Effects of Nicotine on Cognitive Task Performance and Brain Activity as Measured by fMRI

Objective:

Experiments in this protocol employ fMRI to address the interactions of nicotine with such cognitive processes as working memory, attention, and the executive functions of inhibitory control, conceptual reasoning and attention switching, in addition to reward and temporal error reward processing. The effects of nicotine on these cognitive processes will also be assessed outside the MRI scanner. Assessments of genetic variants will be done with the hypothesis that these will account for some inter-individual differences in the brain imaging data.

Study Population:

The study population will consist of adult (18-50 y.o.) non-treatment seeking smokers and age and gender matched non-smoking control subjects. The control subjects will provide normative data on cognitive task performance and corresponding neural activation, as well as providing control for any time effects (e.g. practice effect on repeated cognitive task performance). Smokers will smoke at least 10 cigarettes per day for a period of 1 year. Both smokers and controls will be suitable for fMRI scanning. Subjects may not be dependent on any other drug except nicotine or caffeine.

Design:

In a within subjects design, experienced smokers will perform cognitive tasks involving memory encoding and consolidation, selective/divided and sustained attention, as well as reward and temporal error reward processing two hours following single blind application of a nicotine patch (21 mg/24 hr) and during a separate session on a different day, following application of a placebo patch. The tasks will be performed during fMRI scanning. Not all of the tasks will be done at the same time, rather, groups of tasks are run in series as task sets: Task set A: Selective/divided attention task and Intention/ attention task; Task set B: The SARAT (Spatial Attentional Resource Allocation task) which is designed to enable dissociation of top-down and stimulus driven processes of visuospatial selective attention as well as the CEFER task which is a measure of central executive function task which isolates the allocation of attentional resources within working memory; Task set C: Monetary Incentive Delay and Temporal Delay Error processing tasks; Task set D: Affective Forecasting and Loss Aversion task. Control subjects will do the tasks during scanning without a patch. Blood will be drawn from all participants for analysis of genetic variants and for smokers, plasma nicotine and cotinine will be measured.

Outcome:

We will determine the acute effects of nicotine on attentional and other cognitive mechanisms and how emotional processes such as the anticipation and receipt of reward affects the neuronal activation properties of acute nicotine administration in experienced smokers. In addition, we will determine whether genetic polymorphisms predict BOLD response during cognitive tasks pertinent to nicotine addiction. Plasma nicotine and cotinine will be included as a factor in analyses of nicotine-induced effects on fMRI signal to take account of potentially large inter-individual variability in circulating nicotine concentrations.

• INCLUSION CRITERIA:

• Subjects must be between the ages of 18-50.
• Subject must be in good health based on history and physical exams.
• Subjects must be right-handed.
• Smoking subjects must demonstrate that they are experienced users based upon urine cotinine levels of at least 100ng/ml, and must smoke a minimum of 10 cigarettes/day with duration of use of at least 1 year.
• Subjects may be users of alcohol and/or marijuana but may not meet criteria for dependence on either substance.

Exclusion criteria

• Are pregnant or breast feeding. Urine pregnancy tests will be performed on all female volunteers of child-bearing potential before each experimental session.
• Have implanted metallic devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts) or claustrophobia rendering them unable to undergo fMRI scanning.
• Have major medical illnesses to include, but not limited to, hypertension, cardiovascular disease, asthma, diabetes, peripheral vascular diseases, coagulopathies, syncope, history of superficial or deep vein thrombosis, HIV, or other clinically significant infectious diseases.
• Have current major psychiatric disorders to include, but not limited to, mood, anxiety, psychotic disorders, or substance-induced psychiatric disorders.
• Have neurological illnesses to including, but not limited to, seizure disorders, migraine, multiple sclerosis, movement disorders, or history of head trauma, CVA, CNS tumor.
• Have significant alcohol or other drug use, other than nicotine dependence.
• Have gros structural abnormalities onT1 weighted images.
• Have cognitive impairment as assessed by screening WASI vocabulary subtest below 48, corresponding to full IQ of 85 (in that case on screening, a full WASI will be done to verify IQ of 85 or above). Justification: Cognitive impairment and learning disabilities are associated with alterations in brain regions used to accomplish tasks, and, therefore, may introduce significant variably into the data.
• Are engaged in or actively seeking smoking cessation treatment.