Background: "Theory of mind" (TOM) refers to the ability to attribute mental states (ie, beliefs and goals) to one's self and others and to recognize that behaviors are guided by these mental states. This capacity, critical for social competence, is impaired in schizophrenia. We undertook a study of TOM in a group of patients with schizophrenia and healthy controls. Method: We used positron emission tomography to identify the neural circuits recruited during a verbal task that required participants to attribute mental states to a character in a story of their creation. The comparison task consisted of reading aloud a neutral story, controlling for the speech component of the task. Results: Patients and controls generated the same percentage of TOM utterances. However, the two groups had markedly different patterns of brain activation. Compared with controls, patients had a lower blood flow in multiple regions in the left hemisphere including the frontal and visual association cortices, posterior hippocampus, and insula. The flow was also lower in contralateral areas in the lateral cerebellum and vermis, thalamus, and posterior insula. On the other hand, the flow was higher in the patients predominantly in the right hemisphere, including multiple frontal and parietal regions, insula, visual association cortex, and pulvinar. Discussion: The areas of lower flow are consistent with previous studies indicating impairment in recruiting cortical-cerebellar circuitry in schizophrenia. The areas of higher flow may reflect a need to draw on the right hemisphere to compensate for deficits in left hemisphere networks that include frontal cortex, anterior cingulate, cerebellum, and thalamus.

Recent studies provide considerable evidence that schizophrenia and bipolar disorder may share overlapping etiologic determinants. Identifying disease-related genetic effects is a major focus in schizophrenia and bipolar disorder research, with implications for clarifying diagnosis and developing specific treatments for various impairments in these 2 disorders. Efforts have been multifaceted, with the ultimate goal of describing causal paths from specific genetic variants, to changes in neuronal functioning, and to behavioral and functional impairments. Parallel efforts have identified and refined several alternative phenotypes that are stable, heritable, some with known biological substrates, and are associated with psychosis liability. These alternative phenotypes are likely to aid search for liability genes in schizophrenia and bipolar disorders and likely to be informative regarding the extent to which the 2 disorders share etio-pathophysiology.

The social significance of imitation is that it provides internal tools for understanding the actions of others by simulating or forming internal representations of these actions. Imitation plays a central role in human social behavior by mediating diverse forms of social learning. However, imitation and simulation ability in schizophrenia has not been adequately addressed. The major aim of the present study was to investigate imitation ability in schizophrenia patients and healthy individuals by examining simple motor imitation that involved the replication of meaningless manual and oral gestures, and the imitation of emotional facial expressions, which has implications for mentalizing. A secondary aim of the present study was to investigate the relationships among imitation ability, social functioning, and working memory. Subjects were asked to mimic hand gestures, mouth movements, and facial expressions of others, online. Clinical symptoms, social competence, and working memory were also assessed. Patients with schizophrenia were significantly impaired on all imitation tasks. Imitation errors were significantly correlated with reduced social competence and increased negative symptoms. However, imitation ability was only weakly associated with working memory. To summarize, the present study examined the ability of patients with schizophrenia to imitate the behaviors demonstrated by others. The results indicate a fundamental impairment in imitation ability in schizophrenia and implicate a possible difficulty in simulation. Further research to determine the neural and developmental origins of this difficulty could be extremely helpful in elucidating the role of simulation in schizophrenia and to establish the complex relationships among mental representation, imitation, and social cognition.

Previous work examining the neurobiological substrates of social cognition in healthy individuals has reported modulation of a social cognitive network such that increased activation of the amygdala, fusiform gyrus, and superior temporal sulcus are evident when individuals judge a face to be untrustworthy as compared with trustworthy. We examined whether this pattern would be present in individuals with schizophrenia who are known to show reduced activation within these same neural regions when processing faces. Additionally, we sought to determine how modulation of this social cognitive network may relate to social functioning. Neural activation was measured using functional magnetic resonance imaging with blood oxygenation level dependent contrast in 3 groups of individuals—nonparanoid individuals with schizophrenia, paranoid individuals with schizophrenia, and healthy controls—while they rated faces as either trustworthy or untrustworthy. Analyses of mean percent signal change extracted from a priori regions of interest demonstrated that both controls and nonparanoid individuals with schizophrenia showed greater activation of this social cognitive network when they rated a face as untrustworthy relative to trustworthy. In contrast, paranoid individuals did not show a significant difference in levels of activation based on how they rated faces. Further, greater activation of this social cognitive network to untrustworthy faces was significantly and positively correlated with social functioning. These findings indicate that impaired modulation of neural activity while processing social stimuli may underlie deficits in social cognition and social dysfunction in schizophrenia.

Schizophrenia patients show impairments in identifying facial affect; however, it is not known at what stage facial affect processing is impaired. We evaluated 3 event-related potentials (ERPs) to explore stages of facial affect processing in schizophrenia patients. Twenty-six schizophrenia patients and 27 normal controls participated. In separate blocks, subjects identified the gender of a face, the emotion of a face, or if a building had 1 or 2 stories. Three ERPs were examined: (1) P100 to examine basic visual processing, (2) N170 to examine facial feature encoding, and (3) N250 to examine affect decoding. Behavioral performance on each task was also measured. Results showed that schizophrenia patients’ P100 was comparable to the controls during all 3 identification tasks. Both patients and controls exhibited a comparable N170 that was largest during processing of faces and smallest during processing of buildings. For both groups, the N250 was largest during the emotion identification task and smallest for the building identification task. However, the patients produced a smaller N250 compared with the controls across the 3 tasks. The groups did not differ in behavioral performance in any of the 3 identification tasks. The pattern of intact P100 and N170 suggest that patients maintain basic visual processing and facial feature encoding abilities. The abnormal N250 suggests that schizophrenia patients are less efficient at decoding facial affect features. Our results imply that abnormalities in the later stage of feature decoding could potentially underlie emotion identification deficits in schizophrenia.

The evolutionary origins of one of the most dramatic and seemingly deleterious behavioral phenotypes, the syndrome known as schizophrenia, are mysterious. Schizophrenia occurs in all cultures and is inherited. Although most phenotypes are said to be "selected for" based on adaptive qualities, it is difficult to understand how the genetic basis of schizophrenia could have operated under a similar framework. This has lead several theorists analyzing the proposed evolutionary origins of other disease states to that of schizophrenia. To date, several models have been applied. We have tried to conceptualize schizophrenia in a compensatory advantage framework whereby incomplete penetrance of the full disorder, or alternatively, the inheritance of risk alleles insufficient in number to manifest as the classic clinical syndrome, may manifest as a behavioral phenotype with adaptive advantages (eg, creative behavior or novel illuminating ideas). The idea that even full penetrance can also be advantageous has been offered as applied to religious experience and ancient social standing, but is unlikely. Can complex behavioral phenotypes such as schizophrenia, and particularly those that seem purely deleterious, be explained by mechanisms of Darwinian psychiatry? Can models from other disease classes be applied successfully to schizophrenia? Such ideas have generated intense speculation, but often in the absence of testable models. In this article, we will examine some of these proposed ideas and offer suggestions for future research.

Since Emil Kraepelin proposed in 1919 that dementia praecox (schizophrenia) be differentiated from manic depression (bipolar disorder), the concept of nosological dichotomy has greatly influenced the diagnosis, treatment, and research of pathogenesis of these 2 disorders. However, this concept has recently been challenged by increasing evidence showing biological overlap between schizophrenia and bipolar disorder. This article reviews some of the previous evidence for phenomenological and molecular overlaps between these 2 disorders. We then discuss approaches for examining shared etiological mechanisms with a concentration on genetic factors. We have put a particular emphasis on incorporating the concept of endophenotypes in research of shared genetic liability for these 2 disorders.

Endophenotypes represent intermediate phenotypes on the putative causal pathway from the genotype to the phenotype. They offer a potentially valuable strategy to examine the molecular etiopathology of complex behavioral phenotypes such as schizophrenia. Neurocognitive and neurophysiological impairments that suggest functional impairments associated with schizophrenia have been proposed as endophenotypes. However, few studies have examined the structural variations in the brain that might underlie the functional impairments as useful endophenotypes for schizophrenia. Over the past three decades, there has been an impressive body of literature supporting brain structural alterations in schizophrenia. We critically reviewed the extant literature on the neuroanatomical variations in schizophrenia in this paper to evaluate their candidacy as endophenotypes and how useful they are in furthering the understanding of etiology and pathophysiology of schizophrenia. Brain morphometric measures meet many of the criteria set by different investigators, such as being robustly associated with schizophrenia, heritable, quantifiable, and present in unaffected family members more frequently than in the general population. We conclude that the brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Some caveats for the utility of endophenotypes are discussed. A proposal to combine more than one endophenotype ("extended endophenotype") is suggested. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.

The search for liability genes of the world's 2 major psychotic disorders, schizophrenia and bipolar disorder I (BP-I), has been extremely difficult even though evidence suggests that both are highly heritable. This difficulty is due to the complex and multifactorial nature of these disorders. They encompass several intermediate phenotypes, some overlapping across the 2 psychotic disorders that jointly and/or interactively produce the clinical manifestations. Research of the past few decades has identified several neurophysiological deficits in schizophrenia that frequently occur before the onset of psychosis. These include abnormalities in smooth pursuit eye movements, P50 sensory gating, prepulse inhibition, P300, mismatch negativity, and neural synchrony. Evidence suggests that many of these physiological deficits are distinct from each other. They are stable, mostly independent of symptom state and medications (with some exceptions) and are also observed in non-ill relatives. This suggests a familial and perhaps genetic nature. Some deficits are also observed in the BP-I probands and to a lesser extent their relatives. These deficits in physiological measures may represent the intermediate phenotypes that index small effects of genes (and/or environmental factors). The use of these measures in genetic studies may help the hunt for psychosis liability genes and clarify the extent to which the 2 major psychotic disorders share etio-pathophysiology. In spite of the rich body of work describing these neurophysiological measures in psychotic disorders, challenges remain: Many of the neurophysiological phenotypes are still relatively complex and are associated with low heritability estimates. Further refinement of these physiological phenotypes is needed that could identify specific underlying physiological deficits and thereby improve their heritability estimates. The extent to which these neurophysiological deficits are unique or overlap across BP-I and schizophrenia is unclear. And finally, the clinical and functional consequences of the neurophysiological deficits both in the probands and their relatives are not well described.

Psychiatric disorders are genetically complex and represent the end product of multiple biological and social factors. Links between genes and disorder-related abnormalities can be effectively captured via assessment of phenotypes that are both associated with genetic effects and potentially contributory to behavioral abnormalities. Identifying intermediate or allied phenotypes as a strategy for clarifying genetic contributions to disorders has been successful in other areas of medicine and is a promising strategy for identifying susceptibility genes in complex psychiatric disorders. There is growing evidence that schizophrenia and bipolar disorder, rather than being wholly distinct disorders, share genetic risk at several loci. Further, there is growing evidence of similarity in the pattern of cognitive and neurobiological deficits in these groups, which may be the result of the effects of these common genetic factors. This review was undertaken to identify patterns of performance on neurocognitive and affective tasks across probands with schizophrenia and bipolar disorder as well as unaffected family members, which warrant further investigation as potential intermediate trait markers. Available evidence indicates that measures of attention regulation, working memory, episodic memory, and emotion processing offer potential for identifying shared and illness-specific allied neurocognitive phenotypes for schizophrenia and bipolar disorder. However, very few studies have evaluated neurocognitive dimensions in bipolar probands or their unaffected relatives, and much work in this area is needed.

Patients with schizophrenia have difficulty in decoding facial affect. A study using event–related functional neuroimaging indicated that errors in fear detection in schizophrenia are associated with paradoxically higher activation in the amygdala and an associated network implicated in threat detection. Furthermore, this exaggerated activation to fearful faces correlated with severity of flat affect. These findings suggest that abnormal threat detection processing may reflect disruptions between nodes that comprise the affective appraisal circuit. Here we examined connectivity within this network by determining the pattern of intercorrelations among brain regions (regions of interest) significantly activated during fear identification in both healthy controls and patients using a novel procedure CORANOVA. This analysis tests differences in the interregional correlation strength between schizophrenia and healthy controls. Healthy subjects' task activation was principally characterized by robust correlations between medial structures like thalamus (THA) and amygdala (AMY) and middle frontal (MF), inferior frontal (IF), and prefrontal cortical (PFC) regions. In contrast, schizophrenia patients displayed no significant correlations between the medial regions and either MF or IF. Further, patients had significantly higher correlations between occipital lingual gyrus and superior temporal gyrus than healthy subjects. These between-group connectivity differences suggest that schizophrenia threat detection impairment may stem from abnormal stimulus integration. Such abnormal integration may disrupt the evaluation of threat within fronto-cortical regions.

Social cognition in schizophrenia is a rapidly emerging area of study. Because the number and diversity of studies in this area have increased, efforts have been made to better define terms and provide organizing frameworks. A key challenge confronting the study of social cognition in schizophrenia is building bridges between clinical scientists and social neuroscientists. The articles in this theme summarize data-based studies that have attempted to build or strengthen such bridges to better understand the neural bases of social cognitive impairment in schizophrenia.

Understanding schizophrenia requires consideration of patients’ interactions in the social world. Misinterpretation of other peoples’ behavior is a key feature of persecutory ideation. The occurrence and intensity of hallucinations is affected by the social context. Negative symptoms such as anhedonia, asociality, and blunted affect reflect difficulties in social interactions. Withdrawal and avoidance of other people is frequent in schizophrenia, leading to isolation and rumination. The use of virtual reality (VR)—interactive immersive computer environments—allows one of the key variables in understanding psychosis, social environments, to be controlled, providing exciting applications to research and treatment. Seven applications of virtual social environments to schizophrenia are set out: symptom assessment, identification of symptom markers, establishment of predictive factors, tests of putative causal factors, investigation of the differential prediction of symptoms, determination of toxic elements in the environment, and development of treatment. The initial VR studies of persecutory ideation, which illustrate the ascription of personalities and mental states to virtual people, are highlighted. VR, suitably applied, holds great promise in furthering the understanding and treatment of psychosis.

The metal manganese is a potent magnetic resonance imaging (MRI) contrast agent that is essential in cell biology. Manganese-enhanced magnetic resonance imaging (MEMRI) is providing unique information in an ever-growing number of applications aimed at understanding the anatomy, the integration, and the function of neural circuits both in normal brain physiology as well as in translational models of brain disease. A major drawback to the use of manganese as a contrast agent, however, is its cellular toxicity. Therefore, paramount to the successful application of MEMRI is the ability to deliver Mn²⁺ to the site of interest using as low a dose as possible while preserving detectability by MRI. In the present work, the different approaches to MEMRI in translational neuroimaging are reviewed and challenges for future identified from a practical standpoint.

This overview describes the goals and objectives of the second conference conducted as part of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative. This second conference was informed by a series of online surveys and brought together basic and clinical scientists from academia and industry to address the concerns central to each field of research. Our goal was to develop recommendations for future research addressing the psychometric and practical challenges involved in translating paradigms from cognitive neuroscience into tasks that are feasible for use in the treatment discovery and development process. In this overview article, we describe the series of talks that were presentations at the conference. This article serves as an introduction to the set of articles included in this special issue that provide overviews and discussions of the issues raised and the recommendations made in these talks and in the subsequent discussions at the meeting. In addition, we describe the online surveys conducted in the month before the conference that were used to obtain suggestions from the field as to important task selection criteria and to generate initial benchmark goals for psychometric development for cognitive neuroscience tasks.

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.

The primary goal in designing a randomized controlled clinical trial (RCT) is to minimize bias in the estimate of treatment effect. Randomized group assignment, double-blinded assessments, and control or comparison groups reduce the risk of bias. The design must also provide sufficient statistical power to detect a clinically meaningful treatment effect and maintain a nominal level of type I error. An attempt to integrate neurocognitive science into an RCT poses additional challenges. Two particularly relevant aspects of such a design often receive insufficient attention in an RCT. Multiple outcomes inflate type I error, and an unreliable assessment process introduces bias and reduces statistical power. Here we describe how both unreliability and multiple outcomes can increase the study costs and duration and reduce the feasibility of the study. The objective of this article is to consider strategies that overcome the problems of unreliability and multiplicity.

Multisite clinical trials aimed at cognitive enhancement across various neuropsychiatric conditions have employed standard neuropsychological tests as outcome measures. While these tests have enjoyed wide clinical use and have proven reliable and predictive of functional disability, a number of implementation challenges have arisen when these tests are used in clinical trials. These issues are likely to be magnified in future studies when cognitive neuroscience (CN) procedures are explored in these trials, because in their current forms CN procedures are less standardized and more difficult to teach and monitor. For multisite trials, we anticipate that the most challenging issues will include assuring tester competence, monitoring tester performance, specific challenges with complex assessment methods, and having resources available for adequate monitoring of data quality. Suggestions for overcoming these implementation challenges are offered.

While cognitive impairment in schizophrenia is easy to demonstrate, it has been much more difficult to measure a specific cognitive process unconfounded by the influence of other cognitive processes and noncognitive factors (eg, sedation, low motivation) that affect test scores. With the recent interest in the identification of neurophysiology-linked cognitive probes for clinical trials, the issue of isolating specific cognitive processes has taken on increased importance. Recent advances in research design and psychometric theory regarding cognition research in schizophrenia demonstrate the importance of (1) maximizing between-group differences via reduction of measurement error during both test development and subsequent research and (2) the development and use of process-specific tasks in which theory-driven performance indices are derived across multiple conditions. Use of these 2 strategies can significantly advance both our understanding of schizophrenia and measurement sensitivity for clinical trials. Novel data-analytic strategies for analyzing change across multiple conditions and/or multiple time points also allow for increased reliability and greater measurement sensitivity than traditional strategies. Following discussion of these issues, trade-offs inherent to attempts to address psychometric issues in schizophrenia research are reviewed. Finally, additional considerations for maximizing sensitivity and real-world significance in clinical trials are discussed.

Many cognitive tasks have been developed by basic scientists to isolate and measure specific cognitive processes in healthy young adults, and these tasks have the potential to provide important information about cognitive dysfunction in psychiatric disorders, both in psychopathology research and in clinical trials. However, several practical and conceptual challenges arise in translating these tasks for patient research. Here we outline a paradigm development strategy—which involves iteratively testing modifications of the tasks in college students, in older healthy adults, and in patients—that we have used to successfully translate a large number of cognitive tasks for use in schizophrenia patients. This strategy makes it possible to make the tasks patient friendly while maintaining their cognitive precision. We also outline several measurement issues that arise in these tasks, including differences in baseline performance levels and speed-accuracy trade-offs, and we provide suggestions for addressing these issues. Finally, we present examples of 2 experiments, one of which exemplifies our recommendations regarding measurement issues and was a success and one of which was a painful but informative failure.