Bruce Wexler - US grants

DESCRIPTION (Adapted from abstract): The candidate seeks an ISA in order to develop expertise in a new research method, functional MRI. Without an ISA, ongoing clinical-administrative responsibilities would prohibit this career development. The aims of the candidate's research over the past 20 years have been twofold. First, he has sought to identify and assess aspects of human brain functions that involve the integrated action of many cells in functional systems often distributed through several brain regions. To this end he has developed and applied dichotic listening and visual half-field single hemisphere stimulation techniques, and studied dual task interactions and effects of emotion or changes in physiological state. Second, he has applied these techniques to the study of major psychosis especially schizophrenia. There the goals have been to elucidate pathophysiological processes and contribute to the development of a physiologically based nosology. fMRI is a new technique particularly well-suited for these goals. It yields individual subject data with superior anatomic and temporal resolution, and can evaluate the same individual with multiple variations of task and/or in multiple clinical or experimental states. Two physicists who have played leading roles in the worldwide effort to develop fMRI are on the faculty at Yale. The candidate has developed productive collaborations with both, and with outstanding scientists on their faculty in neuroanatomy, neuroradiology and statistics. An ISA would enable him to gain knowledge necessary to critically apply and help develop further this new methodology in collaboration with this interdisciplinary team. The candidate proposes to gain the requisite knowledge through formal course work and weekly tutorial in fMRI technology, weekly tutorial and an interactive computer based course in neuroanatomy, and didactic interactions during the course of collaborative investigation. The proposed research uses fMRI to identify frontal and temporal lobe components of the human auditory working memory system, evaluate the function of these regions and this system in patients with schizophrenia, and eventually, to compare the effects of emotion on this system in patients and healthy controls.

schizophrenia; cognition disorders; neuropsychological tests; neuroanatomy; memory; sound perception; verbal learning; auditory stimulus; temporal lobe /cortex; frontal lobe /cortex; brain electrical activity; auditory discrimination; bioimaging /biomedical imaging; functional magnetic resonance imaging; human subject; magnetic resonance imaging; clinical research;

DESCRIPTION (provided by applicant): This is a revised application for renewal of a K02 Independent Scientist Award. During the initial award period, the PI gained expertise in functional magnetic resonance imaging (fMRI). Skill development focused on learning basic aspects of fMRI methodology, increasing knowledge of human neuroanatomy, developing activation tasks for use during fMRI with particular relevance for studying the neuropathology of schizophrenia, and learning to use the image processing and data analysis software developed at the Yale fMRI Center. Skill development during the requested K02 renewal has two goals: 1) to acquire skills necessary to study inter-regional structural and functional connectivity; and 2) to learn to use image analysis software developed by research groups other than the Yale group with which the PI has been working. Work done during the initial funding period has led to 18 published peer-reviewed research papers and 5 more research papers are currently under review. The PI is first author on 9 of these papers and senior author on 11. During this period he has been the primary research mentor for 9 younger researchers. They have received 1 R01 grant and 3 foundation grants on which he is the senior co-investigator, and 1 B-START and 5 NARSAD Young Investigator Awards on which he is the primary mentor. Another R01 grant is being resubmitted after an encouraging review. The proposed research comes almost entirely from two funded R01 projects. On one the applicant is the PI; on the other he is the co-investigator and his colleague, Morris Bell, is the PI. The first R01 supports continued work using memory tests, structural MRI and fMRI to subtype schizophrenia. The second project supports continued development and evaluation of computerized exercises to treat the cognitive deficits in people with schizophrenia. Both projects provide opportunities to develop and apply skills in measurement of inter-regional brain connectivity and in use of new analytic software.

DESCRIPTION (provided by applicant): Cognitive dysfunctions are major and debilitating features of schizophrenia and schizoaffective disorder (scz-sza). Even after clinical symptom remission, persistent cognitive deficits limit school and work performance and response to behavioral treatments. Some of the most prominent and problematic of these dysfunctions, those in working memory and certain types of problem solving, are thought to reflect frontal lobe dysfunction. Since frontal lobe dysfunction is central in current models of the pathophysiology of scz-sza, cognitive deficits are of relevance both to patient quality of life and to the pathophysiology of the illness. Because of this, new efforts to understand and treat the cognitive deficits of scz-sza are significant for both understanding and for treating the disorders. Most currently available treatments are of limited benefit for the cognitive deficits of scz-sza. One possible, promising exception are new behavioral treatments developed specifically to address the cognitive deficits with varying mixes of instructions and drill and practice. We have been leaders in the development and evaluation of these treatments, and have provided preliminary evidence of substantial and enduring improvements in cognitive function. At this early state in the research, there are several important questions about the relationship between the observed improvements in cognitive function and possible changes in underlying brain dysfunctions. Answers to these questions are important for understanding the nature of the treatments, optimizing further development of the treatments and assessing the potential of the treatments to fundamentally alter the course of illness. An R-0l funded evaluation of behavioral effects of cognitive treatment is ongoing in our laboratory. R-21 support is requested to support exploratory and developmental fMRI studies that will provide preliminary data on changes in regional brain activation associated with behavioral treatment of cognitive dysfunctions, and develop methods for fuller study of these changes.

[unreadable] DESCRIPTION (provided by applicant): This is a revised R-25 application to create a 2-year education program for PG4 and 5 psychiatric residents focused on developing clinical research expertise necessary to study chronic or recurrent mental illnesses during the long periods between acute symptom exacerbations. Approximately 95% of our patients' lives are lived between the short periods of acute symptomatology and it is here that the cumulative burden of illness takes its greatest toll. Yet as we develop an evidence-base to support treatment, the greatest research attention has focused on the episodes of symptom exacerbation. We aim to help create a cadre of new researchers with the special skills necessary to study patients in their communities. Through didactic and experiential education, the research fellows will develop skills in: 1) critical analysis of the literature, 2) formulation of research questions, 3) study design, 4) development and evaluation of research methods from cognitive tests to cost assessments, 5) data management and statistical analysis, 6) interpretation of findings, 7) verbal and written communication of scientific methods and findings, and 8) development and implementation of strategies to obtain research support. Knowledge and skills will be gained through an integrated series of core seminars and a mentored research experience that includes design, implementation, analysis, and publication of a research study. Optional, advanced courses are available through Yale University's School of Medicine. The supervised research experience will draw on a broad array of interdisciplinary, on-going research in which the fellows will be embedded and from which the fellows can develop an independent project. Fellows will be matched during recruitment with nationally recognized, psychiatric researchers at the CMHC, who direct research programs of relevance to treatment of chronic or recurrent mental illness and community psychiatry. The special strengths of the proposed research education program include a distinguished history of clinical research at the CMHC, the breadth and depth of available research mentors, a highly productive research environment, a didactic research curriculum designed specifically for psychiatric residents [unreadable] accompanied by individualized education plans, and an outstanding pool of trainee candidates. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Social interactions are abnormal in many people with schizophrenia even during childhood before their illnesses are manifest and diagnosed. Limitations in social connectedness discomfort in social interactions poorly developed social skills, blunted and/or socially inappropriate emotion, and emotion- related disturbances of cognition are all features of schizophrenia once manifest and diagnosed. Despite the recognized importance of this complex of social, affective and cognitive disturbances, the associated neurobiological abnormalities have been little studied and are poorly understood. We have developed a new paradigm for studying regional brain activations with fMRI during simulated emotion-evoking social interactions. We created video tapes of actors talking directly to the subjects about happy or sad past personal experiences, and displaying the full range of facial, voice and body manifestations of the emotion. This multidimensional, dynamic and socially contextualized stimulation has greater real world validity than the sequential presentation of still photographs of people's faces typically used in brain imaging studies of social-emotional activation. By comparing brain activations in healthy subjects during these tapes to activations when the actors talked about emotionally-neutral experiences, we identified regional brain activations common to both socially generated emotions and activations specific to each emotion. We also created tapes in which actors pretended to use cocaine or prepare to gamble and asked the subjects to join them as they did. With these and the original tapes we identified brain activation abnormalities in cocaine addicts and pathological gamblers related to their primary pathological behaviors and to emotion-evoking social interactions. The studies proposed in this application would be the first to apply this method to the study of schizophrenia. In earlier work, we demonstrated that cognition and brain laterality were abnormally affected by negative emotion in people with schizophrenia. To investigate this further, we incorporated a working memory task within the video tapes of simulated emotion-evoking social interactions. In preliminary studies of healthy subjects we have demonstrated that happy emotion leads to enhanced cognition-related activation of basal ganglia-thalamocortical circuits. We also propose to use this new methodology to study the effects of socially generated emotion on cognition related brain activation in people with schizophrenia. We predict that positive emotion-evoking social interactions will not enhance cognition-related brain activity in people with schizophrenia as it does in healthy people. Many people with schizophrenia have problems with the expression and understanding of emotion essential in social interactions. These problems precede the diagnosis of illness, are present to some degree in family members, limit patient quality of life and even the ability to participate in treatments. In this project we will use new knowledge from social neuroscience research and newly developed brain imaging procedures to study brain aspects of the patient problems in social-emotional function.

DESCRIPTION (provided by applicant): This project will evaluate and refine an innovative multi-component, neuroscience based, non- pharmacologic intervention for Attention Deficit Hyperactivity Disorder (ADHD). ADHD affects >5% of children, disrupts psychosocial development, and has broad negative outcomes. Pharmacotherapy is often of limited benefit, subject to misuse and associated with unwanted side effects. The proposed treatment program is innovative in: use of a computer based "treatment delivery system" to apply new knowledge of neuroplasticity in clinical care;transformation of existing approaches to physical education based on cognitive neuroscience;and use of an evidence based intervention from social psychology to enhance delivery and effectiveness of neuroscience based interventions. Synergistic integration of brain, body and social interventions provides a paradigm appropriate to address the complexities of neurodevelopmental disorders. The innovative computer programs have multiple newly patented capabilities not present in any previous computerized cognitive treatment exercises. Innovative physical exercises activate the same neurocognitive systems targeted by the computer exercises but in the context of whole body and inter-personal activity, particularly important for ADHD. The social level intervention facilitates participation in the computer and physical activities and it itself also activates target self-regulatory systems. Neuroplastic potential upon which our intervention is based has been dramatically demonstrated in animal and human studies. It has been successfully harnessed for treatment of adult neuropathology but application to childhood disorders has been remarkably absent despite greater plasticity during childhood. As with other clinically relevant advances in basic science, advances are also necessary in methods for treatment delivery if the new discoveries are to be applied effectively. Based on preliminary studies and discussions with the children using prototype programs, we have created innovative game-like computer programs that engage and activate targeted neurocognitive systems with the intensity and consistency that preclinical studies indicate is necessary. Moreover, new research also demonstrates the complexity of neurodevelopment disorders and their treatment due to the interplay of genetic, environmental, physiological, psychological, social, primary and compensatory processes. For example, core features of ADHD alter interactions with the environment in ways that aggravate the symptoms themselves, create additional problems and block effective delivery of treatment. New paradigms that synergistically integrate brain, behavior and social perspectives and methods are therefore needed to treat these disorders. Our program is designed for six to eight year old children in order to intervene precisely when the clinically relevant neurofunctional systems are actively developing and when clinical symptoms first appear. PUBLIC HEALTH RELEVANCE: This project will evaluate and refine an innovative multi-component, neuroscience based, non-pharmacologic intervention for Attention Deficit Hyperactivity Disorder. The intervention is innovative in: use of a newly patented computer based "treatment delivery system" to apply new knowledge of neuroplasticity in clinical care;transformation of existing approaches to physical education based on cognitive neuroscience;and use of a classroom game to enhance participation by children with attention problems.

The identification of cognitive impairments in early childhood provides the best opportunity for successful remedial intervention, because brain plasticity diminishes with age. Attention deficit hyperactivity disorder (ADHD) is a psychiatric neurodevelopmental disorder that is very hard to diagnose or tell apart from other disorders. Symptoms include inattention, hyperactivity, or acting impulsively, all of which often result in poor performance in school and persist later in life. In this project, an interdisciplinary team of computer and neurocognitive scientists will develop and implement transformative computational approaches to evaluate the cognitive profiles of young children and to address these issues. The project will take advantage of both physical and computer based exercises already in place in 300 schools in the United States and involving thousands of children, many of whom have been diagnosed with ADHD or other learning disabilities. Project outcomes will have important implications for a child's success in school, self-image, and future employment and community functioning. The PIs will discover new knowledge about the role of physical exercise in cognitive training, including correlations between individual metrics and degree of improvement over time. They will identify important new metrics and correlations currently unknown to cognitive scientists, which will have broad impact on other application domains as well. And the PIs will develop an interdisciplinary course on computational cognitive science and one on user interfaces for neurocognitive experts.

The research will involve four thrusts. The PIs will devise new human motion analysis and computer vision algorithms that can automatically assess embodied cognition during structured physical activities, and which will constitute a breakthrough in improving the accuracy and efficiency of cognitive assessments of young children. Intelligent mining techniques will be used to discover new knowledge about the role of physical exercise in cognitive training and to find correlations between individual metrics and degree of improvement over time. A methodology will be developed using advanced multimodal sensing to collect and process huge amounts of evidence based assessment data with intelligent mechanisms that learn about a child's executive function capabilities and help uncover possible causes of cognitive dysfunctions. And a closed loop cognitive assessment system will be designed and implemented to understand and monitor a child's progress over time and provide recommendations and decision support to cognitive experts so they can make better treatment decisions.