Functional MR of the Effects of D-Serine

Mclean Hospital, Belmont MA

Investigators

Linked publications & trials

Abstract

This project will test the hypothesis that schizophrenia is associated with NMDA hypofunction by examining[unreadable] in-vivo brain data acquired through the combined use of proton magnetic resonance spectroscopy (MRS)[unreadable] and BOLD functional magnetic resonance imaging (fMRI). We propose to measure proton metabolite[unreadable] concentrations, including N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG), in temporal and[unreadable] prefrontal cortical regions in schizophrenic patients and healthy controls. MRS data will be acquired on a 4T[unreadable] scanner with newly developed methods that provide improved resolution of peaks and signal components[unreadable] within the proton spectrum, thus improving interpretability of NAA measurements, as well as extending MRS[unreadable] capabilities to include quantification of NAAG. The quantification of these metabolites is relevant for the main[unreadable] hypothesis of the center grant as work from our group has reported reduced NAA in temporal cortex[unreadable] bilaterally. Further, NAAG has been implicated in NMDA hypofunction. At present in-vivo measurements of[unreadable] these metabolites, have not been concurrently characterized in schizophrenia. Moreover, it has been shown[unreadable] that NMDA receptors in the hippocampus are essential for spatial learning and that pharmacological[unreadable] blockade of NMDA receptors impairs spatial navigation. Therefore, as an exploratory endpoint, we propose[unreadable] to acquire fMRI data on a 3Tscanner during the completion of a virtual analogue of a spatial navigation task,[unreadable] the water maze, to assess spatial memory performance. We will also acquire fMRI data during a transitive[unreadable] inference task to assess relational memory, and during a facial recall challenge, tasks previously shown to[unreadable] be mediated by the hippocampus. Finally, in collaboration with Dr. Don Goff (Clinical Trials Section), we will[unreadable] enroll 60 schizophrenic patients into a placebo-controlled trial of D-serine, an agonist at the glycine site on[unreadable] the NMDA receptor. Patients will be imaged with the MRS/fMRI protocols described above to examine the[unreadable] effects of D-serine treatment on spatial and relational memory performance, BOLD activation and NAA and[unreadable] NAAG concentrations.