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.
Highlights
Cognition, perception, and consciousness require synchronized gamma-band oscillations (GBO) [1]
Posthoc t-tests showed that the Positive and Negative Syndrome Scale (PANSS) total score and all subscores were significantly increased after ketamine administration compared to placebo administration and baseline values
Using a placebo-controlled, randomized, pharmacological 64channel-EEG crossover study design, we showed for the first time that ketamine reduces the ability to increase the auditory-evoked gamma-band response (aeGBR) power, phase-locking factor (PLF) and its generator within the dorsal anterior cingulate cortex (ACC) in response to a cognitively demanding auditory choice reaction task in healthy subjects
Summary
Perception, and consciousness require synchronized gamma-band oscillations (GBO) [1]. The auditory-evoked gamma-band response (aeGBR) has been observed in the timeframe of 25–100 ms after a stimulus and has been shown to be sensitive to task-related cognitive demands [7, 8]. The NMDAR-antagonists ketamine and phencyclidine (PCP) are known to induce psychopathological changes similar to those seen in schizophrenia with respect to positive, negative, and cognitive symptoms [16]. This led to the assumption that the. The aeGBR is one of the best established neurophysiological markers for schizophrenia and the relationship between GBO and NMDAR-mediated glutamatergic neurotransmission is remarkable, the aeGBR has not been explored in a paradigm sensitive to task-related cognitive demands under ketamine administration in healthy volunteers so far. Based on previous EEG und MEG studies [7, 8], we expected a specific decrease in the generator of the aeGBR in the anterior cingulate cortex (ACC)
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