand, sd.muthu@auckland.ac.nz.
Suresh D
SD
Muthukumaraswamy
Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff CF103AT, United Kingdom.
Alexander D
http://orcid.org/0000-0001-5741-7526
AD
Shaw
Department of Anaesthetics, Intensive Care and Pain Medicine, Cwm Taf University Health Board, Llantrisant CF72 8XR, United Kingdom.
Laura E
http://orcid.org/0000-0002-0263-9479
LE
Jackson
Department of Anaesthetics, Intensive Care and Pain Medicine, Cwm Taf University Health Board, Llantrisant CF72 8XR, United Kingdom.
Judith
J
Hall
Virginia Tech Carilion Research Institute, Bradley Department of Electrical and Computer Engineering, Roanoke, Virginia 24016, and.
Rosalyn
R
Moran
Department of Anaesthetics, Intensive Care and Pain Medicine, Cwm Taf University Health Board, Llantrisant CF72 8XR, United Kingdom, Department of Anaesthetics, Intensive Care and Pain Medicine, School of Medicine, Cardiff University, Cardiff CF144XW, United Kingdom.
Neeraj
N
Saxena
D000328:Adult; D000778:Anesthetics, Dissociative / Q000008:administration & dosage; D000928:Antidepressive Agents / Q000008:administration & dosage; D001931:Brain Mapping; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D010296:Parietal Lobe / Q000187:drug effects / Q000502:physiology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055815:Young Adult
D000778:Anesthetics, Dissociative; D000928:Antidepressive Agents; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
alpha rhythms; depression; dynamic causal modelling; gamma rhythms; ketamine; magnetoencephalography