Network-Level Effects of Nitrous Oxide in the Human Brain
Study Details
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 |
---|---|---|
|
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
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
- Functional Connectivity During Nitrous Oxide [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.
- Functional Connectivity Associated With Tonic Stimulus [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
- Tonic Stimulus Intensity During Nitrous Oxide [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).
- Spectral Power of Sub-anesthetic Dose of Nitrous Oxide [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
Criteria
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | 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)
More Information
Publications
None provided.- HUM00096321
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | A total of 21 participants consented to participate but 2 participants did not participate in any part of the research. |
Arm/Group Title | Nitrous Oxide - Inhaled |
---|---|
Arm/Group Description | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanalgesic levels (35% inhaled concentration) over 30 minutes. |
Period Title: Screening | |
STARTED | 21 |
COMPLETED | 19 |
NOT COMPLETED | 2 |
Period Title: Screening | |
STARTED | 19 |
COMPLETED | 16 |
NOT COMPLETED | 3 |
Baseline Characteristics
Arm/Group Title | Nitrous Oxide - Inhaled |
---|---|
Arm/Group Description | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanalgesic levels (35% inhaled concentration) over 30 minutes. |
Overall Participants | 21 |
Age (years) [Mean (Full Range) ] | |
Mean (Full Range) [years] |
25
|
Sex: Female, Male (Count of Participants) | |
Female |
11
52.4%
|
Male |
10
47.6%
|
Ethnicity (NIH/OMB) (Count of Participants) | |
Hispanic or Latino |
0
0%
|
Not Hispanic or Latino |
21
100%
|
Unknown or Not Reported |
0
0%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
4
19%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
2
9.5%
|
White |
14
66.7%
|
More than one race |
0
0%
|
Unknown or Not Reported |
1
4.8%
|
Outcome Measures
Title | Functional Connectivity During Nitrous Oxide |
---|---|
Description | 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. |
Time Frame | Baseline to 50 minutes |
Outcome Measure Data
Analysis Population Description |
---|
Three participants had missing data because they did not complete the full scanning protocol. |
Arm/Group Title | Pre-Nitrous | Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Arm/Group Description | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected as they receive oxygen (20 minutes) followed Functional connectivity (Fisher's r to z transformed) between the left anterior insula and superior frontal gyrus were measured at baseline. | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected as they received subanesthetic dose of nitrous oxide at (35% inhaled concentration) over 30 minutes. Functional connectivity (z-score) between the left anterior insula and superior frontal gyrus were measured during administration of subanesthetic nitrous oxide. |
Measure Participants | 16 | 16 |
L superior frontal gyrus |
0.1123
(0.0639)
|
0.0358
(0.0620)
|
R superior frontal gyrus |
0.1492
(0.1179)
|
0.0394
(0.0950)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Pre-Nitrous, Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Comments | Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. Hypothesis was that the results would be deemed significant at false discovery rate (FDR) cluster level corrected p < 0.05 derived from a voxel-wise uncorrected p-value < 0.001. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.001 |
Comments | ||
Method | t-test, 2 sided | |
Comments |
Title | Functional Connectivity Associated With Tonic Stimulus |
---|---|
Description | 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. |
Time Frame | Baseline to 50 minutes |
Outcome Measure Data
Analysis Population Description |
---|
Number of participants scanned. |
Arm/Group Title | Pre-Tonic Cuff | Tonic Cuff Stimulus |
---|---|---|
Arm/Group Description | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected as they receive oxygen (20 minutes) at rest and during a tonic cuff stimulus applied to the leg (6 minutes). Functional connectivity (Fisher's r to z score transformed) between the left anterior insula and the postcentral gyrus prior to (baseline) and during a tonic cuff stimulus. | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected while a tonic cuff stimulus was applied to the calf of the left leg (6 minutes). Functional connectivity (z score) was measured between the left anterior insula and the right postcentral gyrus from the fMRI data during the tonic cuff stimulus. |
Measure Participants | 19 | 19 |
Mean (Standard Deviation) [Z score] |
-0.0509
(0.0822)
|
0.0486
(0.1001)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Pre-Nitrous, Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Comments | Paired t-test were conducted on subject specific beta maps to identify changes in connectivity associated with nitrous oxide in SPM12. Hypothesis was that results would be deemed significant at false discovery rate (FDR) cluster level corrected p < 0.05 derived from a voxel-wise uncorrected p-value < 0.001. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.006 |
Comments | ||
Method | t-test, 2 sided | |
Comments |
Title | Tonic Stimulus Intensity During Nitrous Oxide |
---|---|
Description | 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). |
Time Frame | Baseline to 50 minutes |
Outcome Measure Data
Analysis Population Description |
---|
Three participants had missing data because they did not complete the full scanning protocol. |
Arm/Group Title | Pre-nitrous | Nitrous Oxide - 35% Inhaled Concentration |
---|---|---|
Arm/Group Description | Participants will receive a tonic (6 minutes) pressure applied to the lower leg prior to (baseline) and during administration of 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. | Participants will receive a tonic (6 minutes) pressure applied to the lower leg prior to (baseline) and during administration of 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. |
Measure Participants | 16 | 16 |
Mean (Standard Deviation) [score on a scale] |
4.9688
(1.217)
|
2.500
(2.309)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Pre-Nitrous, Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Comments | Paired-t tests were conducted to determine whether changes in stimulus intensity: post stimulus at baseline and under subanesthetic dose of nitrous oxide. Statistical tests were completed in SPSS 26 and determined by p < 0.05. | |
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.01 |
Comments | ||
Method | t-test, 2 sided | |
Comments |
Title | Spectral Power of Sub-anesthetic Dose of Nitrous Oxide |
---|---|
Description | 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 |
Time Frame | Baseline to 50 minutes |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Pre-Nitrous | Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Arm/Group Description | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected as they receive oxygen (20 minutes) followed | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected as they received subanesthetic dose of nitrous oxide at (35% inhaled concentration) over 30 minutes. |
Measure Participants | 16 | 16 |
Delta |
13.31
(2.20)
|
14.65
(2.56)
|
Theta |
11.88
(1.89)
|
12.80
(1.87)
|
Alpha |
6.72
(1.92)
|
6.97
(2.05)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Pre-Nitrous, Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Comments | Delta | |
Type of Statistical Test | Other | |
Comments | Paired T-test comparing baseline to nitrous | |
Statistical Test of Hypothesis | p-Value | 0.0622 |
Comments | ||
Method | Paired t-test | |
Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Pre-Nitrous, Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Comments | Theta | |
Type of Statistical Test | Other | |
Comments | Paired T-test comparing baseline to nitrous | |
Statistical Test of Hypothesis | p-Value | 0.0292 |
Comments | ||
Method | Paired t-test | |
Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Pre-Nitrous, Nitrous Oxide - Subanesthetic Dose |
---|---|---|
Comments | Alpha comparison | |
Type of Statistical Test | Other | |
Comments | Paired T-test comparing baseline to nitrous | |
Statistical Test of Hypothesis | p-Value | 0.5905 |
Comments | ||
Method | Paired t-test | |
Comments |
Adverse Events
Time Frame | Adverse event data was collected for 24 hours. | |
---|---|---|
Adverse Event Reporting Description | The definition of adverse event and/or serious adverse event does not differ from the clinicaltrials.gov definition. | |
Arm/Group Title | Nitrous Oxide - Inhaled | |
Arm/Group Description | Each volunteer will participate in one scanning visit in which simultaneous fMRI/EEG data will be collected wherein they receive placebo (20 minutes) followed by inhaled nitrous oxide at subanalgesic levels (35% inhaled concentration) over 30 minutes. A total of 21 participants consented to participate but 2 participants did not participate in any part of the research and thus no adverse events data could have been collected. | |
All Cause Mortality |
||
Nitrous Oxide - Inhaled | ||
Affected / at Risk (%) | # Events | |
Total | 0/19 (0%) | |
Serious Adverse Events |
||
Nitrous Oxide - Inhaled | ||
Affected / at Risk (%) | # Events | |
Total | 0/19 (0%) | |
Other (Not Including Serious) Adverse Events |
||
Nitrous Oxide - Inhaled | ||
Affected / at Risk (%) | # Events | |
Total | 2/19 (10.5%) | |
General disorders | ||
Tachycardia | 1/19 (5.3%) | 1 |
Emesis | 1/19 (5.3%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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.
Results Point of Contact
Name/Title | Richard Harris |
---|---|
Organization | University of Michigan |
Phone | 734-998-6996 |
reharris@umich.edu |
- HUM00096321