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3. Evidence for neurodevelopment disturbances in anterior cingulate cortex of post-mortem schizophrenic brain
187 concomitant pathology should all be taken into account when searching for astrocytosis. If these limitations are observed, gliosis can produce valuable information for the interpretation of any concomitant brain lesion, e.g., in the case of entorhinal cortex pathology in schizophrenia, a preliminary study suggests that absence of astrocytosis indicates a static lesion which occurred well before the demise of the patient.
Bruton. C.J., Crow, T.J.. Frith. C.D., Johnston, E.C., Owens, D.G.C. and Roberts, G.W. (1990) Schizophrenia and the brain: a prospective chnico-neuropathological study. Psychol. Med. 20, 2855304. Casanova, M.F.. Stevens, J.R. and Kleinman, J.E. (1991) Quantitation of astrocytes in the molecular layer of the dentate gyrus: a study in schizophrenia and Alzheimer’s disease patients. Psychiatry Res., in press. Friede. R.L. (1989) Developmental Neuropathology. SpringerVerlag, New York. Hirano, A. and Zimmerman. H.M. (1962) Alzheimer’s neurofibrillary changes. A topographic study. Arch. Neural. 7, 227m 242. Lynch, G., Rose, C., Gall. C. and Cotman. C.W. (1975) The response of the dentate gyrus to partial deafferentitation. In: M. Santini (Ed.), The Golgi Symposium Proceedings. Raven Press, New York, pp. 3055317. Nieto, D. and Escobar, A. (1972) Major psychosis. In: J. Minckler (Ed.), Pathology of the Nervous System, Vol. 3. McGraw Hill, New York. pp. 2654-2665. Polak, M., Haymaker, W.. Johnson, J.E., D’Amelio. F. and Hager. H. (1982) Neuroglia and thetr reaction. In: W. Haymaker and R.D. Adams (Eds.), Histology and Histopathology of the Nervous System. Vol. I. Charles C Thomas, New Springfield. IL, ch. 5. pp. 3633480. Roberts, G.W.. Colter. N.. Lofthouse, R., Bogerts, B., Zech, M. and Crow. T.J. (1986) Gliosis in schizophrenia: a survey. Biol. Psychiatry 21. 1043~1050. Stevens, C.D.. Altshuler. L.L., Bogerts, B. and Falkai, P. (1988) Quantitative study of gliosis in schizophrenia and Huntington’s chorea. Biol. Psychiatry 24. 697-700. Stevens, J.R. (1982) Neuropathology of schizophrenia. Arch. Gen. Psychiatry 39, 1131~1139.
3. EVIDENCE FOR NEURODEVELOPMENT DISTURBANCES IN ANTERIOR CINGULATE CORTEX OF POST-MORTEM SCHIZOPHRENIC BRAIN Francine
M. Benes
Mullmun Research Center, McLeun Hospirul, Belmont. MA, U.S.A.. and Deprtment of Psychiatry and rhe Program in Neuroscience. Harvard Medical School, Bo.ston, MA. b’.S.A. Recent post-mortem investigations (Bogerts et al., 1985; Brown et al., 1986; Jakob and Beckmann. 1986; Benes and Bird, 1987) have demonstrated a variety of structural abnormalities in different components of the corticolimbic system of schizophre-
nic brain. It is not known, however, whether any of these morphological alterattons are related to risk factors for schizophrenia, such as a genetic liability (Kety and Rosenthal. 1968) or an obstetrical complication (Jacobsen and Kinney, 1975). Toward this end, a careful examination of these post-mortem findings may reveal some clues regarding the mechanism(s) through which such abnormalities have been established in the brains of schizophrenic patients. Interestingly, several structural differences found in the anterior cingulate cortex of schizophrenics have occurred preferentially in layer II, a superficial lamina predominantly involved in the relay of incoming associative fibers. These alterations in layer II of cingulate cortex in schizophrenic brain have included smaller neuronal clusters (Benes and Bird, 1987) reduced numbers of interneurons (Benes et al., 1991) and supernumerary vertical (associative) axons (Benes et al., 1987). While the axon counts were performed in layer II to maximize the probability of including associative afferents in the analysis (Benes et al., 1987) the finding of abnormalities in the size of neuronal clusters and the numbers of interneurons in the same lamina was fortuitous because all six layers of the cortex were analyzed and layer II showed the most striking differences in schizophrenics (Benes and Bird, 1987). For this reason, it seemed appropriate to consider whether layer II abnormalities may be of particular significance to the pathophysiology of schizophrenia and possibly reflect one or more risk factors for this disorder. Basic investigations of normal ontogeny have demonstrated that the human cortex develops in an ‘inside-out’ fashion (Sidman and Rakic, 1973), such that the deeper layers appear earlier and the superficial layers appear later, with layer II being the last lamina to be established. Interestingly. at the time of birth in humans, pyramidal neurons of layer II are moderately differentiated, while interneurons, such as basket cells, are quite immature and continue their process of differentiation well into the first post-natal year (Marin-Padilla, 1970). Since the cortex follows a carefully timed developmental program, perturbations of this process at particular stages of ontogeny could result in alterations of the cytoarchitecture and cellular composition of certain layers of the cerebral cortex. while sparing others. With neurons in layer II, particularly inhibitory basket cells, actively differentiating during the perinatal period in humans. it is possible that obstetrical complications could result in abnormalities found preferentially within this lamina. In view of what is known about the development of the cerebral cortex in human brain, it seems plausible that schizophrenics exposed to perinatal insults might be expected to show changes in superficial laminae. Accordingly, the decreased size of neuronal clusters (Benes and Bird, 1987) and the diminished numbers of interneurons (Benes et al., 1991) observed in layer II of the anterior cingulate cortex might conceivably have resulted from such an early insult to the brain. It does not seem likely, however, that the increased numbers of vertical axons (Benes et al.. 1987) arose through this same mechanism because incoming afferents would be expected to be decreased, rather than increased, if their post-synaptic follower cells had droppedout in response to an injury during the perinatal period. If the above model to explain abnormalities in schizophrenic cortex were valid. it would predict that there would be many different brain regions affected by a diffuse injury to these
188 Individuals. In this regard. it is noteworthy that structural abnormalities have not been confined to the anterior cingulate cortex in schizophrenia. For example, disturbances in layer II of the prefrontal (Benes et al.. 1991) and entorhinal cortex (Jakoh and Beckman. 1986: Falkai et al., 198X) in schizophrenics have also been reported and a disturbance of early brain ontogeny has been similarly proposed for the entorhmal region (Jakoh and Beckmann, 1986). Thus. studies in independent lahoraiories have yielded data in support of a neurodevelopmental model of schizophrenia in which pcrinatal complications play a role (Weinherger. 1987; Benes. 1989). To obtain further support for such an hypothesis, it wjill he necessary to determine whether individuals without schizophrenia who were also exposed to obstetrical complications might also show alterations in the structure of cortical layer II. Moreover. since it is unlikely that perinatal insults alone can explain the occurrence of schizophrenia in ccrtaln individuals. it will he important to determine whether there are additional structural changes that may he associated with other risk factors for schizophrenia. such as an abnormal gene. To do this. It will he necessary to develop strntcgics for determining whether other microscopic differences in schizophrenic brain. such as excess numbers of associative connections in anterior cingulate cortex (Benes et al.. 1987). not explainable by a perinatal injury. may hc related to an inhcrlted trait. In this way, it may eventually he possible to derive a two-factor model of schizophrenia expressed in terms of discrete alterations in brain circuitry. Ac~hno~c~/edgcr?~c~nt.s. Supported by grants from the NatIonal Institute of Mental Health MHOO423 and MH42261, and a grant from the Scottish Rite Foundation for Schizophrenia Research.
Benes. F.M. and Bird. E.D. (1987) An analysis of the arrangemcnt of neurons in the cingulatc cortex of schizophrenic patients. Arch. Gen. Psychiatry 44. 60X-616. Benes, F.M.. Davidson. J. and Bird. E.D. (1984) Quantitative morphomctric studies of schizophrenic cortex. Clin. Neuropharmacol. 7, 4X9-499. Benes, F.M.. Majocha. R.. Bird. E.D. and Marrotta. C.A. (1987) Increased vertical axon numbers in cingulate cortex of schizophrenics. Arch. Gen. Psychiatry 44, IOl7- IO:! I, Benes. F.M.. McSparren, J.. Bird. E.D.. Vincent. S.L. and SanGiovanni. J.P. (1991) Deficits in small interneurons 1n schizophrenic cortex. Arch. Gcn. Psychiatry. in press. Bogcrts. B.. Meertr. E. and Schonfieldt-Bausch. R. (1985) Basal ganglia and Iimhic system pathology in schizophrenia: A morphometric study of brain volume and shrinkage. Arch. Gcn. Psychiatry 42. 784-791. Brown, R.. Colter, N., Corsellis. J.A.N.. Crow. T.J.. Frith, C.D.. Jagoe. R.. Johnstone. E.C. and Marsh. L. (1986) Postmortem evidence for structural brain changes in schizophrenia. Differences in hrain weight. temporal horn area and parahippocampal gyrus width as compared with affective disorder. Arch. Gen. Psychiatry 43. 36-42. Falkai. P., Bogerts, B. and Rozumek, M. (1988) Cell loss and volume reduction in the entorhinal cortex of schizophrenics. Biol. Psychiatry 24. 515-521, Jacobsen. B. and Kinney. D.K. (1975) Pcrinatal complications
m adopted and non-adopted schizophrenics and their controls: Preliminary results. Acta Psychiatr. Sand. 103-123. Jakoh. H. and Beckmann. H. (19X6) Prenatal developmental disturbances In the limhic allocortex in schlzophrenic~. J. Neural Transmiss. 65, 303 326. Kety. S. and Rosenthal. D. (196X) The type and prevalence 01 mental illness in the biological and adoptive families, 01 adopted schizophrenics. In: D. Rosenthal and S. Key (Eds.). The Transmission of Schi7ophrcnia. Pregamon Press. Oxford. Man-Padilia. M. (1970) Prenatal and early post-natal ontogenesIs of the human motor cortex. A. Golgi study. II. The Basket-pyranudal system. Brain Rcs. 23. 185 191. Sidman. R. and Rakic. P. (1973) Neuronal migration v,ith special reference to developing human brain. Brain Rcs. 62. l-35. Wcinberger, D.R. (1987) Implications of normal brain developmcnt for the pathogencsls of schizophrema. Arch. Gen Psychiatry 44. 660 669.
4. THE AGE DEPENDENCIES OF MRI ABNORMALITIES IN SCHIZOPHRENIA SUGGEST EARLY VENTRICULAR ENLARGEMENT BUT LATER PROMINENCE OF CORTICAL ATROPHY John L. Waddington’. Eadbhard O’Callaghan*, Peter Buckley2. Conall Larkin’. Oonagh Redmond3. John Stack3 and Joseph T. Ennis”
Abnormalities of cerebral morphology in schizophrenia. most commonly Identified as ventricular enlargement on computed tomography. were held imtially to indicate an actilc and progressive disease process that resulted 111loss of bran substance. However, over recent years the neurodevelopmcntal hypothesis of schizophrenia has held centre stage. This posited very early etiological events which result in failure to establish certain fundamental aspects of cerebral structure; such an early. ‘static’ lesion then gives rise to typical diagnostic symptoms only on the subsequent functional maturatmn of critical cerebral systems (Murray and Lewis. 1987: Weinhergcr. 19X7). Much subsequent neuropathological. magnetic resonance imaging (MRI) and clinical research has sustained and elaborated the neurodcvelopmental hypothesis. but of late there has hccn some re-consideration of whether there might suhscquently he active and progressive elements to the disease process (see Waddington and Torrey, 1991). We give here a preliminary outline of a recent MRI study which has hecn analysed so as to address these issues. 25 normal. volunteer controls (I5 M. IO F. mean age 34.4* I I .5. range 19-64) and 47 outpatients satisfying DSM Ii1
Bruton. C.J., Crow, T.J.. Frith. C.D., Johnston, E.C., Owens, D.G.C. and Roberts, G.W. (1990) Schizophrenia and the brain: a prospective chnico-neuropathological study. Psychol. Med. 20, 2855304. Casanova, M.F.. Stevens, J.R. and Kleinman, J.E. (1991) Quantitation of astrocytes in the molecular layer of the dentate gyrus: a study in schizophrenia and Alzheimer’s disease patients. Psychiatry Res., in press. Friede. R.L. (1989) Developmental Neuropathology. SpringerVerlag, New York. Hirano, A. and Zimmerman. H.M. (1962) Alzheimer’s neurofibrillary changes. A topographic study. Arch. Neural. 7, 227m 242. Lynch, G., Rose, C., Gall. C. and Cotman. C.W. (1975) The response of the dentate gyrus to partial deafferentitation. In: M. Santini (Ed.), The Golgi Symposium Proceedings. Raven Press, New York, pp. 3055317. Nieto, D. and Escobar, A. (1972) Major psychosis. In: J. Minckler (Ed.), Pathology of the Nervous System, Vol. 3. McGraw Hill, New York. pp. 2654-2665. Polak, M., Haymaker, W.. Johnson, J.E., D’Amelio. F. and Hager. H. (1982) Neuroglia and thetr reaction. In: W. Haymaker and R.D. Adams (Eds.), Histology and Histopathology of the Nervous System. Vol. I. Charles C Thomas, New Springfield. IL, ch. 5. pp. 3633480. Roberts, G.W.. Colter. N.. Lofthouse, R., Bogerts, B., Zech, M. and Crow. T.J. (1986) Gliosis in schizophrenia: a survey. Biol. Psychiatry 21. 1043~1050. Stevens, C.D.. Altshuler. L.L., Bogerts, B. and Falkai, P. (1988) Quantitative study of gliosis in schizophrenia and Huntington’s chorea. Biol. Psychiatry 24. 697-700. Stevens, J.R. (1982) Neuropathology of schizophrenia. Arch. Gen. Psychiatry 39, 1131~1139.
3. EVIDENCE FOR NEURODEVELOPMENT DISTURBANCES IN ANTERIOR CINGULATE CORTEX OF POST-MORTEM SCHIZOPHRENIC BRAIN Francine
M. Benes
Mullmun Research Center, McLeun Hospirul, Belmont. MA, U.S.A.. and Deprtment of Psychiatry and rhe Program in Neuroscience. Harvard Medical School, Bo.ston, MA. b’.S.A. Recent post-mortem investigations (Bogerts et al., 1985; Brown et al., 1986; Jakob and Beckmann. 1986; Benes and Bird, 1987) have demonstrated a variety of structural abnormalities in different components of the corticolimbic system of schizophre-
nic brain. It is not known, however, whether any of these morphological alterattons are related to risk factors for schizophrenia, such as a genetic liability (Kety and Rosenthal. 1968) or an obstetrical complication (Jacobsen and Kinney, 1975). Toward this end, a careful examination of these post-mortem findings may reveal some clues regarding the mechanism(s) through which such abnormalities have been established in the brains of schizophrenic patients. Interestingly, several structural differences found in the anterior cingulate cortex of schizophrenics have occurred preferentially in layer II, a superficial lamina predominantly involved in the relay of incoming associative fibers. These alterations in layer II of cingulate cortex in schizophrenic brain have included smaller neuronal clusters (Benes and Bird, 1987) reduced numbers of interneurons (Benes et al., 1991) and supernumerary vertical (associative) axons (Benes et al., 1987). While the axon counts were performed in layer II to maximize the probability of including associative afferents in the analysis (Benes et al., 1987) the finding of abnormalities in the size of neuronal clusters and the numbers of interneurons in the same lamina was fortuitous because all six layers of the cortex were analyzed and layer II showed the most striking differences in schizophrenics (Benes and Bird, 1987). For this reason, it seemed appropriate to consider whether layer II abnormalities may be of particular significance to the pathophysiology of schizophrenia and possibly reflect one or more risk factors for this disorder. Basic investigations of normal ontogeny have demonstrated that the human cortex develops in an ‘inside-out’ fashion (Sidman and Rakic, 1973), such that the deeper layers appear earlier and the superficial layers appear later, with layer II being the last lamina to be established. Interestingly. at the time of birth in humans, pyramidal neurons of layer II are moderately differentiated, while interneurons, such as basket cells, are quite immature and continue their process of differentiation well into the first post-natal year (Marin-Padilla, 1970). Since the cortex follows a carefully timed developmental program, perturbations of this process at particular stages of ontogeny could result in alterations of the cytoarchitecture and cellular composition of certain layers of the cerebral cortex. while sparing others. With neurons in layer II, particularly inhibitory basket cells, actively differentiating during the perinatal period in humans. it is possible that obstetrical complications could result in abnormalities found preferentially within this lamina. In view of what is known about the development of the cerebral cortex in human brain, it seems plausible that schizophrenics exposed to perinatal insults might be expected to show changes in superficial laminae. Accordingly, the decreased size of neuronal clusters (Benes and Bird, 1987) and the diminished numbers of interneurons (Benes et al., 1991) observed in layer II of the anterior cingulate cortex might conceivably have resulted from such an early insult to the brain. It does not seem likely, however, that the increased numbers of vertical axons (Benes et al.. 1987) arose through this same mechanism because incoming afferents would be expected to be decreased, rather than increased, if their post-synaptic follower cells had droppedout in response to an injury during the perinatal period. If the above model to explain abnormalities in schizophrenic cortex were valid. it would predict that there would be many different brain regions affected by a diffuse injury to these
188 Individuals. In this regard. it is noteworthy that structural abnormalities have not been confined to the anterior cingulate cortex in schizophrenia. For example, disturbances in layer II of the prefrontal (Benes et al.. 1991) and entorhinal cortex (Jakoh and Beckman. 1986: Falkai et al., 198X) in schizophrenics have also been reported and a disturbance of early brain ontogeny has been similarly proposed for the entorhmal region (Jakoh and Beckmann, 1986). Thus. studies in independent lahoraiories have yielded data in support of a neurodevelopmental model of schizophrenia in which pcrinatal complications play a role (Weinherger. 1987; Benes. 1989). To obtain further support for such an hypothesis, it wjill he necessary to determine whether individuals without schizophrenia who were also exposed to obstetrical complications might also show alterations in the structure of cortical layer II. Moreover. since it is unlikely that perinatal insults alone can explain the occurrence of schizophrenia in ccrtaln individuals. it will he important to determine whether there are additional structural changes that may he associated with other risk factors for schizophrenia. such as an abnormal gene. To do this. It will he necessary to develop strntcgics for determining whether other microscopic differences in schizophrenic brain. such as excess numbers of associative connections in anterior cingulate cortex (Benes et al.. 1987). not explainable by a perinatal injury. may hc related to an inhcrlted trait. In this way, it may eventually he possible to derive a two-factor model of schizophrenia expressed in terms of discrete alterations in brain circuitry. Ac~hno~c~/edgcr?~c~nt.s. Supported by grants from the NatIonal Institute of Mental Health MHOO423 and MH42261, and a grant from the Scottish Rite Foundation for Schizophrenia Research.
Benes. F.M. and Bird. E.D. (1987) An analysis of the arrangemcnt of neurons in the cingulatc cortex of schizophrenic patients. Arch. Gen. Psychiatry 44. 60X-616. Benes, F.M.. Davidson. J. and Bird. E.D. (1984) Quantitative morphomctric studies of schizophrenic cortex. Clin. Neuropharmacol. 7, 4X9-499. Benes, F.M.. Majocha. R.. Bird. E.D. and Marrotta. C.A. (1987) Increased vertical axon numbers in cingulate cortex of schizophrenics. Arch. Gen. Psychiatry 44, IOl7- IO:! I, Benes. F.M.. McSparren, J.. Bird. E.D.. Vincent. S.L. and SanGiovanni. J.P. (1991) Deficits in small interneurons 1n schizophrenic cortex. Arch. Gcn. Psychiatry. in press. Bogcrts. B.. Meertr. E. and Schonfieldt-Bausch. R. (1985) Basal ganglia and Iimhic system pathology in schizophrenia: A morphometric study of brain volume and shrinkage. Arch. Gcn. Psychiatry 42. 784-791. Brown, R.. Colter, N., Corsellis. J.A.N.. Crow. T.J.. Frith, C.D.. Jagoe. R.. Johnstone. E.C. and Marsh. L. (1986) Postmortem evidence for structural brain changes in schizophrenia. Differences in hrain weight. temporal horn area and parahippocampal gyrus width as compared with affective disorder. Arch. Gen. Psychiatry 43. 36-42. Falkai. P., Bogerts, B. and Rozumek, M. (1988) Cell loss and volume reduction in the entorhinal cortex of schizophrenics. Biol. Psychiatry 24. 515-521, Jacobsen. B. and Kinney. D.K. (1975) Pcrinatal complications
m adopted and non-adopted schizophrenics and their controls: Preliminary results. Acta Psychiatr. Sand. 103-123. Jakoh. H. and Beckmann. H. (19X6) Prenatal developmental disturbances In the limhic allocortex in schlzophrenic~. J. Neural Transmiss. 65, 303 326. Kety. S. and Rosenthal. D. (196X) The type and prevalence 01 mental illness in the biological and adoptive families, 01 adopted schizophrenics. In: D. Rosenthal and S. Key (Eds.). The Transmission of Schi7ophrcnia. Pregamon Press. Oxford. Man-Padilia. M. (1970) Prenatal and early post-natal ontogenesIs of the human motor cortex. A. Golgi study. II. The Basket-pyranudal system. Brain Rcs. 23. 185 191. Sidman. R. and Rakic. P. (1973) Neuronal migration v,ith special reference to developing human brain. Brain Rcs. 62. l-35. Wcinberger, D.R. (1987) Implications of normal brain developmcnt for the pathogencsls of schizophrema. Arch. Gen Psychiatry 44. 660 669.
4. THE AGE DEPENDENCIES OF MRI ABNORMALITIES IN SCHIZOPHRENIA SUGGEST EARLY VENTRICULAR ENLARGEMENT BUT LATER PROMINENCE OF CORTICAL ATROPHY John L. Waddington’. Eadbhard O’Callaghan*, Peter Buckley2. Conall Larkin’. Oonagh Redmond3. John Stack3 and Joseph T. Ennis”
Abnormalities of cerebral morphology in schizophrenia. most commonly Identified as ventricular enlargement on computed tomography. were held imtially to indicate an actilc and progressive disease process that resulted 111loss of bran substance. However, over recent years the neurodevelopmcntal hypothesis of schizophrenia has held centre stage. This posited very early etiological events which result in failure to establish certain fundamental aspects of cerebral structure; such an early. ‘static’ lesion then gives rise to typical diagnostic symptoms only on the subsequent functional maturatmn of critical cerebral systems (Murray and Lewis. 1987: Weinhergcr. 19X7). Much subsequent neuropathological. magnetic resonance imaging (MRI) and clinical research has sustained and elaborated the neurodcvelopmental hypothesis. but of late there has hccn some re-consideration of whether there might suhscquently he active and progressive elements to the disease process (see Waddington and Torrey, 1991). We give here a preliminary outline of a recent MRI study which has hecn analysed so as to address these issues. 25 normal. volunteer controls (I5 M. IO F. mean age 34.4* I I .5. range 19-64) and 47 outpatients satisfying DSM Ii1