Reduced auditory evoked gamma-band response and schizophrenia-like clinical symptoms under subanesthetic ketamine

Abstract

Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior. In a placebo-controlled, randomized crossover design, the aeGBR power, phase-locking factor (PLF) during a choice reaction task, the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale were assessed in 25 healthy subjects. Ketamine was applied in a subanaesthetic dose. Low-resolution brain electromagnetic tomography was used for EEG source localization. Significant reductions of the aeGBR power and PLF were identified under ketamine administration compared to placebo (p < 0.01). Source-space analysis of aeGBR generators revealed significantly reduced current source density (CSD) within the anterior cingulate cortex during ketamine administration. Ketamine induced an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01) and increased response times (p < 0.001) and error rates (p < 0.01). Only negative symptoms were significantly associated with an aeGBR power decrease (p = 0.033) as revealed by multiple linear regression. These findings argue for a substantial role of the glutamate system in the mediation of dysfunctional gamma band responses and negative symptomatology of schizophrenia and are compatible with the NMDAR hypofunction hypothesis of schizophrenia.

Fig. 1

Bar charts of the mean values of reactions times (a) and error rates (b) with error bars representing ±1 standard errors of the mean (***p < 0.001)

Fig. 2

Bar charts of the mean values of the five PANSS subscores (a) and the 5D-ASC-scale total and subscores (b) with error bars representing ±1 standard errors of the mean, Bonferroni-corrected for multiple comparisons (***p < 0.001, **p < 0.01). AUA auditory alterations, DED dread of ego dissolution, OBN oceanic boundlessness, VIR vigilance reduction, VRS visionary restructuralization

Fig. 3

a Time–frequency analysis of the mean difference (placebo-ketamine) of the auditory evoked gamma-band response (aeGBR) power in the timeframe between 50 ms pre-stimulus and 200 ms post-stimulus. The aeGBR can be seen as an increased activity about 50 ms after stimulus presentation (dashed line) and around 40 Hz in the frequency range. Scalp topographies are displayed for each condition as well as a difference topography in the same scaling as the time–frequency analysis. The scalp topographies were calculated for the timeframe 50–75 ms and a frequency of 40 Hz. The aeGBR power (b) and phase-locking factor (PLF) (c) are displayed as the results of the wavelet analysis (complex Morlet wavelet) focused on the activity around 40 Hz for the ketamine condition (red line) and the placebo condition (black line) (**p < 0.01)

Fig. 4

a Mean current source density (µA/m²) in the dACC-ROI, BA-41-ROI, and BA-42-ROI with error bars representing ±1 standard errors of the mean (*p < 0.05; n.s. = not significant). b Difference map of low-resolution brain electromagnetic tomography (LORETA) source activity in the gamma-frequency band (35–45 Hz) comparing the current source density (CSD) of the aeGBR between the placebo and ketamine conditions. The red voxels represent areas of significant voxel-wise differences after correction for multiple comparisons (p < 0.05). Red voxels show a reduced CSD in the dorsal anterior cingulate cortex (dACC) under ketamine

Fig. 5

Positive correlation between the relative decrease of aeGBR power and the Positive and Negative Syndrome Scale (PANSS) negative factor (Pearson’s r = 0.342)