Healthy
Conditions
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.
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).
Interventions
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.
Sponsors
University of Michigan
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 40 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Pre-assignment details
A total of 21 participants consented to participate but 2 participants did not participate in any part of the research.
Participants by arm
| Arm | Count |
|---|---|
| Nitrous Oxide - Inhaled 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. | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Received Intervention | Did not complete nitrous administration | 3 |
| Screening | Physician Decision | 2 |
Baseline characteristics
| Characteristic | Nitrous Oxide - Inhaled |
|---|---|
| Age, Continuous | 25 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 19 |
| other Total, other adverse events | 2 / 19 |
| serious Total, serious adverse events | 0 / 19 |
Outcome results
Primary
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.
Time frame: Baseline to 50 minutes
Population: Number of participants scanned.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre-Nitrous | Functional Connectivity Associated With Tonic Stimulus | -0.0509 Z score | Standard Deviation 0.0822 |
| Nitrous Oxide - Subanesthetic Dose | Functional Connectivity Associated With Tonic Stimulus | 0.0486 Z score | Standard Deviation 0.1001 |
Comparison: 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.p-value: 0.006t-test, 2 sided
Primary
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.
Time frame: Baseline to 50 minutes
Population: Three participants had missing data because they did not complete the full scanning protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre-Nitrous | Functional Connectivity During Nitrous Oxide | L superior frontal gyrus | 0.1123 Fisher's r transformed z score | Standard Deviation 0.0639 |
| Pre-Nitrous | Functional Connectivity During Nitrous Oxide | R superior frontal gyrus | 0.1492 Fisher's r transformed z score | Standard Deviation 0.1179 |
| Nitrous Oxide - Subanesthetic Dose | Functional Connectivity During Nitrous Oxide | L superior frontal gyrus | 0.0358 Fisher's r transformed z score | Standard Deviation 0.062 |
| Nitrous Oxide - Subanesthetic Dose | Functional Connectivity During Nitrous Oxide | R superior frontal gyrus | 0.0394 Fisher's r transformed z score | Standard Deviation 0.095 |
Comparison: 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.p-value: 0.001t-test, 2 sided
Secondary
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
Time frame: Baseline to 50 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pre-Nitrous | Spectral Power of Sub-anesthetic Dose of Nitrous Oxide | Theta | 11.88 dB (decibels) | Standard Deviation 1.89 |
| Pre-Nitrous | Spectral Power of Sub-anesthetic Dose of Nitrous Oxide | Delta | 13.31 dB (decibels) | Standard Deviation 2.2 |
| Pre-Nitrous | Spectral Power of Sub-anesthetic Dose of Nitrous Oxide | Alpha | 6.72 dB (decibels) | Standard Deviation 1.92 |
| Nitrous Oxide - Subanesthetic Dose | Spectral Power of Sub-anesthetic Dose of Nitrous Oxide | Theta | 12.80 dB (decibels) | Standard Deviation 1.87 |
| Nitrous Oxide - Subanesthetic Dose | Spectral Power of Sub-anesthetic Dose of Nitrous Oxide | Delta | 14.65 dB (decibels) | Standard Deviation 2.56 |
| Nitrous Oxide - Subanesthetic Dose | Spectral Power of Sub-anesthetic Dose of Nitrous Oxide | Alpha | 6.97 dB (decibels) | Standard Deviation 2.05 |
Comparison: Deltap-value: 0.0622Paired t-test
Comparison: Thetap-value: 0.0292Paired t-test
Comparison: Alpha comparisonp-value: 0.5905Paired t-test
Secondary
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).
Time frame: Baseline to 50 minutes
Population: Three participants had missing data because they did not complete the full scanning protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pre-Nitrous | Tonic Stimulus Intensity During Nitrous Oxide | 4.9688 score on a scale | Standard Deviation 1.217 |
| Nitrous Oxide - Subanesthetic Dose | Tonic Stimulus Intensity During Nitrous Oxide | 2.500 score on a scale | Standard Deviation 2.309 |
Comparison: 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.p-value: <0.01t-test, 2 sided