Working memory has traditionally been characterized as providing temporary memory storage and guidance of ongoing behavior and depending on recurrent excitation of prefrontal neurons. It is hypothesized that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists interfere with working memory. The NMDAR antagonist, ketamine, can produce in healthy humans temporary deficits in working memory performance and accompanying prefrontal activation. Theories and preclinical research link these phenomena to cortical disinhibition. However, these theories have not been tested in humans because no imaging modality could appropriately quantify both the deficits in working memory related activation and performance and putative changes in baseline cortical metabolism. Recently, a technique called calibrated functional magnetic resonance imaging has become available for use in humans. We propose to use this technique in healthy persons to measure baseline cortical oxidative metabolism. This method will be combined with conventional functional magnetic resonance imaging and a spatial working memory paradigm to measure working memory deficits during infusion with the NMDAR antagonist ketamine. We will test three key hypotheses: 1) that the NMDAR antagonist ketamine increases prefrontal cortical oxidative metabolism as measured with calibrated fMRI; 2) that increases in prefrontal cortical oxidative metabolism are related to decreases in working- memory related activation measured with conventional functional magnetic resonance imaging; and 3) that increases in prefrontal cortical oxidative metabolism are related to reductions in working memory accuracy. The results of this study would increase understanding of working memory deficits and could be helpful in developing and testing novel therapeutics for working memory dysfunction. They may be particularly important in schizophrenia because there is strong evidence of glutamatergic dysfunction in the disorder and working memory function predicts functional recovery.

The proposed study tests a key neuroscience hypothesis that relates N-methyl-D-aspartate receptor deficits to difficulties in temporary memory storage and the ability to guide goal- oriented behavior. It would be, to our knowledge, the first study to use a new imaging technique, calibrated functional magnetic resonance imaging, as part of a neuropharmacological study. This study has broad implications for individuals with cognitive dysfunction, especially individuals with schizophrenia, and introduces to translational research calibrated fMRI, a key tool for measuring cerebral oxidative metabolism produced by pharmacological agents or present in clinical groups.