There is an encouraging convergence between neuronal and synaptic findings in schizophrenia. In particular, the decreases in presynaptic and dendritic markers are in keeping with the smaller neuronal cell bodies, since the size of the latter is proportional to the dendritic and axonal spread of the neurone. It is also consistent with the findings of increased neuronal density, in that dendrites and synapses are the major component of the neuropil and, if this is reduced, neurones will pack more closely together. Moreover, it also corresponds to the results of proton magnetic resonance spectroscopy studies of schizophrenia, which have shown reductions of the neuronal marker ^-acetyl-aspartate, as one would predict if the neurones are on average smaller and have less extensive projections.
Postmortem studies are limited to chronic schizophrenia, so it is impossible to prove that the cytoarchitectural abnormalities are not the result of the illness or its treatment. However, several lines of evidence suggest that this is not the case. First, as the structural brain abnormalities and lower W-acetyl-aspartate signals occur in unmedicated and first-episode schizophrenia, it is reasonable to assume that the cytoarchitectural differences which putatively underlie them are also present at this time. Second, no correlations with the duration of disease or medication exposure have been seen in any of the postmortem studies. Third, although antipsychotic treatment does have morphological consequences, the effect is largely restricted to the basal ganglia. (33>
Interpretation of the neuropathology Neuropathology and neurodevelopment
The neurodevelopmental model of schizophrenia (see ChapteL4.i3.5.1) has become the prevailing pathogenic hypothesis; indeed the principle is now largely unchallenged. The neurobiological data form an important component of the evidence in its favour ( TableS).
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Table 3 Neuropathological evidence for a neurodevelopmental origin of schizophrenia
A specific version of the theory is that the pathology of schizophrenia originates in the middle stage of intrauterine life. (34> An earlier timing is excluded since overt brain abnormalities would be seen if neurogenesis were affected, whilst the lack of gliosis is taken to mean that the changes must have occurred prior to the third trimester. However, this 'strong' form of the neurodevelopmental model is weak on two grounds. First, because of the limitations of the absence-of-gliosis argument mentioned earlier. Second, the types of cytoarchitectural disturbance adduced in favour (neuronal disarray, malpositioning) are those suggestive of aberrant neuronal migration, a process which occurs at the appropriate gestational period; yet, as mentioned, these cytoarchitectural abnormalities have not been unequivocally shown in schizophrenia. By comparison, the other cytoarchitectural findings, such as alterations in neuronal size, synapses, and dendrites, are modifiable throughout life and hence could originate much later.
Other forms of the neurodevelopmental theory advocate processes such as cell adhesion, apoptosis, myelination, and synaptic pruning. Overall, a parsimonious view is that the neuropathological data are indicative merely of an essentially developmental, as opposed to degenerative, disease process, rather than as pointing to a particular mechanism or timing.
Bleuler's view that the key symptoms of schizophrenia are those of 'psychic splitting' now have their counterparts in the functional imaging studies and neuropsychological models described above, which have implicated aberrant functional connectivity between different brain regions as the putative mechanism of psychosis. It is suggested that the cytoarchitectural features of schizophrenia represent its neuroanatomical basis. (31) However, functional connectivity does not presuppose an anatomical substrate, and the pathological evidence in schizophrenia must be considered on its own merits before attempts are made to integrate structure with function. Certainly, schizophrenia is not a disconnectivity syndrome akin to Alzheimer's disease, in which there is a frank loss of synapses and neurones, but rather a dysconnectivity or misconnectivity syndrome resulting from a disturbance in the precise organization of the neural circuitry ( Fig 1).
Fig. 1 Diagram of the putative cytoarchitectural features of schizophrenia. The grey matter (labelled I—VI) contains an unchanged number of neurones, but the pyramidal neurones (D) are smaller and more densely packed. The cortex is slightly thinner, especially laminae II and III. Both the reduced neuronal size and increased neuronal density are correlates of a reduced neuropil volume, which in turn reflects abnormalities affecting the axonal (thick vertical lines) and dendritic (thin vertical lines) arborizations of neurones. For example, there may be less extensive, or otherwise aberrant, synaptic connections formed by both incoming corticocortical fibres (hollow lines, shown as having restricted terminations on dendritic spines, which are denoted by thin horizontal lines) and axon collaterals (thick horizontal lines in lamina IV) of efferent pyramidal neurones. Glia (•) are unaffected. Although the figure illustrates the situation in the prefrontal neocortex, a similar diagram could be drawn for the hippocampus. For clarity, possible differences in the distribution and synaptic organization of interneurones (ellipses) and white matter (wm) neurones in schizophrenia are omitted.
Many neuropathological, neurochemical, neuropsychological, and electrophysiological studies of schizophrenia report lateralized abnormalities. Although there are also important negative findings, alterations in normal asymmetries and a left-sided preference of the pathology for the brain do seem to be more common than one would expect by chance. Two explanatory hypotheses exist. Crow's evolutionary theory is that schizophrenia, asymmetry, handedness, and language are causally linked to each other and to the same gene.(35> Alternatively, altered asymmetry in schizophrenia is viewed as an epiphenomenon of its in utero origins, a process which interferes with subsequent brain lateralization.(36) The issue remains under active investigation.
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