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Francine M. Benes, MD, PhD; Jennifer McSparren; Edward D. Bird, MD; John Paul SanGiovanni; Stephen L. Vincent, PhD

Arch Gen Psychiatry. 1991;48(11):996-1001.

Abstract
• A recent report suggested that neurons in the prefrontal, anterior cingulate, and primary motor cortex of the brains of schizophrenic subjects may be less dense than those in the brains of nonschizophrenic subjects. We have determined whether pyramidal neurons and/or interneurons are preferentially reduced in schizophrenic subjects. Twelve control subjects and 18 schizophrenic subjects were studied in a blind, quantitative analysis of the density of pyramidal cells, interneurons, and glial cells in each of the six layers of the anterior cingulate and prefrontal cortex. The results showed that numbers of small neurons (interneurons) were reduced in most layers of the cingulate cortex in schizophrenic subjects compared with nonschizophrenic subjects, with the differences being greatest in layer II. In the prefrontal area, interneuronal density was also lower in layer II and, to a lesser extent, in layer I in schizophrenic subjects compared with control subjects. In most cases, the differences were similar, although more significant, in schizophrenic subjects who had had superimposed mood disturbances than in schizophrenic subjects who had not had such comorbidity. Numbers of pyramidal neurons generally were not different between control and schizophrenic subjects, except in layer V of the prefrontal area, where schizophrenic subjects showed higher densities of these neurons. Glial numbers did not differ between the control and schizophrenic subjects, suggesting that a neurodegenerative process did not cause the reduced interneuronal density observed. Using multiple regression analysis and analysis of covariance, decreases in the density of layer II interneurons could not be adequately explained by the effects of various confounding variables, such as age, postmortem interval, duration of specimen fixation, or administration of neuroleptic agents. Two younger patients who had not received neuroleptic agents also had reduced numbers of small neurons, suggesting that reduction in numbers of small neurons is not due to the effects of antipsychotic medication. Reductions of interneurons, possibly ones that are inhibitory in nature, may occur within intrinsic cortical circuits, and may be an important aspect of the pathophysiology of schizophrenia.

Author Affiliations
From the Department of Psychiatry and Program in Neuroscience, Harvard Medical School, Cambridge, Mass (Drs Benes, Bird, and Vincent), and the Mailman Research Center, McLean Hospital, Belmont, Mass (Drs Benes, Bird, and Vincent; Ms McSparren; and Mr SanGiovanni).

Footnotes
Accepted for publication October 5, 1990.

Reprint requests to the Mailman Research Center, McLean Hospital, 115 Mill St, Belmont, MA 02178 (Dr Benes).

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ABSTRACT  

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ABSTRACT  

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ABSTRACT  

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Lee and Tobin
Arch Gen Psychiatry 1995;52:267-268.
ABSTRACT  

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Lewis
Arch Gen Psychiatry 1995;52:269-273.
ABSTRACT  

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Arch Gen Psychiatry 1995;52:279-288.
ABSTRACT  

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Benes
Neuroscientist 1995;1:104-115.
ABSTRACT  

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Andreasen et al.
Science 1994;266:294-298.
ABSTRACT  

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Benes et al.
Arch Gen Psychiatry 1994;51:477-484.
ABSTRACT  

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Laruelle et al.
Arch Gen Psychiatry 1993;50:810-818.
ABSTRACT  

Altered Distribution of Nicotinamide-Adenine Dinucleotide Phosphate--Diaphorase Cells in Frontal Lobe of Schizophrenics Implies Disturbances of Cortical Development
Akbarian et al.
Arch Gen Psychiatry 1993;50:169-177.
ABSTRACT  

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Akbarian et al.
Arch Gen Psychiatry 1993;50:178-187.
ABSTRACT  

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Bloom
Arch Gen Psychiatry 1993;50:224-227.
ABSTRACT  

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Johnson et al.
Science 1992;258:665-667.
ABSTRACT  

Subnucleus-specific loss of neurons in medial thalamus of schizophrenics
Popken et al.
Proc. Natl. Acad. Sci. USA 2000;97:9276-9280.
ABSTRACT | FULL TEXT