Nicotinic Modulation of the Default Network

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.

• Placebo (Drug): Participants are administered a placebo patch and a placebo capsule
• Nicotine (Drug), also known as Nicotine CQ: Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule
• Mecamylamine (Drug): Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 21 Years to 50 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• Reaction Time (Primary), Mean, ms: Intervention: Placebo 512 (485 to 539); Intervention: Nicotine 492 (464 to 520); Intervention: Mecamylamine 524 (489 to 559)
• Signal Detection Performance (Primary), Mean, percentage of all targets: Intervention: Placebo 86.4 (81.4 to 91.4); Intervention: Nicotine 93.8 (90.1 to 97.5); Intervention: Mecamylamine 85.2 (79.7 to 90.7)
• Default Network Activity (Primary), Mean, percentage of task-induced signal change: Intervention: Placebo -0.29 (-0.41 to -0.17); Intervention: Nicotine -0.24 (-0.39 to -0.09); Intervention: Mecamylamine -0.21 (-0.33 to -0.09)
• Subjective State (Secondary), Mean, units on a scale: Intervention: Placebo -6.7 (-12.3 to -1.1); Intervention: Nicotine -9.9 (-15.4 to -4.4); Intervention: Mecamylamine -5.8 (-12 to 0.4)
• Systolic Blood Pressure (Secondary), Mean, mmHG: Intervention: Placebo 120.2 +/- 11.4; Intervention: Nicotine 120.9 +/- 16.7; Intervention: Mecamylamine 119.3 +/- 14.8
• Diastolic Blood Pressure (Secondary), Mean, mmHG: Intervention: Placebo 74.4 +/- 8.0; Intervention: Nicotine 71.6 +/- 10.0; Intervention: Mecamylamine 73.4 +/- 10.1

Adverse events

Time frame: 1 day (on each of separate 3 test days)

Other adverse events by term

• Hahn B, Ross TJ, Yang Y, Kim I, Huestis MA, Stein EA. Nicotine enhances visuospatial attention by deactivating areas of the resting brain default network. J Neurosci. 2007 Mar 28;27(13):3477-89. doi: 10.1523/JNEUROSCI.5129-06.2007. PMID 17392464

• Britta Hahn, Ph.D., Principal investigator, University of Maryland, College Park

NIH grants: R21DA027894