GABA-glutamate interaction as neurochemical basis of cerebral resting-state dysfunction in depression and schizophrenia: A 7 tesla multimodal imaging project

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In depression and schizophrenia, dysfunctions in the glutamate (Glu) and gamma-amino-butyric acid (GABA) systems have been postulated as important neurochemical characteristics of the disorders. Proton magnetic resonance spectroscopy (MRS) offers the unique possibility to determine local glutamate and GABA concentrations non-invasively, in vivo in the human brain. Since it remains difficult to reliably quantify Glu and, especially GABA, significant efforts will be invested to optimize the corresponding MRS methodology. To overcome the sensitivity constraints of lower B0 fields (1.5 and 3 tesla) we propose to take advantage of the enhanced sensitivity at the ultrahigh field strength of 7 tesla for MRS and functional magnetic resonance imaging (fMRI). In 30 unmedicated depressive patients, 30 unmedicated schizophrenic patients and 60 healthy controls, MRS measurements will be carried out at 7 tesla. In the same session, resting-state fMRI will target another pathobiological characteristic of both diseases, namely ventromedial prefrontal cortex (vmPFC) hyperactivations in depression and hypoactivations in schizophrenia (Kühn & Gallinat 2013; Schizophr Bull). Dysfunctional vmPFC activation will be further characterized with a self-referential paradigm during fMRI acquisition to predict clinical symptom profil of both diseases. The project focuses particularly the proposed coupling of neurochemical and functional cerebral disturbance as a core pathomechanism of two major psychiatric diseases. Based on our previous work we hypothesize that in the region of interest, the vmPFC: (1) depressed patients show increased glutamate and decreased GABA concentrations together with resting-state hyperactivation compared to controls, (2) schizophrenic patients have decreased glutamate and increased GABA concentrations together with resting state hypoactivation compared to healthy controls, and (3) the concentration of glutamate is positively correlated with resting-state activity while GABA shows an inverse relationship. (4) the activation during self-related processing is positively correlated with severity of ruminations in major depression and negatively associated with insight in schizophrenic patients. The project will clarify the pathobiological role of two crucial neurotransmitter systems for psychotic and affective disorders and their functional consequences, allows the identification of biological subgroups within the two diagnostic entities, establishes the knowledge for future pharmacotherapy apart from current models of dysfunctional neuromodulators (e.g. serotonin), and will help to develop MRS methodology at 7 tesla to pave the way for applications at ultrahigh B0.