title: Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia.
abstract: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia.
  
  
  
  In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared.
  
  
  
  N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85).
  
  
  
  Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.
authors.affiliation: University of California, San Francisco.
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Kort
authors.affiliation: University of California, San Francisco; San Francisco Veterans Affairs Medical Center.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Northern California Institute for Research and Education, San Francisco, California.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Roach
authors.affiliation: Yale University School of Medicine, New Haven; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
authors.forename: Handan
authors.initials: H
authors.lastname: Gunduz-Bruce
authors.affiliation: Yale University School of Medicine, New Haven; Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut.
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.affiliation: Clinical Development AstraZeneca Pharmaceuticals, Wilmington, Delaware.
authors.forename: Judith
authors.initials: J
authors.lastname: Jaeger
authors.affiliation: Yale University School of Medicine, New Haven.
authors.forename: Robert M G
authors.initials: RM
authors.lastname: Reinhart
authors.affiliation: University of California, San Francisco; San Francisco Veterans Affairs Medical Center. Electronic address: daniel.mathalon@ucsf.edu.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Mathalon
mesh_terms: D000161:Acoustic Stimulation; D000328:Adult; D002540:Cerebral Cortex / Q000503:physiopathology*; D018592:Cross-Over Studies; D004569:Electroencephalography; D005071:Evoked Potentials; D005260:Female; D006801:Humans; D007649:Ketamine; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012559:Schizophrenia / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D013067:Speech Perception / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: Electroencephalography; Ketamine; N-methyl-D-aspartate glutamate receptor; Predictive coding; Schizophrenia; Speech motor control