Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 11/2009; 35(3):632-40. DOI: 10.1038/npp.2009.168
Source: PubMed


Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal-clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl-D-aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal-retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40-85 Hz, p=0.006) and reduced low-frequency oscillations (delta band at 1-5 Hz, p<0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal-retardation symptoms experienced during ketamine administration (p=0.02). Ketamine also reduced gating of the theta-alpha (5-12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.

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Available from: Patricio O'Donnell, Mar 19, 2015
    • "Determining the synaptic, cellular, and neuronal network mechanisms involved in ketamine's psychotomimetic and antidepressant actions, and the interrelationship between these actions, would have a great impact on our understanding of these neuropsychiatric disorders and in developing novel therapies. The neurophysiological changes caused by acute administration of ketamine and believed to be associated with the psychotomimetic effects are broadly described (Hong et al, 2010; Javitt et al, 2008, 2012; Kocsis, 2012a; Kocsis et al, 2013). In contrast, neurophysiological mechanisms that may underlie the antidepressive effects of ketamine are much less explored. "
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    ABSTRACT: Ketamine, a pan-NMDA receptor channel blocker, and CP-101,606, an NR2B-selective negative allosteric modulator, have antidepressant effects in humans that develop rapidly after the drugs are cleared from the body. It has been proposed that the antidepressant effect of ketamine results from delayed synaptic potentiation. To further investigate this hypothesis and potential mechanistic underpinnings we compared the effects of ketamine and CP-101,606 on neurophysiological biomarkers in rats immediately after drug administration and after the drugs had been eliminated. Local field and auditory evoked potentials (AEPs) were recorded from primary auditory cortex and hippocampus in freely-moving rats. Effects of different doses of ketamine or CP-101,606 were evaluated on amplitude of AEPs, auditory gating, and absolute power of delta and gamma oscillations 5 to 30 min (Drug-On) and 5 to 6 h (Drug-Off) after systemic administration. Both ketamine and CP-101,606 significantly enhanced AEPs in cortex and hippocampus in the Drug-Off phase. In contrast, ketamine but not CP-101,606 disrupted auditory gating and increased gamma band power during the Drug-On period. While both drugs affected delta power, these did not correlate with increase in AEPs in the Drug-Off phase. Our findings show that both ketamine and CP-101,606 augment AEPs after drug elimination, consistent with synaptic potentiation as a mechanism for antidepressant efficacy. However, these drugs had different acute effects on neurophysiological parameters. These results have implications for understanding the underlying mechanisms for the rapid onset antidepressant effects of NMDA receptor inhibition and for the use of electrophysiological measures as translatable biomarkers.Neuropsychopharmacology accepted article preview online, 25 September 2015. doi:10.1038/npp.2015.298.
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    • "Conversely, decreases in the slow NMDA conductance at pyramidal- FS neuron model synapses increased gamma power in the network model. Similarly, NMDAR antagonists enhance gamma power in animal models (Pinault, 2008; Roopun et al., 2008; Hakami et al., 2009; Pietersen et al., 2009) or human subjects (Hong et al., 2009). Our simulations therefore suggest that rapid FS neuron activation (Jonas et al., 2004; Hu et al., 2010) is crucial for the production of gamma oscillations. "
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    • "The NMDA receptor (NMDAR) antagonist ketamine induces a transient state in healthy human subjects that resembles some aspects of SZ (Luby et al., 1959; Krystal et al., 1994; Malhotra et al., 1996) and is widely used to study underlying mechanisms of the disorder in both human and animal studies. NMDAR antagonists are hypothesized to produce psychotomimetic effects by altering excitation-inhibition balance in cortical circuits, yielding alterations in oscillatory activity (Braun et al., 2007; Homayoun and Moghaddam, 2007; Pinault, 2008; Hakami et al., 2009; Hong et al., 2010). Cortical GABAergic interneurons strongly regulate network oscillations, particularly in the gamma band (Cardin et al., 2009; Sohal et al., 2009), and dysfunction in these cells is a hypothesized mechanism of SZ (Akbarian et al., 1995; Hashimoto et al., 2003). "
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