Nicotinic Modulation of the Default Network

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT01223404
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 21
• Locations: 2
• Arms: 6
• Actual Duration (Months): 35
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Magnetic Resonance Imaging; Cognition; Nicotine; Mecamylamine	Drug: Placebo; Drug: Nicotine; Drug: Mecamylamine	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, 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.
• Primary Purpose: Basic Science
• Official Title: Nicotinic Modulation of the Default Network of Resting Brain Function
• Actual Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Reaction Time [1 day]

   average reaction time on cognitive task performed in the MR scanner

2. 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.

3. 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 Outcome Measures

1. 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.

2. 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)

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institute on Drug Abuse, Intramural Research Program	Baltimore	Maryland	United States	21224
2	Maryland Psychiatric Research Center	Baltimore	Maryland	United States	21228

Sponsors and Collaborators

• University of Maryland, Baltimore
• National Institute on Drug Abuse (NIDA)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: Britta Hahn, Associate Professor, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT01223404
• Other Study ID Numbers: HP-00042696; R21DA027894
• First Posted: Oct 19, 2010
• Last Update Posted: Aug 19, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Britta Hahn, Associate Professor, University of Maryland, Baltimore: nicotine; mecamylamine; attention; default network; fMRI
• Additional relevant MeSH terms: Mecamylamine; Nicotine

Study Results

Participant Flow

Arm/Group Title	Placebo, Nicotine, Mecamylamine	Nicotine, Placebo, Mecamylamine	Placebo, Mecamylamine, Nicotine	Nicotine, Mecamylamine, Placebo	Mecamylamine, Placebo, Nicotine	Mecamylamine, Nicotine, Placebo
Arm/Group Description	First session: Placebo patch and placebo capsule (filler: methylcellulose) Second session: Nicotine patch and Placebo capsule (filler: methylcellulose) Third session: Placebo patch and Mecamylamine capsule	First session: Nicotine patch and placebo capsule (filler: methylcellulose) Second session: Placebo patch and Placebo capsule (filler: methylcellulose) Third session: Placebo patch and Mecamylamine capsule	First session: Placebo patch and Placebo capsule (filler: methylcellulose) Second session: Placebo patch and Mecamylamine capsule Third session: Nicotine patch and Placebo capsule (filler: methylcellulose)	First session: Nicotine patch and placebo capsule (filler: methylcellulose) Second session: Placebo patch and Mecamylamine capsule Third session: Placebo patch and Placebo capsule (filler: methylcellulose)	First session: Placebo patch and Mecamylamine capsule Second session: Placebo patch and Placebo capsule (filler: methylcellulose) Third session: Nicotine patch and Placebo capsule (filler: methylcellulose)	First session: Placebo patch and Mecamylamine capsule Second session: Nicotine patch and Placebo capsule (filler: methylcellulose) Third session: Placebo patch and Placebo capsule (filler: methylcellulose)
Period Title: First Intervention (1 Day)
STARTED	4	3	4	5	2	3
COMPLETED	4	3	4	4	2	3
NOT COMPLETED	0	0	0	1	0	0
Period Title: First Intervention (1 Day)
STARTED	4	3	4	4	2	3
COMPLETED	3	3	4	4	2	3
NOT COMPLETED	1	0	0	0	0	0
Period Title: First Intervention (1 Day)
STARTED	3	3	4	4	2	3
COMPLETED	3	3	4	3	2	3
NOT COMPLETED	0	0	0	1	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Participants in each of the six arms received all three interventions (placebo, nicotine, mecamylamine).
Overall Participants	21
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	21 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	9 42.9%
Male	12 57.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	13 61.9%
White	7 33.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

18 healthy male and female adult non-smokers. Only study completers are included, due to the within-subject design.

Arm/Group Title	Intervention: Placebo	Intervention: Nicotine	Intervention: Mecamylamine
Arm/Group Description	A placebo patch and a placebo capsule are administered.	A nicotine patch and a placebo capsule is administered.	A placebo patch and a mecamylamine capsule are administered.
Measure Participants	18	18	18
Attention task reaction time	512	492	524
Working memory task reaction time	541	533	573

2. Primary Outcome

Title	Signal Detection Performance
Description	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

Outcome Measure Data

Analysis Population Description

Healthy adult non-smokers (only study completers).

Arm/Group Title	Intervention: Placebo	Intervention: Nicotine	Intervention: Mecamylamine
Arm/Group Description	A placebo patch and a placebo capsule are administered.	A nicotine patch and a placebo capsule are administered.	A placebo patch and a mecamylamine capsule are administered.
Measure Participants	18	18	18
Attention task correct identifications	86.4	93.8	85.2
Working memory task correct detections	89.6	95.5	88.6

3. Primary Outcome

Title	Default Network Activity
Description	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

Outcome Measure Data

Analysis Population Description

Healthy non-smokers (only study completers).

Arm/Group Title	Intervention: Placebo	Intervention: Nicotine	Intervention: Mecamylamine
Arm/Group Description	A placebo patch and a placebo capsule is administered.	A nicotine patch and a placebo capsule are administered.	A placebo patch and a mecamylamine capsule are administered.
Measure Participants	18	18	18
Mean (95% Confidence Interval) [percentage of task-induced signal change]	-0.29	-0.24	-0.21

4. Secondary Outcome

Title	Subjective State
Description	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

Outcome Measure Data

Analysis Population Description

Healthy non-smokers (only study completers).

Arm/Group Title	Intervention: Placebo	Intervention: Nicotine	Intervention: Mecamylamine
Arm/Group Description	A placebo patch and a placebo capsule are administered.	A nicotine patch and a placebo capsule are administered.	A placebo patch and a mecamylamine capsule were administered.
Measure Participants	18	18	18
Mean (95% Confidence Interval) [units on a scale]	-6.7	-9.9	-5.8

5. Secondary Outcome

Title	Systolic Blood Pressure
Description	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)

Outcome Measure Data

Analysis Population Description

Healthy non-smokers

Arm/Group Title	Intervention: Placebo	Intervention: Nicotine	Intervention: Mecamylamine
Arm/Group Description	A placebo patch and a placebo capsule were administered.	A nicotine patch and a placebo capsule were administered.	A placebo patch and a mecamylamine capsule were administered.
Measure Participants	18	18	18
Pre-patch	120.2 (11.4)	120.9 (16.7)	119.3 (14.8)
2 hours post patch	116.1 (11.9)	114.3 (10.7)	112.3 (8.6)
4 hours post patch	120.1 (16.7)	119.1 (9.9)	114.4 (11.4)
6 hours post patch	120.3 (12.9)	122.7 (12.7)	118.2 (14.1)
Post-scan	129.7 (16.1)	127.4 (9.8)	121.5 (13.8)

6. Secondary Outcome

Title	Diastolic Blood Pressure
Description	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).

Outcome Measure Data

Analysis Population Description

Healthy non-smokers (only study completers).

Arm/Group Title	Intervention: Placebo	Intervention: Nicotine	Intervention: Mecamylamine
Arm/Group Description	Placebo patch and placebo capsule.	Nicotine patch and placebo capsule.	Placebo patch and mecamylamine capsule.
Measure Participants	18	18	18
Pre-patch	74.4 (8.0)	71.6 (10.0)	73.4 (10.1)
2 hours post patch	73.4 (10.0)	71.9 (9.9)	73.2 (9.7)
4 hours post patch	73.7 (9.7)	71.1 (7.9)	72.4 (6.9)
6 hours post patch	75.8 (6.6)	75.3 (5.8)	75.2 (8.1)
Post-scan	81.3 (5.4)	81.1 (5.7)	79.6 (9.4)

Adverse Events

Time Frame	1 day (on each of separate 3 test days)
Arm/Group Title	Intervention: Placebo		Intervention: Nicotine		Intervention: Mecamylamine
Arm/Group Description	Participants receive a placebo patch and a placebo capsule.		Participants receive a nicotine patch and a placebo capsule.		Participants receive a placebo patch and a mecamylamine capsule.
All Cause Mortality
	Intervention: Placebo		Intervention: Nicotine		Intervention: Mecamylamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/19 (0%)
Serious Adverse Events
	Intervention: Placebo		Intervention: Nicotine		Intervention: Mecamylamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Intervention: Placebo		Intervention: Nicotine		Intervention: Mecamylamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		2/21 (9.5%)		0/19 (0%)
Gastrointestinal disorders
Vomiting	0/20 (0%)	0	2/21 (9.5%)	2	0/19 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.