John H. Gilmore - US grants

Dopamine receptor development has been implicated in the etiology and pathophysiology of schizophrenia. The goal of this research is to characterize the development of dopamine receptor subtypes in human brain and to study potential developmental alterations of dopamine in the brains of subjects with schizophrenia. There has been very little work done in this important area. This study will provide new and important information about dopamine receptor development in human postmortem brain tissue using neurochemical and molecular techniques, and will test the overall hypothesis that dopamine receptor subtypes undergo subtype specific changes in localization and density during development. This characterization of dopamine receptor ontogeny will provide the basis for understanding the role that the development of dopamine receptors, both normal and abnormal, play in the etiology and pathophysiology of schizophrenia. Further, this study will test the hypothesis that there are developmental alterations in dopamine receptor expression in schizophrenia. Dopamine receptor development will be studied two brain regions implicated in schizophrenia, the prefrontal cortex and the striatum, including the nucleus accumbens. Tissue from a variety of ages subjects will be collected from three local sources. Using receptor autoradiography, the age specific changes of Dl and D2 dopamine receptor density and localization will be characterized. In addition, the developmental expression of dopamine receptor subtype mRNA will be characterized using in situ hybridization. Finally these techniques will be used to explore the potential developmental alterations in dopamine receptors in the postmortem brain tissue of adult subjects with schizophrenia. This study will provide important basic information about dopamine receptor development in humans, and may provide evidence that dopamine receptor development is altered in schizophrenia. In addition, it may provide insights into the role of dopamine receptor development in other neurodevelopmental diseases such as Tourette's syndrome, autism, and attention deficit disorder, and may provide the basis for the development of subtype selective drugs useful in the treatment of these diseases.

DESCRIPTION (adapted from applicant's abstract): The causes of schizophrenia remain elusive, though there is strong evidence that pre- and perinatal complications, including prenatal exposure to infection, increase the risk of a person ultimately developing schizophrenia. In spite of their etiological importance, not only for schizophrenia, but also for other neurodevelopmental diseases (including lissencephaly, neural tube defects, autism, and mental retardation), the mechanisms by which clinical pre- and perinatal risk factors such as infection alter the developing brain have remained largely unstudied. It is hypothesized that pro-inflammatory cytokines, including interleukin-lbeta (IL-1B), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-A), generated by the maternal, and/or placental immune system in response to infection play a key role in the association between prenatal infection and schizophrenia. Amniotic fluid and fetal cord blood levels of cytokines are increased in human pregnancies complicated by infection. IL-1B, IL-6, and TNF-A can all be neurotoxic to developing cortical neurons; the actions of cytokines on developing neurons are consistent with abnormalities of cortical neuron number, size, and "connectivity" found in the brains of patients with schizophrenia. There is also evidence that cytokines regulate more classic neurotrophic factors. The goal of this research is to characterize cytokine (IL-1B, IL-6, TNF-A) and neurotrophic factor [brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF)] responses to prenatal infection and to study cytokine regulation of cortical neuron development. A clinical study of amniotic fluid obtained at amniocentesis from human pregnancies with and without prior exposure to infection will be used to determine cytokine and neurotrophic factor response to prenatal infection. Pre-clinical studies in a rat model of early infection (E. coli lipopolysaccaride exposure) will investigate the regulation of cytokine and neurotrophic factor (BDNF, NT-3, NGF) protein in the developing cortex. In addition, in vitro primary cell culture techniques will be used to study cytokine regulation of embryonic cortical neuron survival, growth, and synapse formation. These studies will provide a better understanding of how this clinically important risk factor for schizophrenia and other neurodevelopmental disorders can alter cortical neuron development, and may ultimately provide a rational basis on which to develop preventative treatment strategies.

DESCRIPTION (provided by applicant): Despite the widespread belief that schizophrenia is a disorder of abnormal early brain development and numerous theories to that effect, there is little direct evidence to support this idea. This is in part due to the fact that until recently, the clinical study of human fetal and neonatal brain development was limited by a lack of appropriate tools with which to carry out such studies. Ultrasound and magnetic resonance imaging (MRI) are ideal techniques for the study of brain development in the human fetus, neonate, and child. Using ultrasound, it is possible to image the developing lateral cerebral ventricles in utero. Using high resolution MRI, it is possible to examine brain structure and its development from the neonatal period through childhood and into the period of risk for the onset of schizophrenia. The primary hypothesis of this research program is that abnormalities of brain structure and development, reflected in ventricle size and shape, along with abnormalities in total brain volume and white matter integrity in fetal and neonatal brain, are markers of abnormal development of thalamo-limbic-cortical circuits, associated abnormal GABA interneuron development, and ultimate susceptibility to schizophrenia. This will be the first study to use ultrasound to prospectively study prenatal and neonatal brain development in the offspring of women with schizophrenia. It will also prospectively study the development of fetuses with mild enlargement of the lateral ventricles, a structural abnormality that is hypothesized to represent an endophenotype of risk for schizophrenia. Subjects will have 2D ultrasounds in the second and third trimesters, and a 3D ultrasound and an MRI at 2 weeks after birth. Early childhood development will be followed prospectively at ages 1 and 2 years with the Mullen Scales of Early Learning and an assessment of working memory and attention, neurocognitive processes in which GABA interneurons play an important role. The identification of the timing of ventricle enlargement will provide a focus for studies of neurodevelopmental mechanisms that underlie schizophrenia. Understanding the causes of early abnormalities of ventricle structure will provide important information about genetic and environmental risk factors in schizophrenia. Finally, the study of lateral ventricle development will allow the early identification of children at high risk for schizophrenia and other neurodevelopmental disorders, ultimately making early intervention possible to prevent or mitigate this risk.

[unreadable] DESCRIPTION (provided by applicant): This application is the competitive renewal of T32 MH 19111-13 "Fellowship: Clinical Neuroscience and Pharmacology". The purpose of the training program is to attract physicians to careers in clinical, basic, and translational neuroscience research, and to provide effective training that will enable fellows to become productive, independent investigators who will contribute to the future advance of knowledge in psychiatry. The Fellowship will address the national shortage of physician-scientists in psychiatry. The program is situated in the Department of Psychiatry at the University of North Carolina at Chapel Hill, a Department with a rich history of clinical and basic research and research training in psychiatric disorders as well as extensive clinical and basic research resources. The Department is the home of an NIMH-sponsored Mental Health Clinical Research Center/Conte Center, which provides fellows with a broad research infrastructure on which to base their training. The Program's guiding philosophy is that a broad based education in the disciplines relevant to study of psychiatric disease, including pharmacology, cognitive neuroscience, neuroimaging, molecular neurobiology, and genetics provides an essential background and context for a sustained career as a creative investigator. The fellowship provides a "hands-on" experience in all phases of research, including 1) the formulation of clear and testable research questions, 2) the design of appropriate research plans, utilizing effective and well-chosen methodologies, 3) the collection and management of data, and 4) the analysis, interpretation, and clear presentation of results. The program also provides a foundation for the integration of basic neuroscience research with clinical research and for the advancement of translational research. Fellows are given the opportunity to work in one of several basic labs of the faculty of the program, and those fellows who focus on clinical research also receive didactic instruction in basic research techniques (and consequent interactions with basic scientists). This training program emphasizes ethical issues and the responsible conduct of research, in addition, fellows receive training in the important skills that are essential for successful academic careers, including critical reading of the literature, manuscript and grant preparation, and presentations at meetings and lectures. The graduates of this research training program have an outstanding record of success as investigators, including several who have successfully pursued research directions that integrate basic and clinical research. The training program has an excellent record of recruiting individuals from underrepresented ethic groups as well. This research training program competitive renewal requests support for four post-doctoral trainees a year for years 14-19, so that it can continue to train the next generation of physician-scientists in psychiatry. [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Twin studies have provided fundamental information about how genes and environment contribute to individual differences in brain structure and cognitive function in health and psychiatric disease and how these influences change during development. Previous twin studies in older children, adolescents and adults indicate that genetic and environmental influences are region/structure specific and change with age. Early childhood is period of rapid structural and functional brain development that is implicated in the pathogenesis of many psychiatric disorders. Therefore, there is a critical need to understand the role of genetic and environmental contributions to brain structure and function in this crucial period of development. The Early Brain Development in Twins study has been the first, and to our knowledge the only, twin study of early childhood brain development. To date we have enrolled and studied over 275 twin pairs, at birth, 1, 2, 4, and 6 years and provided novel and previously unknown information about genetic and environmental influences on brain development in early childhood. In the next funding cycle, we propose to complete our twin study of early childhood brain development by following the current cohort to age 6. MRIs, including structural, diffusion tensor, and resting state functional imaging, will be done at ages , 4, and 6 years. Cognitive development, including RDoC constructs of language and working memory will be assessed. Additional innovations for this funding cycle include the application of a recently developed methodology for delineating cortical thickness and surface area in very young children, and the addition of resting state fMRI. Knowledge gained in this study will improve our basic understanding of human brain development, allow us to determine how modifiable abnormal developmental trajectories associated with risk for psychiatric disease may be, and help us determine when in development early interventions would have the greatest impact. Relevance New knowledge gained in this study will provide a dramatically improved framework for understanding genetic and environmental influences on early childhood brain development, a period of risk for many neuropsychiatric disorders and will provide the fundamental information critical for developing preventative strategies for these disorders.

[unreadable] DESCRIPTION (as provided by applicant): Schizophrenia is associated with subtle abnormalities of brain structure on MRI, including enlarged lateral ventricles, reduced cortical gray matter volumes, reduced hippocampal volumes, as well as abnormal diffusion properties in white matter. While it has been hypothesized that these brain abnormalities arise during early brain development, there has been little direct evidence to support this idea. In the first funding period of this Conte Center project, we developed the magnetic resonance image (MRI) acquisition and image analysis tools to study very early brain development in children at high risk for schizophrenia. These included a genetic high risk group - the offspring of women with schizophrenia, and a "structural" high risk group - children with prenatal isolated mild ventriculomegaly. Our results to data indicate that compared to normal controls, the offspring of mothers with schizophrenia have reduced cortical gray matter volumes on neonatal MRI. This is the first concrete evidence that early cortical development is compromised by genetic vulnerability. The perinatal and early postnatal period is one of the critical periods in the development of cortical connectivity - a time of rapid synapse growth - one that is a focus of this Conte Center. In addition, we have developed a large cohort of normal controls. In the second funding period, we propose to continue our study of every early brain development in normal and high risk children, applying our novel image analysis methodologies to study gray and white matter development in an expanding cohort, and to study longitudinal brain developmental changes as we follow our cohort into mid childhood. Specifically we will study longitudinal brain development in children at high risk for schizophrenia with 3T MRI (including diffusion tensor imaging) and neurodevelopmental assessments at ages 0, 1, 2, 4, and 6 years of age. We will also study early brain development in the offspring of mothers with bipolar illness as a comparison group for non-specific effects of medication and chronic illness. Finally, we have obtained DNA and MRIs on a large group of normal neonates and will determine if polymorphisms of risk genes influence cortical development at this earliest stage of life. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The first years of life are the most dynamic and perhaps the most critical phase of postnatal brain development. Abnormalities in early childhood brain development have been implicated in neurodevelopmental disorders, including autism and schizophrenia, though very little is known about this crucial time period. In the previous grant cycle, we studied brain development in a unique cohort of normal children longitudinally followed and scanned at birth, 1 and 2 years of age, including 386 neonates, 297 one year olds and 251 two year olds. In addition, we have developed the innovative image analysis tools necessary to study brain development in very young children. Our studies found rapid gray matter development and white matter maturation in the first 2 years of life, with marked regional differences in the cortex and in white matter tracts, consistent with temporal patterns of sensory/motor and higher integrative function development. We also found significant relationships between white matter maturation and working memory. Preliminary data indicates that regional gray matter volume and white matter tract diffusivity in neonates is predictive of subsequent gray matter volume and white matter structure at ages 1 and 2 years. These findings indicate that neonatal brain structure, reflective of prenatal brain development and the rapid growth trajectories of the first two years of life, likely play an important role in longer trm outcome. In this competitive renewal, we will extend follow-up of our cohort to 6 years of age and focus on structure/function relationships and the predictive value of early brain structure for later childhood brain structure and cognitive function. MRIs, including structural and diffusion tensor imaging, will be done at ages 1, 2, 4, and 6 years. Cognitive development, including general cognitive function and working memory will also be assessed. Developmental trajectories of cortical gray matter (including cortical thickness and surface area) and white matter (including tract-based spatial statistics and quantitative tractography) will be studied. We predict that neonatal brain structure and developmental trajectories in the first two years of life are critical for, and predictive of, subsequent structural and cognitive development. Relevance New knowledge gained in this study will provide a dramatically improved framework for understanding abnormalities of early childhood brain development in neurodevelopmental disorders such as autism and schizophrenia and will provide the fundamental information critical for developing preventative strategies for these disorders.

behavioral /social science research tag

? DESCRIPTION: The Department of Biostatistics, the Department of Psychiatry, and the Biomedical Research Imaging Center at the University of North Carolina at Chapel Hill (UNC) propose a research training program in mental health biostatistics with an emphasis on neuroimaging and genomics that will support three predoctoral students and two postdoctoral scholars. The objective is to develop independent investigators, who are able to use a wide range of analytical approaches in biostatistics to answer important scientific questions in mental health research. The program is built upon existing collaborative relationships among biostatistics, mental health, radiology, computer science, and psychology research faculty in the Department of Biostatistics (BIOS), the Department of Statistics & Operation Research (STAT), the Department of Psychiatry (PSYCH), the Department of Radiology (RADIO), the Department of Genetics (GNET), the Department of Computer Science (CS), the Department of Psychology (PSY), and the Biomedical Research Imaging Center (BRIC). Training will usually be 2-3 years in duration for predoctoral students and postdoctoral/research scholars. The training program is designed to: (i) provide solid training of the biostatistical methods for mental health research; (i) provide broad expertise of mentors in biostatistics, radiology, genetics, psychology, and psychiatry; (iii) rotate trainees through different laboratories in psychiatry and psychology durin their training; and (iv) prepare trainees to pursue academic research careers in developing methods and collaborations needed in mental health research. Major strengths of the program include: (i) the prestigious training programs in biostatistics and psychiatry, including comprehensive courses on big data, genomics and neuroimaging methods available to trainees; (ii) the wide-ranging experience of the biostatistics, psychiatry, and psychology faculty in multiple areas of biostatistics methods and mental health research; (iii) a highly productive research environment in BIOS, STAT, PSYCH, RADIO, CS, PSY, GNET, and BRIC designed to support education and training in mental health biostatistics; (iv) access to a large number of mental health research projects in PSYCH, BIOS, BRIC, and PSY; (v) access to high throughput genetic and neuroimaging facilities; and (vi) the long history of successful research training programs offered by PSYCH and BIOS. The resources available to trainees include a broad array of ongoing mental health neuroimaging and genomics and biostatistics research projects; UNC-CH's commitment to collaborative research and training; and the broad range of expertise and experiences of faculty participating in this training program.

Project Summary This application is in response to the RFA-MH-16-160, entitled ?Lifespan Human Connectome Project (HCP): Baby Connectome?. Investigators at The University of North Carolina at Chapel Hill (UNC) and The University of Minnesota (UMN) will join forces to accomplish the goals outlined by this RFA. The team at UNC has over 10 years of experience in recruiting and imaging typically developing and at-risk children, scanning over 1000 children from birth to five years1-40. Well established infrastructure at the Biomedical Research Imaging Center (BRIC) at UNC and Center for Magnetic Resonance Research (CMRR) at UMN are in place to recruit and retain pediatric subjects and facilitate the coordination of pediatric imaging studies. Our past and ongoing studies for imaging children (birth ? five years of age) without sedation have achieved an overall success rate of 81% and attrition rate of 29.3%. Our track record demonstrates that we possess the critical and essential components to successfully conduct longitudinal pediatric imaging studies focusing on early brain development, a critically-important aspect of this RFA. Our ability to recruit, retain, and image non-sedated, typically developing children is further strengthened by our image analysis team, which has developed novel image analysis tools specifically for early brain development. The expertise at UNC is complementary to and strengthened by the expertise of the team at UMN. The CMRR at UMN has been one of the leading groups in the HCP project and has developed novel MR imaging approaches to dramatically shorten data acquisition time. Furthermore, the team at UMN has extensive experience in behavioral and cognitive studies of early child development. Together, our combined team is well positioned to accomplish the goals of this RFA. To this end, a total of 500 typically developing children between birth and five years of age will be recruited across two data collection sites in a sequential cohort, accelerated longitudinal study design. The participants are divided into two main groups, longitudinal (n=285) and cross-sectional (n=215) groups, respectively. This hybrid longitudinal and cross-sectional design enables detailed characterization of early brain development from both brain structural/functional using MRI and behavioral aspects using behavioral assessments. All of the acquired images and behavioral assessments will undergo extensive quality assurance and control processes to ensure that high quality data is obtained and transferred to the Central Connectome Facility at Washington University. In addition, we will integrate novel image analysis tools, developed by our team onto the existing HCP pipelines.

Abstract It has been hypothesized for years that most psychiatric disorders are the result of abnormal trajectories of early childhood brain development and a major priority for NIMH is to better understand how risk for psychiatric disorders unfold in childhood, to inform early intervention strategies that prevent or mitigate risk and illness severity. The UNC Early Brain Development Study is a longitudinal study that has followed children, enrolled prenatally, with imaging and developmental assessments at birth and at ages 1, 2 4, and 6 years. Children from this cohort are now reaching pre-adolescence, a period in which cognitive and behavioral abnormalities associated with psychiatric disease, including executive function, attention, and anxiety, are emerging. Very little is currently known about the relationship between brain structure and development and risk phenotypes in pre-adolescence; this represents is a major gap in our knowledge and a critical need for study. We propose to follow 446 children in our longitudinal cohort at ages 8 and 10 years of age. MRIs, including structural, diffusion tensor, and resting state functional imaging, will be performed. Cognitive development and behavioral development will be assessed, with a focus on the phenotypes of executive function, attention, and anxiety, consistent with RDoC constructs and important for psychiatric disorder risk. Knowledge gained in this study will improve our basic understanding of human brain development in childhood, allow us to delineate childhood predictors of risk phenotypes in late childhood, and ultimately help target periods of childhood development for early intervention. Relevance New knowledge gained in this study will provide a dramatically improved framework for understanding childhood brain development and its relationship to cognitive and behavioral outcomes in late childhood, and to risk for subsequent psychiatric disorders.

Rescuing Missed Longitudinal MRI visits in the UNC Early Brain Development Studies Database PROJECT ABSTRACT In our ongoing R01 (MH123747-01A1) ?The Development of Individual Differences in Adolescent Brain Structure and Risk?) project, we aim to characterize the portion of individual differences in brain structure in the early adolescent brain is already present in the earlier years of life. Early adolescence and puberty is a major period of postnatal brain development, characterized by dynamic structural and functional brain maturation and reorganization, and emerging risk for psychiatric disorders, though it is not known how this period of development contributes to individual differences in brain structure and risk. The UNC Early Brain Development Study (EBDS) is a unique and innovative longitudinal study that has followed children, enrolled prenatally, with imaging and cognitive/behavioral assessments at birth, 1, 2, 4, 6, 8, and 10 years. 482 children from this cohort are now reaching adolescence, and we are following these children at 12, 14, and 16 years of age via MRI, cognitive and behavioral assessments, with a focus on the phenotypes of executive function, attention, and anxiety, consistent with RDoC constructs important for psychiatric disorder risk. One particular aim is to investigate the use of machine learning (ML) for the predictive analysis of early brain development to cognitive and behavioral outcomes in adolescence and to risk for subsequent psychiatric disorders. Yet, most machine learning (ML) algorithms applied to longitudinal data do not perform well (or at all) when data points are missing, as ML methods need both complete data and large sample sizes. As longitudinal studies suffer commonly from significant missing data at different time points due to acquisition failure as well as participant attrition, even a rich database like the UNC EBDS is reduced to a significantly lower sample size by selecting only complete datasets to apply predictive ML (less than a third of the datasets of EBDS data from age 1 ? 10 years is complete). Here, we propose to rescue missing EBDS timepoints (at ages 1 - 10 yrs) of structural MR image data via multi-modal, multi-timepoints image predictions. This image data imputation includes cross-modality image generation (generating missing MRI data from existing MRI data at the same time), where available, as well as multi-timepoints imputation of longitudinal data (generating missing MRI data from existing MRI data at different time points). We will then apply our out-of-distribution model to provide additional information on the appropriateness of the imputed data. Subsequently, the same image processing that was applied to the original EBDS MRI data will be applied to the imputed/generated MRI data to compute missing information of morphometric measures (regional volumes, cortical thickness, surface area, and white matter fiber tract properties). This imputed data will be a highly significant resource for longitudinal ML/AI studies of brain development performed on the EBDS dataset, as it would allow for an increase in training data of over 200%. The original MR images, the imputed MR images, and the morphometric measures will all be shared via NDA, alongside the trained imputation network for use by others.