Protocol 371: Effects of Nicotine on Brain Activity as Measured by fMRI? This protocol investigates various central pharmacodynamic properties of nicotine using phMRI. In the past FY, we continued to investigate the neural response to IV-administered nicotine as a function of the rate of administration (3 possible rates). 9 participants were scanned over 31 scan sessions. While data analysis for these sessions is still in the quality control stage, we will likely have a sufficient cohort for this experiment. Additionally, we have started two other parts of this protocol. New tasks were developed and one participant was scanned for the subpart designed to look at the effects of tolerance by scanning two injections separated by either 15, 45 or 180 minutes. Finally, new tasks were developed and recruitment started on the experiment designed to look at the neural activation from nicotine given in a more ?naturalistic? administration designed to more closely match that of a smoker taking multiple puffs.? ? Protocol 372: Effects of Nicotine on Cognitive Task Performance and Brain Activity as Measured by fMRI? This protocol investigates mechanisms of nicotine-induced attentional enhancement. The effects of nicotine are being tested using 4 tasks assessing different attentional functions (visuospatial, selected/divided, intention/attention and central-executive). The tasks are performed 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. 27 subjects were scanned over 53 scan sessions.? ? Protocol 372B ? SARAT: Experiments exploring the effects of transdermal nicotine in a task of visuospatial selective attention were completed. Smokers were tested once with a placebo patch and once with a nicotine patch, while controls were tested twice without drug. Data from 22 controls and 17 smokers were analyzed. Control data were published, and results on the effects of nicotine were submitted for publication (see below). The major finding with nicotine was that drug-induced deactivation of regions that generally maintain resting brain functions was associated with drug-induced performance improvements.? Data from the intention/attention task have been presented at meetings this year. ? Protocol 372A ? SD task: The effects of transdermal nicotine in a task designed to distinguish between selective and divided attention were explored. While experiments have been completed in both smokers and controls, no further results have been obtained since the last progress report. ? ? Protocol 376: Brain Activity Alterations As Measured By fMRI During Nicotine Self-Administration? This protocol employs fMRI to define neural sites and mechanisms underlying nicotine self-administration (SA) in humans. 7 participants have completed the initial dose finding experiment. Most participants self-administer nicotine to a greater extent than saline even at doses that do not produce robust subjective or physiological responses. The project was moved to the MRI scanner and the first scanner experiment was revised to further explore the fact that participants often self-administer nicotine (at some low doses) over saline despite a lack of conscious knowledge of the behavior or subjective effect. There are 3 completers in this first MRI experiment.? ? Protocol 384: Automatic versus evaluative components of cue reactivity? This protocol aims to dissociate components of cue reactivity by embedding drug-related pictures into different versions of the N-back task, thus varying the amount of processing resources available for picture processing. Pilot studies in the mock scanner were completed. 17 overnight-deprived smokers and 17 non-smokers completed experiments. The results suggested two components of cue reactivity: one dependent on the availability of processing resources, arousing and positively associated with craving, and one not competing for processing resources and negatively associated with craving, but with a trend towards a positive relationship with actual smoking behavior. These findings will be published and will also be reported in a platform presentation at the 2006 Annual meeting of the Society for Neuroscience. A parallel pilot experiment in crack cocaine users and controls has yielded ambiguous results because smoking control participants displayed cue reactivity to pictures of individuals smoking crack-cocaine. Since it was not possible to interpret effects in cocaine users, the majority of whom smoked, as reactivity to cocaine-related cues, the cocaine part of the protocol was discontinued. The smoking part of the protocol has entered phase 2, where experiments are repeated in the MRI scanner. 8 participants have completed the experiment. ? ? Protocol 394: Neurobiology and Pharmacokinetics of Acute MDMA Administration? This protocol employs fMRI to define neural sites and mechanisms underlying the cognitive effects of orally administered MDMA (ecstasy) in humans. 7 controls and 7 users have completed this study. Due to severe difficulty in recruiting MDMA users who do not smoke significant quantities of marijuana, the protocol was revised to accept heavy marijuana users, and includes drug-matched and non-drug-using control groups. Preliminary results from the control participants found that left inferior frontal gyrus demonstrated activation patterns that mimicked reaction times across conditions in a semantic categorization task designed to manipulate difficulty of decision making. This result confirms the role of the left IFG in executive functions during semantic processing. ? ? Protocol 396: Brain Activity Alterations During Cocaine Self-Administration? This protocol employs fMRI to define neural sites and mechanisms underlying cocaine self-administration (SA) in humans. 4 participants have completed the study. No data analysis has been performed yet.? ? Protocol 399: Reward Processing in Cocaine Addiction? The goal of this investigation is to use fMRI to ascertain the function of neural systems that respond to cocaine in human participants, and to determine the role that they play in the processing of different types of rewarding stimuli during episodes when individuals are drug-free and when they use cocaine. 14 controls and 6 cocaine-dependent subjects have completed the study. The major issue in conducting this study has been the low rate of study completion in the cocaine group. Withdrawal has mostly been due to participants? physical health issues which are independent of study manipulations. To address the low completion rate we recently received IRB approval for an increase in study recruitment numbers. ? ? Protocol: 401: Dopamine Function and Reward Processing in Schizophrenia? The study aims to examine the impact of dopamine dysfunction in schizophrenia on reward learning and the anticipation of reward, and to determine the neural underpinnings of changes in reward processing in schizophrenia. This study is examining performance of two reward measures in schizophrenic participants and healthy controls, during functional MRI. 5 controls and 6 schizophrenics have completed the study. Some individuals may have to be recalled to complete additional scanning sessions due to technical difficulties. A major challenge in conducting this study has been the strict exclusion/inclusion criteria for schizophrenic patients; a significant proportion of the study population has health problems that preclude them from participating. In order to increase the availability of eligible participants we are revisiting the exclusion/inclusion criteria for future enrollment.
