Memory & Conditioning Under Anesthesia

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

92 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-07-30

Study Completion Date

2024-04-22

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Anesthesia Pain

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Placebo-controlled, within-subject, crossover between no-drug and assigned drug (in randomized order)

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

SINGLE

Participants

single-blind

Study Groups

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Dexmedetomidine

Subjects in this group will receive dexmedetomidine during the drug portion of the experiment.

Group Type EXPERIMENTAL

Dexmedetomidine

Intervention Type 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.

Peripheral Nerve Stimulation

Intervention Type 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.

Placebo

Intervention Type DRUG

Crystalloid IV solution will be infused, with no active drug.

Propofol

Subjects in this group will receive propofol during the drug portion of the experiment.

Group Type EXPERIMENTAL

Propofol

Intervention Type 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.

Peripheral Nerve Stimulation

Intervention Type 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.

Placebo

Intervention Type DRUG

Crystalloid IV solution will be infused, with no active drug.

Fentanyl

Subjects in this group will receive fentanyl during the drug portion of the experiment.

Group Type EXPERIMENTAL

Fentanyl

Intervention Type 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

Intervention Type 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.

Placebo

Intervention Type DRUG

Crystalloid IV solution will be infused, with no active drug.

Interventions

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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.

Intervention Type 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.

Intervention Type 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.

Intervention Type DRUG

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.

Intervention Type DEVICE

Placebo

Crystalloid IV solution will be infused, with no active drug.

Intervention Type DRUG

Other Intervention Names

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Precedex Diprivan fentanyl citrate Electric Nerve Stimulation saline, IV fluid

Eligibility Criteria

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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)

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

* 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

Minimum Eligible Age

18 Years

Maximum Eligible Age

39 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes