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.
authors.affiliation: 1] Department of Psychiatry, Connecticut Mental Health Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Neurology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Driesen
authors.forename: Gregory
authors.initials: G
authors.lastname: McCarthy
authors.forename: Zubin
authors.initials: Z
authors.lastname: Bhagwagar
authors.forename: Michael H
authors.initials: MH
authors.lastname: Bloch
authors.forename: Vincent D
authors.initials: VD
authors.lastname: Calhoun
authors.forename: Deepak C
authors.initials: DC
authors.lastname: D'Souza
authors.forename: Ralitza
authors.initials: R
authors.lastname: Gueorguieva
authors.forename: George
authors.initials: G
authors.lastname: He
authors.forename: Hoi-Chung
authors.initials: HC
authors.lastname: Leung
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Ramani
authors.forename: Alan
authors.initials: A
authors.lastname: Anticevic
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Suckow
authors.forename: Peter T
authors.initials: PT
authors.lastname: Morgan
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
mesh_terms: D000328:Adult; D001931:Brain Mapping; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D007839:Functional Laterality / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007649:Ketamine / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D017397:Prefrontal Cortex / Q000098:blood supply / Q000187:drug effects*; D013028:Space Perception / Q000187:drug effects; D013997:Time Factors; D055815:Young Adult
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D010100:Oxygen