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Memory & Conditioning Under Anesthesia (MCA)

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ClinicalTrials.gov Identifier: NCT04062123
Recruitment Status : Recruiting
First Posted : August 20, 2019
Last Update Posted : June 15, 2021
Sponsor:
Collaborator:
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
Keith M. Vogt, MD, PhD, University of Pittsburgh

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Anesthesia Pain Drug: Dexmedetomidine Drug: Propofol Drug: Fentanyl Device: Peripheral Nerve Stimulation Drug: Placebo Phase 1

Detailed Description:

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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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Placebo-controlled, within-subject
Masking: Single (Participant)
Masking Description: single-blind
Primary Purpose: Basic Science
Official Title: Modulation of Memory and Conditioning by Pain During Sedation With Anesthetics
Actual Study Start Date : July 30, 2020
Estimated Primary Completion Date : June 1, 2023
Estimated Study Completion Date : June 1, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Memory
Drug Information available for: Fentanyl

Arm Intervention/treatment
Experimental: Dexmedetomidine
Subjects in this group will receive dexmedetomidine during the drug portion of the experiment.
Drug: Dexmedetomidine
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.
Other Name: Precedex

Device: Peripheral Nerve Stimulation
Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired randomly with some of the experimental cues.
Other Name: Electric Nerve Stimulation

Drug: Placebo
Crystalloid IV solution will be infused, with no active drug.
Other Name: saline, IV fluid

Experimental: Propofol
Subjects in this group will receive propofol during the drug portion of the experiment.
Drug: Propofol
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.
Other Name: Diprivan

Device: Peripheral Nerve Stimulation
Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired randomly with some of the experimental cues.
Other Name: Electric Nerve Stimulation

Drug: Placebo
Crystalloid IV solution will be infused, with no active drug.
Other Name: saline, IV fluid

Experimental: Fentanyl
Subjects in this group will receive fentanyl during the drug portion of the experiment.
Drug: Fentanyl
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.
Other Name: fentanyl citrate

Device: Peripheral Nerve Stimulation
Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired randomly with some of the experimental cues.
Other Name: Electric Nerve Stimulation

Drug: Placebo
Crystalloid IV solution will be infused, with no active drug.
Other Name: saline, IV fluid




Primary Outcome Measures :
  1. Explicit memory performance [ Time Frame: 24-hrs post-experiment ]
    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.


Secondary Outcome Measures :
  1. Brain activity in hippocampus and amygdala [ Time Frame: Immediately after each experimental item ]
    Blood-oxygen level dependent (BOLD) weighted MRI images of the brain will be obtained every 1 second during the drug+pain experimental procedure. Local changes in blood flow, which correlate to increased neuronal activity, can be detected that correlate in time to experimental events. This will allow drug vs. placebo comparisons for brain activity for successful vs unsuccessful memory encoding. The output data will include anatomical localization of brain activity differences, along with the statistical intensity (z-score) of such differences.

  2. Heart rate response [ Time Frame: Immediately after each experimental item ]
    Heart rate changes (measured by electrocardiogram, EKG) will 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.

  3. Skin response [ Time Frame: Immediately after each experimental item ]
    Electrodermal activity (galvanic skin) response will 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 39 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Adults, age 18-39, who are native English speakers with at least a high school education
  • have normal hearing and memory
  • be of normal body-weight
  • be generally healthy (free from significant chronic disease)
  • have none of the specific exclusion criteria
  • have a valid email address and valid phone number throughout the study
  • anticipate ability to participate in all visits required for the phase of the study in which they are enrolled

Exclusion Criteria:

  • Pregnancy
  • Body mass index > 35 (obese) or < 18 (underweight)
  • Use of psychotropic medications, including anti-epileptics, anti-psychotics, anxiolytics, anti-depressants, stimulants, sleep-aids, anti-histamines, or analgesics
  • History of adverse reaction to OR abuse of: dexmedetomidine (Precedex), propofol (Diprivan) or the opioids class of medications (fentanyl, morphine, hydromorphone, etc)
  • History of clinically significant memory or hearing loss
  • History of obstructive sleep apnea
  • History of neurologic or psychiatric disease, including benign tremor
  • History of significant cardiac disease, including high blood pressure or arrhythmia
  • History of significant pulmonary disease
  • History of diabetes or neuropathy
  • History of chronic pain, or other pain processing disorder
  • Have an implanted medical electronic device
  • Have indwelling or implanted metal in their body that is not MRI-compatible
  • Have claustrophobia
  • Have a history of drug abuse

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04062123


Contacts
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Contact: Keith M Vogt, MD, PhD 4126473147 vogtkm@upmc.edu

Locations
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United States, Pennsylvania
University of Pittsburgh Medical Center Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Keith M Vogt, MD, PhD    412-647-3147    vogtkm@upmc.edu   
Principal Investigator: Keith M Vogt, MD, PhD         
Sub-Investigator: James W Ibinson, MD, PhD         
Sponsors and Collaborators
Keith M. Vogt, MD, PhD
National Institute of General Medical Sciences (NIGMS)
Investigators
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Principal Investigator: Keith M Vogt, MD, PhD University of Pittsburgh
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Responsible Party: Keith M. Vogt, MD, PhD, Assistant Professor of Anesthesiology & Perioperative Medicine and Bioengineering, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT04062123    
Other Study ID Numbers: STUDY19030183
K23GM132755 ( U.S. NIH Grant/Contract )
First Posted: August 20, 2019    Key Record Dates
Last Update Posted: June 15, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Keith M. Vogt, MD, PhD, University of Pittsburgh:
propofol
dexmedetomidine
fentanyl
functional MRI
electric nerve stimulation
sedation
functional connectivity
Additional relevant MeSH terms:
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Fentanyl
Dexmedetomidine
Propofol
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Analgesics, Opioid
Narcotics
Adjuvants, Anesthesia