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.

Keywords: functional connectivity; gamma-band oscillations; glutamate hypothesis; ketamine model of schizophrenia; negative-symptoms; resting state; theta-band oscillations.

Figure 1

Bar charts of the mean values of the five PANSS subscales; pos positive symptoms, neg negative symptoms, dis disorganisation, exc excitement, edis emotional distress; with error bars representing ±1 standard errors of the mean (***p < 0.001).

Figure 2

Bar charts of the mean values of the 11 subscales of the 5D-ASC-scale with error bars representing ±1 standard errors of the mean (**p < 0.01;***p < 0.001).

Figure 3

EEG resting-state power spectra during the ketamine and placebo condition. The shaded areas represent the standard deviation (red = ketamine, gray = placebo). (A) frequency-range 3,5 Hz- 30Hz, (B) frequency-range 30–100 Hz (the vertical dashed line indicates scale-break between 45 and 55 Hz) and (C) ratio of power between ketamine (numerator) and placebo (denominator) (range: 3.5–100 Hz). The horizontal line represents a ratio of 1.

Figure 4

Scalp-topography [ketamine, placebo, and difference (ketamine-placebo)] in the (A) gamma- (30–40 Hz) and (B) theta-band (4–8 Hz).

Figure 5

The networks of increased resting-state (A) gamma- and (B) theta-band connectivity during the ketamine compared to placebo administration. The size of each node represents its number of connections within the network (degree). The thickness and color of connections represent the t-value. Labels are provided for nodes with at least three connections. As shown in Table 3, these nodes are involved in more than 50% of total interactions within the theta-network and more than 70% of total interactions within the gamma-network. The figure was created using BrainNet Viewer (http://www.nitrc.org/projects/bnv/).

Figure 6

Mean (A) gamma- and (B) theta-band connectivity across the nodes of the significant networks for the ketamine and placebo condition, ***p < 0.001 (Bonferroni-corrected).

Figure 7

(A) Significant multivariate analysis of variance result, with the mean connectivity within the significant 45 connections involving gamma-network as dependent variable and the 5D-ASC changed meaning of percepts scale as predictor (bivariate Pearson's r = −0.534; n = 21; p = 0.008); (B) Correlation between the CSD in the significant regions as revealed by the multivariate analysis of variance results and post-hoc t-testing; the bivariate correlations between PANSS-negative factor increase and the middle frontal region (solid green line) (Pearson's r = −0.541; n = 22; p = 0.005), the middle temporo-central region (densely dotted red line) (Pearson's r = −0.562; n = 22; p = 0.003), the posterior middle region (dashed dark blue line) (Pearson's r = −0.627; n = 22; p = 0.001) and the right posterior region (dashdotted light blue line) (Pearson's r = −0.412; n = 22; p = 0.028) were Bonferroni corrected.