Network-Level Effects of Nitrous Oxide in the Human Brain

Study Overview
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Brief Summary
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The purpose of this study is to understand how a commonly used drug, nitrous oxide, acts on the brain to reduce pain. Nitrous oxide is commonly used in anesthesiology but there is limited knowledge on how this drug affects functional networks in the brain.

Detailed Description
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The objective of this study is to identify the network transformations that account for the analgesic effects of nitrous oxide. Our hypothesis is that analgesic doses of nitrous oxide increase network efficiency and disrupt normal pain processingOur approach is to administer subanesthetic nitrous oxide during the acquisition of fMRI (functional magnetic resonance imaging) and EEG (electroencephalogram).

Official Title
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Network-Level Effects of Nitrous Oxide in the Human Brain

Conditions
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Healthy

Intervention / Treatment
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* Drug: Nitrous Oxide Gas for Inhalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index <30 Must be right-handed Must be capable of giving written informed consent Exclusion Criteria: History of obstructive sleep apnea; History of a difficult airway with a previous anesthetic Gastroesophageal reflux; Hypertension or other cardiovascular abnormalities; Pulmonary hypertension; History of recreational drug use; History of chronic alcohol abuse Having any chronic medical illness involving pain; History of major depression; History of psychosis or bipolar disorder; History of methylenetetrahydrofolate reductase deficiency; History of a known hypersensitivity to ketamine, midazolam, Zofran, labetalol or glycopyrrolate History of seizures or other neurologic disorders; Pregnant or nursing mothers; Tattoos on the head or neck region - all other tattoos are subject to determination by investigators; Contraindications to neuroimaging methods; Any impairment, activity or situation that in the judgment of the Study Coordinator or Principal Investigators would prevent satisfactory completion of the study protocol.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nitrous Oxide - inhaled<br>Each volunteer will participate in one scanning visit in which simultaneous functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanalgesic levels (35% inhaled concentration) over 40 minutes. | Drug: Nitrous Oxide Gas for Inhalation<br>* Each volunteer will participate in one scanning visit in which simultaneous functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanesthetic levels (35% inhaled concentration) over 40 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Connectivity During Nitrous Oxide | Functional connectivity measures will be assessed at rest (baseline) and during sub anesthetic dose nitrous oxide (nitrous oxide). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of the BOLD timeseries between two brain regions. Higher z-scores are associated with higher correlations in timeseries and correspond with higher functional connectivity between two brain regions. | Baseline to 50 minutes | 
| Functional Connectivity Associated With Tonic Stimulus | Functional connectivity measures will be assessed at rest (baseline) and during a tonic cuff stimulus (6-minutes). Seed-to-whole brain functional connectivity (Fisher's r-transformed z) will be measured from the left anterior insula, previously shown to be involved in pain and sensory processing. Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. The z-score descriptors represent the Fishers-r-to-z transformed. Here the z-score is a transformation of the Pearson's (r) correlation coefficient of the BOLD timeseries between two brain regions. Higher z-scores are associated with higher correlations in timeseries and correspond with higher functional connectivity between two brain regions. | Baseline to 50 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tonic Stimulus Intensity During Nitrous Oxide | Participants will receive a tonic (6 minutes) pressure applied to the lower leg at baseline and under subanesthetic dose of nitrous oxide (35% inhaled concentration). Following each pressure stimulus, participants will rate the pain intensity of the tonic stimulus (0 =no pain, 10= worst pain imaginable, Visual Analog Scale, e.g pain intensity). | Baseline to 50 minutes | 
| Spectral Power of Sub-anesthetic Dose of Nitrous Oxide | Brain imaging data were obtained from functional magnetic resonance imaging (fMRI) data recorded simultaneously with electroencephalography (EEG) data at baseline and under a sub-anesthetic dose of nitrous oxide. Spectral data were averaged from EEG data at all electrodes collected during the baseline and sub-anesthetic dose (35%) of nitrous oxide to observe changes in spectral power. The EEG power spectrum was divided into three frequency bands: Delta = 1-3 Hz; Theta = 4-7 Hz; and Alpha = 8 - 13 Hz | Baseline to 50 minutes |