Memory & Conditioning Under Anesthesia (MCA)

Modulation of Memory and Conditioning by Pain During Sedation With Anesthetics

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.

Study Overview

• Status: Recruiting
• Conditions: Pain; Anesthesia
• Intervention / Treatment: Drug: Dexmedetomidine; Device: Peripheral Nerve Stimulation; Drug: Placebo; Drug: Propofol; Drug: Fentanyl

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.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Keith M Vogt, MD, PhD; Phone Number: 4126473147; Email: vogtkm@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • University of Pittsburgh Medical Center
      • Principal Investigator: Keith M Vogt, MD, PhD
      • Sub-Investigator: James W Ibinson, MD, PhD
      • Contact: Keith M Vogt, MD, PhD; Phone Number: 412-647-3147; Email: vogtkm@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 37 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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 Names: Electric Nerve Stimulation; Drug: Placebo; Crystalloid IV solution will be infused, with no active drug.; Other Names: saline, IV fluid
Experimental: Propofol; Subjects in this group will receive propofol during the drug portion of the experiment.	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 Names: Electric Nerve Stimulation; Drug: Placebo; Crystalloid IV solution will be infused, with no active drug.; Other Names: saline, IV fluid; 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 Names: Diprivan
Experimental: Fentanyl; Subjects in this group will receive fentanyl during the drug portion of the experiment.	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 Names: Electric Nerve Stimulation; Drug: Placebo; Crystalloid IV solution will be infused, with no active drug.; Other Names: saline, IV fluid; 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 Names: fentanyl citrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain activity in hippocampus and amygdala	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.	Immediately after each experimental item
Heart rate response	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.	Immediately after each experimental item
Skin response	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.	Immediately after each experimental item

Collaborators and Investigators

• Sponsor: Keith M. Vogt, MD, PhD
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Keith M Vogt, MD, PhD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2020
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: July 11, 2019
• First Submitted That Met QC Criteria: August 19, 2019
• First Posted (Actual): August 20, 2019

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: July 3, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: functional MRI; dexmedetomidine; fentanyl; sedation; propofol; functional connectivity; electric nerve stimulation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Adjuvants, Anesthesia; Fentanyl; Propofol; Dexmedetomidine
• Other Study ID Numbers: STUDY19030183; R35GM146822 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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