title: Mechanisms of Working Memory Impairment in Schizophrenia.
abstract: The neural correlates of working memory (WM) impairment in schizophrenia remain a key puzzle in understanding the cognitive deficits and dysfunction of dorsolateral prefrontal cortex observed in this disorder. We sought to determine whether patients with schizophrenia exhibit an alteration in the inverted-U relationship between WM load and activation that we recently observed in healthy individuals and whether this could account for WM deficits in this population.
  
  
  
  Medicated (n = 30) and unmedicated (n = 21) patients with schizophrenia and healthy control subjects (n = 45) performed the self-ordered WM task during functional magnetic resonance imaging. We identified regions exhibiting an altered fit to an inverted-U relationship between WM load and activation that were also predictive of WM performance.
  
  
  
  A blunted inverted-U response was observed in left dorsolateral prefrontal cortex in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex during WM was reduced in patients and was associated with poorer WM capacity in patients. Finally, activation of visual cortex in the cuneus was elevated in patients and associated with improved WM capacity. Together, these findings explained 55% of the interindividual variance in WM capacity when combined with diagnostic and medication status, which alone accounted for only 22% of the variance in WM capacity.
  
  
  
  These findings identify a novel biomarker and putative mechanism of WM deficits in patients with schizophrenia, a reduction or flattening of the inverted-U relationship between activation and WM load observed in healthy individuals in left dorsolateral prefrontal cortex.
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York; Cognitive Neuroscience, New York, New York. Electronic address: jxv1@cumc.columbia.edu.
authors.forename: Jared X
authors.initials: JX
authors.lastname: Van Snellenberg
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York.
authors.forename: Ragy R
authors.initials: RR
authors.lastname: Girgis
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Horga
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York; Department of Nuclear Medicine, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Elsmarieke
authors.initials: E
authors.lastname: van de Giessen
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York.
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York.
authors.forename: Najate
authors.initials: N
authors.lastname: Ojeil
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York.
authors.forename: Jodi J
authors.initials: JJ
authors.lastname: Weinstein
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Integrative Neuroscience, New York, New York.
authors.forename: Holly
authors.initials: H
authors.lastname: Moore
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; New York State Psychiatric Institute, New York, New York.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.affiliation: Department of Psychology, Columbia University, New York, New York.
authors.forename: Daphna
authors.initials: D
authors.lastname: Shohamy
authors.affiliation: Cognitive Neuroscience, New York, New York; Department of Psychology, Columbia University, New York, New York.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Smith
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; Divisions of Translational Imaging, New York, New York.
authors.forename: Anissa
authors.initials: A
authors.lastname: Abi-Dargham
mesh_terms: D000328:Adult; D001931:Brain Mapping; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000503:physiopathology* / Q000523:psychology*; D008570:Memory, Short-Term; D009434:Neural Pathways / Q000503:physiopathology; D009483:Neuropsychological Tests; D009778:Occipital Lobe / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000503:physiopathology; D012559:Schizophrenia / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D055815:Young Adult
keywords: Cognitive impairment; Functional magnetic resonance imaging; Inverted-U; Schizophrenia; Short-term memory; Working memory