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
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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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    Reviews in the neurosciences 01/2015; 26(3). DOI:10.1515/revneuro-2014-0085 · 3.33 Impact Factor
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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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    ABSTRACT: The auditory steady state response (ASSR), which measures the ability of neural ensembles to entrain to rhythmic auditory stimuli, has been used in human EEG studies to assess sensory processing and electrical oscillatory deficits. Patients with schizophrenia (SZ) show a deficit in ASSR at 40 Hz, and therefore this may be a useful biomarker to study this disorder. we used ASSR recordings from the primary auditory (A1) cortex, hippocampus, and vertex EEG sites in awake behaving rats to determine whether pharmacological impairment of excitatory or inhibitory neurotransmission mimic ASSR abnormalities in SZ. We found the most robust response to auditory stimuli in the A1 cortex, in line with previous studies suggesting this region is the primary generator of the ASSR in humans. Acute MK-801 (0.1 mg/kg i.p.) increased A1 cortex intertrial coherence (ITC) during ASSR at 20 and 40 Hz. Chronic MK-801 (21 days exposure at this daily dose) had no significant effect on 40 Hz ASSR. Furthermore, we found no effect of acute or chronic picrotoxin (PTX, a GABA-A antagonist) on ITC. Our data indicate that acute N-methyl-D-aspartate (NMDA) receptor antagonism increases synchronous activity in the A1 cortex in a frequency-specific manner, supporting the widely held view that acute NMDA antagonism augments gamma oscillations. Thus, rodent ASSR could be a valuable method to study the cortical ability to support synchronous activity at specific frequencies. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(7). DOI:10.1093/ijnp/pyu118 · 4.01 Impact Factor
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    • "Losing control under ketamine RJ Moran et al with rodent data, ketamine has been reported to augment gamma oscillations, while reducing lower frequency (1–5 Hz) oscillations in humans (Hong et al, 2009). In light of recent suggestions that stochastic bursts of gamma may act to synchronize neuronal activity (Xing et al, 2012), sustained and elevated gamma power induced by ketamine may constitute 'noise', disrupting information processing by pyramidal cell assemblies. "
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    ABSTRACT: Systemic doses of the psychotomimetic ketamine alter the spectral characteristics of hippocampal and prefrontal cortical network activity. Using dynamic causal modelling (DCM) of cross-spectral densities, we quantify the putative synaptic mechanisms underlying ketamine effects in terms of changes in directed, effective connectivity between dorsal hippocampus and medial prefrontal (dCA1-mPFC) cortex of freely-moving rats. We parameterise dose-dependent changes in spectral signatures of dCA1-mPFC local field potential recordings, using neural mass models of glutamatergic and GABAergic circuits. Optimising DCMs of theta and gamma frequency range responses, model comparisons suggest that both enhanced gamma and depressed theta power result from a reduction in top-down connectivity from mPFC to the hippocampus, mediated by postsynaptic NMDA receptors (NMDARs). This is accompanied by an alteration in the bottom-up pathway from dCA1 to mPFC, which exhibits a distinct asymmetry: here, feed-forward drive at AMPA receptors increases in the presence of decreased NMDAR-mediated inputs. Setting these findings in the context of predictive coding suggests that NMDAR antagonism by ketamine in recurrent hierarchical networks may result in the failure of top-down connections from higher cortical regions to signal predictions to lower regions in the hierarchy, which consequently fail to respond consistently to errors. Given that NMDAR dysfunction plays a central role in pathophysiological theories of schizophrenia and that theta and gamma rhythm abnormalities are evident in schizophrenic patients, the approach followed here may furnish a framework for the study of aberrant hierarchical message passing (of prediction errors) in schizophrenia - and the false perceptual inferences that ensue.Neuropsychopharmacology accepted article preview online, 23 July 2014; doi:10.1038/npp.2014.184.
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