Peter J. Gianaros - US grants

Little is known about how the gastrointestinal system responds to stressful events or how the gastrointestinal, cardiovascular, and autonomic components of the stress response may be related. In the proposed study, participants will be exposed to laboratory stressors with known effects on the autonomic nervous system while gastrointestinal, cardiovascular, and autonomic-cardiac function are simultaneously assessed. This methodology will be used to determine the specific patterns of autonomic nervous system activity that may contribute to gastrointestinal and cardiovascular stress responses. Further, this methodology will be used to evaluate the relationships between subjective and physiological response systems during periods of stress. The proposed research is relevant to public health issues for two primary reasons: (1) altered gastrointestinal, cardiovascular, and autonomic function are common features of a number of anxiety disorders and (2) stress and anxiety are thought to play a role in the development and maintenance of several gastrointestinal and cardiovascular disorders.

DESCRIPTION (provided by applicant): Exaggerated cardiovascular responses to stress may increase one's risk for hypertension and atherosclerosis. Biobehavioral models of the relationship between stress reactivity and cardiovascular disease assume that the perception of stressful events and the translation of stressor perceptions into cardiovascular responses are mediated by a central nervous system network that regulates both cardiovascular and cognitive/emotional states. Thus, processes that trigger potentially pathogenic cardiovascular stress responses are believed to be initiated within the central nervous system. Few studies in humans, however, have examined the central pathways that regulate cardiovascular stress responses. In the present study, functional magnetic resonance imaging (fMRI) will be used to test the hypotheses that (a) patterns of cardiovascular reactivity to laboratory stressors correlate with the activation of brain areas that are presumably involved in both cardiovascular control and cognitive/emotional processes, and (b) that a difference exists in the stressor-induced activation of these brain regions between a group of individuals who have previously demonstrated exaggerated cardiovascular stress reactivity and a group of individuals who have previously demonstrated attenuated cardiovascular reactivity. Results from this study are expected to enhance our understanding of the central control of cardiovascular stress responses, which may influence an individual's cardiovascular risk profile.

[unreadable] DESCRIPTION (provided by applicant): The educational aim of the proposed Mentored Research Scientist Development Award (MRSDA) is to train the candidate in functional magnetic resonance imaging (fMRI) and cardiovascular behavioral medicine research methods. Training in these two research methods will support the candidate's long-term professional objective of understanding the central nervous system regulation of cardiovascular reactions to stress in humans. Because individuals who show large increases in blood pressure during stress are at an increased risk for atherosclerosis and hypertension, an enhanced understanding of the central regulation of cardiovascular stress reactions will increase our knowledge about the origins of a risk factor for the leading worldwide cause of death: cardiovascular disease. To accomplish the educational aim of the proposed MRSDA, the candidate will (1) complete coursework in neuroscience, statistics, and research ethics; (2) attend methodology workshops on fMRI, neuroimaging data analysis, and behavioral medicine; (3) be instructed by expert mentors and consultants on fMRI methodology and central cardiovascular control; and (4) execute an fMRI study on the central control of blood pressure reactions to stress. This fMRI study has two Specific Aims: Aim 1 is to test the hypothesis that larger blood pressure reactions to laboratory stressors are associated with concurrently greater activation (as revealed by greater blood oxygen level-dependent [BOLD] signal intensities) in cortical (ventromedial prefrontal, insular, and anterior cingulate) and subcortical (amygdala and hypothalamus) brain systems that putatively support stressor processing and cardiovascular regulation. Aim 2 is to test the hypothesis that individuals who have shown large-magnitude blood pressure reactions to stress in the past will also show greater activation in these cortical or subcortical brain systems than a matched sample of low cardiovascular-reactive individuals during stress. By supporting interdisciplinary training and research in fMRI and cardiovascular behavioral medicine, the proposed MRSDA will foster a new course of study on the central nervous system origins of a salient risk factor for cardiovascular disease. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): A person's tendency to show exaggerated blood pressure reactions to acute psychological stressors is associated with an increased risk for preclinical atherosclerosis in the carotid arteries, which is a known predictor of premature disability and death by coronary heart disease. However, the neural pathways that link psychological stress to exaggerated blood pressure reactivity and risk for carotid atherosclerosis in humans are unknown. Supported by preliminary results, this project tests the central hypothesis that exaggerated blood pressure reactivity to psychological stress and greater preclinical carotid atherosclerosis are commonly associated with stress-induced hyperactivity in a network of brain systems that both process psychological stressors and regulate autonomic, neuroendocrine, and cardiovascular activity. These brain systems include functional subdivisions of the cingulate cortex, insula, and amygdala. To test specific predictions of this central hypothesis, three specific aims will be evaluated in a representative community sample of 75 men and 75 women (aged 30-50 years) who are asymptomatic for clinical cardiovascular disease and who are well characterized for known and emerging demographic, anthropometric, biological, and psychosocial cardiovascular risk factors. Participants will complete a battery of psychological stress tasks to elicit blood pressure reactivity in a functional magnetic resonance imaging (fMRI) session; they will also complete a non-invasive carotid ultrasound protocol to assess preclinical atherosclerosis. Aim 1 tests the prediction that exaggerated blood pressure reactivity to the stressor battery will be associated with a greater activation (as revealed by greater fMRI blood oxygen level-dependent [BOLD] responses) in the perigenual, dorsal, and posterior cingulate cortex, the anterior insula, and the amygdala. Aim 2 tests the prediction that greater activation in these brain systems to the stressor battery, but not to a non-stressor control task, will be associated with more preclinical atherosclerosis (as indicated by greater carotid intima-media thickness) after accounting for other cardiovascular risk factors. Aim 3 tests the prediction that stressor-induced activation in these brain systems is a stable response tendency of individuals, as determined by the test-retest reliability of stressor-induced fMRI BOLD responses in 30 participants who will be tested in 2 repeat fMRI sessions separated by 8 weeks. Health-related significance: The proposed study is designed to specify the neural pathways that may link psychological stress to exaggerated cardiovascular reactivity and preclinical atherosclerosis. The information provided by this study may reveal a novel stress-related neural phenotype that could be targeted by brain-based interventions for early modification in pre-symptomatic people at high risk for coronary heart disease. PUBLIC HEALTH RELEVANCE: Submitted in response to PA-07-046: Research on Mind-Body Interactions and Health. The broad objective of this project is to delineate the human brain systems that centrally link individual differences in cardiovascular reactions to stress and risk for coronary heart disease (CHD). From a public health perspective, it is important to delineate these brain systems to (1) understand the neural pathways by which psychological stress leads to cardiovascular reactions that may increase CHD risk and (2) identify markers of stress-related neural activity that could be objectively identified and possibly targeted for early modification in people at risk for future CHD. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Most Americans consume low quantities of long-chain omega-3 (-3) fatty acids, despite clinical evidence that increasing dietary intake of long-chain -3 fatty acids by fish consumption or fish oil supplementation reduces major cardiovascular disease (CVD) events. Moreover, despite clinical evidence of their efficacy, the mechanisms by which long-chain -3 fatty acids protect against CVD events remain uncertain. Because long- chain -3 fatty acids are concentrated in the brain and appear to have efficacy in the treatment of psychiatric disorders that are highly co-morbid with CVD, -3 fatty acid CVD protection may derive, in part, from salutary effects on brain-mediated behavioral risk factors for heart disease. In line with this suggestion, this 2-year ancillary research plan seeks to augment data collection of an ongoing randomized and placebo-controlled trial of -3 fatty acid supplementation, which is a component of our current NHLBI Program Project, "Biobehavioral Studies of Cardiovascular Disease" (HL040962). The aims of this ongoing trial are to test the effects of increasing intake of the key -3 fatty acids - eicosapentaenoic and docosahexaenoic acids (EPA, DHA) - on targets of CVD prevention, including systemic inflammation, cardiac autonomic control, and two brain-mediated behavioral CVD risk factors: negative affect (e.g., depressive symptomatology, hostility, and anger-related traits), and reward-related impulsive decision-making and delay discounting (predisposing to health-impairing habits of lifestyle). To augment our ongoing clinical trial in light of converging neurobiological evidence, we specifically propose to utilize contemporary structural and functional brain imaging techniques to examine the longitudinal effects of -3 fatty acids on brain systems implicated in affect regulation and impulsive decision- making. In this way, the proposed research would determine if increased EPA and DHA consumption reduces (from pre-to-post trial assessments) the reactivity of the amygdala to negative affect-related stimuli, and if increased EPA and DHA consumption the reduces reactivity of the ventral striatum to reward-related stimuli. Finally, the proposed research would explore possible longitudinal effects of increased intake of -3 fatty acids on gray matter morphology in prefrontal, amygdalar, hippocampal, or striatal areas implicated in affective and reward-related behaviors. PUBLIC HEALTH RELEVANCE: Omega-3 fatty acids are essential nutrients for both cardiovascular and behavioral health, and recent trials demonstrate that increasing dietary intake of omega-3 fatty acids protects against cardiovascular disease events. This proposal would augment our ongoing clinical trial in healthy adults by providing for longitudinal assessments of structural and functional brain imaging data, enabling us to determine the potential neural mechanisms for the putative effects of omega-3 fatty acids on two behavioral risk factors for cardiovascular disease - negative affect and impulsive decision-making (as related to health behavior choices).

DESCRIPTION (provided by applicant): A person's tendency to show exaggerated blood pressure reactions to acute psychological stressors is associated with an increased risk for preclinical atherosclerosis in the carotid arteries, a known predictor of premature disability and death by coronary heart disease (CHD). Prior work supported by this R01 (HL089850) has characterized a network of brain systems that regulate stressor-evoked blood pressure reactions, encompassing subdivisions of the cingulate cortex, insula, and amygdala. Additional cross-sectional work showed that stressor-evoked functional activity in these brain systems is associated with preclinical carotid atherosclerosis. This continuation project extends HL089850 by testing the organizing hypothesis that stressor-evoked functional activity in the cingulate cortex, insula, and amygdala predicts the 3-year longitudinal progression of preclinical atherosclerosis. It also extends HL089850 by testing the new hypothesis that individual differences in cingulate cortex, insula, and amygdala activity during the regulation of negative emotional experiences also accounts for cross-sectional and longitudinal variation in preclinical atherosclerosis. To test specific predictions derived from these hypothesis, three specific aims will be pursued in a community sample of men and women (aged 30-50 years) who are asymptomatic for clinical cardiovascular disease and who are well characterized for known demographic, anthropometric, biological, and psychosocial cardiovascular risk factors. Participants will complete a battery of psychological stress reactivity and emotion regulation tasks in a functional magnetic resonance imaging (fMRI) session with concurrent peripheral physiological monitoring. They will also complete a non-invasive carotid artery ultrasound protocol to assess preclinical atherosclerosis, as well as protocols to assess other known and emerging CHD risk factors at a baseline time point (Time 1) and at a follow-up time point 3-years later (Time 2). Aim 1 tests whether stressor-evoked functional connectivity between the anterior cingulate cortex, anterior insula, and amygdala predicts the progression of preclinical atherosclerosis (as measured by carotid intima-media thickness and adventitial diameter) after accounting for known cardiovascular risk factors. Aim 2 tests whether stressor-evoked blood pressure reactivity partially mediates the associations between stressor-evoked functional connectivity and the progression of preclinical atherosclerosis. Aim 3 tests whether the functional connectivity between the anterior cingulate cortex, anterior insula, and amygdala during the cognitive reappraisal of negative emotional stimuli associates with preclinical atherosclerosis at Time 1 and progression to Time 2. PUBLIC HEALTH RELEVANCE: The human brain systems linking individual differences in stress and emotion regulation processes to risk for coronary heart disease (CHD) are uncertain. From a public health perspective, it is important to specify these brain systems to (1) understand the mechanistic pathways by which stress and emotion regulation increase or protect against CHD risk and (2) identify markers of stress- and emotion-related neural activity that could be objectively identified and possibly targeted for modification in otherwise healthy people at risk for future CHD.

There have been great advances in in-vivo imaging techniques, which allow neuroscientists to visualize molecular, cellular and system physiology and functions. To fully utilize neuroimaging techniques, it is important to understand underlying principles, data detection, and data modeling and visualization. Furthermore, each technique has its' own strengths and limitations. In order to train students the synergy of multiple complementary neuroimaging modalities, we propose to continue the Multimodal Neuroimaging Training Program (MNTP) jointly run by both the University of Pittsburgh and Carnegie Mellon University, which consists of the pre-doctoral graduate program and a short-term 6-week Summer Workshop. The MNTP graduate program within the existing Center for Neural Basis of Cognition Graduate Program has the following specific aims; 1) Students for all participating disciplines receive basic neuroscience training for integrative neuroimaging research. 2) Students understand underlying principles, modeling, and applications of MRI, diffusion tensor imaging, functional MRI, positron emission tomography, magnetoencephalography, electroencephalography, functional near-infrared spectroscopy, and optical imaging. 3) Students integrate multiple methods and carry out multimodal neuroimaging projects. In addition to the pre-doctoral T90/R90 program, a short-term MNTP Summer Workshop is proposed to continue offering the six-week program for teaching the synergy of multi-modal neuroimaging to targeted students and investigators who have experience in one imaging modality and want to expand their training to other modalities. The Summer program will consist of basic lectures, hands-on team projects, integration of imaging projects, and multimodal symposium, emphasizing the methodologies of multiple imaging modalities. During the last funding period, this unique Summer program has been well-developed. Our Summer program enables trainees to utilize synergetic, complementary imaging modalities for investigating neuroscience questions. The short-term program has the following specific aims: 1) To ensure that all participating trainees learn the underlying principles, potentials, and limitations of several technologies. 2) To ensure trainees learn how to design paradigms, collect and process neuroimaging data, and to interpret their results. 3) To ensure trainees integrate multiple methods synergistically and carry out multi-modal neuroimaging projects in their home institutes. Our proposed program will train researchers for adequate handling of the increasing complexity of combining multimodal neuroimaging data with the knowledge of various data acquisition and processing approaches, and appropriate interpretations. This will speed up the synergistic application of multiple imaging modalities to basic and clinical neuroscience research in animals and humans.

Coronary heart disease (CHD) remains the leading cause of premature death among adults in the U.S. and other postindustrial nations. Predicting CHD risk - especially for a particular individual - remains a fundamental challenge. This project will investigate the application of statistical machine learning approaches to multimodal brain imaging, behavioral, biological, and related data to enhance the prediction of CHD risk. It specifically addresses the question of whether particular patterns of human brain activity during psychological stress reliably predict known risk markers of CHD; namely, stress-related rises in blood pressure and arterial morphology. From a basic science perspective, this research will advance our mechanistic understanding of how the brain relates to our physical health. From a public health perspective, this research will help to identify markers of brain activity that could be objectively identified and possibly targeted for modification in otherwise healthy people at risk for future CHD.

The key challenge with mapping neuroimaging data to CHD risk lies in being able to very precisely regress observed psychological stress reactions on the time-series of brain activity recorded in thousands of voxels, and identify which brain regions are most relevant for the regression. Conventional analytic approaches involve forming coarse temporal summaries by committing to specific parametric models, such as a generalized linear model and a fixed model for hemodynamic response, that result in poor accuracy. This award supports initiation of a collaborative research project that brings together a highly cross-disciplinary team of statistical machine learning, neuroimaging and health psychology researchers to tackle the following two goals: 1) identify a generalizable model and neuromarkers that predict individual differences in cardiovascular risk factors based on neural dynamics under psychological stress. This will be enabled through novel methods for functions-to-real and functions-to-function lasso regression; 2) characterize how neural patterns can be integrated with other physiological and anthropometric factors to personalize individual risk scores and neuro-biomarkers. This award is supported by the National Institutes of Health Big Data to Knowledge (BD2K) Initiative in partnership with the National Science Foundation Division of Mathematical Sciences.

Project Summary/Abstract Health is not randomly distributed across people or across space: it tracks a socioeconomic gradient that extends from individuals to the areas in which they live. Individual- and area-level attributes of socioeconomic disadvantage confer risk for a broad range of interrelated physical and neurocognitive health outcomes. This risk is especially apparent in midlife when pathophysiological trajectories of neurocognitive aging that predict risk for dementia in later life begin to accelerate. In this regard, we have provided some of the first evidence that individual- and area- level socioeconomic disadvantage associate with reduced cortical tissue volume and white matter integrity, aspects of brain morphology that show normative shrinkage and integrity loss with age in association with poorer cognitive outcomes. Pathways linking socioeconomic disadvantage to accelerated neurocognitive aging remain unclear. Recent evidence, including our own, suggests that metabolic factors may play a role. Individuals who develop metabolic syndrome, pre-diabetes or type 2 diabetes mellitus are at increased risk for accelerated neurocognitive aging. Furthermore, our recent cross-sectional findings suggest that metabolic risk factors contribute to the associations of area-level disadvantage with brain morphology among midlife adults. Here, we aim to extend this work by longitudinally examining metabolic pathways linking individual- and area-level disadvantage to neurocognitive aging across a 10 year period of midlife. For this purpose, we propose reassessing a sample of 300 cognitively normal midlife adults on whom we collected baseline measures of socioeconomic parameters, metabolic risk, brain morphology and cognitive function 9-10 years ago (mean age at follow-up = 52). Our primary aims examine whether individual- and area-level measures of socioeconomic disadvantage predict changes in brain morphology and cognitive function that decline with age and whether associations of disadvantage with neurocognitive aging are explained by metabolic risk and associated inflammation. We anticipate that this study will contribute to new knowledge to the neurobiology of disparities in cognitive aging.

ABSTRACT Administrative Core (Peter J. Gianaros, CL) The Administrative Core will be responsible for the overall administrative and intellectual coordination of the Program Project, from participant accrual to dissemination of findings. It will provide centralized fiscal management of the Program and ensure adherence to NIH and institutional grants management policies and IRB compliance. The Core will implement recruitment procedures for subject enrollment; oversee development of the Manual of Operations governing procedures of data collection; and issue payments to study participants. In its oversight role, the Core will monitor data collection, entry and verification through reporting protocols for subject tracking, protocol adherence, and problem identification. Finally, the Core will organize and coordinate regularly scheduled scientific interactions among collaborating investigators, consultants, and laboratories; foster training of junior scientist collaborators; and, aid in disseminating findings for use by the broader scientific community through the program's Data Sharing Plan. In his role as Program Director and Core Leader, Dr. Gianaros will be supported by an Operations Director for coordination of key day-to-day activities (Dr. Manuck) and advised by an Executive Committee, Internal Scientific Advisory Committee, and an External Advisory Board composed of senior scientists from other institutions.

ABSTRACT Biobehavioral Studies of Cardiovascular Disease (PO1-HL040962) This Program Project (P01) continuation application focuses on the human brain substrates of behavioral and socio-environmental influences on cardiovascular disease (CVD) risk in midlife adults. Proposed are 3 Projects that are conceptually cross-linked and supported by 3 Core Units. Collaborative investigators represent multiple disciplines, including psychology, neuroscience, biophysics, medicine, psychoneuroimmunology, epidemiology, machine learning, bioinformatics, and statistics. Project 1 aims to elucidate functional and structural brain phenotypes that predict the multiyear progression of preclinical vascular disease and dysfunction, with a focus on neural circuitries for visceral control that coordinate autonomic, neuroendocrine, hemodynamic, and immune physiology with stress- and emotion-related behavioral processes. Project 2 aims to establish whether functional characteristics of these visceral control circuits moderate the influences of stress-related environmental exposures on the progression of preclinical vascular disease and dysfunction, tracking individuals' behavior and cardiovascular physiology in daily life to test a novel neuro-diathesis model of CVD risk. Project 2 also tests for the first time whether daily life physical activity associates with daily life stress physiology through its effects neural circuits for visceral control. Project 3 aims extend those of the other Projects by elucidating the neural and peripheral processes linking physical activity with physiological and psychophysiological markers of CVD risk (including daily life affect and stress physiology) using an experimental intervention methodology. These P01 aims are unique in cardiovascular behavioral medicine, and they will be pursued in the context of multi-component data collection efforts that satisfy all project-specific aims. As a result, the P01 will create new opportunities for integrative and translational science on the human neurobiology of CVD risk that cuts across multiple methods and levels of analysis. Helping to advance its parent field, the P01 will generate and disseminate original and expansive public-domain resources and tools to the broader scientific and clinical communities through comprehensive data and software sharing and educational objectives. Enabling a precise focus on early CVD etiology, the study cohorts comprise nearly 900 midlife adults without clinically apparent CVD, and study methods will include novel combinations of neuroimaging, ecological momentary assessments of experienced environments, ambulatory hemodynamic monitoring, autonomic, neuroendocrine, immune, and vascular assessments, laboratory clinical evaluations, hetero-method health behavior assessments, and arterial imaging. The 3 Core Units of this P01 provide for synergy and inter-project coordination by administrative, data management and participant accrual services; measurement and instrumentation support; and direction in cutting-edge bio-statistical and data-intensive (machine learning) analyses. The present application thus represents a thematic continuation and next- generation extension of translational neurobiological research on CVD by this P01, which was initiated in 1988.

ABSTRACT Project 1 (Peter J. Gianaros, PL) Stress, Emotion, and Neural Circuits for CVD Risk Project 1 (P1) aims to identify features of visceral control circuits of the brain (brain phenotypes) that account for the influence of stress- and emotion-related processes on physiological mediators of cardiovascular disease (CVD) risk in midlife. P1 has a specific focus on indicators of autonomic cardiovascular control, glucocorticoid regulation, stressor-evoked cardiovascular reactivity, and systemic inflammation. We posit that individual differences in the expression of these mediators of CVD risk will be explained in part by multivariate classes of brain phenotypes derived from: (i) fMRI activation and connectivity changes evoked by a standardized battery of psychological-stressor and emotion-processing and regulation tasks; (ii) intrinsic functional network connectivity metrics derived from resting-state fMRI; as well as (iii) structural metrics of white matter fascicles that enable communication within visceral control circuits. A second objective is to test whether brain phenotypes for visceral control predict the multiyear progression of preclinical markers of vascular disease and dysfunction, as reflected by carotid artery morphology, arterial stiffness, and endothelium dependent vasodilation. A third objective is to test whether multi-system physiological mediators of CVD risk account for the prospective associations between brain phenotypes for visceral control and the progression of preclinical markers of vascular disease and dysfunction. Finally, we test whether the latter prospective associations depend on a known cardio-protective health behavior that may modify visceral control circuits, as well as stress and emotion processes; namely, physical activity. To these ends, we propose a 8.5-to-11 yr follow-up of systemic physiological mediators and markers of preclinical CVD in 360 men and women from two study cohorts ? the AHAB2 and PIP cohorts ? established by unique NHLBI-supported neuroscience studies of CVD risk in midlife. We also seek to recruit and longitudinally follow for 32 months a de novo sample of 350 midlife adults who will complete similar and expanded assessment batteries as implemented in AHAB2 and PIP, including detailed assessments of brain function and structure, biological, behavioral, and socio-demographic risk factors for CVD, as well as markers of preclinical vascular disease and dysfunction. In synergy with the other projects of this P01, P1 affords novel tests of whether individual differences in risk for CVD are partly explained or modified by brain phenotypes for visceral control. If so, this work will advance our understanding of the human neural substrates for biological and behavioral influences on the development of CVD.

ABSTRACT Biobehavioral Studies of Cardiovascular Disease (PO1-HL040962) This Program Project (P01) continuation application focuses on the human brain substrates of behavioral and socio-environmental influences on cardiovascular disease (CVD) risk in midlife adults. Proposed are 3 Projects that are conceptually cross-linked and supported by 3 Core Units. Collaborative investigators represent multiple disciplines, including psychology, neuroscience, biophysics, medicine, psychoneuroimmunology, epidemiology, machine learning, bioinformatics, and statistics. Project 1 aims to elucidate functional and structural brain phenotypes that predict the multiyear progression of preclinical vascular disease and dysfunction, with a focus on neural circuitries for visceral control that coordinate autonomic, neuroendocrine, hemodynamic, and immune physiology with stress- and emotion-related behavioral processes. Project 2 aims to establish whether functional characteristics of these visceral control circuits moderate the influences of stress-related environmental exposures on the progression of preclinical vascular disease and dysfunction, tracking individuals' behavior and cardiovascular physiology in daily life to test a novel neuro-diathesis model of CVD risk. Project 2 also tests for the first time whether daily life physical activity associates with daily life stress physiology through its effects neural circuits for visceral control. Project 3 aims extend those of the other Projects by elucidating the neural and peripheral processes linking physical activity with physiological and psychophysiological markers of CVD risk (including daily life affect and stress physiology) using an experimental intervention methodology. These P01 aims are unique in cardiovascular behavioral medicine, and they will be pursued in the context of multi-component data collection efforts that satisfy all project-specific aims. As a result, the P01 will create new opportunities for integrative and translational science on the human neurobiology of CVD risk that cuts across multiple methods and levels of analysis. Helping to advance its parent field, the P01 will generate and disseminate original and expansive public-domain resources and tools to the broader scientific and clinical communities through comprehensive data and software sharing and educational objectives. Enabling a precise focus on early CVD etiology, the study cohorts comprise nearly 900 midlife adults without clinically apparent CVD, and study methods will include novel combinations of neuroimaging, ecological momentary assessments of experienced environments, ambulatory hemodynamic monitoring, autonomic, neuroendocrine, immune, and vascular assessments, laboratory clinical evaluations, hetero-method health behavior assessments, and arterial imaging. The 3 Core Units of this P01 provide for synergy and inter-project coordination by administrative, data management and participant accrual services; measurement and instrumentation support; and direction in cutting-edge bio-statistical and data-intensive (machine learning) analyses. The present application thus represents a thematic continuation and next- generation extension of translational neurobiological research on CVD by this P01, which was initiated in 1988.

This is a resubmission application for the Cardiovascular Behavioral Medicine Research Training grant (HL07560), continuously funded since 1983. The purposes of our program are to provide advanced training in cardiovascular behavioral medicine research methods and knowledge to postdoctoral and predoctoral fellows. Specifically, our training program for the postdoctoral and predoctoral trainees is designed to foster proficiency in four distinct areas: ? Principles of behavior and behavior change, through which the theoretical underpinnings of behavioral risk factors are understood and interventions designed. ? Research methods and statistics, whereby the skills necessary for designing and conducting research and for drawing valid inferences from empirical data are developed, with exposure to analytic approaches to complex longitudinal data. ? Cardiovascular physiology and psychophysiology, through which an understanding is established of the cardiovascular and metabolic functioning in the healthy human. ? Cardiovascular diseases, including disparities among populations and principles of pathophysiology as related to disorders of the heart and vasculature and state of the art approaches to assessing biomarkers of risk and imaging subclinical and clinical cardiovascular diseases. Based on these foundations, our program facilitates the development of independent clinical research scientists who take a multidisciplinary approach within the following three primary areas of concentration: mechanistic pathways, determinants and consequences of health behaviors; and behavioral interventions to reduce cardiovascular risk. These areas and program goals align themselves closely with the NHLBI special programmatic emphases for training and the NHLBI Strategic vision for research in the next 5 to 10 years, and fill an important niche in the NHLBI T32 portfolio. Our training program benefits from the participation of enthusiastic and committed faculty who mentor our trainees from the Departments of Psychiatry, Psychology, Medicine, Health and Physical Activity, and Epidemiology and newly appointed training faculty who are physician scientists. The diverse faculty provide collaborative and innovative research training in the above three primary areas. Our program also benefits from the availability of appropriate course offerings; the history of multidisciplinary research and training efforts by the above departments; and training resources at the University of Pittsburgh?s School of Medicine, including the Clinical and Translational Science Research Institute, and Dietrich School of Arts and Sciences. Support is requested to continue the program at the level of 4 postdoctoral and 4 predoctoral trainees.