Keith Nuechterlein - US grants

DESCRIPTION (Adapted from the Applicant's Abstract): The Developmental Processes in Schizophrenic Disorders project involves an ongoing series of longitudinal follow-through studies of individuals with a recent onset of schizophrenia. The proposed new protocol focuses particularly on developmental processes affecting work outcome in this initial period after onset of schizophrenia, drawing on findings that link cognitive deficits in schizophrenia to functional outcome. This initial period precedes any chronic disability patterns and is therefore of particular public health significance. The new protocol will determine the effects on work outcome of an intervention designed to enhance search for appropriate work or schooling and to increase ability to maintain work or school activities more successfully. The protocol will determine the predictors of level of work functioning attained in the context of the new work-focused intervention and maintenance on risperidone. Potential neurocognitive and environmental predictors of work and social functioning and clinical course will be examined. Aspects of early perceptual processing, allocation of attention, working memory, secondary verbal memory, and conceptual flexibility that are implicated as enduring vulnerability factors in schizophrenia and influences on functional outcome will be assessed, as will potential stresses and supportive influences in the environment. Schizophrenic patients from an earlier recent- onset cohort will be reassessed at an average of 8 years after their initial outpatient testing to examine the stability of hypothesized cognitive and psychophysiological vulnerability factors and their relationship to long-term outcome. Assessments of individuals focus on cognitive performance, Assessments of possible environmental factors examine stressful life events, social support, and use of coping strategies.

schizophrenia; cognition disorders; cognition; neural information processing; psychophysiology; biomedical facility; neuropsychological tests; psychomotor reaction time; brightness discrimination; remission /regression; disease /disorder proneness /risk; galvanic skin response; visual perception; memory; startle reaction; behavioral /social science research tag; clinical research; human subject;

[unreadable] DESCRIPTION (provided by applicant): This training program is designed to train investigators in the basic skills needed to conduct clinical research with individuals who have schizophrenia or mood disorders. The program emphasizes four major research domains that are consistent with the research directions of the participating faculty: (1) cognitive and psychophysiological abnormalities in patients with schizophrenia and mood disorders and in their relatives, and the contributions of these core deficits to functional impairment, psychiatric symptoms, and treatment response; (2) psychosocial and environmental contextual factors in the course and outcome of schizophrenia and mood disorders and their relevance to treatment response; (3) development and evaluation of improved rehabilitative interventions for schizophrenia and mood disorders; and (4) evaluation of psychopharmacological interventions for symptoms and for cognitive deficits in these disorders. The program emphasizes training in the translation of behavioral science concepts and paradigms into clinical research on these disorders. The program has five components: (1) development by trainees of individual clinical research projects closely supervised by program mentors, (2) active participation in ongoing weekly core research seminar, (3) acquisition of skills in research assessment of diagnosis, clinical outcome, and functional outcome and in clinical research design, (4) training in the preparation of scientific presentations, publications, and research grant applications, and (5) academic course work appropriate to the selected research domains. There are two related training programs, one for predoctoral trainees who are students admitted to the Ph.D. program in clinical psychology at UCLA and a second for postdoctoral trainees. The latter program is available to persons who have received a Ph.D. in psychology or an M.D. followed by a psychiatric residency. Trainees are assigned to primary and secondary mentors who provide hands-on clinical research experience and facilitate development of research careers. [unreadable] [unreadable]

DESCRIPTION (Adapted from Applicant's Abstract): This application for a new Institutional National Research Service Award is a response to the new program announcement, NIMH Postdoctoral Research Training in Intervention Trials. This application is designed to support a postdoctoral program for Intervention Research Training for the Psychoses. The program will train clinical investigators in the basic skills necessary to develop, conduct, and interpret intervention trials research that focuses on treatment, rehabilitation, and prevention of schizophrenia and major mood disorders. The program will include training relevant to conducting well-controlled initial studies of the efficacy of new treatments and intervention trials that broaden the evaluation of the impact of treatments to incorporate a public health perspective. Thus, the training program will include experiences with intervention trials in which generalization of treatment effects is examined across outcomes including work and social functioning as well as symptom resolution, in different academic and community clinical settings, and with patients with diverse socioeconomic characteristics. Training in evaluation of psychosocial rehabilitation, cognitive remediation, and psychopharmacological intervention strategies will be available in this program through the inclusion of mentors with a range of specific areas of expertise. The program has several components: (1) participation in an ongoing weekly core clinical research seminar, (2) academic coursework tailored to individual needs, (3) hands-on experience with ongoing intervention trials research and development by trainees of affiliated intervention research supervised by program mentors, (4) skill training in the systematic assessment of work and social functioning, symptoms, and cognitive anomalies in these severe mental illnesses, and (5) training in the preparation of posters, articles, and research grant applications. This postdoctoral training will be available to parsons who have received a M.D. followed by a psychiatric residency or a Ph.D. in clinical psychology or comparable professional health degree. Half of the postdoctoral trainees are expected to be M.D.s and the other half Ph.D.s. Trainees will be assigned to primary and secondary mentors who will supervise their training activities in an individualized research mentorship model.

The Aftercare Research Program is an outpatient research clinic at the UCLA Neuropsychiatric Institute that will provide the clinical site for the recruitment, pharmacological and psychosocial interventions, and assessments of symptoms and functional outcome for first-episode patients who are participating in research projects in this Center. The primary mission of the Aftercare Program is to provide a structured and high quality clinical care setting within which this Center research can take place. The Aftercare Research Program will provide a centralized and standardized process for screening and diagnosing first-episode schizophrenia patient participants, providing their clinical services, and completing high-quality longitudinal assessments of symptoms, work functioning, and social functioning. As detailed in the budget justification section for this Core, this centralization will result in great savings to the multiple individual projects that involve Aftercare Program patients, compared to costs if these research projects were carried out independently. Furthermore, by utilizing a shared group of first-episode patients, opportunities for integrative data analyses across projects will become available. A second function is to optimize the level of patient participation in Center-related research projects. A third function is to provide a sample of normal subjects, demographically comparable to the first-episode patients, for potential participation in Center-affiliated projects. A fourth function of the Aftercare Research Program is to provide a convenient group of patient volunteers for the piloting of new measures being developed by individual projects and by the Diagnosis and Symptom Assessment Core and the Functional Outcome Core. A fifth function is to offer a research training site for predoctoral and post-doctoral research fellows to encourage development of new translational researchers. Two psychiatrists and three masters level therapists will provide the clinical interventions and research assessments in space allocated to the Program in the UCLA Medical Plaza.

DESCRIPTION (provided by applicant): This is a revised application to establish a Translational Research Center in the Behavioral Sciences, consistent with the NIMH program announcement PAR-01-027. The proposed "Center for Neurocognition and Emotion in Schizophrenia" has been developed through the formation of newly formed research teams that integrate basic behavioral researchers and clinical researchers to facilitate meaningful and novel collaborations. We will focus on two basic behavioral domains that are fundamental to schizophrenia: neurocognition and emotion. The three primary overarching aims of the proposed Center are: 1) to translate major advances in basic behavioral research on cognitive and emotional processes into new clinical research; 2) to advance our understanding of the fundamental role that core neurocognitive and affective abnormalities play in functional outcome for individuals with schizophrenia; and 3) to examine different phases of illness as well as the shortterm developmental course of schizophrenia as means of shedding much more light on the roles of the core neurocognitive and emotional abnormalities in illness onset, progression, or recovery. To do this, we have formed teams of clinical investigators and basic behavioral investigators for six research projects. The projects range from those addressing relatively basic neurocognitive processes ("Development of Automaticity", "Encoding and Retrieval Processes in Long-Term Memory", "Attention and Dual-Task Interference") to one addressing primarily emotional processes ("Stress and Emotional Reactivity"), with two projects at the interface between neurocognitive and emotional processes ("Social Cognition: Interpersonal and Emotional Processes", "Associative Learning and Emotion Regulation"). The formation of new teams of basic and clinical investigators will permit us to study processes relevant to schizophrenia that have not been studiedthrough these novel paradigms. Seven cores will directly serve the needs of the research projects and the translational behavioral science mission of the Center: 1) the Administration and Training Core, 2) three service cores (a Data and Methodology Core, a Functional Outcomes Core, and a Diagnosis and Symptom Assessment Core), and 3) three clinical cores (Prevention Research Program, Aftercare Research Program, and Chronic Schizophrenia Recruitment and Assessment Core).

We propose to use a translational behavioral science strategy to bring paradigms with greater analytic power to the study of attention in schizophrenia and also to develop further basic paradigms of relevance to schizophrenia. Dual-task interference studies have particular promise for clarifying the processes involved in attentional limitations in schizophrenia. They allow direct tests of whether impairments during performance of two overlapping tasks are due to specific forms of central structural bottlenecks, as opposed to the graded capacity sharing that would be predicted by processing resource limits. Using a specific type of dual-task paradigm, the Psychological Refractory Period paradigm, it is also possible to identify the locus of structural processing bottlenecks, that is, processing points at which certain cognitive operations cannot be completed simultaneously. Five studies at UCLA with 96 prodromal, 100 first-episode, and 80 chronic patients and equal numbers of demographically comparable normal subjects will use Psychological Refractory Period paradigms that have well-documented utility in basic cognitive research for detecting and locating a processing bottleneck in dual-task performance. The first four will test whether the "cognitive architecture" affecting dual-task interference is altered in persons with prodromal symptoms or in first-episode or chronic schizophrenia patients, such that the processing bottleneck includes perceptual encoding or response production in addition to response selection processes. The fifth clinical study will examine whether retrieval from long-term memory is a component of the central bottleneck as it is in normal subjects and, if so, whether memory retrieval causes an abnormally large disruption (i.e. longer delay) in dual-task performance in the patients. Short-term longitudinal studies will determine whether certain components of dual-task interference become more severe over time, predict psychosis onset, and are particularly strong predictors of functional outcome. Predictive contributions of perceptual encoding, memory retrieval, response selection, and response production processes will be differentiated. While these initial clinical studies are completed, development of basic cognitive paradigms at UCSD will address critical issues concerning preparatory processes in dual-task situations. Deficits in other preparatory processes and in working memory in schizophrenia indicate the relevance of developing these new paradigms, which will later be applied in refined form with clinical samples at UCLA. This research should substantially increase our understanding of the links between specific forms of attentional impairment, symptom development, and functional outcome in schizophrenia.

COREl: ADMINISTRATION AND TRAINING CORE The Administration Core will coordinate the administrative activities of the Center for Neurocognition and Emotion in Schizophrenia. Center policy decisions will be made at monthly Steering Committee meetings, consisting ofthe Principal Investigators of all four Projects and the directors of the six Cores. The Steering Committee meetings will facilitate the overall coordination and interfacing among the Projects and Cores ofthe Center. The excellent collaborative atmosphere among the Investigators in this Center will be useful in stimulating additional translational research;identifying, encouraging, and reinforcing young investigators with potential interests in the translational research domains of this Center;and creating and maintaining collaborative links with investigators outside of UCLA. The Co- Principal Investigators will assist the Principal Investigator in arranging and coordinating training activities for young investigators and trainees. The three co-Principal Investigators in this Center (Drs. Cannon, Green, and Yee-Bradbury) will also assist the Principal Investigator in supervising the maintenance and content of the public website, will arrange for public speaking engagements forthe purposes of dissemination of research findings to clinicians and consumers, will assist in departmental responsibilities, aid in the preparation of IRB correspondence, will help plan for and participate in the Annual Planning and Evaluation retreats, and will help arrange the Research Advisory Board meetings in grant years two and four. The Senior Administrative Analyst will be responsible for organizing, supporting and sustaining administrative, grant management, fiscal, personnel, and purchasing activities ofthe Center, and will assist the Clinical Core Directors in the preparation of IRB materials. The offices ofthe Principal Investigator and Co-Principal Investigators are provided by the Departments of Psychiatry and Psychology.

CORE 5: AFTERCARE RESEARCH PROGRAM The Aftercare Research Program is an outpatient research clinic at the UCLA Semel Institute for Neuroscience &Human Behavior that will provide the clinical site for the recruitment, pharmacological and psychosocial interventions, and assessments of symptoms and functional outcome for first-episode patients who are participating in research projects in this Center. The primary mission of the Aftercare Program is to provide a structured and high quality clinical care setting within which this Center research can take place. The Aftercare Research Program will provide a centralized and standardized process for screening and diagnosing first-episode schizophrenia patient participants, providing their clinical services, and completing high-quality longitudinal assessments of symptoms, work functioning, and social functioning. As detailed in the budget justification section for this Core, this centralization will result in great savings to the multiple individual projects that involve Aftercare Program patients, compared to costs if these research projects were carried out independently. Furthermore, by utilizing a shared group of first-episode patients, opportunities for integrative data analyses across projects will become available. A second function is to optimize the level of patient participation in Center-related research projects. A third function is to provide a sample of normal subjects, demogi'aphically comparable to the first-episode patients, for potential participation in Center-affiliated projects. A fourth function ofthe Aftercare Research Program is to provide a convenient group of patient volunteers for the piloting of new measures being developed by individual projects and by the Functional Outcome and Symptom Assessment Core. A fifth function is to offer a research training site for predoctoral and post-doctoral research fellows to encourage development of new translational researchers. Three psychiatrists, and one doctoral level and two masters level therapists, will provide the clinical interventions and research assessments in space allocated to the Program in the UCLA Medical Plaza.

PROJECT SUMMARY (See instructions); PROJECT 2: ATTENTION AND DUAL-TASK INTERFERENCE We continue to use a translational behavioral science strategy to bring paradigms with greater analytic power to the study of attention in schizophrenia. The collaboration between Dr. Pashler of UCSD and clinical researchers Drs. Nuechterlein and Subotnik of UCLA has yielded strong evidence in favor of specific models of structural processing bottlenecks in divided attention in schizophrenia. Beyond this, sites of marked structural processing bottlenecks in schizophrenia have been isolated in response selection processes and response production processes. Thus, while perceptual encoding proceeds normally without causing dual-task interference in schizophrenia patients, response selection processes and response production (motoric) processes in one task markedly interfere with doing another task. While many aspects of dual-task interference are abnormal across phases of illness, some component of an abnormally severe processing bottleneck tend to progress in severity from prodromal to later phases of schizophrenia. Motoric interference also predicts later work functioning independently from memory and social cognition deficits, suggesting that it has a distinctive role. In the next phase ofthis project, several new steps are proposed. First, to integrate findings in the memory project with the findings ofthis attention project, we will examine whether declarative memory processes interfere with other simultaneous processing in a way that involves a particularly severe structural processing bottleneck in schizophrenia. Second, we will extend the findings ofthis project to situations that involve motivated decisions with hedonic consequences, rather than only simple pre-designated response selections. Third, we will examine further whether the contribution of motor processes to attentional dysfunction and functional outcome is distinct from the contribution of memory processes. Finally, we will examine the extent to which indicators of particular processing bottlenecks in schizophrenia serve as contributors to functional capacity and through it contribute to everyday functional leve

DESCRIPTION (provided by applicant): This new postdoctoral clinical research training program focuses on developing research scientists who focus on cognitive and affective dysfunctions in psychotic disorders. The program will utilize a training model that emphasizes the skills needed to bring concepts and paradigms from cognitive science and cognitive, social, and affective neuroscience into patient- oriented, clinical research on core deficits in neurocognition, social cognition, and emotion in schizophrenia and related psychoses. Direct mentoring interactions with both clinical investigators and cognitive scientists/neuroscientists wil be a key feature of this program, with the focus being on development and implementation of clinical research with individuals with psychotic disorders and those at risk for such disorders. Co-mentoring by clinical investigators and cognitive scientists/neuroscientists will ensure the development of an understanding of the principles and methods for adapting paradigms for use in research on psychotic disorders. Additional training themes of this program will be an emphasis on research on the links between core cognitive and affective dysfunctions and functional outcome in psychotic disorders and on research that examines these processes across prodromal, first episode, and chronic phases of schizophrenia and related psychotic disorders. The new training program will focus on individuals with Ph.D. in clinical psychology, cognitive science, cognitive neuroscience, or affective neuroscience, and on individuals with an M.D. followed by a psychiatric residency who plan to pursue a research career. The training program will include (1) extensive hands-on training in the development and implementation of translational clinical research on cognitive and affective dysfunctions in psychotic disorders through interactions with the co-mentors, (2) a weekly Research Seminar on the Psychosis taught jointly by clinical researchers and cognitive scientists/neuroscientists, (3) a monthly Research Career Development Seminar, (4) an intensive regional career development retreat, (5) coursework, workshops, and laboratory training tailored to individual research interests, and (6) training in responsible conduct of research. The training will be closely interfaced with a number of clinical research opportunities that allow access to research participants with schizophrenia and related psychotic disorders.

DESCRIPTION (provided by applicant): This R34 application is designed to move our innovative treatment approach to improving cognition in schizophrenia from the feasibility stage to the pilot intervention trial stage. We propose a randomized controlled 6-month trial of the efficacy of a novel intervention combining neuroplasticity-based cognitive training with neurotrophin-releasing aerobic exercise, compared to the same cognitive training alone. Both of these treatments address the NIMH Strategic Plan and NIMH Director Tom Insel's request to create innovative interventions that can be disseminated broadly and readily taught to the existing workforce with minimal cost. The primary treatment targets are overall cognitive deficit level and impairment in independent living skills. A secondary outcome variable will be a key neurotrophic growth factor, brain-derived neurotrophic factor (BDNF). We hypothesize that combining neuroplasticity-based computerized cognitive training and neurotrophin-enhancing physical exercise will produce large cognitive and functional improvements, even relative to cognitive training alone. Based on theoretical considerations and our initial pilot data, the new cognitive training plus aerobic exercise intervention has the potential to make a real difference in the lives of individuals with severe mental illness. Adding aerobic exercise to our cognitive training program will have the additional benefit of helping to ameliorate medication side effects, reduce the risk for developing metabolic syndrome, and help to prevent the deterioration in physical health that usually follows the onset of schizophrenia and its pharmacologic treatment. Cognitive deficits in persons with schizophrenia present an enormous challenge when helping them to return to functioning in the community. Cognitive remediation and physical exercise have each been shown separately to have promise for improving cognitive deficits in schizophrenia, but used separately yield moderate effects. Our initial pilot data suggest that integrating these two interventions produces larger cognitive gains than the cognitive training alone. We posit that the increases in neurotrophic factors associated with regular aerobic exercise provide a platform which allows neuroplasticity-based cognitive training to impact cognition to a greater degree than is typically observed in studies of cognitive training alone. We target the period shortly after a first episode of schizophrenia to maximize the generalization of cognitive improvement to functional outcome, before chronic disability is established.

ABSTRACT This R01 application involves a confirmatory efficacy clinical trial of our innovative treatment approach to improving cognition in schizophrenia, using an experimental therapeutic design that NIMH has advocated. Our intervention approach combines neurotrophin-releasing aerobic exercise training with neuroplasticity-based cognitive training to enhance the impact of cognitive training on cognition and functional outcome. Both cognitive training and exercise address the NIMH strategic research priorities for creating innovative interventions that can be ?disseminated broadly? and ?readily taught to the existing workforce with minimal cost.? Cognitive remediation and physical exercise have each been shown separately to have promise for improving cognitive deficits in schizophrenia, but used separately yield moderate effects in chronic schizophrenia patients. We will use brain-derived neurotrophic factor (BDNF) as our target and cognition and functional outcome as our clinical outcomes. We hypothesize that the increases in BDNF associated with regular aerobic exercise provide a platform which allows neuroplasticity-based cognitive training to enhance cognition to a greater degree than is typically observed in studies of cognitive training alone. We hypothesize that combining physical exercise with cognitive training will produce larger cognitive and functional improvements, relative to cognitive training alone. This confirmatory efficacy clinical trial is guided by evidence from our current R34 pilot randomized controlled trial comparing the combined treatment with cognitive training without physical exercise. We find compelling evidence of BDNF target engagement, differential improvement in cognition and functional outcome, and prediction of later outcome from initial BDNF gain that strongly supports the movement to a fully powered confirmatory efficacy clinical trial. Cognitive deficits in persons with schizophrenia present an enormous challenge to successful return to functioning in the community. We target the period shortly after a first episode of schizophrenia to maximize the generalization of cognitive improvement to real-world functional outcome, before chronic disability is established. The cognitive training plus aerobic exercise intervention has the potential to examine a hypothesized mechanism of action and to make a meaningful difference in the lives of individuals with severe mental illness.

Abstract This clinical research training program emphasizes developing research scientists who focus on schizophrenia and other psychotic disorders. It particularly emphasizes training in cognitive and affective deficits in psychotic disorders, influences on clinical and functional outcomes, and intervention research to improve clinical and functional outcomes. Training will include core didactic coursework and direct experiences in designing and conducting clinical research with patients with psychotic illnesses, including randomized clinical trials to evaluate efficacy of interventions and research into mechanisms of action of interventions. Direct mentoring by clinical investigators and other scientists and statisticians is a key feature of this program, with the focus being on development and implementation of clinical research with individuals with schizophrenia, severe mood disorders, and other psychotic disorders and those at risk for such disorders. This postdoctoral training program will focus on individuals with Ph.D. in clinical psychology and those with an M.D. followed by a psychiatry residency. In addition, individuals with a Ph.D. in cognitive or affective neuroscience and similar fields who focus on research on psychotic disorders will be welcomed. The training program includes (1) extensive hands-on training in the development and implementation of clinical research on cognitive and affective factors in outcomes and on interventions to improve clinical and functional outcomes, (2) a weekly Research Seminar on the Psychoses taught jointly by clinical researchers and other scientists focused on research methods, recent research results, and grant preparation issues, (3) a set of core courses in research design, statistics, and implementation of clinical trials and other clinical research, (4) other coursework, workshops, and laboratory training tailored to individual research interests, (5) an intensive career development retreat and other career development sessions, and (6) training to enhance the responsible conduct and reproducibility of research. The training will be closely interfaced with many clinical research opportunities that allow access to research participants with schizophrenia and other psychotic disorders.