Effects of Nicotine on Brain Activity as Measured by fMRI This protocol investigates various central pharmacodynamic properties of nicotine using phMRI, specifically, the neural response to IV-administered nicotine as a function of the rate of administration (3 possible rates). This protocol has proven difficult to recruit for. In the past year, 7 participants were scanned over a total of 20 scan sessions. Data analysis is still in the early stages given the relatively low number of subjects. Effects of Nicotine on Cognitive Task Performance and Brain Activity as Measured by fMRI This protocol investigates mechanisms of nicotine-induced attentional enhancement. In two sub-parts (A and B), the effects of nicotine are being tested in three different tasks assessing different attentional functions in two separate scan sessions. Smokers are tested once with a placebo patch and once with a nicotine patch, while controls are tested twice without drug. Part A employs a task designed to distinguish between selective and divided attention and a task designed to separate attentional and motor sets in response to cues allowing for different types of response preparation. Part B employs a central executive task requiring the concomitant update of two separate silent counts, and a task of visuospatial attentional resource allocation that parametrically varies demands on bottom-up and top-down processes of attentional selection. Control data from all tasks (behavioral and fMRI) have been presented in abstract form. Control data from the visuospatial attention task have been submitted for publication. Experiments in smokers are still in progress but are approaching completion. In the past year, 26 participants were scanned for this protocol over a total of 57 scan sessions. Automatic versus evaluative components of cue reactivity This protocol investigates mechanisms by which drug-related stimuli influence behavior of dependent individuals (smokers and cocaine users). Drug-related pictures are embedded in a cognitive task that parametrically varies processing load. The degree to which the concomitantly presented cues can be cognitively evaluated is thereby manipulated. This allows for the influence of processing depth to be evaluated on different measures of cue reactivity, including performance indices, craving responses, psychophysiological parameters and regional brain activation. A pilot study in a mock scanner is approaching completion in smokers and non-smoking controls. The data indicate distinct effects of drug-related cues on task performance and heart-rate when presented against different task backgrounds. As such, smoking pictures disrupt the consistency of attentional task focus only when embedded in a minimally demanding task, indicating competition for attentional resources. By contrast, the same pictures enhance target detection compared to neutral pictures when embedded in a highly demanding task, and this effect is accompanied by an increased heart-rate, indicative of an alerting or behaviorally mobilizing function. The study is soon to be repeated in the MR scanner to identify brain regions that may differentially mediate those qualitatively different effects of smoking cues. A parallel pilot experiment in cocaine users and controls is still in progress. Brain Activity Alterations As Measured By fMRI During Nicotine Self-Administration The overall goal of this protocol is to employ functional magnetic resonance imaging (fMRI) to define neural sites and mechanisms underlying nicotine self-administration (SA) in humans. Six subjects have completed the initial dose finding experiment. Initial results are promising with most participant's clearly self-administering nicotine to a greater extent than saline, even at doses that do not produce robust subjective or physiological responses. Dose selection is expected to be completed shortly with the project progressing to the MRI experiments. The Effects of Expectation on Natural and Drug-Induced Rewards This protocol will compare cocaine dependent and drug naive control participants on various aspects of response to reward cues and reward receipt. fMRI will be used to assess neuronal response, while rating scales will be used to assess subjective responses. The first experiment will use the natural reward of a small squirt of flavored liquid under the tongue. A visual or olfactory stimulus will cue the coming reward. Occasionally, the reward will be delayed or the 'wrong' reward will be delivered, thus violating the expectation of the participant. The second experiment will deliver a drug-induced reward in the form of 15 mg/70kg of methylphenidate (Mph) delivered IV. In four separate sessions, participants will be cued twice that they will receive MPh and twice that they will receive saline. One saline cue and one MPh cue will be inaccurate. Tasks and equipment for this protocol are being tested. No participants have been enrolled to date. Psychobiology of Reward and Punishment: Functional and Molecular Brain Imaging and Monoaminergic Genetic Correlates Aims: (1) To examine the effect of Mph on measures of cognition and affect in both normal healthy adults and adults with cocaine-dependence. (2) To determine the relationship between dopamine receptor distribution and both brain activity and behavior. Current status: Experimental sessions for this study have not yet commenced. A new PI has taken over as lead investigator, the tasks have been modified, we have added a cocaine-dependent participant group, changed the route of administration of Mph and changed the dose and schedule for AMPT. These experiments will begin when we obtain an IND. Reward processing in cocaine dependent individuals before and after cocaine administration Participants in this study include cocaine dependence and healthy, matched controls. Participants will undertake two experimental paradigms, each of which will ascertain different aspects of reward processing, while undergoing functional MRI- a modification of Knutson's Monetary Incentive Delay task, and a modification of McClure's passive conditioning task. Both aspects of reward processing have been linked to aspects of dopamine (DA) function in normal healthy adults. Given the multifaceted nature of drug addiction, we will also examine how aspects of personality, or temperament, such as sensation- and novelty-seeking contribute to the performance of addicts and will examine the rate and relationship of polymorphism in genes that may be linked to substance abuse and dependence, such as DRD2 and COMT. Pilot testing of the tasks have begun in the mock scanner with 14 participants (5 controls and 9 cocaine-dependent), and 5 control participants completed. Brain Activity Alterations During Cocaine Self-Administration The overall goal of this new protocol is to employ fMRI to define neural sites and mechanisms underlying cocaine self-administration (SA) in humans.
Specific Aims i nclude: a) determination of neural activation patterns during simple SA behavior and compare the magnitude and time course of its subjective, behavioral, and CNS effects before and after IV injections, b) determining the effect of self- vs. passive- administration of cocaine on the parameters listed above, c) and to determine the role that conditioned cues play in cocaine's activation properties by comparing neural activation patterns during normal SA (in which the cue presentation is accompanied by drug infusion) with those associated with response-contingent presentation of cues during extinction conditions. This project has just been approved by the IRB and recruitment for participants has begun.
