Sensory deficits and distributed hierarchical dysfunction in schizophrenia

Objective: Schizophrenia is characterized by widespread cognitive deficits that reflect distributed dysfunction across multiple cortical regions. Here the authors examined the relationship between lower- and higher-level dysfunction within the auditory domain using the event-related brain potentials mism atch negativity (MMN) and P300. Method: Event-related brain potentials were obtained from 50 schizophrenia patients and 21 healthy subjects in two conditions: a standard condition employing fixed differences between standard tones and pitch deviants and a novel individualized condition employing tones matched to each individual's tone-discrimination threshold. The relationship among measures was assessed by multiple regression analysis and structural equation modeling. Results: In the standard fixed-deviance condition, schizophrenia patients showed deficits of large effect size in generation of MMN (d>1.26) and P300 (d=1.08) relative to comparison subjects. Assessm ent of deviance-detection thresholds showed that patients required significantly elevated tone-m atching thresholds relative to comparison subjects (d=0.97). When tone differences were individually adjusted to equate tone-m atching performance across groups, the groups no longer differed significantly in MMN amplitude during deviant pitch tones, and the degree of deficit in P300 generation was significantly reduced. In both multiple regression analysis and structural equation modeling, MMN and diagnostic group were significant independent predictors of reduced P300 amplitude. MMN generation was well explained (>90% variance) by dipoles seeded within the bilateral auditory cortex. Conclusions: These findings confirm and extend previous reports of im paired basic sensory processing in schizophrenia and demonstrate significant contributions of early sensory processing dysfunction to higher-order cognitive im pairments. Overall, the findings support distributed, hierarchical models of cognitive im pairment in schizophrenia, consistent with glutam atergic and other widespread neurochemical models of the disorder.