Nicotinic Modulation of the Default Network

Nicotinic Modulation of the Default Network of Resting Brain Function

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.

Study Overview

• Status: Completed
• Conditions: Magnetic Resonance Imaging; Cognition; Nicotine; Mecamylamine
• Intervention / Treatment: Drug: Placebo; Drug: Nicotine; Drug: Mecamylamine

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21228
      • Maryland Psychiatric Research Center
    • Baltimore, Maryland, United States, 21224
      • National Institute on Drug Abuse, Intramural Research Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo, Nicotine, Mecamylamine; Participants undergo 3 test sessions: In the first session ("placebo"), a placebo patch and a placebo capsule is administered. In the second session ("nicotine"), a nicotine patch (7 mg/24 hrs) and a placebo capsule is administered. In the third session ("mecamylamine"), a placebo patch and a mecamylamine capsule is administered.	Drug: Placebo; Participants are administered a placebo patch and a placebo capsule; Drug: Nicotine; Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule; Other Names: Nicotine CQ; Drug: Mecamylamine; Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine
Experimental: Nicotine, Placebo, Mecamylamine; Participants undergo 3 test sessions: In the first session ("nicotine"), a nicotine patch and a placebo capsule is administered. In the second session ("placebo"), a placebo patch (7 mg/24 hrs) and a placebo capsule is administered. In the third session ("mecamylamine"), a placebo patch and a mecamylamine capsule is administered.	Drug: Placebo; Participants are administered a placebo patch and a placebo capsule; Drug: Nicotine; Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule; Other Names: Nicotine CQ; Drug: Mecamylamine; Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine
Experimental: Placebo, Mecamylamine, Nicotine; Participants undergo 3 test sessions: In the first session ("placebo"), a placebo patch and a placebo capsule is administered. In the second session ("mecamylamine"), a placebo patch (7 mg/24 hrs) and a mecamylamine capsule is administered. In the third session ("nicotine"), a nicotine patch and a placebo capsule is administered.	Drug: Placebo; Participants are administered a placebo patch and a placebo capsule; Drug: Nicotine; Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule; Other Names: Nicotine CQ; Drug: Mecamylamine; Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine
Experimental: Nicotine, Mecamylamine, Placebo; Participants undergo 3 test sessions: In the first session ("nicotine"), a nicotine patch and a placebo capsule is administered. In the second session ("mecamylamine"), a placebo patch (7 mg/24 hrs) and a mecamylamine capsule is administered. In the third session ("placebo"), a placebo patch and a placebo capsule is administered.	Drug: Placebo; Participants are administered a placebo patch and a placebo capsule; Drug: Nicotine; Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule; Other Names: Nicotine CQ; Drug: Mecamylamine; Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine
Experimental: Mecamylamine, Placebo, Nicotine; Participants undergo 3 test sessions: In the first session ("mecamylamine"), a placebo patch and a mecamylamine capsule is administered. In the second session ("placebo"), a placebo patch (7 mg/24 hrs) and a placebo capsule is administered. In the third session ("nicotine"), a nicotine patch and a placebo capsule is administered.	Drug: Placebo; Participants are administered a placebo patch and a placebo capsule; Drug: Nicotine; Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule; Other Names: Nicotine CQ; Drug: Mecamylamine; Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine
Experimental: Mecamylamine, Nicotine, Placebo; Participants undergo 3 test sessions: In the first session ("mecamylamine"), a placebo patch and a mecamylamine capsule is administered. In the second session ("nicotine"), a nicotine patch (7 mg/24 hrs) and a placebo capsule is administered. In the third session ("placebo"), a placebo patch and a placebo capsule is administered.	Drug: Placebo; Participants are administered a placebo patch and a placebo capsule; Drug: Nicotine; Participants are administered a nicotine patch (7 mg/24 hrs) and a placebo capsule; Other Names: Nicotine CQ; Drug: Mecamylamine; Participants are administered a placebo patch and a capsule containing 7.5 mg of mecamylamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reaction Time	average reaction time on cognitive task performed in the MR scanner	1 day
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.	1 day
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.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	1 day
Systolic Blood Pressure	Systolic blood pressure (mmHg)	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	Diastolic blood pressure in mmHg.	Bi-hourly: prior to patch application, 2 hours, 4 hours, and 6 hours after, and after the MRI scan (~8 hours after patch application).

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Britta Hahn, Ph.D., University of Maryland, College Park

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2010
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: October 13, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (Estimate): October 19, 2010

Study Record Updates

• Last Update Posted (Actual): August 19, 2019
• Last Update Submitted That Met QC Criteria: August 15, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: fMRI; nicotine; attention; mecamylamine; default network
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Ganglionic Blockers; Nicotinic Antagonists; Nicotine; Mecamylamine
• Other Study ID Numbers: HP-00042696; R21DA027894 (U.S. NIH Grant/Contract)