Progressive brain changes Two different types of progressive brain change have been described in schizophrenia. First, treatment with traditional antipsychotics appears to cause progressive enlargement of the basal ganglia, with these structures returning to their original size when patients are transferred to the atypical antipsychotic clozapine (Frazier et al. 1996). Secondly, there is evidence of progressive volume reductions in the temporal and frontal lobes during the first 2 - 3 years after the onset of schizophrenia (Gur et al. 1998). In the NIMH study of childhood onset schizophrenia, longitudinal repeated MRI scans through adolescence have revealed a progressive increase in ventricular volume and progressive decrease in cortical volume with frontal (11% decrease)  and temporal lobes (7% decrease) disproportionately affected (Rapoport et al.  1997,  1999).  Both patients and controls showed progressive reductions in frontal and parietal lobe volumes, with schizophrenic subjects showing a relatively greater loss of temporal lobe volume than controls (Jacobsen et al. 1998).  The reduction seen in temporal lobe structures may occur rather later in the illness course than the reduction in frontal lobe and midsagittal thalamic structures.  Progressive changes appear to be time limited to adolescence with the rate of volume reduction in frontal and temporal structures declining as subjects reach adult life. Because progressive brain changes have been described after the onset of psychosis, it is possible that they are a consequence of neurotoxic effects of psychosis or,  possibly,  antipsychotic medication. Evidence that progressive brain changes precede the onset of psychosis is very limited. Pantelis et al. (2000) have provided a preliminary report of brain MRI findings in high-risk subjects scanned before and after the transition into psychosis. For those subjects who developed psychosis there were longitudinal volume reductions in the medial temporal region (hippocampus,  entorhinal cortex,  inferior frontal and fusiform gyrus). There were no significant longitudinal changes in cases that remained non-psychotic. These are potentially important findings which, if replicated, would provide strong support for the idea that excessive developmental reductions in temporal lobe volume have a key role in the onset of psychosis. Functional brain imaging The emergence of functional brain imaging technology has provided a unique opportunity to link symptoms and cognitive deficits in schizophrenia to underlying brain activity. Liddle et al. (1992) studied the relationship between symptom dimensions (negative, positive and disorganization) in adult schizophrenic subjects and regional cerebral blood flow (rCBF) using PET.  Negative symptoms (e.g.  affective blunting,  avolition and alogia) were associated with reduced rCBF in the dorsolateral prefrontal cortex (DLPFC). Disorganization (e.g. formal thought disorder and bizarre behaviour) was associated with reduced rCBF in the right ventrolateral prefrontal cortex and increased rCBF in the anterior cingulate. Positive symptoms (e.g. hallucinations and delusions) were associated with increased rCBF in the left medial temporal lobe, and reduced rCBF in the posterior cingulate and left lateral temporal lobe. The most consistent association in the literature, across a variety of imaging methods, has been between negative symptoms and reduced frontal activity. However, a simple description of ‘hypofrontality’ in schizophrenia does not capture the complex pattern of changes involving interconnected frontal areas and changes across time. In a PET study in childhood onset schizophrenia using the Continuous Performance Test (CPT), Jacobsen et al. (1997b) reported reduced activation compared with healthy controls in the mid and superior frontal gyrus,  and increased activation in the inferior frontal, supramarginal gyrus and insula. The finding of hypofrontality in schizophrenia is a dynamic state-related phenomenon with evidence of remission of hypofrontality in asymptomatic patients (Spence et al.  1998).  Localizationist models based on focal cerebral dysfunction in schizophrenia have tended to give way to more dynamic models of cerebral ‘disconnectivity’ based on dysfunctional neural networks or systems. Models of cerebral connectivity view normal higher brain function as depending on the integrated activity of widely distributed neurocognitive networks, rather than the activity of discrete brain areas in isolation (Bullmore et al. 1997). In normal individuals,  the functional anatomy of a verbal fluency task (generation of words beginning with a given letter) can be examined using PET and has consistently shown activation of the left DLPFC and reciprocal deactivation of the superior temporal gyrus (STG). A number of investigators have reported a failure of normal STG deactivation (disconnectivity) in schizophrenic patients during a verbal fluency task (Friston et al. 1995; Dolan et al. 1996). However, left DLPFC - STG disconnectivity appears to be a state-related marker of psychosis as it is not found in asymptomatic schizophrenic patients (Dye et al. 1999; Spence et al. 2000) and may possibly be associated with active auditory hallucinations (Spence et al. 2000). In contrast, schizophrenic patients in remission do show reduced connectivity between the left DLPFC and anterior cingulate cortex relative to normal controls (Spence et al. 2000). In summary, models of cerebral disconnectivity fit well with both neuropathological and functional neuroimaging data. What is becoming clear is that functional disconnectivity may both identify state-related changes associated with current symptomatology as well as more stable trait-related markers of neurocognitive vulnerability to psychosis.