Macroscopic brain changes

Key findings

Contemporary research into the structural basis of schizophrenia can be traced to a seminal report describing dilatation of the lateral ventricles and cerebral atrophy, as seen on CT scans, in chronic schizophrenia. (!.9> This finding, which was consistent with earlier pneumoencephalographic data, has been followed by many other CT and MRI studies with ever-improving resolution and sophistication of analysis. The key results are described below and in TableJ.

Table 2 Structural brain abnormalities in schizophrenia

There is enlargement of the cerebral ventricles. Comprehensive reviews of the lateral ventricle-to-brain ratio indicate an increase of 20 to 75 per cent, with an effect size of 0.70, corresponding to a 43 per cent non-overlap between cases and controls. (2 21' Volumetric MRI shows a median 40 per cent increase in ventricular size.(22) The ventricular enlargement is accompanied by a loss of cortical volume averaging 3 per cent.(2 23) Greater reductions occur in temporal lobe (4-12 per cent), especially medial temporal structures (hippocampus, parahippocampal gyrus, and amygdala).(24) Several, though not all, postmortem studies of schizophrenia have confirmed these features, which have recently been shown in childhood-onset cases as well.

Monozygotic twins discordant for schizophrenia have provided valuable information. In virtually all pairs, the affected twin has the larger ventricles and smaller cortical and hippocampal size.(25> The discordant-monozygotic twin study design allows two conclusions to be drawn. First, that structural abnormalities are a consistent finding in schizophrenia, their identification being aided by controlling for random genetic and environmental influences on neuroanatomy. Second, that the alterations are associated with expression of the schizophrenia phenotype rather than merely with the underlying shared genotype. Family studies support this interpretation, in that schizophrenics have bigger ventricles and smaller brains than their unaffected relatives. However, relatives who are obligate carriers (that is to say those unaffected by schizophrenia but who seem to be transmitting the gene(s)) have larger ventricles than other relatives; moreover both groups of relatives have larger ventricles and smaller brain structures than control subjects from families without schizophrenia.(26) These data indicate that a proportion of the structural pathology of schizophrenia may be a marker of genetic liability to the disorder. (A similar conclusion applies to the neuropsychological and neurophysiological indices mentioned above.)

Imaging studies have not established clearly whether there are volume differences in subcortical structures in schizophrenia; one firm conclusion is that the striatal enlargement sometimes reported is, unlike all other volume changes, due to antipsychotic medication. Finally, good evidence for a reduced size of the thalamus has emerged from postmortem studies.

Progression, heterogeneity, and clinicopathological correlations

Ventricle-to-brain ratio in schizophrenia follows a unimodal distribution, indicating that ventricular enlargement is not restricted to a subgroup but is present to a degree in all cases.(20) Conversely, it is important to emphasize that, despite group differences, there is a significant overlap between subjects with schizophrenia and controls for every structural parameter. For this reason, and the fact that the changes are of uncertain diagnostic specificity, schizophrenia remains a clinical rather than a neurobiological diagnosis.

The structural abnormalities are present in first-episode cases, excluding the possibility that they are merely a consequence of chronic illness or its treatment. Furthermore, their magnitude does not correlate with duration of the disease, suggesting that the alterations are largely static after onset. However, some longitudinal studies, spanning 4 to 8 years, find continuing divergence from controls. The issue, which remains controversial, is important as it bears upon the timing, progressive nature, and possible heterogeneity of schizophrenia (see below).

Some studies indicate that male schizophrenics show greater structural changes than do females, but other studies do not. Similarly, there are few established correlations between brain structure and the symptoms or course of schizophrenia. For example, the expectation that enlarged ventricles might be a correlate of poor outcome has not been consistently demonstrated.

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