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

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 ϭ 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.

Thalamo-cortical communication, glutamatergic neurotransmission and neural oscillations: A unique window into the origins of ScZ?

“…The finding of elevated TC-interactions at beta/gamma-band frequencies is consistent with preclinical data (Dawson et al, 2013), highlighting that acute Ketamine administration affects prominently thalamo-cortical interactions (but see (Muthukumaraswamy et al, 2015) for a recent MEG-study reporting a different finding on connectivity patterns). Moreover, several resting-state fMRI studies reported increased functional connectivity between thalamus and cortical regions (Anticevic et al, 2013a;Hoflich et al, 2015;Klingner et al, 2014;Woodward et al, 2012), albeit some report mixed findings (Woodward et al, 2012).…”

“…In-vivo and in-vitro electrophysiological studies using NMDA-R antagonists have revealed an increase of spontaneous power at both low (30-60 Hz) and high (60-130 Hz) gamma-band ranges as well as at ripple frequencies (130-200 Hz) (Hunt and Kasicki, 2013)(see also (Hong et al, 2010;Muthukumaraswamy et al, 2015) for similar findings in EEG/MEG-data). Specifically, our findings of enhanced gamma-band activity in the hippocampus and thalamus is consistent with data by Zhang et al (2012) who reported gamma-activity increase after ketamine injection by 308% in the hippocampus and 258% in the thalamus.…”

“…However, it should be noted that this pattern, which is consistent with the effects of NMDA-R hypofunctioning in healthy volunteers (Rivolta et al, 2015), has not been replicated in some other studies that investigated EEG-data in at-risk cohorts for spectral signatures during resting-state EEGactivity (Ramyead et al, 2015). Moreover, ketamine administration in healthy volunteers is also associated with elevated high-frequency activity during perceptual and motor-paradigms (Hong et al, 2010;Muthukumaraswamy et al, 2015), a finding that is commonly not observed in either FEP or chronic ScZ-patients Sun et al, 2013).…”

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

“…A non-invasive method used to assess ketamine-activated circuitry in both humans and rodents is the quantitative electroencephalography (qEEG) measurement of gamma-band power, which is dependent upon activation of fast ionotropic excitatory receptors, including AMPA receptors [28][29][30] . We show that, similar to ketamine, (2R,6R)-HNK administration acutely increases gamma power measured via surface electrodes in vivo (Fig.…”

Ketamine: 50 Years of Modulating the Mind

“…Wong et al (2016) found that subanesthetic ketamine administration disrupted functional connectivity between the subgenual anterior cingulate cortex, which is involved with the modulation of mood (Davey et al, 2012), and a network cluster involving the thalamus, hippocampus and the retrosplenial cortex. Using a ketamine infusion dose often used for the treatment of depression, Muthukumaraswamy et al (2015) demonstrated reduced functional connectivity in frontoparietal networks concomitant with an increase in blissful feelings. Thus, modulation of brain connectivity patterns might also provide a network-level mechanism for ketamine’s effects on depression.…”