PROJECT SUMMARY – The glutamate hypothesis of schizophrenia has generated significant interest in the utility of Magnetic Resonance Spectroscopy and Spectroscopic Imaging (MRS/MRSI) to study the pathophysiology of schizophrenia in recent times. The glutamate hypothesis provides a complementary perspective to the well-established dopaminergic hypothesis, suggesting that dysfunction of the glutamatergic system plays a role in the etiology of schizophrenia. Previous MRS/MRSI studies conducted have reported alterations of glutamate (Glu) and glutamine (Gln) and Glx (Glu + Gln) in various brain regions, consistent with neuronal dysfunction in chronic stages of the disease. The robust and reliable acquisition of MRSI data is however hindered by extracranial lipid contaminants. Most extracranial lipid suppression methods reported to-date provide inadequate lipid signal suppression, to allow artifact-free spectroscopic evaluation of cortical grey matter proximal to the skull. As a result, MRSI studies in schizophrenia conducted to-date at 3 T have two major limitations: 1) exclusion of cortical tissue proximal to extracranial lipids, and 2) uncertainties associated with Glu/Gln separation, thus predominantly reporting Glx changes. Because glutamatergic activity is inferred from the Glu/Gln ratio, it is critical to develop accurate and separate quantitation of Glu and Gln to further the value of testing the glutamate hypothesis. This work involves the development of a high resolution (~ 5 x 5 x 10 mm3) 3D proton MRSI method using ECLIPSE, a second order gradient insert, for highly selective elliptical localization over an axial plane. High selectivity and unparalleled extracranial lipid suppression was previously demonstrated with ECLIPSE, which allows artifact-free interrogation of cortical tissue adjacent to the skull. The MRSI acquisition will be extended with an optimized multiple-echo time (TE) acquisition combined with a macromolecule targeted inversion recovery component to nullify the macromolecular baseline. In combination the proposed MRSI method is expected to allow reliable quantification of Glu/Gln. Following development of the MRSI sequence, robustness, reproducibility metrics, and Glu/Gln quantification performance will be evaluated in phantom and on a healthy cohort of volunteers, followed by tolerance and translatability of the methods evaluated on a heterogenous cohort of first episode psychosis or patients with recent onset schizophrenia spectrum disorders. The successful completion of the proposed methods will allow reliable quantitative MRS images of Glu and Gln, among other commonly detected metabolites, over an axial slab including frontal cortical gray matter proximal to the skull. Given that the frontal region is the most significantly impacted by schizophrenia, the ability provided for reliable metabolic images that are sensitive to altered glutamatergic activity is expected to have a high impact by providing a reliable metabolic imaging tool for characterizing disease severity, heterogeneity, and treatment effects in patients. The development of reliable Glu/Gln quantification with MRSI at 3 T has further clinical significance, since the 3 T field strength is the most accessible high field MRI system in the clinical setting.

PROJECT NARRATIVE– Magnetic Resonance Spectroscopic Imaging (MRSI) is a valuable and complementary modality to MRI, that can detect glutamate dysfunction by mapping glutamate and glutamine levels in the brain. Alterations in the glutamatergic system have been implicated in a variety of brain diseases such as schizophrenia, though the application of MRSI to schizophrenia and other disorders has been hampered by skull lipid contamination preventing reliable measurements in critical regions such as the frontal cortex. The significance of this proposal is that we will develop and validate novel MRSI methods on a clinical 3 T MRI system that largely eliminate lipid contamination allowing high quality maps of glutamate and glutamine levels throughout the frontal lobe and other brain regions, and evaluate tolerance and translatability of the methods on a clinical cohort of patients.