Brain, Vol. 127, No. 3, 457-459, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh113
Functional neuroimaging of schizophrenia: from a genetic predisposition to the emergence of symptoms
Schizophrenia is common, chronic and disabling. While psychotic features, i.e. delusions, hallucinations and disordered thinking, are critical to diagnosis, accompanying cognitive deficits are receiving increasing attention. Such deficits, occurring early in the course of the disease, are incapacitating, perhaps more so than the psychotic features (Harvey et al., 2003
), and have prognostic significance (Fujii and Wylie, 2003). They may be seen in apparently unaffected relatives of people with schizophrenia (Faraone et al., 1995). In this issue of Brain, Whalley et al. (2004) demonstrate changes in brain responses to cognitive demands in a group of people who are at risk of developing schizophrenia (having two or more first- or second-degree relatives with the disease). Furthermore, a distinctive pattern of brain activation characterizes those in whom the disease may be emerging.
At-risk subjects and matched controls underwent functional MRI (fMRI) while silently completing sentences that varied from strongly constrained (e.g. ‘He mailed the letter without a .........’) to weakly constrained (e.g. ‘Rushing out, he forgot to take his.........’). Four levels of constraint were used to manipulate task difficulty (higher constraint = easier sentence completion). At-risk subjects showed abnormal responses to increasing task difficulty in frontal, thalamic and cerebellar regions. None of the subjects met diagnostic criteria for a psychotic illness. Moreover, none were on any medication and none sought treatment or even considered themselves unwell. In a subgroup (40%), detailed questioning elicited evidence of psychotic features, and this was associated with an additional change in parietal cortex.
These observations, made in individuals at an age when the onset of the disease is most likely to occur, complement earlier evidence that the genetic predisposition to schizophrenia may be seen at the neurophysiological level (Blackwood et al., 1999; Callicott et al., 2003). Moreover, the presence of changes in cortico-thalamo-cerebellar circuitry is consistent with previous studies of schizophrenia (Andreasen et al., 1996) and of its predisposition (Callicott et al., 2003). Although sentence completion was silent during scanning, the authors provide evidence that performance was unimpaired. Functional neuroimaging is therefore offering a sensitive index of subtle differences—differences not seen using behavioural measures. Furthermore, this study provides direct evidence for differences in trait- and state-related brain abnormalities and perhaps provides a unique observation of the earliest indicators of brain change that accompany the emergence of psychosis.
It is worth looking closely at the pattern of brain changes reflecting trait (predisposition) and state (symptoms) effects. Over-activation of the left parietal lobe appears to reflect symptoms rather than predisposition, a finding consistent with previous work (Spence et al., 1997). Of course, as with every functional imaging study of an altered state, abnormal activation could be attributable to any of ‘the three Cs’ (Lewis, 2000), i.e. the parietal over-activation may be a cause of, a consequence of, or a compensation for the psychotic symptoms. What is very interesting here, and may eventually prove clinically useful, is that the imaging findings are present in a group in whom symptoms are subtle, isolated and pre-diagnostic. The possibility of a sensitive, objective measure of the early signs of illness is very appealing and may be one area in which the much-vaunted functional imaging techniques have real value for the clinician and the patient.
Patterns of activity in medial prefrontal/anterior cingulate cortex, thalamus and cerebellum suggest that the genetic predisposition to schizophrenia is associated with failure to increase activity in this network in order to meet increasing cognitive demands. While the chosen tasks are sufficiently undemanding that this failure of activation does not embarrass performance, the authors predict that, as demands increase, any compensatory changes would become insufficient and performance deficits would emerge. This suggests a high sensitivity of fMRI to deficits that might be deemed pre-behavioural. While we must be cautious in view of the fact that identification of trait effects was reliant upon a null finding (no difference between symptomatic and asymptomatic people), the authors have been unusually careful in ensuring that this is not a false negative. A further, noteworthy and, prima facie, anomalous observation was made: the greatest differences in these regions were between control subjects and at-risk individuals without accompanying psychotic symptoms. Symptomatic subjects showed less task-related attenuation. Whalley et al. (2004) are naturally cautious in interpreting this unexpected and seemingly inconsistent finding: why should subjects who do not show signs of illness show greater abnormalities than those who do? Perhaps this commentary offers an opportunity to be more speculative. It is possible that these findings are interpretable with respect to an inverted U model of regional brain response to task difficulty. Certain brain regions (including thalamus) appear to show ‘capacity constraint’ reflected in an initial increase in task-dependent activation which then reaches a plateau before falling away as task demands increase further (Callicott et al., 1999). Perhaps schizophrenia, and a predisposition to it, is associated, in some regions, with a leftward shift in this profile such that lower demands produce higher activation initially. This activation falls away sooner than in controls when demands increase. As speculated in Fig. 1, leftward shifts of varying degrees (greater in symptomatic people) in the demand–activation curve for the at-risk subjects could be invoked to explain the pattern of findings peculiar to key regions in this study.
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Speculation aside, Whalley et al. (2004
) demonstrate a distinctive pattern of task-dependent brain activation in people genetically predisposed to schizophrenia: a pattern that is modified further with the emergence of pre-diagnostic psychopathology. A fuller understanding of brain function and dysfunction in at-risk individuals ultimately may prove important in understanding the predisposition to schizophrenia, in elucidating the mechanisms by which the predisposition transforms into illness and in identifying those at-risk individuals in whom this transition is likely to occur. The current findings will be especially valuable as part of a longitudinal study: might early neuroimaging findings help to predict later development and severity of the illness? Since early therapeutic interventions may be critical in mitigating the impact of the illness (Wyatt and Henter, 2001), this is important.
1 Wellcome Trust Senior Research Fellow in Clinical Science, University of Cambridge, UK
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