Prediction of treatment response and course of disease in schizophrenia using EEG high frequency oscillations as a correlate of glutamatergic neurotransmission

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Recently, an imbalance between excitation and inhibition (E/I-balance) towards elevated excitability has been implicated in the pathophysiology of schizophrenia. The E/I-balance is thought to be crucially dependent on a circuit mechanism involving inhibitory GABAergic and excitatory glutamatergic signaling. Critical evidence supporting this assumption comes from animal models, genetic work, postmortem studies, neuroimaging studies in patients, glutamatergic treatment effects and pharmacological models of schizophrenia. The applicant’s previous electroencephalography (EEG) work on altered high-frequency oscillatory activity (reduction of the auditory evoked gamma-band response) in different stages of schizophrenia also contributes to this evidence, as the microcircuit involving parvalbumin-positive GABAergic interneurons and glutamatergic pyramidal cells plays a crucial role for the generation of gamma oscillations. The reversal of gamma oscillation alterations has been shown to be predictive of antipsychotic activity with a unique profile for clozapine in animal work. However, to date, no study has comprehensively addressed the relationship between these findings in a single cohort of schizophrenia patients by combining magnetic resonance spectroscopy (MRS) measurements of GABA/glutamate concentrations utilizing a high MR field strength of 7-Tesla, EEG measurements of task evoked as well as ongoing resting state gamma oscillations and effects of pharmacological modulation with clozapine on these measures. Thus, the present proposal aims to integrate findings from MRS studies on glutamate and GABA concentrations, from EEG studies on high frequency gamma oscillations and about glutamatergic effects of clozapine treatment in schizophrenia patients. Using MR field strength of 7-Tesla at the Melbourne Brain Centre will improve the accuracy of MRS in examining the metabolites glutamate, GABA and glutathione compared to previous studies. The proposal wants to contribute to a better understanding of alterations of the E/I-imbalance in the pathophysiology of schizophrenia. For instance, linking EEG gamma measures and in vivo measures of glutamate and GABA of identical subjects is supposed to further reveal the nature of the apparent contradiction between increased resting state and diminished task evoked gamma oscillatory activity in schizophrenia. Furthermore, the proposal wants to contribute to the development of new biological markers for the prediction of treatment response to glutamatergic treatment strategies. If directly related to in vivo measures of glutamate and GABA, EEG high frequency oscillations as a correlate of neurotransmission might be a cheap and easily applicable alternative compared to MRS in future clinical routine. Finally, the proposed research aims to examine the applicability of resting state gamma network alterations in the prediction of the course of psychosis.