title: Neural substrates of normal and impaired preattentive sensory discrimination in large cohorts of nonpsychiatric subjects and schizophrenia patients as indexed by MMN and P3a change detection responses.
abstract: OBJECTIVE
  Schizophrenia (SZ) patients have information processing deficits, spanning from low level sensory processing to higher-order cognitive functions. Mismatch negativity (MMN) and P3a are event-related potential (ERP) components that are automatically elicited in response to unattended changes in ongoing, repetitive stimuli that provide a window into abnormal information processing in SZ. MMN and P3a are among the most robust and consistently identified deficits in SZ, yet the neural substrates of these responses and their associated deficits in SZ are not fully understood. This study examined the neural sources of MMN and P3a components in a large cohort of SZ and nonpsychiatric control subjects (NCS) using Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) in order to identify the neural sources of MMN and P3a as well as the brain regions associated with deficits commonly observed among SZ patients.
  
  
  METHODS
  410 SZ and 247 NCS underwent EEG testing using a duration-deviant auditory oddball paradigm (1-kHz tones, 500ms SOA; standard p=0.90, 50-ms duration; deviant tones P=0.10, 100-ms duration) while passively watching a silent video. Voxel-by-voxel within- (MMN vs. P3a) and between-group (SZ vs. NCS) comparisons were performed using eLORETA.
  
  
  RESULTS
  SZ had robust deficits in MMN and P3a responses measured at scalp electrodes consistent with other studies. These components mapped onto neural sources broadly distributed across temporal, frontal, and parietal regions. MMN deficits in SZ were associated with reduced activations in discrete medial frontal brain regions, including the anterior-posterior cingulate and medial frontal gyri. These early sensory discriminatory MMN impairments were followed by P3a deficits associated with widespread reductions in the activation of attentional networks (frontal, temporal, parietal regions), reflecting impaired orienting or shifts of attention to the infrequent stimuli.
  
  
  CONCLUSIONS
  MMN and P3a are dissociable responses associated with broadly distributed patterns of neural activation. MMN deficits among SZ patients appear to be primarily accounted for by reductions in medial prefrontal brain regions that are followed by widespread dysfunction across cortical networks associated with P3a in a manner that is consistent with hierarchical information processing models of cognitive deficits in SZ patients. Impairments in automatic stimulus discrimination may contribute to higher-order cognitive and psychosocial deficits in SZ.
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Rissling
authors.affiliation: The KEY Institute for Brain-Mind Research, University Hospital of Psychiatry, Zurich, Switzerland.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pascual-Marqui
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kirihara
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Marlena
authors.initials: M
authors.lastname: Pela
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; VISN-22 Mental Illness, Research, Education and Clinical Center, VA San Diego Healthcare System, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sprock
authors.affiliation: Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; VISN-22 Mental Illness, Research, Education and Clinical Center, VA San Diego Healthcare System, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
authors.affiliation: VISN-22 Mental Illness, Research, Education and Clinical Center, VA San Diego Healthcare System, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA. Electronic address: glight@ucsd.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
mesh_terms: D000328:Adult; D001288:Attention / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D015331:Cohort Studies; D004569:Electroencephalography; D005071:Evoked Potentials / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia / Q000503:physiopathology*; D012815:Signal Processing, Computer-Assisted
keywords: Cognition; EEG; Endophenotype; LORETA; MMN; Mismatch negativity; P300; P3a; Schizophrenia; Sensory information processing; Source localization