Michael F. Green - US grants

schizophrenia; neuropsychology; behavior; attention; neuroendocrine system;

DESCRIPTION (provided by applicant): We propose to continue a bi-directional research program that starts with careful characterization of visual processing deficits in schizophrenia and moves systematically into exploration of neural substrates on the one hand and functional outcome on the other. Our research program rests on the premise that considerable information about schizophrenia can be obtained by a close examination of a well- characterized neurocognitive deficit, in the case of this research program, it is early visual processing. The current application takes this program of research in three new directions: First, we plan to assess separately feed forward and reentrant processes of visual processing. Feed forward processes involve the flow of information from retina to and through visual cortex. Reentrant processes, which have become a focus in cognitive science, involve iterative feedforward-feedback processing loops within the cortex. We will examine these processes with performance, electrophysiological, and functional neuroimaging approaches. Second, we will move beyond the earliest components of visual processing that are assessed with visual masking tasks to consider visual short-term memory. Our masking procedures have typically assessed the first 150 ms of visual processing, whereas visual short-term memory represents the first 200 - 500 ms of processing. We will assess this component with versions of the attentional blink task that can be administered during EEC recordings and in the fMRI scanner. Third, we will apply structural equation modeling to explore further the paths between early visual processing and functional outcome in schizophrenia. Our previous studies have reported consistent relationships between early visual processing and social cognition, and between social cognition and functional outcome. Structural equation modeling which is very well suited for these questions, but requires large sample sizes. To accomplish these goals, we plan to recruit 200 patients with schizophrenia and 60 healthy comparison subjects over the 5 years of the project. Subjects will receive interviews, assessments of visual processing (visual masking and attentional blink), and electrophysiology (EEC during visual processing tasks). A subset of participants will receive visual processing tasks in the fMRI scanner. Knowledge from this research program will lead to information on the underlying neural substrates of visual processing in schizophrenia and may lead to innovative treatments, as well as alternative ways of developing and testing new treatments. Knowledge of the relationships between perceptual deficits and daily activities and the mechanisms for these relationships will help us to understand limitations on functional outcome in schizophrenia, help make predictions about outcome, and lead to design of targeted interventions.

Neurocognitive deficits are among the most consistent correlates and predictors of functional outcome in schizophrenia, and we have proposed that the relationships between neurocognition and functional outcome are probably mediated by key intervening variables, including social cognition. Social cognition refers to the mental operations underlying social interactions, which includes the human capacity to perceive the intentions and dispositions of others. The goal of this project is to work closely with noted basic behavioral scientists to apply innovative social cognitive measures to the study of schizophrenia. Because the proposed measures were developed within theoretical models, they will yield a better understanding about how core components of these areas of social cognition are related to functional outcome in schizophrenia. First, we will extend previous studies of face and voice emotion perception in schizophrenia. For this goal, we will work with Peter Salovey from Yale University who, along with his colleagues, has developed an influential multidimensional model and test of emotional processing. Second, we plan to extend the previous studies of social perception in schizophrenia that have involved perception of situational contexts or social roles and social relationships. We will build on the pioneering basic work of Alan Fiske, a Professor in the Department of Anthropology at UCLA, and Nicholas Haslam, a consultant to this project, to test how well patients identify the types of interpersonal relationships that are described in various vignettes. Third, we will examine measures of theory of mind (ToM) that involve the ability of subjects to attribute mental states to other people. Alan Fiske will be the basic behavioral expert for these last two components of the proposal. We plan to test three clinical samples (prodromal, first episode and chronic) and demographically-comparable controls to assess the magnitude of the deficit at each stage. We will examine prospective associations between these measures and 12-month changes in functional outcome in prodromal and first episode patients, and course of illness in the chronic sample. Lastly, we will examine relationships between these tests of social cognition and selected measures from other Center projects.

DESCRIPTION (provided by applicant): Neurobiological deficits that serve as informative endophenotype markers have been demonstrated in schizophrenia by a number of different paradigms. Neurophysiological deficits are prominent in P50 event related suppression, prepulse inhibition (PPI) of the startle response, and the antisaccade (AS) task for eye movement dysfunction. Neurocognitive deficits in schizophrenia are revealed by poor performance on the CPT, verbal memory, and tests of working memory. Each of these deficits has also been demonstrated in clinically unaffected relatives of schizophrenia patients, which is evidence that they may reflect part of the heritable risk for the illness. This conclusion is reinforced by findings of deficits in non-psychotic, unmedicated schizophrenia patients, and schizotypal patients. The null hypothesis is that all 6 deficits reflect a single, common underlying heritable dysfunction in all schizophrenia patients. A test of that hypothesis requires measurement of all of these deficits in the same group of schizophrenia patient probands and their relatives. If they are all manifestations of the same genetic dysfunction (although perhaps expressed in different brain areas), then a multivariate analysis would show that they all contribute to a single dimension in both relatives and schizophrenia patients. An alternative hypothesis is that only one or a small subset of deficits is present in each family, which is consistent with the heterogeneity found in current genetic linkage studies. In that case, the multivariate analysis would show the different measures or subsets of them loading onto different dimensions. Schizophrenia itself is likely to be the result of multiple deficits in any individual. Therefore, the analysis is performed in the same cohort of schizophrenia patient probands and their relatives to take advantage of Mendel's second law, which holds that genetically independent deficits segregate independently. Hence, although schizophrenia patient probands themselves have multiple deficits, if the deficits are caused by different genetic factors, then they will segregate to different groups of relatives. This 7 site collaborative RO1 project will gather a combined total of 420 pedigrees (1680 subjects) and 525 normal subjects over 5 years (each site will contribute 1/7th of these totals). Findings of heritable deficits in specific measures will be used to guide the next generation of studies of the genetics of schizophrenia.

The primary function of the Chronic Schizophrenia Recruitment and Assessment Core will be to recruit and clinically assess chronic schizophrenia patients and demographically comparable normal subjects for participation in studies of the Center for Neurocognition and Emotion in Schizophrenia. By centralizing the recruitment of chronic patients in a single Core, the aim is to increase the efficiency of the process and eliminate the need for individual projects to set up redundant recruitment mechanisms. To maximize the demographic similarity of the chronic sample to the other samples in the Center, chronic schizophrenia subjects will be recruited from former participants in prior longitudinal studies of first-episode patients conducted at the Aftercare Research Program who have had their onset of illness at least five years prior to enrollment in the Center research. This Core will screen, recruit, and conduct diagnostic interviews with the potential patient subjects and the normal comparison subjects. Staff from this Core will also complete ratings of symptom severity and functional outcome (work/school, social, and independent living domains) for all chronic schizophrenia patients who participate in Center projects. In addition, this Core will facilitate and coordinate the involvement of these patient and control subjects in Center projects, including the coordination of laboratory access at UCLA. Unlike the Prodromal Research Program and the Aftercare Research Program, no treatment is provided for thes patients as part of their Center participation. The Specific Aims of this core are to: 1) To screen and recruit patients with chronic schizophrenia from former participants of the UCLA Aftercare Program, according to locally-approved procedures, 2) To provide diagnostic interviews and clinical assessment of potential subjects for Center projects, 3) To screen, recruit, and conduct diagnostic interviews with demographically comparable normal comparison subjects. 4) To facilitate interactions between subjects to the staff of the respective Center projects, and 5) To coordinate the subjects' participation in all Center projects.

DESCRIPTION (provided by applicant): This proposal is being submitted under challenge area "03: Biomarker discovery and validation" with the specific topic "03-MH-101: Biomarkers in mental disorders." It will lead to the hiring or retention of three fulltime staff members. In addition to the challenge area from the American Recovery and Reinvestment Act, the current proposal is consistent with two of the four objectives of the NIMH Strategic Plan: Objective 1 (Promote Discovery in Brain and Behavioral Sciences) and Objective 3 (Develop New and Better Interventions that Incorporate the Diverse Needs and Circumstances of People with Mental Illnesses). It is increasingly clear that recent advances in the treatment of the clinical symptoms of bipolar disorder (BPD) have not improved its functional outcome, which remains disappointing. BPD is highly disabling;based on recent data from the World Health Organization, BPD is the 7th leading cause of years lost to disability for men, and the 8th leading cause for women. Studies suggest that the functional recovery for BPD is no better now, and may even be worse, than it was 30 years ago. This poor functional outcome has little to do with the mood symptoms or mood syndromes. Instead, other factors must be involved, but have yet to be identified. The overarching challenge and knowledge gap addressed by this grant is that we do not know the determinants of daily functioning in BPD. In fact, there are no evidence-based strategies for improving functioning in BPD, resulting in a therapeutic gap. An extensive literature in schizophrenia research has established that basic (non-social) cognition is a key determinant of functional outcome in schizophrenia and that social cognition acts as a mediator between basic cognition and functioning. Hence, to resolve this critical gap and understand the determinants of functioning in BPD, we need to bridge two other gaps. First, we need a much better understanding of social cognition in BPD. Second, it is critical to understand how social cognition influences daily functioning in BPD. Identifying these determinants of outcome is a necessary first step before we can start to develop effective treatments to improve functional outcome in this disorder. To accomplish the goals of this project, we assembled a group of clinical scientists with experience in recruiting and assessing BPD and schizophrenia samples and the necessary range of expertise (performance assessment in chronic mental illness, clinical trial design, electrophysiology, social neuroscience, and biostatistics). Study aims will be evaluated over 2 years in a sample of 48 euthymic BPD outpatients and 36 healthy controls. We will also include 36 clinically stable schizophrenia outpatients to evaluate the relative magnitude of any impairment in BPD. Participants will be recruited from the Mood Disorder Clinic and Schizophrenia Clinic at UCLA, and mental health clinics at the VA Greater Los Angeles Healthcare System. The goals of the project will be achieved by assessing participants on five types of measures: social cognition (performance and EEG), early visual perception, basic cognition, clinical, and functional. This project has three aims: For the first aim, we will evaluate the level and pattern of impairment relative to healthy controls of social cognition biomarkers in euthymic BPD patients using performance measures from two separate domains of social cognition (recognizing social-affective stimuli, and making high-level mental inferences) and an EEG procedure. We hypothesize that BPD patients will show clear deficits on these procedures. For the second aim, we will evaluate whether euthymic BPD patients show impairment compared with healthy controls on factors that influence social cognition, including basic cognition and early visual perception. For the third aim, we will evaluate associations within the BPD sample among social cognition, its determinants (basic cognition, early visual perception) and functioning (functional capacity and community functioning). The activities in this proposal are early, but critical, steps toward larger research goals. The disability of BPD is substantial and represents an unmet therapeutic need. The longer-term objective of this research program is to understand the mechanisms and identify the determinants of functioning in BPD so that this information can guide new pharmacological and training approaches to improve functioning in this disorder. PUBLIC HEALTH RELEVANCE: The disability of bipolar disorder is substantial and represents an unmet therapeutic need -- there are no evidence-based strategies for improving functioning in bipolar disorder. The goal of this grant is to identify important determinants of daily functioning in bipolar disorder, with a focus on social cognition. The long-term objective of this research program is to understand the mechanisms and identify the determinants of functioning in bipolar disorder and to use this information to guide new pharmacological and training approaches to improve functioning in this disorder.

DESCRIPTION (provided by applicant): The Consortium on the Genetics of Schizophrenia (COGS-2) is a 6-site collaborative linked R01 study that aims to understand the genetic architecture of functionally important quantitative neurophysiological and neurocognitive endophenotypes and the qualitative phenotype of schizophrenia in 2,000 patients and 1,000 community comparison subjects (CCS). During the initial support period, the COGS-1 project developed a robust research platform for subject recruitment, careful clinical characterization, acquisition, quality assurance, and analysis of these endophenotypes in probands (N=305), clinically unaffected family members (N=1,014) and CCS (N=505). In addition, COGS-1 developed novel statistical genetics methods that take full advantage of the unique findings that have emerged to date. The COGS-2 renewal will extend the use of the original 3 neurophysiological and 3 neurocognitive endophenotypes, as well as additional heritable endophenotypes derived from COGS-1 using the Computerized Neurocognitive Battery (CNB). Given the increased importance of the relationship of these endophenotypes to functional outcome, COGS-2 will also add a functional status assessment battery, consisting of observer-based, surrogate and real-world functional status. COGS-2 will complete the originally proposed linkage analysis in the COGS-1 sample, as well as conduct a candidate gene study from the COGS-1 database using the custom COGS 1536 SNP Chip. COGS-2 will focus on ascertaining, testing and obtaining DNA from new samples of 2,000 schizophrenia patients and 1,000 CCS recruited via Specific Aim 1. In Specific Aim 2, a genome wide association study (GWAS) using the current and most informative platform at the Center for Inherited Disease Research (CIDR) will be performed using the COGS-2 case-control data on the 9 COGS-2 quantitative endophenotypes and the qualitative diagnosis of schizophrenia. A complementary association study, using many strong-inference derived SNPs not included in the CIDR platform, will utilize the COGS SNP Chip array (94 candidate genes, 1536 SNPs) to assess SNP and copy-number variations (CNVs) associated with endophenotype deficits in schizophrenia as well as schizophrenia itself. In Specific Aim 3, SNPs and CNVs associated with these endophenotypes and schizophrenia will be compared with those in publicly available databases (e.g., GAIN, CATIE, BROAD). Furthermore, we will continue to develop the COGS platform and related innovative statistical genetics methods to identify and interrogate crucial genetic data in order to enhance the search for schizophrenia vulnerability genes, enhance the endophenotype strategy and ultimately identify molecular targets for the treatment and improved function of schizophrenia patients.

CORE 6: CHRONIC SCHIZOPHRENIA ASSESSMENT AND RECRUITMENT CORE The primary function ofthe Chronic Schizophrenia Recruitment and Assessment Core will be to recruit andclinically assess chronic schizophrenia patients and demographically comparable normal subjects for participation in projects ofthe Center for Neurocognition and Emotion in Schizophrenia. By centralizing the recruitment of chronic patients in a single Core, the aim is to increase the efficiency ofthe process and eliminate the need for individual projects to set up redundant recruitment mechanisms. To maximize the demographic similarity ofthe chronic sample to the other samples in the Center, chronic schizophrenia subjects will be recruited from former participants in prior longitudinal studies of first-episode patients conducted at the Aftercare Research Program who have had their onset of illness at least five years prior to enrollment in the Center research. This Core will screen, recruit, and conduct diagnostic interviews with the patient subjects and the normal comparison subjects. Staff from this Core will also complete ratings of symptom severity, functional capacity, functional outcome, and neurocognition for all subjects participating in this Core. In addition, this Core will facilitate and coordinate the involvement of these patient and normal subjects in Center projects, including the coordination of laboratory access at UCLA. Unlike the Prodromal Research Program and the Aftercare Research Program, no treatment is provided for these patients as partof their Center participation. The specific aims ofthis Core are to: 1) recruit and evaluate patients with chronic schizophrenia from former participants ofthe UCLA Aftercare Program, 2) To conduct diagnostic, symptom, functional outcome, and neurocognitive assessments of Chronic patients who will be participating in Center project protocols, 3) To recruit, screen, and complete diagnostic, symptom, functional outcome, and neurocognitive assessments with demographically comparable normal comparison subjects, 4) To facilitate and coordinate the participation of chronic schizophrenia patients and demographically comparable normal subjects in the Center projects.

PROJECT 3: SOCIAL COGNITION Social cognition refers to mental operations required for adaptive social functioning, Including perceiving, interpreting, and generating responses to the intentions, emotions, and behaviors of others. In the first grant period, we selected three behavioral measures that assess processes considered essential for meaningful communication, including relationship perception, Theory of Mind, and emotion processing. Prodromal, recent-onset, and chronic patients all performed significantly worse than their matched controls on these measures, with comparable effect sizes across illness phases. The next phase of this research program will extend findings from the first phase in several ways. First, we will look beyond static measures of social cognition and will test both social (facial affect perception) and non-social (problem solving) dynamic measures of malleability in response to brief intervention probes. Second, we wil evaluate the nature of the relationships among basic cognition, social cognition, and functional outcome using a subset of social cognitive measures from the current study. We will examine whether social cognitive measures explain unique variance in functional outcome beyond basic cognition as measured by the MCCB, and whether these measures serve as mediators between basic cognition and outcome. Third, going beyond the findings of short-term stability of performance, we will examine long-term stability on specific measures of social cognition after an average of 5 years. Fourth, we will assess recollection and familiarity of social stimuli with a newly developed version of the Remember-Know (R-K) paradigm. We will compare recollection versus familiarity indices for their relationships to outcome, and compare these results to a non-social R-K paradigm administered in the Memory Project. Despite receiving adequate treatment, many individuals with schizophrenia have problems in social communication and independent functioning. The proposed research will shed light on the developmental course and malleability of social cognitive deficits that impact functioning in schizophrenia. This information can inform the development of new treatments for social cognitive deficits that may improve community functioning in schizophrenia.

DESCRIPTION (provided by applicant): Social cognition is defined in various ways, and generally refers to mental operations that underlie social interactions, including perceiving, interpreting, managing, and generating responses to the intentions and behaviors of others. Social cognitive impairments are determinants of community functioning in schizophrenia and are increasingly viewed as targets of intervention. To evaluate social cognition as a treatment endpoint, it is necessary to include reliable and valid social cognitive measures in clinical trials. The current proposal is framed in a translational context, in which we have turned to social neuroscience to select measures that have good validity and that are highly promising for clinical studies with schizophrenia patients. To this end, we assembled scientific experts in experimental psychopathology, social neuroscience, clinical trial methodology, and psychometrics from UCLA, Columbia University, and University of North Carolina. The project has three aims: The first aim is to determine the extent to which selected measures from social neuroscience are suitable for use in clinical trials of schizophrenia. The second aim is to use these measures to account for unexplained variance in a functioning in schizophrenia. The third aim is to better understand the ways in which social cognition acts as a mediator between basic (non-social) cognition and functioning in schizophrenia. These study aims will be evaluated in a sample of 240 schizophrenia patients (tested twice at a 4-week interval) and 50 healthy comparison subjects (tested once). Participants will be recruited equally at two performance sites (Los Angeles and Chapel Hill). This proposal is submitted under NIMH Funding Opportunity Announcement (FOA) PA-08-255 Functioning of People with Mental Disorders and it addresses two objectives of the NIMH Strategic Plan. Within Objective 1 (Promote Discovery in Brain and Behavioral Sciences) this project is consistent with the goal to deconstruct clusters of complex behaviors and attempt to link these to underlying neurobiological systems. In this study we will: 1) deconstruct basic cognition and social cognition in schizophrenia and 2) differentiate subprocesses within social cognition. Within Objective 3 (Develop new and better interventions), our project is consistent with the goal to broaden the focus by what is meant by outcome measures in treatment research. We will evaluate measures from social neuroscience for their use in clinical trials of cognition enhancement in schizophrenia with a broad focus on improving overall functioning. The long-term goals of this project are to: 1) understand the determinants of community functioning in schizophrenia and 2) facilitate the development of effective drugs for social cognitive deficits that will help individuals with schizophrenia acquire skills and function better in their daily lives.

DESCRIPTION (provided by applicant): Visual processing abnormalities in schizophrenia (SZ) are pervasive, seen in a variety of paradigms, and typically large in magnitude. Despite their informative value, these impairments have received far less research attention than impairments associated with frontal and temporal cortical systems. Visual processing paradigms often have well-established neural bases and provide a direct way to investigate neural functioning in SZ. Partly as a result of reduced research emphasis there are fundamental gaps in our knowledge. One such gap is the absence of an integrated theory that satisfactorily explains the patterns of findings across the range of visual processing measures. A second is that we do not know the degree to which visual processing impairment extends across diagnoses for chronic mental illness, including SZ and bipolar disorder (BD). Although abnormalities in visual processing have been found in BD, few attempts have been made to examine performance in BD in a detailed manner across visual processing stages. The current application will test a theory of a core process that might help explain the range of visual processing impairment observed in SZ and BD. We hypothesize that an array of findings from our laboratory, and others, might be explained most parsimoniously as an abnormality in the tuning of neurons for object features (i.e., neurons are less able to generate specific neural responses to preferred visual objects versus visually similar objects; referred to as visual tuning). Visual processing for objects or object features occurs in the lateral occipital complex (LO). Although the literature on visual processing abnormalities in BD is smaller than that in SZ, such impairments have been found. The current application will evaluate whether such deficits in BD also stem from problems in visual tuning. The proposed study will recruit 90 SZ patients, 90 BD patients and 90 healthy controls that will be group- matched on key demographic variables. The subjects will participate in perceptual performance, electrophysiological (EEG), cognition, and functional magnetic resonance imaging (fMRI) procedures to address the following three aims: 1) To examine visual neural tuning in SZ using specialized EEG and fMRI methods; 2) To examine visual neural tuning cross-diagnostically among SZ, BD, and healthy controls with specialized EEG and fMRI methods; and 3) To examine the implications of visual tuning deficits in SZ, BD, and healthy controls, including perception, higher-level cognition, and functioning. This program of research is consistent with several components of the NIMH Strategic Plan and the NIMH Research Domain Criteria project. Results from this research program will lead to information on the similarities and differences in visual processing between SZ and BD, and the underlying neural substrates of visual processing impairment in these conditions. Visual tuning is modifiable and can be reliably assessed in humans and animals, so this information will have implications for treatment development.

PROJECT ABSTRACT Social disconnectedness (SD; long-standing lack of social / family relationships and minimal participation in social / family activities) is a huge public health problem that is associated with a wide range of negative effects. SD has negative mental and physical health consequences, with an increased risk of early mortality comparable to that of smoking. Importantly, SD exists on a continuum. It is common among individuals with severe mental illness (SMI) such as the schizophrenia spectrum (SzS), and to a lesser extent, in bipolar disorder (BD). Social functioning impairment in these disorders has barely changed with the introduction of psychoactive medications, and it translates into the very high rates of disability associated with SzS and BD throughout the world. SD also exists in individuals in the general community. Very large gaps remain in our understanding of which factors contribute to SD, particularly the neuroscience basis for SD. Understanding the determinants of SD across a spectrum is important because it can guide recovery-based treatment interventions that target such determinants. From our previous work, we know that the determinants of social functional impairment in SzS include: 1) ability (e.g., social communication) and 2) motivation (e.g., for social approach). But we have a poor understanding of the determinants of SD across a severity spectrum that extends to the general community. In this project, we will evaluate social processing constructs from the NIMH Research Domains Criterion (RDoC) Project to identify determinants of SD in mental illness and people with SD from the community. The social processing constructs include: social approach and avoidance motivation, reception of facial communication, and understanding mental states of others. These constructs can be reliably measured at units of analysis, including: behavior (performance), physiology (electrophysiology, EEG), and circuits (functional magnetic resonance imaging, fMRI). To examine the determinants of SD across a severity spectrum, we will recruit a total 350 participants: 75 SzS, 75 BD, 75 from the community who are socially connected, and 125 from the community who report longstanding SD. A subset of 160 subjects will receive fMRI. The study aims are: 1) to evaluate the degree to which social motivation (i.e., social approach and social avoidance motivation) measured by performance, EEG, and fMRI paradigms determine SD across a severity spectrum, and 2) to evaluate the degree to which ability (i.e., social communication, perception / understanding of others) measured by performance, EEG, and fMRI paradigms determine SD across a severity spectrum. We also have two exploratory aims: 1) to determine whether there are significant interactions between the two ability constructs and social motivation in determining degree of SD, and 2) to evaluate the degree to which the RDoC social constructs are associated with subjective loneliness, controlling for SD.

PROJECT ABSTRACT Social disconnectedness (SD; long-standing lack of social / family relationships and minimal participation in social / family activities) is a huge public health problem that is associated with a wide range of negative effects. SD has negative mental and physical health consequences, with an increased risk of early mortality comparable to that of smoking. Importantly, SD exists on a continuum. It is common among individuals with severe mental illness (SMI) such as the schizophrenia spectrum (SzS), and to a lesser extent, in bipolar disorder (BD). Social functioning impairment in these disorders has barely changed with the introduction of psychoactive medications, and it translates into the very high rates of disability associated with SzS and BD throughout the world. SD also exists in individuals in the general community. Very large gaps remain in our understanding of which factors contribute to SD, particularly the neuroscience basis for SD. Understanding the determinants of SD across a spectrum is important because it can guide recovery-based treatment interventions that target such determinants. From our previous work, we know that the determinants of social functional impairment in SzS include: 1) ability (e.g., social communication) and 2) motivation (e.g., for social approach). But we have a poor understanding of the determinants of SD across a severity spectrum that extends to the general community. In this project, we will evaluate social processing constructs from the NIMH Research Domains Criterion (RDoC) Project to identify determinants of SD in mental illness and people with SD from the community. The social processing constructs include: social approach and avoidance motivation, reception of facial communication, and understanding mental states of others. These constructs can be reliably measured at units of analysis, including: behavior (performance), physiology (electrophysiology, EEG), and circuits (functional magnetic resonance imaging, fMRI). To examine the determinants of SD across a severity spectrum, we will recruit a total 350 participants: 75 SzS, 75 BD, 75 from the community who are socially connected, and 125 from the community who report longstanding SD. A subset of 160 subjects will receive fMRI. The study aims are: 1) to evaluate the degree to which social motivation (i.e., social approach and social avoidance motivation) measured by performance, EEG, and fMRI paradigms determine SD across a severity spectrum, and 2) to evaluate the degree to which ability (i.e., social communication, perception / understanding of others) measured by performance, EEG, and fMRI paradigms determine SD across a severity spectrum. We also have two exploratory aims: 1) to determine whether there are significant interactions between the two ability constructs and social motivation in determining degree of SD, and 2) to evaluate the degree to which the RDoC social constructs are associated with subjective loneliness, controlling for SD.