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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nitrous Oxide - inhaled | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nitrous Oxide Gas for Inhalation | Drug | 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Richard Harris, PhD | Associate Professor of Anesthesiology and Associate Professor of Internal Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Michigan Medicine - University of Michigan | Ann Arbor | Michigan | 48109 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37031827 | Derived | Dai R, Larkin TE, Huang Z, Tarnal V, Picton P, Vlisides PE, Janke E, McKinney A, Hudetz AG, Harris RE, Mashour GA. Classical and non-classical psychedelic drugs induce common network changes in human cortex. Neuroimage. 2023 Jun;273:120097. doi: 10.1016/j.neuroimage.2023.120097. Epub 2023 Apr 7. |
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A total of 21 participants consented to participate but 2 participants did not participate in any part of the research.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Screening |
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| Received Intervention |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Average age of participant, continuous |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Three participants had missing data because they did not complete the full scanning protocol. | Posted | Mean | Standard Deviation | Fisher's r transformed z score | Baseline to 50 minutes |
|
Adverse event data was collected for 24 hours.
The definition of adverse event and/or serious adverse event does not differ from the clinicaltrials.gov definition.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Tachycardia | General disorders | Non-systematic Assessment | Tachycardia |
Data for the Spectral Power of Sub-anesthetic Dose of Nitrous Oxide outcome measure will be analyzed within the coming year and the ClinicalTrials.gov record will be updated at that time.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Richard Harris | University of Michigan | 734-998-6996 | reharris@umich.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 23, 2020 | Apr 20, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D045462 | Endothelium-Dependent Relaxing Factors |
| D001239 | Inhalation |
| ID | Term |
|---|---|
| D014665 | Vasodilator Agents |
| D002317 | Cardiovascular Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
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|
| 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 |
|
| Mean |
| Full Range |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Pre-Nitrous |
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. |
| OG001 | Nitrous Oxide - Subanesthetic Dose | 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. |
|
|
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| 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. | Number of participants scanned. | Posted | Mean | Standard Deviation | Z score | Baseline to 50 minutes |
|
|
|
|
| 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). | Three participants had missing data because they did not complete the full scanning protocol. | Posted | Mean | Standard Deviation | score on a scale | Baseline to 50 minutes |
|
|
|
|
| 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 | Posted | Mean | Standard Deviation | dB (decibels) | Baseline to 50 minutes |
|
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|
|
| 0 |
| 19 |
| 0 |
| 19 |
| 2 |
| 19 |
| Emesis | General disorders | Non-systematic Assessment |
|
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| D020164 |
| Chemical Actions and Uses |
| D015656 | Respiratory Mechanics |
| D012119 | Respiration |
| D012143 | Respiratory Physiological Phenomena |
| D002943 | Circulatory and Respiratory Physiological Phenomena |
| Alpha |
|
| 0.0292 |
| Other |
Paired T-test comparing baseline to nitrous |
| Alpha comparison | Paired t-test | 0.5905 | Other | Paired T-test comparing baseline to nitrous |