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Background and Hypothesis: The current study investigated the extent to which changes in attentional control contribute to performance on a visual perceptual discrimination task, on a trial-by-trial basis in a transdiagnostic clinical sample., Study Design: Participants with schizophrenia (SZ; N = 58), bipolar disorder (N = 42), major depression disorder (N = 51), and psychiatrically healthy controls (N = 92) completed a visual perception task in which stimuli appeared briefly. The design allowed us to estimate the lapse rate and the precision of perceptual representations of the stimuli. Electroencephalograms (EEG) were recorded to examine pre-stimulus activity in the alpha band (8-13 Hz), overall and in relation to behavior performance on the task., Study Results: We found that the attention lapse rate was elevated in the SZ group compared with all other groups. We also observed group differences in pre-stimulus alpha activity, with control participants showing the highest levels of pre-stimulus alpha when averaging across trials. However, trial-by-trial analyses showed within-participant fluctuations in pre-stimulus alpha activity significantly predicted the likelihood of making an error, in all groups. Interestingly, our analysis demonstrated that aperiodic contributions to the EEG signal (which affect power estimates across frequency bands) serve as a significant predictor of behavior as well., Conclusions: These results confirm the elevated attention lapse rate that has been observed in SZ, validate pre-stimulus EEG markers of attentional control and their use as a predictor of behavior on a trial-by-trial basis, and suggest that aperiodic contributions to the EEG signal are an important target for further research in this area, in addition to alpha-band activity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Research suggests that effort-cost decision-making (ECDM), the estimation of work required to obtain reward, may be a relevant framework for understanding motivational impairment in psychotic and mood pathology. Specifically, research has suggested that people with psychotic and mood pathology experience effort as more costly than controls, and thus pursue effortful goals less frequently. This study examined ECDM across psychotic and mood pathology., Hypothesis: We hypothesized that patient groups would show reduced willingness to expend effort compared to controls., Study Design: People with schizophrenia (N = 33), schizoaffective disorder (N = 28), bipolar disorder (N = 39), major depressive disorder (N = 40), and controls (N = 70) completed a physical ECDM task. Participants decided between completing a low-effort or high-effort option for small or larger rewards, respectively. Reward magnitude, reward probability, and effort magnitude varied trial-by-trial. Data were analyzed using standard and hierarchical logistic regression analyses to assess the subject-specific contribution of various factors to choice. Negative symptoms were measured with a clinician-rated interview., Study Results: There was a significant effect of group, driven by reduced choice of high-effort options in schizophrenia. Hierarchical logistic regression revealed that reduced choice of high-effort options in schizophrenia was driven by weaker contributions of probability information. Use of reward information was inversely associated with motivational impairment in schizophrenia. Surprisingly, individuals with major depressive disorder and bipolar disorder did not differ from controls., Conclusions: Our results provide support for ECDM deficits in schizophrenia. Additionally, differences between groups in ECDM suggest a seemingly similar behavioral phenotype, reduced motivation, could arise from disparate mechanisms., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Hypothesis: Impairments in function (ie, the ability to independently accomplish daily tasks) have been established in psychotic disorders. Identifying factors that contribute to these deficits is essential to developing effective interventions. The current study had several goals: examine potential differential relationships across domains of neurocognition, assess whether reinforcement learning is related to function, identify if predictors of function are transdiagnostic, determine whether depression and positive symptoms contribute to function, and to explore whether the modality of assessment impacts observed relationships., Study Design: Data from 274 participants were examined with schizophrenia/schizoaffective disorder (SZ; n = 195) and bipolar disorder (BD; n = 79). To reduce dimensionality, a PCA was completed on neurocognitive tasks which resulted in 3 components. These components and clinical interview data were used to investigate predictors of functional domains across measures of function (self- and informant-report SLOF and UPSA)., Results: Two components, working memory/processing speed/episodic memory (βs = 0.18-0.42), and negative/positive reinforcement learning (β = -0.04), predicted different functional domains. Predictors of function were largely transdiagnostic with two exceptions: reinforcement learning had a positive association with self-reported interpersonal relationships for SZ and a negative association for BD (β = 0.34), and the negative association between positive symptoms and self-reported social acceptability was stronger for BD than for SZ (β = 0.93). Depression robustly predicted self-reported but not informant-reported function, and anhedonia predicted all domains of informant-reported function., Conclusions: These findings imply that reinforcement learning may differentially relate to function across disorders, traditional domains of neurocognition can be effective transdiagnostic targets for interventions, and positive symptoms and depression play a critical role in self-perceived functional impairments., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Motivational deficits in people with psychosis may be a result of impairments in reinforcement learning (RL). Therefore, behavioral paradigms that can accurately measure these impairments and their change over time are essential., Methods: We examined the reliability and replicability of 2 RL paradigms (1 implicit and 1 explicit, each with positive and negative reinforcement components) given at 2 time points to healthy controls (n = 75), and people with bipolar disorder (n = 62), schizoaffective disorder (n = 60), and schizophrenia (n = 68)., Results: Internal consistency was acceptable (mean α = 0.78 ± 0.15), but test-retest reliability was fair to low (mean intraclass correlation = 0.33 ± 0.25) for both implicit and explicit RL. There were no clear effects of practice for these tasks. Largely, performance on these tasks shows intact implicit and impaired explicit RL in psychosis. Symptom presentation did not relate to performance in any robust way., Conclusions: Our findings replicate previous literature showing spared implicit RL and impaired explicit reinforcement in psychosis. This suggests typical basal ganglia dopamine release, but atypical recruitment of the orbitofrontal and dorsolateral prefrontal cortices. However, we found that these tasks have only fair to low test-retest reliability and thus may not be useful for assessing change over time in clinical trials., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Our understanding of belief formation, maintenance, and change is in its infancy, yet it is absolutely essential to make progress in understanding these processes to parse the puzzle of psychotic delusions. In this companion to Bebbington and Freeman, I consider a number of Research Domain Criteria constructs that may be helpful for exploring these processes but ultimately conclude (following Risen) that delusions are likely the result of several systems failing. I close with 4 recommendations for making progress: (1) prepare to study a variable space defined by several relevant constructs, (2) include the study of "unsanctioned" constructs, (3) examine the relationships between brain regions, rather than the local abnormalities, and (4) develop rigorous computational models of delusions., (© The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Patients with schizophrenia (SZ) previously demonstrated specific deficits in an executive function known as goal maintenance, associated with reduced middle frontal gyrus (MFG) activity. This study aimed to validate a new tool-the Dot Pattern Expectancy (DPX) task-developed to facilitate multisite imaging studies of goal maintenance deficits in SZ or other disorders. Additionally, it sought to arrive at recommendations for scan length for future studies using the DPX. Forty-seven SZ and 56 healthy controls (HC) performed the DPX in 3-Tesla functional magnetic resonance imaging (fMRI) scanners at 5 sites. Group differences in DPX-related activity were examined with whole brain voxelwise analyses. SZs showed the hypothesized specific performance deficits with as little as 1 block of data. Reduced activity in SZ compared with HC was observed in bilateral frontal pole/MFG, as well as left posterior parietal lobe. Efficiency analyses found significant group differences in activity using 18 minutes of scan data but not 12 minutes. Several behavioral and imaging findings from the goal maintenance literature were robustly replicated despite the use of different scanners at different sites. We did not replicate a previous correlation with disorganization symptoms among patients. Results were consistent with an executive/attention network dysfunction in the higher levels of a cascading executive system responsible for goal maintenance. Finally, efficiency analyses found that 18 minutes of scanning during the DPX task is sufficient to detect group differences with a similar sample size., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Previous work suggests that individuals with schizophrenia display accelerated aging of white matter integrity, however, it is still unknown whether functional brain networks also decline at an elevated rate in schizophrenia. Given the known degradation of functional connectivity and the normal decline in cognitive functioning throughout healthy aging, we aimed to test the hypothesis that efficiency of large-scale functional brain networks supporting overall cognition, as well as integrity of hub nodes within those networks, show evidence of accelerated aging in schizophrenia. Using pseudo-resting state data in 54 healthy controls and 46 schizophrenia patients, in which task-dependent signal from 3 tasks was regressed out to approximate resting-state data, we observed a significant diagnosis by age interaction in the prediction of both global and local efficiency of the cingulo-opercular network, and of the local efficiency of the fronto-parietal network, but no interaction when predicting both default mode network and whole brain efficiency. We also observed a significant diagnosis by age interaction for the node degree of the right anterior insula, left dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex. All interactions were driven by stronger negative associations between age and network metrics in the schizophrenia group than the healthy controls. These data provide evidence that is consistent with accelerated aging of large-scale functional brain networks in schizophrenia that support higher-order cognitive ability., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cognitive remediation training (CRT) for schizophrenia has been found to improve cognitive functioning and influence neural plasticity. However, with various training approaches and mixed findings, the mechanisms driving generalization of cognitive skills from CRT are unclear. In this meta-analysis of extant imaging studies examining CRT's effects, we sought to clarify whether varying approaches to CRT suggest common neural changes and whether such mechanisms are restorative or compensatory. We conducted a literature search to identify studies appropriate for inclusion in an activation likelihood estimation (ALE) meta-analysis. Our criteria required studies to consist of training-based interventions designed to improve patients' cognitive or social functioning, including generalization to untrained circumstances. Studies were also required to examine changes in pre- vs posttraining functional activation using functional magnetic resonance imaging or positron emission tomography. The literature search identified 162 articles, 9 of which were appropriate for inclusion. ALE analyses comparing pre- and posttraining brain activation showed increased activity in the lateral and medial prefrontal cortex (PFC), parietal cortex, insula, and the caudate and thalamus. Notably, activation associated with CRT in the left PFC and thalamus partially overlapped with previous meta-analytically identified areas associated with deficits in working memory, executive control, and facial emotion processing in schizophrenia. We conclude that CRT interventions from varying theoretic modalities elicit plasticity in areas that support cognitive and socioemotional processes in this early set of studies. While preliminary, these changes appear to be both restorative and compensatory, though thalamocortical areas previously associated with dysfunction may be common sources of plasticity for cognitive remediation in schizophrenia., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The goal of the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium was to develop measures of discrete cognitive processes, allowing for the interpretation of specific deficits that could be linked to specific neural systems. Here we report on the intertask, clinical, and functional correlates of the 4 tasks that were investigated in large groups of patients with schizophrenia (>100) and healthy controls (>73) at 5 sites across the United States. In both healthy and patient groups, the key dependent measures from the CNTRACS tasks were minimally intercorrelated, suggesting that they are measuring discrete abilities. Correlations were examined between CNTRACS tasks and measures of functional capacity, premorbid IQ, symptom severity, and level of community functioning. Performance on tasks measuring relational memory encoding, goal maintenance, and visual gain control were correlated with premorbid IQ and the former 2 tasks with the functional capacity. Goal maintenance task performance was negatively correlated with negative symptom severity and informant reports of community function. These correlations reflect the relationship of specific abilities with functional outcome. They are somewhat lower than functional outcome correlations observed with conventional neuropsychological tests that confound multiple cognitive and motivational deficits. The measures of visual integration and gain control were not significantly correlated with clinical symptoms or function. These results suggest that the CNTRACS tasks measure discrete cognitive abilities, some of which relate to aspects of functional capacity/outcome in schizophrenia.

The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative has formed with the expressed intent of identifying constructs and paradigms that would identify biomarkers of psychosis. The manipulation of these biomarkers would serve as targets for treatment interventions. The second phase of CNTRICS consisted of critical discussions evaluating brain mapping (functional neuroimaging and brain electrical activity) paradigms as biomarkers to measure specific constructs. Among the constructs identified in, CNTRICS I was socio-emotional processing, specifically focused on affect recognition. Here, we provide a critical appraisal of the ability of candidate socio-emotional tasks to identify putative biomarkers and recommendations for future directions in this rapidly moving research domain.

Objectives: The Relational and Item-Specific Encoding task (RISE) was designed to assess contributions of specific encoding and retrieval processes to episodic memory in schizophrenia. This manuscript describes how a cognitive neuroscience functional imaging paradigm was translated for clinical research., Methods: The RISE manipulates encoding by requiring participants to decide whether stimuli are "living/nonliving" (item-specific) or whether one stimulus fits inside the other (relational) and estimates familiarity (F) and recollection (R) by examining receiver operator characteristics (ROC) and assessing item and associative recognition. Two studies examined psychometric characteristics and tested the hypothesis that patients have differential deficits in relational vs item-specific encoding and disproportionate impairments in recollection vs familiarity., Results: Study 1, using visual objects, provided support for the encoding hypotheses and revealed good internal consistency and alternate forms reliability, with small differences between test forms. ROC analysis revealed R and F deficits, with F deficits most prominent following relational encoding. Study 2 used word stimuli, which lowered item recognition, but patients had difficulty understanding task demands, and words were less desirable for non-English speaking clinical trials, leading to the decision to proceed with the original task., Conclusions: The RISE is a valid and reliable measure of item-specific and relational memory that is well tolerated, with good psychometric characteristics and equivalent forms to facilitate treatment studies. Results indicate that episodic memory in schizophrenia is most preserved under conditions promoting item-specific encoding that is supported by familiarity-based recognition and is most impaired under relational encoding and recollection-based retrieval conditions.

Background: We 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., Methods: We 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., Results: We 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., Conclusions: The best compromise between task duration and interpretability occurred on a version with a short ISI and a strong prepotency.

Temporal lobe abnormalities and emotion recognition deficits are prominent features of schizophrenia and appear related to the diathesis of the disorder. This study investigated whether temporal lobe structural abnormalities were associated with facial emotion recognition deficits in schizophrenia and related to genetic liability for the disorder. Twenty-seven schizophrenia patients, 23 biological family members, and 36 controls participated. Several temporal lobe regions (fusiform, superior temporal, middle temporal, amygdala, and hippocampus) previously associated with face recognition in normative samples and found to be abnormal in schizophrenia were evaluated using volumetric analyses. Participants completed a facial emotion recognition task and an age recognition control task under time-limited and self-paced conditions. Temporal lobe volumes were tested for associations with task performance. Group status explained 23% of the variance in temporal lobe volume. Left fusiform gray matter volume was decreased by 11% in patients and 7% in relatives compared with controls. Schizophrenia patients additionally exhibited smaller hippocampal and middle temporal volumes. Patients were unable to improve facial emotion recognition performance with unlimited time to make a judgment but were able to improve age recognition performance. Patients additionally showed a relationship between reduced temporal lobe gray matter and poor facial emotion recognition. For the middle temporal lobe region, the relationship between greater volume and better task performance was specific to facial emotion recognition and not age recognition. Because schizophrenia patients exhibited a specific deficit in emotion recognition not attributable to a generalized impairment in face perception, impaired emotion recognition may serve as a target for interventions.

Background: Schizophrenia is characterized by a lack of integration between thought, emotion, and behavior. A disruption in the connectivity between brain processes may underlie this schism. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were used to evaluate functional and anatomical brain connectivity in schizophrenia., Methods: In all, 29 chronic schizophrenia patients (11 females, age: mean=41.3, SD=9.28) and 29 controls (11 females, age: mean=41.1, SD=10.6) were recruited. Schizophrenia patients were assessed for severity of negative and positive symptoms and general cognitive abilities of attention/concentration and memory. Participants underwent a resting-fMRI scan and a DTI scan. For fMRI data, a hybrid independent components analysis was used to extract the group default mode network (DMN) and accompanying time-courses. Voxel-wise whole-brain multiple regressions with corresponding DMN time-courses was conducted for each subject. A t-test was conducted on resulting DMN correlation maps to look between-group differences. For DTI data, voxel-wise statistical analysis of the fractional anisotropy data was carried out to look for between-group differences. Voxel-wise correlations were conducted to investigate the relationship between brain connectivity and behavioral measures., Results: Results revealed altered functional and anatomical connectivity in medial frontal and anterior cingulate gyri of schizophrenia patients. In addition, frontal connectivity in schizophrenia patients was positively associated with symptoms as well as with general cognitive ability measures., Discussion: The present study shows convergent fMRI and DTI findings that are consistent with the disconnection hypothesis in schizophrenia, particularly in medial frontal regions, while adding some insight of the relationship between brain disconnectivity and behavior., (© The Author 2009. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.)

There is a growing literature on brain activity in the nonpsychotic first-degree relatives of patients with schizophrenia as measured using functional imaging. This systematic review examined 20 studies in 4 domains of cognition, including cognitive control (7 samples), working memory (5 samples), long-term memory (4 samples), and language (4 samples). While the literature was widely divergent, these studies did consistently find activation differences between patients' relatives and controls. The most consistent increases in activation within hemisphere were found in right ventral prefrontal cortex (PFC) and right parietal cortex. Abnormal activity, defined as significant increases or decreases in activation relative to controls irrespective of hemisphere, was found in about two-thirds of contrasts in the cerebellum, dorsal prefrontal, lateral temporal, and parietal cortices, and thalamus, with basal ganglia and ventral PFC showing abnormalities in approximately half of those contrasts. Anterior cingulate was generally spared in patients' relatives. The diversity of findings in studies of patients' relatives may derive from differences between the cognitive demands across studies. We identify avenues for building a more accurate and cumulative literature, including symmetrical inclusion criteria for relatives and controls, recording in-scanner responses, using both a priori and whole-brain tests, explicitly reporting threshold values, reporting main effects of task, reporting effect sizes, and quantifying the risk of false negatives. While functional imaging in the relatives of schizophrenia patients remains a promising methodology for understanding the impact of the unexpressed genetic liability to schizophrenia, no single region or mechanism of abnormalities has yet emerged.

The article summarizes the process used to distill schizophrenia science into 22 facts. These facts consist of 6 basic facts, 3 etiological facts, 6 pharmacological and treatment facts, 5 pathology facts, and 2 behavioral facts that were critically reviewed by the scholarly community through a special initiative in cooperation with the Schizophrenia Research Forum. A subset of 10 of these facts was selected to form a common set of findings to be explained from the different theoretical perspectives included in this special section of Schizophrenia Bulletin. The rationale for this exercise is to distinguish more precisely the areas of agreement and disagreement between theories of schizophrenia and to highlight where more thought and data can make the greatest impact for understanding this disease.

Tasks developed for basic cognitive neuroscience are often ill suited for experimental psychopathology. The development of the expectancy variant of AX continuous performance task to test theories about context processing in schizophrenia is used as an illustration of how this has been done in one research program. Four design principles are recommended: tasks should (1) have a foundation in existing literature and therefore stay as close as possible to an existing task; (2) be simple, which is frequently accomplished by paring down a task to evaluate the function of interest; (3) probe a mechanism of interest, with conditions that selectively manipulate this mechanism; and (4) have the potential to distinguish a specific deficit on the mechanism of interest from a generalized impairment. Data from a number of studies support several aspects of context-processing theory; however unpredicted results have also been reported. The development of the expectancy AX paradigm continues, and future developments that may enhance its usefulness are also described.

Accumulated evidence suggests that schizophrenia is associated with subtle gray matter deficits throughout the cerebral cortex and regional cortical thinning. Although findings are not entirely consistent, healthy relatives of schizophrenia patients also show abnormalities in cortical gray matter volume, suggesting that this may be one aspect of an unexpressed genetic liability to the disorder. Cortical thickness and surface area are additional indicators of cortical cytoarchitectural integrity. To investigate the nature of cortical abnormalities in the healthy relatives of patients, this study used magnetic resonance imaging to evaluate gray matter volume, surface area, and thickness of 13 regions using an automated parcellation methodology. Compared with controls (n = 22), relatives (n = 19) had decreased volume and surface area in the right cingulate gyrus, a bilateral decrease in cingulate thickness, and decreased surface area in the superior temporal lobe. In addition, relatives had a subtle increase in gray matter volume and surface area in the left hemisphere, bilaterally in the parahippocampal gyri, and in the left middle temporal lobe. The results of this study suggest that the cortical regions most affected by the unexpressed genetic liability to schizophrenia may be the cingulate and temporal regions--regions associated with higher level cognitive, affective, and memory functions.

Cognitive deficits may index genetic liability for schizophrenia and are candidate endophenotypes for the illness. In order to compare the degree of sensitivity among cognitive tasks to group differences between healthy relatives and controls and the influence of moderator variables, this review reports mean effect sizes for 43 cognitive test scores from 58 studies of cognitive performance in the unaffected adult relatives of schizophrenia patients. Results indicate reliable relative-control differences, in the small to medium effect size range, over a diverse array of tasks, with the largest effect sizes seen in complex versions of continuous performance tasks, auditory verbal learning, design copy tests, and category fluency. Three study design features were found to have significant effects on overall effect size magnitude: groups unmatched on education, groups unmatched on age, and asymmetric psychiatric exclusion criteria. After excluding studies with the latter 2 design features, reliable performance differences were still observed over a smaller subset of cognitive test variables, with the largest effect sizes seen in Trails B (d = 0.50) and performance measures from both simple (d = 0.56) and complex (d = 0.60-0.66) versions of continuous performance tasks. Four of the 6 largest effect sizes reflect tasks with high executive control demands in common, such as working memory demands, set shifting, and inhibition of prepotent responses. Cognitive deficits, particularly those tapping such executive control functions, should continue to prove valuable as endophenotypes of interest in the search for specific genetic factors related to schizophrenia.