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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.

SUBMITTER: Curic S

PROVIDER: S-EPMC8222814 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10-3 ), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = -.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.

Project description:Alterations in cortical inter-areal functional connectivity, and aberrant glutamatergic signalling are implicated in the pathophysiology of schizophrenia but the relationship between the two is unclear. We used multimodal imaging to identify areas of convergence between the two systems. Two separate cohorts were examined, comprising 195 participants in total. All participants received resting state functional MRI to characterise functional brain networks and proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate concentrations in the frontal cortex. Study A investigated the relationship between frontal cortex glutamate concentrations and network connectivity in individuals with schizophrenia and healthy controls. Study B also used 1H-MRS, and scanned individuals with schizophrenia and healthy controls before and after a challenge with the glutamatergic modulator riluzole, to investigate the relationship between changes in glutamate concentrations and changes in network connectivity. In both studies the network based statistic was used to probe associations between glutamate and connectivity, and glutamate associated networks were then characterised in terms of their overlap with canonical functional networks. Study A involved 76 individuals with schizophrenia and 82 controls, and identified a functional network negatively associated with glutamate concentrations that was concentrated within the salience network (p < 0.05) and did not differ significantly between patients and controls (p > 0.85). Study B involved 19 individuals with schizophrenia and 17 controls and found that increases in glutamate concentrations induced by riluzole were linked to increases in connectivity localised to the salience network (p < 0.05), and the relationship did not differ between patients and controls (p > 0.4). Frontal cortex glutamate concentrations are associated with inter-areal functional connectivity of a network that localises to the salience network. Changes in network connectivity in response to glutamate modulation show an opposite effect compared to the relationship observed at baseline, which may complicate pharmacological attempts to simultaneously correct glutamatergic and connectivity aberrations.

Project description:BackgroundHow oscillatory brain rhythms alone, or in combination, influence cortical information processing to support learning has yet to be fully established. Local field potential and multi-unit neuronal activity recordings were made from 64-electrode arrays in the inferotemporal cortex of conscious sheep during and after visual discrimination learning of face or object pairs. A neural network model has been developed to simulate and aid functional interpretation of learning-evoked changes.ResultsFollowing learning the amplitude of theta (4-8 Hz), but not gamma (30-70 Hz) oscillations was increased, as was the ratio of theta to gamma. Over 75% of electrodes showed significant coupling between theta phase and gamma amplitude (theta-nested gamma). The strength of this coupling was also increased following learning and this was not simply a consequence of increased theta amplitude. Actual discrimination performance was significantly correlated with theta and theta-gamma coupling changes. Neuronal activity was phase-locked with theta but learning had no effect on firing rates or the magnitude or latencies of visual evoked potentials during stimuli. The neural network model developed showed that a combination of fast and slow inhibitory interneurons could generate theta-nested gamma. By increasing N-methyl-D-aspartate receptor sensitivity in the model similar changes were produced as in inferotemporal cortex after learning. The model showed that these changes could potentiate the firing of downstream neurons by a temporal desynchronization of excitatory neuron output without increasing the firing frequencies of the latter. This desynchronization effect was confirmed in IT neuronal activity following learning and its magnitude was correlated with discrimination performance.ConclusionsFace discrimination learning produces significant increases in both theta amplitude and the strength of theta-gamma coupling in the inferotemporal cortex which are correlated with behavioral performance. A network model which can reproduce these changes suggests that a key function of such learning-evoked alterations in theta and theta-nested gamma activity may be increased temporal desynchronization in neuronal firing leading to optimal timing of inputs to downstream neural networks potentiating their responses. In this way learning can produce potentiation in neural networks simply through altering the temporal pattern of their inputs.

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

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