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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.

SUBMITTER: Curic S

PROVIDER: S-EPMC6785009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated as a possible mechanism underlying cognitive deficits and aberrant neuronal dynamics in schizophrenia. To test this hypothesis, we first administered a sub-anaesthetic dose of S-ketamine (0.006 mg/kg/min) or saline in a single-blind crossover design in 14 participants while magnetoencephalographic data were recorded during a visual task. In addition, magnetoencephalographic data were obtained in a sample of unmedicated first-episode psychosis patients (n = 10) and in patients with chronic schizophrenia (n = 16) to allow for comparisons of neuronal dynamics in clinical populations versus NMDAR hypofunctioning. Magnetoencephalographic data were analysed at source-level in the 1-90 Hz frequency range in occipital and thalamic regions of interest. In addition, directed functional connectivity analysis was performed using Granger causality and feedback and feedforward activity was investigated using a directed asymmetry index. Psychopathology was assessed with the Positive and Negative Syndrome Scale. Acute ketamine administration in healthy volunteers led to similar effects on cognition and psychopathology as observed in first-episode and chronic schizophrenia patients. However, the effects of ketamine on high-frequency oscillations and their connectivity profile were not consistent with these observations. Ketamine increased amplitude and frequency of gamma-power (63-80 Hz) in occipital regions and upregulated low frequency (5-28 Hz) activity. Moreover, ketamine disrupted feedforward and feedback signalling at high and low frequencies leading to hypo- and hyper-connectivity in thalamo-cortical networks. In contrast, first-episode and chronic schizophrenia patients showed a different pattern of magnetoencephalographic activity, characterized by decreased task-induced high-gamma band oscillations and predominantly increased feedforward/feedback-mediated Granger causality connectivity. Accordingly, the current data have implications for theories of cognitive dysfunctions and circuit impairments in the disorder, suggesting that acute NMDAR hypofunction does not recreate alterations in neural oscillations during visual processing observed in schizophrenia.

Project description:ObjectivesPeople with Schizophrenia (SZ) show deficits in auditory and audiovisual speech recognition. It is possible that these deficits are related to aberrant early sensory processing, combined with an impaired ability to utilize visual cues to improve speech recognition. In this electroencephalography study we tested this by having SZ and healthy controls (HC) identify different unisensory auditory and bisensory audiovisual syllables at different auditory noise levels.MethodsSZ (N = 24) and HC (N = 21) identified one of three different syllables (/da/, /ga/, /ta/) at three different noise levels (no, low, high). Half the trials were unisensory auditory and the other half provided additional visual input of moving lips. Task-evoked mediofrontal N1 and P2 brain potentials triggered to the onset of the auditory syllables were derived and related to behavioral performance.ResultsIn comparison to HC, SZ showed speech recognition deficits for unisensory and bisensory stimuli. These deficits were primarily found in the no noise condition. Paralleling these observations, reduced N1 amplitudes to unisensory and bisensory stimuli in SZ were found in the no noise condition. In HC the N1 amplitudes were positively related to the speech recognition performance, whereas no such relationships were found in SZ. Moreover, no group differences in multisensory speech recognition benefits and N1 suppression effects for bisensory stimuli were observed.ConclusionOur study suggests that reduced N1 amplitudes reflect early auditory and audiovisual speech processing deficits in SZ. The findings that the amplitude effects were confined to salient speech stimuli and the attenuated relationship with behavioral performance in patients compared to HC, indicates a diminished decoding of the auditory speech signals in SZs. Our study also revealed relatively intact multisensory benefits in SZs, which implies that the observed auditory and audiovisual speech recognition deficits were primarily related to aberrant processing of the auditory syllables.

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

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