Although meta-analyses suggest that schizophrenia (SZ) is associated with a more severe neurocognitive phenotype than mood disorders such as bipolar disorder, considerable between-subject heterogeneity exists in the phenotypic presentation of these deficits across mental illnesses. Indeed, it is unclear whether the processes that underlie cognitive dysfunction in these disorders are unique to each disease or represent a common neurobiological process that varies in severity. Here we used latent profile analysis (LPA) across 3 distinct cognitive domains (cognitive control, episodic memory, and visual integration; using data from the CNTRACS consortium) to identify distinct profiles of patients across psychotic illnesses. LPA was performed on a sample of 223 psychosis patients (59 with Type I bipolar disorder, 88 with SZ, and 76 with schizoaffective disorder). Seventy-three healthy control participants were included for comparison but were not included in sample LPA. Three latent profiles ("Low," "Moderate," and "High" ability) were identified as the underlying covariance across the 3 domains. The 3-profile solution provided highly similar fit to a single continuous factor extracted by confirmatory factor analysis, supporting a unidimensional structure. Diagnostic ratios did not significantly differ between profiles, suggesting that these profiles cross diagnostic boundaries (an exception being the Low ability profile, which had only one bipolar patient). Profile membership predicted Brief Psychiatric Rating Scale and Young Mania Rating Scale symptom severity as well as everyday communication skills independent of diagnosis. Biological, clinical and methodological implications of these findings are discussed.

Background: In recent years, psychiatry research has increasingly focused on understanding mental illnesses from a cross-diagnostic, dimensional perspective in order to better align their neurocognitive features with underlying neurobiological mechanisms. In this multi-site study, we examined two measures of cognitive control (d-prime context and lapsing rate) during the Dot Probe Expectancy (DPX) version of the AX-Continuous Performance Task in patients with either schizophrenia (SZ), schizoaffective disorder (SZ-A), or Type I bipolar disorder (BD) as well as healthy control (HC) subjects. We hypothesized significantly lower d-prime context and higher lapsing rate in SZ and SZ-A patients and intermediate levels in BD patients relative to HC. Methods: 72 HC, 84 SZ, 77 SZ-A, and 58 BD patients (ages 18-56) were included in the final study sample. Results: Significant main effects of diagnosis were observed on d-prime context (F(3,279) = 9.59, p < 0.001) and lapsing (F(3,279) = 8.08, p < 0.001). A priori linear contrasts suggesting intermediate dysfunction in BD patients were significant (p < 0.001), although post-hoc tests showed the BD group was only significantly different from HC on d-prime context. Group results for d-prime context remained significant after covarying for lapsing rate. Primary behavioral measures were associated with mania and disorganization symptoms as well as everyday functioning. Conclusions: These findings suggest a continuum of dysfunction in cognitive control (particularly d-prime context) across diagnostic categories in psychiatric illness. These results further suggest that lapsing and d-prime context, while related, make unique contributions towards explaining deficits in cognitive control in these disorders. (C) 2019 Elsevier B.V. All rights reserved.

BACKGROUND Working memory (WM) has been a central focus of cognitive neuroscience research because WM is a resource that is involved in many different cognitive operations. The goal of this study was to evaluate the clinical utility of WM paradigms developed in the basic cognitive neuroscience literature, including methods designed to estimate storage capacity without contamination by lapses of attention. METHODS A total of 61 people with schizophrenia, 49 with schizoaffective disorder, 47 with bipolar disorder with psychosis, and 59 healthy volunteers were recruited. Participants received multiple WM tasks, including two versions each of a multiple Change Detection paradigm, a visual Change Localization paradigm, and a Running Span task. RESULTS Healthy volunteers performed better than the combined patient group on the visual Change Localization and running span measures. The multiple Change Detection tasks provided mixed evidence about WM capacity reduction in the patient groups, but a mathematical model of performance suggested that the patient groups differed from controls in their rate of attention lapsing. The 3 patient groups performed similarly on the WM tasks. Capacity estimates from the Change Detection and Localization tasks showed significant correlations with functional capacity and functional outcome. CONCLUSIONS The patient groups generally performed in a similarly impaired fashion across tasks, suggesting that WM impairment and attention lapsing are general features of psychotic disorders. Capacity estimates from the Change Localization and Detection tasks were related to functional capacity and outcome, suggesting that these methods may be useful in a clinical context.

Motivational and hedonic impairments are core features of a variety of types of psychopathology. An important aspect of motivational function is reinforcement learning (RL), including implicit (i.e., outside of conscious awareness) and explicit (i.e., including explicit representations about potential reward associations) learning, as well as both positive reinforcement (learning about actions that lead to reward) and punishment (learning to avoid actions that lead to loss). Here we present data from paradigms designed to assess both positive and negative components of both implicit and explicit RL, examine performance on each of these tasks among individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis, and examine their relative relationships to specific symptom domains transdiagnostically. None of the diagnostic groups differed significantly from controls on the implicit RL tasks in either bias toward a rewarded response or bias away from a punished response. However, on the explicit RL task, both the individuals with schizophrenia and schizoaffective disorder performed significantly worse than controls, but the individuals with bipolar did not. Worse performance on the explicit RL task, but not the implicit RL task, was related to worse motivation and pleasure symptoms across all diagnostic categories. Performance on explicit RL, but not implicit RL, was related to working memory, which accounted for some of the diagnostic group differences. However, working memory did not account for the relationship of explicit RL to motivation and pleasure symptoms. These findings suggest transdiagnostic relationships across the spectrum of psychotic disorders between motivation and pleasure impairments and explicit RL.

The goal of the current study was to examine the relationships between insight and both cognitive function and depression in schizophrenia and schizoaffective disorder, and to determine if there were similar relationships across diagnostic categories. We examined discrepancies between self and informant reports of function on the Specific levels of function scale as a metric of insight for interpersonal, social acceptance, work and activities. We examined two samples of individuals with schizophrenia and/or schizoaffective disorder (Ns of 188 and 67 respectively). In Sample 1, cognition was measured using the Dot Probe Expectancy Task. In Sample 2, cognition was measured by averaging several subtests from the MATRICS consensus cognitive battery, as well as additional measures of working memory. In both samples, depression was measured using the Brief Psychiatric Rating Scale. In both samples, we found significant relationships between worse cognition and overestimations of work function, as well as between higher depression levels and underestimation of interpersonal function. These relationships were specific to interpersonal and work function, with significantly stronger correlations with interpersonal and work function compared to the other areas of function. Similar results were found across diagnostic categories. These results have important implications for treatment planning, as they suggest the need to take into account depression and cognitive function when evaluating the patient's self-report of function, and highlight the utility of informant reports in evaluating function and treatment planning. Further, they add to the literature on the similarity across schizophrenia and schizoaffective disorder in a variety of pathological mechanisms.

Executive function is an important concept in neuropsychological and cognitive research, and is often viewed as central to effective clinical assessment of cognition. However, the construct validity of executive function tests is controversial. The switching, inhibition, and updating model is the most empirically supported and replicated factor model of executive function (Miyake et al., 2000). To evaluate the relation between executive function constructs and nonexplicitly executive cognitive constructs, we used confirmatory factor reanalysis guided by the comprehensive Cattell-Horn-Carroll (CHC) model of cognitive abilities. Data from 7 of the best studies supporting the executive function model were reanalyzed, contrasting executive function models and CHC models. Where possible, we examined the effect of specifying executive function factors in addition to the CHC factors. The results suggested that little evidence is available to support updating as a separate factor from general memory factors; that inhibition does not separate from general speed; and that switching is supported as a narrow factor under general speed, but with a more restricted definition than some clinicians and researchers have conceptualized. The replicated executive function factor structure was integrated with the larger body of research on individual difference in cognition, as represented by the CHC model.

Goal maintenance is an aspect of cognitive control that has been identified as critical for understanding psychopathology according to criteria of the NIMH-sponsored CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) and Research Domain Criteria (RDoC) initiatives. CNTRICS proposed the expectancy AX-CPT, and its visual-spatial parallel the dot probe expectancy (DPX), as valid measures of the cognitive and neural processes thought to be relevant for goal maintenance. The goal of this study was to specifically examine the functional neural correlates and connectivity patterns of both goal maintenance tasks in the same subset of subjects to further validate their neural construct validity and clarify our understanding of the nature and function of the neural circuitry engaged by the tasks. Twenty-six healthy control subjects performed both the letter (AX) and dot pattern (DPX) variants of the CPT during fMRI. Behavioral performance was similar between tasks. The 2 tasks engaged the same brain networks including dorsolateral prefrontal cortex (DLPFC) and dorsal parietal regions, supporting their validity as complementary measures of the goal maintenance construct. Interestingly there was greater engagement of the frontal opercular insula region during the expectancy AX-CPT (letter) and greater functional connectivity between the PFC and medial temporal lobe in the DPX (dot pattern). These differences are consistent with differential recruitment of phonological and visual-spatial processes by the two tasks and suggest that additional long-term memory systems may be engaged by the dot probe version.

The goals of the present study were to assess the interrelationships among tasks from the MATRICS and CNTRACS batteries, to determine the degree to which tasks from each battery capture unique variance in cognitive dysfunction in schizophrenia, and to determine the ability of tasks from each battery to predict functional outcome. Subjects were 104 schizophrenia patients and 132 healthy control subjects recruited as part of the CNTRACS initiative. All subjects completed four CNTRACS tasks and two tasks from the MATRICS battery: Brief Assessment of Cognition in Schizophrenia Symbol Coding and the Hopkins Verbal Learning Test. Functional outcome was also assessed in the schizophrenia subjects. In both the patient and control groups, we found significant intercorrelations between all higher order cognitive tasks (episodic memory, goal maintenance, processing speed, verbal learning) but minimal relationships with the visual task. For almost all tasks, scores were significantly related to measures of functional outcome, with higher associations between CNTRACS tasks and performance-based measures of function and between one of the MATRICS tasks and self-reported functioning, relative to the other functioning measures. After regressing out variance shared by other tasks, we continued to observe group differences in performance among task residuals, particularly for measures of episodic memory from both batteries, although these residuals did not correlate as robustly with functional outcome as raw test scores. These findings suggest that there exists both shared and specific variance across cognitive tasks related to cognitive and functional impairments in schizophrenia and that measures derived from cognitive neuroscience can predict functional capacity and status in schizophrenia.

Research in schizophrenia has increasingly focused on incorporating measures from cognitive neuroscience, but little is known about their psychometric characteristics. Here, we extend prior research by reporting on temporal stability, as well as age and sex effects, for cognitive neuroscience paradigms optimized as part of the Cognitive Neuroscience Test Reliability and Clinical applications for Schizophrenia consortium. Ninety-nine outpatients with schizophrenia and 131 healthy controls performed 5 tasks assessing 4 constructs at 3 sessions. The constructs were (1) Goal maintenance (Dot Probe Expectancy [DPX] and AX continuous performance tasks [AX-CPT]); (2) Episodic memory (Relational and Item-Specific Encoding and Retrieval task [RiSE]); (3) Visual integration (Jittered Orientation Visual Integration task [JOVI]); and (4) Perceptual gain control (Contrast-Contrast Effect Task [CCE]). Patients performed worse than controls on all but the CCE, and the magnitude of these group differences was stable across sessions, with no sex differences observed. Improvements over sessions were seen for the AX-CPT, the DPX, and the JOVI though practice effects for the AX-CPT and the DPX were primarily present in older participants. For the AX-CPT and the JOVI, practice effects were larger for T1 to T2 than for T2 to T3. Age was associated with poor associative recognition on the RiSE and accuracy on the JOVI. Test-rest reliability ranged from poor for the JOVI threshold score to adequate to good for the DPX, AX-CPT, and JOVI accuracy measures, with RiSE and CCE measures in the moderate range. These results suggest that group differences in DPX, AX-CPT, RiSE, and JOVI are robust and consistent across repeated testing.

BackgroundCognition is increasingly being recognized as an important aspect of psychotic disorders and a key contributor to functional outcome. In the past, comparative studies have been performed in schizophrenia and schizo-affective disorder with regard to cognitive performance, but the results have been mixed and the cognitive measures used have not always assessed the cognitive deficits found to be specific to psychosis. A set of optimized cognitive paradigms designed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium to assess deficits specific to schizophrenia was used to measure cognition in a large group of individuals with schizophrenia and schizo-affective disorder.MethodA total of 519 participants (188 with schizophrenia, 63 with schizo-affective disorder and 268 controls) were administered three cognitive paradigms assessing the domains of goal maintenance in working memory, relational encoding and retrieval in episodic memory and visual integration.ResultsAcross the three domains, the results showed no major quantitative differences between patient groups, with both groups uniformly performing worse than healthy subjects.ConclusionsThe findings of this study suggests that, with regard to deficits in cognition, considered a major aspect of psychotic disorder, schizophrenia and schizo-affective disorder do not demonstrate major significant distinctions. These results have important implications for our understanding of the nosological structure of major psychopathology, providing evidence consistent with the hypothesis that there is no natural distinction between cognitive functioning in schizophrenia and schizo-affective disorder.

OBJECTIVE:Clozapine is underutilized in the management of treatment-resistant schizophrenia. To understand contributing factors, we analyzed the frequency and causes of clozapine discontinuations that occurred over a 15-year period in a clinical setting.METHOD:Data were extracted from computerized records and from mandatory termination reports for discontinuation events 1993-2007. The reasons for termination were analyzed.RESULTS:Over half of the patients (n = 183/320; 57%) had at least one discontinuation (median time 609 days). The two most common causes for discontinuation were non-adherence (35%) and side-effects (28%). Hematological side-effects accounted for 45% of all side-effect associated discontinuations; most such patients remained eligible for clozapine treatment, and a significant fraction remained on clozapine after rechallenge. Central nervous system side-effects accounted for 35% of side-effect induced discontinuations. General factors significantly associated with discontinuation were African American race, older age at initiation of clozapine and less improvement in psychiatric symptoms.CONCLUSION:In addition to anticipating and addressing causes of non-adherence, psychiatrists should consider clozapine rechallenge in eligible patients and implement measures to mitigate clozapine-associated sedation, seizures, and other side-effects. Future studies should particularly address why African American and older patients may be more likely to discontinue clozapine.

Contour integration (CI) refers to the process that represents spatially separated elements as a unified edge or closed shape. Schizophrenia is a psychiatric disorder characterized by symptoms such as hallucinations, delusions, disorganized thinking, inappropriate affect, and social withdrawal. Persons with schizophrenia are impaired at CI, but the specific mechanisms underlying the deficit are still not clear. Here, we explored the hypothesis that poor patient performance owes to reduced feedback or impaired longer-range lateral connectivity within early visual cortex—functionally similar to that found in 5- to 6-year old children. This hypothesis predicts that as target element spacing increases from .7 to 1.4° of visual angle, patient impairments will become more pronounced. As a test of the prediction, 25 healthy controls and 36 clinically stable, asymptomatic persons with schizophrenia completed a CI task that involved determining whether a subset of Gabor elements formed a leftward or rightward pointing shape. Adjacent shape elements were spaced at either .7 or 1.4° of visual angle. Difficulty in each spacing condition depended on the number of noise elements present. Patients performed worse than controls overall, both groups performed worse with the larger spacing, and the magnitude of the between-group difference was not amplified at the larger spacing. These results show that CI deficits in schizophrenia cannot be explained in terms of a reduced spatial range of integration, at least not when the shape elements are spaced within 1.5°. Later-developing, low-level integrative mechanisms of lateral connectivity and feedback appear not to be differentially impaired in the illness.

BACKGROUNDWe sought to develop a Dot Pattern Expectancy task (DPX) to assess goal maintenance for use in clinical trials. Altering the standard task created 5 versions of the DPX to compare-a standard version and 4 others. Alterations in the interstimulus interval (ISI) length and the strength of a learned prepotent response distinguished the different tasks. These adjustments were designed to decrease administration time and/or improve reliability of the data.METHODSWe determined participant eligibility in an initial session (the first of 3) using clinical interviewing tools. The initial session also included a demographic assessment and assessments of community functioning and symptom severity. All versions of the DPX were administered, across 3 sessions. Specific deficits on the context processing compared with difficulty control condition were evaluated using mixed-effects logistic regression within a hierarchical linear model.RESULTSWe analyzed the data from 136 control participants and 138 participants with schizophrenia. Relative to a difficulty control condition, patients performed worse than controls on context processing conditions that required goal maintenance. ISI did not predict errors. Stronger prepotency was associated with increased errors in the difficulty control relative to context processing condition for controls, which improved the interpretability of findings for patients. Reliability was acceptable for a version of the task with a 10-minute running time.CONCLUSIONSThe best compromise between task duration and interpretability occurred on a version with a short ISI and a strong prepotency.

The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia initiative highlighted a contour integration test as a promising index of visual integration impairment because of its well-established psychometric properties; its prior validation in healthy adults, patients, and nonhuman primates; and its potential sensitivity to treatment effects. In this multisite study, our goals were to validate the task on the largest subject sample to date, clarify the task conditions and number of trials that best discriminate patients from controls, and determine whether this discrimination can occur in standard clinical trial settings. For our task, subjects briefly observed a field of disconnected, oriented elements and attempted to decide whether a subset of those elements formed a leftward- or rightward-pointing shape. Difficulty depended on the amount of orientational jitter that was added to the shape's elements. Two versions of this Jittered Orientation Visual Integration task (JOVI) were examined. Study 1 did not reveal between-group differences in threshold (ie, the jitter magnitude needed to reach a performance level of ∼80%), but this likely owed to the wide sampling distribution of jitter levels and resulting floor/ceiling effects in many conditions. Study 2 incorporated a narrower range of difficulty levels and revealed lower thresholds (worse performance) among patients (p < .001). This group difference remained even when only the first half of the trials was analyzed (p = .001). Thus, the JOVI-2 provides a brief, sensitive measure of visual integration deficits in schizophrenia. Neural implications and potential future applications of the JOVI are discussed.

Introduction: Contour integration tests have clarified mechanisms of perceptual organization in humans and monkeys, in children and the elderly, and in disorders such as amblyopia and schizophrenia. However, the test-retest reliability of the contour integration paradigm is unexplored. Establishing this aspect of the paradigm is useful for assessing the effects of aging, pathology, or response to treatment. Methods: Participants with schizophrenia and healthy age-matched controls completed 3 contour integration assessments, 7 and then 14 days apart. On each trial, subjects judged whether a subset of otherwise randomly oriented Gabor elements formed a leftward or rightward pointing shape. Task difficulty depended on the amount of orientation jitter added to the target elements: 0°, 7°, 9°, 11°, 13°, 15°. The number of controls and patients for the three sessions were: 1) 122, 93; 2) 120, 93; 3) 118, 93. Test-retest reliability was calculated for accuracy and fitted-Weibull threshold estimates, using both intraclass correlation (ICC) and Spearman rho methods. Results: ICC estimates for accuracy varied with jitter condition. For conditions in which controls could reliably perceive contours, the ICC values for accuracy scores ranged from .62-.80 across Times 1-2, and from .56-.86 across Times 2-3. For schizophrenia patients, value ranges were .59-.86 and .71-.87, respectively. ICC values of threshold estimates were .56 and .46 for controls, and .28 and .64 for patients. Spearman rho values for threshold estimates for controls were .46 and .50 for Times 1-2 and 2-3, and .47 and .49 for patients. Additional analyses examined reliability across Times 1-3, and differences when subjects with poor acuity were excluded. Conclusion: This version of the contour integration test has fair-very good test-retest reliability. Reliability varied as a function of subject group (patient vs. control), calculation method (ICC vs. correlation), and unit of analysis (accuracy level vs. threshold estimate). Meeting abstract presented at VSS 2012