Jack Blanchard - US grants

The accurate identification of individuals prone to the development of schizophrenia is necessary for the study of environmental and biological factors that heighten or reduce the probability of developing this disorder. The detection of such vulnerable individuals would also help in prevention efforts. Unfortunately, prior research on the psychometric detection of schizophrenia-proneness has been limited in that what has been detected is more generally psychosis-proneness. Also, there are concerns that prior research is limited by the study of non-minority college students that are not representative of the general population. In this revised application it is proposed that social anhedonia may be a promising indicator of the latent liability for schizophrenia. The role of social anhedonia in the development of schizophrenia will be studied in a randomly ascertained community sample of 18 year-olds who will be selected independently of race, education, or socio-economic status. First, this study will examine the hypothesis that taxometrically identified socially anhedonic individuals are at risk for schizophrenia and schizophrenia-spectrum disorders. Subjects (social anhedonics and controls) will be assessed for schizophrenia and other Axis I disorders, schizophrenia-spectrum personality disorders, and psychotic-like experiences at a base assessment and again at a 3-year follow-up. Second, to understand the range of outcomes in at-risk individuals, other individual difference variables will be assessed that may potentiate the expression of schizophrenia and schizophrenia-spectrum disorders. It is hypothesized that, in vulnerable individuals, reduced social support, elevated trait negative affect, and attentional impairment at the base assessment will increase the probability of clinically diagnosable illnesses and generally poorer functioning at the follow-up assessment. Third, the proposed investigation will examine the hypothesized genetic risk for schizophrenia associated with social anhedonia by directly assessing schizophrenia-related diagnoses and characteristics in the biological parents of social anhedonics and controls.

[unreadable] DESCRIPTION (provided by applicant): This is a revised application requesting funds to support a minimum of two years of predoctoral training in schizophrenia research. The predoctoral training program is designed to develop future schizophrenia researchers capable of translating basic behavioral, cognitive, developmental and neuroscience principles into research on the psychopathology of schizophrenia. The proposed training program will involve four predoctoral students in the Ph.D. clinical psychology program at the University of Maryland, College Park (UMCP). The predoctoral focus of the program was selected in order to place training at an early point in students' careers and thus allow for the greatest impact on trainee's research skills and scientific orientation as well as their future interests in maintaining a career focus within schizophrenia. This training program emphasizes a multidisciplinary orientation that includes diverse course work and the involvement of research mentors at UMCP, the University of Maryland Medical School, and the Maryland Psychiatric Research Center. The program will have five components to achieve multidisciplinary training in schizophrenia research: 1) trainees will complete core courses in schizophrenia involving the psychopathology of this disorder as well as psychosocial aspects of functioning and treatment, 2) additional courses in behavioral, cognitive, developmental and neurosciences will be taken as part of the program curriculum, 3) trainees will participate in a thematically integrated weekly core seminar that includes presentations by core faculty, visiting schizophrenia scientists, and faculty from related fields such as developmental psychology and neuroscience, 4) trainees will participate in a year-long clinical externship focusing on the assessment and treatment of schizophrenia and severe mental illness, and 5) throughout the training program, fellows will have intensive research experiences within Mentor labs conducting a range of basic and applied research in schizophrenia. Mentors represent a diverse array of schizophrenia research (largely extramurally-funded) including ethical issues in the study of schizophrenia, neuropsychological aspects of functioning, neuropharmacology, neurological models of symptomatology, emotion and stress reactivity in schizophrenia, social impairment and psychosocial remediation, detection of risk for the development of schizophrenia, assessment and diagnosis, gender differences, comorbidity, family issues, and service models. In sum, the proposed NRSA would establish a unique and much needed predoctoral training program that will develop scientists who are trained and devoted to the study of the causes and treatments of schizophrenia. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This is an application for an Independent Scientist Award (K02) that would enable the PI to further develop his research on emotional and social impairment within schizophrenia. The career development plan will allow the PI to obtain training in affective and social neuroscience research that can then serve as the basis for additional translational research in the study and treatment of schizophrenia. This training will involve the following interrelated areas: developmental perspectives on peer relationship formation and socialization, developmental approaches to the understanding of individual differences in temperament and emotion, psychophysiological methods in the study of emotion, and social neuroscience approaches to the study of social behavior and emotion. These career development goals will be met through consultation, research activities, and collaborations with senior researchers in the areas of developmental psychology, basic emotion research, and social neuroscience. Classroom and technical training as well as attendance at scientific meetings and workshops will complement these consulting activities. The proposed didactic and career development activities are closely coupled with the research plan that is, in part, based on the PI's current funded research on anhedonia in schizophrenia and schizotypy (R01 MH512460). Ongoing and planned research will focus on understanding how emotion is altered in schizotypy and schizophrenia including how these emotional changes contribute to disturbances in affiliation and resulting social impairment. This research will span community samples involving schizophrenia-spectrum disorders as well as planned studies on schizophrenia. In sum, an Independent Scientist Award will provide the needed protected time for the PI to develop new skills in the study of emotion and social behavior from a basic science perspective. These new skills will be applied by the PI to future translational research aimed at understanding the profound emotional and social deficits occurring in schizophrenia and will have direct benefit to the development of future interventions in schizophrenia.

DESCRIPTION (provided by applicant): Negative symptoms are distinct clinical features of schizophrenia that are major determinants of the poor community functioning and poor long-term outcome that characterize the disorder. However, they are only minimally responsive to available treatments and are a substantial burden for care-givers. To address this critical unmet treatment need, the NIMH recently sponsored a consensus development conference to identify research priorities to stimulate the development of novel treatments for negative symptoms. The number one recommendation for advancing research and moving towards new treatment development in this area was to develop a "next generation" assessment instrument that solves the conceptual and methodological problems of existing measures. For the instrument to achieve widespread acceptance, the conference participants concluded that it is essential to follow a transparent, rigorous scale development process using large, diverse, and representative samples. As members of the NIMH-MATRICS Negative Symptoms Workgroup, the Principal Investigators have collaborated with experts from academia, the pharmaceutical industry, and government agencies to develop a new instrument, the Negative Symptom Rating Scale (NSRS). The proposed four-site Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS), including the Universities of Maryland, Pennsylvania, California-Los Angeles, and California-Berkeley, is designed to carry out the recommendations of this NIMH initiative over a three-year period. These four sites represent areas of ongoing research in schizophrenia and negative symptoms, with the necessary infrastructure and unique expertise to carry out the proposed studies. Study 1 will evaluate the psychometric properties of the beta version of the NSRS in 300 schizophrenia outpatients. Results will guide data-driven refinements of the instrument based on state-of-the-art data analytic techniques, including Item Response Theory analyses and item level factor analyses that will allow us to ascertain how well the NSRS items assesses the underlying negative symptom construct and its putative sub-components, the dimensional structure of the measure, and gender invariance. Study 2 will evaluate the psychometric properties, test-retest reliability, and factor structure via confirmatory factor analysis of the revised NSRS in160 patients with schizophrenia. Convergent/discriminant validity with respect to a range of other clinical and neurocognitive features of schizophrenia, as well as measures of social and emotional functioning will also be evaluated. The multi-site structure of the CANSAS will permit an efficient evaluation of the NSRS in large ethnically and clinically diverse samples, enabling us to rapidly disseminate a final version of the scale to researchers conducting clinical trials and other types of negative symptom research. PUBLIC HEALTH RELEVANCE: Negative symptoms are major determinants of poor functional outcome in schizophrenia and available treatments are largely ineffective for these symptoms. The proposed Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS) will carry out the main recommendation of the recent NIMH Consensus Development Conference to create and validate a new assessment instrument, the Negative Symptom Rating Scale, for use in clinical trials and other types of research. This state-of-the art instrument will play a central role in the NIMH initiative to stimulate the development of new treatments aimed at reducing the disability associated with negative symptoms.

As defined by the RDoC Social Processes Workshop, affiliation is the engagement in positive social interactions with others. The desire to affiliate has been described as a fundamental human motivation. However, impairments in the drive to affiliate occur across multiple clinical disorders and these affiliative impairments have devastating consequences for individuals, their family members, and society. Despite the major clinical significance of impairments in social affiliation, the factors that contribute to affiliative impairment are poorly understood. We propose a multi-method assessment of a large and diverse clinical sample to examine how social affiliative deficits are associated with a) the social regulation of neural systems relating to emotion as assessed through a novel fMRI paradigm for studying the in vivo social regulation of emotion in the context of affiliative relationships, b) neural processes associated with social reward, c) learning of the positive affective value of others, and d) behavioral affiliative skills. Consistent with the RDoC, this application will include assessment of affiliation processes across units of analyses including circuits, behavior, and self-report within a transdiagnostic sample of individuals with psychotic disorders. With regard to the study of neural systems, a powerful mechanism that may underlie the motivation for social contact is the social regulation of emotion, particularly the social regulation of threat responding. We propose the use of a novel paradigm to create affiliative relationships within the lab and subsequently will examine how this affiliative relationship regulates emotional responding to a stressor (a key function of affiliative relationships) within an fMRI scan. Specifically, we will examine the hypothesis that affiliative deficits are associated with the failure of social contact to down regulate neural activity in the context of a stressor. In addition to the benefits that affiliation provides when responding to threat, the motivation for social relationships may derive from activation of neural systems involved in reward. We will also explore the contribution of reward circuits to affiliative impairment using both social and monetary reward paradigms. Beyond neural responding, the proposed study will examine how individuals form behavior-based impressions of others in ways that may facilitate or impede social affiliation. We will examine the hypothesis that deficits in affiliation are associated with impairments in the ability to use behavior-based person information to form positive impressions concerning the affective value of others in the social environment. Finally, behavioral social skills form the basis for effective communication and are thought to be critical to social competence. We will examine the hypothesis that impairments in social affiliation are specifically related to deficits in behavioral affiliative skills. The proposed study will provide an integrative perspective to advance our understanding of the neural and behavioral factors that give rise to impairments in social affiliation within clinical populations and this research will provide insights that will inform the development of interventions to address such impairments in affiliation.

Paranoid ideation?the mistaken belief that intentional harm is likely to occur?spans a continuum, from mild suspicion to persecutory delusions. Among patients with schizophrenia and other psychosis disorders, elevated levels of paranoia are common, debilitating, and challenging to treat. The cues (public environments, strangers) and processes (anxiety) that promote paranoia have grown increasingly clear, but the brain bases of these pathways are unknown, thwarting the development of mechanistic models and, ultimately, the development of more effective or tolerable biological interventions. Leveraging our team?s unique multidisciplinary expertise and productive track record of NIH-sponsored research, this project will use an innovative combination of paranoia assessments, advanced neuroimaging techniques, and smartphone-based experience sampling to clarify the factors governing paranoia. We will enroll the full spectrum of paranoia without gaps or discontinuities?including psychosis patients with frank persecutory delusions and matched community controls. These data will allow us to rigorously examine the hypothesized contribution of brain circuits responsible for triggering anxiety and evaluating the threat potential of everyday social cues, such as faces. Integrating neuroimaging measures with experience-sampling data will enable us to extend these insights to the real world?a key step to establishing therapeutic relevance?for the first time. It has become increasingly clear that categorical psychiatric diagnoses (e.g. schizophrenia) present significant barriers to understanding pathophysiology. Our focus on dimensional measures of paranoia overcomes many of these barriers and dovetails with the National Institute of Mental Health?s Strategic Objectives and Research Domain Criteria (RDoC) initiative. This work would provide a potentially transformative opportunity to test and refine theory, deepen our understanding of etiology, guide the development of new translational models, discover new treatment targets, and provide an integrative biopsychosocial framework for unifying research across investigators, approaches, and scholarly guilds.