John Monterosso - US grants

DESCRIPTION: (Provided by Applicant) The goal of this K01 proposal is to provide John Monterosso, Ph.D., with the training and support to become an independent investigator in the field of clinical substance abuse research. The research plan builds on the candidate's expertise in animal models of impulsivity; its basic aim is to measure analogous constructs in cocaine dependent patients and to use these measurements in conjunction with cue reactivity to better characterize patients and to better predict treatment outcomes. The training plan provides extensive clinical exposure, individual mentoring in areas related to the research, and structured didactics. Both the research and training plans are opportunistic, utilizing readily-available patient populations from ongoing research, and seasoned investigators in the University of Pennsylvania research community. Dr. Anna Rose Childress will provide primary mentorship and daily supervision in the proposed research; her expertise lies in the phenomenology of cocaine dependence, cue-induced craving, and its brain substrates. Dr. Ronald Ehrman will provide expertise in the laboratory measurement of cue reactivity, and in statistical modeling. Dr. Charles O'Brien will provide expertise on the neurobiology of addiction, will ensure support for successful execution of the project, and will chair an Advisory Board of selected investigators who will be a resource to the candidate and monitor his development. Relapse is a cardinal feature of the addictions, and the one which exacts the greatest human and economic costs. Understanding its mechanisms is critical to reducing these costs. Though cue-induced craving and arousal have been offered by us, and by others, as one possible mechanism, craving has been an imperfect predictor of drug use: not every craving episode eventuates in relapse, and patients vary in their ability to manage these episodes. Host variables may help explain this variability. Since the reward of drug is immediate and the benefits of abstinence are delayed, individual differences in sensitivity to future consequences may be an important variable. Tasks have recently been developed for assessing this dimension: one derived from an animal model of impulsivity, and two others from neuropsychological research with orbitofrontal patients, who show extreme behavioral "myopia" (Damasio, 1994). We have combined these methods into a "Myopia Battery (MB)" for use in the proposed studies. We have conducted a large pilot study with encouraging results. Differences in myopia may be particularly useful for understanding the disconnect between reported craving and drug use/relapse. In Study 1, cocaine-dependent patients participating in a large-scale treatment outcome study (n= 120) will be assessed on cue reactivity/craving, ASP, Impulsivity, I.Q. and will be administered the MB. The MB will also be administered to a group of matched controls (n=80). In Study 2, the MB will be administered to cocaine patients (n=60) participating in ongoing PET studies that directly assess orbitofrontal activity. Our primary hypotheses are: 1) cocaine-dependent patients will perform worse on the MB than controls; 2) performance on the MB will be especially poor in cocaine-dependent patients with ASP; 3) performance on the MB will be related to the variability of patients' ability to manage craving states without relapsing, and 4) MB performance will be correlated with orbitofrontal functioning. The link between severe myopia and orbitofrontal impairment is particularly exciting given emerging evidence (including that collected recently in our own lab) of orbitofrontal deficits in cocaine addicts relative to controls. Whether the dysfunction is a predisposing factor for, or a consequence of, stimulant use - or both - it could undermine an important psychological resource for recovery.

[unreadable] DESCRIPTION (provided by applicant): Appetitive processes (e.g., reward-seeking and some aspects of craving) represent only one side of addiction; failed attempts to exert "self-control" over one's drug use are built-in to the clinical diagnosis of substance dependence. Attempts to study brain substrates of self-control have generally relied on laboratory models, such as decision-making tasks (e.g., the Iowa Gambling Task) and speeded tests of inhibitory control (e.g., the Go/No-Go Task) that have uncertain relevance to abstaining from drug use. We propose to identify substrates of self-control more directly using functional Magnetic Resonance Imaging (fMRI) in conjunction with a specialized apparatus that allows cigarette smoke inhalation in the scanning environment. Fifty cigarette smokers (abstinent 12 h) will complete a "Smoking Self-Control Challenge" that has been developed through successful pilot work. The task includes two types of 20-sec trials: "Smoke Unavailable" trials in which participants are signaled that a valve allowing cigarette smoke inhalation is closed, and "Smoke Available" trials, in which smoke is immediately available, but participants are encouraged to "try not to smoke on as many of these rounds as you can manage". The primary functional measure will be the difference in fMRI signal between Smoke Available trials in which the participant abstains, and trials in which smoke was not available ("Voluntary Abstinence" - "Smoke Unavailable"). Craving will be measured on every trial (by button presses) to allow for its covariation, as well as to allow assessment of its potential moderating effect on neural activity during voluntary abstinence. The fMRI task will be given during two sessions separated by approximately two weeks. Based on preliminary data, we anticipate that voluntary abstinence will be associated with increased neural activity in the right ventrolateral and dorsolateral prefrontal cortex as well as in the dorsal anterior cingulate cortex and supplementary motor area. Standard psychometric techniques will be applied to assess the reliability and short-term stability of performance and of fMRI signal change during the task. Two additional days of behavioral testing will allow performance on the task to be related to established measures of decision-making, inhibitory control, and personality. The proposed method will allow imaging studies of neural systems underlying self-control, complimenting existing imaging methods used to study craving for cigarettes and drugs of abuse. With the primary procedures already operational and in use, this 2-year project should yield valuable insights into the substrates of self-control, with both basic science and clinical implications. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): A major challenge in developing treatments for drug abuse disorders, including nicotine dependence, derives from the fact that the desirable effects of drugs are immediate, and often outweigh their aversive effects, which are predominantly delayed. The decrease in preference for a reward as a function of its delay ("delay discounting") is one conceptualization of impulsivity. Delay discounting is assessed based on preference between larger-later and smaller-sooner alternatives. Numerous demonstrations of high delay discounting in drug abusers suggest that high discounting may be a risk-factor for drug abuse disorders. It is not known, however, whether abnormalities in discounting directly reflect abnormalities in valuation of delayed rewards, or rather abnormalities in decision-making processes engaged during delay-reward tradeoffs. A group of 60 cigarette smokers and another of 40 nonsmoker comparison subjects will complete a battery of behavioral assessments related to impulsivity, and will participate in two fMRI probe task. In the first task ("Choice Delay Discounting Task"), participants will choose between smaller-sooner and larger-later monetary rewards according to an established procedure in which each individual is given choices tailored to their predetermined level of delay discounting (Monterosso et al, 2007). In the second task ("Incentive Delay Task"), participants win rewards that vary in amount and delay. Previous work (Knutson et al, 2001) indicates that the increase in signal measured in the ventral striatum during anticipation of reward is related to reward size, and our pilot work indicates that the same is true with respect to reward immediacy. The two tasks will allow us to measure: 1) the direct effect of delay on valuation of rewards as indexed by responses in the ventral striatum, and 2) brain activity recruited during decision-making during delay-amount tradeoffs. We will compare data from both assessments in smokers and nonsmokers to determine the contributions of valuation and of decision-making to the abnormal delay discounting exhibited by cigarette smokers. Relevance: Substance abuse exacts an enormous toll on the public heath, with cigarette smoking contributing to >400,000 deaths per year in the US. Abnormal delay discounting appears to be an important factor. We will disassociate the roles that valuation and decision-making play in the phenomenon, and relate each to clinical characteristics of smokers, thereby identifying better informed therapeutic targets. PUBLIC HEALTH RELEVANCE: Cigarette smoking contributing to >400,000 deaths per year in the US, and research indicates that smoking is associated with difficulty delaying gratification. The proposed research uses brain imaging to examine the basis of smokers' deficits in delay of gratification, which can then be targeted in treatment. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): The attribution of value to prospects is a fundamental element of decision-making, as most day- to-day decisions involve comparing items. Studies on aging document behaviors reflecting difficulties in making comparisons between options, in particular when those options are complex. Given the growing complexity of economic products (insurance, savings, mortgages or even telephone plans), older adults may have difficulty making decisions that accurately reflect their underlying preferences. It is plausible that this difficulty is linked to age-related brain function decline within sectors of the lateral prefrontal cortex implicated in working memory and cognitive control. This study assesses age-related changes in how the brain computes value and makes value comparisons using a well-established economic paradigm, the generalized axiom of revealed preference (GARP) Task, that tests the internal consistency of a subject's preferences by offering repeated choices between bundles of goods. Our preliminary study suggests that aging is associated with greater GARP-Task inconsistency. Although the neural correlates of GARP inconsistency have not been directly established, indirect evidence suggests that the medial orbitofrontal cortex is important in all value-based decision-making, and that areas in the lateral prefrontal and parietal cortices (fronto-parietal network) are important for maintaining consistency in complex decisions (e.g., multi-attribute decisions). Aging is associated with structural and functional deficits withn the fronto-parietal network. Therefore, we believe that studying the neural correlates of the GARP-Task is a promising approach to investigate decision-making deficits in aging. We will recruit 45 young adults, and 45 old adults. Participants will complete the GARP-Task and an fMRI variant designed to isolate neural correlates of valuation of single items, of multiple instances of the same item (scaling) and of sets of distinct items (bundles). Brain activity wil be related to diagnosis and to variance in GARP-Task inconsistency. Given the prominence of age-related decline in working memory, we hypothesize that age will be associated with higher GARP-Task inconsistency and to deficits in conditions that require manipulation of value signals (scaling and bundles). We anticipate that these deficits will be associated with low recruitment within the fronto-parietal network and with reduced functional connectivity between this network and the medial OFC.

Metabolic state affects behavior, in large part to defend homeostasis. However, the pathways linking metabolism to decision-making are not well understood. The core idea of this revised proposal is that by combining insights and methods from endocrinology and neuroeconomics, we can better identify mechanisms linking food consumption and behavior. Here we focus specifically on comparing the effects of two sugars (glucose and fructose) on reward signaling and ?delay discounting? (the tendency to value rewards less as a function of their delay). Glucose and fructose have dramatically different effects on endocrine function (including greater circulating insulin and GLP-1 after glucose) and central nervous system activity (including greater attenuation of dopamine release within the VTA and substantia nigra after glucose). There is reason to believe that these identified differences may lead to differences in delay discounting. Specifically, we hypothesize that the tendency to prefer immediate reward over larger but more delayed reward will be greater after fructose consumption than after glucose consumption. Given links between immediate-oriented decision making and negative health consequences like obesity and problem drug use, this would have significant health implications. Participants (N = 36) will complete three functional Magnetic Resonance Imaging (fMRI) sessions, each after overnight fast followed by consumption of either: water, a 75g fructose drink, or a 75g glucose drink. Outside the scanner participants will complete a task that uses convex budgets to estimate utility and discount functions. During fMRI, participants will complete: 1) a modified ?Monetary Incentive Task? with immediate and delayed rewards, and 2) a ?Delay-Discounting Task? in which the participant makes choices between immediate and delayed money. In the latter, options will be individualized to be difficult (the immediate and delayed options similarly attractive given the participant?s discounting and utility). Neuroimaging analyses will focus on established reward pathways and on fronto-parietal networks recruited during the decision making task. By attaching to an ongoing separate study that includes measurement of endocrine responses to the same sugars, we will also be able to investigate whether variance in the primary study measures is associated with (and possibly mediated by) individual differences in endocrine response to glucose and fructose.