Thought Disorder in Schizophrenia and Bipolar Disorder Probands, Their Relatives, and Nonpsychiatric Controls.

Thought disorder (TD) has long been associated with schizophrenia (SZ) and is now widely recognized as a symptom of mania and other psychotic disorders as well. Previous studies have suggested that the TD found in the clinically unaffected relatives of SZ, schizoaffective and bipolar probands is qualitatively similar to that found in the probands themselves. Here, we examine which quantitative measures of TD optimize the distinction between patients with diagnoses of SZ and bipolar disorder with psychotic features (BP) from nonpsychiatric controls (NC) and from each other. In addition, we investigate whether these same TD measures also distinguish their respective clinically unaffected relatives (RelSZ, RelBP) from controls as well as from each other. We find that deviant verbalizations are significantly associated with SZ and are co-familial in clinically unaffected RelSZ, but are dissociated from, and are not co-familial for, BP disorder. In contrast, combinatory thinking was nonspecifically associated with psychosis, but did not aggregate in either group of relatives. These results provide further support for the usefulness of TD for identifying potential non-penetrant carriers of SZ-risk genes, in turn enhancing the power of genetic analyses. These findings also suggest that further refinement of the TD phenotype may be needed in order to be suitable for use in genetic studies of bipolar disorder.

Bipolar and schizophrenic patients differ in patterns of visual motion discrimination.

BACKGROUND: Since Kraepelin's early distinction between bipolar disorder and schizophrenia, it has been assumed that these disorders represent two different pathophysiological processes, although they share many clinical symptoms. Previous studies showed that velocity discrimination, a sensitive psychophysiological measure of the visual motion system, is deficient in schizophrenia. Here we examined whether the motion processing impairment found in schizophrenia also occurs in bipolar disorder. METHODS: We compared 16 bipolar patients, 25 schizophrenic patients, and 25 normal controls on a velocity discrimination task. We measured the psychophysical threshold for velocity discrimination and contrast detection (as a control task) in all subjects. RESULTS: Bipolar patients showed normal velocity discrimination thresholds at intermediate velocities, the range in which velocity cues dominate velocity discrimination, and at low velocities. Schizophrenic patients, however, showed elevated velocity discrimination thresholds at intermediate and low velocities. At higher velocities, both bipolar and schizophrenic patients showed elevated thresholds. All subjects showed normal contrast detection thresholds. CONCLUSIONS: Normal velocity discrimination in the intermediate range of velocity indicates unimpaired motion processing in bipolar disorder. The abnormal velocity discrimination of both schizophrenic and bipolar patients at higher velocities may reflect impaired temporal processing rather than impaired motion processing per se. These results suggest that the pathophysiological processes of bipolar disorder and schizophrenia diverge at the stage of visual motion processing, a sensory component mediated primarily in the extrastriate cortex.

Aging and visual motion discrimination in normal adults and schizophrenia patients.

Motion perception is impaired in many neuropathological conditions, including schizophrenia. Motion perception also declines in the course of normal aging. In this study, we ask whether aging is an additive factor in the motion-discrimination deficits of schizophrenia patients. We examined motion perception in schizophrenia patients (n=44) and non-psychiatric controls (n=40) whose ages ranged from 18 to 55. The tasks included velocity discrimination and contrast detection. Thresholds for each of the two tasks were determined for each subject using psychophysical methods. Schizophrenia patients showed significantly increased thresholds (degraded performance) for velocity discrimination compared with the controls. Degraded performance in patients was not related to age. In controls, however, velocity discrimination thresholds were significantly increased beginning by age 45. Performance on a contrast-detection task, which does not require precise discrimination of motion signals, was not significantly affected by age in either group. Aging, even in its early stages, degrades motion discrimination in normal adults. Aging, however, does not adversely affect motion-discrimination deficits in schizophrenia patients through age 55. A similar motion-discrimination deficit in schizophrenia patients and aging normal adults suggests that the mechanisms underlying motion processing in schizophrenia and normal aging may be associated.

Visual motion integration in schizophrenia patients, their first-degree relatives, and patients with bipolar disorder.

Many schizophrenia patients show degraded detection of coherent motion. This visual deficit may (1) be a consequence of having a specifically schizophrenic psychosis, (2) be a non-specific effect of suffering from a severe illness (i.e., "generalized deficit"), or (3) reflect properties of the visual motion processing system that play an antecedent, possibly causal role in the pathophysiology of a disposition to schizophrenia. To distinguish among these possibilities, we measured the accuracy of detecting the direction of coherent motion in 29 schizophrenia patients, 20 first-degree relatives of schizophrenia patients, 19 patients with bipolar disorder and 33 normal controls. The task requires the integration of dynamic signals from stochastic random dot patterns in order to discern the direction of their motion. Schizophrenia patients, as a group, showed significantly elevated thresholds for detecting the direction of coherent motion, but relatives of schizophrenia patients and patients with bipolar disorder did not differ from normal controls on this task. The results indicate that visual motion integration, normally mediated in motion-sensitive brain areas such as the Middle Temporal Area, is impaired in patients with a clinically manifest schizophrenic psychosis, but is intact in patients with a non-schizophrenic psychosis (bipolar disorder) and in the relatives of schizophrenia patients. Our findings suggest that deficiencies in integrating motion signals, while specific for schizophrenia, do not seem to be a co-familial trait.

Intact hemispheric specialization for spatial and shape working memory in schizophrenia.

OBJECTIVE: Using functional MRI, we investigated whether, like healthy subjects, patients with schizophrenia show a relative hemispheric specialization in ventrolateral prefrontal cortex (PFC) for spatial and shape working memory (WM). We hypothesized that reduced specialization in schizophrenia would reflect a failure to adopt optimal domain-specific strategies and would contribute to WM deficits. METHODS: Twelve healthy subjects and 16 schizophrenia patients performed spatial and shape WM tasks and a non-WM control task. Direct comparisons of the spatial and shape WM tasks assessed specialization. RESULTS: Despite deficient WM performance, both patients and controls showed a relative hemispheric specialization in ventrolateral PFC for spatial (right) and shape (left) WM and did not differ in this regard. CONCLUSIONS: The finding of intact hemispheric specialization in ventrolateral PFC suggests that patients employ the same domain-specific strategies as healthy subjects during spatial and shape WM. Rather than reflecting a failure to adopt the optimal strategy, we hypothesize that WM deficits in schizophrenia reflect impairments of executive processes that are required for WM performance regardless of domain. These processes are associated with activity in the dorsolateral PFC, a region that has been repeatedly implicated in studies of WM.

Quantitative Measures of Craniofacial Dysmorphology in a Family Study of Schizophrenia and Bipolar Illness.

Several laboratories, including ours, have reported an overrepresentation of craniofacial (CF) anomalies in schizophrenia (SZ). How might this dysmorphology arise in a brain-based disorder? Because the brain and face derive from shared embryologic primordia and morphogenetic forces, maldevelopmental processes may result in both CF and brain dysmorphology.Our approach is 2-pronged. First, we have employed, for the first time in the study of psychiatric disorders, objective measures of CF morphology that utilize an extensive normative database, permitting computation of standardized scores for each subject. Second, we have rendered these findings biologically interpretable by adopting principles of embryology in the analysis of dysmorphology.Dependent measures in this investigation focused on derivatives of specific embryonic primordia and were contrasted among probands with psychotic disorders, their first-degree relatives, and normal controls (NC). Subject groups included patients with a diagnosis of SZ (N = 39) or bipolar (BP) disorder with psychotic features (N = 32), their clinically unaffected relatives (N = 82 and N = 41, respectively), and NC (N = 95) subjects.Anomalies involving derivatives of frontonasal and mandibular embryonic primordia showed a clear association with psychotic illness, as well as familial aggregation in relatives in both diagnostic groups. In contrast, one class of CF anomalies emerged only among SZ probands and their first-degree relatives: dysmorphology arising along the junction of the frontonasal and maxillary prominence derivatives, manifested as marked asymmetries. This class was not overrepresented among the BP patients nor among their relatives, indicating that this dysmorphology appears to be specific to SZ and not a generalized feature of psychosis. We discuss these findings in light of embryologic models that relate brain regions to specific CF areas.

Compromised late-stage motion processing in schizophrenia.

BACKGROUND: Visual motion processing is compromised in schizophrenia, as shown in deficient velocity discrimination. Processing of motion signals comprises progressive stages along the geniculate-striate-extrastriate-cortex pathway. Based on neurophysiologic and brain lesion studies, a velocity discrimination deficit can implicate early-stage motion processing if it is contrast-dependent or late-stage motion processing if it is contrast-independent. METHODS: To determine which stage underlies the deficient velocity discrimination in schizophrenia, we examined the effects of visual contrast on velocity discrimination. We measured velocity discrimination thresholds in schizophrenia patients (n = 34) and normal control subjects (n = 17) at both low and high contrasts, using each subject's contrast detection threshold to equate contrast levels. RESULTS: Schizophrenia patients showed poor velocity discrimination that improved little with high contrast, whereas normal control subjects showed enhanced velocity discrimination with increased contrast. CONCLUSIONS: The finding that the velocity discrimination deficit in schizophrenia is independent of contrast modulation implicates the later, rather than the earlier, stages of motion processing, which is mediated in the extrastriate cortex.

Effects of typical, atypical, and no antipsychotic drugs on visual contrast detection in schizophrenia.

OBJECTIVE: Visual contrast detection has been reported in some studies to be normal in schizophrenia patients, but in other studies impairments have been reported. Because contrast detection in the visual processing system is mediated by dopamine, and because the pharmacotherapy of schizophrenia involves blocking dopamine postsynaptic receptor sites, the authors investigated the effects of dopamine-blocking antipsychotic drugs on visual contrast detection in schizophrenia. METHOD: Visual contrast detection thresholds were measured in healthy subjects and schizophrenia patients receiving typical and atypical antipsychotic drugs; a two-alternative, forced-choice psychophysical method was used. Also included were six patients receiving no antipsychotic treatment as well as clinically unaffected first-degree relatives of the schizophrenia patients. RESULTS: Patients receiving atypical antipsychotic drugs showed unimpaired visual contrast detection, those given typical antipsychotic drugs exhibited higher visual contrast detection thresholds, and the unmedicated schizophrenic patients showed visual contrast detection thresholds significantly below those of healthy subjects. CONCLUSIONS: Dopamine modulation via D(2) receptor blockade affects sensory processes in schizophrenia, shifting visual contrast detection from hypersensitivity in the unmedicated state to normal and even to hyposensitive levels. Thus, antipsychotic drug treatment may account for the inconsistent reports concerning visual contrast detection in schizophrenia.

Visual and cognitive control of attention in smooth pursuit.

In this chapter, we describe the role of attention in the control of smooth pursuit eye movements. As a voluntary and continuous eye movement, smooth pursuit is driven by both visual and cognitive signals. Here we show that whereas the entire process of smooth pursuit requires visual attention, the post-onset phase of the initiation and the maintenance smooth pursuit are under an additional sustained non-visual cognitive attention control. The temporal dynamics of these complementary controls of visual and non-visual cognitive attention support the continuous generation of smooth pursuit so that eye tracking of a moving target can be prompt and accurate.

Transitive inference in schizophrenia: impairments in relational memory organization.

Transitive inference (TI) describes a fundamental operation of relational (e.g., explicit) memory organization [Eichenbaum, H., Cohen, N.J., 2001. From Conditioning to Conscious Recollection: Memory Systems of the Brain. Oxford Univ. Press]. Here we investigate TI in schizophrenia (SZ), a neurocognitive disorder associated with explicit but not implicit memory dysfunction. SZ patients and healthy controls were trained on a series of learned discriminations that were hierarchically organized (A>B, B>C, C>D, and D>E). They were then tested on each training pair and two novel "inference" pairs: AE, which can be evaluated without consideration of hierarchical relations, and BD, which can only be evaluated by hierarchical relations. SZ patients and controls successfully learned the training pairs and correctly responded to the nonrelational AE pairs. However, SZ patients were less accurate than controls in responding to the relational BD pairs, consistent with the hypothesis that higher-level memory processes associated with relational memory organization are impaired in SZ. The results are discussed with respect to the relational memory model and candidate neuro-cognitive mechanisms of TI.

Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis.

Poor performance on the antisaccade (AS) task has been interpreted as a potential indicator of genetic liability that may enhance the power of linkage studies of a multidimensional phenotype for schizophrenia. Every study has replicated the finding of significantly worse performance in schizophrenia patients regardless of which specific antisaccade paradigm was employed. In some studies involving a standard version of the antisaccade task, relatives of schizophrenia patients made an increased number of errors, but in other studies that used this same paradigm, relatives of schizophrenia patients did not differ from controls. In this paper, we report the results of a meta-analysis on studies that used the standard antisaccade paradigm. The meta-analysis shows that those studies that reported large effect sizes and statistically significant differences between relatives of schizophrenia patients and controls used inclusion/exclusion criteria that were not symmetrical between the two groups, whereas those studies that reported small and nonsignificant differences between relatives of schizophrenia patients and controls used symmetrical inclusion/exclusion criteria. Specifically, studies that applied stricter psychopathology exclusion criteria to controls than to relatives of schizophrenia patients had larger effect sizes than studies that applied comparable exclusion criteria to both groups, suggesting that antisaccade performance is compromised by psychopathology in general rather than by schizophrenia per se. Since symmetrical inclusion/exclusion criteria between relatives of schizophrenia patients and controls are essential for a genetic analysis, and those studies that did apply symmetrical criteria had small effect sizes, the available data suggest that poor antisaccade performance is unlikely to be useful in identifying clinically unaffected carriers of genes for schizophrenia.

Antisaccade performance is abnormal in schizophrenia patients but not in their biological relatives.

Numerous studies have replicated the finding that schizophrenia patients make an increased number of errors on an antisaccade task. Some studies have reported that relatives of schizophrenia patients also make an increased number of antisaccade errors, a finding that has been interpreted to support the usefulness of compromised antisaccade performance as an index of genetic liability for schizophrenia. We examined performance on an antisaccade task in schizophrenia patients, nonpsychiatric controls, first-degree relatives of schizophrenia patients and first-degree relatives of nonpsychiatric controls. Schizophrenia patients made significantly more errors than did nonpsychiatric controls, but relatives of schizophrenia patients did not differ from relatives of controls or from all controls. Increased antisaccade errors on the standard version of the antisaccade task are associated with schizophrenia, but do not seem to be a co-familial trait for schizophrenia.

Idiom processing in schizophrenia: literal implausibility saves the day for idiom priming.

Schizophrenia patients have difficulty processing nonliteral forms of discourse such as idiomatic expressions. We hypothesized that schizophrenia patients would show impaired idiom processing for literally plausible idioms (e.g., kick the bucket) but not for literally implausible idioms (e.g., be on cloud nine). Thirty-two patients and 36 controls listened to sentences containing literally plausible and implausible idioms and made lexical decisions about idiom-related or literal-related targets. Schizophrenia patients showed reduced priming for literally plausible idioms but intact priming for literally implausible idioms compared with controls. Both groups showed evidence of literal word priming. These results are consistent with the notion that schizophrenia patients make normal use of context under conditions that minimize the need for controlled processing.

Spatial and object working memory impairments in schizophrenia patients: a Bayesian item-response theory analysis.

This study reports evidence that schizophrenia patients are significantly impaired in both spatial and object (shape) working memory. A 3-s delay between exposure and recall of targets was used and Bayesian item-response theory was applied to compensate for the tasks' differential difficulty while simultaneously taking account of missing data from participant attrition. Weaker evidence was found that in schizophrenia both domains are equally impaired on average, that spatial and object working memory appear to be more highly correlated with each other in the schizophrenia population than in the normal population, and that schizophrenia patients show greater variability in spatial than object working memory performance.

Differential activation patterns of occipital and prefrontal cortices during motion processing: evidence from normal and schizophrenic brains.

Visual motion perception is normally mediated by neural processing in the posterior cortex. Focal damage to the middle temporal area (MT), a posterior extrastriate region, induces motion perception impairment. It is unclear, however, how more broadly distributed cortical dysfunction affects this visual behavior and its neural substrates. Schizophrenia manifests itself in a variety of behavioral and perceptual abnormalities that have proved difficult to understand through a dysfunction of any single brain system. One of these perceptual abnormalities involves impaired motion perception. Motion processing provides an opportunity to clarify the roles of multiple cortical networks in both healthy and schizophrenic brains. Using fMRI, we measured cortical activation while participants performed two visual motion tasks (direction discrimination and speed discrimination) and one nonmotion task (contrast discrimination). Normal controls showed robust cortical activation (BOLD signal changes) in MT during the direction and speed discrimination tasks, documenting primary processing of sensory input in this posterior region. In patients with schizophrenia, cortical activation was significantly reduced in MT and significantly increased in the inferior convexity of the prefrontal cortex, an area that is normally involved in higher level cognitive processing. This shift in cortical responses from posterior to prefrontal regions suggests that motion perception in schizophrenia is associated with both deficient sensory processing and compensatory cognitive processing. Furthermore, this result provides evidence that in the context of broadly distributed cortical dysfunction, the usual functional specificity of the cortex becomes modified, even across the domains of sensory and cognitive processing.

The antisaccade task and neuropsychological tests of prefrontal cortical integrity in schizophrenia: empirical findings and interpretative considerations.

To date, every published study of the antisaccade task has replicated the finding that schizophrenia patients make an increased number of errors. This finding has been interpreted as support for frontal and/or basal ganglia dysfunction in schizophrenia, primarily because neurological patients with pathology in these brain regions also make large numbers of errors on the antisaccade task. Here, we compared the performance of schizophrenia patients and nonpsychiatric controls on an antisaccade task and on two neuropsychological tests, the Wisconsin Card Sorting Test, which is assumed to tap frontal lobe functioning, and the interference condition of the Stroop Test, which is thought to tap dorsolateral prefrontal cortex/anterior cingulate functioning. We examined the pattern of intercorrelations among these tasks. Schizophrenia patients made significantly more errors on the antisaccade task, made more perseverative errors and achieved fewer categories on the Wisconsin Card Sorting Test, and were significantly slower during the interference condition of the Stroop Test than were nonpsychiatric controls. Antisaccade errors were significantly correlated with interference performance on the Stroop in schizophrenia patients and in controls, but were not significantly correlated with the measures of Wisconsin Card Sorting Test performance in either group. The pattern of intercorrelation suggests that these tasks should not be thought of as representing a unitary variable of "frontal cortical integrity". Although aspects of these tasks tap the ability to inhibit prepotent responses, each task is also behaviorally complex. The multifaceted nature of these tasks makes it difficult to isolate which brain regions are part of the network underlying the specific act of inhibiting a prepotent response (for example, the reflexive saccade toward the novel peripheral target) and which regions participate in aspects of task performance that are related to non-inhibitory components (for example, executing an antisaccade). A broadly distributed network is undoubtedly involved in both processes. Parsing the various components of cognitively complex tasks may help to clarify both the specific behaviors that are anomalous and their underlying neural substrates. We also address the complexity of inferring localized brain dysfunction in schizophrenia patients based on seemingly analogous behavioral deficits in neurological populations.

Permutation tests for detecting and estimating mixtures in task performance within groups.

We propose a two-sample permutation test incorporating mixture models as a general tool for detecting and quantifying effects on task performance. We illustrate the proposed method with examples where the dependent measures under investigation are recorded for normal controls and relatives of patients with schizophrenia on a delayed response, spatial and object working memory task. Our mixture modelling in relatives allows the component distributions to arise from different continuous parametric families. We also investigate the effects of the within-family correlation and the prior distribution of the mixing proportion on the test results. The power of the test depends on sample sizes, the mixing proportion, the difference in component means and the ratio of component variances.

Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: additional evidence.

Establishing the genetics of physiological traits associated with schizophrenia may be an important first step in building a neurobiological bridge between the disease phenotype and its genetic underpinnings. One of the best known of the traits associated with schizophrenia is a disorder of smooth pursuit eye tracking (ETD), which is present in 50-80% of schizophrenia patients. ETD is more than three times more prevalent in the families of a schizophrenia patient than is schizophrenia itself. Arolt et al. [1999] estimated LOD scores for ETD of 2.85 for D6S282 and 3.70 for D6S271, two markers on 6p21.1, as well as obtaining an indication of possible linkage for schizophrenia. Our sample comprised two large families in Denmark. Markers in the region that was implicated by the study of Arolt et al. [1996, 1999] were analyzed as part of a genome scan using the "latent trait (L.T.) model" for the co-transmission of schizophrenia and ETD that we had previously fitted to segregation analysis data from Norway. We obtained a LOD score of 2.05 for D6S1017, a marker within 3 cM of the positive markers obtained by Arolt et al. [1996, 1999]. We regard our results as independent evidence supporting the findings of Arolt et al. [1996, 1999] and also as support for the L.T. model as a way of combining the traits ETD and schizophrenia.

Hemispheric specialization of the lateral prefrontal cortex for strategic processing during spatial and shape working memory.

OBJECTIVE: We investigated whether spatial working memory (WM) is associated with functional specialization of the right prefrontal cortex (PFC) relative to WM for shapes. We designed spatial and shape WM tasks that are relatively easy to perform and that minimize both task-switching and manipulation demands. The tasks use identical stimuli and require the same motor response. METHODS: We presented 12 subjects with target shapes that appeared in particular locations. Subjects maintained either the location or the shape of the targets in WM and responded to each probe by indicating whether it was a target. During a non-WM control task, subjects indicated whether the probe appeared on the right or left side of the screen. Subjects were scanned with a 3.0 T Siemens scanner and data were analyzed using SPM99. The WM tasks were compared to identify PFC activation that was different for spatial versus shape WM. Each WM task was also compared to the control task. RESULTS: compared with shape WM, spatial WM performance was faster and more accurate and was associated with increased right ventrolateral and frontopolar PFC activation. In contrast, compared to spatial WM, shape WM was associated with increased left ventrolateral PFC activity. CONCLUSIONS: These findings demonstrate hemispheric specialization for spatial versus shape WM in the ventrolateral PFC. The increased activity in the right PFC for spatial WM cannot be attributed to increased task difficulty, the stimuli used, or the response requirements. Rather, we propose that differences in performance and activation reflect the use of configural processing strategies for spatial WM.