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

Abstract

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 ¼ 0.006) and reduced lowfrequency oscillations (delta band at 1-5 Hz, po0.001) 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 ¼ 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.

Losing Control Under Ketamine: Suppressed Cortico-Hippocampal Drive Following Acute Ketamine in Rats

“…Reductions in gamma synchrony among disparate brain areas have been observed in patient populations Mulert et al, 2011) and have been proposed as a framework for understanding inappropriate sensory binding Uhlhaas and Singer, 2010). Consistent 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.…”

Differential Effects of an NR2B NAM and Ketamine on Synaptic Potentiation and Gamma Synchrony: Relevance to Rapid-Onset Antidepressant Efficacy

“…The acute effects of ketamine have been broadly studied, in part to investigate mechanisms by which this drug mimics numerous symptoms of schizophrenia (Hong et al, 2010;Javitt et al, 2011;Kocsis et al, 2013). Therefore, in our studies we measured additional neurophysiological markers; some, such as auditory gating, are clearly linked to information processing and known to be impacted in psychiatric patients (Hajós, 2006).…”

“…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, 2008Javitt et al, , 2012Kocsis, 2012a;Kocsis et al, 2013). In contrast, neurophysiological mechanisms that may underlie the antidepressive effects of ketamine are much less explored.…”

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Conversely, correlated pre-and post-synaptic activity causes synaptic unsilencing (Durand et al, 1996;Isaac et al, 1995;Liao et al, 1995). Synchronization of neuronal activity is a plausible mechanism for the effects of ketamine, which induces glutamate outflow and gamma oscillations in human and rodent brain (Hong et al, 2010;Nicolas et al, 2011;Pinault, 2008). Such oscillations may override the specific activity pattern required for silent synapse formation, or unsilence already formed silent synapses.…”