Cortical Development and Thalamic Pathology in Schizophrenia 1

In this article, morphological data suggesting that brain development may be altered in schizophrenia are reviewed in relation to the major events in neural development In the absence of severe defects in brain structure in individuals with schizophrenia, developmental processes governing the establishment, refinement, and maintenance of connections are potential sites of pathological involvement Alterations in connectional patterns are likely to result in activity-dependent changes in gene expression for molecules involved in the neurotransmission process, with functional consequences. Loss of cells in the thalamus may be primary or secondary to cortical or other subcortical pathology. Loss of thalamic cells and/or of corticothalamic inputs could lead to disintegration of thought processes by a failure in functional brain states dependent on collective oscillation of large ensembles of cortical and thalamic neurons. Schizophrenia Bulletin, 23(3):483-501,1997. Many theories have suggested that brain development is affected in schizophrenia and that the psychopathology of schizophrenia may derive from alterations of brain organization secondary to defective ontogenesis. The developmental hypothesis of schizophrenia has its origins in studies of psychomotor and neuropsychological development in individuals with schizophrenia and in children genetically at risk for schizophrenia (Bender 1947; Bender and Freedman 1952; Fish 1957; O'Neal and Robins 1958; Sobel 1961); it has received support from more recent prospective studies (Fish et al. 1992). Because those who will develop schizophrenia tend to show alterations in the normal pattern of psychomotor and intellectual development during their early postnatal years, the development and maturation of the cerebral cortex and related structures are likely to be compromised in the disease. However, ascertaining the nature of a putative developmental insult and then finding evidence of its effects in the brains of individuals with schizophrenia are challenges of considerable magnitude. Several observations made in recent years hold out the hope that some breakthrough may be imminent at the histological level: Defective migration of young neurons during the latter stages of cerebral cortical development has been invoked as a potential cause of putatively disturbed patterns of cytoarchitecture in the hippocampus and entorhinal cortex of brains of individuals with schizophrenia (Scheibel and Kovelman 1981; Jakob and Beckmann 1986, 1989; Kovelman and Scheibel 1986; Arnold et al. 1991a), and alterations in the distribution of interstitial neurons of the white matter of the temporal and frontal lobes have been ascribed to either defective migration or altered programmed cell death (Akbarian et al. 1993a, 1993c, 1994). At a grosser level, the significant increase in the volume of the lateral and third ventricles that has been reported fairly consistently in individuals with schizophrenia may also reflect altered brain development since it is present from the early stages and does not progress (Johnstone et al. 1976, 1989; Hyde and Weinberger 1990; Roberts and Bruton 1990; Pfefferbaum and Zipursky 1991). Other macroscopic alterations, such as partial agenesis of the corpus callosum (Swayze et al. 1990; Degreef et al. 1992) and aberrant gyration of the insular and temporal cortex (Jakob and Beckmann 1986), are inconsistently present. These macroscopic observations, together with the lack of gliosis and of other major signs of neuronal degeneration in the forebrains of individuals with schizophrenia (Benes et al. 1986, 1991; Roberts et al. 1987), make it difficult to view the pathology of schizophrenia as a primarily neurodegenerative process. Indeed, the rather modest anatomical changes that have been described, although suggestive, do not nec'This article was received for publication in 1994. Reprint requests should be sent to Dr. E.G. Jones, Dept. of Anatomy and Neurobiology, University of Califomia-Irvine, Irvine, CA 92717. 483 D ow naded rom http/academ ic.p.com /schizophreniabulle-abstract/23/3/483/1886191 by gest on 10 April 2019 Schizophrenia Bulletin, Vol. 23, No. 3, 1997 E.G. Jones essarily imply that brain development is compromised in schizophrenia or that they are phenomena that occur secondary to a developmental or degenerative insult. Support for a causal relationship between disturbed brain ontogenesis and schizophrenia comes from epidemiological studies that have identified several risk factors acting during pregnancy that increase the incidence of schizophrenia in offspring. Studies of the incidence after maternal infection with influenza virus in the second trimester, although the numbers of cases involved are small, have had a major influence (Mednick et al. 1988; Mednick and Cannon 1991; Mednick and Hollister 1994). Even in the absence of an imposed risk factor of this type, the proven genetic influence in schizophrenia could exert its effect upon brain development. Much of the emphasis in the search for a neuropathology of schizophrenia has focused on the cerebral cortex as the obvious site in which a pathological insult is likely to disrupt cognitive function. Cortical function is, however, dependent on connections with such subcortical structures as the thalamus and the basal ganglia, with the former providing many re-entrant loops that serve to cement the relationships among multiple cortical areas upon which cognitive function depends. Pathology, developmental or otherwise, in one of these structures is not only likely to have anterograde, retrograde, and activitydependent effects on the others, but potentially may spread throughout the cortico-thalamic-basal ganglia network and beyond. This possible spread must always be borne in mind when assessing the significance of many of the observations made to date in the neuropathology of schizophrenia. In this article, I review the major events in the development of the forebrain in relation to what is known of the neuropathology of schizophrenia, attempting to point out the likelihood of that pathology being produced by a disturbance of one or more of the developmental processes. The focus is on the development of the primate brain for obvious reasons and on the circuitry linking cerebral cortex, thalamus, and basal ganglia, the dysfunction of which appears to be of fundamental importance in the pathophysiology of schizophrenia.