The prefrontal cortex in schizophrenia and other neuropsychiatric diseases: in vivo physiological correlates of cognitive deficits.
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Brain Diseases↗
Biomedical subjects
K F Berman
Publications and source records attributed to K F Berman.
Lateralisation of cortical function during cognitive tasks: regional cerebral blood flow studies of normal individuals and patients with schizophrenia.
To assess cognitively-related regional asymmetries of brain function, regional cerebral blood flow (rCBF) was determined by the xenon inhalation method while normal subjects performed 10 different tasks and also while they were at rest. In addition to healthy subjects, patients with schizophrenia were also studied. A total of 447 rCBF studies were carried out during the following conditions: the Wisconsin Card Sort Test, a numbers matching test, a symbols matching test, Raven's Progressive Matrices, an auditory discrimination test, an auditory control task, two versions of a visual continuous performance task, line orientation, semantic classification, and resting. On the whole, those tasks that seem to require or allow for internal verbalisation resulted in the greatest activation of the left hemisphere compared with the right; right hemisphere activation predominated only in the two tasks primarily involving attention and vigilance. Furthermore, a consistent regional topography of normal cerebral functional laterality was seen: under most conditions left prefrontal cortical activity exceeded that of right prefrontal cortex; during all non-auditory tasks, parieto-occipital cortical activity had an opposite pattern-greater right than left. During most conditions the schizophrenic patients displayed the same pattern. While several cognitively specific between-group differences were found, no single cortical region was consistently implicated and no specific direction of abnormal asymmetry predominated. These data suggest that there is a predominant task-independent functional pattern of cortical activity emphasising relatively greater left anterior and right posterior activation. This pattern may reflect the verbal and attentional primacy of these areas, respectively.
Adult↗
Cerebral muscarinic receptors in primary degenerative dementia as evaluated by SPECT with iodine-123-labeled QNB.
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Alzheimer Disease↗
Anxiety and cerebral blood flow during behavioral challenge. Dissociation of central from peripheral and subjective measures.
To investigate the relationship between anxiety and regional cerebral blood flow, we administered behavioral challenges to 10 patients with obsessive-compulsive disorder while measuring regional cerebral blood flow with the xenon 133 inhalation technique. Each patient was studied under three conditions: relaxation, imaginal flooding, and in vivo (actual) exposure to the phobic stimulus. Subjective anxiety, obsessive-compulsive ratings, and autonomic measures (heart rate, blood pressure) increased significantly, but respiratory rate and PCO2 did not change across the three conditions. Regional cerebral blood flow increased slightly (in the temporal region) during imaginal flooding, but decreased markedly in several cortical regions during in vivo exposure, when anxiety was highest by subjective and peripheral autonomic measures. These results demonstrate that intense anxiety can be associated with decreased rather than increased cortical perfusion and that ostensibly related states of anxiety (eg, anticipatory and obsessional anxiety) may be associated with opposite effects on regional cerebral blood flow.
Adult↗
Behavioral and electroencephalographic effects of the adenosine1 agonist, L-PIA.
The effects of N6-(L-2-phenylisopropyl)-adenosine (L-PIA), an A1 agonist, were measured on both spontaneous locomotor activity and electroencephalographic (EEG) measures of sleep in rats. L-PIA strongly inhibited motor activity at 100 micrograms/kg intraperitoneally (IP), a dose which had no statistically significant effects on EEG-defined sleep. A higher dose of L-PIA (200 micrograms/kg) increased the latency to sleep initiation and inhibited later REM sleep. These results demonstrate that L-PIA can produce a state of apparent behavioral quiescence in the presence of EEG-defined arousal.
Adenosine↗
The effect of apomorphine on regional cerebral blood flow in schizophrenia.
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.
Adult↗
Met5-enkephalin-Arg6-Gly7-Leu8 immunoreactivity in rat and human cerebrospinal fluid: influence of neuroleptic drugs and electroconvulsive shock.
Met5-Enkephalin-Arg6-Gly7-Leu8 immunoreactivity was quantitated in both rat and human cerebrospinal fluid (CSF) by radioimmunoassay with a carboxy-terminal directed antiserum. The immunoreactivity in CSF was chromatographically characterized in both species and was found to consist almost exclusively of high molecular weight forms. In human CSF there was approximately 300 fmol/ml and in the rat 1,500 fmol/ml of immunoreactivity. The possibility of a rostro-caudal gradient was examined in the human by analyzing the first and the twenty-fifth ml of CSF drawn during a lumbar puncture: none was found. The immunoreactivity was fairly stable; no loss of immunoreactivity was observed after 24 h of incubation of rat CSF at 37 degrees C. Electroconvulsive shock (ECS) produced a significant elevation in CSF content but only after a course of chronic administration; a single acute ECS produced no increase. Human subjects with schizophrenia who were being treated with antipsychotic drugs had elevated levels of immunoreactivity in comparison to non-mediated patients and normals. The high levels of this immunoreactivity in CSF, its stability and the evidence that the content can change with physiological and pharmacological manipulation indicate that Met5-Enkephalin-Arg6-Gly7-Leu8 immunoreactivity can serve as a new and useful CSF marker for investigating the CNS enkephalin system in neurological or psychiatric disorders.
Animals↗
Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism.
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.
Adult↗
Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. IV. Further evidence for regional and behavioral specificity.
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.
Adult↗
Speculation on the meaning of cerebral metabolic hypofrontality in schizophrenia.
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.
Energy Metabolism↗
Mesocortical dopaminergic function and human cognition.
In summary, we have reviewed rCBF data in humans that suggest that mesoprefrontal dopaminergic activity is involved in human cognition. In patients with Parkinson's disease and possibly in patients with schizophrenia, prefrontal physiological activation during a cognitive task that appears to depend on prefrontal neural systems correlates positively with cognitive performance on the task and with clinical signs of dopaminergic function. It may be possible in the future to examine prefrontal dopamine metabolism directly during prefrontal cognition using positron emission tomography and tracers such as F-18 DOPA.
Cerebral Cortex↗
Prefrontal cortical blood flow and cognitive function in Huntington's disease.
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.
Adult↗
Performance of schizophrenic patients on putative neuropsychological tests of frontal lobe function.
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.
Female↗
Regional cerebral blood flow in severe developmental dyslexia.
Regional cerebral blood flow was measured under three task conditions in 14 men with severe developmental dyslexia and their control subjects using a xenon 133 inhalation technique. No group differences in overall level or in pattern of gray matter flow were seen under relatively undemanding cognitive conditions. Despite minimal group differences in performance, the dyslexic group showed an increased hemispheric asymmetry (left greater than right) on a semantic classification task and a reduced anteroposterior difference on a line orientation task relative to controls. The exaggerated asymmetry suggests the possibility of less efficient information processing or inadequate bihemispheric integration. The reduced anteroposterior gradient may reflect a deficit in the ability of frontal systems to respond adequately to cognitive demands.
Adult↗
Further evidence for dementia of the prefrontal type in schizophrenia? A controlled study of teaching the Wisconsin Card Sorting Test.
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.
Adult↗
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."
Adult↗
A relationship between anatomical and physiological brain pathology in schizophrenia: lateral cerebral ventricular size predicts cortical blood flow.
The authors studied the relationship between lateral cerebral ventricular size and regional cerebral blood flow during mental activation in 30 patients with schizophrenia. Patients with large ventricles had diffusely lower cortical gray matter blood flow than patients with small ventricles. In addition, an inverse correlation between ventricular size and prefrontal blood flow was observed while patients were attempting to solve a neuropsychological test specifically related to the prefrontal cortex. These data suggest that structural brain pathology impairs prefrontal physiology in schizophrenia, implicating a neural mechanism for the intellectual deficits characteristic of this disorder.
Adolescent↗
Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence.
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.
Adult↗