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November 1991, Vol 48, No. 11 >
Article | November 1991

Deficits in Small Interneurons in Prefrontal and Cingulate Cortices of Schizophrenic and Schizoaffective Patients

Francine M. Benes, MD, PhD; Jennifer McSparren; Edward D. Bird, MD; John Paul SanGiovanni; Stephen L. Vincent, PhD
[+] Author Affiliations

Accepted for publication October 5, 1990.

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


Arch Gen Psychiatry. 1991;48(11):996-1001. doi:10.1001/archpsyc.1991.01810350036005
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• 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.

REFERENCES

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Josephy J.  Beitrage zur Histopathologie der Dementia Praecox . Z Gesamte Neurol Psychiatry . 1923;;86:391-461.
2 +
Winkelman NW, Book MH.  Observations on the histopathology of schizophrenia . Am J Psychiatry . 1949;;105:889-896.
3 +
Vogt O. Proposition de fonder une organisation internationale pour l'etude de l'anatomie pathologique de la schizophrenie et d'autres psychoses dite fonctionelle. In: Proceedings of the First International Congress on Neuropathology; September 8-13, 1952; Torina, Italy. 1952;3:674-677.
4 +
Dunlap CB.  Dementia praecox . Am J Psychiatry . 1924;;80:403-420.
5 +
Spielmeyer W.  The problem of the anatomy of schizophrenia . J Nerv Ment Dis . 1930;;72:241-244.
6 +
Corsellis JAN.  Psychoses of obscure pathology . In: Blackwood W, Corsellis JAN, eds. Greenfield's Neuropathology . Baltimore, Md: Edward Arnold Publishers Ltd; 1976;:903-915.
7 +
Benes FM.  Microscopic analyses of schizophrenic brain . Psychiatr Dev . 1988;;6:213-226.
8 +
Benes FM, Davidson J, Bird ED.  Quantitative cytoarchitectural analyses of the cerebral cortex of schizophrenics . Arch Gen Psychiatry . 1986;;43:31-35.
9 +
Benes FM, Bird ED.  An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients . Arch Gen Psychiatry . 1987;;44:608-616.
10 +
Benes FM, Majocha R, Bird ED, Marotta CA.  Increased vertical axon numbers in the cingulate cortex of schizophrenics . Arch Gen Psychiatry . 1987;;44:1017-1021.
11 +
Feighner JP, Robin E, Guze SB, Woodruff RA, Winokur G, Munoz R.  Diagnostic criteria for use in psychiatric research . Arch Gen Psychiatry . 1972;;26:57-63.
12 +
Dunnett C, Goldsmith C.  When and how to do multiple comparisons . In: Buncher RG, Tsay l-Y, eds. Statistics in the Pharmaceutical Industry . New York, NY: Marcel Dekker Inc; 1981;:397-435.
13 +
Kim J, Kohout F.  Multiple regression analysis . In: Nie NH, Hull C, Jenkins J, Steinbrenner K, Bent D, eds. SPSS Statistical Package for the Social Sciences . 2nd ed. New York, NY: McGraw-Hill International Book Co; 1975;:306-367.
14 +
Kim J, Kohout F.  Analysis of variance and covariance . In: Nie NH, Hull C, Jenkins J, Steinbrenner K, Bent D, eds. SPSS Statistical Package for the Social Sciences . 2nd ed. New York, NY: McGraw-Hill International Book Co; 1975;:398-433.
15 +
Blinkov SM, Glezer II. The Human Brain in Figures and Tables: A Quantitative Handbook . New York, NY: Plenum Publishing Corp; 1968;:201-213.
16 +
Coleman PD, Flood DG.  Neuron numbers and dendritic extent in normal aging and Alzheimer's disease . Neurobiol Aging . 1987;;8:521-545.
17 +
Benes FM, Paskevich P, Domesick V.  Haloperidol-induced plasticity in rat substantia nigra . Science . 1983;;221:969-971.
18 +
Benes FM, Paskevich P, Davidson J, Domesick V.  The effect of haloperidol on synaptic patterns in the rat striatum . Brain Res . 1985;;329:265-274.
19 +
Benes FM, Paskevich P, Davidson J, Domesick V.  Synaptic re-arrangements in medial prefrontal cortex of haloperidoltreated rats . Brain Res . 1985;;348:15-20.
20 +
Emson PC, Koob GF.  The origin and distribution of dopamine-containing afferents to rat frontal cortex . Brain Res . 1978;;142:249-267.
21 +
Lindvall O, Bjorklund A, Divac I.  Organization of catecholamine neurons projecting to frontal cortex in rat . Brain Res . 1978;;142:1-24.
22 +
Bleuler E. Dementia Praecox or the Group of Schizophrenias . New York, NY: New York International Universities Press Inc; 1950;:40-52.
23 +
Kety S, Rosenthal D, Wender PH, Schulsinger F.  The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics . In: Rosenthal D, Kety S, eds. The Transmission of Schizophrenia . Elmsford, NY: Pergamon Press Inc; 1968;:345-362.
24 +
Kety SS, Matthysse S.  Prospects for research on schizophrenia: an overview . Neurosci Res Bull . 1972;;10:456-467.
25 +
Kendler KS, Gruenberg A, Tsuang MT.  Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients . Arch Gen. Psychiatry . 1985;;42:770-779.
26 +
Levitt JJ, Tsuang MT.  The heterogeneity of schizoaffective disorder . Am J Psychiatry . 1988;;145:926-936.
27 +
Fowler RC.  Remitting schizophrenia as a variant of affective disorder . Schizophr Bull . 1978;;4:68-77.
28 +
Jacobsen B, Kinney DK.  Perinatal complications in adopted and non-adopted schizophrenics and their controls . Acta Psychiatr Scand Suppl . 1980;;238:337-338.
29 +
Parnas J, Schulsinger F, Teasdale TW, Schulsinger H, Feldman PM, Mednick SA.  Perinatal complications and clinical outcome within schizophrenic spectrum . Br J Psychiatry . 1982;;140:416-420.
30 +
Dom R.  Neostriatal and thalamic interneurones . Acta Psychiatr Scand . 1975; ( (suppl) ):103-123.
31 +
Falkai P, Bogerts B.  Cell loss in the hippocampus of schizophrenics . Eur Arch Psychiatr Neurol Sci . 1986;;236:154-161.
32 +
Falkai P, Bogerts B, Rozumek M.  Cell loss and volume reduction in the entorhinal cortex of schizopohrenics . Biol Psychiatry . 1988;;24:515-521.
33 +
Roberts GW, Colter N, Lofthouse R, Bogerts B, Zech M, Crow TJ.  Gliosis in schizophrenia: a survey . Biol Psychiatry . 1986;;21:1043-1050.
34 +
Windle WF, Becker RF.  Alterations in brain structure after asphyxiation at birth . J Neuropathol Exp Neurol . 1944;;3:224-238.
35 +
Sidman RL, Rakic P.  Neuronal migration with special reference to developing human brain . Brain Res . 1973;;62:1-35.
36 +
Marin-Padilla M.  Prenatal and early postnatal ontogenesis of the human motor cortex, a Golgi study, I: the sequential development of the cortical layers . Brain Res . 1970;;23:167-183.
37 +
Jakob H, Beckman H.  Prenatal developmental disturbances in limbic allocortex of schizophrenics . J Neural Transm . 1986;;65:303-326.
38 +
Falkai P, Bogerts B.  Cell loss and volume reduction in the entorhinal cortex of schizophrenics . Biol Psychiatry . 1988;; 24:515-521.
39 +
Galaburda AM, Pandya DN.  The intrinsic architectonic and connectional organization of the superior temporal region of the rhesus monkey . J Comp Neurol . 1983;;221:169-184.
40 +
Jones EG, Hendry SHC.  Basket cells . In: Peters A, Jones EG eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:309-336.
41 +
Peters A.  Chandelier cells . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:361-380.
42 +
Somogy P, Cowey A.  Double bouquet cells . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:337-360.
43 +
Lund JS.  Spiny stellate neurons . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:255-308.
44 +
Tombol T.  Layer VI cells . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:479-519.
45 +
Marin-Padilla M.  Neurons of layer I: a developmental analysis . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:474-478.
46 +
Bird ED, Spokes EGS, Iversen LL.  Increased dopamine concentration in limbic areas of brain from patients dying with schizophrenia . Brain . 1979;;102:347-360.
47 +
Hanada S, Mita T, Nishinok N, Tanaka C.  3H-muscimol binding sites increased in autopsied brains of chronic schizophrenics . Life Sci . 1987;;40:259-266.
48 +
Roberts E.  An hypothesis suggesting that there is a defect in the GABA system in schizophrenia . Neurosci Res Bull . 1972;;10:469-482.
49 +
Perry TL, Buchanan J, Kish SJ, Hansen S.  Gammaaminobutyric acid deficiency in brains of schizophrenic patients . Lancet . 1979;;1:237.
50 +
Cross AJ, Crow TJ, Owen F.  Gamma-aminobutyric acid in the brain in schizophrenia . Lancet . 1979;;1:560-561.
51 +
Benes FM, Vincent SL, SanGiovanni JP.  High resolution imaging of receptor binding in analyzing neuropsychiatric diseases . Biotechniques . 1989;;7:970-979.

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Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Josephy J.  Beitrage zur Histopathologie der Dementia Praecox . Z Gesamte Neurol Psychiatry . 1923;;86:391-461.
2 +
Winkelman NW, Book MH.  Observations on the histopathology of schizophrenia . Am J Psychiatry . 1949;;105:889-896.
3 +
Vogt O. Proposition de fonder une organisation internationale pour l'etude de l'anatomie pathologique de la schizophrenie et d'autres psychoses dite fonctionelle. In: Proceedings of the First International Congress on Neuropathology; September 8-13, 1952; Torina, Italy. 1952;3:674-677.
4 +
Dunlap CB.  Dementia praecox . Am J Psychiatry . 1924;;80:403-420.
5 +
Spielmeyer W.  The problem of the anatomy of schizophrenia . J Nerv Ment Dis . 1930;;72:241-244.
6 +
Corsellis JAN.  Psychoses of obscure pathology . In: Blackwood W, Corsellis JAN, eds. Greenfield's Neuropathology . Baltimore, Md: Edward Arnold Publishers Ltd; 1976;:903-915.
7 +
Benes FM.  Microscopic analyses of schizophrenic brain . Psychiatr Dev . 1988;;6:213-226.
8 +
Benes FM, Davidson J, Bird ED.  Quantitative cytoarchitectural analyses of the cerebral cortex of schizophrenics . Arch Gen Psychiatry . 1986;;43:31-35.
9 +
Benes FM, Bird ED.  An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients . Arch Gen Psychiatry . 1987;;44:608-616.
10 +
Benes FM, Majocha R, Bird ED, Marotta CA.  Increased vertical axon numbers in the cingulate cortex of schizophrenics . Arch Gen Psychiatry . 1987;;44:1017-1021.
11 +
Feighner JP, Robin E, Guze SB, Woodruff RA, Winokur G, Munoz R.  Diagnostic criteria for use in psychiatric research . Arch Gen Psychiatry . 1972;;26:57-63.
12 +
Dunnett C, Goldsmith C.  When and how to do multiple comparisons . In: Buncher RG, Tsay l-Y, eds. Statistics in the Pharmaceutical Industry . New York, NY: Marcel Dekker Inc; 1981;:397-435.
13 +
Kim J, Kohout F.  Multiple regression analysis . In: Nie NH, Hull C, Jenkins J, Steinbrenner K, Bent D, eds. SPSS Statistical Package for the Social Sciences . 2nd ed. New York, NY: McGraw-Hill International Book Co; 1975;:306-367.
14 +
Kim J, Kohout F.  Analysis of variance and covariance . In: Nie NH, Hull C, Jenkins J, Steinbrenner K, Bent D, eds. SPSS Statistical Package for the Social Sciences . 2nd ed. New York, NY: McGraw-Hill International Book Co; 1975;:398-433.
15 +
Blinkov SM, Glezer II. The Human Brain in Figures and Tables: A Quantitative Handbook . New York, NY: Plenum Publishing Corp; 1968;:201-213.
16 +
Coleman PD, Flood DG.  Neuron numbers and dendritic extent in normal aging and Alzheimer's disease . Neurobiol Aging . 1987;;8:521-545.
17 +
Benes FM, Paskevich P, Domesick V.  Haloperidol-induced plasticity in rat substantia nigra . Science . 1983;;221:969-971.
18 +
Benes FM, Paskevich P, Davidson J, Domesick V.  The effect of haloperidol on synaptic patterns in the rat striatum . Brain Res . 1985;;329:265-274.
19 +
Benes FM, Paskevich P, Davidson J, Domesick V.  Synaptic re-arrangements in medial prefrontal cortex of haloperidoltreated rats . Brain Res . 1985;;348:15-20.
20 +
Emson PC, Koob GF.  The origin and distribution of dopamine-containing afferents to rat frontal cortex . Brain Res . 1978;;142:249-267.
21 +
Lindvall O, Bjorklund A, Divac I.  Organization of catecholamine neurons projecting to frontal cortex in rat . Brain Res . 1978;;142:1-24.
22 +
Bleuler E. Dementia Praecox or the Group of Schizophrenias . New York, NY: New York International Universities Press Inc; 1950;:40-52.
23 +
Kety S, Rosenthal D, Wender PH, Schulsinger F.  The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics . In: Rosenthal D, Kety S, eds. The Transmission of Schizophrenia . Elmsford, NY: Pergamon Press Inc; 1968;:345-362.
24 +
Kety SS, Matthysse S.  Prospects for research on schizophrenia: an overview . Neurosci Res Bull . 1972;;10:456-467.
25 +
Kendler KS, Gruenberg A, Tsuang MT.  Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients . Arch Gen. Psychiatry . 1985;;42:770-779.
26 +
Levitt JJ, Tsuang MT.  The heterogeneity of schizoaffective disorder . Am J Psychiatry . 1988;;145:926-936.
27 +
Fowler RC.  Remitting schizophrenia as a variant of affective disorder . Schizophr Bull . 1978;;4:68-77.
28 +
Jacobsen B, Kinney DK.  Perinatal complications in adopted and non-adopted schizophrenics and their controls . Acta Psychiatr Scand Suppl . 1980;;238:337-338.
29 +
Parnas J, Schulsinger F, Teasdale TW, Schulsinger H, Feldman PM, Mednick SA.  Perinatal complications and clinical outcome within schizophrenic spectrum . Br J Psychiatry . 1982;;140:416-420.
30 +
Dom R.  Neostriatal and thalamic interneurones . Acta Psychiatr Scand . 1975; ( (suppl) ):103-123.
31 +
Falkai P, Bogerts B.  Cell loss in the hippocampus of schizophrenics . Eur Arch Psychiatr Neurol Sci . 1986;;236:154-161.
32 +
Falkai P, Bogerts B, Rozumek M.  Cell loss and volume reduction in the entorhinal cortex of schizopohrenics . Biol Psychiatry . 1988;;24:515-521.
33 +
Roberts GW, Colter N, Lofthouse R, Bogerts B, Zech M, Crow TJ.  Gliosis in schizophrenia: a survey . Biol Psychiatry . 1986;;21:1043-1050.
34 +
Windle WF, Becker RF.  Alterations in brain structure after asphyxiation at birth . J Neuropathol Exp Neurol . 1944;;3:224-238.
35 +
Sidman RL, Rakic P.  Neuronal migration with special reference to developing human brain . Brain Res . 1973;;62:1-35.
36 +
Marin-Padilla M.  Prenatal and early postnatal ontogenesis of the human motor cortex, a Golgi study, I: the sequential development of the cortical layers . Brain Res . 1970;;23:167-183.
37 +
Jakob H, Beckman H.  Prenatal developmental disturbances in limbic allocortex of schizophrenics . J Neural Transm . 1986;;65:303-326.
38 +
Falkai P, Bogerts B.  Cell loss and volume reduction in the entorhinal cortex of schizophrenics . Biol Psychiatry . 1988;; 24:515-521.
39 +
Galaburda AM, Pandya DN.  The intrinsic architectonic and connectional organization of the superior temporal region of the rhesus monkey . J Comp Neurol . 1983;;221:169-184.
40 +
Jones EG, Hendry SHC.  Basket cells . In: Peters A, Jones EG eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:309-336.
41 +
Peters A.  Chandelier cells . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:361-380.
42 +
Somogy P, Cowey A.  Double bouquet cells . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:337-360.
43 +
Lund JS.  Spiny stellate neurons . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:255-308.
44 +
Tombol T.  Layer VI cells . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:479-519.
45 +
Marin-Padilla M.  Neurons of layer I: a developmental analysis . In: Peters A, Jones EG, eds. Cerebral Cortex: Cellular Components of the Cerebral Cortex . New York, NY: Plenum Publishing Corp; 1984;;1:474-478.
46 +
Bird ED, Spokes EGS, Iversen LL.  Increased dopamine concentration in limbic areas of brain from patients dying with schizophrenia . Brain . 1979;;102:347-360.
47 +
Hanada S, Mita T, Nishinok N, Tanaka C.  3H-muscimol binding sites increased in autopsied brains of chronic schizophrenics . Life Sci . 1987;;40:259-266.
48 +
Roberts E.  An hypothesis suggesting that there is a defect in the GABA system in schizophrenia . Neurosci Res Bull . 1972;;10:469-482.
49 +
Perry TL, Buchanan J, Kish SJ, Hansen S.  Gammaaminobutyric acid deficiency in brains of schizophrenic patients . Lancet . 1979;;1:237.
50 +
Cross AJ, Crow TJ, Owen F.  Gamma-aminobutyric acid in the brain in schizophrenia . Lancet . 1979;;1:560-561.
51 +
Benes FM, Vincent SL, SanGiovanni JP.  High resolution imaging of receptor binding in analyzing neuropsychiatric diseases . Biotechniques . 1989;;7:970-979.

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