Modulation of Long-term Memory by the Experience of Pain During Sedation With Anesthetics
Phase: PHASE1
Conditions: Amnesia, Pain, Anesthesia
Sponsor: University of Pittsburgh

 
 
January 30, 2019 
 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
TITLE:  Modulation of long-term memory by the experience of pain during sedation with anesthetics 
 
NCT NUMBER: NCT02515890   
 
PRINCIPAL INVESTIGATOR: 
 
Keith M. Vogt, M.D., Ph.D. 
Dept. of Anesthesiology  
Montefiore Hospital, Suite 467 
3459 Fifth Avenue, Pittsburgh, PA  15213 
Telephone: 412-999-8570 
 
CO-INVESTIGATORS: 
 
 
 
 
 
 
 
 
 
 
SOURCE OF SUPPORT:  Foundation for Anesthesia Education and Research 
 
 
 
 Department of Anesthesiology, UPMC  
 
IRB APPROVAL:  Last Approval Date 1/30/19 
 
 
 Study closed before 2020 Continuing Review Due  
 
  
 
 
 
UPMC | 
University of Pittsburgh 
Medical Center 
Department of Anesthesiology 
Julie Fiez, PhD  
Psychology & Neuroscience 
605 LRDC 
3939 0'Hara Street 
Pittsburgh, PA 15260 
James W. Ibinson, MD, PhD 
Anesthesiology 
Montefiore Hospital, Suite 467 
3459 Fifth Avenue, Pittsburgh, PA  15213 

 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
TITLE:  Modulation of long-term memory by the experience of pain during sedation with anesthetics 
 
Description of research activities 
 
 
The study will be performed in 2 phases.  All subjects will undergo Phase 1, and a subset will undergo 
functional MRI while performing the same experimental protocol during Phase 2.  Adult subjects (age 18-59) will 
be enrolled from the general population.  Exclusion criteria are designed to prevent confounding results by factors 
known to affect memory performance or anesthetic drug responsiveness: age greater than or equal to 60 years, 
psychotropic medication use, and BMI>30.  Because of the inherent use of words in the experiment, subjects will be 
excluded if English is not their primary language.  Further exclusion criteria are to prevent harm from the anesthetics 
including pregnancy and any contraindications to anesthetic care.  Subjects will additionally be excluded from Phase 
2 if they have any MRI-incompatible implants or foreign bodies.  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 the visits of 
the study that involve medications. 
 
 
Phase 1 of the study will occur over the course of three visits, with two anesthetics to be tested in 
randomized, cross-over fashion.  A phone call and email prior to the 1st session will screen subjects for any 
exclusion criteria and describe all experimental procedures and the risks.  On arrival for the first session, the 
research protocol will be reviewed, and consent obtained after all questions answered.  Subjects will then complete 
psychological tests for sleepiness (using the Epworth sleepiness scale), stress (using the Brief Inventory of Perceived 
Stress), depression (using the Beck Depression inventory 2), and anxiety (using the State-Trait Inventory for 
Cognitive and Somatic Anxiety, STICSA).  An electric nerve simulator (EZStim II, Life Tech Inc., approved by the 
FDA and under PRO10020252) will be applied to the subject’s left index finger and current level slowly titrated to 
their subjective rating of 5/10 pain, as in previous studies.  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. 
 
 
The memory encoding experiment will involve listening to a list of 90 recorded words played via 
headphones.  One-third (30) of these words will be consistently paired with painful ENS, and the order of these 
randomized among words not paired.  Words will be displayed for 1s and the shock (if present) will be 1 s in 
duration coinciding with the word appearance.  The subjects will then have 2 s to perform a categorization cognitive 
task for each word, which has previously been shown to produce “deep” memory encoding.  By pressing of one of 
two buttons (with different fingers), subjects will indicate, for example, if the cue word represents something living 
versus non-living.  Response time and accuracy will be electronically recorded.  When the first decision-making 
battery is complete, the decision task will change.  For example, subjects may be instructed to now decide if the 
word represents something abstract or concrete.   The same list of 90 words will then be repeated, in random order, 
with the same 30 words paired with ENS.  A similar (but distinct) lexical decision task will be used for a third 
battery, giving three total encoding opportunities for the word list under the no-drug condition.   The entire set of 3 
tests is anticipated to take 15 minutes. 
UPMC | 
University of Pittsburgh 
Medical Center 
Department of Anesthesiology 

 
 
 
 
Based on a computer-generated random number, the subjects will be randomized into two equal groups that 
determine which anesthetic drug they will receive in the first visit.  All subjects will then receive the other drug in 
the second visit; all subjects will receive both drugs in counter-balanced fashion.  Whichever anesthetic has been 
randomized to be administered first will be titrated using a target-controlled infusion strategy for effect-site 
concentration; doses previously shown produce 40% amnesia (60% long-term recall).  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.  Certainly, if any subject fails to respond to 
the auditory cues, the infusion will be stopped or decreased to empirically guide the dosing strategy to a level of 
light sedation in which they are able to respond to the auditory stimuli that are required for the experiment.  The 
initial effect-site concentrations to be targeted will be 0.15 ng/ml for dexmedetomidine and 0.4 ng/ml for 
midazolam.  These targeted concentrations may also be adjusted based on a preliminary analysis of the level of long-
term memory observed from the first 2 subjects, with a range of 40-70% amnesia acceptable.  The infusion 
parameters will be custom calculated, using the well-established STANPUMP software (from Steven Shafer, MD, 
Palo Alto VAMC) for each subject based on age, gender, weight, and height.  Doses will not exceed the 
manufacturer’s recommended doses for procedural sedation for both agents.  All sedation will be performed in the 
MRRC, and the standards for monitoring during anesthetic administration established by the American Society of 
Anesthesiologists will be used; this standard has been uploaded as an attachment to the protocol. 
 
 
Once drug steady state is reached, approximately 10 minutes later, subjects will undergo three batteries of 
decision-making tasks with a second independent list of words, using the procedures described for the no-drug 
condition.  This second set of 3 batteries of memory encoding is expected to take 15 minutes.  Immediately after the 
experimental procedures, subjects will be asked to again complete the STICSA, to account for changes in anxiety 
level as a result of the experimental procedures and/or drug administration.  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 this expected to take between 1 and 2 hours.  The total time spent for the visit will thus be between 2 and 3 
hours. 
 
 
The second visit in Phase 1 will occur 1 - 3 days later.  Subjects will begin with long-term memory testing 
for the items from visit 1, using the remember-know procedure.  In brief, all words from both lists will be played in 
random order, with some intermixed novel distractor words (to account for guessing).  Subjects will decide for each 
if they remember it (specifically recall), know it (feel is familiar), or think the word is totally novel.  This testing is 
expected to take 30 minutes.  Subjects will then repeat all the experimental procedures described for visit 1, using 
two different words lists and the drug not used in visit 1.  The total time for the memory encoding experiment will 
again take 1 hour, with 1-2 hours for anesthetic recovery.  Thus, visit 2 will be a total duration of 2.5 to 3.5 hours. 
 
 
The third visit in phase 1 will be scheduled 1 - 3 days after visit 2 and consist only of long-term memory 
testing as described.  This brief visit will only take 30 minutes.  The total time spent for all 3 visits will vary between 
5 to 7 hours.  As each visit is separated by 1 to 3 days (to accommodate subject’s scheduled), all procedures for 
Phase 1 of the study and will occur over 3 to 9 day period.  
 
 
Phase 2 of the study will include a subset of subjects from Phase 1.  Any subject that is available and 
willing to participate in Phase 2 will be eligible to do so as long as there were no technical issues with their 
behavioral data from Phase 1.  That is, if the subjects had an inadequate or excessive response to one or both of the 
anesthetics, or if they did not properly perform any aspect of the learning task or memory tasks they will be 
excluded.  Subjects will also be excluded from Phase 2 if they cannot tolerate the scanner due to discomfort or 
claustrophobia, which will be assessed by a mock scanner session prior to Phase 2 - Visit 1, during which the actual 
scanner will be used for data acquisition.  Subjects will further be excluded from Phase 2 if the MRI environment 
would be unsafe for them (and this either changed or somehow failed screening during Phase 1),  if they have a 
positive pregnancy test (this will be administered to all females with child-bearing potential prior to Phase 2).  
Because the imaging portion of the study would be futile without the successful formation of long term memories 
under the sedation, subjects will be also be excluded from Phase 2 if they have less than 10% long-term retention of 
presented cues from their least successful session.  In addition, subjects planned to participate in Phase 2 will first 

 
 
 
undergo a short session in which they can familiarize themselves with a MRI scanner mock-up, to ensure they can 
perform the experiment while lying in a tube without undue anxiety or discomfort.  All experimental protocols are 
intentionally designed to be portable to the MRI environment.  Thus, in Phase 2, the subject’s brains will be imaged 
while performing the same auditory memory task with periodic pain stimulation under no-drug and both drug 
conditions, again randomized.  Repeat visits with memory testing and subject cross-over to the other drug condition 
will occur in the same manner and on the same timeline as in Phase 1.  Thus Phase 2 consists of 3 visits of lengths of 
2-3 hours, 2.5-3.5 hours, and 30 minutes. 
 
 
For each visit in Phase 2, subjects will complete the same psychometric testing items described for Phase 1.  
They will then be screened with the standard questionnaire by the MRRC staff to ensure safety within the MRI.  The 
volunteer will then change into MR safe clothing, if necessary, and this would be in private.  Next, they will meet 
with the anesthesiologist who will administer the sedation and monitor their vital signs during the experiment.  The 
anesthesiologist will review the subject’s medical history, perform a focused history and physical, and obtain 
intravenous access.  The nerve stimulator will be adjusted to their subjective rating of 5/10 pain, in the same manner 
previously used.  The subject will be positioned in the scanner, given appropriate hearing protection, and re-
familiarized with the response button equipment to be used for the experiment. 
 
 
Imaging will performed using a Siemens 3.0 T Trio Scanner (Siemens Medical Solutions, Malvern, PA).   
The imaging protocol will consist of continuous BOLD imaging during the learning experiments.  All fMRI data 
will be acquired with a BOLD-weighted gradient echo sequence with the following parameters:  TR (repetition 
time) 2 s, TE (echo time) 30 ms, flip angle 90, matrix 64 x 64, in-plane resolution 3.125 x 3.125 mm and slice 
thickness 4 mm.  Thirty-five contiguous axial slices will collected in an interleaved fashion, providing whole brain 
coverage.   For each subject, a high-resolution T1-weighted image will be acquired during titration of the study drug.  
This anatomical image will be acquired with a 3-D magnetization prepared rapid acquisition gradient-echo 
(MPRAGE) sequence with following parameters: TR 2.5 s, TE 5 ms, flip angle 35, matrix size 256 x 192, field of 
view  20 cm, in-plane resolution 1.2 mm, and slice thickness 2.8 mm, contiguous.  Timing from the scanner will be 
synchronized such that the image at the time of presentation of a word cue can be retrospectively analyzed 
separately for successful vs unsuccessful encoding into long-term memory.