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Objective: Disturbed neuronal interactions may be involved in schizophrenia because it is without clear regional pathology. Aberrant connectivity is further suggested by theoretical formulations and neurochemical and neuroanatomical data. The authors applied to schizophrenia a recently available functional neuroimaging analytic method that permits characterization of cooperative action on the systems level., Method: Thirteen medication-free patients and 13 matched healthy comparison subjects performed a working memory (n-back) task and sensorimotor baseline task during positron emission tomography. "Functional connectivity" patterns, reflecting distributed correlated activity that differed most between groups, were extracted by a canonical variates analysis., Results: More than half the variance was explained by a single pattern showing inferotemporal, (para-)hippocampal, and cerebellar loadings for patients versus dorsolateral prefrontal and anterior cingulate activity for comparison subjects. Expression of this pattern perfectly separated all patient scans from comparison scans, thus showing promise as a trait marker. This result was validated prospectively by successfully classifying unrelated scans from the same patients and data from a new cohort. An additional 19% of variance corresponded to the pattern activated by the working memory task. Expression of this pattern was more variable in patients during working memory but not the control condition, suggesting inability to sustain a task-adequate neural network, consistent with the disconnection hypothesis., Conclusions: Pronounced disruptions of distributed cooperative activity in schizophrenia were found. A pattern showing disturbed frontotemporal interactions showed promise as a trait marker and may be useful for future investigations.

We attempted to identify brain regions functionally lateralized during cognitive tasks traditionally linked to the prefrontal cortex (PFC) by measuring regional cerebral blood flow with H2(15)O positron emission tomography (PET). Fourteen normal subjects were scanned six times while performing six different cognitive conditions comprising three task paradigms putatively sensitive to PFC integrity: the Wisconsin Card Sort (WCS), Delayed Response Alternation (DA), and the Spatial Delayed Response (SDR) Tasks, and three matched sensorimotor control tasks. Multivariate and repeated measures analyses indicated that for all three cognitive paradigms there were no significant hemisphere, hemisphere-by-condition, or hemisphere-by-region effects. However, with more liberal statistical comparison (paired t tests), the superior frontal gyrus showed lateralization during both the WCS and SDR tasks (both R > L). These results suggest that, although some asymmetries may be found using liberal analyses, there is less evidence of lateralized brain function during performance of these tasks of PFC function, than in language and motor systems. Implications for testing PFC function in neuropsychiatric groups are discussed.

Many patients with schizophrenia show clinical signs of frontal lobe dysfunction, including blunted affect, difficulty with problem solving, and impoverished thinking. The authors present cytoarchitectural, neuropsychological, and functional neuroanatomical evidence of frontal abnormalities from recent studies of frontal dysfunction in schizophrenia. It is suggested that the failure of intracortical connectivity of the prefrontal cortex accounts for both cognitive and psychotic manifestations of this illness.

We addressed several questions regarding hypofunction of the prefrontal cortex ("hypofrontality") in schizophrenia by measuring regional cerebral blood flow during three different cognitive conditions in monozygotic twins who were discordant or concordant for schizophrenia or who were both normal. These questions included the prevalence of hypofrontality, the importance of genetic predisposition, and the role of long-term neuroleptic treatment. Significant differences between affected and unaffected discordant twins were found only during a task linked to the prefrontal cortex, the Wisconsin Card Sorting Test. During this condition, all of the twins with schizophrenia were hypofrontal compared with their unaffected co-twins, suggesting that, if appropriate cognitive conditions and control groups are used, hypofrontality can be demonstrated in the majority of, if not all, patients with schizophrenia. When unaffected co-twins of patients with schizophrenia were compared with twins who were both normal, no differences were observed, suggesting that nongenetic factors are important in the cause of the prefrontal physiologic deficit that appears to characterize schizophrenia. When concordant twins with a high- vs a low-dose lifetime history of neuroleptic treatment were compared, the twin receiving the higher dose was more hyperfrontal in six of eight pairs, suggesting that long-term neuroleptic treatment does not play a major role in hypofrontality.

Objective: The authors previously reported that in monozygotic twins discordant for schizophrenia the affected twin almost invariably had a smaller anterior pes hippocampus, measured with magnetic resonance imaging (MRI), and invariably had less regional cerebral blood flow (rCBF) in the dorsolateral prefrontal cortex during performance of the Wisconsin Card Sorting Test. The present study was an investigation of the relationship between hippocampal pathology and prefrontal hypofunction in the same twin pairs., Method: Nine pairs of monozygotic twins discordant for schizophrenia underwent MRI scanning for determination of anterior hippocampal volume and xenon-inhalation rCBF testing for determination of prefrontal physiological activation associated with the Wisconsin Card Sorting Test., Results: The differences within twin pairs on the MRI and rCBF measures were strongly and selectively correlated. Specifically, the more an affected twin differed from the unaffected twin in left hippocampal volume, the more they differed in prefrontal physiological activation during the Wisconsin Card Sorting Test. In the affected twins as a group, prefrontal activation was strongly related to both left and right hippocampal volume. These relationships were not found in the group of unaffected twins., Conclusions: This finding is consistent with the notion that schizophrenia involves pathology of and dysfunction within a widely distributed neocortical-limbic neural network that has been implicated in, among other activities, the performance of cognitive tasks requiring working memory.

To examine the relationship between cortical physiology and dementia in Huntington's disease, rCBF during three different behavioural conditions, one of which emphasised prefrontal cognition, was determined by xenon-133 inhalation in 14 patients with Huntington's disease and in matched controls. Cortical rCBF was not reduced in Huntington's disease patients even while they manifested overt prefrontal-type cognitive deficits. Caudate atrophy on CT and rCBF were significantly correlated, but only during the prefrontal behaviour where the correlation was positive. These results suggest a qualification of the subcortical dementia concept as applied to Huntington's disease and implicate an interaction between pathology that is subcortical and cognitive function that is cortical.

A double-blind, placebo-controlled crossover study of the effects of apomorphine on regional cerebral blood flow (rCBF) during a prefrontal cortex activation task was undertaken to explore the role of dopamine on cortical function. The subjects were eight drug-free, chronically psychotic patients; six patients had schizophrenia. In each, apomorphine increased the relative prefrontal flow. The results suggest that enhanced prefrontal dopamine activity may reverse deficits in prefrontal cortex metabolism in schizophrenia.

We conducted two xenon Xe 133 inhalation regional cerebral blood flow (rCBF) studies to clarify earlier findings of dorsolateral prefrontal cortex (DLPFC) dysfunction in medication-free patients with chronic schizophrenia. In the first study, 24 neuroleptic-treated patients and 25 normal controls underwent three rCBF procedures, first while at rest, then during the Wisconsin Card Sort (WCS), which tests DLPFC cognitive function, and during a number-matching task that controlled for aspects of the WCS-rCBF experience not specifically related to DLPFC. The results were qualitatively identical to those previously reported for medication-free patients. In the second study, rCBF was determined while 18 medication-free patients and 17 normal control subjects each performed two versions of a visual continuous performance task (CPT). No differences in DLPFC blood flow between the two groups were found during either CPT condition. These data suggest that DLPFC dysfunction in schizophrenia is independent of medication status and not determined simply by state factors such as attention, mental effort, or severity of psychotic symptoms. Dysfunction of DLPFC appears to be a cognitively linked physiologic deficit in this illness.

Recent physiological and cognitive studies of schizophrenia have implicated dysfunction of prefrontal cortex as a possible explanation for some of the disabling intellectual and social aspects of the disorder. To investigate the potential reversibility of cognitive deficits and the role of state variables, eg, attention and motivation, three groups of patients with schizophrenia were administered the Wisconsin Card Sorting Test on six consecutive occasions. Two of the groups received incremental information on how to do the test, including explicit card-by-card instruction. The third group served as a control. Regardless of the degree of instruction, patients who could not do the test could not learn it. The deficit did not appear generalized, as patients were able to learn word lists on the Selective Reminding memory test and were not globally demented on the Mini-Mental State Examination. These data suggest that prefrontal-type cognitive deficits in schizophrenia may be more profound than is generally appreciated.

To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC-specific cognitive test, and while performing a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.

Though individual tests thought to assess frontal lobe function have been administered to patients with schizophrenia for many years, approaches in which a number of tests thought to tap a single function or brain region have rarely been used. Such an approach might define a critical test or a common dysfunctional cognitive process. In the present study four putative neuropsychological tests of frontal lobe integrity, namely, the Wisconsin Card Sorting Test, the Category Test, Trail Making B, and verbal fluency, were administered to 28 patients with schizophrenia. Seventy-five percent performed abnormally on at least one test. However, relationships among the test results were difficult to characterize, either by correlation or factor analysis. A hierarchical arrangement in which "higher order" tests proscribe performance on "lower order" tests did not appear to be present. Regarding sensitivity, Trails B, the only timed test, was most frequently impaired and verbal fluency was least frequently impaired. The results suggest that the tests assess somewhat different aspects of frontal lobe function, and that no single frontal lobe test is uniquely sensitive to cognitive impairment in schizophrenia.

We previously reported that compared with normals, patients with chronic schizophrenia have reduced regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) during performance of the Wisconsin Card Sort Test (WCS), a DLPFC-related cognitive task, but not during nonprefrontal tasks, such as a simple number-matching (NM) test. We also found that unlike normals, patients failed to activate DLPFC during the WCS over their own baseline (NM) level. To explore the reproducibility of these findings, a new cohort of 16 medication-free patients underwent a series of xenon 133 inhalation rCBF studies under the following conditions: at rest, while performing the WCS, and while performing NM. The results confirmed our earlier findings. In addition, the concentrations in cerebrospinal fluid of homovanillic acid and 5-hydroxyindoleacetic acid correlated with prefrontal rCBF during the WCS but not during the NM test or at rest. The results show that behavior-specific hypofunction of DLPFC in schizophrenia is reproducible, and they implicate a monoaminergic mechanism.

Cerebral metabolic hypofrontality in schizophrenia is a controversial research finding. In this article we discuss some of the issues that fuel this controversy, and we speculate on the neural mechanisms that may be responsible for the finding. Most regional cerebral blood flow (rCBF) studies using radioactive xenon have found hypofrontality; the results of positron emission tomography (PET) studies have been less consistent. Several technical factors are discussed that might contribute to the inconsistencies, including airway artifacts with xenon, limitations of tomography in studying the cortex, and approaches to data analysis. The possibility that hypofrontality is a result of medication is also critically examined. The medication factor is still unclear, but most studies of patients before and after neuroleptic medication find that cerebral metabolism goes up, not down, after treatment. The role of patient behavior and experience during an rCBF or PET procedure is an important variable that has not been adequately controlled in most studies. We suggest that this has been the most important variable in interpreting cerebral metabolic data in schizophrenia. Studies of patients examined during a behavior that normally activates prefrontal cortex have consistently found hypofrontality. One theoretical mechanism that could account for hypofrontality as well as many clinical and research findings in schizophrenia is dysfunction of dopaminergic neural transmission at the level of the prefrontal cortex.

Patients with schizophrenia have memory deficits when compared to other neuropsychiatric and normal samples, but the mechanism by which the deficits arise is obscure. In the present study, 13 older, less educated normal subjects, and 31 inpatients with schizophrenia were administered the Selective Reminding test. In addition, the schizophrenic patients received the Mini Mental State Exam and the Brief Psychiatric Rating Scale. While normal subjects performed at a higher level on various measures of recall, a significant effect of repeated trials was present for each group for each measure, indicating that both groups learned. Normal subjects also outperformed the patients on a test of recognition memory. However, the patients exhibited a significantly greater disparity between recognition and recall than did the normal subjects, suggesting they were better able to acquire new information than to retrieve it ('forgetting to remember'). Moreover, anergia, a factor measure on the Brief Psychiatric Rating Scale, correlated significantly with recall, but not recognition memory, in the patient group. The data are suggestive of prefrontal-type cognitive and behavioral deficits in schizophrenia.

In previous studies we found that patients with chronic schizophrenia had lower regional cerebral blood flow (rCBF) in dorsolateral prefrontal cortex (DLPFC) than did normal subjects during performance of the Wisconsin Card Sort Test, an abstract reasoning task linked to DLPFC function. This was not the case during less complex tasks. To examine further whether this finding represented regionally circumscribed pathophysiology or a more general correlate of abstract cognition, 24 medication-free patients and 25 age- and sex-matched normal control subjects underwent rCBF measurements with the xenon 133 technique while they performed two tasks: Raven's Progressive Matrices (RPM) and an active baseline control task. While performing RPM, normal subjects activated posterior cortical areas over baseline, but did not activate DLPFC, as had been seen during the Wisconsin Card Sort Test. Like normal subjects, patients showed maximal rCBF elevations posteriorly and, moreover, they had no significant DLPFC or other cortical deficit while performing RPM. These results suggest that DLPFC dysfunction in schizophrenia is linked to pathophysiology of a regionally specific neural system rather than to global cortical dysfunction, and that this pathophysiology is most apparent under prefrontally specific cognitive demand.