Terry L. Jernigan - US grants

The aim of the proposed study is to gain more information about functional and anatomical changes very early in the course of Alzheimer's Disease (AD). One of the obstacles to such studies is the difficulty of identifying individuals with very early AD before their impairments become clinically significant. The approach taken here is to recruit a group of nondemented subjects considered to be at risk for developing AD by virtue of age and a positive history of AD in one or more first-degree relatives. Sixty family history negative (FH-) and 40 matched family history positive (FH+) subjects with normal scores on dementia rating scales will be followed in the ADRC with the core neuropsychological battery; and will be examined annually with a high-resolution MRI protocol. Morphometric analysis will be employed to estimate the volumes of mesial temporal lobe (MTL) structures, temporal neocortex, and prefrontal neocortex. Since parenchymal volume loss is often accompanied by increased volume of adjacent CSF spaces, it is possible that peri- hippocampal fluid volume will be a more sensitive index of MTL loss than will the volume of the remaining tissue. Therefore, the volume of the fissures and sulci surrounding the mesial temporal lobe structures will also be measured. The model guiding the study design can be summarized as follows: In the earliest years after the onset of the disease, AD is characterized by rapid degeneration in mesial temporal lobe structures, with more gradual degeneration in neocortical association areas. During this stage of the illness, memory impairment is relatively isolated and manifests primarily in a decreasing ability to discriminate recently studied from unstudied items, and in an increasing propensity to make intrusion errors in free recall. In the later stages of the illness, the onset of clinically significant dementia coincides with an increasing rate of degeneration in neocortical association areas. Based on this model, the following primary hypotheses are advanced: 1. Nondemented subjects with a positive family history for AD will show loss in mesial temporal lobe structures, over five years, relative to matched subjects without a family history for AD. 2. Furthermore, the loss over time in the MTL of FH+ subjects will be significantly greater than losses in neocortical regions. 3. MTL losses over the study period will be specifically related to worsening performance on sensitive measures of memory function.

Previous behavioral studies indicate that reduced speed of information processing and impaired learning and attention are often observed in HIV- infected individuals. The psychomotor slowing and impaired attention are suggestive of cortico-striatal, particularly fronto-striatal dysfunction. Although the learning deficits in some ways resemble those experienced by patients with subcortical damage, pilot data indicate that even recognition memory is sometimes affected, suggesting cortico-limbic dysfunction as well. Evidence from pathological studies supports the existence of damage in both cortico-striatal and cortico-limbic systems, and raises questions about the role of a number of putative HIV-related neurotoxic mechanisms. This project has two overall objectives: first, to employ experimental behavioral paradigms and MRI morphometrics to better define two forms of HIV-related CNS dysfunction - namely cortico-striatal and cortico-limbic; and second, to gamer evidence regarding the pathological mechanisms involved in these forms of dysfunction by examining relationships between MRI morphometrics and neuropathological data obtained in autopsy studies. To pursue these general aims we propose two studies: an MRI/Behavior study of 150 patients meeting criteria for AIDS and 50 matched controls; and an MRI/Neuropathology study of approximately 60 subjects, involving antemortem and postmortem MRI examinations as well as detailed neuropathological examinations of brain specimens. The individuals studied in the MRI/Neuropathology study will be screened at autopsy for the presence of opportunistic infections of the CNS other than CMV.

Our brain imaging studies of subjects with Williams Syndrome (WMS) have attempted to identify anatomical distinctions between WMS subjects and different control groups that might shed some light on the neural bases for their distinctive behavioral profiles. our results suggest that structures in the basal ganglia and diencephalon are preserved in size relative to cortical structures in Down Syndrome (DNS) subjects. Furthermore, frontal cortical structures are disproportionately affected. In contrast, WMS subjects exhibit relatively normal frontal and limbic cortices, in addition to cerebellar size preservation. These observations serve as the basis for the following working hypotheses about relationships between behavioral and neuroanatomical features of WMS and DNS: It may be that relative preservation of superior temporal and related frontal cortical and insular structures, and possibly neocerebellar preservation, underly the sparing of linguistic functions in WMS. Similarly, preserved affective function and social abilities may emerge as a result of sparing of structures such as amygdala and related limbic structures, and mesial and orbitofrontal cortices. The disproportionate impairment on visuo-motor tasks may be related to particular vulnerability of parieto-occipital cortical structures in WMS. The goal of the proposed anatomical studies is to garner evidence relevant to these working hypotheses, and to extend our anatomical findings by using a higher-resolution imaging protocol and obtaining more specific anatomical measures in larger groups of WMS subjects and controls. With a standardized MR imaging protocol and brain morphometric analysis, we propose to study 100 WMS subjects, 50 IQ-matched DNS subjects, and 30 normal age-matched controls over five years.

Little is known about the brain abnormalities associated with schizophrenia and related psychoses in late life. In the proposed research, we will use morphometric and qualitative analyses of magnetic resonance images (MRI) to examine qualitative and quantitative brain structural features that underlie late-life psychosis. The research will be guided by the following questions: (1) Are brain abnormalities different in quality or number in the various late-onset psychoses? In older schizophrenia patients: (2) Do brain abnormalities differ with age-of-onset? (3) How do brain abnormalities in older schizophrenia patients relate to clinical, psychosocial, or treatment outcomes? (4) How do the patterns of brain morphology in schizophrenia patients relate to impairments in executive function, information processing, and sensory gating? (5) Is there evidence for abnormalities in thalamo-cortical circuits that may be associated with schizophrenic symptomatology? Our working model is that schizophrenic symptomatology may be a result of dysfunction in the cortical-subcortical circuitry. This dysfunction may be due to problems in the functional balance between basal ganglia, thalamic, and cortical function, leading to dysfunction in cortical- subcortical circuits. Particular abnormalities in the relations among these structures may bear relationships to the particular clinical, neuropsychological and psychophysiological features exhibited by individual patients. Thus, the variety of brain abnormalities may be linked to the heterogeneous nature of symptomatology of schizophrenia and other psychoses in late life. Our findings thus far suggest that there may be specific brain morphometric differences between early-onset and late-onset forms of schizophrenia, particularly in the thalamus and in ventricle size. In the next funding period we will study larger numbers of subjects with varied ages of onset so that we can examine morphometric differences in greater detail. We will also attempt to understand the heterogeneity of behavioral disturbance in schizophrenia on the basis of brain morphology. In addition, we will formulate specific hypotheses that can be tested using functional imaging methods now in use (e.g., SPECT) or under development within our facilities (e.g., functional MRI). We will attempt to study all subjects from the Center. Subjects will receive MRI examinations, and all MRIs will be rated quantitatively for abnormalities. In addition, we will study a subset of schizophrenia and normal comparison subjects using quantitative MR image analytic methods that measure volumes of many cortical and subcortical brain regions. MRI measures will be related to age-of-onset, clinical features (including outcomes), and neuropsychological and psychophysiological function.

Quantitative volumetric studies of brain morphological changes between childhood, adolescence, and you adulthood have yielded interesting results. Past neurodevelopmental studies have, however, been limited by the technology available for magnetic resonance image (MRI) acquisition, image analysis, and ultimately computering power to best exploit imaging data. The methods proposed for this study of normal brain maturation will include very high resolution structural images, tissue segmentation, brain surface renderings for aid in detailed cortical anatomical segmentation, and surface and volume (voxel based) modeling spatial localization techniques. With these relatively sophisticated methods, questions abut the etiology of maturational changes in the brain (e.g., myelination vs. Synaptic pruning) may be further examined Perhaps more importantly, assessing the spatial anatomical location of these maturational changes will be possible. Specific Aims a) To spatially localize structural maturational changes in the developing human brain b) Quantify the statistical significance of localized changes in hypothesized regions of greatest change relative to regions predicted to show little age-related structural change. Williams syndrome is a rare metabolic disorder labeled in 1961 by the British cardiologist J.C. P. Williams. who described a syndrome which includes a specific heart defect. mental retardation, and a peculiar facial appearance. Williams subjects also exhibit a unique fractionation of higher cortical functioning. specifically. selective preservation of complex syntax in the face of marked and severe cognitive deficits. While it is widely known that specific language deficits can exist without any accompanying cognitive deficit, the opposite pattern in which linguistic abilities are spared despite overall cognitive deficits is rare. It seems likely that the marked and specific deficits in behavioral development, and resultant neuropsychological profile in Williams patients result from unique patterns of aberrant brain development. 1. To understand the brain morphometric differences between Williams Syndrome and developmentally normal children using a high resolution imaging protocol. 2). Use morphometric findings to analyze factors which may account for the distinctive behavioral profiles found in this population.

neuropathology; AIDS /HIV neuropathy; magnetic resonance imaging; histopathology; HIV infections; methamphetamine; drug abuse; cerebral degeneration; cognition disorders; bioimaging /biomedical imaging; postmortem; human subject; clinical research;

The primary goal of the proposed study is to identify the brain mechanisms underlying abnormalities in social communication in children. Brain structure, assessed using Magnetic Resonance Imaging (MRI), brain biochemistry, assessed using Magnetic Resonance Spectroscopy (MRS), and social communication, assessed by discourse. repair and thought disorder measures will be compared in three groups of children: 1) children with autistic disorder, 2) children with specific developmental language disabilities (DLD), and 3) age. IQ, socioeconomic status (SES) and sex matched normal children. Specific Aims 1. Using reliable and valid measures of social communication and formal thought disorder, we predict that the social communication deficits in the autistic children will be directly related to severity of the disorder as judged by scores on the ADI. 2. The social communication deficits of the autistic subjects but not the DLD subjects will be associated with structural and functional CNS abnormalities 3. Based on preliminary, results from our pilot study and findings of abnormal cell densities in autistic brains, we predict that we will detect H-1 MRS increases in Nacetylaspartate (NAA) in the frontal lobes of the autistic children, decreases in the choline and myoinositol peaks of temporal lobe areas and increases in the glycine peak of the cerebellum in the autistic subjects but not in the DLD subjects, or the normal subjects. 4. Volumetric measures and grey/white matter ratios of the limbic system and area measurements of cerebellar structures will be smaller in the high functioning autistic subjects as compared to the DLD subjects and the normal children matched by age, IQ, gender and socioeconomic status (SES).

The existing resource of longitudinal data from the NHLBI Twin Study, the relatively large sample size, the use of comprehensive and state-of-the-art measures of brain function and structure will provide us with an unprecedented opportunity to examine previously unexplored associations between CVD risk factors and indices of brain aging in older twins. 1. Conduct a fourth exam in an estimated 641 individuals including, 120 monozygotic (MZ) and 120 dizygotic (DZ) intact pairs, that will repeat a core battery of assessments given in previous examinations and add new neuropsychological tests and cerebral NM scanning. 2. Evaluate the prospective and cross-sectional relationships of cardiovascular risk factors collected over 23 to 25 years of follow-up (e.g., blood pressure, lipids, obesity, smoking) and MRI indices of brain morphology assessed at the fourth exam. 3. Determine the extent that twins discordant for essential hypertension or non-insulin dependent diabetes mellitus (NIDDM) or cardiovascular disease (CVD) show different MRI profiles. 4. Characterize the neuropsychological changes In performance from Exam 3 to Exam 4 and determine the contribution of genes and the environment to stability or change. 5. Use the data from exams I to 3 to investigate prospective relationships between CVD risk factors and decline in cognitive performance from Exam 3 to Exam 4. 6. Determine the heritability of the new measurements obtained for the first time at the fourth examination cycle [e.g., MRI measures of white matter hyperintensities (WMHIs), infarct area and location, and ventricular volumes]. 7. Conduct multivariate genetic analyses to determine the contribution of genes and the environment to the covariation among physical, physiological, and neuropsychological variables.

DESCRIPTION (Provided by applicant): High levels of CSF HIV-1 RNA, and associated neurobehavioral deficits, have been reported without commensurate serum viral levels (Ellis et al., 2000; Ellis et al., 1997; McArthur et al., 1997; Staprans et al., 1999; Wong et al., 1997). The implication is that serial lumbar puncture, although invasive, may be the best available method for monitoring the progression of HIV-related neurodegenerative processes. Sensitive noninvasive methods for detecting and monitoring HIV-related CNS effects are needed. The aim of the proposed studies is to evaluate the application of structural (SMRI) and functional (FMRI) imaging methods for predicting CNS viral replication. The approach is guided by previous studies suggesting that neurodegeneration in the striatum and diffuse cerebral white matter damage are the two most consistent structural abnormalities present in this population (Jernigan et al., 1993; Stout et al., 1998) and psychomotor slowing is the most prominent functional deficit. Since CSF HIV-1 RNA is currently the best available index of CNS viral replication, this measure will be the primary dependent variable for the proposed studies. Groups of neurobehaviorally impaired and unimpaired seropositive individuals, and yoked seronegative controls, will be studied with repeated sMRI/fMRI examinations at baseline, and 6 and 12 weeks after initiation (in the seropositive subjects) of aggressive HAART therapy aimed at reducing CSF HIV-1 RNA levels. Measures of white matter signal change, of caudate nucleus volume, and of task-related change in blood oxygenation in the caudate nucleus (during motor tasks) will be correlated with levels of CSF HIV-1 RNA within the seropositive subjects. The utility of these SMRI and FMRI measures in predicting CSF viral levels will be compared with that of behavioral measures, and possibly with that of other noninvasive methods (such as MR spectroscopy), in univariate and multivariate prediction models.

DESCRIPTION: (Adapted from the Investigator's Abstract) Priming refers to the fact that the mere processing of an item can facilitate subsequent processing of that same item. Priming effects can occur in the absence of conscious recollection of the prior study episode, and it has, therefore, been suggested that priming and explicit memory disorder patients is critical for this hypothesis, since if it is possible to link the breakdown of explicit memory and priming to damage to different brain regions this would strengthen the independent memory systems hypothesis. Difficulties associated with evaluating priming effects in memory impaired subjects include that priming measures may be less sensitive than explicit memory measures, and that the priming obtained in a given task is related to baseline performance, with poorer baseline performance resulting in greater priming. Therefore, it patients have even mild information processing deficits this may make priming impairments. The proposed project will investigate these issues in normal subjects and alcoholic patients with varying degrees of memory and processing deficits. The proposed project will investigate these issues in normal subjects and alcoholic patients with varying degrees of memory and processing deficits. The proposed experiments are designed to manipulate baseline performance level and sensitivity of the priming measures. Measures of priming, baseline performance, and explicit memory will be obtained. The subjects will be normal controls and chronic alcoholic patients who differ in the severity of their explicit memory defects, ranging from non amnesic patients without noticeable memory impairments through "borderline Korsakoff" patients with only mild memory deficits to severely amnesic patients with Korasoff's syndrome. Measures of volume loss in specific brain structures will be obtained from MRI. These measures will be related to the behavioral indices, using a multiple regression approach, to determine the specific role of each brain region in perceptual. lexical processing, explicit memory and magnitude of priming.

DESCRIPTION (adapted from investigator's abstract): Priming is a form of implicit memory, and refers to the fact that the mere processing of an item can facilitate subsequent processing of that same item. Priming effects can occur in the absence of conscious recollection of the prior study episode, and it has been suggested that priming and explicit memory are mediated by different memory systems. Evidence from memory disordered patients is critical for this hypothesis, since if it is possible to link the breakdown of explicit memory and priming to damage to different brain regions this would strengthen the independent memory systems hypothesis. Many studies have found normal priming effects in amnesic patients and some investigators have reported impaired priming in patients with Alzheimer's disease. However, many difficulties are associated with evaluating priming effects in memory impaired subjects. The priming measures may be less sensitive than explicit memory measures, and the lack of group differences on priming measures may simply reflect low measurement sensitivity. The degree of priming obtained in a given task is related to processing efficiency (i.e., baseline performance) with less efficient processing resulting in greater priming. Therefore, if patients have even mild processing deficits this may mask priming impairments. The proposed project consists of a series of experiments designed to manipulate baseline performance and sensitivity of the priming measures. Normal control subjects across the adult age range and three groups of patients will be investigated; patients with probable Alzheimer's disease, patients with Huntington's disease and amnestic patients. These patient groups differ in the severity of their explicit memory deficits and in the extent to which different component processes contributing to their baseline performance are compromised. In addition to the behavioral measures, measures of volume loss in specific brain structures will be obtained from MRI. These brain measures will be related to the behavioral indices, using a multiple regression approach, to determine the specific role of each brain region in baseline processing speed, explicit memory, and strength of priming. Specific hypotheses about the relationship between the behavioral and structural brain measures derived from the investigators' previous studies will be tested.

brain morphology; developmental neurobiology; biomedical resource; clinical research;

This is a revised application for Project by Jernigan. During the previous funding period, we defined and contrasted the patterns of HIV- and METH-related brain structural alterations. Striatal and parietal cortex volumes are increased in METH (possibly related to strong microglial and astrocytic activation), while there are widespread volume losses in HIV (probably reflecting greater neural damage associated with neurotoxic viral products). Importantly, specific damage in caudate nucleus is associated with HIV, and disproportionate effects in parietal cortex associated with METH. We focus here on the implications of these changes for cognitive-motor processing, and hypothesize that the METH-related parietal lobe alterations (previously unexplored) interact with striatal changes and produce disproportionate attentional deficits. The major aim of the project is to establish links between the structural alterations and the neuromotor and neurocognitive deficits present in HIV and METH. The studies are driven by specific hypotheses about the roles that the distinct neural alterations of HIV and METH play in producing neuromotor and neurocognitive deficits. Combining multimodal imaging with sophisticated neurobehavioral and biomarker indices, we will study the following age- and education-matched groups: HIV-/METH-, HIV-/METH+, HIV+/METH-, and HIV+/METH+. Because we have observed structural alterations associated with each risk factor, we will determine whether baseline perfusion abnormalities exist in the structures affected by HIV and/or METH. Arterial spin labeling (ASL) methods will be used to measure baseline perfusion. To test hypotheses about HIV-related and METH-related neurocognitive and nueromotor impairment, BOLD effects will be obtained using 2 activation paradigms expected to elicit different (impaired) responses in the two risk groups: responsive motor switching (RMS) and global/local divided attention (Glo/Loc). The findings of these studies will advance the understanding of manifestations and mechanisms of neural abnormalities associated with HIV and METH.

DESCRIPTION (provided by applicant): An existing NIH-funded contract (CHARTER) supports a multi-site longitudinal study of CNS alterations in a sample of 600 HIV-infected (HIV+) individuals. This sample is representative of infected groups in the communities where they are recruited: most are treated with combination ARVs and a significant proportion are co-infected with HCV. In addition to comprehensive neuromedical and neurobehavioral assessments this study involves annual neuroimaging examinations for assessment of structural brain abnormalities using MR morphometry techniques. Within 149 participants examined in this contract at baseline, the degree of damage in cerebral white matter is associated with disease factors such as CDC classification and the presence of HCV antibodies in serum. The neurocognitive impairment measured in these participants is associated with both increased white matter damage and volume loss in cerebral cortex, and the two factors, which show only modest correlation, appears to contribute independently to severity of neurocognitive impairment. The pattern of the results suggests that damage to the cerebral white matter is an important mediator of HIV-related neurocognitive impairment and may also mediate increases in impairment associated with co-infection with HCV. Multiple lines of evidence suggest that white matter damage and cortical degeneration to some extent reflect distinct pathogenetic mechanisms. The proposed study would take advantage of the existence of the CHARTER longitudinal study to identify 20 individuals at the UCSD site in whom there is evidence of evolving white matter damage (and 10 apparently unaffected individuals with comparable disease characteristics). These targeted individuals would then be studied semiannually with an extended high field (3T) neuroimaging investigation which would include multispectral sMRI, computational morphometry, diffusion tensor imaging (DTI), and chemical shift imaging (CSI). These additional neuroimaging data would be used to address questions about the evolution of white matter damage over time;about the relationship between the white matter damage and the damage to cerebral cortex;and about the role of immune activation and viral levels in mediating this damage.

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): The early school age period is a time of significant developmental change in both cognitive abilities and neural systems. Yet little is known about how, specifically, these developmental processes that occur concurrently are linked to each other, or about the nature of critical interactions of biological factors with childhood experiences and environments. The proposed project takes a critical first step in addressing this problem by examining, in unprecedented detail, the development of basic cognitive processes and of the neural systems that mediate them during the child's transition to formal schooling. The design is a longitudinal study of 100 typically- developing children inducted at age 6 and assessed with behavioral measures and MRI annually on 5 occasions. The behavioral measures to be collected, of language, visuospatial processing, working memory, and cognitive control, have exhibited high sensitivity to developmental change over this age range. MR imaging of the children will involve recently developed, improved methods for image acquisition and computational modeling of the results. Diffusion parameters from specific brain fiber tracts as well as regional measures of cortical surface area and thickness will be measured. The focus of the study is on differences in the rate of fiber tract development from 6 to 10 years of age and links between this variability and the pace of cognitive development. Relationships between the neural parameters and early academic achievement will also be examined. The study is novel, not only because the imaging methods to be applied will produce more detailed information about the brains of children than is currently available, but also because of the conceptual focus of the project on the degree of concordance between trajectories of brain and behavioral development. The long-term significance of the study lies in its potential to guide us toward interventions that are more adaptive to individual differences and therefore promote positive outcomes in more children.

The overall goal of the Neuroimaging Core is to provide the HNRC and collaborative investigators with resources for: 1) in vivo detection of HlV-related brain injury using a broad array of techniques, including structural, functional, metabolic, susceptibility and diffusion weighted MRI, and positron emission tomography (PET); 2) post-mortem MR imaging for elucidation of pathological mechanisms that give rise to this damage; 3) investigations of the cognitive consequences and neuromedical correlates of these imaging effects; and 4) identification of potential biomarkers for treatment success. In the current funding period, the Core has supported more than 30 projects, resulting in, for example, findings linking detectable CSF HIV viral load at baseline with increases in white matter damage over time; integration of structural, diffusion and histopathological evidence of white matter damage; correlation of reduced white matter tract diffusivity with cognitive impairment; and HIV-associated reductions in cerebral blood flow in lenticular regions. Training and consultation were provided for 31 individuals, resulting in recruiting new investigators to the study of HIV and expanding the use of neuroimaging techniques in national and international settings. Additional collaborations have advanced our goals to expand the range of valid neuroimaging methods available for use in HIV research. Our aims in the proposed renewal period are to: a) provide resources, consultation, and technical assistance for neuroimaging; b) acquire and analyze in vivo and postmortem images to support clinico-anatomic work and pilot studies; c) contribute data and expertise for the development of improved image acquisition and analytic methods for use in HIV; and d) educate research communities regarding promising new imaging approaches for neuroAIDS research. The expanded Core includes vascular and PET amyloid imaging, to advance the study of an aging HIV population. Furthermore, through local, national, and international collaborations, the Core will emphasize method validation and data integration across imaging modalities for use in HIV, approaches that may lead to a better understanding of the CNS effects of HIV infection. This Core will enhance HNRC transdisciplinary aims through close collaboration with the Neurobehavioral, Neuromedical, Neurovirology, and Neurobiology Cores. These broad-ranging functions ensure state of the art support for HNRC-associated studies, close integration with the interdisciplinary HNRC investigative team, and participation in national and international neuroimaging communities.

DESCRIPTION (provided by applicant): In this set of applications, we propose to initiate a new Learning Disabilities Research Hub focusing initially on high risk for mathematics failure. We proposed to situate this new Hub within an existing strong infrastructure for pediatric neurobehavioral and imaging research, the Pediatric Neurocognition, Imaging, and Genetics (PING) data resource. PING infrastructure provides many important advantages for building a new cross disciplinary and multiple-investigator program, as it has already brought together a strong team of behavioral, clinical, imaging, computational, and genetics investigators as a closely integrated team, and most importantly has attracted a very talented group of young investigators and graduate students focused on the problems addressed in the proposed research. A unifying theme of the studies that our team has proposed is the notion that math failure, and perhaps academic failure more broadly, emerges gradually through interactions of putative early conceptual weaknesses, attributable in some cases to poor functioning and anomalous neural architecture in specific neural systems, with increasing reward-based biases that contribute, additively or non-additively, to suppression of the normal learning trajectory. Consistent with this theme we refer to our proposed research hub as the Roles of Emotion and Choice (REaCh) in Learning Disabilities Research Hub (LDRH). The proposed REaCh Hub has 3 components: a new research project to investigate key questions about learning and the neural architecture during early development in children at high risk for math failure, and two cores. The Administrative Core proposal describes the management plan for the new Hub and the PING infrastructure that will be adapted for the new studies; and focuses on a nested mentoring plan for ensuring close interaction between trainees at different levels with mid-level and senior investigators within focused workgroups. The assets of the Core for within-Hub and extra-Hub data sharing are also described. A Developmental Infrastructure Core proposal describes the administration of a small grant program to support novel work within the Hub by junior investigators, trainees, and investigators from disciplines outside of the original REaCh LDRH group.

PROJECT SUMMARY Here we request funds to continue work begun in the first funding period to pursue the following augmented aims that expand the original scope of the ABCD study: · Address important questions about the possible roles of gender identity, sexual identity, and sexual health in modifying important health, mental health, and other outcomes measured in ABCD. · Enhance the capacity within ABCD to answer important questions about sexual health in adolescents, particularly about normative trajectories of gender and sexuality. To accomplish these new aims, the ABCD consortium must make modifications to the design of the study, adding, and sometimes developing, new methods for measuring, in a developmentally sensitive and developmentally informed manner, the gender identity, sexual identity, and sexual health of participants in the ABCD study. Other modifications of the assessments across multiple domains are needed to ensure that the study can adequately assess risks that may be increased in sexual and gender minority teens in the ABCD study; risks that may contribute to health disparities previously reported in this group of youth. Since receiving supplemental funding for this project, a new Gender Identity and Sexual Health (GISH) workgroup was established, with membership from the ABCD investigator group, NIH, and CDC. As such this workgroup functions like other expert workgroups in ABCD with responsibility for a specific set of interactions with the CC, DAIRC, and other advisory and oversight groups within and external to the consortium. In the proposal, we describe the CC-DAIRC-workgroup interactions required to generate, evaluate, integrate, monitor, update, interpret, and share all data collected within the ABCD Study. Continued funding is needed to continue revising gender assessments in ABCD, ensuring youth acceptance and validity of proposed revisions, and to offset additional costs to the centers and sites of expanding their assessment processes to include this set of protocol elements within the current ABCD study design. As described above, the GISH workgroup relies on integrated support from both the CC and the DAIRC to accomplish these aims.