@article{a7bed6b7946a43a7a126e852f9edb554,
title = "The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity",
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.",
keywords = "NMDA, connectivity, ketamine, prefrontal cortex, schizophrenia, working memory",
author = "Driesen, {Naomi R.} and Gregory McCarthy and Zubin Bhagwagar and Bloch, {Michael H.} and Calhoun, {Vincent D.} and D'Souza, {Deepak C.} and Ralitza Gueorguieva and George He and Leung, {Hoi Chung} and Ramachandran Ramani and Alan Anticevic and Suckow, {Raymond F.} and Morgan, {Peter T.} and Krystal, {John H.}",
note = "Funding Information: Zubin Bhagwagar is employed by Bristol-Myers Squibb and owns stock in the company. Deepak Cyril D{\textquoteright}Souza has in the past three years or currently received research grant support administered through Yale University School of Medicine from Astra Zeneca, Abbott Laboratories, Eli Lilly Inc., Forest Laboratories, Organon, Pfizer Inc., and Sanofi. He is a consultant for Bristol Myers Squibb and Johnson & Johnson. John Krystal consults for several pharmaceutical and biotechnology companies, with compensation less than $10 000 per year. These companies include AbbVie, Inc.; Amgen; AstraZeneca Pharmaceuticals; Bristol-Myers Squibb; Eli Lilly and Co.; Janssen Research & Development; Lundbeck Research USA; Otsuka Pharmaceutical, Development & Commercialization, Inc.; Sage Therapeutics, Inc.; Shire Pharmaceuticals; Sunovion Pharmaceuticals, Inc.; Takeda Industries; and Teva Pharmaceutical Industries, Ltd. Dr Krystal is a member of the following scientific advisory boards: CHDI Foundation, Inc.; Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc.; Naurex, Inc.; and Pfizer Pharmaceuticals. In addition, Dr Krystal is a board member of the Coalition for Translational Research in Alcohol and Substance Use Disorders, president of the American College of Neuropsychopharmacology, editor of Biological Psychiatry; and an employee of the Yale University School of Medicine and the VA CT Health System. He is an originator on the following patent: Seibyl JP, Krystal JH, and Charney DS; Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia; Patent #:5 447 948; 5 September 1995. In addition, he is an originator of the following relevant pending patents: (1) Vladimir, Coric; Krystal, John H, Sanacora, Gerard—Glutamate Agents in the Treatment of Mental Disorders No 11/399 188; 5 April 2006 (Pending). (2) Intranasal Administration of Ketamine to Treat Depression (Pending). The remaining authors declare no conflict of interest.",
year = "2013",
month = dec,
doi = "10.1038/npp.2013.170",
language = "English (US)",
volume = "38",
pages = "2613--2622",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "13",
}