Abstract
N-methyl-D-aspartate (NMDA) receptor antagonists administered to healthy humans results in schizophrenia-like symptoms, which preclinical research suggests are due to glutamatergically altered brain oscillations. Here, we examined resting-state electroencephalographic activity in 21 healthy volunteers assessed in a placebo-controlled, double-blind, randomized study involving administration of either a saline infusion or a sub-anesthetic dose of ketamine, an NMDA receptor antagonist. Frequency-specific current source density (CSD) was assessed at sensor-level and source-level using eLORETA within regions of interest of a triple network model of schizophrenia (this model posits a dysfunctional switching between large-scale Default Mode and Central Executive networks by the monitor-controlling Salience Network). These CSDs were measured in each session along with subjective symptoms as indexed with the Clinician Administered Dissociative States Scale. Ketamine-induced CSD reductions in slow (delta/theta and alpha) and increases in fast (gamma) frequencies at scalp electrode sites were paralleled by frequency-specific CSD changes in the Default Mode, Central Executive, and Salience networks. Subjective symptoms scores were increased with ketamine and ratings of depersonalization in particular were associated with alpha CSD reductions in general and in specific regions of interest in each of the three networks. These results tentatively support the hypothesis that pathological brain oscillations associated with hypofunctional NMDA receptor activity may contribute to the emergence of the perceptual/dissociate symptoms of schizophrenia.
Highlights
Blockade of glutamate N-methyl-D-aspartate receptors (NMDAR) by a subanesthetic dose of ketamine in humans transiently induces negative, positive and cognitive symptoms similar to those found in schizophrenia (SZ)
Significant increased self-ratings for amnesia (WSRT = −2.83, df = 1/40, p < 0.005), depersonalization (WSRT = −3.53, df = 1/40, p < 0.0001), and derealisation symptoms (WSRT = −3.36, df = 1/40, p < 0.01) were shown for the ketamine compared to placebo infusion condition
P < 0.005), treatment x region (F = 4.43, df = 2/40, p < 0.02) and treatment × region × laterality interaction effects (F = 4.35, df = 4/80, p < 0.003), alpha current density was significantly diminished in left (p < 0.002) and right (p < 0.01) anterior, middle (p < 0.006) and right (p < 0.004) temporal-central, and posterior regions following ketamine infusion
Summary
Blockade of glutamate N-methyl-D-aspartate receptors (NMDAR) by a subanesthetic dose of ketamine in humans transiently induces negative, positive and cognitive symptoms similar to those found in schizophrenia (SZ). Oscillatory brain activity is considered a fundamental process in the temporal coordination of circuits linked to perceptual, cognitive, and emotional functions This brain activity, as measured by the amplitude/power of electroencephalographic (EEG) rhythms, is increasingly seen as an indicator of intrinsic brain function when assessed during stimulation/task-free states (Spencer, 2014). This activity has been found to be altered in SZ and to vary with symptomatology (Boutros et al, 2008, 2014; Moran and Hong, 2011; Galderisi et al, 2014). The study of the full frequency spectrum and its pharmacological basis is critical for deciphering the complex electrophysiologic abnormalities in SZ patients (Moran and Hong, 2011)
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