1998 — 2000 |
Pfefferbaum, Adolf |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brain Structure/Function in Schizophrenia
DESCRIPTION (Adapted from applicant's abstract): This is a proposal for support to continue several years of research on brain structure and function in schizophrenia by the investigator, who has recently moved his laboratory to a new institution. Over the past ten years, under the direction of the investigator and guided by specific hypotheses, a large body of neuroimaging, neuropsychology and ERP data has been collected on patients with schizophrenia and normal controls. These data provide fertile ground for cross-sectional exploratory investigations, testing of additional hypotheses not initially posed, and the continuation of a longitudinal study of the progression of brain dysfunction and dysmorphology in schizophrenia. Based on the investigator's preliminary longitudinal observations, he proposes the hypothesis that schizophrenia is a progressive neurodegenerative disorder. The specific aims of this proposal are: 1. To test specific hypotheses in cross-sectional studies regarding brain structure and function in schizophrenia with quantitative MRI, neuropsychology, and electrophysiology. What is the pattern of the tissue volume deficits consistently observed in cortical, caudate, cingulate, limbic, and cerebellar regions in patients with schizophrenia? Are there selective relationships between the brain volume abnormalities and specific clinical, neuropsychological, and electrophysiological variables or processes? 2. To test the hypothesis that schizophrenia is a progressive neurodegenerative disorder demonstrable with quantitative MRI, neuropsychology and electrophysiology. Is the progression additive or interactive with age? Is the progression differentially expressed in different brain regions and in different cognitive and electrophysiological measures of brain function?
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1 |
2000 — 2004 |
Pfefferbaum, Adolf |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
In Vivo Diffusion &Spectroscopic Brain Imaging in Alcoh
DESCRIPTION: (Adapted from the Investigator's Abstract) Diffusion Tensor Imaging (DTI), proton MR Spectroscopy (MRS) and MR Spectroscopic Imaging (MRSI) will be used to study in vivo microstructural and biochemical characteristics of the brain in chronic alcoholics compared with controls. DTI yields measures of the diffusion of tissue water (apparent diffusion coefficient [ADC]) and directional coherence of white matter fibers (fractional anisotropy [FA]). MRS provides quantitative measures of several brain metabolites, including N-acetyl compounds (NAc), primarily N-acetyl-aspartate, a marker of living, mature neurons; creatine+phosphocreatine (Cr), a reflection of high-energy phosphate metabolism; choline (Cho), an index of membrane turnover; and myo-inositol (mI), an index of neuronal degeneration. Measurement of these indices of brain deterioration and recovery at different times in the course of abstinence and resumed drinking should provide clues to mechanisms underlying both permanent and reversible brain changes associated with alcoholism. Candidate processes include reversible de-and remyelination along with axonal regression and recovery and the permanent processes of neuronal and axonal degeneration. Specific Aims are: 1) To use DTI and single voxel MRS to examine white matter fiber integrity in alcoholics at 3 times post-detoxification-1, 4, and 26 weeks. At 26 weeks 50% of the alcoholics will have remained abstinent and 50% will have relapsed. We will test the following hypotheses: a) between weeks 1 and 4 alcoholics, relative to controls, will show increases in white matter FA and NAc and decreases in ADC, Cho and mI, even though white matter volume changes may not be detectable; b) between weeks 4 and 26, alcoholics who abstain will show increases in white matter volume, FA and NAc concentration whereas those who relapse will show decreases in white matter volume, FA and NAc and increases in ADC, Cho and mI. 2) To use MRSI to examine gray matter and white matter metabolite concentrations in longer-term abstinent alcoholic men and women. We will test the hypothesis that longer-term abstinent alcoholics will exhibit residual gray and white matter deficits, greatest in the frontal lobes, and that chronic alcoholics, abstinent for at least a year, will have widespread abnormally low NAc and high Cho, more prominent in frontal than posterior brain regions. 3) To characterize White Matter Hyperintensities (WMHI), which occur with greater frequency in alcoholics than controls. We will develop high-resolution DTI and MRSI acquisition procedures in order to sample multiple diffusion and spectroscopic voxels within WMHIs.
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1 |
2001 — 2005 |
Pfefferbaum, Adolf |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Inia: Imaging Core
DESCRIPTION (provided by applicant): The INIA Imaging Core will develop and employ tools for quantifying, cross-sectionally and longitudinally, the effects of excessive alcohol exposure at macrostructural and cellular levels in animal models of alcoholism. Accordingly, we propose that a valid animal model of human chronic alcohol consumption will produce analogous brain structural modification at the neural circuit, cellular, and neuronal morphometric levels of analysis. We hypothesize that the alcohol-related brain changes modify brain reward and executive control circuits involved in the maintenance of excessive alcohol consumption (most notably, the extended amygdala) and that further alcohol exposure results in further deterioration of inhibitory processes to resist alcohol (hypothesized to axise from limbic and frontocerebellar systems damage). This core will develop methods to examine alcohol-induced brain changes at in vivo structural (SRI and Stanford) and in vitro cellular and molecular (Indiana and Scripps) levels of analysis. In vivo neuroimaging component will develop magnetic resonance imaging (MRI) acquisition and analysis approaches for the in vivo study of brain tissue macrostructure, microstructure, and chemical composition of brain tissue. This component will develop an in vivo animal model of alcohol-induced brain changes detectable with MRI in rats bred at the Indiana Alcohol Center to drink alcohol (P); develop acquisition and analysis approaches for MR spectroscopy (MRS), MR spectroscopic imaging (MRSI), and diffusion tensor imaging (DTI) in the in vivo study of brain tissue microstructure and chemical composition of brain tissue in rats; and create tools for interested INIA sites to collect and analyze MR neuroimaging data. Cellular imaging component will provide economically efficient facilities for conducting in vitro imaging, analysis using quantitative autoradiography, carrying out in situ hybridization, performing immunocytochemical for c-fos activation and neuroanatomical identification of neurons, microdissecting discrete CNS regions, developing laser capture microdissection techniques, and initiating studies for undertaking in vivo imaging in the alcohol animal model. Neuronal quantification component will apply stereological neuronal quantification and morphometric analysis to brain systems identified with in vivo MR as affected by alcohol. Distribution of neurotransmitters and their receptors and transporters will also be probed using markers for neurotransmitter signal transduction and antibodies for immunocytochemistry or mRNA by in situ hybridization.
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1 |
2001 — 2006 |
Pfefferbaum, Adolf |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Alcohol, Hiv, and the Brain
DESCRIPTION: The longevity of HIV infected individuals (HIV+) has been extended by new therapies, but the disease still follows a progressive course with significant deleterious effects on the brain. High comorbidity with alcohol abuse among HIV+ individuals puts dually afflicted patients at risk for additive or synergistic effects, especially in frontostriatal brain systems that control executive and motor functions. Recent advances in magnetic resonance (MR) imaging, such as MR spectroscopy, MR diffusion tensor imaging, provide new opportunities to study, in vivo, the macrostructural, microstructural, and biochemical bases of the pathophysiology of HIV infection and alcohol abuse. Further, these techniques enable the observation of disease-induced changes over time, and the degree to which these changes relate to clinical state and cognitive and motor performance. In balanced four group, we will compare high and low alcohol consuming HIV+ patients with low-alcohol consuming HIV- subjects over a three year period in a naturalistic design to model the cumulative and progressive deleterious effects on the brain of combined HIV infection and alcohol abuse. We will test dual model of their comorbidity: interactive effects on structures disrupted by both disease (e.g., basal ganglia in HIV+). Three specific aims are proposed: Specific Aim 1: To use neuroimaging and neuropsychological measures to establish patterns of normality and abnormality in HIV+ alone, alcohol abuse alone, and HIV+ with alcohol abuse. Specific Aim 2: To track in neuroimaging measures at 1 and 3 year follow-up sessions. Specific Aim 3: To establish cross-sectional and longitudinal within-subject relationships among nueroimaging, neuropsychological, and clinical measures.
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2004 — 2009 |
Pfefferbaum, Adolf |
P41Activity Code Description: Undocumented code - click on the grant title for more information. R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
In Vivo Diffusion and Spectroscopic Brain Imaging in Alcoholism
DESCRIPTION (provided by applicant): This renewal application extends our prior work demonstrating subtle, yet quantitatively detectible, widespread white matter degradation wit h a frontal predilection in alcoholics. We propose that uncomplicated alcoholics also have subclinical variants of the more profound alcohol-related demyelinating conditions of Marchiafava-Bignami Disease (MBD), affecting corpus callosum, and Central Pontine Myelinolysis (CPM), affecting central pons. We propose to use structural magnetic resonance (MR) imaging wit h diffusion tensor imaging (DTI) and proton MR spectroscopy (MRS) to characterize affected brain regions in recovering, uncomplicated alcoholics and to identify functional liability exerted by disruption of selective white matter systems. Specific Aim 1 will use DTI to examine the distribution of alcoholism-related brain white matter degradation and will test the hypothesis that low fractional anisotropy (FA) and high mean bulk diffusitivity (), measures of white matter integrity, are widespread in alcoholics but have a frontal predilection. Specific Aim 2 will use event-related potential (ERP) and behavioral tasks to examine the functional liability exerted by observed DTI abnormalities in splenium and genu of corpus callosum, longitudinal fasciculi, and frontal and occipital forceps in alcoholics. Specific Aim 3 will use MRS to examine biochemical properties of callosal and pontine white matter in alcoholics and will test the hypotheses that relative to controls, alcoholics will exhibit shortened T2 of tissue-water and major proton metabolites in corpus callosum; pons tissue-water will have a prolonged T2; and high pons choline and normal NAA will support hypothesized demyelination without axonal deletion. Key to understanding how neuroadaptation to alcoholism-induced brain structural and functional deficits contributes to the self-sustaining nature of alcoholism is a detailed elucidation of alcoholism-induced brain damage and investigation of its functional consequences, the objective of this proposal.
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1 |
2006 — 2010 |
Pfefferbaum, Adolf |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuroimaging in Animal Models of Alcoholism
[unreadable] DESCRIPTION (provided by applicant): The brain damage resulting from excessive alcohol exposure may itself contribute to the self-perpetuating nature of human alcoholism. Our goals for this translational research project are twofold: 1) to demonstrate alcohol-induced brain damage in the rat when animals are exposed to high levels of alcohol and scheduled withdrawals and 2) to determine whether rats, selectively bred to drink high amounts of alcohol, drink in a pattern or quantity insufficient to produce neurotoxicity or, alternatively, have also inadvertently been selected for resistance to alcohol neurotoxicity. In the previous INIA funding cycle we found that substantial voluntary drinking by the P rat was only modestly neurotoxic as demonstrated with magnetic resonance (MR) imaging.MR-detectable brain abnormalities were limited to attenuated growth of the corpus callosum, with suggestion of effect in the hippocampus and cerebellum. We now propose to use the alcohol vapor chamber method to increase exposure and to schedule withdrawals, which we predict will enhance alcohol-induced brain damage, detectable with in vivo structural MRI of the whole brain and 2D J-resolved MR spectroscopy of ventromedial subcallosal gray matter. Hypothesis-guided postmortem histological and exploratory gene expression studies will confirm and extend in vivo observations. Specific Aims 1-3 will use two alcoholpreferring/non-preferring rat strains and their selection stock: P, NP, Wistar (W) and HAD-1, LAD-1, N/NIH rats. Our MR developments and expertise will be provided to other investigators through Specific Aim 4. Aim 1: Use in vivo MR to demonstrate structural and brain metabolite abnormalities in P and HAD-1 rats after vapor chamber exposure to and withdrawals from high levels of alcohol starting in peri-adolescence. Hypothesis: Alcohol treatment will result in attenuated growth trajectory of brain tissue, decreased size of selective brain structures, particularly the corpus callosum, frontal cortex, hippocampus, amygdala, and cerebellum, and decreased entromedial subcallosal NAA and choline. Aim 2: Use in vivo MR to determine if P and HAD-1 rats are more robust to deleterious effects of high binge and withdrawal alcohol exposure than their NP and LAD-1 counterparts and their W and N/NIH selection stock. Hypothesis: The magnitude of the MRI and MRS abnormalities will be NP > W> P and LAD-1 > N/NIH > HAD-1. Aim 3: Identify histological and explore gene expression correlates of alcohol-induced brain damage and determine if alcohol-induced brain damage occurs below the limits of detection of in vivo MR studies. Hypothesis: Compared with controls, alcohol-exposed animals will have reduced callosal size, thinner myelin sheathes, and lower neuron counts in gray matter regions predicted to sustain MR-detectable damage. Aim 4: As a resource, provide MR imaging expertise to other INIA-West and INIA-East investigators for in vivo studies of animal models of alcoholism. [unreadable] [unreadable] [unreadable]
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2007 — 2017 |
Pfefferbaum, Adolf Zahr, Natalie M |
P41Activity Code Description: Undocumented code - click on the grant title for more information. U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Tracking Hiv Infection and Alcohol Abuse Cns Comorbidity With Neuroimaging
DESCRIPTION (provided by applicant): he purpose of this application is to elucidate the interaction of HIV infection and alcohol use disorders on central nervous system morbidity and the additional complications of aging arising from extended longevity afforded by advances in anti-HIV pharmacotherapies. Adding to this aging HIV-infected cohort are the increasing numbers of people over 50 years old who are being newly infected. Even in relatively healthy individuals, the aging brain is increasingly vulnerable to endogenous and exogenous insult, an example being the age-alcoholism interaction on brain tissue volume and integrity. Similarly, age-related decline in neural system integrity can compound the HIV-vulnerable brain systems and increase liability for dementia. Further compounding the picture of HIV infection is the common comorbidity of hepatitis C infection (HVC) and the sequelae of AIDS-defining events. Thus, investigation of interactions of normal aging, alcohol use disorders, and HIV infection is now especially germane given the aging HIV-infected population. The proposal builds on our research to date that includes individuals in four groups [HIV + Alcoholism (HIV+ALC), HIV without Alcoholism (HIV), Alcoholics (ALC), Normal Control Subjects (NCS)], examined upwards of 5 times over 8 years with multimodal neuroimaging [structural MRI and diffusion tensor imaging (DTI)], clinical and behavioral assessment, and neuropsychological testing. Results of our analyses demonstrate that the aging brain is highly sensitive to the combined effects of HIV/AIDS, alcoholism, and HCV infection. We now propose to follow our existing longitudinal cohort of over 100 participants (more than half of whom are now over 50 years old) and to recruit an additional 100 individuals age 50 or older who will be followed at 18-month intervals with neuroimaging [MRI, DTI, resting state MRI (rsMRI), and cerebral perfusion measured with pulsed-continuous arterial spin labeling (PCASL)], clinical, neuropsychological, and clinical assessment, including determination of circulating proinflammatory cytokine levels. Aim 1: Establish the pattern of brain pathology with MR imaging and functional measures in an expanded sample of older individuals with HIV infection and the combined morbidity of alcohol abuse. Cross-sectional hypotheses predict a complex pattern of additive and interactive effects. Aim 2: Assess longitudinal disease trajectory (progression or effective control) as modulated by alcohol abuse, HCV infection, and ART compliance by testing the current and new cohorts at 18-month intervals. Aim 3: Establish cross-sectional and longitudinal within-subject relationships among neuroimaging measures, cognitive and motor performance, and clinical status.
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2011 — 2016 |
Pfefferbaum, Adolf |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuroimaging of Alcohol-Induced Neuroadaptation: Translation From Animals to Hum*
DESCRIPTION (provided by applicant): We propose a series of translational studies using in vivo magnetic resonance (MR) neuroimaging and spectroscopy applied across rats and humans and monkeys by a collaboration between INIA-West and INIA-Stress. The goal is to identify and explicate changes in brain morphology, neurocircuitry, and metabolism during the development and maintenance of alcohol dependence. Exploratory studies will include correlation of in vivo MR data with postmortem histological analyses in collaboration with other INIA-West sites. Specific Aim 1: Rat Model of Dependence-Induced Drinking and Neuroadaptation. A primary INIA animal model of high alcohol consumption is withdrawal induced-drinking demonstrated with repeated high dose binge exposure, analogous to the chronic intermittent ethanol (CIE) paradigm. The progression of brain circuitry change over the course of repeated exposure-withdrawal cycles will be demonstrable with functional neuroimaging and a change in the pattern of choline and glutamate levels. Specific Aim 2: Rat-Monkey-Human Translation of High Doses of Chronic Alcohol: Brain Structure and Intrinsic Neural Connectivity. We propose parallel studies in chronic alcoholics and chronically-exposed animals using analogous neuroimaging probes: structural morphometry (MRI) and fcMRI from nodes pertinent to the maintenance of alcohol dependence-withdrawal/negative affect circuitry. We will use a longitudinal design, and a common analysis to be conducted across species: rat, monkey, and human. Specific Aim 3: Rat-Monkey-Human Translation of High Doses of Chronic Alcohol: Brain Metabolites. In vivo MR spectroscopy (MRS) studies report abnormally high choline soon after alcohol withdrawal in human alcoholics and rats chronically exposed to alcohol and in rats with single binge exposures. High glutamate occurs with high chronic alcohol exposure. As potential markers of dependence, we will model this pattern of metabolite changes in collaboration with INIA-Stress and propose parallel rat, monkey, and human studies using a common MRS acquisition and analysis tuned specifically to detect glutamate. The proposed research conceptually casts some alcoholic brain damage as a disorder of neuroconnectivity with structural and functional concomitants with bidirectional translation from humans to animal models and back to humans. We bring forth a paradigm shift from observing the brain's responsivity to external demands to investigating the brain's ongoing intrinsic activity as a concept for explicating the deleterious effects of chronic alcoholism on the brain.
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2011 — 2015 |
Pfefferbaum, Adolf Sullivan, Edith Vioni (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuroimaging of Connectivity in Alcoholism
DESCRIPTION (provided by applicant): In keeping with a mission of NIAAA to increase the understanding of normal and abnormal biological functions and behavior relating to alcohol use, the goal of the proposed studies is to advance knowledge about the unique neuroadaptation of the human brain to the injury caused by chronic alcoholism. In this proposal alcoholic brain damage is viewed as a disorder of neuroconnectivity with structural and functional concomitants. Many brain networks and systems subserving specific functions have well defined architecture. It has recently been recognized that there are also brain networks without a known neuroanatomy that reflect intrinsic brain functioning and are demonstrable only with functional connectivity imaging. This project will apply advanced neuroimaging to interrogate the disruption of neuroconnectivity in alcoholics and their potential compensatory neuroadaptation. Quantitative measurement of brain white matter microstructure will be assessed by fiber tracking with diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI); scalp-recorded EEG and event- related potentials (ERPs) will reflect the synchrony of brain electrical potentials across large cerebral networks and their connectivity; intrinsic and task-related functional connectivity will be identified with functional MRI (fMRI and fcMRI) using both blood oxygen level dependent (BOLD) and noninvasive cerebral blood flow (CBF) acquired with Pulse Continuous Arterial Spin Labeling (PCASL). Knowledge of the extent and specificity of connectivity dysfunction in alcoholism forms a basis for targeting specific rehabilitation strategies and consideration of new treatment approaches. The proposal will study alcoholic men and women and age- and sex-matched nonalcoholic comparison groups with three specific aims, each with explicit testable hypotheses: Specific Aim 1: To probe intrinsic functional networks using resting state fcMRI and PCASL and task- activated fMRI and PCASL to measure changes in regional BOLD and CBF activity. Specific Aim 2: To probe neurocircuitry with resting EEG coherence and ERP time-frequency analyses of a visual GO/NOGO task and multiple component analyses of a conflict resolution task. Specific Aim 3: To determine the extent of alcoholism-induced degradation of white matter circuitry connecting nodes of the task-activated and intrinsic networks using HARDI quantitative fiber tracking. Exploratory analyses will examine the role of age, sex, family history of alcoholism, length of sobriety, smoking, education, intelligence, and impulsivity in adaptation to alcoholism-induced brain connectivity disruption. PUBLIC HEALTH RELEVANCE: Advanced structural, functional, and electrophysiological neuroimaging of brain connectivity networks will be used to further knowledge about the unique neuroadaptation of the human brain to the injury caused by chronic alcoholism. Knowledge of the extent and specificity of brain dysfunction in alcoholism forms a basis for targeting specific rehabilitation strategies and consideration of new treatment approaches.
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2012 — 2016 |
Pfefferbaum, Adolf Pohl, Kilian Maria (co-PI) [⬀] |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
N-Canda: Data Analysis Component
DESCRIPTION (provided by applicant): The National Consortium on Alcohol and NeuroDevelopment in Adolescence (N-CANDA) proposes a longitudinal study of developmental trajectories of brain structure, function, and physiology and their alteration by adolescent alcoho exposure. The prospective design will assess young people before the start of any significant substance use, thereby facilitating identification of antecedent conditions influencing the development of Alcohol Use Disorder (AUD) and the effects thereafter. A synergistic program to assess dependent-variable domains (clinical, neuropsychological, physiological, brain structural and functional), quantified and tracked longitudinally will be combined across 4 collection sites to create a large and rich body of data. An accelerated longitudinal design allows for construction of trajectories over the entire adolescent age range and encompasses the period of brain structural and functional development during the vulnerable time of AUD emergence. The investigators of the N- CANDA Data Analysis, Integration, and Informatics Component will provide fundamental neuroimaging science support for MRI pulse sequence development, acquisition, and analysis protocols. This component will also provide the infrastructure for deposition, organization, storage, archiving, retrieval, and initial analysis of neuroimaging, neuropsychological, and clinical data collected at all four N- CANDA acquisition sites. The Specific Aims of the Data Analysis, Integration, and Informatics Component are to: Aim 1. Develop procedures for collection of neuroimaging, neuropsychological, and clinical assessment data harmonized with existing large-scale neurodevelopmental research efforts. Aim 2. Ensure that quality control measures are in place at each site for the acquisition of imaging data. Aim 3. Develop the informatics infrastructure for data submission, database construction, data analysis, integration, and distribution for all N-CANDA sites through a query system that allows exploration of the multiple domains of the database. Aim 4. Provide a pipeline for macrostructural, microstructural and functional neuroimage data processing and analysis. Aim 5. Develop informatics processes to coordinate the combining of data and the analysis of results across and within research components for a priori hypothesis testing and association discovery and atheoretical data mining in search of relations not previously considered.
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2017 — 2021 |
Pfefferbaum, Adolf Pohl, Kilian Maria (co-PI) [⬀] |
U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
Ncanda: Data Analysis Resource
PROJECT SUMMARY / ABSTRACT During young adulthood, drinking dramatically increases, with binge-level drinking peaking at age 22 and nearly half of individuals who drink report binge-level alcohol use. Frequent binge alcohol use during the protracted neuromaturation extending into the mid 20s may result in greater brain and cognitive effects than similar alcohol use in later adulthood. This application is in response to RFA-AA-17-005, Continuation of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) Data Analysis Resource (U24) to determine the predictors and effects of accelerated alcohol use in adolescence and young adulthood. NCANDA-2 will follow the initial cohort of 831 participants (ages 12-21 at first visit) from 5 collection sites and acquire the necessary data to advance our understanding of adolescent development and the effects of alcohol use on the adolescent and young adult brain using multimodal neuroimaging, cognitive testing, and behavioral assessment. The examination of alcohol consequences will focus on structural and functional maturation of brain areas that actively develop during adolescence, are involved in psychological regulation, respond to rewards, and appear vulnerable to deleterious effects of alcohol. With the additional longitudinal data provided by this renewal, we will determine the effects of alcohol exposure on the developmental trajectory of the adolescent human brain and identify preexisting psychobiological vulnerabilities that may put an adolescent or young adult at elevated risk for an alcohol use disorder. The Data Analysis Resource (DAR) will 1) oversee data collection with standardization and comparability across sites; 2) perform data analysis for core measures collected at each site; 3) facilitate across-site pooling and centralized data storage; 4) create a database across assessment modalities for efficient retrieval; 5) coordinate data and resource sharing; 6) harmonize data across sites; and 7) create and implement novel, multimodality analyses using machine learning to engage broad spectrum data. The DAR has 5 Specific Aims: Aim 1. Maintain standardized procedures for collection of neuroimaging, neuropsychological, and clinical assessment data and harmonize with existing large-scale neurodevelopmental research efforts. Aim 2. Ensure across-site quality control for imaging and neuropsychological data acquisition. Aim 3. Maintain and advance informatics infrastructure for data submission, analysis, and distribution. a) Maintain a database integrating the diverse and comprehensive data from all NCANDA sites. b) Provide data to consortium PIs for hypothesis testing within and across experimental domains. Aim 4. Provide macrostructural, microstructural, and fMRI neuroimage processing and analysis. Aim 5. Develop and maintain a data sharing and distribution system for the scientific public.
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2017 — 2021 |
Pfefferbaum, Adolf Zahr, Natalie M |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuroimaging of Alcohol-Induced Neuroadaptation: Translation From Animals to Humans
PROJECT SUMMARY/ABSTRACT This competing renewal application, U01 AA013521, Neuroimaging of Alcohol-Induced Neuroadaptation: Translation from Animals to Humans, is submitted in response to RFA-AA-16-004 (U01). The overarching aim of this proposal is to identify in vivo markers related to the pathogenesis of alcohol use disorder (AUD) related to altered stress (amygdala) circuitry and neuroimmune recruitment. Recent resting- state functional magnetic resonance imaging (rs-fMRI) studies will determine the differential circuitry of the amygdala as a function of withdrawal frequency in AUD. The potential for neuroimmune recruitment in AUD pathology will be evaluated using a multi-B-value diffusion tensor imaging (DTI) analysis of free water, which is proposed as an index of neuroinflammation. These in vivo biomarkers will be collected in humans, monkeys, and rodents and contribute to the validity of the animal models and provide a framework for evaluating pharmacological agents to aid in AUD recovery. Optogenetic stimulated functional MRI in rodents will further explore specific brain circuits relevant to AUD. Specific Aim 1 will use rs-fMRI and multi-B-value DTI in humans with AUD and their controls to test the hypothesis that greater withdrawal frequency will be associated with more symptoms of anxiety, changes in amygdala rs-fMRI connectivity (stronger functional connectivity between the CMA and anterior cingulate cortex [ACC] and between BLA and anterior insula; weaker connectivity between the CMA and posterior cingulate cortex [PCC]), and more free water in amygdala, hippocampus, and cingulate cortex. Specific Aim 2 will analyze rs-fMRI and multi-B-value DTI data in monkeys at baseline and following 3 cycles of EtOH exposure and withdrawal collected by INIA-Stress to test the hypothesis that greater withdrawal frequency will be associated with exacerbated anxiety, higher EtOH consumption, changes in amygdala rs-fMRI connectivity, and more free water in amygdala, hippocampus, and cingulate cortex. Specific Aim 3 will rs-fMRI and multi-B-value DTI in rats exposed to chronic intermittent ethanol (CIE) via vapor chambers to test the hypothesis that longer periods of CIE will result in the accrual of anxiety-like behavior, stronger functional connectivity between the amygdala and downstream targets (e.g., brainstem), and more free water in amygdala, hippocampus, and cingulate cortex. It is also hypothesized that apremilast, a phosphodiesterase-4 inhibitor will normalize affected behavioral, functional, and free water changes, thereby supporting neuroimmune mechanisms in AUD. Specific Aim 4 will use optogenetic and chemogenetic methods and fMRI to determine the neurocircuitry recruited by direct stimulation of the rat central nucleus of the amygdala (CeA) corticotropin releasing factor (CRF) neurons. The hypothesis to be tested is that direct stimulation of CeA CRF neurons will result in similar functional connectivity patterns as observed following multiple CIE exposures.
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2018 |
Pfefferbaum, Adolf Pohl, Kilian Maria (co-PI) [⬀] |
U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
Ncanda Administrative Supplement For Clinical Readings and Analysis
PROJECT SUMMARY / ABSTRACT A significant outcome of prospective studies using noninvasive neuroimaging with Magnetic Resoance Imaging (MRI) is the recognition that brain structural anomalies occur even in individuals apparently free of neurological disorders. Recently, we found that 0.6% of 833 adolescent and young adult participants in a large, NIAAA- funded project (NCANDA) had anomalies identified as gray matter heterotopias. These isolated clumps of gray matter neurons located in the wrong part of the brain are thought to be associated with seizures. This incidence of heterotopias was high given that participants with a history of a seizure disorder were excluded from study. We pursued this finding by investigating heterotopia incidence in another larger NIAAA-funded project (ABCD). In a computerized search of 7,863 neuroradiological readings, 84 (1.07%) participants were identified with gray matter heterotopias. Given that heterotopias have been reported in animal models of fetal alcohol exposure, we sought to examine the relation between hetertopias and prenatal alcohol exposure in the ABCD data. Retrospective questioning of mothers of ABCD participants indicated a high incidence of heterotopias in offspring of mothers who answered in the affirmative that they had drunk alcohol while but before finding out they were pregnant. These findings raise the possibility that the incidence of heterotopias in a population enriched with fetal alcohol exposure (FAE) and fetal alcohol syndrome (FAS) should be higher than in unaffected controls and would support the inference that prenatal alcohol exposure causes heterotopias in the cortex of exposed individuals. Accordingly, in collaboration with a clinical neuroradiologist, we will oversee blind clinical readings of the MRIs of 60 FAE, 60 FAS, and 60 control subjects to seek gray matter heterotopias, in addition to other structural anomalies, in these subjects with known outcomes of prenatal alcohol exposure. Such a finding would be novel and clinically significant, serving as a warning to health-care providers of the potential of seizures and as further reason to refrain from drinking alcohol when intending to become pregnant.
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2019 — 2021 |
Pfefferbaum, Adolf Sullivan, Edith Vioni (co-PI) [⬀] Zahr, Natalie M |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Tracking Hiv Infection & Alcohol Abuse Cns Comorbidity With Neuroimaging
PROJECT SUMMARY ABSTRACT As the successfully treated population of Human Immunodeficiency Virus (HIV)-infected individuals age, cognitive and health challenges of normal aging ensue, burdened by HIV, treatment side effects, and high prevalence comorbidities, notably, Alcohol Use Disorder (ALC) and hepatitis C virus (HCV). The aging brain is increasingly vulnerable to endogenous and exogenous insult which, coupled with HIV infection, can lead to HIV-Associated Neurocognitive Disorder (HAND) and sensorimotor disturbances. Our goal is to explicate the role of aging in magnetic resonance (MR)-detectable HIV pathology in the context of common comorbidities (ALC, HCV), while considering HIV-relevant variables (nutrition, medication adherence and toxicity, liver integrity). As common HIV-associated comorbidities of ALC and HCV may intensify inflammatory cascades and potentiate HIV pathology, a corollary aim is to consider whether circulating markers of inflammation (microbial dislocation, monocyte-related immune activation, peripheral cytokine elevations) corroborate proposed imaging markers of neuroinflammation. We will follow 140 participants from our existing cohort and recruit 100 new subjects, with a focus on older HIV-infected individuals, using MR metrics consistent with our longitudinal database. In keeping with the requirements of the RFA, we propose four specific aims: 1. Investigate the cross-sectional and longitudinal pattern of brain and cognitive changes in terms of disease and age trajectories using quantitative MR imaging and neurocognitive measures. 2. Identify factors that modify HIV disease trajectory, including age, sex, alcohol consumption, HCV and its treatment, nutrition, medication adherence and toxicity, and hepatic integrity. Exploratory factors include measures of depressive symptoms, fatigue, sleep quality, and impulsivity. 3. Establish evidence for neuroinflammatory markers using free water DTI and brain metabolites quantified by magnetic resonance spectroscopy. 4. Quantify the extent of postural instability and truncal tremor in relation to comorbid factors and normal or accelerated aging. Accomplishment of these aims will enhance understanding of factors contributing to age and disease- related cognitive decline, sensorimotor problems, and neurodegeneration. Convergent evidence from blood biomarkers (elevations in microbial dislocation, monocyte activation, and proinflammatory cytokines), MRS metabolites [myo-Inositol (mI), choline-containing compounds (Cho), macromolecules (MM09+Lip09] and glutathione (GSH)], and DTI metrics (free water) may provide initial support for a constellation of in vivo markers of neuroinflammation.
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