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

• Published in: Frontiers in psychiatry Vol. 12; p. 671007
• Main Authors: Curic, Stjepan, Andreou, Christina, Nolte, Guido, Steinmann, Saskia, Thiebes, Stephanie, Polomac, Nenad, Haaf, Moritz, Rauh, Jonas, Leicht, Gregor, Mulert, Christoph
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 10.06.2021
• Subjects: functional connectivity; gamma-band oscillations; glutamate hypothesis; ketamine model of schizophrenia; Psychiatry; resting state; theta-band oscillations
• ISSN: 1664-0640; 1664-0640
• DOI: 10.3389/fpsyt.2021.671007

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.