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November 1987, Vol 44, No. 11 >
Article | November 1987

Increased Vertical Axon Numbers in Cingulate Cortex of Schizophrenics

Francine M. Benes, MD, PhD; Ronald Majocha, PhD; Edward D. Bird, MD; Charles A. Marotta, MD, PhD
[+] Author Affiliations

Accepted for publication Feb 17, 1987.

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


Arch Gen Psychiatry. 1987;44(11):1017-1021. doi:10.1001/archpsyc.1987.01800230097015
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• Data generated from an earlier study have suggested a model in which greater numbers of long, vertical, associative axons may occur in the anterior cingulate cortex of schizophrenic patients relative to control subjects. This hypothesis has now been tested using neuron-specific antibodies raised against the 200-kilodalton neurofilament subunit, a component of neuronal cytoskeleton, to immunostain axons of human postmortem cingulate cortex. A manual method for counting axons in the region of layer II and sublamina IIIA has been designed and applied blindly to parallel control and schizophrenic immunoprocessed specimens. The results show that there are 25% more vertical axons in the schizophrenic than in the control specimens. Preferentially higher numbers of both long vertical axons (62%) and axons associated with blood vessels (52%) have also been noted in the schizophrenic specimens. By contrast, the number of large-caliber horizontal axons was the same in the two groups; therefore, the greater number of vertical axons in schizophrenic specimens does not appear to represent a nonspecific effect. When these data are corrected for the effects of several confounding variables using analysis of covariance, the overall pattern of the results persists. These findings suggest the possibility that there might be an increase of associative inputs into the anterior cingulate cortex of schizophrenic patients, although it is not clear at present whether the differences noted, if replicative, may be primarily or perhaps only secondarily related to the disorder.

REFERENCES

1 +
Johnstone EC, Crow TJ, Frith CD, Husband J, Kreel L:  Cerebral ventricular size and cognitive impairment in chronic schizophrenia . Lancet 1976;;2:924-926.
2 +
Weinberger DR, Torrey EF, Neophytides AN, Wyatt RJ:  Structural abnormalities in the CT scans of schizophrenic patients . Arch Gen Psychiatry 1979;;36:935-939.
3 +
Corsellis JAN:  Psychoses of obscure pathology , in Blackwood W, Corsellis JAN (eds): Greenfield's Neuropathology . Chicago, Year Book Medical Publishers Inc, 1976;, pp 903-915.
4 +
Benes FM, Davidson J, Bird ED:  Quantitative cytoarchitectural studies of cerebral cortex of schizophrenics . Arch Gen Psychiatry 1986;;43:31-35.
5 +
Benes FM, Matthysse SW, Bird ED, Marotta CA, Majocha R, Davidson J:  Formulating strategies for studying cortical cytoarchitecture in schizophrenia , in Shagass C, Bridger WH, Weiss KJ, Stoff D, Simpson GM (eds): Biological Psychiatry . Amsterdam, Elsevier Science Publishers, 1986;, pp 1115-1118.
6 +
Bogerts B, Meertz E, Schonfeldt-Bausch R:  Basal ganglia and limbic system pathology in schizophrenia: A morphometric study of brain volume and shrinkage . Arch Gen Psychiatry 1985;;42:784-791.
7 +
Kovelman JA, Scheibel AB:  A neurohistological correlate of schizophrenia . Biol Psychiatry 1984;;19:1601-1621.
8 +
Crow TJ, Brown R, Colter N, Corsellis JAN, Frith CD, Jagoe R, Johnstone EC:  Brain weight and parahippocampal cortical width are decreased and temporal horn area is increased in schizophrenia by comparison with affective disorder . Arch Gen Psychiatry 1986;;43:36-42.
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 +
Stevens JR:  An anatomy of schizophrenia? Arch Gen Psychiatry 1973;;29:196-210.
11 +
Emson PC, Koob GF:  The origin and distribution of dopaminecontaining afferents to rat frontal cortex . Brain Res 1978;;142:249-267.
12 +
Lindvall O, Bjorklund A, Divac I:  Organization of catecholamine neurons projecting to frontal cortex in the rat . Brain Res 1978;;142:1-24.
13 +
Baleydier G, Maugierre F:  The duality of the cingulate gyrus in monkey: Neuroanatomical study and functional hypothesis . Brain 1980;;103:525-554.
14 +
McGhie A, Chapman J:  Disorders of attention and perception in early schizophrenia . Br J Med Psychol 1961;;34:103-115.
15 +
Kornetsky C, Orzack MH:  Physiological and behavioral correlates of behavior dysfunction in schizophrenic patients , in Wynn LC (ed): The Nature of Schizophrenia . New York, John Wiley & Sons Inc, 1978;, pp 196-204.
16 +
Papez JW:  A proposed mechanism of emotion . Arch Neurol Psychiatry 1937;;38:725-743.
17 +
Domesick VB:  Projections from the cingulate cortex in the rat . Brain Res 1969;;12:196-230.
18 +
Pandya DN, Van Hoesen, GW, Mesulam MM:  Efferent connections of the cingulate gyrus in the rhesus monkey . Exp Brain Res 1981;;42:319-330.
19 +
Vogt BA, Miller M:  Cortical connections between rat cingulate cortex and visual, motor and post-subicular cortices . J Comp Neurol 1983;;216:192-210.
20 +
Pandya DH, Dye P, Butters N:  Efferent cortico-cortical projections of the prefrontal cortex in the rhesus monkey . Brain Res 1971;;31:35-46.
21 +
Beckstead RM:  Autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection (prefrontal) cortex in the rat . Brain Res 1979;;184:43-62.
22 +
Weinberger DR, Berman KF, Zec RF:  Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence . Arch Gen Psychiatry 1986;;43:114-125.
23 +
Berman KF, Zec RF, Weinberger DR:  Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: II. Role of neuroleptic treatment, attention, and mental effort . Arch Gen Psychiatry 1986;;43:126-135.
24 +
Levin S:  Frontal lobe dysfunctions in schizophrenia: I. Eye movement impairments . J Psychiatr Res 1984;;18:27-55.
25 +
Erwin BJ, Rosenbaum G:  Parietal lobe syndrome and schizophrenia: Comparison of neuropsychological deficits . J Abnormal Psychol 1979;;88:234-241.
26 +
Goldman-Rakic PS:  Development and plasticity of primate frontal association cortex , in Schmitt FO, Worden FG, Adelman G, Dennis SG (eds): The Organization of the Cerebral Cortex . Cambridge, Mass, MIT Press, 1981;, pp 69-97.
27 +
Majocha RE, Marotta CA, Benes FM:  Immunostaining of neurofilament protein in human postmortem cortex: A sensitive and specific approach to the pattern analysis of human cortical cytoarchitecture . Can J Biochem Cell Biol 1985;;63:577-584.
28 +
Marotta CA: Neurofilaments . Minneapolis, University of Minnesota Press, 1983;.
29 +
Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Muñoz R:  Diagnostic criteria for use in psychiatric research . Arch Gen Psychiatry 1972;;26:57-63.
30 +
Cork LC, Sternberger NH, Sternberger LA, Casanova MF, Struble RG, Price DL:  Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease . J Neuropathol Exp Neurol 1986;;45:55-64.
31 +
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 , ed 2. New York, McGraw-Hill International Book Co, 1975;, pp 320-367.
32 +
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 , ed 2. New York, McGraw-Hill International Book Co, 1975;, pp 398-433.
33 +
Bigelow LB, Nasrallah HA, Rauscher FP:  Corpus callosum thickness in chronic schizophrenia . Br J Psychiatry 1983;;142:284-287.
34 +
Nasrallah HA, Andreasen NC, Coffman JA, Olson SC, Dunn VD, Ehrhardt JC, Chapman SM:  A controlled magnetic resonance imaging study of corpus callosum thickness in schizophrenia . Biol Psychiatry 1986;;21:274-282.
35 +
Parnas J, Teasdale TW, Schulsinger H:  Institutional rearing and outcome of schizophrenic mothers . Arch Gen Psychiatry 1985;;42:762-769.
36 +
Kendler KS, Gruenberg A, Tsuang MT:  Psychiatric illness in firstdegree relatives of schizophrenic and surgical control patients . Arch Gen Psychiatry 1985;;42:770-779.
37 +
Jacobsen B, Kinney DK:  Perinatal complications in adopted and nonadopted schizophrenics and their controls: Preliminary results . Acta Psychiatr Scand Suppl 1980;;238:337-338.

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1 +
Johnstone EC, Crow TJ, Frith CD, Husband J, Kreel L:  Cerebral ventricular size and cognitive impairment in chronic schizophrenia . Lancet 1976;;2:924-926.
2 +
Weinberger DR, Torrey EF, Neophytides AN, Wyatt RJ:  Structural abnormalities in the CT scans of schizophrenic patients . Arch Gen Psychiatry 1979;;36:935-939.
3 +
Corsellis JAN:  Psychoses of obscure pathology , in Blackwood W, Corsellis JAN (eds): Greenfield's Neuropathology . Chicago, Year Book Medical Publishers Inc, 1976;, pp 903-915.
4 +
Benes FM, Davidson J, Bird ED:  Quantitative cytoarchitectural studies of cerebral cortex of schizophrenics . Arch Gen Psychiatry 1986;;43:31-35.
5 +
Benes FM, Matthysse SW, Bird ED, Marotta CA, Majocha R, Davidson J:  Formulating strategies for studying cortical cytoarchitecture in schizophrenia , in Shagass C, Bridger WH, Weiss KJ, Stoff D, Simpson GM (eds): Biological Psychiatry . Amsterdam, Elsevier Science Publishers, 1986;, pp 1115-1118.
6 +
Bogerts B, Meertz E, Schonfeldt-Bausch R:  Basal ganglia and limbic system pathology in schizophrenia: A morphometric study of brain volume and shrinkage . Arch Gen Psychiatry 1985;;42:784-791.
7 +
Kovelman JA, Scheibel AB:  A neurohistological correlate of schizophrenia . Biol Psychiatry 1984;;19:1601-1621.
8 +
Crow TJ, Brown R, Colter N, Corsellis JAN, Frith CD, Jagoe R, Johnstone EC:  Brain weight and parahippocampal cortical width are decreased and temporal horn area is increased in schizophrenia by comparison with affective disorder . Arch Gen Psychiatry 1986;;43:36-42.
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 +
Stevens JR:  An anatomy of schizophrenia? Arch Gen Psychiatry 1973;;29:196-210.
11 +
Emson PC, Koob GF:  The origin and distribution of dopaminecontaining afferents to rat frontal cortex . Brain Res 1978;;142:249-267.
12 +
Lindvall O, Bjorklund A, Divac I:  Organization of catecholamine neurons projecting to frontal cortex in the rat . Brain Res 1978;;142:1-24.
13 +
Baleydier G, Maugierre F:  The duality of the cingulate gyrus in monkey: Neuroanatomical study and functional hypothesis . Brain 1980;;103:525-554.
14 +
McGhie A, Chapman J:  Disorders of attention and perception in early schizophrenia . Br J Med Psychol 1961;;34:103-115.
15 +
Kornetsky C, Orzack MH:  Physiological and behavioral correlates of behavior dysfunction in schizophrenic patients , in Wynn LC (ed): The Nature of Schizophrenia . New York, John Wiley & Sons Inc, 1978;, pp 196-204.
16 +
Papez JW:  A proposed mechanism of emotion . Arch Neurol Psychiatry 1937;;38:725-743.
17 +
Domesick VB:  Projections from the cingulate cortex in the rat . Brain Res 1969;;12:196-230.
18 +
Pandya DN, Van Hoesen, GW, Mesulam MM:  Efferent connections of the cingulate gyrus in the rhesus monkey . Exp Brain Res 1981;;42:319-330.
19 +
Vogt BA, Miller M:  Cortical connections between rat cingulate cortex and visual, motor and post-subicular cortices . J Comp Neurol 1983;;216:192-210.
20 +
Pandya DH, Dye P, Butters N:  Efferent cortico-cortical projections of the prefrontal cortex in the rhesus monkey . Brain Res 1971;;31:35-46.
21 +
Beckstead RM:  Autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection (prefrontal) cortex in the rat . Brain Res 1979;;184:43-62.
22 +
Weinberger DR, Berman KF, Zec RF:  Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: I. Regional cerebral blood flow evidence . Arch Gen Psychiatry 1986;;43:114-125.
23 +
Berman KF, Zec RF, Weinberger DR:  Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia: II. Role of neuroleptic treatment, attention, and mental effort . Arch Gen Psychiatry 1986;;43:126-135.
24 +
Levin S:  Frontal lobe dysfunctions in schizophrenia: I. Eye movement impairments . J Psychiatr Res 1984;;18:27-55.
25 +
Erwin BJ, Rosenbaum G:  Parietal lobe syndrome and schizophrenia: Comparison of neuropsychological deficits . J Abnormal Psychol 1979;;88:234-241.
26 +
Goldman-Rakic PS:  Development and plasticity of primate frontal association cortex , in Schmitt FO, Worden FG, Adelman G, Dennis SG (eds): The Organization of the Cerebral Cortex . Cambridge, Mass, MIT Press, 1981;, pp 69-97.
27 +
Majocha RE, Marotta CA, Benes FM:  Immunostaining of neurofilament protein in human postmortem cortex: A sensitive and specific approach to the pattern analysis of human cortical cytoarchitecture . Can J Biochem Cell Biol 1985;;63:577-584.
28 +
Marotta CA: Neurofilaments . Minneapolis, University of Minnesota Press, 1983;.
29 +
Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Muñoz R:  Diagnostic criteria for use in psychiatric research . Arch Gen Psychiatry 1972;;26:57-63.
30 +
Cork LC, Sternberger NH, Sternberger LA, Casanova MF, Struble RG, Price DL:  Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease . J Neuropathol Exp Neurol 1986;;45:55-64.
31 +
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 , ed 2. New York, McGraw-Hill International Book Co, 1975;, pp 320-367.
32 +
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 , ed 2. New York, McGraw-Hill International Book Co, 1975;, pp 398-433.
33 +
Bigelow LB, Nasrallah HA, Rauscher FP:  Corpus callosum thickness in chronic schizophrenia . Br J Psychiatry 1983;;142:284-287.
34 +
Nasrallah HA, Andreasen NC, Coffman JA, Olson SC, Dunn VD, Ehrhardt JC, Chapman SM:  A controlled magnetic resonance imaging study of corpus callosum thickness in schizophrenia . Biol Psychiatry 1986;;21:274-282.
35 +
Parnas J, Teasdale TW, Schulsinger H:  Institutional rearing and outcome of schizophrenic mothers . Arch Gen Psychiatry 1985;;42:762-769.
36 +
Kendler KS, Gruenberg A, Tsuang MT:  Psychiatric illness in firstdegree relatives of schizophrenic and surgical control patients . Arch Gen Psychiatry 1985;;42:770-779.
37 +
Jacobsen B, Kinney DK:  Perinatal complications in adopted and nonadopted schizophrenics and their controls: Preliminary results . Acta Psychiatr Scand Suppl 1980;;238:337-338.

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