Network-Level Effects of Nitrous Oxide in the Human Brain

• ClinicalTrials.gov Identifier: NCT03435055
• Recruitment Status: Completed
• First Posted: February 15, 2018
• Results First Posted: July 9, 2021
• Last Update Posted: November 30, 2021
• Sponsor: University of Michigan
• Information provided by (Responsible Party): Richard Harris, University of Michigan

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: Nitrous Oxide Gas for Inhalation	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Network-Level Effects of Nitrous Oxide in the Human Brain
• Actual Study Start Date: July 21, 2017
• Actual Primary Completion Date: October 11, 2019
• Actual Study Completion Date: October 11, 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Functional Connectivity During Nitrous Oxide [ Time Frame: Baseline to 50 minutes ]
   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.
2. Functional Connectivity Associated With Tonic Stimulus [ Time Frame: Baseline to 50 minutes ]
   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.

Secondary Outcome Measures :

1. Tonic Stimulus Intensity During Nitrous Oxide [ Time Frame: Baseline to 50 minutes ]
   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).
2. Spectral Power of Sub-anesthetic Dose of Nitrous Oxide [ Time Frame: Baseline to 50 minutes ]
   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

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 40 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

United States, Michigan

Michigan Medicine - University of Michigan

Ann Arbor, Michigan, United States, 48109

Sponsors and Collaborators

University of Michigan

Investigators

• Principal Investigator: Richard Harris, PhD; Associate Professor of Anesthesiology and Associate Professor of Internal Medicine

  Study Documents (Full-Text)

Documents provided by Richard Harris, University of Michigan:

Study Protocol and Statistical Analysis Plan  [PDF] July 23, 2020

More Information

• Responsible Party: Richard Harris, Associate Professor of Anesthesiology and Associate Professor of Internal Medicine, University of Michigan
• ClinicalTrials.gov Identifier: NCT03435055
• Other Study ID Numbers: HUM00096321
• First Posted: February 15, 2018
• Results First Posted: July 9, 2021
• Last Update Posted: November 30, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Nitrous Oxide; Anesthetics, Inhalation; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents