Network-Level Effects of Nitrous Oxide in the Human Brain

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Nitrous Oxide Gas for Inhalation

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Michigan Medicine - University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Body mass index <30
2. Must be right-handed
3. Must be capable of giving written informed consent

Exclusion Criteria:

1. History of obstructive sleep apnea;
2. History of a difficult airway with a previous anesthetic
3. Gastroesophageal reflux;
4. Hypertension or other cardiovascular abnormalities;
5. Pulmonary hypertension;
6. History of recreational drug use;
7. History of chronic alcohol abuse
8. Having any chronic medical illness involving pain;
9. History of major depression;
10. History of psychosis or bipolar disorder;
11. History of methylenetetrahydrofolate reductase deficiency;
12. History of a known hypersensitivity to ketamine, midazolam, Zofran, labetalol or glycopyrrolate
13. History of seizures or other neurologic disorders;
14. Pregnant or nursing mothers;
15. Tattoos on the head or neck region - all other tattoos are subject to determination by investigators;
16. Contraindications to neuroimaging methods;
17. Any impairment, activity or situation that in the judgment of the Study Coordinator or Principal Investigators would prevent satisfactory completion of the study protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nitrous Oxide - inhaled; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Principal Investigator: Richard Harris, PhD, Associate Professor of Anesthesiology and Associate Professor of Internal Medicine

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 21, 2017
• Primary Completion (ACTUAL): October 11, 2019
• Study Completion (ACTUAL): October 11, 2019

Study Registration Dates

• First Submitted: January 25, 2018
• First Submitted That Met QC Criteria: February 14, 2018
• First Posted (ACTUAL): February 15, 2018

Study Record Updates

• Last Update Posted (ACTUAL): November 30, 2021
• Last Update Submitted That Met QC Criteria: November 2, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Anesthetics, Inhalation; Nitrous Oxide
• Other Study ID Numbers: HUM00096321

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No