Nicotine Related Brain Activity: The Influence of Smoking History and Blood Nicotine Levels

Study Overview
=================
Brief Summary
-----------------
In this study, we sought to explore brain activity in nicotine-dependent men in response to acute intravenous nicotine using pharmacological magnetic resonance imaging (phMRI).

Detailed Description
-----------------
phMRI was used to evaluate brain activity in response to 1.5 mg/70 kg intravenous nicotine or saline. The nicotine and saline were administered on different visits. The time courses of individual subjects' nicotine levels were used as regressors to assess neural activity relating to the infusions. The influence of Smoking history and physiological measures on the response to nicotine were also investigated.

Official Title
-----------------
Nicotine Related Brain Activity: The Influence of Smoking History and Blood Nicotine Levels, an Exploratory Study

Conditions
-----------------
Nicotine Dependence

Intervention / Treatment
-----------------
* Drug: Intravenous Nicotine
* Other: Saline - placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women between the ages of 18 and 40 who currently smoke at least 15 cigarettes every day, and who fulfill DSM-IV diagnostic criteria for nicotine dependence will be eligible for participation. No evidence of clinically significant disease based upon complete medical history and physical examination by a qualified physician. Absence of DSM-IV Axis I Disorders other than nicotine dependence (305.10) as measured by the Structured Clinical Interview (SCID). Routine laboratory blood tests including complete blood count, electrolytes, BUN and creatinine, liver function tests, hepatitis panel and urinalysis will be performed. Laboratory parameters must be within the normal range. HBsAg must be negative but subjects who have hepatitis serology consistent with previous exposure to Hepatitis A, Hepatitis B, or Hepatitis C, but who do not have clinical and biochemical evidence of acute infection, will be acceptable. Hematocrit levels ≥ 39% for males and ≥ 35% for females. Serum pregnancy test (hCG beta subunit) results must be negative within 24 hrs of the study day. Normal ECG. A Body Mass Index (BMI-ratio of weight (W) to height (H) squared; W/H2=kg/m2) of between 18.0 and 27.0 for women and 21.4 to 29 for men. Subjects must be able to read and understand instructions, as well as provide a valid informed consent. Exclusion Criteria: Participants with any lifetime DSM-IV Axis I disorder other than nicotine dependence. Participants with clinically significant medical disorders. Women who are pregnant as determined by laboratory testing for serum beta hCG. Women who use hormonal contraceptive medications will not be accepted, because this would confound the hormonal measures. Women with a mean BMI of outside the range 18.0-27.0 and men with a BMI outside the range 21.4-29.0. Participants with ferromagnetic implants or other contraindications to fMRI Cardiac pacemakers Metal clips on blood vessels (also called stents) Artificial heart valves Artificial arms, hands, legs, etc. Brain stimulator devices Implanted drug pumps Ear implants Eye implants or known metal fragments in eyes Exposure to shrapnel or metal filings (wounded in military combat, sheet metal workers, welders, and others) Other metallic surgical hardware in vital areas Certain tattoos with metallic ink Transdermal patches (eg. Orthro Evra, Nicoderm CQ) Metal IUD (s) Participants who describe themselves as seeking treatment will not be selected but will be referred to local smoking cessation programs.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intravenous Nicotine (1.5 mg/70 kg)<br>Participants are given a siingle infusion of nicotine (1.5 mg/70 kg), administered over 1 minute into the antecubital vein 10 minutes into their MRI scans | Drug: Intravenous Nicotine<br>* Subjects received a single infusion of nicotine, 1.5 mg/70kg (New England Compounding Center, Framingham, MA), administered over 1 minute into the antecubital vein 10 minutes into their MRI scans.<br>* Other names: IV Nicotine;|
| Placebo Comparator: Saline - placebo<br>Participants are given physiological saline, administered over 1 minute into the antecubital vein 10 minutes into their MRI scans | Other: Saline - placebo<br>* Subjects received a single infusion of saline, administered over 1 minute into the antecubital vein 10 minutes into their MRI scans.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Nicotine Levels | Peak nicotine level in each participant | 0, 2, 4, 6, 8, 10, 12, 14, 16, 20, 30 minutes post-infusion | 
| Number of Brain Regions With a Change in Brain Activity Relative to Saline | PhMRI analysis of the differential response of nicotine compared to the saline condition when analyzed with the nicotine time course. The main dependent variable in this study, Blood Oxygen Level Dependent (BOLD) measures of brain activity (via fMRI) data does not exist in a vacuum-it is always relative to another measure of brain activity, typically collected at rest or after a placebo injection. So we collected the data after the IV placebo injection alone and the IV nicotine injection alone, but then need applied mathematical CONTRASTS to the data. This procedure results in the brain activity maps. | 40 minutes after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Brain Regions With a Change in Brain Activity Relative to Saline When Analyzed With the Nicotine Time Course Controlling for Smoking History | PhMRI analysis of the differential response of nicotine compared to the saline condition when analyzed with the nicotine time course controlling for smoking history (pack years). The main dependent variable in this study, Blood Oxygen Level Dependent (BOLD) measures of brain activity (via fMRI) data does not exist in a vacuum-it is always relative to another measure of brain activity, typically collected at rest or after a placebo injection. So we collected the data after the IV placebo injection alone and the IV nicotine injection alone, but then need applied mathematical CONTRASTS to the data. This procedure results in the brain activity maps. | 40 minutes after infusion | 
| Number of Brain Regions With a Change in Brain Activity Relative to Saline When Analyzed With Smoking History Controlling for Nicotine | PhMRI analysis of the differential response of nicotine compared to the saline condition when analyzed with smoking history (pack years) controlling for nicotine. The main dependent variable in this study, Blood Oxygen Level Dependent (BOLD) measures of brain activity (via fMRI) data does not exist in a vacuum-it is always relative to another measure of brain activity, typically collected at rest or after a placebo injection. So we collected the data after the IV placebo injection alone and the IV nicotine injection alone, but then need applied mathematical CONTRASTS to the data. This procedure results in the brain activity maps. | 40 minutes after infusion | 
| Final Nicotine Levels | Final nicotine level in each participant | 30 minutes post-infusion |