Format

Send to

Choose Destination
J Neurosci. 2015 Aug 19;35(33):11694-706. doi: 10.1523/JNEUROSCI.0903-15.2015.

Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans.

Author information

1
Schools of Pharmacy and Psychology, The University of Auckland, Auckland 1142, New Zealand, sd.muthu@auckland.ac.nz.
2
Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff CF103AT, United Kingdom.
3
Department of Anaesthetics, Intensive Care and Pain Medicine, Cwm Taf University Health Board, Llantrisant CF72 8XR, United Kingdom.
4
Virginia Tech Carilion Research Institute, Bradley Department of Electrical and Computer Engineering, Roanoke, Virginia 24016, and.
5
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.

Abstract

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.

SIGNIFICANCE STATEMENT:

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.

KEYWORDS:

alpha rhythms; depression; dynamic causal modelling; gamma rhythms; ketamine; magnetoencephalography

PMID:
26290246
PMCID:
PMC4540803
DOI:
10.1523/JNEUROSCI.0903-15.2015
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center