Cary R. Savage - US grants

[unreadable] DESCRIPTION (provided by applicant): This is the second revised application for an R21 entitled: Predicting Response to Memory Training in TBI with fMRI. Traumatic brain injury (TBI) is a leading cause of disability in young otherwise healthy adults. The consequences of TBI are highly variable, with some individuals showing good recovery and others suffering chronic disability with profound cognitive and social impacts. Long-term outcome from TBI is difficult to predict using standard measures of injury severity, cognitive impairment, and conventional neuroimaging. Cognitive activation studies using fMRI may offer improved methods for outcome prediction in TBI. fMRI paradigms enable quantification of neural network function during cognitive challenges, providing in vivo measures of functional integrity. We predict that these data will be useful in quantifying the degree of functional neural impairment, understanding neural mechanisms underlying cognitive impairment in individuals with TBI, and ultimately predicting long-term outcome. This project aims to identify mechanisms of recovery from TBI by examining brain systems supporting the use of semantic strategies during non-cued and cued verbal learning using functional magnetic resonance imaging (fMRI). The study addresses two Specific Aims: 1. Assess the ability of TBI patients and matched healthy control (HC) participants to utilize semantic strategies under both non-cued and cued conditions and define how patterns of brain activation change to support this process. 2. Examine specific patterns of brain activation with fMRI in predefined regions of interest (ROI) in TBI and HC groups and determine how individual differences in brain activation relate to cognitive functioning and behavior in natural settings. This work is innovative and at an early stage of development, and thus appropriate for the R21 mechanism. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by investigator): This is a revised application for an R01 grant entitled: Brain function predictors and outcome of weight loss and weight loss maintenance. Obesity rates are on the rise and associated with serious public health consequences and rising health care costs. Eating behavior is influenced by a convergence of processes in the brain, including homeostatic factors and motivational and reward processing. Motivational and reward processing are especially important contributors to overeating in humans. Our initial functional imaging studies have identified brain regions that respond differently to visual food cues in obese and healthy weight individuals, and are positively correlated with reports of hunger in obese participants. While shedding some light on mechanisms of overeating, many important questions remain. For instance, it is not yet known whether brain activation patterns change after dieting, or if they change differentially in successful and unsuccessful dieters. In addition, little is currently understood regarding biological processes that contribute to long-term maintenance of healthy weight. We will scan obese and healthy weight participants with a food motivation fMRI paradigm during a baseline state and after obese participants have completed a twelve- week diet-based weight loss intervention. Obese participants will then be followed though a 6-month weight maintenance period. The study will address three Specific Aims: 1. Characterize brain activation underlying increased food motivation and impulsive eating in obese individuals. 2. Identify brain activation changes and predictors of initial weight loss. 3. Identify brain activation predictors of weight loss maintenance. Findings from this study will have significant implications for understanding mechanisms of obesity, weight loss, and weight maintenance, and may ultimately lead to more effective interventions. PUBLIC HEALTH RELEVANACE: Results of this work are highly significant to public health and could lead to a better understanding of how differences in brain activation relate to obesity. Dietary interventions, while generally effective, do not work for everyone, and weight regain is a significant problem. Findings from this study will have significant implications for understanding mechanisms of obesity, weight loss, and weight maintenance, and may ultimately lead to more effective interventions.

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DESCRIPTION (provided by applicant): African American (AA) women have the highest rates of obesity in the U.S. Despite this, AA women are underrepresented in weight loss trials, and when they are represented, they lose less weight than Caucasian participants. Eating behavior is influenced by a convergence of processes in the brain, including homeostatic factors and motivational and reward processing. Initial functional magnetic resonance imaging (fMRI) studies from our group have identified brain regions, implicated in motivation and reward processing that respond differently to visual food cues in obese and healthy weight individuals, and are positively correlated with reports of hunger in obese participants. In addition, hormones and metabolic factors are important contributors to weight gain and loss. Though shedding some light on neural and hormonal contributions to overeating, we do not know whether results from our previous work in mixed racial groups (predominantly Caucasian) generalize to under-represented minority populations. Given the high treatment failure rates among obese AA women, efforts are needed to further characterize treatment responders and non-responders in this population. We will scan obese and healthy weight female AA participants with a food motivation fMRI paradigm during a baseline state and after obese participants have completed a diet-based weight loss intervention. Obese participants will then be followed though a 6-month weight maintenance period. We will also acquire measures of metabolism and hormones (adiponectin, ghrelin, and leptin). The study will address three Specific Aims: 1. Examine brain activation, metabolic and hormonal baseline differences between obese and healthy weight AA women. 2. Identify brain activation, metabolic, and hormonal changes in initially obese AA women following successful weight loss or unsuccessful weight loss. 3. Identify brain activation, metabolic, and hormonal predictors of weight loss and weight loss maintenance in obese AA women. Findings from this study will have significant implications for understanding mechanisms of obesity, weight loss, and weight loss maintenance in AA women and may ultimately lead to more effective interventions. PUBLIC HEALTH RELEVANCE: Results from this work are highly significant to public health and could lead to a better understanding of how differences in brain activation, metabolism, and hormones relate to obesity in AA women. Dietary interventions, while generally effective, do not work for everyone, and weight regain is a significant problem. Treatment failure is especially a problem in AA women. Findings from this study may ultimately lead to more effective and targeted interventions for inducing weight loss in AA women.

DESCRIPTION (provided by applicant): This is a new application for an R01 grant, in response to RFA-DK-08-009, entitled: Neuroimaging studies of reward, impulsivity, and adherence to an exercise program. Obesity is the result of chronic imbalances between energy intake and expenditure. Regular exercise is a critical component of maintaining energy balance and it is associated with health benefits, including enhanced brain function. Health-related decisions are influenced by a convergence of processes in the brain, as individuals weigh the perceived balance between the rewarding and punishing aspects of the behavior, and whether gratification is immediate or delayed. Healthy behaviors, such as regular exercise, are in part difficult to maintain because they are less immediately gratifying. In fact, exercise may initially be perceived as aversive. Despite this challenge, some people are able to persevere and experience long-term benefits. We hypothesize that brain processes underlying reward processing and impulse control will help us better understand mechanisms of obesity and health-related decision making. We will scan sedentary obese and sedentary healthy weight (HW) participants with reward prediction and delay discounting fMRI paradigms before and after a nine-month exercise intervention. The study will address three Specific Aims: 1. Characterize brain activation underlying reward processing and impulse control in obese and healthy eight individuals. 2. Identify brain activation predictors, from the Baseline Session, of adherence and success in the exercise program. 3. Identify the beneficial effects of exercise and increased fitness on brain activation. We predict that measures of brain activation will be useful in identifying neural contributions to obesity, determinants of adherence to a long-term exercise program, and the beneficial effects of exercise on brain function. PUBLIC HEALTH RELEVANCE: Results of this work are highly significant to public health and could lead to a better understanding of how differences in brain activation relate to obesity and exercise adherence. Exercise interventions have numerous health benefits, but adherence is generally low. Findings from this study will have significant implications for understanding mechanisms of obesity, exercise adherence, and the beneficial effects of exercise on brain function in obese and healthy weight populations. Findings may eventually lead to more effective interventions.

Project Summary Obesity is among the most prevalent and costly conditions in the United States. To face this pivotal public health challenge, there is a need for ground-breaking research aimed at explicating modifiable factors associated with the development of obesity to inform interventions. Studies aimed at elucidating neural vulnerability factors for obesity ? including high food reward sensitivity and poor food regulation ? hold particular promise. However, relatively little is known about the modifiable factors that contribute to these neural vulnerabilities, thus precluding the development of potentially powerful interventions to promote healthy long-term weight trajectories. Further, the limited research in this area lacks critical developmental and environmental context. The current proposal addresses these gaps by examining the roles of selected modifiable cognitive (executive control), behavioral (diet, sleep), affective (negative affect), and environmental (obesogenic environment) factors throughout childhood and adolescence in predicting emerging neural vulnerabilities for obesity during the pivotal transition to young adulthood. The study leverages rich data from a unique existing longitudinal study spanning preschool through adolescence, and adds new data collection using functional neuroimaging paradigms to assess neural vulnerability factors for obesity in young adulthood. The long-term goal is to inform novel interventions targeting key modifiable factors during childhood and adolescence to reduce long-term obesity risk. The objective of the proposed research, therefore, is to elucidate the impact of theoretically-relevant cognitive, behavioral, affective, and environmental factors on emerging neural vulnerability factors in the context of a longitudinal study spanning preschool to young adulthood. The central hypothesis is that emerging neural vulnerabilities for obesity are significantly influenced by a multidimensional set of modifiable factors in childhood and adolescence. The specific aims are to: 1) Determine the impact of executive control development across childhood and adolescence on food reward sensitivity and regulation in young adulthood; 2) Determine the impact of a set of behavioral and affective factors in adolescence (i.e., diet, sleep, negative affect) on food reward sensitivity and regulation in young adulthood; and 3) Explore the impact of the obesogenic environment encountered in adolescence on food reward sensitivity and regulation in young adulthood. The project is innovative in its unique leveraging of rigorous existing longitudinal data; cutting-edge neuroimaging paradigms; and novel attention to the interplay between brain, environment, behavior, and health. The significance of this research is that it will yield unprecedented insight into modifiable factors that contribute to neural vulnerabilities for obesity, all within rich developmental and environmental context. These insights will inform novel obesity interventions targeting critical individual and environmental factors at key points in development to reduce long-term obesity risk.