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| ID | Type | Description | Link |
|---|---|---|---|
| R35GM146822 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of General Medical Sciences (NIGMS) | NIH |
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The purpose of this study is to determine the effects of pain on long-term memory and conditioned physiologic responses in the presence and absence of distinct intravenous anesthetics. Functional magnetic resonance imaging will be used to identify the neural correlates of these phenomena The study will occur over 5 visits and involves no long-term follow up.
Purpose: Sedative-hypnotic and analgesic agents (termed "anesthetics") are routinely used during medical procedures to prevent or ease suffering, suppressing the conscious experience of pain and its encoding into memory. While overt awareness under general anesthesia is a rare clinical event, implicit memory may still form. Further, at sub-hypnotic anesthetic doses, animals show enhanced fear conditioning and humans may have enhanced amygdala activity. This motivates the investigator's study, as poorly-contextualized aversive memories are theorized to initiate anxiety-spectrum disorders, which may explain the high incidence of post-traumatic stress disorder after anesthetic awareness.
Objective: How anesthetics facilitate or inhibit poorly-contextualized aversive memories is incompletely understood, with little mechanistic work done in human subjects. Thus, there is a critical need to understand how anesthetics modulate the memory and threat response systems during painful stimulation. The overall scientific objective is to determine the memory-modulating effects of propofol, dexmedetomidine, and fentanyl in the context of periodic painful stimulation.
Aim 1: Determine how behavioral and physiologic measures of memory are modulated by pain and the individual effects of three pharmacologically distinct drugs: propofol, dexmedetomidine, and fentanyl. Hypotheses: Based on previous results, 1a) explicit memory will be significantly reduced by propofol and dexmedetomidine, but only modestly by fentanyl. Consistent with my preliminary data, 1b) priming effects will be seen for pain-paired words under all drugs. Electrodermal activity changes still occur with opioids and propofol, thus 1c) pain-related physiologic responses will persist with these two drugs but be blunted by the anti-adrenergic effect of dexmedetomidine.
Aim 2: Determine the brain structures differentially engaged in memory encoding under pain and drug conditions. Task-related functional magnetic resonance imaging (MRI) activity for behavioral measures of explicit or implicit memory will be determined, comparing pain-paired vs non-pain items across drug and no-drug datasets. Functional connectivity (FC) MRI (fcMRI) will be compared between task and drug conditions. The entire brain will be explored, but predictions for key structures follow. Hypotheses: 2a) Hippocampal activity, will be blunted by propofol and dexmedetomidine, while fentanyl will have minimal effect. 2b) Amygdala activity, responsible for physiologic responses, will parallel the predictions in 1c across drug and pain conditions. 2c) Insula activity will be greater for pain-paired items, and this will be attenuated by fentanyl > dexmedetomidine > propofol, corresponding to their anticipated analgesic effect. 2d) Pain has been shown to affect fcMRI during a cognitive task, and thus FC between the key regions in 2a-c will be reduced by all three drugs, in characteristic patterns.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dexmedetomidine | Experimental | Subjects in this group will receive dexmedetomidine during the drug portion of the experiment. |
|
| Propofol | Experimental | Subjects in this group will receive propofol during the drug portion of the experiment. |
|
| Fentanyl | Experimental | Subjects in this group will receive fentanyl during the drug portion of the experiment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dexmedetomidine | Drug | Subjects in this group will receive a intravenous infusion of this drug, during a portion of the study. Dose will be targeted to a brain effect site concentration of 0.15 ng/ml, using pharmacokinetic modelling within the STANPUMP algorithm that accounts for subject's age, gender, height, & weight. |
| Measure | Description | Time Frame |
|---|---|---|
| Explicit Memory Performance | Recognition memory testing, using the Remember-Know procedure, in which subjects indicate whether they recognize previously experienced experimental items among novel items (not previously in the experiment). This allows calculation of interdependent measures of recollection & familiarity using the signal detection statistic, d'. d' is calculated as the cumulative Gaussian distribution of false positive responses subtracted from the cumulative Gaussian distribution of correctly identified previously-experienced items. d' is on a (theoretically infinite) scale of standard deviation units, with negative values representing performance worse than chance guessing and positive values representing stand deviations of performance above chance. | 24-hrs post-experiment |
| Measure | Description | Time Frame |
|---|---|---|
| Brain Activation in the Hippocampus for Successful Memory Formation: Placebo Condition Minus Drug Condition | The Z-score is calculated by linear regression of the task timing against the MRI signal time-course (MRI data is in arbitrary units with no maximum or minimum) at each voxel (single data point in brain). The outcome is listed for the hippocampus, but similar scores are calculated throughout the brain. Z-score of 0 indicates no task-related changes. Z-scores further from zero indicate a larger difference in brain activity, with positive values indicating decreases under the drug condition, while negative Z-scores indicate increases under drug, compared to control. This outcome is reported as a number, as it is calculated using all the data across subjects combined into one statistical measure for the overall strength of difference in MRI signal change between two groups of data. Dispersion measures cannot be calculated for the summary Z-score. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Keith M Vogt, MD, PhD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | 15213 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Propofol | Subjects in this group received propofol during the drug portion of the experiment. |
| FG001 | Dexmedetomidine | Subjects in this group received dexmedetomidine during the drug portion of the experiment. |
| FG002 | Fentanyl | Subjects in this group received fentanyl during the drug portion of the experiment. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Propofol | Subjects in this group received intravenous propofol, during a portion of the study. Dose was targeted to an effect site concentration of 1.0 mcg/ml, using pharmacokinetic modelling that accounts for subject's age, gender, height, & weight. |
| BG001 | Dexmedetomidine |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Explicit Memory Performance | Recognition memory testing, using the Remember-Know procedure, in which subjects indicate whether they recognize previously experienced experimental items among novel items (not previously in the experiment). This allows calculation of interdependent measures of recollection & familiarity using the signal detection statistic, d'. d' is calculated as the cumulative Gaussian distribution of false positive responses subtracted from the cumulative Gaussian distribution of correctly identified previously-experienced items. d' is on a (theoretically infinite) scale of standard deviation units, with negative values representing performance worse than chance guessing and positive values representing stand deviations of performance above chance. | Posted | Mean | 95% Confidence Interval | units on a scale | 24-hrs post-experiment |
|
Adverse event data was collected throughout the entire study period, at 5 study visits taking place over up to 3 months.
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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 | Propofol | Subjects in this group received intravenous propofol, during a portion of the study. Dose was targeted to an effect site concentration of 1.0 mcg/ml, using pharmacokinetic modelling that accounts for subject's age, gender, height, & weight. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| nausea | Gastrointestinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Keith Vogt, MD, PhD | University of Pittsburgh | 4126473147 | vogtkm@upmc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 2, 2024 | Mar 6, 2025 | Prot_001.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 2, 2024 | Mar 6, 2025 | SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 2, 2024 | Jun 27, 2024 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D010146 | Pain |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D020927 | Dexmedetomidine |
| D015742 | Propofol |
| D005283 | Fentanyl |
| D004561 | Transcutaneous Electric Nerve Stimulation |
| D012965 | Sodium Chloride |
| D005440 | Fluid Therapy |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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Placebo-controlled, within-subject, crossover between no-drug and assigned drug (in randomized order)
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single-blind
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| Propofol | Drug | Subjects in this group will receive a intravenous infusion of this drug, during a portion of the study. Dose will be targeted to a brain effect site concentration of 0.7 mcg/ml, using pharmacokinetic modelling within the STANPUMP algorithm that accounts for subject's age, gender, height, & weight. |
|
|
| Fentanyl | Drug | Subjects in this group will receive a intravenous infusion of this drug, during a portion of the study. Dose will be targeted to a brain effect site concentration of 0.9 ng/ml, using pharmacokinetic modelling within the STANPUMP algorithm that accounts for subject's age, gender, height, & weight. |
|
|
| Peripheral Nerve Stimulation | Device | Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired randomly with some of the experimental cues. |
|
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| Placebo | Drug | Crystalloid IV solution will be infused, with no active drug. |
|
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| Immediately after each experimental item |
| Heart Rate Response | Heart rate changes (measured by electrocardiogram, EKG) were planned to be determined following experimental stimuli that delivered as part of the experiment. A 1-6 second window of physiologic data will be analyzed for changes in the peak of the EKG response (R-wave), allowing calculation of instantaneous heart rate. Increases in heart rate are well-known to correlate to sympathetic nervous system activity increases. | Immediately after each experimental item |
| Skin Response | Electrodermal activity (galvanic skin) response was planned to be determined following experimental stimuli that delivered as part of the experiment. A 1-6 second window of physiologic data will be analyzed for changes in electrodermal activity, measured from the palm of subjects' hand. this well-established measure indicates sweat gland activity and is correlated to sympathetic nervous system activity increases. | Immediately after each experimental item |
Subjects in this group received intravenous dexmedetomidine, during a portion of the study. Dose was targeted to an effect site concentration of 0.15 ng/ml, using pharmacokinetic modelling that accounts for subject's age, gender, height, & weight. |
| BG002 | Fentanyl | Subjects in this group received intravenous fentanyl, during a portion of the study. Dose was targeted to a brain effect site concentration of 0.9 ng/ml, using pharmacokinetic modelling that accounts for subject's age, gender, height, & weight. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Propofol | Data from subjects assigned to propofol group, from experimental session in which they were under a steady-state effect site concentration of propofol of 1.0 mcg/ml. |
| OG002 | Dexmedetomidine | Data from subjects assigned to dexmedetomidine group, from experimental session in which they were under a steady-state effect site concentration of dexmedetomidine of 0.15 ng/ml. |
| OG003 | Fentanyl | Data from subjects assigned to fentanyl group, from experimental session in which they were under a steady-state effect site concentration of fentanyl of 0.9 ng/ml. |
|
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| Secondary | Brain Activation in the Hippocampus for Successful Memory Formation: Placebo Condition Minus Drug Condition | The Z-score is calculated by linear regression of the task timing against the MRI signal time-course (MRI data is in arbitrary units with no maximum or minimum) at each voxel (single data point in brain). The outcome is listed for the hippocampus, but similar scores are calculated throughout the brain. Z-score of 0 indicates no task-related changes. Z-scores further from zero indicate a larger difference in brain activity, with positive values indicating decreases under the drug condition, while negative Z-scores indicate increases under drug, compared to control. This outcome is reported as a number, as it is calculated using all the data across subjects combined into one statistical measure for the overall strength of difference in MRI signal change between two groups of data. Dispersion measures cannot be calculated for the summary Z-score. | Posted | Number | Z-score for difference | Immediately after each experimental item |
|
|
|
| Secondary | Heart Rate Response | Heart rate changes (measured by electrocardiogram, EKG) were planned to be determined following experimental stimuli that delivered as part of the experiment. A 1-6 second window of physiologic data will be analyzed for changes in the peak of the EKG response (R-wave), allowing calculation of instantaneous heart rate. Increases in heart rate are well-known to correlate to sympathetic nervous system activity increases. | Acquisition of EKG data was not possible in the scanner, due to interference from the magnetic field. This is why the outcome cannot be reported. | Posted | Immediately after each experimental item |
|
|
| Secondary | Skin Response | Electrodermal activity (galvanic skin) response was planned to be determined following experimental stimuli that delivered as part of the experiment. A 1-6 second window of physiologic data will be analyzed for changes in electrodermal activity, measured from the palm of subjects' hand. this well-established measure indicates sweat gland activity and is correlated to sympathetic nervous system activity increases. | Acquisition of skin conductance data was not possible in the scanner, due to interference from the magnetic field. This is why the outcome cannot be reported. | Posted | Immediately after each experimental item |
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 0 |
| 30 |
| EG001 | Dexmedetomidine | Subjects in this group received intravenous dexmedetomidine, during a portion of the study. Dose was targeted to an effect site concentration of 0.15 ng/ml, using pharmacokinetic modelling that accounts for subject's age, gender, height, & weight. | 0 | 29 | 0 | 29 | 0 | 29 |
| EG002 | Fentanyl | Subjects in this group received intravenous fentanyl, during a portion of the study. Dose was targeted to a brain effect site concentration of 0.9 ng/ml, using pharmacokinetic modelling that accounts for subject's age, gender, height, & weight. | 0 | 33 | 0 | 33 | 2 | 33 |
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| D010636 |
| Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D010880 | Piperidines |
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D026741 | Physical Therapy Modalities |
| D012046 | Rehabilitation |
| D000698 | Analgesia |
| D000760 | Anesthesia and Analgesia |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D004358 | Drug Therapy |