Peggy C. Nopoulos - US grants

Clefts of the lip and palate are developmental craniofacial abnormalities that result from a failure of neural crest cells to migrate properly. As a group, clefting disorders are comprised of those that are isolated to facial clefts only (non-syndromic) and those in which the facial cleft is part of a well-defined syndrome of additional anomalies. Non-syndromic clefting has been shown to be associated with cognitive dysfunction. In syndromic clefting disorders, cognitive dysfunction is ubiquitous and often severe. The fact that clefts of the lip and/or palate are associated with brain abnormalities is intuitive as the development of the brain and face are intimately related. However, the systematic study of the types of brain anomalies present in patients with clefts of the lip and/or palate (and the functional consequences thereof) has been almost completely overlooked. This is an application for a Mentored Patient Oriented Research Career Development Award. During the award period, the candidate proposes an organized program of training and supervised research. While the candidate has training in structural imaging of the brain, she requires additional training in developmental biology, cognitive assessment, clinical assessment of genetic syndromes, and molecular and quantitative genetics. This training will be integrated with a research project in which the candidate proposes to phenotype Van der Woude Syndrome (VDWS), an autosomal dominant disorder manifesting as isolated clefts of the lip and/or palate and lip pits, by: 1) evaluating brain structure of patients using Magnetic Resonance Imaging, and 2) evaluating brain function in these patients using neuropsychological tests. In addition, these patients with VDWS will be screened for microdeletions using an allele loss assay. This will allow direct phenotype/genotype correlations to explore the relationship between the genetic determinants of facial clefting and brain structure/function. These findings will lead to a better understanding of the neurobiology underlying the cognitive dysfunction that significantly impairs the life of many patients with facial clefts. In turn, these findings may lead to early intervention with detection and treatment of cognitive deficits. This award would provide the candidate with the necessary background for further studies into brain structure and function in other craniofacial syndromes as well as into the genetic determinants of brain development. This award will also provide the candidate with the background necessary for ongoing research and funding leading to an independent research career.

DESCRIPTION (provided by applicant): This study is designed to evaluate brain structure and function in children with non-syndromic clefts of the lip and/or palate (NSCLP). In addition, the study will evaluate the relationship between measures of brain structure/function and genes associated with oral clefts. The etiology of non-syndromic oral clefts is complex, involving both genetic and environmental factors. Cognitive dysfunction is frequently associated with oral clefts. In syndromic clefting disorders, cognitive dysfunction is ubiquitous and often severe (mental retardation). The cognitive dysfunction associated with non-syndromic clefts is less severe but should not be underestimated. The fact that clefts of the lip and/or palate are associated with structural brain abnormalities is intuitive as the development of the brain and face are intimately related. However, the systematic study of the types of brain anomalies present in patients with clefts of the lip and/or palate (and the functional consequences thereof) has been almost completely overlooked. In the first study of its kind, the principal investigator of this grant has evaluated brain structure and function using Magnetic Resonance Imaging (MRI) in a group of adult males with NSCLP. The findings from that study indicate a pattern of cognitive dysfunction involving language and executive functions. In addition, there were robust abnormalities in volume and tissue composition of the cerebrum and cerebellum. Moreover, the abnormalities in brain structure were directly related to the abnormalities in cognitive function. Several studies have documented the cognitive dysfunction of children with NSCLP. Findings include global mild deficits with specific problems with language function. Although it has been hypothesized that these abnormalities are due to a primary problem in brain structure and function, no study to date has evaluated brain structure in this population. Evaluating brain structure in this group and its relationship to brain function will be key information to the search for understanding the neurobiology of cognitive dysfunction in this group. In addition, several genes have been associated with non-syndromic oral clefting and may play a key role in its pathoetiology (e.g. MSX1, TGFB3, TGFA). It is likely that the genetic determinants of non-syndromic clefting are related to the accompanying abnormalities in brain structure and function. Evaluating the relationship between brain structure/function and genes known to be associated with non-syndromic clefts may shed light on possible etiologic mechanisms at the molecular level.

brain morphology; neuropathology; neurophysiology; neurofibromatosis; neuropsychology; cognition; child behavior; children; clinical research; magnetic resonance imaging; brain imaging /visualization /scanning; human subject; neuropsychological tests;

DESCRIPTION (provided by applicant): This is a competitive renewal application for the grant "Brain Structure, Function, and Growth in Children with Oral Clefts" (5RO1 DEO14399-05). The study is designed to evaluate brain structure / function, and growth in subjects with non-syndromic or `isolated clefts of the lip and/or palate'(ICLP). In addition, the study will evaluate the relationship between measures of brain structure/function and genes associated with oral clefts. Clefts of the lip/palate are an aberration in development. In addition to the facial defect, subjects with ICLP also suffer from significant problems in speech, behavior, and cognition. The etiology of these deficits have typically been considered as `secondary'to factors such as hearing deficits during development from chronic otitis media (which is ubiquitous in children with clefts) or even the psychological factors of living with a cleft. However our lab has been the first to consider the notion that the deficits in speech, behavior, and cognition of subjects with ICLP may well be due to a primary problem in brain structure / function. The development of the face and the development of the brain are intimately related, thus it follows logically that an abnormality in facial development may also be accompanied by an abnormality in brain development. However, the study of the neurobiology of ICLP has been virtually non-existent. The initial phase of the proposal has shown that children with ICLP have significantly abnormal brain structure and function. Moreover, these abnormalities are directly related to speech, cognitive function, and behavioral abnormalities. However, the pattern of the brain abnormalities seen in children with ICLP are strikingly different from the pattern of brain abnormalities seen in adults with ICLP. The brain takes an exceedingly long time to develop with late maturational processes of synaptic pruning and myelination taking place through the second decade of life. Therefore, the current proposal is a combination cross-sectional and longitudinal study evaluating the developmental trajectories of brain growth and development from child to adult, ages 7-30 years. Subjects with ICLP will be matched by age and sex to healthy controls. The determinants of brain structure are highly genetic. In addition, several genes have been associated with non-syndromic oral clefting and may play a key role in its pathoetiology (e.g., MSX1, IRF6). It is likely that the genetic determinants of isolated clefting are related to the accompanying abnormalities in brain structure and function. Evaluating the relationship between brain structure/function and genes known to be associated with isolated clefts may shed light on possible etiologic mechanisms at the molecular level. PUBLIC HEALTH RELEVANCE: The study is designed to evaluate brain structure / function, and growth in subjects with non-syndromic or `isolated clefts of the lip and/or palate'(ICLP). In addition, the study will evaluate the relationship between measures of brain structure/function and genes associated with oral clefts.

DESCRIPTION (provided by applicant): Huntington's disease (HD) is an autosomal dominant disease manifested in a triad of cognitive, psychiatric, and motor signs and symptoms. This disease has classically been conceptualized as a "neurodegenerative disease of the striatum". However, recent evidence challenges this concept. Several lines of evidence have suggested that in addition to the degenerative process, there may be an important developmental component to the etiology of this disease. For example, studies in our laboratory show that adult subjects who are gene positive for HD but have not yet manifested the illness (presymptomatic gene carriers or PSGCs) have significant changes in the structure of their brain, specifically, decreased intracranial volume, decreased volume of cerebral white matter, and increased volume of cerebral cortex. These changes support the possibility that these subjects may have had abnormal brain development. A growing body of research evaluating PSGCs compared to Non-Gene Carriers (NGCs) supports the notion that PSGCs not only have structural brain changes as described above, they also have subtle but significant deficits in cognitive, motor, and psychiatric symptoms. Thus, although brain changes and symptoms are present prior to diagnosis, when do they begin? Is it possible that these changes are present from birth and then progress during the course of the disease process? In an effort to better understand the developmental aspects of this brain disease, the current study proposes to evaluate brain structure and function in children (ages 6-12) who are at risk for developing HD. Brain structure will be evaluated using Magnetic Resonance Imaging (MRI) with quantitative measures of the entire brain, including general measures such as cerebrum and cerebellar volume as well as regional measures such as cerebral cortex, cerebral white matter, and subcortical nuclei (caudate, putamen, thalamus). Brain function will be assessed by cognitive tests, neurologic evaluation, and behavioral assessment. Subjects that are PSGCs will be compared to subjects who are NGCs. Changes in brain structure and/or function in the PSGCs would lend significant support to the notion that this disease has an important developmental component. If proven, a developmental model of HD could identify disease pathways that are dysfunctional prior to degeneration. This could lead to intervention techniques that could target and protect these pathways, preventing the disease. PUBLIC HEALTH RELEVANCE: This is a revised application for the proposal "Brain Structure and Function in Children at Risk for Huntington's Disease (1RO1 NS055903-01). The study is designed to evaluate the brain structure (using Magnetic Resonance Imaging) and brain function (using cognitive and behavioral assessment) of children (ages 6 - 12 years) at risk for Huntington's Disease. Changes in brain structure and/or function in the gene positive group would lend significant support to the notion that this disease has an important developmental component.

The University of Iowa Carver College of Medicine (CCOM) has a long history supporting medical student research with a successful and growing research training program that began more than 30 years ago. The NIH has continuously funded the program with an NRSA T35 training grant since 1980. Under the auspices of the T35 short-term training grant, students are given the opportunity to be involved in a research project of their choosing for 12 weeks in the summer following the first year of medical school. Students choose a mentor from any of 19 clinical and 6 basic science departments in the Carver College of Medicine. Nearly 200 faculty mentors with ideas for short term projects are listed on a searchable online database from which students may sort options by department, type of research or by key word. The student is required to submit a proposal, which is competitively reviewed by the Research Committee of the CCOM. Student applications are rank-ordered by the score received and those with the best scores are chosen for the 40 NIH T35 short-term training stipends with another 50 to 60 stipends funded by the CCOM. The program exposes the students to the entire research process, from writing a research proposal, then working with their mentor before submitting their research accomplishments in the form of an abstract and presentation of their research at the Annual Medical Student Research Day. This experience accomplishes several goals. It permits the student to acquire skills such as application of scientific methods, critical evaluation of previous related experimental work, statistical approaches to data analysis, and to gain knowledge and develop skills related to a specific research project while working closely with a faculty sponsor who serves as a role model and mentor. The program has led to a substantial number of student presentations at National Meetings and numerous publications in peer reviewed journals and an increasing interest in the Research Distinction Track, an honors program for CCOM students with a sustained commitment to research. It is hoped the experience will encourage the student to pursue other research opportunities in medical school as well as to consider a academic career that includes biomedical research.

Red blood cell (RBC) transfusion management includes the criteria used to determine when transfusion should occur in preterm infants. There is controversy regarding whether more restrictive or more liberal criteria would best serve the goal of optimal brain development. Although some studies have indicated that liberal transfusions may be neuroprotective, our findings from the previous 4 years of this PPG indicate that liberal transfusions result in poor long-term brain development, and this is particularly true for females. The overall aim of Project #3 is to evaluate the neurodevelopmental outcomes of differential transfusion practices from a mechanistic viewpoint. We hypothesize that liberal transfusion will result in poorer neurodevelopmental outcomes compared to restrictive transfusion practices. Potential mechanisms explored for this phenomenon include inflammation and/or erythropoietin (Epo) suppression that result from liberal RBC transfusion. Cerebral white matter and sex effects will be of particular interest. Specific Aim 1 will be to measure the relationships between serum biomarkers (average hematocrit (HCT), iron, ferritin, c-reactive proteins, cytokines and Epo), and brain structure (using MRI) in preterm infants that are randomized to either restricted or liberal transfusion. Biomarkers and MRI scan will be obtained during the NICU stay. Specific Aim 2 will examine the effects of differential transfusion on brain development using a longitudinal assessment of the same infants at 12 months and 24 months. Follow-up assessments will include a comprehensive battery of cognitive and developmental measures as well as a follow-up MRI scan. The current proposal is designed to 'extend' an NICHD Neonatal Research Network trial to evaluate the relationship between neonatal transfusion approach and neurodevelopmental outcome. This study is called the Impact of a Liberal Red Blood Cell Transfusion Strategy on Neurologically-lntact Survival of Extremely- Low-Birth-Weight Infants: The Transfusion and Brain Injury (TABI) Trial. The TABI protocol will be the foundation for recruitment of subjects, our current proposal would extend the TABI by: 1) assessing transfusion status and neurodevelopmental impairment (NDI) as continuous measures rather than dichotomous measures; 2) use additional assessments that more sensitively and more specifically quantify brain structure and function; and 3) explore specific proposed mechanisms by which differential transfusion may impact brain development (inflammation and Epo suppression).

DESCRIPTION (provided by applicant): This proposal is a competitive renewal for a unique study that measures the volume, function, and development of the striatum in children at risk for Huntington's Disease (HD). HD is a neurodegenerative disease caused by a DNA triplet repeat (CAG) expansion and manifests in cognitive, behavioral, and motor changes. Average age of onset is 40 yrs. The disease eventually affects most brain regions, yet the primary pathology is located in the striatum. Degeneration is a key component in the disease process, yet research in the past few years has supported the notion that a crucial component of the pathoetiology of HD is abnormal brain development. The grant was funded in 2009 to investigate this hypothesis by the study of children at risk for HD (those with a parent with HD). As HD is an autosomal dominant disease, each child has a 50% chance of inheritance. The at-risk participants are genotyped and those who are gene-expanded (GE) are compared to those who are gene non-expanded (GNE); a 3rd comparison group is healthy control children (HC) (no HD in family). Assessments include MRI and measures of motor function, cognitive skills, and behavior. The current proposal is designed to extend our studies by conducting a more thorough evaluation of the growth and development of the striatum. The original study evaluated volumes using structural Magnetic Resonance Imaging (sMRI) and white matter integrity using Diffusion Tensor Imaging (DTI). Results (shown in progress report) indicate volume deficits in the striatum with relative sparing or enlargement of the thalamus and cerebellum; and abnormal fractional anisotropy (FA) in multiple tracks. The new protocol will add: 1) evaluation of striatal resting state functional connectivity MRI (fcMRI), 2) Molecular measures of striatal integrity using (1)H magnetic resonance spectroscopy (MRS), and 3) the evaluation of developmental trajectories (growth between ages 6-18 years) of brain structure via an 'accelerated longitudinal' format. Compensatory mechanisms such as overgrowth of the cerebellum and thalamus will also be investigated. Functional assessment will include measures of cognition and motor skill. Information gained from this proposal could be key to identifying the earliest possible time-frame for neuroprotective interventions.

? DESCRIPTION (provided by applicant): Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, is a multi-faceted genetic disease caused by CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. Some of the primary symptoms are muscle myotonia and weakness, yet patients and family members report that some of the most disabling symptoms of the disease are cognitive and behavioral. Therefore, the involvement of the brain has recently come to attention and has prompted the scientific community to better understand the role of the brain in this disease. Neuroimaging studies in DM1 are very limited. Results of these studies are quite variable, however what is consistent is that, compared to controls, white matter is particularly affected in DM1 subjects with decrements in cerebral white matter volume (WM), an increased number of white matter lesions (WML), and Diffusion Weighted Imaging (DWI) measures, which appear to be the most abnormal. Although these studies represent an increased interest in brain aspects of DM1, understanding the effects of DM1 on brain structure and function is still in its infancy. Lacking from the literature is a lage brain imaging study with a homogenous sample (adult onset only) combined with a comprehensive assessment of cognition, motor, and behavioral measures. In addition, the neuromuscular aspects of DM1 are progressive and there is some evidence to suggest that the cognitive changes in DM1 are also progressive. However, there is not one single study evaluating longitudinal changes in brain structure. This dearth of knowledge about the CNS effects of DM1 is in sharp contrast to where the field is moving in regard to therapeutics. The effectiveness of gene therapy using Antisense Oligonucleotides (ASOs) in treatment of an animal model of DM1 has been shown, setting the stage for human trials which have already begun. In order for the field to be ready to begin any trials of CNS treatment in DM1, a substantial amount of work needs to be done. There is an urgent need for comprehensive baseline characterization of brain structure and function in order to identify biomarkers that are: 1) disease-specific and clinically relevant; and 2) can track CNS disease progression. The overall aim of this study is to investigate the use of MRI measures of white matter health (WM, WML, DWI) as biomarkers of DM1 CNS disease. Subjects will undergo MRI scans and a comprehensive battery of cognitive, motor, and behavioral tests. Compared to matched healthy controls, the DM1 subjects are hypothesized to have specific changes in measures of white matter health in brain imaging, as well as cognitive and behavioral deficits. All subjects will be assessed at baseline and again at 1 and 2 year follow-ups. Evaluating brain measures over time will help to establish them as useful biomarkers of CNS progression, making them vital tools for clinical trials in DM1.

This revised application requests continuation of funding for a successful and long-standing training program (dating back to 1991). At a critical juncture of change in leadership, the program strives to maintain a strong foundation with the opportunity for growth and restructuring. Rebranded as the Iowa Neuroscience Specialty Program In Research Education (INSPIRE) this program seeks to integrate training in translational neuroscience with an emphasis on a lifespan trajectory perspective. Our approach is to re-shape and reframe our research opportunities based on the NIMH's Research Domain Criteria (RDoC) project by focusing on mechanisms of psychopathology based on functional dimensions rather than the diagnostic criteria that define patient populations. The ultimate goal is to train a group of young investigators who will combine a high level of sophistication about the complexities of the human brain's functional domains, how these systems develop over time, and the mechanisms that may lead to pathologic functioning. . This program is at a pivotal point in time. Nancy Andreasen, a pioneer of brain imaging in the study of schizophrenia, conceptualized and directed this program from 1991 until now. The current Co-PI of the program, Peg Nopoulos, is an alumnus of the program herself and will now be responsible for directing the program. She is joined by John Wemmie, the new Co-PI of the program. This change in leadership has afforded the opportunity to retain the solid foundation, but also to re-shape the program substantially in two broad areas: 1) a focus on the study of neurobiologic mechanisms of psychiatric illness across the lifespan, and 2) implementing a more highly structure training program with emphasis on translational science. In expanding the content of the program beyond the major psychoses, we partner with a new and growing Molecular Psychiatry division, adding six new MD/PhD and PhD scientists as mentors. This helps expand the program to include basic science PhDs, a new phenotype of fellow, and allows for the creation of an interdisciplinary cohort or trainees. This mix of types of trainees adds an addition layer of exposure to translational research with a strong emphasis on team science. Central to the training program is the Master's in Translational Biomedicine (TBM) program which is hosted by our Institute for Clinical and Translational Sciences (ICTS). This program is designed to be individualized and flexible. The INSPIRE program will recruit a total of 4 fellows at the post-doctoral level who are MD, MD/PhD, or PhD trained. Each fellow will be `matched' with an outstanding mentor as well as a mentor team to oversee the primary activity of mentored research activity. In addition, each fellow will develop a program through the TBM that suits their needs while fulfilling requirements (such as Training in Responsible Conduct in Research), utilizing both formal didactics and career development activities. A degree (certificate or Master's) is an option, but not a requirement. The training period is typically 2 years in length but can be expanded to 3 years.

PROJECT 4: PROJECT SUMMARY Red blood cell (RBC) transfusion management includes the criteria used to determine when transfusion should occur in preterm infants. There is controversy regarding whether more restrictive or more liberal criteria would best serve the goal of optimal brain development. Although some studies have indicated that liberal transfusions may be neuroprotective, our findings from a long-term outcome study in conjunction with this PPG (2006-2010) suggested a significant sex effect with females in the liberal transfusion group having the worst neurodevelopmental outcomes. Those findings were unexpected, but led us to focus the next PPG project (2010 ? present) on short term outcomes (neonatal period). We hypothesized that transfusion-induced inflammation was a possible mechanism of poor outcome related to liberal transfusion. Our current neonatal assessment was `piggy- backed' onto the large multi-site Transfusions of Prematurity (TOP) clinical trial where preterm infants are randomized to either liberal or restricted RBC transfusion. Inflammatory cytokines were measured during the first weeks of life before and after transfusions. This was followed by an MRI brain scan at the end of the NICU stay. The overall aim was to evaluate the neurodevelopmental outcomes of differential transfusion from a mechanistic viewpoint, evaluating the role of inflammation. The preliminary data are striking and support the notion of an interaction between transfusion and inflammation with direct effects of brain structure. Moreover those changes in the brain occur in a sex specific manner. We now move into a vital timeframe in further assessment of the TOP infants. This trial presents an unprecedented and time-limited opportunity to evaluate neurodevelopmental outcomes in the context of the anemia of prematurity and its treatment (RBC transfusion). The current proposal will assess long-term neurodevelopmental outcomes of brain structure (using MRI) and brain function (using standardized tests) in children previously enrolled in TOP. Initial assessment will be done at age 5 with annual assessments at ages 6 and 7 years as change over time (developmental trajectory) is more sensitive to group differences than one cross sectional comparison. .Finally, in addition to the data from the TOP we also have cytokine data from their NICU stay, allowing assessment of the effects of early inflammation on later neurodevelopment.

PROJECT SUMMARY This proposal is a competitive renewal for a unique study that measures the volume, function, and development of striatal-cerebellar circuity in children at risk for Huntington's Disease (HD). The standard assumption is that HD is a degenerative disease of the striatum. However, research supports supported the notion that a crucial component of the pathoetiology of HD is abnormal brain development. The grant was originally funded in 2009 and dubbed the Kids-HD program, designed to investigate this hypothesis by the study of children at risk for HD (those with a parent or grandparent with HD). The at-risk participants are genotyped and those who are gene-expanded (GE) are compared to those who are gene non-expanded (GNE). Gene knock-down therapy ? Antisense Oligonucleotides or ASOs ? are currently entering Phase III studies and hold promise for treatment of patients in early stages of disease (by preventing further decline). If ASOs fulfill that promise, the next step will be preventive therapy ? giving the ASO early enough (potentially to children) to prevent symptoms from occurring. The growth and development of the striatum is vital to understand as this is the primary site of disease pathology. Yet, knocking down a gene that is vital to development of these structures must be approached with an abundance of caution. Human brain development is prolonged, with striatal maturational changes occurring up through 30 years of age. Therefore, discriminating ongoing development/maturation with the degenerative phase of the disease may be key in knowing when to administer and ASO. Our preliminary data suggest that a novel blood biomarker ? Neurofilament light (NfL) rises within roughly 20 years of onset but is normal prior to that, suggesting it is not present in development, but is seen at the very beginning phases of degeneration. Rationale for renewal and expansion (5 sites across the US) include: 1) increase sample size for replication of original findings with sufficient power to detect CAG-specific effects and 2) model the entire period of brain development (up to age 30 rather than only up to age 18); 3) evaluate the utility of a blood biomarker of neural dysfunction, Neurofilament light (NFl) that may help delineate the earliest phases of degeneration.

PROJECT SUMMARY This proposal is a competitive renewal for a unique study that measures the volume, function, and development of striatal-cerebellar circuity in children at risk for Huntington's Disease (HD). The standard assumption is that HD is a degenerative disease of the striatum. However, research supports supported the notion that a crucial component of the pathoetiology of HD is abnormal brain development. The grant was originally funded in 2009 and dubbed the Kids-HD program, designed to investigate this hypothesis by the study of children at risk for HD (those with a parent or grandparent with HD). The at-risk participants are genotyped and those who are gene-expanded (GE) are compared to those who are gene non-expanded (GNE). Gene knock-down therapy ? Antisense Oligonucleotides or ASOs ? are currently entering Phase III studies and hold promise for treatment of patients in early stages of disease (by preventing further decline). If ASOs fulfill that promise, the next step will be preventive therapy ? giving the ASO early enough (potentially to children) to prevent symptoms from occurring. The growth and development of the striatum is vital to understand as this is the primary site of disease pathology. Yet, knocking down a gene that is vital to development of these structures must be approached with an abundance of caution. Human brain development is prolonged, with striatal maturational changes occurring up through 30 years of age. Therefore, discriminating ongoing development/maturation with the degenerative phase of the disease may be key in knowing when to administer and ASO. Our preliminary data suggest that a novel blood biomarker ? Neurofilament light (NfL) rises within roughly 20 years of onset but is normal prior to that, suggesting it is not present in development, but is seen at the very beginning phases of degeneration. Rationale for renewal and expansion (5 sites across the US) include: 1) increase sample size for replication of original findings with sufficient power to detect CAG-specific effects and 2) model the entire period of brain development (up to age 30 rather than only up to age 18); 3) evaluate the utility of a blood biomarker of neural dysfunction, Neurofilament light (NFl) that may help delineate the earliest phases of degeneration.

PROJECT SUMMARY: NEUROCIRCUITRY AND BEHAVIOR CORE (NBC) The primary objective of the Neurocircuitry and Behavior Core (NBC) is to provide state-of-the-art services that foster studies of intellectual and developmental disability (IDD) across the lifespan?from conception to adulthood, tailored to a rural population. The Core will support research projects affiliated with the Hawk- IDDRC that utilize both animals and humans as well as those that cross-fertilize a translational approach to the study of IDD from a lifespan perspective. The Core is made up of two units: 1) Neuroimaging Division (NID) and 2) Neural Circuits and Behavior Division (NCBD). The NID will assist in the development, implementation, and completion of neuroimaging research studies in animal models as well as humans. Neuroimaging modalities will focus on imaging techniques to assess brain structure, function, and metabolism. The resources provided will include expertise in the following aspects of brain imaging: a) development of novel imaging tools, pulse sequences, and equipment; b) implementation of protocols for image acquisition; c) implementation and deployment of standard image analysis pipelines; d) development of novel image analysis strategies; and e) data management, bioinformatics, and statistical support for imaging data. The NCBD will provide expertise in neural circuit function, behavior (e.g. social interaction, sleep), and cognition (e.g. learning and memory) in animal models and humans using tools that are often not available within individual laboratories. For studies using animal models, the NCBD will provide facilities and services to aid investigators performing behavioral assays. For human studies, the NCBD has significant expertise in studying human behavior and cognition across the lifespan and will design and implement cognitive paradigms to study neural circuits, which can be applied to individuals with intellectual and developmental disabilities as well as controls. Finally, the NID and NCBD are able to conduct experiments as requested by investigators, or will provide the necessary training to enable laboratory personnel to perform experiments in the facility. The NBC will integrate and capitalize upon strong existing resources currently available at the University of Iowa including the Iowa Institute for Biomedical Imaging (IIBI) and the Iowa Neuroscience Institute (INI). Tools that are developed as part of the NBC will be shared with IDD investigators across the country. The NBC will support 27 federally funded projects ($11.3 million per year) and will build upon strong existing collaborations between basic scientists who use animal models and clinical scientists engaged in human brain studies. In addition, the NBC will help strengthen the relationship between scientists and the IDD community and their families, many of whom live in rural areas, helping foster collaborations that will enable a better understanding of IDD from a lifespan perspective.