Stephen J. Wilson - US grants

DESCRIPTION (provided by applicant): Drug addiction is characterized by a blunted response to non-drug incentives and rewards. This attenuation appears to be especially pronounced when addicted individuals anticipate that drug use soon will be possible. Non-human animal studies indicate that there are large individual differences in the extent to which non-drug rewards are devalued when drug delivery is expected. Moreover, animal research suggests that several clinically-relevant aspects of addictive behavior are predicted by individual differences in the expectancy- related devaluation of non-drug rewards. To date, individual differences in the effects of drug use expectancy on the processing of non-drug rewards, and the functional correlates of such individual differences, have not been investigated in human drug users. The goal of this proposal is to address this knowledge gap by examining the nature and implications of individual differences in the effects of drug use expectancy on neural responses to non-drug rewards in human smokers (n=60). The specific aims of the proposed research are: 1) To examine the effects of a novel within-subjects smoking expectancy manipulation on neural responses to non-drug (i.e., monetary) rewards in human smokers;and 2) To examine how individual differences in the effects of smoking expectancy on neural responses to non-drug rewards relate to the ability to resist smoking in order to obtain an incentive. We hypothesize that individuals will vary significantly in the degree to which non-drug rewards are devalued when drug use is anticipated. As the ability of non-drug incentives to serve as an effective reinforcer for abstinence behavior likely depends substantially upon the extent to which they maintain their value in the face of an opportunity to use drugs, we also hypothesize that individual differences in the expectancy-induced devaluation of non-drug rewards will be predictive of the capacity to refrain from smoking in order to obtain money. This proposal serves as an initial step towards a long-term research plan aimed at investigating the reward-processing biases that play an important role in maintaining addictive behavior. Specifically, if our predictions are supported, future studies will extend the proposed research by seeking to identify variables that modulate the expectancy-related devaluation of non-drug rewards (e.g., the magnitude and delay of the non-drug reward), elucidating approaches for minimizing reward devaluation within individuals (e.g., individually tailored incentives), and examining changes in expectancy-related devaluation associated with the implementation of such approaches. PUBLIC HEALTH RELEVANCE: Cigarette smoking remains one of the leading preventable causes of death and disease in the world. Accordingly, developing a better understanding of the motivational factors that underlie the maintenance of nicotine addiction and, ultimately, how to more effectively treat the disorder will have substantial public health benefits. Moreover, results from this project will be applicable to several other disorders characterized by aberrant motivational processing (e.g., other substance use disorders, eating disorders).

DESCRIPTION (provided by applicant): Cigarette smoking is the leading preventable cause of cancer in the United States. Helping smokers quit thus is one of the most effective means for reducing cancer burden in this country. Because most smokers find it incredibly difficult to stop smoking, enhancing the motivation to remain abstinent from cigarettes is widely seen as an essential step for improving their chances of success. Attempting to motivate quitting smokers to remain abstinent using nondrug rewards (e.g., money) is a particularly common intervention strategy. Although the use of nondrug rewards to aide quitting smokers is grounded in sound behavioral principles, mounting evidence indicates that nondrug rewards may be the least effective at reinforcing abstinence precisely when they are needed most (i.e., when smokers are tempted by an opportunity to smoke). Namely, simply anticipating having access to cigarettes in the near future appears to dampen the response to nondrug rewards in brain regions supporting reward valuation and motivational processing. This blunting is associated with a corresponding decrease in the willingness to resist smoking for a nondrug incentive, thus directly undermining the effectiveness of reward-based approaches to promoting cigarette abstinence. The proposed research addresses RFA-CA-13-017 (PQA1): Research Answers to NCI's Provocative Questions-Group A (PQA1) by testing the novel hypothesis that increasing brain responses to nondrug rewards may be an effective way to enhance the influence that such stimuli have on behavior in smokers. We propose to examine this idea using a technique called real-time functional magnetic resonance imaging (fMRI) neurofeedback. Real-time fMRI neurofeedback is a type of biofeedback that involves training individuals to control brain responses by presenting them with information about ongoing brain activity. Daily smokers (n=90) will be randomly assigned to three groups (intervention, sham neurofeedback control, and no feedback control; n=30 each). Those in the intervention group will receive valid real-time fMRI neurofeedback aimed at training them to volitionally increase activity in brain reward regions. The control groups will undergo nearly identical procedures but receive sham [placebo] neurofeedback and no neurofeedback, respectively. We hypothesize that only smokers provided with valid neurofeedback will learn to reliably and voluntarily increase activation in reward-related brain regions using cognitive strategies (Aim 1). We predict that this learning will be durable, such tha smokers will be able to continue using cognitive strategies to increase reward-related brain activity after neurofeedback is removed (Aim 2). We also predict that this learning will be functional, such that clinically-relevant decision making (the willingness to choose a nondrug reward over smoking) is influenced when smokers use the same strategies outside of the scanner (Aim 3). If successful, the proposed study will open new avenues for using neurofeedback to expedite scientific discovery and facilitate the development of effective smoking interventions that can be used by smokers on a broad scale.

DESCRIPTION (provided by applicant): According to the CDC, cigarette smoking is associated with profound morbidity and mortality. In the United States alone, cigarette smoking is responsible for about 443,000 deaths per year and it costs the nation nearly $200 billion annually. About 20% of all adults smoke in the United States and by 12th grade, 42% of students report having smoked. Unfortunately, cigarette smoking is a disease of chronic relapse. Indeed, smokers will make as many as 20 quit attempts before they are successful and abstinence rates can be as low as 7%, even following nicotine replacement therapy (NRT) with the patch, gum, or nasal spray. As with other addictions, cue-induced craving contributes to relapse following a quit attempt. Along with cue-induced craving and relapse, addicts also suffer from drug-induced devaluation of natural rewards as evidenced by less responding for a sweet in rats and a weaker striatal response to monetary rewards in humans waiting to smoke. Indeed, those subjects (rats and humans) found least responsive to the natural reward are, in turn, most responsive to drug. Here we propose a novel alternative to the steady-state delivery of nicotine (i.e., to the standard patch), for the treatment of cigarette addiction. Specifically, we propose t use an oral film to treat smokers wishing to quit with random, rather than steady-state, delivery of nicotine prior to and following the quit date. On the basis of promising preclinical and clinica data, we hypothesize that, relative to steady state delivery, random nicotine delivery will be safe well-tolerated, and will facilitate smoking cessation, dissociation of nicotine-paired cues from drug, and a reduction in drug-induced devaluation of natural rewards. Specific Aim 1 will test the pharmacokinetics and safety of a range of doses of the nicotine film in human smokers. Specific Aim 2 will test whether smoking cessation is facilitated when human smokers are treated with random vs. steady-state delivery of nicotine before and after the quit date. Finally, Specific Aim 3 will use fMRI and published procedures to test whether random nicotine delivery also will reduce the neural (striatal) response to nicotine-paired cues and augment the neural response to an alternative monetary reward. If our random delivery hypothesis is confirmed, this novel approach will revolutionize treatment of substance abuse and addiction.

DESCRIPTION (provided by applicant): Cigarette smoking is one of the leading causes of preventable death in the United States, with health-related economic costs that exceed $193 billion per year. As with other forms of addiction, impairments in reward processing are thought to serve as important markers for nicotine dependence. Public health campaigns and addiction research have primarily focused on heavy smokers (those smoking >10 cigarettes per day). Daily light smokers (defined as those smoking 1-5 cigarettes per day) have received comparatively less attention despite the substantial public health impact of low-level cigarette use. Rates of light smoking have increased dramatically in recent years, particularly among emerging adults (individuals aged 18-25). Light smokers demonstrate many clinically relevant symptoms of nicotine dependence (e.g., nicotine withdrawal, inability to quit), but vary greatly in terms of the extent to which they exhibit these symptoms. In addition to variability in nicotine dependence, light smoking during emerging adulthood also varies in terms of smoking trajectory. Many light smokers are at risk of progressing to higher rates of smoking and increased dependence, whereas others experience little dependence and ultimately discontinue smoking. Currently, little is known about the widely varying levels of nicotine dependence and divergent smoking trajectories observed among light smokers during emerging adulthood. The goal of proposed pilot study is to address this knowledge gap by testing the overarching hypothesis that sensitivity to non-drug rewards serves as an important marker for nicotine dependence severity in light smoking emerging adults. Focusing on this population, the proposed research has two specific aims: 1) To examine the relationship between level of nicotine dependence and reward-contingent inhibitory control; and 2) To examine the relationship between level of nicotine dependence and the ability to refrain from smoking in order to obtain non-drug incentives. If successful, future research will extend this pilot project y using a combination of brain imaging and longitudinal methods to characterize the neural mechanisms underlying individual differences in the sensitivity to non-drug rewards and to examine changes in the behavioral and neural responsiveness to non-drug rewards that occur as smoking patterns evolve over time in light smoking emerging adults (i.e., as they progress to heavier or lighter smoking). Results from this pilot study and the subsequent program of research it is used to support will have important implications for developing strategies aimed at identifying light smokers who are likely to exhibit an escalation in cigarette use and addiction severity. In addition, findings will be informative for interventions that target the motivational mechanisms perpetuating smoking behavior in this understudied population. Given the enormous costs associated with cigarette use, including at relatively low levels, even a modest improvement in smoking prevention and treatment gained through such techniques would have significant benefits for public health.

? DESCRIPTION (provided by applicant): The use of rewards (defined as anything for which an individual will work) to increase motivation is one of the most common strategies for trying to encourage cigarette smokers to quit and remain abstinent. In general, this approach is consistent with basic behavioral principles. However, recent functional brain imaging research suggests that potential rewards may be least effective at promoting smoking abstinence in the very situation they are needed most - when smokers are tempted by access to cigarettes. Specifically, smokers exhibit a significant decrease in the sensitivity of brain reward regions to nondrug (monetary) rewards when cigarettes will soon be available. Recent findings further suggest that the magnitude of this observed decrease predicts clinically relevant behavior. Thus, characterizing the effects of cigarette availability on reward sensitivity is an innovative ad significant approach to understanding vulnerability to, and prevention of, smoking relapse. In the proposed project, functional magnetic resonance imaging (fMRI) and ecological momentary assessment (EMA) methods will be integrated to address key unresolved questions about the effect of cigarette availability on sensitivity to nondrug rewards. Specifically, adult daily smokes (N = 160) will first complete laboratory sessions to measure the effects of an experimental cigarette availability manipulation on distinct phases of the neural response to nondrug (monetary) rewards using fMRI. Then, EMA will be used to measure the within- person effects of naturally time-varying perceived cigarette availability on reward sensitivity under real-world conditions over 10 days of monetarily reinforced cigarette abstinence. Our overarching hypothesis is that availability-related decreases in reward sensitivity are driven by increases in negative affect, leading to specific predictions about how neural and subjective responses to rewards will be altered. These predictions will be tested across three specific aims: 1) To examine the effect of cigarette availability on neural activity during anticipation and receipt of rewards; 2) To examine the effect of cigarette availability on subjective responses to rewards in daily life; and 3) To determine whether the effect of cigarette availability on neural responses to rewards predicts subsequent reward-related behavior outside of the laboratory. Results from the project will advance basic knowledge regarding the effect of perceived cigarette availability on neural and subjective responses to nondrug rewards in the laboratory and in daily life. This knowledge, in turn, will inform the development and implementation of novel approaches to reduce the negative impact of cigarette availability on reward functioning (e.g., ecological momentary interventions dynamically tailored to the person and situation).

Functional neuroimaging has become a widely used approach for studying substance use and addiction. This is particularly true in the area of research on cigarette smoking, which remains one of the largest threats to public health in the world. Neuroimaging research on the use of cigarettes and other substances has focused largely on characterizing brain activity associated with drug craving (an intense urge or desire to use drugs). This reflects the prevailing view that craving plays a central role in the maintenance of addiction and serves as a major barrier to treatment and recovery. Over the past several years, researchers using neuroimaging to study craving have benefitted from a number of significant methodological advances (e.g., increasingly sophisticated data analysis methods). However, the methods that are used for subjective affective experience have changed very little, and investigators must largely rely upon the same self-report measures that have been available since the earliest days of neuroimaging craving research. Used in isolation, self-report measures typically lack the sensitivity and precision that are needed to relate momentary affective experience to craving-related brain activity ? an important limitation given the intimate relationship between craving and affect. The goal of the proposed research is to address this barrier to progress in the field by developing a novel method for measuring subjective affective experience in neuroimaging craving research that harnesses the unique strengths of facial expression analysis. Specifically, this method entails recording participants' facial expressions using a magnetic resonance imaging (MRI) compatible camera and then using facial coding analysis to derive a time course of affective reactions from the videos. By providing a way to unobtrusively capture moment-to-moment changes in affect, facial coding is an ideal method for connecting fluid affective reactions to dynamic changes in brain activity in the context of craving. The proposed strategy of integrating the assessment of facial expressions of affect with neuroimaging methods will be tested in a sample of adult daily smokers. Facial expressions will be recorded as participants complete a functional MRI (fMRI) protocol that has proven to be highly effective for provoking strong cigarette cravings. The specific aims of the project are: 1) To demonstrate the feasibility of measuring affect by analyzing video recordings of facial expressions displayed during fMRI; and 2) To demonstrate that moment-to-moment changes in affect are meaningfully associated with ongoing brain activity under conditions designed to produce robust craving. If successful, the proposed project will provide a foundation for using this new method to explore a variety of questions that are currently very difficult to address (e.g., characterizing how affect changes dynamically in relation to brain activity when smokers attempt to regulate their craving). Accordingly, this comprehensive and multimodal approach to assessment has the potential to make a major impact by providing new insights into the links between brain activity and affect in the domain of drug addiction and in many other areas, more broadly.