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Human Recordings, Computer Simulation, and an Animal Model

Robert Freedman, MD; Lawrence E. Adler, MD; Marina Myles-Worsley, PhD; Herbert T. Nagamoto, MD; Christine Miller, PhD; Michael Kisley, MS; Kara McRae; Ellen Cawthra, RN; Merilyne Waldo, PhD

Arch Gen Psychiatry. 1996;53(12):1114-1121.

Abstract
Background
Altered sensory response is a prominent feature of schizophrenia. Inhibitory gating mechanisms, shown by diminished P50 evoked responses to repeated auditory stimuli, seem to be deficient in schizophrenic persons. These inhibitory mechanisms usually are studied by averaging the electroencephalographic responses to many presentations of pairs of stimuli. Although averaging increases signal-to-noise ratio, it may obscure trial-to-trial differences. We compared differences between schizophrenic and normal persons in single trials and averages of P50 response.

Methods
Recordings from 10 schizophrenic patients and 10 normal subjects were analyzed using conventional averaging and single-trial measurements. A computer simulation of both methods examined their ability to extract evoked responses from background activity. Related single-neuron activity in the hippocampus in an animal model also was studied, because neuronal action potentials can be reliably identified in single trials.

Results
Averaged evoked potentials showed significant suppression of the P50 response to the second stimulus of the pair in normal patients, but not in schizophrenic patients. Single-trial analysis did not detect a response above background activity. Computer simulations gave similar results, suggesting that failure to detect suppression in single trials comes from inadequate differentiation of signal from noise. Recordings in animals confirmed almost complete suppression of the response of hippocampal pyramidal neurons to the second stimulus.

Conclusions
The normal inhibition of response to repeated auditory stimuli seems to be compromised in schizophrenia. This loss of inhibitory gating could reflect a physiological deficit of hippocampal interneurons that is consonant with other evidence for interneuron pathologic defects in schizophrenia.

Author Affiliations
From the Department of Psychiatry, Denver Veterans Administration Medical Center and University of Colorado Health Sciences Center, Denver, Colo (Drs Freedman, Adler, Nagamoto, Miller, and Waldo and Mss McRae and Cawthra and Mr Kisley); and the Department of Psychiatry, University of Utah School of Medicine, Salt Lake City (Dr Myles-Worsley).

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