Functional disconnection between the visual cortex and right fusiform face area in schizophrenia.

Patients with schizophrenia show impairment in processing faces, including facial affect and face detection, but the underlying mechanisms are unknown. We used functional magnetic resonance imaging (fMRI) to characterize resting state functional connectivity between an independent component analysis (ICA)-defined early visual cortical network (corresponding to regions in V1, V2, V3) and a priori defined face-processing regions (fusiform face area [FFA], occipital face area [OFA], superior temporal sulcus [STS] and amygdala) using dual regression in 20 schizophrenia patients and 26 healthy controls. We also investigated the association between resting functional connectivity and neural responses (fMRI) elicited by a face detection paradigm in a partially overlapping sample (Maher et al., 2016) that used stimuli equated for lower-level perceptual abilities. Group differences in functional connectivity were found in right FFA only; controls showed significantly stronger functional connectivity to an early visual cortical network. Functional connectivity in right FFA was associated with (a) neural responses during face detection in controls only, and (b) perceptual detection thresholds for faces in patients only. The finding of impaired functional connectivity for right FFA (but not other queried domain-specific regions) converges with findings investigating face detection in an overlapping sample in which dysfunction was found exclusively for right FFA in schizophrenia during face detection.

Subunit interactions within the Saccharomyces cerevisiae DNA polymerase epsilon (pol epsilon ) complex. Demonstration of a dimeric pol epsilon.

Saccharomyces cerevisiae DNA polymerase epsilon (pol epsilon) is essential for chromosomal replication. A major form of pol epsilon purified from yeast consists of at least four subunits: Pol2p, Dpb2p, Dpb3p, and Dpb4p. We have investigated the protein/protein interactions between these polypeptides by using expression of individual subunits in baculovirus-infected Sf9 insect cells and by using the yeast two-hybrid assay. The essential subunits, Pol2p and Dpb2p, interact directly in the absence of the other two subunits, and the C-terminal half of POL2, the only essential portion of Pol2p, is sufficient for interaction with Dpb2p. Dpb3p and Dpb4p, non-essential subunits, also interact directly with each other in the absence of the other two subunits. We propose that Pol2p.Dpb2p and Dpb3p.Dpb4p complexes interact with each other and document several interactions between individual members of the two respective complexes. We present biochemical evidence to support the proposal that pol epsilon may be dimeric in vivo. Gel filtration of the Pol2p.Dpb2p complexes reveals a novel heterotetrameric form, consisting of two heterodimers of Pol2p.Dpb2p. Dpb2p, but not Pol2p, exists as a homodimer, and thus the Pol2p dimerization may be mediated by Dpb2p. The pol2-E and pol2-F mutations that cause replication defects in vivo weaken the interaction between Pol2p and Dpb2p and also reduce dimerization of Pol2p. This suggests, but does not prove, that dimerization may also occur in vivo and be essential for DNA replication.

Quantitative characterization of eye tracking dysfunction in schizophrenia.

The purpose of this study was to characterize the nature of the processes that are involved in eye tracking dysfunction (ETD). We identified a combination of quantitative measures that best distinguished qualitatively normal eye tracking from qualitatively abnormal eye tracking, using discriminant analysis. Discriminant scores distinguished schizophrenics with ETD from both schizophrenics with normal eye tracking and normal controls, but did not distinguish schizophrenics with normal eye tracking from normal controls, underscoring the heterogeneity of schizophrenic patients with respect to eye tracking. The results of the discriminant analysis indicated that ETD is a multivariate process involving a primary impairment in the smooth pursuit system characterized by increased catch-up saccades and reduced gain, and, secondarily, disinhibition of intrusive saccades, especially square-wave jerks. Quantitative characterization of ETD makes it possible to consider eye tracking as a quantitative trait in genetic investigations of a multidimensional phenotype.

Contextual insensitivity in schizophrenic language processing: evidence from lexical ambiguity.

The authors investigated whether contextual failures in schizophrenia are due to deficits in the detection of context or the inhibition of contextually irrelevant information. Eighteen schizophrenia patients and 24 nonpsychiatric controls were tested via a cross-modal semantic priming task. Participants heard sentences containing homonyms and made lexical decisions about visual targets related to the homonyms' dominant or subordinate meanings. When sentences moderately biased subordinate meanings (e.g., the animal enclosure meaning of pen), schizophrenia patients showed priming of dominant targets (e.g., paper) and subordinate targets (e.g., pig). In contrast, controls showed priming only of subordinate targets. When contexts strongly biased subordinate meanings, both groups showed priming only of subordinate targets. The results suggest that inhibitory deficits rather than context detection deficits underlie contextual failures in schizophrenia.

Intermittent degradation in performance in schizophrenia.

In a series of repeated trials, schizophrenic patients often fluctuate in performance. Our data suggest that it may be useful, not just to report an increased variance relative to nonschizophrenics, but to model these fluctuations concretely as transitions between a relatively normal and an abnormal cognitive state - an intermittent degradation in performance that may be related to transient abnormalities in CNS functioning. We define 'dialipsis' as a temporary substitution of a less efficient process of task performance. This phenomenon is mentioned in the literature, but the descriptions of dialipsis are heuristic rather than based on a statistical model. We present a mixture model in which the ordinary and degraded states are described by distinct ANOVA structures, each with its own task, subject and interaction effects, with transitions between them occurring at random times. We discuss ways of detecting dialipsis and comparing the mixture model statistically with alternative models.

Analysis of the essential functions of the C-terminal protein/protein interaction domain of Saccharomyces cerevisiae pol epsilon and its unexpected ability to support growth in the absence of the DNA polymerase domain.

As first observed by Wittenberg (Kesti, T., Flick, K., Keranen, S., Syvaoja, J. E., and Wittenburg, C. (1999) Mol. Cell 3, 679-685), we find that deletion mutants lacking the entire N-terminal DNA polymerase domain of yeast pol epsilon are viable. However, we now show that point mutations in DNA polymerase catalytic residues of pol epsilon are lethal. Taken together, the phenotypes of the deletion and the point mutants suggest that the polymerase of pol epsilon may normally participate in DNA replication but that another polymerase can substitute in its complete absence. Substitution is inefficient because the deletion mutants have serious defects in DNA replication. This observation raises the question of what is the essential function of the C-terminal half of pol epsilon. We show that the ability of the C-terminal half of the polymerase to support growth is disrupted by mutations in the cysteine-rich region, which disrupts both dimerization of the POL2 gene product and interaction with the essential DPB2 subunit, suggesting that this region plays an important architectural role at the replication fork even in the absence of the polymerase function. Finally, the S phase checkpoint, with respect to both induction of RNR3 transcription and cell cycle arrest, is intact in cells where replication is supported only by the C-terminal half of pol epsilon, but it is disrupted in mutants affecting the cysteine-rich region, suggesting that this domain directly affects the checkpoint rather than acting through the N-terminal polymerase active site.

Eye-tracking dysfunction and birth-month weather in schizophrenia.

The prevalence of eye-tracking dysfunction (ETD) is significantly elevated in individuals with a diagnosis of schizophrenia and in their nonschizophrenic relatives, suggesting that ETD marks a familial (most likely genetic) risk factor for schizophrenia. Birth in a season with intemperate weather is also a widely reported risk factor for schizophrenia and is particularly marked for the subgroup with no family history of the disorder. This study examined how these two risk factors covaried in 78 patients with a Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; American Psychiatric Association, 1987) diagnosis of schizophrenia. Eye tracking and birth-month weather were independently assessed. As hypothesized, patients without ETD were significantly more likely to be born in months with intemperate weather (both hot and cold) than either patients with ETD or people in the general population. Etiologic factors associated with severe weather near birth may be important sources of nonfamilial schizophrenia.

Psychophysical isolation of a motion-processing deficit in schizophrenics and their relatives and its association with impaired smooth pursuit.

Schizophrenia patients and many of their relatives show impaired smooth pursuit eye tracking. The brain mechanisms underlying this impairment are not yet known, but because reduced open-loop acceleration and closed-loop gain accompany it, compromised perceptual processing of motion signals is implicated. A previous study showed that motion discrimination is impaired in schizophrenia patients. Motion discrimination can make use of position and contrast as well as velocity cues. Here, we report that the motion discrimination deficit, which occurs in both schizophrenic patients and in their first-degree relatives, involves a failure of velocity detection, which appears when judging intermediate target velocities. At slower and faster velocities, judgments of velocity discrimination seemed normal until we experimentally disentangled velocity cues from nonmotion cues. We further report that compromised velocity discrimination is associated with sluggish initiation of smooth pursuit. These findings point to specific central nervous system correlates of schizophrenic pathophysiology.

Dependence of impaired eye tracking on deficient velocity discrimination in schizophrenia.

BACKGROUND: Abnormal smooth pursuit eye movements have been found in many schizophrenic patients and in about 40% of their first-degree biological relatives. A velocity discrimination deficit has also been demonstrated in schizophrenic patients. In this study, we address the relation between deficient velocity discrimination and impaired smooth pursuit eye movements, inasmuch as the brain regions responsible for processing velocity signals are implicated in generating and maintaining smooth pursuit. METHODS: Horizontal eye movements of 15 schizophrenic patients and 8 normal controls were recorded in response to sine wave (predictable) and step-ramp (nonpredictable) targets. Smooth pursuit eye movements were assessed during both the initiation and maintenance periods. Correlations were computed between measures of smooth pursuit (qualitative rating, peak gain, saccade frequency, and initial acceleration) and contrast sensitivity for velocity discrimination. RESULTS: Contrast sensitivity for fine velocity discrimination was significantly correlated both with initial acceleration of smooth pursuit and with peak gain, but was not significantly correlated with saccade frequency and qualitative ratings of pursuit integrity. No significant correlations were found within the normal control group. CONCLUSION: Deficient processing of velocity information seems to be one component that contributes to a dysfunction in the initiation and maintenance of smooth pursuit in schizophrenia.

Motion perception in schizophrenia.

BACKGROUND: Eye-tracking dysfunction has been found in many patients with schizophrenia and in about 40% of their first-degree biological relatives. We hypothesized that a deficit in motion processing is associated with eye-tracking dysfunction because both motion signals and the brain regions responsible for processing motion signals are implicated in the generation of smooth pursuit. We examined several aspects of visual perception, including motion perception, in patients with schizophrenia. METHODS: To evaluate motion perception, contrast sensitivity for velocity discrimination was measured in patients with schizophrenia (n=15) and normal control subjects (n=18). Contrast sensitivities for orientation discrimination and contrast detection were measured as control tasks. RESULTS: Patients with schizophrenia showed significantly lower contrast sensitivity (ie, higher thresholds) than normal controls for the discrimination of small velocity differences (eg, 11 vs 9 degrees/s). This reduction in contrast sensitivity was severe (up to 10-fold) in about 40% of the patients. No group differences were found on the other tasks. CONCLUSION: The discrimination of small velocity differences is impaired in a subgroup of patients with schizophrenia.

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.

Role of the putative zinc finger domain of Saccharomyces cerevisiae DNA polymerase epsilon in DNA replication and the S/M checkpoint pathway.

It has been proposed that C-terminal motifs of the catalytic subunit of budding yeast polymerase (pol) epsilon (POL2) couple DNA replication to the S/M checkpoint (Navas, T. A., Zheng, Z., and Elledge, S. J. (1995) Cell 80, 29-39). Scanning deletion analysis of the C terminus reveals that 20 amino acid residues between two putative C-terminal zinc fingers are essential for DNA replication and for an intact S/M cell cycle checkpoint. All mutations affecting the inter-zinc finger amino acids or the zinc fingers themselves are sensitive to methylmethane sulfonate and have reduced ability to induce RNR3, showing that the mutants are defective in the transcriptional response to DNA damage as well as the cell cycle response. The mutations affect the assembly of the pol epsilon holoenzyme. Two-hybrid assays show that the POL2 subunit interacts with itself, and that the replication and checkpoint mutants are specifically defective in the interaction, suggesting (but not proving) that direct or indirect dimerization may be important for the normal functions of pol epsilon. The POL2 C terminus is sufficient for interaction with DPB2, the essential and phylogenetically conserved subunit of pol epsilon, but not for interaction with DPB3. Neither Dpb3p nor Dpb2p homodimerizes in the two-hybrid assay.

Inverse relationship of perinatal complications and eye tracking dysfunction in relatives of patients with schizophrenia: evidence for a two-factor model.

OBJECTIVE: Because both smooth pursuit eye tracking dysfunction and obstetrical complications are significant risk factors for schizophrenia, the authors tested the predictions of a two-factor model of how eye tracking dysfunction and obstetrical complications covary in patients with schizophrenia, their siblings, and comparison subjects. METHOD: Psychiatric diagnoses, eye tracking dysfunction, and obstetrical complications noted in birth records were independently assessed in 18 patients with schizophrenia, 16 of their siblings without schizophrenia, and 49 comparison subjects with neither personal nor family histories of schizophrenia. RESULTS: As hypothesized, 1) the combination of eye tracking dysfunction and perinatal obstetrical complications discriminated patients with schizophrenia significantly from subjects without schizophrenia, including siblings of patients with schizophrenia, and 2) eye tracking dysfunction and perinatal obstetrical complications manifested a significant inverse association in the nonschizophrenic siblings of patients with schizophrenia. CONCLUSIONS: These results support a two-factor model in which obstetrical complications often interact with genetic liability, indicated by eye tracking dysfunction, to produce schizophrenia.

Thought disorder in adolescent-onset schizophrenia.

The nature of the thinking disturbances found in adolescent-onset psychotic conditions is not as well-characterized as the thought disorders found in adult psychotic patients. We used the Thought Disorder Index to examine whether schizophrenic patients in whom psychotic symptoms appear in adolescence show the same characteristic features of thought disorder as do adult schizophrenics. Quantitative and qualitative features of thought disorder were assessed in psychiatric inpatients with adolescent-onset schizophrenia, psychotic depression, and nonpsychotic conditions compared with normal control adolescents. Elevated thought disorder occurred in all groups of adolescents hospitalized for an acute episode of psychiatric illness. The magnitude of the elevation and the frequency of occurrence of disordered thinking were greatest in the psychotic adolescents. The qualitative features of the thought disturbances found in the schizophrenic adolescents were distinct from those observed in adolescents with psychotic depression. The thinking of the schizophrenic adolescents resembled that of adult schizophrenics. In both conditions thought disorder is characterized by idiosyncratic word usage, illogical reasoning, perceptual confusion, loss of realistic attunement to the task, and loosely related ideas.

Thought disorder, perceptual aberrations, and schizotypy.

Empirical links between schizophrenia and schizotypic psychopathology were examined. The Perceptual Aberration Scale (PerAb; L. J. Chapman, J. O. Chapman, & M. L. Raulin, 1978) was used to identify putative schizotypic individuals and a contrast group of nonschizotypic controls. The Thought Disorder Index (TDI; M. J. Coleman et al., 1993) was used to quantify and classify thought disorder in these individuals. High PerAb participants, selected for having an increased number of self-reported perceptual and body image aberrations, showed an elevation in the amount and frequency of thought disorder as well as an increased number of idiosyncratic verbalizations. This supports the hypothesis that psychometrically identified schizotypic individuals display thought disorder similar to that shown by schizophrenic patients and some of their 1st-degree relatives, suggesting that there is a relation between schizotypic psychopathology, as tapped by the PerAb scale, and clinical schizophrenia.

Hantavirus pulmonary syndrome. Outbreak of a new disease caused by a new virus.

Only months after the first report of a brief prodromal illness followed by rapidly progressive noncardiogenic pulmonary edema and death, the causative agent was tentatively identified as a previously unknown hantavirus. Although hantaviral infections are well known in Asia, none had ever been reported in the United States. A collaborative effort between local, state, regional, and federal authorities allowed rapid identification of a new set of clinical and laboratory findings, now known as the hantavirus pulmonary syndrome. Inclusion, exclusion, and confirmatory criteria have been established to help identify potential cases. However, tests for the infection are still experimental, so physicians should send samples to the Centers for Disease Control and Prevention for testing in suspected cases. Ribavirin (Virazole) may be beneficial early in the course of hantavirus pulmonary syndrome, and supportive care is essential. Rodents, particularly the deer mouse in the Southwest, are the natural hosts for the hantaviruses. Prevention of this new syndrome centers on avoidance of contact with and inhalation of saliva, urine, and feces of infected rodents.

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.

Season of birth and obstetrical complications in schizophrenics.

Many studies indicate that both obstetrical complications (OCs) and birth in winter or early spring are risk factors for schizophrenia, but few studies have examined how these risk factors covary in the same subjects. We assessed pre- and perinatal OCs, while blind to diagnosis, using medical data recorded at the time of subjects' births, in 29 probands with DSM-III schizophrenia or schizoaffective disorder and 39 of their unaffected adult sibs. Pre- and perinatal OCs were both significantly more common in probands than sibs. Schizophrenics not born during the winter or early spring had significantly more total and perinatal OCs than schizophrenics born in other months, but did not differ for prenatal OCs. Results indicate that OCs increase risk for schizophrenia, but also suggest the possibility that the impact of OCs on this risk may be affected by season of birth.