Modulation of Memory and Conditioning by Pain During Sedation With Anesthetics
Phase: PHASE1
Conditions: Anesthesia, Pain
Sponsor: Keith M Vogt

ClinicalTrials.gov Document cover page 
Official Title: Memory and Conditioning Under Anesthesia 
ClinicalTrials.gov ID (NCT number): NCT04062123 
Document Date: 4/2/2024 
 
 

Overview: 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. 
Background: 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. 
 
 
 

Subjects that are interested and think that they are eligible will be scheduled for a memory pre-
screening visit. During this <30 min visit they will undergo a memory task and be paid $10 for 
completing this test. This will be subsequently scored by the investigators. Subjects whose 
performance is > 1 standard deviations above random chance (guessing) will be eligible for further 
participation. If able to be scheduled for further study visits, the subjects will be contacted to 
undergo phone screening. This call involves reviewing detailed medical information by one of the 
study physicians, to ensure they are an appropriately low-risk subject for the sedation portion of the 
study. Substance use history will be assessed with the NIDA “Quick Screen." Absence of illicit 
substance use will be confirmed with a urine drug screen at each session. If the subject is eligible 
and still interested, they will be enrolled as a subject in the study. Text messaging and email will be 
used for appointment reminders and to address and scheduling issues. 
 
Full study procedures begin after completing all screening procedures. Prior to study visits, 
Subjects will be instructed to abstain from solid food and any glucose or caffeine for 8 hours, and 
from clear liquids for 2 hours prior to visits that will involve drug administration. Subjects will be 
reminded that they are free to withdraw at any time. Subjects will not be permitted to drive after 
receiving the sedative agents, and will be advised to plan for alternative transportation after visits of 
the study that involve medications. 
 
The study will occur over multiple visits. During the first of these visits, subjects will receive saline, 
and during the other they will receive one of the three anesthetic medications (propofol, 
dexmedetomidine, or fentanyl). They will not be informed whether they are receiving drug or saline, 
and will not be told which drug they received until the study is completed. 
 
On arrival for the first study visit, the research protocol will be reviewed, and consent obtained after 
all questions answered. The screening consent will include consent for the medical history and 
NIDA screening if subject is eligible from memory screening test. Surveys will be completed via 
REDCap. Subjects will complete psychological tests for sleepiness, stress, depression and anxiety, 
using a combination of the Epworth sleepiness scale, Brief Inventory of Perceived Stress), State-
Trait Inventory for Cognitive and Somatic Anxiety, STICSA, and portions of the NIH toolbox. Subjects 
will also complete the Pain-Anxiety Symptom scale, the Pain Vigilance and Awareness 
Questionnaire, and the Pain Catastrophizing Scale. As in previous studies, an electric nerve 
simulator will be applied to the subject’s finger(s) and current level slowly titrated to their subjective 
rating of 5-7/10 pain. Subjects will specifically assess whether the level of pain will impair their 
ability to participate in the experiment. This self-adjusted current level will be employed for brief 
painful stimulation during memory encoding. These screening and psychometric tests are expected 
to take 15 minutes total. Physiologic monitoring of the electrodermal activity (also called galvanic 
skin response) and the electrocardiogram will be obtained throughout the experiment, to measure 
subject’s sympathetic response to the painful shock, or experimental items previously paired with 
pain. 
 
The memory encoding experiment will involve exposure to a number of experimental cues (typically 
recorded tones and spoken words). Some of these cues will be paired with a painful shock, and the 
order of these randomized among other non-pain-paired cues. Subjects may respond to the 

experimental cue by pressing a button, allowing response time to be electronically recorded. 
Several repetitions of the experimental cues will be employed to produce a conditioned response to 
some stimuli and later asses for memory encoding. The entire conditioning/encoding portion of the 
experiment is anticipated to take 20-30 minutes. 
 
The anesthetic to be administered during the visit will be titrated using a target-controlled infusion 
strategy for effect-site concentration doses previously shown produce amnesia for 40-60% of 
experimental cues. This approach should achieve and maintain, based on subject parameters and 
drug pharmacokinetics, a steady-state plasma concentration of the drug that is equal across 
subjects. Because the subject’s sedative response to the medications is known to vary (in fact, this 
is one of the dependent variables to be measured in the study) drugs are not dosed or titrated to a 
specific observer-rated level of sedation. However, the level of sedation is expected to range 
between no perceptible sedation to light sedation, in which subjects follow verbal commands. 
 
The infusion parameters will be custom calculated, using well-established pharmacokinetic 
models for each drug that account for each subject’s age, gender, weight, and height. Total doses 
(over 20-30 min) will vary between subjects and also by the length of the experiment (some of which 
is subject-paced). These are low doses compared to those used clinically, especially since the total 
dose will not be administered as a single bolus, but rather, predominantly as an infusion that slowly 
decreases in rate over time to maintain a steady-state concentration. These doses do not exceed 
the manufacturer’s recommended doses for procedural sedation or analgesia for these agents. The 
standards for monitoring during anesthetic administration established by the American Society of 
Anesthesiologists will be used. 
  
At the conclusion of the experiment, subjects will be allowed to fully recover from the anesthetic 
prior to discharge and asked not to operate a car or machinery the rest of the day. The recovery 
period will vary based on each individual subject’s recovery profile, and is expected to take less 
than 1 hour. The total time spent for the visit will thus be between 2 and 3 hours. 
 
The follow-up memory testing visit will occur 1 day later in Study Visit 2. Subjects will begin with 
long-term memory testing for the items from the previous visit. Psychometric questionnaires to 
assess factors that may have affected memory consolidation since the encoding session will be 
administered (caffeine intake, over-the-counter medication use, and sleep logs, and Pittsburgh 
Sleep Quality Index). This testing visit is expected to take about 1 hour. 
 
During the third and fourth study visits, subjects will then repeat all the experimental procedures 
described above for visits 1 & 2, using different experimental cues, and receiving either saline or 
drug (whichever they did not receive previously). The total time for the memory encoding 
experiment will again take 1.5-2 hours, with 1 hour for anesthetic recovery. Thus, subsequent 
conditioning and encoding visits will also be a total duration between 2 and 3 hours. The follow-up 
memory testing study visit (study visit #4) will be scheduled 1 day after visit #3, and consist of long-
term memory testing and psychometric data collection, as described for the first set of visits. This 
brief visit will take about 1 hour. The total time spent for the screening visit and all 4 experimental 
visits will vary between 6 to 8 hours.