The functional architecture of the prefrontal cortex and schizophrenia.

Findings from a number of studies have implicated the prefrontal cortex (PFC), especially the dorsolateral region, as a site of dysfunction in schizophrenia (Goldberg et al. 1989). For example, in contrast to controls, schizophrenics fail to activate the dorsolateral PFC while engaged in the Wisconsin Card Sort Task (Weinberger et al. 1986), and they exhibit an inability to learn how to perform this task (Goldberg et al. 1987). Schizophrenic subjects also demonstrate significant impairments on oculomotor delayed-response tasks (Park & Holzman, 1992), a behavioural paradigm that in nonhuman primates appears to be a selective and reliable measure of dorsolateral PFC function (Fuster, 1989; Funahashi et al. 1991, 1993). Despite these clear deficits in PFC functioning in schizophrenia, the apparent lack of gross structural abnormalities in the PFC of schizophrenic subjects suggests that this dysfunction may be a consequence of more subtle alterations in the intrinsic neural circuitry of this region. Understanding how such disturbances in connectivity might occur in schizophrenia requires knowledge of the normal functional architecture of the PFC. In addition, the PFC is functionally coupled with multiple other brain regions, some of which may also be impaired in schizophrenia. Consequently, it is important to understand how information processing within the PFC influences, and is influenced by, the activity of these regions. Any hypothesis of PFC dysfunction in schizophrenia also needs to account for the typical onset of the symptoms of this disorder, including impairments in cognitive processes (Heaton et al. 1994), during late adolescence or young adulthood (Carpenter & Buchanan, 1994). In addition, hypotheses of PFC dysfunction in schizophrenia should consider the possible role of dopamine, which has long been considered to play a part in the pathophysiology of this disorder. Although our knowledge of these factors remains limited in many respects, recent advances in understanding the normal functional architecture of the primate PFC, in concert with post-mortem studies of schizophrenic patients, have provided a basis for the generation of novel, testable hypotheses regarding the pathophysiology of PFC dysfunction in this illness.