Memory & Conditioning Under Anesthesia

Phase 1

Completed

Conditions: Anesthesia
Pain

Interventions: Drug: Dexmedetomidine
Drug: Propofol
Drug: Fentanyl
Device: Peripheral Nerve Stimulation
Drug: Placebo

Registration Number: NCT04062123

Lead Sponsor: Keith M Vogt

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 92

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dexmedetomidine	Placebo	Subjects in this group will receive dexmedetomidine during the drug portion of the experiment.
Propofol	Placebo	Subjects in this group will receive propofol during the drug portion of the experiment.
Fentanyl	Placebo	Subjects in this group will receive fentanyl during the drug portion of the experiment.
Propofol	Peripheral Nerve Stimulation	Subjects in this group will receive propofol during the drug portion of the experiment.
Fentanyl	Peripheral Nerve Stimulation	Subjects in this group will receive fentanyl during the drug portion of the experiment.
Dexmedetomidine	Peripheral Nerve Stimulation	Subjects in this group will receive dexmedetomidine during the drug portion of the experiment.
Dexmedetomidine	Dexmedetomidine	Subjects in this group will receive dexmedetomidine during the drug portion of the experiment.
Propofol	Propofol	Subjects in this group will receive propofol during the drug portion of the experiment.
Fentanyl	Fentanyl	Subjects in this group will receive fentanyl during the drug portion of the experiment.

Primary Outcome Measures

Name	Time	Method
Explicit Memory Performance	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

Name	Time	Method
Brain Activation in the Hippocampus for Successful Memory Formation: Placebo Condition Minus Drug Condition	Immediately after each experimental item	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.
Heart Rate Response	Immediately after each experimental item	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.
Skin Response	Immediately after each experimental item	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.