Suzanne Mitchell, Ph.D. - US grants

9350027 Crowe The Arkansas Systemic Initiative Project has at its core a vision that seeks to eliminate barriers to student success in mathematics and science, raise achievement levels of all students in grades K-16 and improve public understanding that quality mathematics and science are crucial for economic development and personal fulfillment. Arkansas intends to restructure mathematics and science education by changing attitudes toward mathematics and science, improving student knowledge and skills and fostering long-term community involvement in the education system. This transformation will occur through the work of regional partnerships, each of which is a coalition of schools, colleges, businesses, parents, and other community leaders. To ensure that needed changes occur, the initiative will develop mathematics and science frameworks, implement large-scale teacher development through the Arkansas Math and Science Crusades, equip every classroom with appropriate materials and technology, bring scientists and mathematicians into classrooms, and place teachers in real-world research settings. Community education and leadership development will involve parents and local leaders in important education system roles. Changes in teacher preparation and certification will ensure that all students have access to quality instruction. The Applied Academics curriculum will restructure vocational education, and appropriate forms of technology will be employed throughout the Initiative. In addition, the State will be developing a new assessment system that will include performance assessment and student portfolios. This new assessment system will be used to monitor the success of the initiative.***

9452721 Ohme The project will conduct a regional self-study to determine optimum strategies to accomplish systemic educational reform and economic development in a region characterized by high poverty and lack of resources. The supervisory Steering Committee will establish Task Forces which will conduct a series of town meetings to facilitate local and regional partnerships, collect and analyze baseline data, and provide recommendations to the Steering Committee, for the development of an integrated plan for sustainable education reform throughout the region. The Steering Committee will hold a series of four area conferences, to inform and include local representatives in the planning and development process.

9454190 Ohme Northeast Louisiana University will host a regional conference focusing on regional strengths, needs and barriers to systemic educational reform of science and mathematics in the Lower Mississippi River Delta region. The dual purpose on the conference is to elicit grassroots involvement in a regional systemic reform effort while creating and expanding an understanding of systemic reform at the local level. ***

DESCRIPTION (provided by applicant): One approach to reducing drug use and abuse is to identify factors that differentiate current users from nonusers (never-users and ex-users) and then to determine whether the factors in question are causally associated with the drug use. If they are causally related, this information may be used to identify at-risk populations, to develop targeted treatments or interventions and to understand how drug exposure impacts brain function. Impulsivity may be one of those factors. A growing body of literature indicates that drug users are more impulsive than nonusers, where impulsivity has been defined variously as a reduced ability to delay gratification or to inhibit behavior, heightened risk- and sensation-seeking, acting without weighing the consequences appropriately, etc. However, the direction of causality between impulsivity and drug use is unclear, and the mechanisms underlying this relationship are unknown. High levels of impulsivity might cause people to experiment with cigarettes, and then continue to use. Alternatively, the actions of nicotine might acutely or chronically increase impulsive decision-making. Indeed it is possible that both processes may be involved - heightened impulsivity precipitating smoking initiation, then doses of nicotine increasing impulsive decision-making, which in turn decreases the likelihood of successful quitting. The current proposal outlines 5 experiments that will address the relationship between impulsivity and several different aspects of drug use using cigarette smoking (nicotine) as the model of drug use under investigation. The first 3 studies examine the relationship between baseline measures of impulsivity and smoking cessation treatment outcomes (Study 1), the subjective aversiveness of short-term withdrawal and relief from withdrawal (Study 2), and the intensity of cigarette smoking (Study 3). These studies will result in a better understanding of how general behavioral traits (a.k.a. personality) can impact how drugs are used and how those traits influence their continued use. The final 2 studies examine how state measures of impulsivity, assessed using laboratory tasks to assess impulsive decision-making, are affected by abstinence from nicotine (Study 4) and increases in systemic nicotine in smokers and nonsmokers (Study 5). It is hoped that these studies will result in a better understanding of the factors impacting drug use and how drug use can impact decision-making.

DESCRIPTION (provided by applicant): Studies of delay discounting in humans have revealed that drug users have an exaggerated preference for small, immediate over large, delayed rewards, even when the immediate reward is substantially smaller than the delayed reward. These studies have been interpreted to mean that drug users are more impulsive than nonusers and, possibly, that drug use has altered the processes by which individuals evaluate the benefits and costs associated with rewards. These processes are believed to determine the efficacy of drug and nondrug reinforcers to control behavior. However there are costs other than delay which can cause the value of a reinforcer to be discounted. Two such costs are uncertainty and effort. Five studies are proposed to evaluate the impact of all three costs on reinforcer efficacy (delay to the receipt of a reward, uncertainty about the receipt of the reward, and the effort required to obtain the reward) using a discounting procedure that was developed by the Principal Investigator and her colleague for use with rats. The basic hypotheses are that 1) the rats that discount delayed rewards more will also discount uncertain and effortful rewards more and 2) that discounting for the three different types of cost will be similarly effected by a series of behavioral and pharmacological manipulations. Experiment 1 determines whether rats discount large, expensive rewards to similar degrees regardless of the cost type by assessing the correlation between delay discounting, uncertainty discounting and effort discounting in the same animals, and examines the impact of chronic injections of nicotine on discounting. Experiment 2 examines how the magnitude of reward affects delay, uncertainty and effort discounting. Experiment 3 determines whether preference switches from the small, cheaper reward to the large, expensive reward when a fixed cost is added to both alternatives. Experiment 4 examines whether exposure to high-reinforcer-cost conditions leads to decreases in delay, uncertainty and effort discounting. Experiment 5 investigates the role of dopamine in modulating delay, uncertainty and effort discounting. These studies will provide information about the variables taken into account when the brain evaluates reinforcer efficacy and procedures that can be used to alter reinforcer efficacy, both of which will have implications for drug abuse treatment. Further, the data collected in these studies will provide a basis for future studies, which will examine whether differences in how individuals evaluate the value of reinforcers are causally related to the initiation, progression and cessation of drug use and abuse.

DESCRIPTION (provided by applicant): The overall aim of the proposed research is to identify the neural substrates of impulsive decision making associated with chronic exposure to drugs of abuse. Such information is potentially important for understanding the development and cessation of habitual drug use. Furthermore, it may provide important insights into the interaction of motivational systems and neurocognitive mechanisms of executive control, which are central to a number of disorders such as drug abuse, ADHD and pathological gambling. In this application, impulsive decision making will be assessed using a temporal discounting paradigm in which we measure preference for small rewards available either immediately or soon versus larger rewards available much later. Accordingly, the specific aim of the research proposed here is to identify differences in brain activation patterns in smokers and nonsmokers corresponding to the behavioral differences on a temporal discounting task using functional magnetic resonance imaging (fMRI) techniques. The study will use an event-related design to compare activation patterns during choice tasks designed to separate processing associate with temporal discounting from processing of reward dimensions like size and relative reward immediacy. We hypothesize that, during temporal discounting, when one reward alternative is available immediately and the other delayed, smokers will exhibit higher levels of activation in ventral striatum (esp. nucleus accumbens), medial OFC, medial prefrontal cortex, posterior cingulate cortex than nonsmokers making these choices (" areas": McClure et al., 2004;2007). In contrast, nonsmokers will exhibit higher levels of activation in ventrolateral and dorsolateral prefrontal cortex, right lateral OFC and posterior parietal cortex (" areas") than smokers. During temporal discounting when both reward alternatives are delayed, we predict that nonsmokers will also exhibit higher levels of activation in the areas compared to smokers. The PI is already engaged in funded research examining the behavioral mechanisms linking temporal discounting and cigarette smoking. The proposed research would permit her to take the first step towards exploring the neural regions and inter-relationships between these regions using fMRI techniques. Potential health impact: This research will identify areas of the brain that are involved when individuals evaluate the subjective value of alternatives differing in their reward size and the delay until their availability. It will also identify areas that are involved when individuals express a preference between the alternatives, and any differences between smokers and nonsmokers in activation patterns underlying these preferences. Understanding which structures are involved in such decision making and their connectivity, may suggest individualized treatment targets for people exhibiting impulsive decision-making due to chronic drug use, accident or stroke.

DESCRIPTION (provided by applicant): Limited data suggest that physical exercise can reduce impulsivity and can also reduce drug use. However, the mechanism by which these effects may occur is unknown. The overall aim of the proposed research is to understand the effects of exercise on impulsivity and drug use, and to determine whether there is a common mechanism underlying these effects. Three experiments are proposed in rats that use parallel structures to increase the ability of data from each to inform interpretation of the others. Experiment 1 (Aim 1) will determine whether repeated treadmill exercise (3 levels: no exercise, 20 min, 60 min) is associated with decreases in impulsivity (delay discounting). Experiment 2 (Aim 2) will determine whether repeated physical exercise is associated with lower rates of acquisition of cocaine self-administration, and a reduction in sensitivity to the reinforcing efficacy of cocaine determined by examining response rates over a range of cocaine doses. Experiment 3 (Aim 3) will examine the dopaminergic activity in the nucleus accumbens and prefrontal cortex following repeated physical exercise and response to a cocaine challenge, as dopamine and these structures have established roles in impulsivity and in drug self-administration. This research will shed light on the neurobiological and behavioral mechanisms by which exercise might influence drug use, and will provide data that can stimulate clinical studies examining exercise both as a treatment and as a potential prophylactic during adolescence and young adulthood. PUBLIC HEALTH RELEVANCE: The studies will determine whether engaging in regular physical exercise decreases impulsive decision-making, which is a known risk factor for initiating a number of dangerous, unhealthy behaviors, and decreases the likelihood of using cocaine. Studies will also try to identify a mechanism underlying these effects, which could be developed later to supplement and increase the effectiveness of exercise on these behaviors.

The long term objective of this component is to understand genetic interrelationships among ethanol withdrawal severity and both basal levels and post-withdrawal escalations in ethanol consumption and impulsivity (behavioral inhibition/disinhibition). Data from a panel of eight inbred strains indicate that indices of behavioral inhibition (anticipatory responding and responding during a No-go cue) are influenced by genotype and that this genetic influence is correlated with genetic contributions to both acute and chronic ethanol withdrawal severity, assessed using the handling-induced convulsion (HIC). Other data indicate a negative genetic relationship between chronic ethanol withdrawal and alcohol intake. The proposed studies will assess these genetic interrelationships by performing in three studies. Study 1 examines whether levels of inhibition in ethanol-naive animals and ethanol withdrawal severity are influenced by some of the same genes by assessing basal inhibition on a Go/No-go task in mice selectively bred for severe (inbred Withdrawal Seizure-Prone; iWSP) versus mild (inbred Withdrawal Seizure-Resistant; iWSR) withdrawal HIC severity after chronic exposure to ethanol vapor. Study 2 examines levels of inhibition following chronic ethanol exposure (72 hrs of continuous ethanol inhalation) to establish when maximal disinhibition is seen and for how long it persists. Like Study 1, Study 2 will address the question of whether some of the same genes that affect withdrawal HIC severity differentially in iWSP and iWSR mice are the same as those affecting inhibition and withdrawal-induced inhibition in these selected lines. Study 3 will examine whether ethanol drinking in alcohol-nondependent animals and ethanol withdrawal severity are influenced by some of the same genes using the iWSP and iWSP mice. The study will also assess genotypic differences in the effects of withdrawal on ethanol drinking following four cycles of chronic intermittent ethanol exposure (each cycle = 16 hours ethanol: 8 hours air for 4 days). Taken together these three studies will permit the development of a broader-based description of ethanol withdrawal that encompasses changes in impulsivity/inhibition and ethanol drinking, as well as provide critical information for future genetic mapping studies to identify the precise genes involved in these processes.

PROJECT SUMMARY Many substance use disorders (SUDs), are characterized by a heightened preference for immediate over larger, delayed rewards (?delay discounting?). Research has successfully related this type of decision-making bias with etiological factors, and with the progression and possibly cessation of SUDs, and has begun to identify its neural and genetic correlates. Despite this success, there has been relatively little research on biases in individual decision-making using reward costs other than delay. One potentially important cost is cognitive effort (CE), which can be defined as the amount to which executive functions must be engaged to earn rewards. Thus, the overall aim of this application is to develop a methodology that can be used to assess cognitive effort (CE) discounting in the lab, a necessary first step towards assessing whether training to enhance willingness to exert CE could assist individuals to adhere to cessation treatment protocols, despite the discomfort associated with behavior change and overcoming withdrawal. Specifically, this project will assess the construct validity of an attentional CE discounting task in cigarette smokers by correlating performance with a second CE discounting task in which CE is memory load. Construct validity will also be assessed by correlating behavior on the CE discounting tasks with responses on self-report questionnaires assessing constructs associated with willingness to work, apathy and procrastination. Predictive validity will be assessed by correlating task performance with behavior in a reinforced abstinence protocol. We hypothesize that individuals who are more affected by the CE requirements will abstain for a shorter period. This relationship will be enhanced for individuals for whom self-control has been reduced using an ego- depletion technique. Finally reliability will be assessed by comparing measures made at the beginning of the session with ones made at the end of the 3-h session, and ones made 7 days later. Having reliable and validated tools is a prerequisite for evaluating putative behavioral and pharmacological manipulations to increase willingness to engage in effortful behavior change. Evaluating the efficacy of such manipulations is important to facilitate treatment for substance use disorder and other psychopathologies, because the lack of willingness to perform cognitive effort has, at least anecdotally, been linked to a resistance to initiate treatment and failure to remain in treatment protocols.

PROJECT SUMMARY This application is responsive to PAR-15-120 (Identification of Genetic and Genomic Variants by Next-Gen Sequencing in Non-Human Animal Models). Substance use disorders are often characterized by heightened preference for small, immediate over larger, delayed rewards (?delay discounting?). Research has successfully related this type of impulsive decision- making bias with etiological factors predictive of drug use, with the progression to regular use, and with the likelihood of succeeding in cessation efforts. Research has also begun to identify the neural and genetic correlates of delay discounting. However, research identifying the specific genes associated with this phenotype remains ambiguous. Accordingly, the primary objective of the proposed work is to increase our understanding of the genetic basis of delay discounting, thereby providing a better understanding of impulsivity. Four aims are proposed to accomplish this objective. Aim 1 will phenotype 600 heterogeneous stock (HS) rats for delay discounting using the adjusting amount procedure (Richards et al. 1997; Wilhelm and Mitchell 2009) so that Genotyping-By-Sequencing (GBS) can detect behavioral quantitative trait loci (bQTLs). Aim 2 will use bi-directional short-term selective breeding on a subset of these HS rats to form high (HD) and low (LD) delay discounting selected lines based on relative preference for the small, immediate reward over the larger later reward. Rats from the 4th generation of selection will be used to identify changes in allele frequency due to selection by genotyping the LD and HD selected lines using GBS and gene dropping. Aim 3 will sequence the brain transcriptome in 200 phenotyped HS rats to characterize the gene expression signatures for delay discounting in three brain regions of interest: nucleus accumbens core, the prelimbic cortex and the basolateral amygdala. The sufficiency of these signatures to predict selection targets will be evaluated by analyzing the transcriptomes (RNA-Seq) from HD and LD selected lines at the 4th generation of selection collected under Aim 2. Aim 4 will examine HD and LD rats' performance on other measures of impulsivity, including performance on a within sessions measure of delay discounting, the stop signal task and the 5-choice serial reaction time task. This will permit us to examine genetic correlates of delay discounting, and lay a foundation for research examining the shared genetic bases of these other behavioral phenotypes of impulsivity. Identifying the genotype and functional genetics for expression of high or low levels of delay discounting will facilitate identification of individuals at risk for developing substance use disorders and other psychopathologies. It will provide information about the transcriptomics of impulsive choice, and encourage future explorations of the neurogenetics of this type of decision-making bias.

PROJECT SUMMARY Unchanged from the original funded award by the proposed supplement. ADHD is defined by behavioral symptoms that are not well defined in relation to underlying neurobiology or mechanisms. Using mechanisms to define its nosology and predict outcomes is expected to be more powerful than the current approach, but this hope has only partially been realized. Surprisingly, the parameters influencing willingness to maintain cognitively effortful activities have not been examined systematically. That is, existing data indicate ADHD is associated with differences in reward valuation and processing, which are influenced by delays to reward delivery. However, it is unknown whether ADHD is associated with higher levels of aversion to exerting cognitive [mental] effort, and altered reward x effort interactions. Accordingly, this application aims to address this knowledge gap by examining individuals' preferences between rewards associated with minimal effort and alternatives with higher payoff but higher effort costs (?effort discounting?). Thus, the overall goal of this proposal is to characterize the differences in biases and tradeoffs during effort- related decision-making in ADHD, using an effort discounting methodology, and to identify factors associated with these differences. To accomplish our overall goal, the proposed research will take advantage of a well- defined sample of ADHD-diagnosed and healthy control individuals initially recruited in 2007 (the ?parent study?) to address three aims: (1) To examine the subjective perception of effort in youth diagnosed with ADHD and healthy controls using tasks in which they are required to exert varying levels of cognitive effort (sustaining attention, engaging working memory processes), (2) To determine whether ADHD is associated with steeper discounting of larger, more effortful rewards than matched controls in tasks where effort requirements have been matched in subjective effort ratings, and (3) To explore relationships amongst indices of effort discounting, and theoretically-related traits (e.g., grit, distress tolerance), biomarkers of effort-related decision- making (eye movements and pupil size), and cognitive measures assessed in the parent study. Successful completion of the aims would permit us to better characterize ADHD-healthy control differences, and lay a foundation for more computational approaches to ADHD diagnostic criteria.

Project Summary/Abstract: The HOPE APP: An Immersive Telehealth Solution Adapted for Older Adults Type 2 diabetes (T2DM) is an epidemic related to obesity, chronic stress, unhealthy eating and inactivity. An estimated 29 million people in the US have T2DM and 84 million have pre-diabetes - nearly half of whom are adults over 65yo, putting many older adults at higher risk of unhealthy aging and cognitive decline. A healthy lifestyle can treat and even reverse T2DM. But making lifestyle changes is hard and many people fail, contributing to $325 billion in US healthcare costs. Diabetes group visits (DGV) and diabetes self- management education and support (DSME/S) help people with T2DM learn and sustain healthy lifestyle behaviors and master complex disease management skills. Access to DSME/S is limited such that participation in DSME/S programs is as low as 7% of all adults with T2DM. New technologies supporting DSME/S programs are emerging, but most fail to meet the unique needs of older adults with limited technology fluency, creating a new digital divide. The See Yourself Health (SYH) team aims to bridge this digital health gap for older adults with a newly designed immersive learning program ? the HOPE APP ? designed to deliver diabetes care, DGV, and DSME/S on demand, tailored for older adults with diabetes and accessible on mobile devices commonly used by this age group. Fortunately, new cloud gaming technology and advances in user interface design will enable our team to design a new immersive learning environment tailored for mobile devices to offer DSME/S to meet the needs and capabilities of older adults. HOPE App consists of 28 actionable DSME/S modules and maintenance programming designed for a virtual world using social gaming strategies that emphasize peer support, brain health, and mastery of diabetes self-management skills to allow users to connect with others and simulate new lifestyle behaviors. Phase I Project: We aim to assess the feasibility, acceptability and usability of the newly designed See Yourself Health immersive learning DSME/S solution ? the HOPE APP - tailored for older adults with diabetes featuring an adapted human interface for use with mobile device by users with low technology fluency. Specific Aim 1: We will design and build the HOPE APP with educational content, simulation experiences, and a user interface tailored for use by older adults with T2DM. Specific Aim 2: To assess the usability of the HOPE APP using the Rapid Iterative Testing and Evaluation (RITE) method with a total of 20 participants from the target population of adults 65+ with diabetes. Specific Aim 3: To test the feasibility of using the HOPE APP by SYH by older adults on mobile devices. Plan for Phase II: Once we demonstrate the feasibility of delivering the See Yourself Health DSME/S program using a cloud gaming solution, we aim to assess the effects of the platform on cognitive function, physical health, and mental health outcomes in a fully powered clinical trial.