Bradley L. Schlaggar - US grants

[unreadable] DESCRIPTION (provided by applicant): An understanding of how skilled reading is achieved is fundamental to generating improved strategies for reading education, and toward identifying, treating, and preventing developmental deficits in reading and spelling. Skilled reading is the consequence of a complex interplay of experience and the development of neurobiological substrates. Investigation of the developmental neurobiology of reading is likely to yield important insight into its skilled performance. This proposal focuses on the linking of visual orthographic (i.e., letters) information to phonology, critical in the acquisition of reading skills. By extension, characterization of the developmental functional neuroanatomy of the relationship between orthographic and phonologic processing will provide an important context for studying the cognitive neuroscience of typical (and atypical) reading development. This proposal aims to identify and characterize the developmental functional anatomy of orthographic knowledge, and of the spelling-to-sound translation processes involved in word reading. The principal investigator (PI) is an academic physician-scientist trained in pediatric neurology and specializing in disorders of cognitive development. Although the PI has substantial experience in developmental neurobiology and the functional neuroimaging of typically and atypically developing children, the added dimension of integrating developmental psycholinguistics supported by this Research Career Award (K02) should provide important insights into mechanisms of the developmental neurobiology of reading and significantly aid the PI in further developing his independent research career. Washington University possesses excellent resources in cognitive neuroscience, access to patient populations, and expert researchers in developmental psycholinguistics and represents an ideal environment for the PI to complete the goals of this proposal. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This proposal focuses on neural substrates of orthographic and phonological processes that must be honed in the developmental acquisition of reading skill. Changes in these processes emerge through development as a young reader gains experience with written words. Behaviorally, adults show processing advantages (i.e. increased speed and/or accuracy), less evident in children, for letters over visually similar letter-like objects, and for legal letter strings over non-letter strings or illegal letter strings. This processing advantage suggests that increasing experience enables a reader to extract specific, orthographic information about the visual features that form letters and words. In concert, extensive evidence suggests that phonological processing provides important support for reading development, and that its interplay with orthographic processes varies as skill develops. Information about how the developmental acquisition of reading expertise relates to putative orthographic and phonological processing regions in the brain should provide an important neurobiological foundation for understanding typical (and atypical) reading development, and inform more targeted future education and remediation strategies. The first specific aim tests the hypothesis that visual processing regions of the brain will show increasing specialization with the developmental acquisition of reading skill. The second specific aim tests the hypothesis that concomitant with increasing reading skill and orthographic specialization comes decreasing reliance on phonological processing mechanisms. The third specific aim uses functional connectivity MRI and graph theory analysis to characterize developmental differences in reading networks between adults and children. Additional proposed analyses include a longitudinal component where a cohort of subjects have repeated scans over a five year period, exploration of individual differences using a multivariate approach combining stable measures of reading/cognitive skill with imaging and in-scanner performance parameters, and an exploration of developmental sex differences. PUBLIC HEALTH RELEVANCE: This proposal focuses on neural substrates of orthographic and phonological processes that must be honed in the developmental acquisition of reading skill. Information about how the developmental acquisition of reading expertise relates to putative orthographic and phonological processing regions in the brain should provide an important neurobiological foundation for understanding typical (and atypical) reading development, and this basic knowledge can be used to inform more targeted future education and remediation strategies.

DESCRIPTION (provided by applicant): This application is the renewal of the Neuro Sciences Academic Development Award (NSADA) that has supported 14 post-residency scholars in pediatric neurology over the past 15 years. The new application reflects the growth and changes in pediatric neurology over the past 20 years, with a focus on the past 5 years, and includes mentors with research and clinical expertise in academic areas that have direct impact on modern pediatric neurology: developmental neuroscience, systems/cognitive neuroscience, neurogenetics, nervous system injury, and epilepsy. The proposed mentors come from within the Department of Neurology (including the Division of Pediatric and Developmental Neurology), as well as the Departments of Anatomy & Neurobiology, Biology, Genetics, Psychology, Psychiatry, Developmental Biology, Pediatrics, Neurosurgery, Medicine, and Radiology. This new application also highlights the enormous and continued growth of resources for basic/translational/clinical neuroscience research at Washington University (an already enriched environment) over the past 5 years. These resources will be readily accessible to the NSADA scholars. The program will be specifically tailored for the three scholars, graduates of our pediatric neurology residency program, and depend heavily upon their prior research experience and career preferences. Scholars who enter the program with extensive research experience will be encouraged to replenish their fund of knowledge and then embark upon new research with the guidance of the mentor, Program Director, and the Internal Advisory Committee. Less experienced scholars may spend up to a year in formal coursework in the Neuroscience Program of the Division of Biology and Biomedical Sciences at Washington University. In either case, scholars will be able to draw upon the resources of not only the 29 faculty committed to this application but also a wider neuroscience community composed of roughly 200 faculty engaged in active research. While scholars will be expected to receive most of their supervision from their mentors, there is enormous interaction between faculty investigators and their respective laboratories so that scholars will have abundant opportunities for contact with experienced researchers. As is demonstrable from the track record of the Washington University NSADA to date, graduates of NSADA scholarship should be competitive for either additional K level support or independent RPG level funding after completion of three years.

DESCRIPTION (provided by applicant): Tourette Syndrome (TS) is a common genetic pediatric neuropsychiatric disorder. Manifest as chronic motor and vocal tics, it affects approximately 0.3-1% of children, with significant negative impact on quality of life. TS is associated with deficits in impulse regulation and executive control functions. The brain's executive control systems are thought to be anatomically separate from downstream moment-to-moment processing systems and to consist of networks of functionally diverse regions. The interactions of these control systems with processing systems have been implicated in TS. A key idea underlying this exploratory proposal is that TS arises from the atypical development of networks of control regions and their interactions, as opposed to the atypical functioning of any particular brain region. Medications that relieve tics in TS may also result in an improvement in control abilities, and a normalization of both evoked activity within control regions and of functional connectivity between regions comprising control networks. We hypothesis that the anomalous patterns of brain activation and functional connectivity observed in TS will be ameliorated by medications that treat TS. Understanding the brain's control networks are affected by medications may lay the foundation for earlier diagnosis and more effective therapies for TS and other pediatric neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: This proposal aims to use longitudinal task-based fMRI and functional connectivity MRI to characterize the development of control networks in pediatric Tourette Syndrome and how those networks respond to pharmacotherapeutic intervention. Understanding how networks of brain regions involved in control are affected by pharmacotherapy in patient with Tourette Syndrome may lay the foundation for earlier diagnosis, more accurate prognosis, and more effective therapies

? DESCRIPTION (provided by applicant): Childhood onset neuropsychiatric disorders are often debilitating and are increasing in prevalence. Tourette Syndrome/Chronic Tic Disorder (TS/CTD), we propose, has a course that lends itself especially well to discovering optimal strategies for early diagnosis and prevention of developmental disorders. Common clinical practice and epidemiological data suggest that a large fraction (10-25%) of all children manifest motor and/or vocal tics at some age. Yet only 1-3% of all children have tics for the full year required for diagnosis of TS/CTD. The objective of the proposed research is to understand the structural and functional neuroimaging features of children with new-onset tics (New Tics), as the neurobiology of this population has not been investigated. Studying children with New Tics should provide the most leverage in understanding why tics remit in some children but not others. This proposal compares neuroimaging features of New Tics to TS/CTD and to controls, implements machine-learning tools to predict whether children with New Tics will remit or develop TS/CTD, and utilizes longitudinal scans to identify within-subject changes that occur as tics remit or persist. The proposed study will apply resting-state functional connectivity MRI (rs fcMRI) and structural MRI methods to investigate children with New Tics. Neuroimaging will be conducted on children with current, new- onset tics, and comparisons will be made to existing MRI data from children with diagnosed TS/CTD and controls. Follow-up evaluation (1 year after tic onset) of New Tics will allow us to identify which children's tics remitted completely and whic were actually in the earliest stages of TS/CTD, thus sorting this group into Remitted Tics and Converted TS/CTD subgroups. Based on the epidemiological data, we expect most of New Tics subjects to fall in the Remitted Tics subgroup. Longitudinal scans of the New Tics children will enable us to assess within-subject changes that occur with remittance or persistence of tics. This study will also apply machine learning tools, specifically Support Vector Machines (SVMs), to characterize features that distinguish Remitted Tics and Existing TS/CTD groups. Those features will then be used to predict whether tics in the New Tics group will remit (Remitted Tics) or persist (Converted TS/CTD) on an individual patient basis. Thus, we will be poised to identify differences, and potentially early predictors, of remittance and TS/CTD. This study will provide innovative, important data on a common clinical presentation: the child with New Tics. Completing our aims successfully will allow individual prediction of remission or progression, or at least will allow a New Tics sample to be enriched for high risk of developing TS/CTD, which would make prevention studies for TS/CTD feasible. We will also gain insight into the neurobiology of New Tics. Finally, this study is an essential first step towards a definitive longitudinal study that can improve diagnostic accuracy and settle questions of cause and effect. With successful completion of our aims, similar methods can be applied to other childhood onset neuropsychiatric disorders, setting the stage for early treatment or prevention of chronicity.

? DESCRIPTION (provided by applicant): The last decade of research in intellectual and developmental disabilities (IDD) has been notably characterized by rapid advances in understanding the nature and complexity of inherited susceptibilities to IDD, but genetic discovery has not yet fulfilled the promise of more effective intervention, even for monogenic IDD syndromes. It is the immediate priority of a next generation of research to capitalize upon knowledge about causation in IDD (both genetic and environmental) and translate it into higher-impact intervention for as many individuals and families affected as possible. In the second cycle of the IDDRC at Washington University in St. Louis (IDDRC@WUSTL), our strategy for contributing to this effort preserves our Center's original focus on characterization of white matter injury to the newborn brain, but extends the scope of Core activity to facilitate a comprehensive approach to understanding and preventing developmental disorders of neural connectivity at the respective levels of cell, synapse, circuit, and behavior, and brings on line major strengths of WUSTL in genomics, behavioral/cognitive neuroscience, and clinical-translational science. The overarching goals of our Center are as follows: (1) To facilitate high-caliber, translational research on the pathogenesis and treatment of IDDs by sustaining an innovative Core structure that attracts and supports qualified, collaborative investigators, and interacts synergistically with complementary Core facilities of other U.S. IDDRCs. We propose to support an Administrative Core, a Developmental Neuroimaging Core, a Model Systems Core (encompassing capacity and expertise for both animal and cellular models of IDD), and a Clinical Translational Core. (2) To cultivate nodes of interdisciplinary scientific activity in frotiers of IDD research which are critical for the derivation of higher-impact treatment and preventive intervention, across 4 major themes: (i) The prevention of prematurity and its neurodevelopmental consequences; (ii) The elucidation of robust intermediate DD phenotypes (as markers of pathogenic processes, targets of early intervention, and indices of response to treatment); (iii) In-depth characterization of the developing human brain, and (iv) Functional genomic approaches to elucidating convergent mechanisms of IDD pathogenesis. (3) To conduct a signature research project that represents a bold, critical step toward higher-impact intervention for IDD, capitalizes upon both the Core structure of our IDDRC and institutional strengths at WUSTL, and epitomizes the manner in which our IDDRC facilitates trans-disciplinary research. Our project is designed to elucidate mechanisms of sex-specific modulation-of-expression of inherited risk for autism spectrum disorders, at the respective levels of cell, brain, and behavior. A goal is to identify compensatory mechanisms underlying resilience among females in ASD-affected families, for the purpose of recapitulating those mechanisms in novel interventions which would be of major relevance to a large proportion of the population of individuals at risk or affected by familial autistic syndromes.

Project Abstract At least 20% of all children have tics at some time in their life, making tic disorders a subject of substantial public health interest. However, only about 3% of all children have tics that last for a year or more. Thus chronic tic disorders, including Tourette syndrome, can be conceptualized as a two- step process: tics start, and then they fail to remit. By the numbers, the second part of this process is the more unusual and perhaps more closely related to disease, yet surprisingly, almost no research has examined this critical period after a first tic appears but before it is clear whether the child will go on to have a chronic tic disorder. Therefore prior research that has identified abnormalities of brain structure and function in children with TS generally does not clarify whether these abnormalities are related to tic appearance or to the more important process of tic disappearance. Furthermore, tic disappearance can be observed prospectively, allowing powerful within-subject analyses to test whether features of brain structure or function shortly after tic onset predict remission of tics before TS is diagnosable, and whether such features are state-related or more durable markers of vulnerability to tics. Colleagues in the TS field have agreed that such studies would be valuable, but have suspected that recruitment would be extremely difficult. However, we have now demonstrated enrollment of subjects with New Tics (defined as beginning within the previous 6 months, median 3.6 months) at a rate of 16 subjects per year when recruitment efforts were at their peak?though still on a shoestring budget without full staffing or media advertisements. We have implemented subject preparation and quality control methods that have allowed us to acquire structural and functional MRI data of high quality in many subjects. We now propose to enroll an additional 70 subjects with New Tics and characterize them carefully at baseline and at the 1-year anniversary of tic onset (when TS can first be diagnosed). Both time points will include clinical data, structural and functional MRI, and neuropsychological measures including ability to suppress tics. We expect that complete data will be available for 55-70 subjects (including those already collected), since MRI is sensitive to movement and we are selecting for subjects with tics and additional difficulty holding still (about half of children with tics also have ADHD). We will compare baseline data from this sample to matched tic-free control subjects, and to matched subjects who already have TS or a chronic tic disorder (leveraging existing data in our laboratories to provide some of the clinical and MRI data for these groups). Analyses will include tests of specific a priori hypotheses as well as machine learning analyses of the complete dataset. These comparisons will allow us to discover whether imaging differences in children with TS are present long before TS can be diagnosed, whether they fade when tics improve, and whether they predict outcome in children with new tics. Investigation of this ?pre-Tourette? population opens an entirely new window for etiologic discovery in tic disorders. It may also have important clinical consequences, if the results identify which newly- ticcing children are at highest risk for development of a chronic tic disorder.

Project Summary / Abstract This is a proposal to provide intensive, mentored research training for pediatric neurologists who are within 5 years after finishing their clinical training in pediatrics and pediatric neurology, and who want to continue in an academic/research position. The name of the program will be the Child Neurologist Career Development Program (CNCDP) that will be sponsored by the NIH/NINDS and it is intended that CNCDP will replace a similar program of mentored research for pediatric neurologists called the Neuroscience Academic Development Award (NSADA). The NSADA program has been operating since 1992, and it has fostered the education of numerous child neurologists in academic positions, but less than half of the graduates of the NSADA program have gone on to become PI's of independent career development grants such as the K08, K23 or R01 awards or continued in the role of independent clinician-scientists. The CNCDP is intended to correct the shortcomings of the NSADA, and the most important change will be that the CNCDP will be a unified national program directed by a single PI with a Steering Committee and a National Advisory Committee (NAC), referred to as he CNCDP leadership. This plan is different from the NSADA program in which nine individual PI's of separate NIH awards reported directly to NIH-NINDS. The new CNCDP structure will include two layers of mentorship: a mentorship team at the scholar's home institution and mentorship from the national CNCDP leadership. Under the CNCDP plan, individual pediatric neurologists and mentorship teams will be able to apply for CNCDP support from any academic institution in the US with a pediatric neurology training program. The CNCDP Steering Committee will work with prospective candidates to find appropriate mentors and to apply for CNCDP support using the same form as for the NIH K08 Award. A separate NAC that includes national and international leaders in pediatric neuroscience will review the applications and choose up to 6 of the most meritorious for funding per year. Over 5 years, a total of 30 trainees are planned for the program. There is a transition plan for current NSADA scholars to complete their mentored research. Successful applicants to the program will present a training program that links scientific research training with a clinical career in pediatric neurology so that they are not separate but integrated. The scientific merit of the program and the quality of the mentors will be outstanding. The program will include training in experimental design, biostatistics and the responsible conduct of research, but generally will not include prolonged didactic work that can detract from the scholar's research and mentorship. Then the CNCDP leadership will continue to participate in the scholar's mentorship through an initial site visit to the scholar's institution, frequent webinar meetings with the scholar and mentoring committee, and a yearly two day retreat meeting in which scholars present their work to the CNCDP leadership and outside experts. CNCDP leadership will strictly enforce the rule that scholars must be protected to do research for 75% of their time.

PROJECT SUMMARY/ABSTRACT This P50 award will continue to support the Intellectual and Developmental Disabilities Research Center (IDDRC), which has been central to the scientific enterprise at the Kennedy Krieger Institute (KKI) and Johns Hopkins University (JHU) for over 30 years?supporting investigators seeking to understand, treat and ameliorate the adverse impact of intellectual and developmental disabilities (IDD), and to disseminate discoveries to the public toward a goal of prevention. The IDDRC continues to be structured around five Cores: (1) Administrative; (2) Clinical Translational; (3) Genomics; (4) Neuroimaging; and, (5) Behavioral Phenotyping, as well an integrated Research Project examining the role of sleep, circadian dysfunction, and brain development in children with autism. The Center's organization and Core structure are aligned with the research priorities of the NICHD IDD branch, including understanding etiology and complex comorbidities of IDD; improving early identification and screening; identification of biomarkers and outcome measures; understanding natural history; and translation of discovery to treatment and, ultimately, to public policy?all with a goal of prevention. The Center's translational science theme centers on progressing knowledge along the continuum from ?labs to clinics to communities.? In keeping with these goals, this Center's aims promote translational science along the full continuum of T4 translation. This emphasis is employed throughout the Center, with added importance on dissemination through the Administrative Core via links to the Institute's UCEDD (Maryland Center for Developmental Disabilities) and Leadership Education in Neurodevelopmental Disabilities (LEND) programs. The Center's aims are to: (1) provide infrastructure, expertise, and services necessary to promote and facilitate interdisciplinary research in the field of IDD; (2) act as the vehicle through which inter-institutional partnerships (including inter-IDDRC partnerships) addressing IDD research are developed and implemented; (3) provide training and technical assistance opportunities related to scientific inquiry within the field of IDD; and (4) serve as a hub (both locally and nationally) for translation and dissemination of scientific discoveries related to IDD toward the goal of informing (and ultimately shaping) public policy.

Project Summary / Abstract Disorders of the developing nervous system are common, affecting roughly 15% of the population. To improve the lives of children (and adults) with such disorders, we are in critical need of an enhanced pipeline of child neurology physician-scientists who will drive the innovative research necessary to lead to improvements in prevention, diagnosis and intervention. We propose, in this renewal application for the Child Neurologist Career Development Program (CNCDP-K12), to build upon our extant program, providing intensive, mentored career development for pediatric neurologists committed to being independently funded physician-scientists. This NINDS funded program is the nationalized version of the Neuroscience Academic Development Award (NSADA), a program granted to individual institutions. While the NSADA supported the research career development of numerous child neurologists, the program has under-delivered at the national level, as measured by the number of funded scholars to receive individual K awards, arguably due to its yoking to up to 10 specific institutions. By contrast, the CNCDP has a single Program Director with an Executive Leadership comprising 8 highly collaborative physician-scientist pediatric neurologists who are national leaders in the discipline. The CNCDP has 2 faculty committees: a 15 member Scientific Advisory & Review Committee (SARC) and a 4 member National Advisory Committee (NAC). The faculty members comprising these committees, all accomplished physician- scientists with over 25% from non-pediatric neurology disciplines, have diverse sets of expertise. The SARC reviews scholar applicants/applications and serves as extra-institutional advisors. The NAC provides to the leadership ongoing critical evaluation of the program. Under the CNCDP, individual pediatric neurologists (within 3 years of completion of clinical training) from any academic institution in the US can apply. The applicant must demonstrate a high quality and feasible research project, a robust career development plan, and institutional environment supportive of physician scientist career development, and an institutional letter of support committing appropriate protected time to research and career development. The Annual Meeting, a 2.5 day retreat attended by all faculty, funded scholars, applicants, NIH staff, and others, constitutes a mechanism for intensive mentoring and career development through small group sessions, one-on-one meetings, scholar presentations of their work (with intensive focus on quality presentations and articulating specific aims), and other career-enhancing curriculum. Program curriculum is also provided year-round through webinars/video conference. At the Annual Meeting, the SARC reviews the applications and recommends typically 6 of the most meritorious for 3 years of funding. A total of 30 scholars (90 scholar-years) are to be funded. The CNCDP provides highly structured oversight of the scholars' progress as well as institutional and scholar commitment to the program's requirements. Success of the program will be measured by a high rate of both scholars and non-funded applicants achieving individual K level funding or the equivalent.