Differences in cerebral activation during smooth pursuit and saccadic eye movements using positron-emission tomography.

BACKGROUND: Abnormalities of smooth pursuit eye movements occur commonly in schizophrenia, but the pathophysiological significance of these abnormalities is unknown. To address this, the authors conducted a pilot study in which we examined differences in regional cerebral activation using positron-emission tomography (PET) in normal volunteers as they performed two types of eye movements. METHODS: Cerebral activation in 10 normal volunteers was studied using C15O2 PET while subjects tracked a visual target using smooth pursuit and saccadic eye movements. A left-hand movement comparison task provided a physiologic landmark for verification of the location of the frontal eye fields (FEFs). RESULTS: Subjects exhibited FEF activation during both smooth pursuit and saccadic eye movements, which was greater in the latter. During smooth pursuit, subjects also exhibited increased cerebral activation in the left temporal-occipital border and left superior frontal cortex and decreased activation in medial superior parietal and insular regions relative to saccades. Other cortical visual and eye-movement brain regions also demonstrated differences in activation between the two visual tasks. CONCLUSIONS: Significant fEF activation appears to underlie both smooth pursuit and saccadic eye movements but may be more critical in the former. Dysfunction of the frontal lobe, and possibly of other areas in the pursuit pathway such as the temporo-occipital motion area, may contribute to observed eye-movement abnormalities in patients with schizophrenia.

Functional neuroanatomy of antisaccade eye movements investigated with positron emission tomography.

Increasing interest in the role of the frontal lobe in relation to psychiatric and neurologic disorders has popularized tests of frontal function. One of these is the antisaccade task, in which both frontal lobe patients and schizophrenics are impaired despite normal performance on (pro)saccadic tasks. We used position emission tomography to examine the cerebral blood flow changes associated with the performance of antisaccades in normal individuals. We found that the areas of the brain that were more active during antisaccades than saccades were highly consistent with the oculomotor circuit, including frontal eye fields (FEFs), supplementary motor area, thalamus, and putamen. Superior parietal lobe and primary visual cortex were also significantly more active. In contrast, prefrontal areas 46 and 9 were not more active during antisaccades than during saccades. Performance of some frontal patients on the antisaccade task has been likened to a bradykinesia, or the inability to initiate a willed movement. It is the necessity to will the movement and inhibit competing responses that intuitively linked this task to the dorsolateral prefrontal cortex in frontal patients. Our data suggest that it is the FEFs in prefrontal cortex that differentiate between conditions in which the required oculomotor response changes while the stimulus remains the same, rather than areas 46 and 9, which, in human studies, have been linked to the performance of complex cognitive tasks. Such a conclusion is consistent with single-unit studies of nonhuman primates that have found that the FEFs, the executive portion of the oculomotor circuit, can trigger, inhibit, and set the target of saccades.

Volumetric sampling strategies for heterogeneous brainstem nuclei.

Many brainstem nuclei are heterogeneous structures in which neuronal and glial populations are unevenly distributed, and focal normal or pathologic deviations in cell density, so-called "features," are found. Examples of features include subnuclei, focal neuronal loss, and focal gliosis. We present a statistical test that justifies an investigator's claim that a feature is present in a nucleus at a selected level of confidence after completion of a cell counting experiment. The computer program developed for the test also indicates the most probable location of the feature within the nucleus, and its most probable density and length, and potentially allows one to make comparisons of feature characteristics among cases. We also present quantitative guidelines for the selection of a sampling periodicity in a heterogeneous nucleus before a cell counting experiment. Sampling periodicity is based upon analysis of computer-generated simulations of the nucleus with features of different sizes; for each feature the probability of Type I (false positives) and Type II (false negatives) errors are examined against one another. Type II error rate is dependent upon feature length and density, acceptable Type I error rate, and sampling periodicity. Feature detection is important for devising sampling strategies in brainstem nuclei.

The spatial distribution of neurons and glia in human cortex based on the poisson distribution.

A method was devised that employs deviations from the Poisson distribution to analyze the spatial arrangement of neurons and glia in human cerebral cortex. A field of randomly distributed points equal in number of a sample field of neuronal or glial cells is generated by computer, and the proportion of cells in the sample field that are closer to the nearest neighboring cells than to the nearest randomly distributed point is determined. We call this proportion the "Poisson ratio." When the cells are randomly distributed, the Poisson ratio is equal to 0.5. If the Poisson ratio is less than 0.5, the cells are farther away from one another than a random distribution would predict (exclusionary pattern); if the Poisson ratio is greater than 0.5, the cells are closer to one another than a random distribution would predict (clustering). A simple nonparametric statistical test is used to determine the significance of differences in the ratios. This method was applied to samples of human cerebral cortex in order to test the hypothesis that patients with schizophrenic psychosis may have an altered pattern of neuronal clustering. The analysis revealed that there is no difference in the nearest-neighbor distribution of either neurons or glia between psychotic patients and controls. It was found, however, that there is a highly significant difference in the spatial distribution of neurons versus glia in human cerebral cortex. Neurons of layers II to VI in the human cortex show greater-than-expected distances among them and are distributed according to an exclusionary pattern, while neurons in layer I show a clustering pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimating the genetic contribution to schizophrenia.

The authors discuss the limitations of the concept of heritability in schizophrenia and, using reported incidence figures, assess two alternatives--the multifactorial and single major locus (SML) models. Both models predict genetic heterogeneity in schizophrenia. For some parameter values, the SML model indicates that homozygotes are rare but at very high risk. According to the multifactorial model, 9.1% of the schizophrenic population has a genetic risk of 99% or more. The authors conclude that neither model adequately accounts for the data but that predictions from both can be used to design sampling procedures which will increase the probability of selecting for study individuals whose illness is highly genetically determined.