Thomas Ernst - US grants

DESCRIPTION (provided by applicant): This is a new application for a K02 Independent Scientist Award. The PI, Dr. Thomas Ernst, is the Director of Medical Physics at the Brookhaven National Laboratory (BNL). Dr. Ernst is an MR physicist with extensive experience in the development of neuroimaging techniques, and has been involved with the application of these exciting neuroimaiging techniques to neuropsychiatric disorders, particularly drug abuse and HIV, for over a decade. Dr. Ernst is PI on one NIH-funded research project (from NIMH), one large DOE-funded program project on biomedical engineering, and co-PI on two additional R01 grants (one from NIDA, and one from NINDS). The K02 award would allow Dr. Ernst to reduce his administrative duties, and re-focus his research on advancing MR techniques for translational research into drug abuse and HIV brain disease. Specifically, Dr. Ernst would spend 30% on methodological developments (10% directly on the MRI scanner), 20% on clinical projects, 10% on educational activities, and 15% on mentoring, for a total of 75% protected research time. The specific Methodological Aims of the proposed research are: 1. To introduce event-related fMRI designs to the study of drug abuse and HIV brain disease, and 2. to apply structural equation modeling (SEM) to the analysis of fMRI data in drug abusers and HIV-positive subjects. These technical advances will make it possible to address the following Clinical Aim: 3. To determine the effects of drug abuse and HIV infection, alone or in combination, on the connectivity of the working-memory network in the brain. The educational activities will be based on the strong collaborations with outstanding scientists and physicians at BNL and SUNY-SB, reading scientific literature, attending local seminars and scientific meetings, as well as participating in advanced educational courses at meetings. Another important part of Dr. Ernst's effort would be mentoring. Over the past decade, Dr. Ernst has mentored 18 young scientists. Eight of the past mentees now have faculty-positions, ten are working in drug abuse and HIV research, and six are currently supported or have applied for funding by NIDA.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of the Magnetic Resonance (MR) Image-processing Core is to provide image-processing support, infrastructure improvements and methodological developments to complement and fully utilize a rapidly expanding MR Research Facility that supports an array of clinical research studies. The MR Research Facility, located on The Queen's Medical Center campus, is a joint effort of the University of Hawaii and The Queen's Medical Center. The MR Research Facility is built around a Siemens 3 Tesla MR scanner. The goals of the MR Image-Processing Core cover four main areas: 1) research support through image-processing support for analyzing MR scans, and development and analysis of pilot studies;2) infrastructure development involving upgrades to the MR scanner, installation of local processing and data storage computers, improved internet connectivity, and improvements to optimize image processing streams;3) methodological improvements to develop and validate image processing tools for clinical research and 4) training of MR Research Facility faculty users and staff in image processing. The services of the MR Image-Processing Core will permit more rapid publication of research results and lead to better evaluation of the effects of drug abuse and chronic diseases on the brain.

DESCRIPTION (provided by applicant): This is a renewal application for 1R01 DA21146-01, a Bioengineering Research Partnership (BRP) to develop real-time prospective motion correction (PMC) for MRI. Magnetic resonance imaging (MRI) is a powerful technique for assessing the structure, function, and physiology of the human brain in vivo. MRI affords high spatial and temporal resolution, is non-invasive and repeatable, and may be performed in children. However, motion continues to be a substantial problem in many MR studies, especially those performed in children, infants, or subjects who are agitated or confused due to anxiety, drug use or sickness, resulting in data with motion artifacts that may prevent accurate diagnoses or assessments. Prospective motion correction can dramatically attenuate motion artifacts by dynamically tracking the motion of the head/brain during a scan, and continuously correcting acquisitions such that they are locked relative to the moving brain. In the initial project period, we made substantial progress in developing optical-based motion tracking and correction for MRI. While the initial prototype system performs well for relatively small and slow movements, the system may fail to sufficiently attenuate motion artifacts during clinically relevant motions (larger amplitudes and higher speed). The proposed competitive renewal will focus on resolving these issues, with the following specific Aims. (1) Improve robustness of motion correction with optical tracking. (2) Develop techniques for motion correction at higher velocities (up to 100mm/s and ?/s), and implement these methods for a set of clinically relevant sequences. (3) Develop reconstruction techniques for data acquired during head motion. (4) Demonstrate clinical efficacy and utility of the motion correction methods developed. The work will be performed by an experienced team of investigators with a track record of collaboration, using modern 3T and 7T scanners. Implementing these innovations will increase the availability of adaptive motion correction technologies for the clinical arena, and promise improved and more robust MR scans in children and patients who have difficulty holding still, both in research and clinical settings.

DESCRIPTION (provided by applicant): This application is submitted by a group of investigators at 9 sites distributed throughout the U.S. where there are active developmental research programs involving substantial numbers of typically developing children, and neuroimaging investigators with experience in multi-site imaging initiatives. We propose to join forces to leverage these ongoing pediatric studies to assemble, over a period of 2 years, a large, cross- sectional imaging-genomics dataset to be used as a shared resource. The major aim of our proposal is to create a database that will include genome-wide association results for a large number of neural architectural phenotypes obtained using multimodal structural imaging. We propose to offer this database - essentially a map depicting the genomic landscape of the developing human brain - as a resource to the scientific community. Across the sites, investigators will administer the brief NIH Neuroscience Blueprint Toolbox Cognitive assessment;acquire standardized structural and diffusion images, and collect DNA samples in 1575 children and adolescents who are participants in their ongoing studies. The DNA samples will be shipped to a central Genetics Core for analysis, the imaging data will be uploaded for quality control and computational morphometry by the Imaging Core, and other data will be uploaded to the Coordinating Core, where an aggregate database of demographic, behavioral, imaging, and genomics deliverables will be compiled from 1400 individuals and maintained for shared access. A large, cross-sectional pediatric dataset would fill a significant gap that currently prevents description of gene and gene-by-age effects on neural architecture in children (i.e., main effects of genetic variation and gene effects on developmental trajectories) that are likely to be relevant to variability in behavioral and neuropsychiatric outcomes. Preliminary results of analyses of large adult cohorts suggest that common genetic variation accounts for substantial variability in brain morphology. The age-span of participants in these studies has made it possible to detect gene-by-age interactions relevant to variability in brain aging. Unfortunately because there are no well-powered studies with data from individuals spanning the childhood and adolescent age range, it is not known whether these neural phenotypes are present in children;and if they are, whether they can be observed early in development or evolve as ongoing remodeling of neural structures proceeds during childhood. This project would address the discrepancy between currently available imaging-genetics data in children of different ages and those available in adults. In addition to providing an informative data resource, the project would create a collaborative hub of investigators prepared to participate in an imaging- genomics adjunct study of the National Children's Study, which is in the early planning stages at this time. PUBLIC HEALTH RELEVANCE: The aim of this project is to assemble, over a period of 2 years, a large, cross-sectional imaging-genomics dataset to be used as a shared resource for investigations of genetic bases of neural phenotypes and age-by- genotype interactions that may represent genetically-mediated differences in developmental trajectories.

DESCRIPTION (provided by applicant): Children with acute lymphoblastic leukemia (ALL) have a relatively good prognosis, but treatment can have tremendous impacts on growth and development, including effects on the central nervous system (CNS). This in turn affects school performance and neurocognitive function, but the relationship between ALL therapy and cognitive deficits is not well understood. Because children diagnosed with ALL typically begin treatment immediately, it is often difficult to evaluate cognitive function prior to therapy. If neurocognitive deficits are recognized later in life, it is unclear if therapy-associated CNS injury occurred, and often too late to institute appropriate interventions. This proposal aims to evaluate CNS structure and chemistry;and cognitive performance, after therapy begins (<6 weeks), and 12 months later. The study fills a void of a current study in the Children's Oncology Group (COG;www.childrensoncologygroup.org), AALL06N1 (Study of Neurocognitive Function in Children Treated for ALL), which is a study for children with high-risk B- lineage and T-cell ALL, but young children (3-6 year old) with ALL with standard- and intermediate-risk ALL are excluded from the study. Therefore, the proposed project bridges an important gap by studying 3-6 year old children with ALL with standard- and intermediate-risk disease who are at risk for CNS toxicity. Use of high resolution structural MRI (HRS-MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) may allow detection of early changes in CNS structure and metabolism prior to detecting abnormal cognitive function. Studies led by Drs. Linda Chang and Thomas Ernst are successfully being conducted in 3-6 year old children with other diseases, using non-invasive advanced MR techniques, including HRS-MRI, MRS, and DTI without conscious sedation, which is important in this age. Our goal is to identify early structural, chemical, and functional CNS changes in children with ALL with the long term objectives to develop interventions to prevent late neurocognitive sequelae and improve prognosis. Our Aims are: 1) To determine the effect of chemotherapy on the brain in children with ALL using high resolution MRI, proton MRS, and DTI within 6 weeks of starting chemotherapy and at 12 months after the initial scans;2) To characterize changes in neurocognitive function from chemotherapy exposure in children with ALL at baseline and at 12-months;3) To assess the relationship of abnormalities on MR scans with cognitive deficits identified from neurocognitive tests;and 4) To measure mitochondrial DNA levels in children and evaluate its association with minimal residual disease, neurocognitive testing, and brain metabolite levels. The significance lies in the potential of using sensitive tools (MRS and DTI) to detect early CNS changes before cognitive abnormalities are noted;and possibly improve morbidity in children who otherwise are not eligible for the open COG study. The proposal is innovative because the project utilizes expertise of Drs. Ernst and Chang in the field of neuroimaging to capture data from young children without the use of sedation to further our understanding of chemotherapy effects on developing brains. PUBLIC HEALTH RELEVANCE: Children diagnosed with acute lymphoblastic leukemia (ALL) have a relatively good prognosis, however treatment can impact a child's future growth and development, including effects on the central nervous system (CNS). This proposal aims to evaluate CNS structure and chemistry;and cognitive performance, after treatment begins (<6 weeks), and 12 months later in children (3-6 year old) with ALL diagnosed with standard- and intermediate-risk ALL.

The four research projects in this P01 application on obesity and cancer will all use imaging-derived measures of body fat compartments as their exposures of interest. Imaging data at the two study sites [University of Hawaii (UH) and University of California (USC)] will be acquired by whole-body Dual X-ray Absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI). Since data acquisition and analysis of imaging measures in a multi-center setting require specialized techniques and knowledge, we propose the creation of a dedicated Body Fat Compartments Imaging Core. The Core's main role will be the quantitative assessment of body fat distribution in 2,000 Multiethnic Cohort participants [800 at USC, 1,200 at the UH]. The Core will be co-directed by Dr. Thomas Ernst, an MR Physicist at the UH Medical School, and Dr. John Shepherd, Associate Professor of Radiology at UCSF. Both are experts in performing and analyzing DXA scans in a multi-center setting. The Core will provide the following services to the projects: Development, implementation and maintenance of optimized and uniform scanning protocols and quality assurance (QA) procedures for the two MEC study sites Data acquisition, archival, distribution, and processing Weekly quality assurance scans and monitoring Ongoing evaluation of technical quality using in vivo data from individual subjects Installation and maintenance of customized post-processing packages The Body Fat Compartments Imaging Core will certify sites and scanners before human studies may be started, perform continuous quality assurance, resolve potential technical issues in a timely manner, and provide intellectual input into the scientific findings of the study. Thus, having a dedicated Body Fat Compartments Imaging Core will ensure that consistent, high-quality imaging data are collected across sites and over time in a cost-effective manner.

? DESCRIPTION (provided by applicant): This cooperative agreement (U01) application responds to NIH RFA-DA-15-015, Adolescent Brain Cognitive Development (ABCD) study. The University of Hawaii (UH) is #2 of 9 Research Sites of the Prospective Research in Studies of Maturation (PRISM) Consortium. The Consortium's objective is to establish a national, multisite, longitudinal cohort to prospectively examine the neurodevelopmental and behavioral effects of substance use (SU) from early adolescence through the period of risk for SU and SU disorders. This 10-year longitudinal study of 11,000 children will measure brain development, SU, cognition, emotion, executive function, mental health, physical health, environment, and collect biospecimens for future genetic and epigenetic studies. The Consortium has an optimized research protocol and 4 specific aims: 1) Using advanced multi-modal neuroimaging to evaluate premorbid factors and the impact associated with diverse patterns of SU on structure and function of the developing brain. 2) Disentangle the predictors and consequences of diverse patterns of SU on physical health, psychosocial and cognitive development, academic achievement, motivation and emotional regulation. 3) Examine how the quantity and combination of substances used affect the expression of psychopathology and, conversely, how the emergence of psychopathology influences SU. 4) Assess how each substance used contributes to the use of other substances (gateway interactions). To further evaluate neurochemical and neurophysiological changes in these youth, we will additionally perform 1H MR spectroscopy (MRS), perfusion MRI (using arterial spin labeling or ASL), and quantitative susceptibility mapping (QSM), in approximately half of our volunteers, in collaboration with PRISM sites at Penn, UCLA, Utah, Hawaii, JHU, and Baylor. We are proposing a multi-PI leadership approach for our site. The PIs have complementary and inter- disciplinary expertise that encompasses all areas required to manage this comprehensive project. We have expertise in SUD research, clinical assessments, subject sampling and recruitment, and MR methodology. Additional unique qualifications of our site are: 1) we have access to a racially diverse population (including Native Hawaiians and Pacific Islanders) that is disproportionately affected by SUD, 2) we have a strong track record of MR research in SUD and at risk populations, such as adolescents, and 3) we have participated in and led several multi-center research studies that involve complex multi-modal MR outcome measures and subject assessments. Therefore, we have all the necessary resources, experience and expertise to conduct the proposed research, and our effort will complement that of other outstanding research sites to collectively achieve the overall goals of the PRISM Consortium.

Project Summary This cooperative agreement (U01) application responds to NIH RFA?DA-15-015, Adolescent Brain Cognitive Development (ABCD) study. The University of Hawaii (UH) is #2 of 9 Research Sites of the Prospective Research in Studies of Maturation (PRISM) Consortium. The Consortium's objective is to establish a national, multisite, longitudinal cohort to prospectively examine the neurodevelopmental and behavioral effects of substance use (SU) from early adolescence through the period of risk for SU and SU disorders. This 10-year longitudinal study of 11,000 children will measure brain development, SU, cognition, emotion, executive function, mental health, physical health, environment, and collect biospecimens for future genetic and epigenetic studies. The Consortium has an optimized research protocol and 4 specific aims: 1) Using advanced multi-modal neuroimaging to evaluate premorbid factors and the impact associated with diverse patterns of SU on structure and function of the developing brain. 2) Disentangle the predictors and consequences of diverse patterns of SU on physical health, psychosocial and cognitive development, academic achievement, motivation and emotional regulation. 3) Examine how the quantity and combination of substances used affect the expression of psychopathology and, conversely, how the emergence of psychopathology influences SU. 4) Assess how each substance used contributes to the use of other substances (gateway interactions). To further evaluate neurochemical and neurophysiological changes in these youth, we will additionally perform 1H MR spectroscopy (MRS), perfusion MRI (using arterial spin labeling or ASL), and quantitative susceptibility mapping (QSM), in approximately half of our volunteers, in collaboration with PRISM sites at Penn, UCLA, Utah, Hawaii, JHU, and Baylor. We are proposing a multi-PI leadership approach for our site. The PIs have complementary and inter- disciplinary expertise that encompasses all areas required to manage this comprehensive project. We have expertise in SUD research, clinical assessments, subject sampling and recruitment, and MR methodology. Additional unique qualifications of our site are: 1) we have access to a racially diverse population (including Native Hawaiians and Pacific Islanders) that is disproportionately affected by SUD, 2) we have a strong track record of MR research in SUD and at risk populations, such as adolescents, and 3) we have participated in and led several multi-center research studies that involve complex multi-modal MR outcome measures and subject assessments. Therefore, we have all the necessary resources, experience and expertise to conduct the proposed research, and our effort will complement that of other outstanding research sites to collectively achieve the overall goals of the PRISM Consortium.