Cortical "stress tests" in schizophrenia: regional cerebral blood flow studies.

A total of 261 regional cerebral blood flow (rCBF) studies were carried out on 34 medication-free patients with chronic schizophrenia and 50 normal subjects. rCBF, an indicator of local cortical metabolism and activity, was measured during the resting state and also during four cognitive activation tasks or "cortical stress tests." The latter included the Wisconsin Card Sort (WCS), a test of prefrontal lobe function; a simple numbers matching task, and two versions of a visual Continuous Performance Task (CPT). Multivariate comparisons of the two subject groups were performed for each of the five testing conditions, and discriminant function analyses for each condition were carried out to define mathematical models that differentiated normal subjects from medication-free patients. The best such model was determined and was then applied to another group of patients who had diagnoses other than schizophrenia or for whom the diagnosis was unclear. This group included two patients with clinical "frontal lobe syndrome" and radiological evidence of frontal lobe damage. The most robust differences between the groups were seen in frontal rCBF during the WCS. In the discriminant function analysis, rCBF during the WCS was the best discriminator between the two groups, retrospectively classifying 85% of the subjects correctly. rCBF during the resting state and one of the CPTs correctly classified subjects at a rate only marginally better than chance. When the model derived from WCS rCBF was applied to a second group of patients, the two patients with known frontal lobe disease were classified as "schizophrenic" with 100% certainty. Three other patients with psychotic illnesses were also assigned to this group with greater than 80% certainty, whereas a patient with character disorder (rule-out affective disorder) was classified as "normal" with a high level of confidence. These data suggest (1) that schizophrenia is characterized by a deficit in prefrontal function that is revealed when regionally specific demand exceeds the physiological capacity, and (2) that functional brain imaging studies, such as rCBF, can best identify brain abnormalities during "cortical stress tests."