Magnetic Resonance Imaging, Cognition, Nicotine, Mecamylamine
Conditions
Keywords
nicotine, mecamylamine, attention, default network, fMRI
Brief summary
Many disorders where attentional problems are a hallmark, such as Alzheimer's disease and schizophrenia, display abnormal regulation of the so-called default network of resting brain function that maintains internally directed thought when the mind is free to wander. There is indication that nicotine may improve attention by aiding the deactivation of the default network, and this mechanism may be of therapeutic benefit for the above disease states. The current project aims at providing a proof of concept by demonstrating that nicotinic drugs modulate default network function. The nicotinic agonist nicotine is hypothesized to improve attention by facilitating the down-regulation of default network activity, and the nicotinic antagonist mecamylamine is hypothesized to impair attention by impeding the down-regulation of default network activity during attentional task performance.
Detailed description
This study only enrolls healthy non-smokers. Participants perform attention tasks while undergoing functional Magnetic Resonance Imaging on three separate days. Across the three days, three difference conditions are tested in a double-blind manner, in randomized order. In all test sessions, participants receive a skin patch and swallow a capsule. In one session, both are a placebo. In another, the patch is a low-dose nicotine patch, and the capsule is a placebo. In another session, the patch is a placebo and the capsule contains a low dose of mecamylamine.
Interventions
DRUGPlacebo
Participants are administered a placebo patch and a placebo capsule
DRUGNicotine
Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule
DRUGMecamylamine
Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine
Sponsors
National Institute on Drug Abuse (NIDA)
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Only the statistician performing the randomization and the pharmacist dispensing the drugs were aware which drug was given on which day.
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 21 through 50. * Did not consume cigarettes, cigarillos, cigars, or other tobacco or nicotine-containing products more than 20 times in lifetime, and did not use any nicotine-containing product at all within the last two years. * Normal or corrected to normal vision (at least 20/80).
Exclusion criteria
* Presence of metal objects in the body, implanted electronic devices, or any other counter indication for MRI. * Claustrophobia. * Major psychiatric disorders including mood, anxiety or psychotic disorders. * Cardiovascular or cerebrovascular disease, such as history of myocardial infarction, heart failure, angina, stroke, severe arrhythmias, or EKG abnormalities. * Kidney or liver disease. * Hypertension (resting systolic BP above 140 or diastolic above 85 mm Hg). * Hypotension (resting systolic BP below 95 or diastolic below 60). * Use of any prescription or over-the-counter drug other than supplements and birth control. * History of or current neurological illnesses, such as stroke, seizures, dementia or organic brain syndrome. * Learning disability, attention deficit disorder, or any other condition that impedes memory and attention. * Glaucoma, organic pyloric stenosis, uremia or renal insufficiency. * Prostatic hypertrophy, bladder neck obstruction or urethral stricture. * Left-handed or ambidextrous. * Pregnant as determined by urine test, or breast-feeding. * History or current diagnosis of drug or alcohol abuse or dependence. * IQ \< 85 as estimated by the WASI vocabulary subtest.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reaction Time | 1 day | average reaction time on cognitive task performed in the MR scanner |
| Signal Detection Performance | 1 day | Signal detection on cognitive tasks performed in the MR scanner. For the attention task, this represents the percentage of trials in which the participant responded when a signal was presented. In the working memory task (N-back task), this represents the percentage of all target sequences to which the participant responded. |
| Default Network Activity | 1 day | Cognitive task-induced default network deactivation, measured by functional Magnetic Resonance Imaging. The default network was probed by five pre-defined ROIs per hemisphere. Task-induced deactivation was averaged across all ROIs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Subjective State | 1 day | End-of-session subjective state is measured by the Profile of Mood States (POMS). We utilize Total Mood Disturbance (TMD) as a summary measure, derived by adding the total scores on the five negative mood scales (tension, depression, anger, fatigue, confusion) and subtracting the score on the one positive mood scale (vigor). The theoretical range of the TMD scale is -32 to 228, with negative values indicating less mood disturbance, i.e., a more positive emotional state. |
| Systolic Blood Pressure | Bi-hourly: prior to patch application, 2 hours, 4 hours, and 6 hours after, and after the MRI scan (~8 hours after patch application) | Systolic blood pressure (mmHg) |
| Diastolic Blood Pressure | Bi-hourly: prior to patch application, 2 hours, 4 hours, and 6 hours after, and after the MRI scan (~8 hours after patch application). | Diastolic blood pressure in mmHg. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants in each of the six arms received all three interventions (placebo, nicotine, mecamylamine). | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Intervention (1 Day) | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Second Intervention (1 Day) | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Third Intervention (1 Day) | Non-compliance (slept) | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 | 0 / 19 |
| other Total, other adverse events | 0 / 20 | 2 / 21 | 0 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 | 0 / 19 |
Outcome results
Primary
Default Network Activity
Cognitive task-induced default network deactivation, measured by functional Magnetic Resonance Imaging. The default network was probed by five pre-defined ROIs per hemisphere. Task-induced deactivation was averaged across all ROIs.
Time frame: 1 day
Population: Healthy non-smokers (only study completers).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intervention: Placebo | Default Network Activity | -0.29 percentage of task-induced signal change |
| Intervention: Nicotine | Default Network Activity | -0.24 percentage of task-induced signal change |
| Intervention: Mecamylamine | Default Network Activity | -0.21 percentage of task-induced signal change |
Primary
Reaction Time
average reaction time on cognitive task performed in the MR scanner
Time frame: 1 day
Population: 18 healthy male and female adult non-smokers. Only study completers are included, due to the within-subject design.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Intervention: Placebo | Reaction Time | Attention task reaction time | 512 ms |
| Intervention: Placebo | Reaction Time | Working memory task reaction time | 541 ms |
| Intervention: Nicotine | Reaction Time | Attention task reaction time | 492 ms |
| Intervention: Nicotine | Reaction Time | Working memory task reaction time | 533 ms |
| Intervention: Mecamylamine | Reaction Time | Attention task reaction time | 524 ms |
| Intervention: Mecamylamine | Reaction Time | Working memory task reaction time | 573 ms |
Primary
Signal Detection Performance
Signal detection on cognitive tasks performed in the MR scanner. For the attention task, this represents the percentage of trials in which the participant responded when a signal was presented. In the working memory task (N-back task), this represents the percentage of all target sequences to which the participant responded.
Time frame: 1 day
Population: Healthy adult non-smokers (only study completers).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Intervention: Placebo | Signal Detection Performance | Attention task correct identifications | 86.4 percentage of all targets |
| Intervention: Placebo | Signal Detection Performance | Working memory task correct detections | 89.6 percentage of all targets |
| Intervention: Nicotine | Signal Detection Performance | Attention task correct identifications | 93.8 percentage of all targets |
| Intervention: Nicotine | Signal Detection Performance | Working memory task correct detections | 95.5 percentage of all targets |
| Intervention: Mecamylamine | Signal Detection Performance | Attention task correct identifications | 85.2 percentage of all targets |
| Intervention: Mecamylamine | Signal Detection Performance | Working memory task correct detections | 88.6 percentage of all targets |
Secondary
Diastolic Blood Pressure
Diastolic blood pressure in mmHg.
Time frame: Bi-hourly: prior to patch application, 2 hours, 4 hours, and 6 hours after, and after the MRI scan (~8 hours after patch application).
Population: Healthy non-smokers (only study completers).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intervention: Placebo | Diastolic Blood Pressure | 6 hours post patch | 75.8 mmHG | Standard Deviation 6.6 |
| Intervention: Placebo | Diastolic Blood Pressure | Post-scan | 81.3 mmHG | Standard Deviation 5.4 |
| Intervention: Placebo | Diastolic Blood Pressure | 2 hours post patch | 73.4 mmHG | Standard Deviation 10 |
| Intervention: Placebo | Diastolic Blood Pressure | 4 hours post patch | 73.7 mmHG | Standard Deviation 9.7 |
| Intervention: Placebo | Diastolic Blood Pressure | Pre-patch | 74.4 mmHG | Standard Deviation 8 |
| Intervention: Nicotine | Diastolic Blood Pressure | 4 hours post patch | 71.1 mmHG | Standard Deviation 7.9 |
| Intervention: Nicotine | Diastolic Blood Pressure | Pre-patch | 71.6 mmHG | Standard Deviation 10 |
| Intervention: Nicotine | Diastolic Blood Pressure | 6 hours post patch | 75.3 mmHG | Standard Deviation 5.8 |
| Intervention: Nicotine | Diastolic Blood Pressure | Post-scan | 81.1 mmHG | Standard Deviation 5.7 |
| Intervention: Nicotine | Diastolic Blood Pressure | 2 hours post patch | 71.9 mmHG | Standard Deviation 9.9 |
| Intervention: Mecamylamine | Diastolic Blood Pressure | Post-scan | 79.6 mmHG | Standard Deviation 9.4 |
| Intervention: Mecamylamine | Diastolic Blood Pressure | 2 hours post patch | 73.2 mmHG | Standard Deviation 9.7 |
| Intervention: Mecamylamine | Diastolic Blood Pressure | 4 hours post patch | 72.4 mmHG | Standard Deviation 6.9 |
| Intervention: Mecamylamine | Diastolic Blood Pressure | 6 hours post patch | 75.2 mmHG | Standard Deviation 8.1 |
| Intervention: Mecamylamine | Diastolic Blood Pressure | Pre-patch | 73.4 mmHG | Standard Deviation 10.1 |
Secondary
Subjective State
End-of-session subjective state is measured by the Profile of Mood States (POMS). We utilize Total Mood Disturbance (TMD) as a summary measure, derived by adding the total scores on the five negative mood scales (tension, depression, anger, fatigue, confusion) and subtracting the score on the one positive mood scale (vigor). The theoretical range of the TMD scale is -32 to 228, with negative values indicating less mood disturbance, i.e., a more positive emotional state.
Time frame: 1 day
Population: Healthy non-smokers (only study completers).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Intervention: Placebo | Subjective State | -6.7 units on a scale |
| Intervention: Nicotine | Subjective State | -9.9 units on a scale |
| Intervention: Mecamylamine | Subjective State | -5.8 units on a scale |
Secondary
Systolic Blood Pressure
Systolic blood pressure (mmHg)
Time frame: Bi-hourly: prior to patch application, 2 hours, 4 hours, and 6 hours after, and after the MRI scan (~8 hours after patch application)
Population: Healthy non-smokers
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intervention: Placebo | Systolic Blood Pressure | 6 hours post patch | 120.3 mmHG | Standard Deviation 12.9 |
| Intervention: Placebo | Systolic Blood Pressure | Pre-patch | 120.2 mmHG | Standard Deviation 11.4 |
| Intervention: Placebo | Systolic Blood Pressure | 2 hours post patch | 116.1 mmHG | Standard Deviation 11.9 |
| Intervention: Placebo | Systolic Blood Pressure | 4 hours post patch | 120.1 mmHG | Standard Deviation 16.7 |
| Intervention: Placebo | Systolic Blood Pressure | Post-scan | 129.7 mmHG | Standard Deviation 16.1 |
| Intervention: Nicotine | Systolic Blood Pressure | 2 hours post patch | 114.3 mmHG | Standard Deviation 10.7 |
| Intervention: Nicotine | Systolic Blood Pressure | Post-scan | 127.4 mmHG | Standard Deviation 9.8 |
| Intervention: Nicotine | Systolic Blood Pressure | 4 hours post patch | 119.1 mmHG | Standard Deviation 9.9 |
| Intervention: Nicotine | Systolic Blood Pressure | 6 hours post patch | 122.7 mmHG | Standard Deviation 12.7 |
| Intervention: Nicotine | Systolic Blood Pressure | Pre-patch | 120.9 mmHG | Standard Deviation 16.7 |
| Intervention: Mecamylamine | Systolic Blood Pressure | Pre-patch | 119.3 mmHG | Standard Deviation 14.8 |
| Intervention: Mecamylamine | Systolic Blood Pressure | 2 hours post patch | 112.3 mmHG | Standard Deviation 8.6 |
| Intervention: Mecamylamine | Systolic Blood Pressure | 6 hours post patch | 118.2 mmHG | Standard Deviation 14.1 |
| Intervention: Mecamylamine | Systolic Blood Pressure | Post-scan | 121.5 mmHG | Standard Deviation 13.8 |
| Intervention: Mecamylamine | Systolic Blood Pressure | 4 hours post patch | 114.4 mmHG | Standard Deviation 11.4 |