Ketamine Alters Functional Gamma and Theta Resting-State Connectivity in Healthy Humans: Implications for Schizophrenia Treatment Targeting the Glutamate System

Abstract

Disturbed functional connectivity is assumed to cause neurocognitive deficits in patients suffering from schizophrenia. A Glutamate N-methyl-D-aspartate receptor (NMDAR) dysfunction has been suggested as a possible mechanism underlying altered connectivity in schizophrenia, especially in the gamma- and theta-frequency range. The present study aimed to investigate the effects of the NMDAR-antagonist ketamine on resting-state power, functional connectivity, and schizophrenia-like psychopathological changes in healthy volunteers. In a placebo-controlled crossover design, 25 healthy subjects were recorded using resting-state 64-channel-electroencephalography (EEG) (eyes closed). The imaginary coherence-based Multivariate Interaction Measure (MIM) was used to measure gamma and theta connectivity across 80 cortical regions. The network-based statistic was applied to identify involved networks under ketamine. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). Ketamine caused an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01). Significant increases in resting-state gamma and theta power were observed under ketamine compared to placebo (p < 0.05). The source-space analysis revealed two distinct networks with an increased mean functional gamma- or theta-band connectivity during the ketamine session. The gamma-network consisted of midline regions, the cuneus, the precuneus, and the bilateral posterior cingulate cortices, while the theta-band network involved the Heschl gyrus, midline regions, the insula, and the middle cingulate cortex. The current source density (CSD) within the gamma-band correlated negatively with the PANSS negative symptom score, and the activity within the gamma-band network correlated negatively with the subjective changed meaning of percepts subscale of the 5D-ASC. These results are in line with resting-state patterns seen in people who have schizophrenia and argue for a crucial role of the glutamate system in mediating dysfunctional gamma- and theta-band-connectivity in schizophrenia. Resting-state networks could serve as biomarkers for the response to glutamatergic drugs or drug development efforts within the glutamate system.

Neurexin1α knockout rats display oscillatory abnormalities and sensory processing deficits back-translating key endophenotypes of psychiatric disorders

“…From a mechanistic perspective, we suggest N-Methyl-d-aspartate receptor (NMDAR) hypofunction to be involved in the oscillatory abnormalities and sensory processing deficits we identified in Nrxn1α −/− rats for two reasons. First, Nrxn1 has been shown to be important for postsynaptic NMDAR recruitment and function [ 3 , 25 ] and second, core endophenotypes found in our study, such as increased spontaneous gamma power and deficits in MMN-like responses can be induced by pharmacological blockade of NMDAR in rat [ 35 , 84 – 86 ], non-human primate [ 87 – 89 ] and human [ 90 – 92 ]. In this regard, our results line up with the NMDAR hypofunction hypothesis for SZ and ASD [ 93 , 94 ] by linking characteristic NMDAR-dependent translational endophenotypes to disease-relevant Nrxn1α deletions with construct validity.…”

Hippocampal phase precession is preserved under ketamine, but the range of precession across a theta cycle is reduced

“…Although the reductions in theta power, theta frequency and firing rates that occurred were similar to those described in previous studies (Caixeta et al, 2013;Kittelberger et al, 2012;Kuang et al, 2010;Lazarewicz et al, 2010;Masuda et al, 2023), we did not observe any differences in gamma power, theta/gamma cross-coupling, or HFO power. This was surprising given that several previous studies have observed gamma range disruptions in humans (Curic et al, 2021;Hong et al, 2010) and animal models (Kittelberger et al, 2012;Lazarewicz et al, 2010), as well as disturbed theta/gamma cross-coupling under ketamine (Ahnaou et al, 2017;Caixeta et al, 2013;Michaels et al, 2018). Furthermore, NMDA receptor antagonists have also resulted in increased HFO power in both animal (Olszewski et al, 2013) and human (Nottage et al, 2023) studies.…”

The effect of ketamine and D-cycloserine on the high frequency resting EEG spectrum in humans

“…A current source density analysis in one study showed increased gamma amplitude in the ventromedial prefrontal cortex, both the anterior and posterior cingulate cortex and the anterior insular (de la Salle et al 2016). In the other study, it was found that ketamine increased gamma connectivity in a network involving occipital, midline and frontal regions (Curic, Andreou et al 2021). We are not aware of any previous EEG or MEG human investigations of frequencies above 90 Hz with ketamine or of any studies of the gamma band or above with DCS.…”