Aysenil Belger - US grants

DESCRIPTION: (Applicant's abstract) Schizophrenia is associated with a fundamental deficit in selectivity that operates at all levels of information processing from basic sensory to higher order semantic processing. However the neurobiological bases of these deficits and their modulation through the course of the disease has not been established. We propose a series of studies that assess information selection deficits in schizophrenia within the framework of a multistage model, comprising an initial stage of sensory filtering or gating, a subsequent stage of sensory discrimination and memory processing, and a final stage of response selection. Parallel experiments will examine the functional and structural substrates of attention deficits in schizophrenia, using converging evidence from behavioral, electrophysiological (ERP) and functional Magnetic Resonance Imaging (fMRI) techniques. Electrophysiological (event-related potential, or ERP) studies will compare ERPs evoked in sensory gating, automatic and voluntary attention allocation, and response selection tasks in groups of schizophrenic patients and healthy controls. These studies will document ERP abnormalities at each level of processing previously observed in schizophrenic patients by the PI and her colleagues. Functional magnetic resonance imaging (functional MRI, or fMRI) studies will then be conducted using the same tasks and patterns of activation will be compared in healthy and schizophrenic subjects. Event-related fMRI analysis will be used to isolate activations evoked by task relevant and irrelevant stimuli. Group differences in activation patterns will be used to identify critical brain regions engaged at these levels of stimulus and response selection. The clinical objective of the proposed studies is to relate selective attention deficits in schizophrenia to symptomatology and chronicity of this illness. Information from these studies will further our understanding of the functional and structural basis of distractibility and information processing deficits in schizophrenia.

DESCRIPTION (provided by applicant): The major goal of the proposed research is to examine the neurobiological correlates of visuospatial processing deficits in Turner syndrome (TS) using functional magnetic resonance imaging (fMRI). TS is a neurodevelopmental syndrome with a homogeneous etiology, and provides a model for the study of brain-behavior relationships. Recent studies have suggested that individuals with TS show significant deficits in visuospatial information processing but not verbal information processing. Furthermore, these domain-specific visuospatial information processing deficits may be secondary to more central working memory problems in this syndrome. Although the cognitive deficits have been well documented to date, the neural circuitry underlying these deficits have not been characterized. Specifically, there have been no published fMRI studies of TS. In the current project the investigators will use fMRI to examine the neural circuits underlying visuospatial impairments in subjects with TS, with a particular focus on working memory. This project capitalizes on the availability of a large sample of individuals with TS, and the expertise of the investigators in conducting fMRI studies. Specific Aim 1 is to use functional magnetic resonance imaging to identify the cortical circuits activated by verbal and nonverbal working memory. The investigators will image 15 control subjects and 15 individuals with TS using a modified version of the working memory tasks developed by Belger et al. Specific Aim 2 is to characterize the neurocognitive functioning of the individuals with this disorder, in particular to explore the hypothesis of domain-specific deficits.

DESCRIPTION (provided by applicant): This project will employ structural (MRI) and functional (fMRI) neuroimaging techniques to examine the neural basis of selected social cognitive, affective, and executive functioning deficits, and ritualistic-repetitive behaviors, in autism. Social deficits and ritualisticrepetitive behaviors are defining features of autism, and deficits in social cognition (e.g., processing emotional and social cues reflected in facial expressions) and executive function (e.g., generating flexible task-appropriate actions while inhibiting task-inappropriate ones) are considered key neuropsychological processes underlying these behaviors. Despite progress in describing these deficits, their neurobiological bases are still largely unknown. We propose to explore the neural circuitry of social cognitive, affective, and executive function processes and ritualistic-repetitive behaviors in autism in four studies designed to: (1) characterize the neural circuitry underlying inferences of social intentionality in autism, (2) examine neural circuitry underlying the processing and appreciation of facial expressions in autism, (3) explore the neural circuitry supporting the initiation and inhibition of taskappropriate/inappropriate behaviors in autism, and (4) characterize the structural integrity and development of frontal-striatal tracts, which we hypothesize to be involved in ritualistic-repetitive behaviors associated with autism. These aims will be addressed in three fMRI studies involving high functioning autistic adolescent and adult males, and in one longitudinal study employing diffusion tensor imaging in a sample of autistic children (ages 2- to 4-years). This project links conceptually to Family Study Project, Mouse Genetics Project, Fragile X Project, and Treatment Project, where these same processes are examined, as well as to a companion, separately funded study of these neuropsychological processes in this same sample of autistic individuals. This project brings together several experienced neuroimaging researchers, new to autism, forming the basis for the development of an integrated program of neuroimaging research to characterize key elements in the neural circuitry of autism. This information should further our understanding of the neural mechanisms as well as refine our notions of the brain and behavioral phenotypes in this disorder.

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The goal of this project is to map the maturation of cortical circuits and higher-order cognitive functions in children and adolescents at genetic risk for schizophrenia. Executive function and social-affective processing deficits are present in both individuals with schizophrenia and in those at genetic-high-risk (GHR) for the illness, and as such they represent cognitive endophenotypes of schizophrenia. Nevertheless, their characteristics in younger GHR individuals, the timing of their onset, and the specific neurodevelopmental mechanisms that accompany them are not known. Puberty is a critical period both for the maturation of these functions, and for the onset of psychosis. The proposed study will probe functional and structural change that accompany peripubertal brain maturation in genetic high risk individuals, and will investigate executive control and social-affective processes in GHR children and adolescents. We'will probe attention and executive and affective processing in fronto-striate-limbic regions in 60 GHR and 60 healthy subjects aged 9-18 using. We will use a multimodal assessment protocol, including (a) neurocognitive testing (b) functional magnetic resonance imaging (fMRI), (c) electrophysiological recordings (ERPs), and (d) structural and diffusion imaging (sMR| and DTI). In Specifc Aim 1, we will compare the neurocognitive profile of genetic high risk (GHR) children and adolescents to healthy subjects cross-sectionally, and further assess group differences in their maturational trajectory with longitudinal follow-ups. Specific Aim 2 will characterize the functional profile of fronto-striate-limbic regions in GHR children and adolescents, using functional magnetic resonance imaging and electrophysiological recordings. The structural profile of fronto-striate-limbic regions in GHR adolescents, including both gray matter and white matter properties, will be assessed in Specific AIMS. Finally, Specific AIM 4 will focus on network level integrative functioning of fronto-striate and fronto- limbic circuitry in GHR children and adolescents by exploring associations between functional connectivity measures, white matter properties and neurocognitive measures. By bringing together a strong clinical high- risk research program and a well established and diverse research infrastructure, this project promises to unveil critical knowledge about the neurodevelopmental changes associated with genetic risk for schizophrenia. The proposed experiments are novel, timely and highly significant for they focus on a unique population and probe a unique stage of cortical development that is critical for understanding the pathophysiology of core neurocognitive deficits in schizophrenia.

The primary aim of the Developmental Neuroimaging Core is to serve the interdisciplinary and translational research needs and goals of the DDRC. Advances in human and animal neuroimaging techniques provide the unique ability to gain insight into the neural circuitry and mechanisms underlying cognition, behavior and neural development in typically developing individuals and those with neurodevelopmental disorders. The strengths of in vivo neuroimaging techniques become particularly evident when included in longitudinal study designs that are particularly well suited for understanding the trajectories of developmental disorders. Neuroimaging studies offer the additional possibility of teasing apart the heterogeneity in complex, behaviorally-defined neurodevelopmental disorders, by providing insights into potential brain phenotypes for these conditions. Even more advanced methods are available for imaging the brain in animals. Genetic studies of neurodevelopmental disorders have led to the identification of a number of disease susceptibility genes and genetic engineering approaches have enabled the creation of genetically altered cells and animals (mice). Invivo multiphoton imaging of these animal and cellular models provides a unique avenue to study distinct aspects of nervous system development and function relevant to neurodevelopmental disorders. While conventional confocal microscopy can be used for high-resolution imaging of fluorescent labeling in fixed tissue, multiphoton laser imaging enables visualization and quantification of XFP filled neurons, glia, and axons in brain slices, or intact brains. Novel scanner technology and acquisition technology has also enabled the study of brain development in animal models via MRI, specifically for non-human primates and rodents. In 2002, the Developmental Neuroimaging Core (DNC) was established in response to the ever-increasing demand for structural and dynamic neuroimaging in humans and animals, and confocal and multiphoton imaging in animals. The DNC is of central importance to the research efforts of the DDRC. Our mission was to create a translational developmental neuroimaging core that would integrate science and research across cellular and systems levels of investigations, and facilitate interdisciplinary collaborations to address the needs of our DDRC investigators (Figure 1). Acquisition of data using magnetic resonance imaging and high-resolution microscopy, and the subsequent image analysis capacity necessary to analyze such data, requires a level of investment beyond the means of most individual investigators. Furthermore, this capacity can only be used fully with the assistance of a team of research scientists with extensive training and established expertise in the range of techniques required for modern neuroimaging approaches. To realize this mission, the core has been specifically configured to promote translational science and to forge interdisciplinary collaborations. During the past 5 years, the image analysis and tool development expertise of investigators in the MRI component of the DNC (codirected by Drs. Belger and Styner), and the cellular imaging expertise and infrastructure of the CMI component (co-directed by Drs. Polleux and Peterson), combined with the extensive expertise in image processing and graphics in computer science, have led to three major accomplishments: [unreadable] Translational neuroimaging research has flourished: The confocal and multiphoton components and the MRI components have developed and implemented new image processing tools for studying neurodevelopmental mechanisms from the cellular to the systemic level. As such, the DNC provides support for the development and implementation of imaging and image analysis methods that bridge research at the cellular level with research at the systems level, as applied to the studies of neurodevelopmental mechanisms and processes in humans, primates, rodents, and drosophila. [unreadable] Interdisciplinary collaborations have been forged between basic scientists, clinicians and computer scientists;integrating skills and expertise across disciplines and between previously divergent areas of science and scientists. [unreadable] Groundbreaking tool developments and research advances have been made in the imaging of early brain development. This core has been structured to satisfy the criteria for the development and organization of cores described in the Introductory Overview. As such, the core services are of critical importance to the maximum number of investigators representing cutting-edge, high-quality scientific practice. The core services are cost-effective, as they provide access to unique computational resources and personnel expertise not available through other campus resources and that would be prohibitively expensive for individual DDRC investigators to develop or support through their own research grants. The DNC advances and promotes interdisciplinary and translational research, consistent with the mission of the Center. This Core further leverages existing University resources by partnering with other relevant Centers/Departments with key relationships to the DDRC (e.g., UNCNC, Psychiatry, Radiology, BRIG). In addition to providing research services, this core has a generative role: it creates new imaging methods, knowledge and image analysis tools otherwise not available to investigators in the Center, such as automated methods for diffusion tensor imaging based analysis, subcortical structure segmentation and cortical thickness analysis for both human and animal brain MRI data, from birth to age 4. This generative role is facilitated by the close interactions between the computer scientists, neuroanatomists and clinical researchers associated with the DNC. By providing support to both human and animal imaging studies this Core integrates methods within and across cores, to produce a whole that is substantially greater than the sum of the individual parts. The core integrates the expertise of clinical imaging researchers, statistical analysts, MR physicists, computer scientists, neuroanatomists and behavioral researchers, for the conduct of human neuroimaging. It further integrates image processing expertise available for human in vivo image analysis, for application to multiphoton/confocal microscopy. Finally, the DNC cost-effectively extends existing resources and improves research quality, by providing training (e.g.. training in image processing software for neuroimaging etc.) to DDRC investigators and laboratory staff.

Abstract The Clinical Translational Core (CTC) of the University of North Carolina Intellectual and Developmental Disabilities Research Center (IDDRC) is a highly successful core that catalyzes key resources to provide two classes of services: (1) the Participant Registries (PR) serve to maximize recruitment of research participants in IDDRC research; and (2) the Brain & Behavior Measurement Laboratory (BBML) assists UNC IDDRC investigators with multi-modal characterization of brain structure and function and behavior to advance the discovery of early risk markers, brain and behavior mechanisms, targets for therapeutics, and outcome metrics for assessing the impact of interventions. In this application, 39 projects from 27 IDDRC investigators are proposed for core access. The BBML further assists investigators with the design, measurement, and analysis of clinical neuroscience studies, and provides assistance with the development of clinical teams. The structure of the PR and BBML promotes cross-disciplinary interactions critical to maximizing the potential to understand the pathogenesis and treatment of IDDs. The Specific Aims of the CTC are: (1) to maximize recruitment of research participants for clinical studies; (2) to develop and provide access to tools and services that maximize the ability of IDDRC investigators to conduct cutting-edge clinical studies of brain and behavior measurement in IDD research; and (3) to facilitate translational IDD research by facilitating linkages between human and preclinical studies and the promotion of interdisciplinary research. The overarching objective of the CTC is to support clinical translational research that advances our understanding of the pathogenesis and treatment of IDDs. The core catalyzes translational IDD research at UNC by providing key support and services, ranging from consultation on the initiation of interdisciplinary projects, to supporting the formation of interdisciplinary teams, assisting in the design of complex experimental protocols, providing access to a large well- characterized pool of participants, to desiging custom-built and project-specific innovative neuroimage analysis tools. By providing access to resources and expertise in IDD research, the CTC integrates cutting-edge cognitive, behavioral, and clinical neuroscience methods to capitalize on our strengths in imaging and, in particular, early brain development. This integration of recruitment, phenotyping, study design, and brain imaging tools and resources in this CTC has catalyzed translational IDD research at UNC. Indeed, the development of novel image analysis tools customized for infant brains, early in the history of this core, has transformed the field?s understanding of infant brain development. The tools developed by this core have played key roles in translational research examining early risk markers of, brain markers of exposure to bio- psycho-social adversity, and characterizing the impact of interventions. 1

? DESCRIPTION (provided by applicant): Adolescence is a peak time for the emergence of the core symptoms of psychopathology. Cognitive disorganization (CD) is a key symptom dimension of psychosis that emerges most commonly in adolescence, reflects a disorganization of thought and is defined by the presence of bizarre behavior, alogia, and impaired attention. CD transcends DSM diagnostic categories, predicts the onset and severity of psychotic disorders, and is associated with neuropsychological impairment. Genetic studies have reported that CD is highly heritable, and therefore has been proposed as a promising phenotype for molecular genetic studies. Despite its critical role in heralding risk for psychosis, little is knon about the neurobiological underpinnings of CD in adolescents. It has been reported however that adolescents experiencing disorganization have significant deficits in working memory capacity (WMC) and arousal/stress regulation (ASR). These two behavioral constructs show dramatic maturational changes during adolescence, which are necessary for the transition to higher-level cognition, affect regulation and psychosocial adaptation. Despite the strong epidemiologic evidence for the role of stress in the etiology of psychosis, and the centrality of working memory impairments in psychosis, little is known about their contribution to CD in adolescence. Examining the neural and physiological systems associated with working memory and stress regulation in adolescence, and their contribution to CD severity, offers a critical step in elucidating the pathophysiological mechanisms that contribute to the onset of psychosis. This approach is consistent with the RDoC framework, which encourages using converging measurements to study the underlying neurobiology of domains (Cognitive System and Arousal Regulation in this proposal), and constructs (working memory capacity and stress regulation) that represent fundamental behaviors expressed by individuals with clinical risk symptoms for psychosis. We will use a multimodal approach integrating functional neuroimaging, electrophysiological, and behavioral measures to ascertain converging measures of working memory and arousal/stress regulation constructs across neural, physiological, and behavioral units, and to characterize the contributions of atypical ASR and impaired WMC in the severity of CD symptoms measured through clinical scales. In Aim 1, we will evaluate the contributions of working memory impairments and atypical arousal/stress regulation in 180 adolescents (ages 9-16) to the severity of CD symptom. In AIM 2 we will model the relationship between WM and ASR constructs and their impact on CD severity. In AIM 3, we will examine the longitudinal trajectory of CD symptom severity, behavioral and electrophysiological measures of WM and ASR, and their associations with baseline neural, behavioral, and physiological measures acquired in AIMs 1 and 2. For each aim, we will explore the modulatory role of sex differences and pubertal maturation on stress-regulation and working memory during adolescence, and their influence in determining functional outcomes. IMPACT: Understanding the neural and physiological systems associated with working memory capacity and stress regulation in adolescence, and their contribution to CD severity, is a crucial step for elucidating the core pathophysiological mechanisms that promote the emergence and exacerbation of psychosis.

? DESCRIPTION (provided by applicant): The Center for Developmental Science (CDS) requests continued support for five predoctoral (two-year program) and five postdoctoral (two-year program) positions associated with its vibrant and accomplished training program, the Carolina Consortium on Human Development (CCHD; T32-HD007376). Located in the rich intellectual environment of central North Carolina, the program brings together a world-class faculty who come from four major research universities (UNC-Chapel Hill, Duke University, North Carolina State University, and UNC-Greensboro) and who span psychology, neuroscience, public health, nursing, education, psychiatry, sociology, public policy, and methodology. The 47 faculty mentors include leaders in the study of children's and adolescent's health and well-being with a strong record of research productivity, grant funding, and training. The program is based on the premise that training in Developmental Science provides a vitally important transdisciplinary model and an associated language for understanding a broad array of health outcomes (e.g., health-risk behaviors, obesity, self-regulation, resilience to early trauma and stress, cognitive functioning). Core principles of Developmental Science now permeate all major perspectives on health and well-being. These principles include, for example, the study of developmental processes (a) as occurring through multilevel, interacting causal fields ranging from culture to biology; (b) as embedded in temporal patterns across levels of analysis as reflected in the study of transitions, trajectories and plasticity; and (c) as incluing on-going bidirectional influences across levels of analysis. The CCHD program is distinctive in its focus on the articulation of these principles and their operationalization in empirical health research. The resulting structured-yet-flexible program is uniquely designed to provide training in core competency areas as well as individually tailored domains. In addition to common elements (i.e., the CCHD proseminar series, research apprenticeships with faculty mentors, and professional and research skill development workshops), trainees select from an extensive menu of tailored experiences that are specific to their training goals as identified through an Individualized Development Plan. We continue to monitor and refine our training program through an extensive evaluation process that involves trainees, mentors, and a national Advisory Board. A total of 54 predoctoral and 29 postdoctoral trainees participated in the program during the last reporting period. The trainees have obtained excellent academic and research positions, have published actively in the research literature, and have shown early success in obtaining grant funding. This track record confirms the effectiveness of the program. The over-arching goal of the CCHD is to give a foundation in Developmental Science to the next generation of scholars as they prepare for innovative and productive research careers. Our trainees speak the language of sophisticated transdisciplinary teams that have the power to transform the scientific study of the origins, natural history, and consequences of health.