Abstract
Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.
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Acknowledgements
Dr Driesen thanks the following individuals: Dr Amy Arnsten provided helpful comments regarding this manuscript and related topics. Drs Michelle Hampson and Pawel Skudlarski provided advice regarding the connectivity analysis. Cheryl Lacadie helped informally with a number of image processing and software issues. Kathleen Maloney, Julie Holub, Cara Cordeaux, and Nikia McFadden served as research assistants. Nursing care was provided by the Yale Center for Clinical Investigation and the Biostudies Unit, Neurobiological Diagnostic Studies Unit of the VA CT Healthcare System, West Haven, CT, USA. MRI technologists Hedy Sarofin and Karen A Martin supplied expert assistance for this complex MRI protocol. This study was supported by Yale-Pfizer Alliance (NRD); National Alliance for Research on Schizophrenia and Depression-Distinguished Investigator Award (JHK) and Young Investigator Award (ZB); Conte Center Calcium Signaling and Prefrontal Deficits in Schizophrenia, NIMH; National Center for Post-Traumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, USA; National Institute on Alcohol Abuse and Alcoholism, 2P50 AA 012870; US Department of Veterans Affairs Alcohol Research Center; NIH National Center for Research Resources CTSA Grant Number UL1 RR024139; NIH Grant Number K23-MH077914; and the State of CT Department of Mental Health and Addiction Services.
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Data from this paper were presented at the May 2012 Biological Psychiatry and June 2013 Human Brain Mapping meetings.
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Driesen, N., McCarthy, G., Bhagwagar, Z. et al. The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity. Neuropsychopharmacol 38, 2613–2622 (2013). https://doi.org/10.1038/npp.2013.170
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DOI: https://doi.org/10.1038/npp.2013.170
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