Establishing a Task-evoked Magnetic Resonance Spectroscopy Approach for Testing the GABA Deficit Hypothesis in Schizophrenia

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PROJECT SUMMARY / ABSTRACT Schizophrenia carries one of the heaviest public health burdens of any illness in the U.S. and worldwide. Among its diverse symptoms, it is now well recognized that cognitive deficits are important contributors to this burden. However, currently available treatments provide, at best, modest benefits for these symptoms. The identification of the neural mechanisms of cognitive deficits will facilitate the development of new treatments and preventative strategies by identifying treatment targets. The GABA deficit hypothesis represents one of the most compelling explanations of the neural basis of cognitive deficits in schizophrenia. It proposes that decreased GABA synthesis in the dorsolateral prefrontal cortex (DLPFC) leads to impairments in local circuit function and cognition in schizophrenia. One of the major impediments to the advancement of this hypothesis has been the inability to obtain clear evidence for the presence of GABA deficits in living individuals with schizophrenia. This evidence would not only provide critical validation of the GABA deficit hypothesis, but would also pave the way for the establishment of biomarkers with research and clinical utility. The foundation of the GABA deficit hypothesis has been the consistent demonstration of reduction in the synthesis capacity for GABA in the post-mortem brains of individuals with schizophrenia. This consistent demonstration strongly predicts reduced concentration of GABA in the DLPFC in schizophrenia, which should be detectable using in vivo magnetic resonance spectroscopy (MRS). However, it has proven difficult to show consistent or robust deficits in schizophrenia using MRS. This has raised concerns that currently available in vivo MRS methods for measuring GABA suffer from too many limitations to adequately test the GABA deficit hypothesis. To address these concerns, we propose establishing a new in vivo method for measuring GABA. This new method takes on a fundamentally different approach compared to current methods. While standard methods measure neurochemical levels at baseline (rest), we will measure task-evoked changes in GABA level compared to baseline. The innovations of this new method have been designed to remediate some of the most important limitations associated with MRS measurements of GABA and to optimize our chances of detecting true GABA deficits in schizophrenia.