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Schizophrenia is a complex mental illness characterized by acute phases of delusions, hallucinations, and thought disorder, and chronically by apathy, ﬂat aﬀect, and social withdrawal. Schizophrenia aﬀects 1 percent of the world’s population, independent of country or culture, and constitutes a severe public health issue (WHO 1975). Schizophrenic patients normally start to display symptoms in their late teens to early twenties, but the time of onset and the course of the illness are very variable (American Psychiatry Association 1987). Approximately a third of patients experience one acute episode after which they make a more or less full recovery. Another third are aﬀected by the illness throughout their lives, but their symptoms are to some extent alleviated by anti-psychotic drugs. The remaining third are so chronically ill that they show little or no improvement, even with medication (Johnstone 1991).
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1. Intellectual Function
There is a striking deterioration in intellectual and cognitive function in schizophrenia (e.g., Johnstone 1991). Patients have diﬃculty in initiating and completing everyday tasks, being distracted easily and tending to give up when confronted by any obstacles. These deﬁcits are similar to the problems in initiation and planning associated with frontal-lobe lesions (Shallice and Burgess 1991). This has led many researchers to suggest that the core deﬁcit of schizophrenia is a failure to activate frontal cortex appropriately during cognitive tasks involving planning and decision making (‘task-related hypofrontality’), a notion supported in part by many functional imaging studies (see below). Schizophrenic patients also show deﬁcits in attention and memory tasks that engage prefrontal, hippocampal, and medial temporal systems, even in drug-free populations (Saykin et al. 1994). In the rest of this entry we shall consider the direct evidence for brain abnormalities in schizophrenia.
2. Post-Mortem Neuropathology
Studies of post-mortem brains (Harrison 1999) have observed a decrease in overall brain size and have linked schizophrenia to structural abnormalities in the prefrontal cortex and temporal lobe, especially the hippocampus and amygdala. Several studies have found that schizophrenic brains tend to have enlarged lateral ventricles compared to nonschizophrenic brains. Histological studies have shown evidence for abnormal synaptic appearance in the cingulate and hippocampal pyramidal cells in schizophrenia. The most reproducible positive anatomical ﬁnding in postmortem hippocampal formation has been the reduced size of neuronal cell bodies in schizophrenia. However, these changes have not been found in all studies.
3. In Vivo Studies Of Brain Structure
3.1 Computerized Tomography (Ct) Studies
The main ﬁnding from CT scan studies is that the lateral ventricles are enlarged in schizophrenic patients compared to normal controls (Van Horn and McManus 1992). Although the ﬁnding of increased ventricular volume in schizophrenic patients is widespread and replicated, the diﬀerence between schizophrenic patients and normal controls is small. Overlap with the normal population is appreciable. Correlation between CT ﬁndings and symptoms has been investigated (Lewis 1990). Enlarged ventricles have been associated with chronicity of illness, poor treatment response, and neuropsychological impairment in many, but not all of these studies.
3.2 Magnetic Resonance Imaging (MRI) Studies
MRI studies (see Harrison 1999) have tended to conﬁrm the ﬁnding of enlarged ventricles in schizophrenic patients, but also permit a more detailed analysis of brain structure. Temporal lobe reductions have been reported, and are especially prominent in the hippocampus, parahippocampal gyrus, and the amygdala, but have not been observed in all studies. Robust relationships between temporal lobe reductions and clinical features have not yet been found. Some studies have found frontal lobe reductions in schizophrenic patients.
Reversal or reduction of normal structural cerebral asymmetries may be related to the pathogenesis of schizophrenia (Crow 1995). Various unusual symmetries have been observed consistent with the hypothesis that failure to develop normal asymmetry is an important component of the pathology underlying some forms of schizophrenia.
There are some MRI data that provide support for a hypothesis of disconnection between brain areas in schizophrenia. These results support the existence of a relative ‘fronto-temporal dissociation’ in schizophrenia. Evidence for such dissociation has also been obtained in functional imaging studies (see below).
All these studies used a ‘regions of interest’ approach in which measurements were restricted to prespeciﬁed brain regions. More recently, techniques have been developed in which diﬀerences can be detected automatically throughout the brain. Using such techniques, Andreasen et al. (1994) observed decreased thalamus size in schizophrenic patients consistent with observations in post-mortem brains.
4. Functional Imaging
4.1 Resting Studies Using Positron Emission Tomography (PET)
More sensitive measures of brain integrity can be obtained by measuring cerebral blood ﬂow in a patient at rest. However, these results are diﬃcult to interpret because the pattern of blood ﬂow may be altered by the current mental state of the patient and by medication. Early studies of this sort observed a relative reduction of blood ﬂow in the frontal lobes of patients with schizophrenia (Ingvar and Franzen 1974). This pattern of activity became known as hypofrontality. However, subsequent studies have not always replicated this observation.
Several studies have looked at clinical correlates associated with hypofrontality, but the results are inconsistent. Among features showing a positive relationship with hypofrontality are chronicity, negative symptoms, and neuropsychological task impairment. Relations have also been observed between the pattern of blood ﬂow and the symptomatology of patients at the time of scanning. For example, patients manifesting ‘psychomotor poverty’ showed reduced blood ﬂow in dorsolateral prefrontal cortex (Liddle et al. 1992).
4.2 The Dopamine Hypothesis
One of the most robust ﬁndings in schizophrenia research has been the observation that drugs which block dopamine receptors are eﬀective in reducing the severity of symptoms such as hallucinations and delusions (Seeman 1986). This led to the dopamine (DA) hypothesis of schizophrenia, which posits that schizophrenia is caused by an overactivity of dopamine receptors (Van Rossum 1966). The best way to investigate the dopamine hypothesis is the in vivo visualization of radioactive ligand binding to quantify dopamine receptor densities in drug-naive patients using PET.
These studies suggest that compared to healthy controls, patients with schizophrenia show a signiﬁcant but mild increase in, and a larger variability of, D2 receptor density (Laruelle 1998). There is also evidence that D1 receptor density is reduced in the prefrontal cortex of schizophrenic patients (Okubo et al. 1997).
5. Cognitive Activation Studies
Functional neuroimaging experiments generally evaluate brain activity associated with performance of cognitive or sensori-motor tasks. Cognitive activation studies have provided further evidence for decreased frontal activity (‘hypofrontality’) in schizophrenia. In addition, there is increasing evidence that schizophrenics show abnormal integration between the frontal cortex and other brain regions, including the temporal lobes, the parietal lobes, and hippocampus, during cognitive tasks.
5.1 Task-Based Studies Of Executive Function
Schizophrenia is characterized largely by impairments in planning and execution, and therefore tasks that involve this kind of planning and modiﬁcation of behavior have been exploited in the scanner. Several studies have found that schizophrenic patients show reduced activity in the dorsolateral prefrontal cortex (DLPFC) while performing the Wisconsin card sorting task, a popular test of planning. In addition to decreased DLPFC activity, schizophrenic patients also showed abnormal responses in the temporal lobes and parahippocampal gyrus (Ragland et al. 1998). The results suggest that schizophrenia may involve a breakdown in the integration between the frontal and temporal cortex, which is necessary for executive and planning demands in healthy individuals. This interpretation moves away from the simple notion that dysfunction in isolated brain regions, explains the cognitive deﬁcits in schizophrenia, and towards the idea that neural abnormality in schizophrenia reﬂects a disruption of integration between brain areas.
5.2 Willed Action
Willed actions are self-generated in the sense that the subject makes a deliberate and free choice to perform one action rather than another. Willed actions are a fundamental component of executive tasks. In normal subjects, willed actions are associated with increased blood ﬂow in the DLPFC. Schizophrenic patients, especially those with negative signs, have diﬃculty with tasks involving free choices, and show an associated lack of activity in DLPFC. Activity in this region normalizes as the symptoms decrease (Spence et al. 1998). This suggests that hypofrontality depends on current symptoms. Studies of willed action also suggest that the underactivity in DLPFC observed in some schizophrenic patients is accompanied by overactivity in posterior brain regions. There is evidence of a lack of the normal reciprocal interaction between the frontal and the superior temporal cortex in schizophrenia, which supports the notion of impaired functional integration (McGuire and Frith 1996).
5.3 Memory Tasks
Memory impairments are an especially enduring feature of schizophrenia. Functional neuroimaging studies of memory have demonstrated hypofrontality, abnormal interaction between temporal and frontal cortex, and a dysfunctional cortico-cerebellar circuit in schizophrenic patients compared to control subjects.
The hippocampus is a brain structure that is well known to be involved in memory. Evidence for impaired hippocampal function in schizophrenia was found in a well-controlled functional imaging study (Heckers et al. 1998). In this study, schizophrenic patients failed to recruit the hippocampus during successful retrieval, unlike normal control subjects. The schizophrenic patients also showed a more widespread activation of prefrontal areas and parietal cortex during recollection than did controls. The authors propose that this overactivation represents an ‘eﬀort to compensate for the failed recruitment of the hippocampus.’ This result supports the idea that neural abnormality in schizophrenia reﬂects a disruption of integration between brain areas. Fletcher et al. (1999) also found evidence for abnormal integration between brain areas in schizophrenia during the performance of a memory task. They demonstrated an abnormality in the way in which left prefrontal cortex inﬂuenced activity in left superior temporal cortex, and suggested that this abnormality was due to a failure of the anterior cingulate cortex to modulate the prefronto-temporal relationship.
6. Imaging Symptoms
Functional neuroimaging is also useful for evaluating neural activity in patients experiencing speciﬁc psychotic symptoms, such as hallucinations and passivity.
Hallucinations, perceptions in the absence of external stimuli, are prominent among symptoms of schizophrenia. Functional neuroimaging studies of auditory hallucinations suggest that they involve neural systems dedicated to auditory speech processing as well as a distributed network of other cortical and subcortical areas (Dierks et al. 1999). There is also evidence that the activity associated with auditory hallucinations resembles that seen when normal subjects are using inner speech (McGuire et al. 1996).
Passivity symptoms, or delusions of control, in which patients claim that their actions and speech are being controlled by an external agent, are common in schizophrenia. Schizophrenic patients with passivity showed hyperactivation of inferior parietal lobe (BA 40), the cerebellum, and the cingulate cortex relative to schizophrenic patients without passivity and to normal controls. When patients no longer experienced passivity symptoms, a reversal of the hyperactivation of parietal lobe and cingulate was seen (Spence et al. 1997). Hyperactivity in parietal cortex may reﬂect the ‘unexpected’ nature of the movement experienced by patients. The movement feels as though it is being caused by an external force (Frith et al. 2000).
There is considerable evidence for structural abnormalities in the brains of patients with schizophrenia, but the abnormalities identiﬁed so far are not speciﬁc to this disorder, are very variable and cannot easily be related to the symptoms. The neurotransmitter dopamine is clearly important in schizophrenia, but its precise role remains unclear. Studies of brain function are still at an early stage, but suggest that schizophrenia may be characterized by disorders of connectivity between cortical and subcortical regions. Some of the symptoms of schizophrenia can be understood in terms of these disconnections. Current advances in imaging techniques aimed at measuring connectivity in the brain are likely to have a major impact on our understanding of schizophrenia.
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