PET scanning and schizophrenia--what progress?

Positron Emission Tomography (PET) provides quantitative three-dimensional images of the physiological processes of the living brain. However, the disturbances of brain physiology in schizophrenia are likely to be subtle. Although recent neuropsychological studies have partially undermined the Bleulerian view that basic intellectual activities are undamaged in schizophrenia, it remains true that the majority of schizophrenic patients can perform within the normal range in most aspects of brain function. It is failure to integrate the separate elements of activity constructively that produces the most devastating effects of the illness. This suggests that the abnormalities of brain function involve the processes that generate and coordinate mental activity. What has PET contributed to the delineation of these putative abnormalities? In view of the seminal role played by the hypothesis of dopaminergic overactivity in schizophrenia, there has been great interest in the use of PET to measure dopamine D2 receptor density in the basal ganglia in untreated schizophrenic patients. Studies using selective D2 ligands have yielded ambiguous results. Farde et al., (1987) found no increase in D2 receptor number in the putamen or caudate nucleus. Wong et al. (1989), who had found an increase in their initial study of schizophrenic patients, subsequently found a similar increase in patients with manic depressive psychosis, raising the possibility that an excess of D2 receptors can be feature of psychotic illness in general. Meanwhile there have been important advances in the use of PET to explore the subtle processes involved in the generation of activity. These developments have been dependent on refinement of PET techniques for measuring regional cerebral blood flow (rCBF). In the era before PET, Ingvar & Franzen (1974) used the xenon infusion technique to demonstrate a relative reduction in blood flow in the frontal lobes in schizophrenic patients. This finding was of great interest because of the role of the frontal lobes in the initiation and organization of mental activity. Subsequent PET studies of blood flow and of cerebral metabolism provided additional evidence of hypofrontality in at least some schizophrenic patients, but studies of unmedicated acute patients found no evidence of hypofrontality (Sheppard et al. 1983, Early et al. 1987). Interest in rCBF as an index of disordered brain function in schizophrenia was revitalized when Weinberger et al. (1986) used the xenon inhalation technique to demonstrate that in some schizophrenic patients blood flow in the dorsolateral prefrontal cortex does not increase above resting levels during performance of the Wisconsin card sorting test, a task requiring flexibility in problem solving. In contrast, blood flow in that brain region does increase in normal individuals performing this task. The physiological mechanisms regulating cerebral blood flow appear to be finely tuned to respond to the brain's requirements. Fox & Raichle (1986) found that rCBF in the sensorimotor cortex during somatosensory stimulation increased by 26%, while the rate of oxygen metabolism in the same region increased by 5%. A similar activation produced an 11 % increase in the rate of glucose metabolism (Raichle et al. 1987). The change in rCBF during brain activation occurs within seconds of the onset of activity. Thus, rCBF can be a sensitive index of brain activity. However, various sources of confounding variation in rCBF measurements which must be taken into account. The major sources of variation are anatomical variation; fluctuation in global cerebral perfusion; idiosyncratic variation in brain activity; and clinical heterogeneity.