Neural Substrates of Cognitive Deficits in Nicotine Withdrawal
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Tobacco Use Disorder
- Sponsor
- University of Pennsylvania
- Enrollment
- 218
- Locations
- 1
- Primary Endpoint
- Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Right Dorsolateral Prefrontal Cortex; Right DLPFC)
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This study will test the hypothesis that a medication called tolcapone (Brand Name: Tasmar) will help reduce cognitive problems that smokers experience when they quit. This study will also determine whether the benefits of this medication differ depending on a smokers' genetic background.
Detailed Description
Tolcapone, an FDA-approved treatment for Parkinson's disease, improves cognitive performance in healthy controls with COMT val/val genotypes, putatively by increasing prefrontal dopamine levels. We propose a within-subject double-blind cross-over neuroimaging study of short-term (11 days) treatment with tolcapone (vs. placebo). Thirty chronic smokers (15 with val/val genotypes and 15 with val/met or met/met genotypes) will undergo blood oxygenation level dependent (BOLD) fMRI during the two medication periods: 1. after 24 hours of monitored abstinence while on tolcapone, and 2. after 24 hours of monitored abstinence while on placebo (medication order counterbalanced with at least a 10-day washout). The BOLD fMRI data will be acquired while subjects perform a working memory task (Fractal N-back), a sustained attention task (Continuous Performance Task; CPT), and a response inhibition task (Go/No-Go). The primary outcome is medication effects (within subject) on task-related BOLD activation after 24 hours of abstinence. Changes in behavioral performance and subjective symptoms will be examined in relation to brain activity changes. The proposed study will provide a critical mechanistic understanding of the role of COMT in abstinence-induced cognitive symptoms that promote smoking relapse. Information obtained in this study may further establish cognitive performance measures as endophenotypes for nicotine dependence.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Smokers who are between 18 and 65 years of age who self-report smoking at least 10 cigarettes (menthol and non-menthol) per day for at least the last 6 months.
- •Healthy as determined by the Study Physician, based on a medical evaluation including medical history and physical examination, psychiatric evaluation, and liver function tests (LFTs and GGT enzyme levels).
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent and HIPAA form.
- •Women of childbearing potential must consent to use a medically accepted method of birth control while participating in the study (e.g., condoms and spermicide, oral contraceptive, Depo-provera injection, contraceptive patch, tubal ligation) and have 3 months of regular menstrual cycles.
- •Capable of providing a Carbon Monoxide (CO) breath test reading greater than 10 parts per million (ppm) at the medical screening visit.
Exclusion Criteria
- •Smoking behavior
- •Current enrollment or plans to enroll in another research or smoking cessation program in the next 3 months.
- •Provide a CO reading less than or equal to 10ppm at the medical screening visit.
- •Plans to use nicotine substitutes (gum, patch, lozenge, e-cigarette) while enrolled in the study.
- •Alcohol/Drug Exclusion:
- •History (past 2 years) or current diagnosis of substance abuse and/or currently receiving treatment for substance abuse (alcohol, THC, cocaine, PCP, amphetamines, methamphetamines, MDMA/ecstasy, opiates, methadone, benzodiazepines, tricyclic antidepressants, and barbiturates).
- •Current alcohol consumption that exceeds 21 standard drinks/week over the last 6 months.
- •Positive urine drug screen (for substances listed previously) at the medical screening visit or either testing day.
- •Breath Alcohol Concentration (BrAC) assessment greater than or equal to 0.01 at medical screening visit or either testing day.
- •Medication Exclusion Criteria:
Arms & Interventions
Placebo (Sugar Pill)
11-day placebo-controlled medication period
Intervention: Placebo
Tolcapone
11-day phase, tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily); oral dosing; medication is encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Intervention: Tolcapone
Outcomes
Primary Outcomes
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Right Dorsolateral Prefrontal Cortex; Right DLPFC)
Time Frame: At fMRI scan sessions - Days 8 and 29
Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, \& 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period. To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Left Dorsolateral Prefrontal Cortex; Left DLPFC)
Time Frame: At fMRI scan sessions - Days 8 and 29
Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, \& 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period. To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Dorsal Cingulate/Medial Prefrontal Cortex; MF/CG)
Time Frame: At fMRI scan sessions - Days 8 and 29
Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, \& 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period. To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Posterior Cingulate Cortex; PCC)
Time Frame: At fMRI scan sessions - Days 8 and 29
Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, \& 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period. To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Ventromedial Prefrontal Cortex; vmPFC)
Time Frame: At fMRI scan sessions - Days 8 and 29
Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, \& 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period. To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.
Secondary Outcomes
- Cognitive Performance: Accuracy(At fMRI scan sessions - Days 8 and 29)
- Cognitive Performance: Reaction Time(At fMRI scan sessions - Days 8 and 29)
- Subjective Symptoms: Smoking Behavior(Days 1 through 7 of each study period)
- Subjective Symptoms: Cigarette Craving(Day 8 (fMRI scanning session) of each study period)
- Subjective Symptoms: Withdrawal Symptoms(Day 8 of each study period)