Francesco Versace, Ph. D. - US grants

DESCRIPTION (provided by applicant): While data from several empirical studies support the idea that smokers process cigarette-related stimuli as motivationally relevant, very few studies have investigated if smokers exhibit reduced sensitivity to natural rewards (i.e., intrinsically pleasant stimuli). Obtaining this knowledge will allow for the implementation of new interventions aimed at enhancing the saliency value of natural rewards, an approach that might increase smoking abstinence. The long-term goal of our research group is to understand the neurophysiologic mechanisms underlying relapse and to improve smoking-cessation interventions. The objective of this proposal is to determine the role of sensitivity to intrinsicaly rewarding (i.e., pleasant) stimuli in the maintenance of smoking addiction. Our central hypothesis is that smokers with reduced sensitivity to intrinsically pleasant stimuli will have mor difficulty quitting smoking and achieving long-term abstinence. This hypothesis was developed thanks to preliminary data collected in our laboratory using event-related potentials (ERPs), a direct measure of neural activity. The rationale for the proposed research is that once we can identify smokers who exhibit reduced sensitivity to intrinsically pleasant stimuli, specific interventions to normalize the reactivity of the brain reward system can be implemented for these individuals. Such individualized interventions (either pharmacological or psychological) will increase long term smoking cessation rates with a significant positive impact on human health. We will test this hypothesis by pursuing three specific aims: 1) Determine the role of nicotine addiction in altering sensitivity to intrinsically pleasant stimuli; 2) Identify the role hat sensitivity to intrinsically pleasant stimuli has on influencing smoking abstinence during a smoking cessation attempt; 3) Build and validate a long-term smoking abstinence predictive model to improve personalized treatment for smoking cessation. This approach is innovative because, by using ERPs to directly measure brain activity evoked by intrinsically emotional stimuli, we will be able to evaluate the role that individual differences in the brain reward syste have in influencing one's ability to quit smoking. The proposed research is significant because it will fundamentally advance our knowledge of the neurobiological processes involved in drug addiction. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because determining if smokers lose sensitivity for intrinsically rewarding stimuli is the necessary preliminary step to developing new treatments aimed at restoring the saliency value of natural reinforcers and significantly increasing the long-term success of smoking cessation interventions. Hence, the project is relevant to the NIDA Clinical Neuroscience Branch's mission of characterizing how abused drugs affect the function of the human central nervous system and understanding the role of individual differences underlying the maintenance of drug addiction.

? DESCRIPTION (provided by applicant): Several factors contribute to nicotine dependence, but dysregulation of brain circuits underlying reward sensitivity play a fundamental role. Chronic drug use is thought to result in the attribution of excessive motivational value to drugs at the expense of natural rewards. The neurobiological processes mediating reduced sensitivity to natural rewards are still obscure. We do not know whether brain reward sensitivity differences are already present in young smokers or whether these differences develop only after long-term nicotine use. Furthermore, we do not yet know how brain reward sensitivity differences are related to behavioral and subjective measures of hedonic capacity (i.e., the tendency to not enjoy pleasurable activities). The objective of this application is to assess the feasibility of usng a newly discovered neural biomarker to characterize youths' individual differences in reward sensitivity. Our central hypothesis is that young smokers will already show blunted brain responses to natural rewards and that these differences will correlate with behavioral and self- report measures of hedonic capacity. To test this hypothesis we will assess reward sensitivity in young smokers and never smokers using dense array event-related potentials (ERPs), behavioral, and self-report measures. This multi-modal approach will allow us to link subjective and behavioral variation in hedonic capacity to its neural underpinnings. We will achieve our objective by pursuing the following Specific Aims: 1) Characterize in young smokers the behavioral correlates of brain reward sensitivity; 2) Determine the role exerted by nicotine on youths' reward sensitivity. Our approach is innovative because the multimodal assessment proposed here will allow us to investigate the relationships existing among neurobiological, behavioral, and subjective domains of the reward-processing construct and to determine how nicotine alters them in young smokers. Determining in youths how neural, behavioral, and subjective measures of reward sensitivity interrelate is significant because it is the necessary preliminary step to understanding how individual differences in hedonic capacity confer vulnerability to nicotine dependence. The results of this project will contribute to the development of new and effective evidence-based prevention strategies for individuals at risk, and to the creation of more successful interventions to promote abstinence in individuals already addicted.

PROJECT SUMMARY Progress in basic neuroscience has improved our understanding of addiction neurobiology, but what has proven difficult is translating this knowledge into effective relapse prevention treatments. Identifying the neurobiological mechanisms underlying relapse will likely promote the development of better targeted therapeutic interventions to prevent it. In our previous funding cycle, we showed that smokers with larger brain responses to cigarette- related cues than pleasant stimuli are more vulnerable to relapse than smokers with the opposite brain reactivity profile. The objective of this renewal is to identify the neuropsychological mechanisms underlying these brain reactivity profiles and determine how these mechanisms affect vulnerability to cue-induced smoking relapse. Our central hypothesis is that the brain reactivity profiles that we isolated in smokers reflect individual differences in the tendency to attribute incentive salience to cues predicting rewards, a trait that increases vulnerability to cue- induced behaviors. Our hypothesis is based on the incentive sensitization theory and it is supported by preclinical findings and our own preliminary data. Animal models show that rats prone to attributing incentive salience to discrete food-related cues (called ?sign-trackers?) are more vulnerable to cue-induced drug seeking behavior than rats not prone to do so (called ?goal-trackers?). Our preliminary data show that the same neuropsychological trait predicts smoking relapse in smokers and cue-induced eating in the general population. We plan to test our hypothesis by pursuing two specific aims: 1) Identify the neuropsychological underpinnings of cue-induced behaviors. We will use the neurophysiological profiles derived from our newly developed cued food delivery task to classify 100 smokers and 100 nonsmokers as sign-trackers or goal-trackers, and predict cue-induced smoking and eating behaviors in the two groups. Our working hypotheses are that a) sign-trackers (both smokers and nonsmokers) will be more prone than goal-trackers to cue-induced eating and b) smokers categorized as sign-trackers in the cued food delivery task will be more prone than goal-trackers to cue-induced smoking in a laboratory model of smoking lapse behavior. 2) Determine the effects of nicotine withdrawal on cue-induced neurobehavioral responses. All participants will undergo two laboratory sessions. At session 2, smokers will be nicotine deprived for 24 hours. We hypothesize that nicotine deprivation will increase cue-induced smoking and eating behaviors in sign-trackers but not in goal-trackers. Our innovative neurobehavioral approach will advance bi-directional translation by allowing us to tie individual neurophysiological profiles to cue-induced be- haviors in humans. This project is significant because it will fundamentally advance our understanding of the mechanisms underlying impulse control disorders, the first step toward identifying new targets for personalized prevention and treatment interventions.