Clinical trial NCT02515890
Conditions: Amnesia Pain Anesthesia
Keywords: midazolam dexmedetomidine memory ketamine
Sponsor: University of Pittsburgh
Start date: 2015-11-19; Completion date: 2018-12-12
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine the effects of pain on facilitating long-term auditory memory in the presence and absence of distinct intravenous anesthetics. The ability to identify previously presented words from a list assessed the degree of memory formation. In a subset of subjects, functional magnetic resonance imaging was used to identify the neural correlates of memory inhibition or facilitation by the combination of pain and anesthetic used.

Detailed description:
This study adds specific details to the current incomplete body of knowledge examining the effect of pain on memory formation under the influence of anesthetic agents.

Pain and anesthetic agents were administered as experimental variables in this study. Healthy adult subjects were played repeated lists of words and performed several decision-making tasks that encourage memory encoding. Some words were consistently paired with painful electric shock, and was anticipated to improve subsequent memory performance specifically for those items. The same experiment was repeated in all subjects during the administration of 1-2 possible agents that reduce memory formation: dexmedetomidine, a predominantly sedative agent, and midazolam, a well-known amnestic agent, and ketamine, a well-known dissociative analgo-sedative. The extent to which pain modulates memory performance under the effects of the anesthetic agents was the primary outcome of interest.

Further, a subset of the subjects performed the same experimental procedures while undergoing functional magnetic resonance imaging, which continuously reflects neuronal activity throughout the brain. Classic memory areas were predicted to be activated by the auditory processing task, but how these neural circuits change under the two anesthetic agents with the concomitant experience of pain were of interest. It was anticipated that pain recruits a parallel memory pathway using limbic structures, known for their involvement in fear conditioning. Additionally, stronger and more diffuse cortical processing likely occurs with concomitant pain, as level of sedation was reduced by this strong stimulus. Discovering the anatomic correlates specific to each experimental variable (pain and anesthetic), and their interplay, may help refine our model of brain function during the dynamics of pain and sedation.

Arms: arm 1: All subjects receive saline (control), followed by a dexmedetomidine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. arm 2: Subjects receive saline (control), followed by midazolam infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. arm 3: All subjects receive saline (control), followed by ketamine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. arm 4: All subjects receive saline (control), followed by midazolam infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation.

Subjects then returned at least 1 week later for another set of experimental sessions with the same design, however the saline was followed by ketamine infusion. arm 5: All subjects receive saline (control), followed by ketamine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation.

Subjects then returned at least 1 week later for another set of experimental sessions with the same design, however the saline was followed by midazolam infusion.
Interventions: intervention 1: Dexmedetomidine intervention 2: Midazolam intervention 3: Peripheral nerve stimulation intervention 4: Ketamine
Intervention descriptions: intervention 1: Selected subjects received this drug during a portion of the study intervention 2: Selected subjects received this drug during a portion of the study intervention 3: Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues. intervention 4: Selected subjects received this drug during a portion of the study

Protocol documents:
ICF_001.pdf: 
 
 
February 23, 2018 
 
 
 
 
 
 
 
 
 
 
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY 
 
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 
 
 
 
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 


                                                                          Page 1 of 8                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
 
 
 
 
 
 
 
 
 
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY 
 
TITLE:  Modulation of long-term memory by the experience of pain during sedation with anesthetics 
 
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 
 
Why is this research being done? 
The purpose of this study is to better understand what factors allow or prevent memory formation while sedated with 
intravenous anesthetic agents and experiencing periodic pain.  Understanding the interaction between these two 
elements may allow future anesthetics to more precisely prevent memory formation during surgery.  
 
Who is being asked to take part in this research study? 
Any adult who is 18-39 years of age, free from any serious medical condition, has never had a history of 
psychological or neurological disease, has never had a reaction to or abused any of the study medications, is not 
pregnant, and can undergo an MRI can participate in this study.   
 
What procedures will be performed for research purposes? 
If you decide to take part in this research study, you will undergo the following procedures: 
 
Screening Procedures: 
Procedures to determine if you are eligible to take part in a research study are called “screening procedures”.   
For this research study, the screening procedures include: 
 
1. Women will be asked questions about the possibility of pregnancy.  Pregnant women will not be allowed to 
take part in this study.  In female subjects with the ability to be pregnant, a commercially available urine 
pregnancy test will be administered at the beginning of each visit that involves drug administration or MRI 
UPMC | 
Julie Fiez, PhD  
Psychology & Neuroscience 
605 LRDC 
3939 0'Hara Street 
Pittsburgh, PA 15260 
University of Pittsburgh 
Medical Center 
Department of Anesthesiology 
James W. Ibinson, MD, PhD 
Anesthesiology 
Montefiore Hospital, Suite 467 
3459 Fifth Avenue, Pittsburgh, PA  15213 


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   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
scanning.  Any subject with a positive pregnancy test will be removed from the study. 
2. All people having an MRI are asked standard questions about the possibility of materials that are 
incompatible (like some metal implants or implanted medical devices) with the strong magnetic field.  Every 
potential subject for this study will be asked these same questions.  
3. Questions will be asked to make sure you are free from any psychiatric or neurologic diseases that may 
interfere with the analysis of the data from this study.  You must not be taking any type of prescription or 
non-prescription drugs that could interfere with memory formation, level of sedation (sleepiness), or with 
pain.  You will be asked about all medications and supplements that you are taking.  Certain items, like birth 
control pills, antacids, and multivitamins are permitted.  Medications like sleep-aids, pain-killers, stimulants, 
anti-anxiety medications, anti-depressants, or anti-psychotics are not allowed.  Over-the-counter 
cold/allergy medicine is allowed, if not taken in the week prior to the study.  You will also be asked to 
describe your tobacco, alcohol, and illicit substance use.  Recent or daily use of these substances may 
disqualify you from the study. 
4. You will be asked questions about your health and medical history to ensure it is safe for you to receive the 
anesthetic agents used in this study. 
 
Experimental Procedures: 
If you qualify to take part in this research study, you will undergo the experimental procedures listed below.  The 
study will occur in two phases; you may be asked to participate in phase 1 or phase 2.  Each involves multiple 
visits, described below.  The experimental procedures for phase 2 are the same as in phase 1, except that 
portions of the experiment are performed in an MRI scanner. 
 
1. Visit 1 begins with completing the written informed consent form.  Afterwards, you will complete several 
questionnaires about your sleep, stress, anxiety, possibility of depression, and your attitudes about pain.  
Your responses will be kept secure and only reported in a way that cannot link your answers to your identity.  
When averaged with other subjects, the results from this survey will be analyzed to determine if these 
factors provide a simple way to predict someone’s response to anesthetic medications.  These will require 
about 15 minutes for you to complete. 
 
2. A nerve stimulator will be connected to your right index finger with two small electrodes.  A small electrical 
current will then be delivered to that finger, starting at zero current.   The intensity will slowly be increased 
until you report a pain of 7 out of 10, where 0 is no pain and 10 is intolerable pain.  The nerve stimulator will 
then be turned off and then used randomly for a few seconds at a time during the rest of the experiment.  
The level of current delivered (pain intensity) will not be changed after adjustment to the level you rate as 7 
out of 10 pain.  
 
3. This study uses low doses of intravenous sedation drugs, dexmedetomidine (Precedex), ketamine (Ketalar), 
and midazolam (Versed).  These drugs are used routinely in the practice of anesthesia.  Subjects receive 
only one drug in a visit.  Some subjects will receive only one medication, while others will be scheduled to 
receive 2 or 3 drugs on different days.  Subjects will know in advance how many drug sessions they will be 
scheduled for.  The drug that was used will be disclosed to subjects after their final memory testing session 
is complete.  For this study, drugs are administered by a physician anesthesiologist (a doctor with 
specialized training in the administration of these medications).  You will be interviewed and examined to 
determine the safety to undergo sedation.  These will include questions about your medical conditions, past 
surgeries, medications, allergies, substance use, and any symptoms that you have during physical activity.  
The examination will consist of (at least) looking in your mouth and listening to your heart and lungs with a 
stethoscope. 
 
 


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   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
4. Intravenous access (an IV) will be placed in your hand or arm.  This will be used to give fluid and the 
sedative medications used in the study.  You will also be connected to vital sign monitors, to measure your 
heart rate, blood pressure, skin conductance, and breathing.   
 
5. You will listen to words played and asked to make a decision about the word, for example if it represents 
something big or small.  You will press different buttons with one of your fingers to indicate your answer.  
This list of words will be repeated 3 times, and you will be instructed to make different decisions in each 
round.  About one-third of the time, the word will be accompanied by a brief electric shock when it is played.  
This part of the experiment will take about 20 minutes. 
 
6. You will receive sedation medication through your IV, which will take 10-15 minutes to reach effect.  You will 
then repeat the procedures in #5 above, using a different list of words.  A qualified anesthesia provider will 
monitor your response to the medication at all times.  This part of the study will take about 20 minutes, after 
this you will have completed the experiment for this visit.  
 
7. You will then be monitored while you recover from the effects of sedation.  Once it is safe to do so, you will 
be discharged, typically 1-2 hours later.  You will be paid $50 for completing this first study visit, which will 
overall take 2 – 3 hours.  You are advised not to drive a vehicle or operate machinery for 24 hours after 
receiving either medication.  You will need to arrange for a way to get home (without driving) from the study 
visits that involve drug administration. 
 
8. You will return for the second study visit the next day, which will be one hour long and consist of memory 
testing.  You will be played a list of words that include the ones you heard in the prior visit.  You will indicate 
whether you remember the word or if it seems new to you by pressing different buttons.  You will be paid 
$10 for completing the procedures involved in this visit.  If you are scheduled to receive only one medication 
(which you will know in advance), then this is your last visit and you will also receive a $30 study completion 
bonus.  Thus, the total compensation is $100 for completing all study procedures (including the $10 you 
already received for the memory screening visit). 
 
9. If you are scheduled to receive 2 study medications over 4 visits (which you will know in advance), 
Study Visit 3 will occur at least 1 day after Study Visit 2, and will involve the procedures described in #1-7.  
This will overall take 2 – 3 hours, and you will be paid $50 for completing this third visit.  Visit 4 will occur the 
next day, will be one hour long and consist of memory testing, similar to visit 2 (described in #8 above).  You 
will be listening to words and deciding if you heard them in the prior visit.  You will be paid $10 for 
completing this visit.  At the end of this visit, you will also receive a bonus of $70 for completing all Study 
Visits.  Thus, subjects enrolled to receive both medications will receive a total of $200 for completing all 
required study procedures, including the payments you already received for previous study visits. 
 
10. If you are scheduled to receive all 3 study medications over 6 visits (which you will know in advance), 
Study Visits 3 and 4 will occur as described in #9 above.  You will be paid $50 for completing this third visit 
and $10 for completing the fourth visit.  According to a similar schedule, you would return for Study Visit 5 
(and undergo procedures described in #1-7) and be paid $50; then you would complete Study Visit 6 
(memory testing) the next day and be paid $10 for completion.  At this last visit, you would additionally 
receive a bonus of $70 for completing all Study Visits.  Thus, subjects enrolled to receive 3 medications will 
receive a total of $260 for completing all required study procedures, including the payments you already 
received for previous study visits. 
s 
11. Phase 2 (MRI scanning) follows the same Study-Visit schedule with the experimental procedures and 
reimbursement described in #’s 1-10 above.  However, in Phase 2, the word-list experiments of Study Visits 


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   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
involving drug administration are performed while in an MRI scanner.  You will know in advance if you are 
being scheduled for Phase 2 or Phase 1. 
 
What are the possible risks, side effects, and discomforts of this research study? 
Performing the decision-making and memory-recall tasks pose no risks to subjects. Other aspects of the study 
involve some risk, which are described below.   
 
Risks related to intravenous (IV) access 
Some discomfort will occur in all subjects with needle insertion.  There is a risk of a small bruise or soreness at the IV 
site for several days after the study.  During IV placement, there is a less than 1% risk of fainting, or nausea/vomiting.  
The risk of serious bleeding or infection is very rare.  There is a risk of IV infiltration (leaking out of the vein), in which 
case fluid would temporarily accumulate in your arm.  This would resolve spontaneously, though this situation poses 
a very small risk of blood clot or tissue damage as a result of the fluid.  There is also an extremely small risk of 
serious bleeding or infection related to IV placement.  Study personnel who are also healthcare professionals will 
implement precautionary measures including ensuring your physical comfort, proper disinfection of the needle 
insertion site, application of pressure after removal of the needle, and constant monitoring for any problems.  
Individuals with sensitive skin may experience some temporary irritation or skin rash from the adhesive dressing or 
tape used to cover the puncture site.   
 
Known risks of the specific medications to be used 
Receiving dexmedetomidine can cause the following effects: 
 
 
 
Receiving ketamine can cause the following effects: 
 
 
 
 
 
 
Common side effects include:
Low or high blood pressure
Slow or fast heart rate
Dry mouth
Shallow breathing
Nausea and/or vomiting
Uncommon possible side effects include:
Difficulty breathing or wheezing
Dizziness / light-headedness
Blurred vision / visual disturbance
Abnormal heart rhythm
Confusion / hallucination
Allergic reactions: rash, itching
Common side effects include:
High blood pressure
Fast heart rate
Sleep disturbances
Visual disturbances
Nausea and/or vomiting
Uncommon possible side effects include:
Difficulty breathing or wheezing
Confusion / hallucination
Allergic reactions: rash, itching
Abnormal heart rhythm
Slow heart rate
Low blood pressure
Airway obstruction
Redness or irritation at injection site
Nightmares


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   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
Receiving midazolam can cause the following effects: 
 
 
Other risks common to anesthetic delivery: 
A corneal abrasion (scratch of the surface of the eye) can occur when under sedation, and you will be reminded not 
to rub your eyes to reduce this risk.  If your breathing were to become significantly impaired at any time, drug 
administration would be stopped and the study will be terminated.  The anesthesiologist on the research team would 
support your airway and breathing using an oxygen mask placed over your face, while lifting on your jaw.  Although 
not anticipated to be necessary, further airway support can include insertion of tubes in your nose, mouth, or throat.  
Such interventions would only be undertaken if necessary, but can result in injury or damage to the lips, teeth, dental 
work, tongue, throat, neck, or vocal cords.  Although extremely unlikely, more severe problems could occur when you 
receive anesthetic agents, including heart, lung, or blood pressure problems that could cause serious illness or 
death.  The effects of anesthetic agents on children and fetuses are less well-known, but probably include 
miscarriage.  For this reason, children and pregnant women cannot participate in this study. 
 
Risks related to painful electric nerve stimulation 
Because the effects of pain on memory are being studied, pain will be repeatedly experienced in this study.  Each 
occurrence of the pain will be brief, and you can have the painful stimulus (and the entire experiment) stopped at any 
time by notifying any research team member.  Once electrical stimulation is stopped, there will be immediate pain 
relief.   
 
Risks of MRI scanning 
It is possible that you can feel nervous and claustrophobic during the MRI scans.  While the MRI is running, you will 
be asked to lie still on a narrow bed inside of the scanner and the scanner will make a loud knocking or beeping 
sound.  The noise level is within safety limits, but you will be asked to wear earplugs, since this noise is 
uncomfortable for some people.  You will be in constant contact with the operator of the MRI machine, and you can 
request that the investigators stop the scanning and remove you from the scanner at any time.  During the scanning 
process, you are lying on your back, and it is possible that you may feel some discomfort related to positioning.  
There are no known side effects from MRI scanning on adults.  The effects of MRI on children and fetuses are less 
well-known, and for this reason children and pregnant women cannot participate in this study.  If your clothing is 
uncomfortable, or contains metal, you will be asked to change (in a private dressing room) into a hospital gown prior 
to entering the MRI scanner. 
 
Risks of Questionnaires 
We will ask you to fill out a set of questionnaires about your current feelings of sleepiness, stress, depression, 
anxiety, and pain. If you feel uncomfortable about answering a question, you can choose not to answer it.  Research 
staff will be available to answer any questions you may have about the questions or your answers. 
 
 
 
Common side effects include:
Hiccups or coughing
Discomfort at injection site
Headache
Nausea and/or vomiting
Redness or irritation at injection site
Drowsiness / sedation
Uncommon possible side effects include:
Difficulty or shallow breathing
Anxiety / restlessness
Lethargy / sleep disturbance
Airway obstruction
Dizziness / light-headedness
Blurred vision / visual disturbance
Abnormal heart rate or rhythm
Confusion / hallucination
Allergic reactions: rash, itching


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   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
Risks of Breach of Confidentiality 
There is a potential risk of breach of confidentiality that is inherent in all research protocols. There is a possibility that 
if research data were to become known, this knowledge could potentially impact a subject's future or have a negative 
impact on family or social relationships. 
 
What are possible benefits from taking part in this study? 
You will receive no direct benefit from taking part in this research study.  Participation in this study will help further the 
understanding of how the brain forms memories when under sedation and experiencing pain.   
 
If I agree to take part in this research study, will I be told of any new risks that may be found during the 
course of the study? 
Although unlikely, you would be promptly notified if any new information develops during the course of this research 
study which suggests that you were put at any increased risk as a result of your participation. 
 
Will my insurance provider or I be charged for the costs of any procedures performed as part of this 
research study? 
Neither you, nor your insurance provider, will be charged for the costs of any of the procedures performed for the 
purpose of this research study (i.e., the Screening Procedures, Experimental Procedures, or Monitoring/Follow-up 
Procedures described above).   
 
Will I be paid if I take part in this research study? 
You will be paid a total of up to either $100 (if enrolled for one drug visit), $200 (if enrolled for 2 drug visits), or $260 
(if enrolled for 3 drug visits) for completing all experimental procedures in the study. 
 
Who will pay if I am injured as a result of taking part in this study?  
If you believe that the research procedures have resulted in an injury to you, immediately contact the Principal 
Investigator who is listed on the first page of this form. Emergency medical treatment for injuries solely and directly 
related to your participation in this research study will be provided to you by the hospitals of UPMC. Your insurance 
provider may be billed for the costs of this emergency treatment, but none of those costs will be charged directly to 
you. If your research-related injury requires medical care beyond this emergency treatment, you will be responsible 
for the costs of this follow-up care. At this time, there is no plan for any additional financial compensation. 
 
What information will be collected about me and who will know about my participation in this research 
study? 
We will not be reviewing your medical record information for the purposes of this study.  However, we will collect 
information directly from you including: demographic information such as age, weight, and height; your responses to 
the questionnaires about pain, sleep, stress, depression, and anxiety; and portions of your medical history (including 
substance use history) necessary to determine your ability to safely undergo sedation and /or MRI scanning.   
 
To protect your privacy, we will store this collected information separately from personal identifiers such as your 
name and contact information.  Thus, your research data will only be identified by a code and not linked to you 
personally.  Although we will do everything in our power to protect your privacy and the confidentiality of your 
records, just as with your medical information for health care purposes, we cannot guarantee the confidentiality of 
your research records.  The identifiable link between your personal formation and your data will be stored for a 
minimum of 7 years after final reporting of study results, and then this link (your personal information) will be 
destroyed.  All de-identified data from this study will be kept securely for an indefinite period of time.  No third party, 
including relatives, personal physicians, or insurance companies will be granted access to the identifiable information 
we collect.  It is possible that we may share the information from this study, so that it may be combined with other 


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     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
data in larger future studies.  However, your information would only be shared with other researchers without any 
personal identifiers, so no one would be able to learn your identity. 
 
For the purpose of monitoring the conduct of this study, authorized representatives from the University of Pittsburgh 
Research Conduct and Compliance Office may review your research information. 
 
 
Is my participation in this research study voluntary? 
Yes!  Your participation in this research study is completely voluntary.  Whether or not you provide your consent for 
participation in this research study will have no effect on your current or future relationship with the investigators, the 
University of Pittsburgh, or UPMC.  Your participation will not affect your current or future medical care at a UPMC 
hospital or affiliated health care provider or your current or future relationship with any healthcare insurance provider. 
 
May I withdraw my consent for participation in this research study? 
You may withdraw your consent for participation in this research study at any time.  Any identifiable research 
information recorded for, or resulting from, your participation in this research study prior to the date that you formally 
withdrew your consent may continue to be used and disclosed by the investigators for the purposes described above. 
 
To withdraw your consent for participation in this research study, contact the principal investigator of this research 
study at the address/phone number listed on the first page of this form. 
 
If I agree to take part in this research study, can I be removed from the study without my consent? 
You may be removed from the study by the researchers if any safety concerns arise that do not allow you to 
participate. 
 
 
 


                                                                          Page 8 of 8                                           
           
   University Of Pittsburgh          
     Institutional Review Board    
 
Approval Date: 2/23/2018 
Renewal Date:  2/22/2019 
 
IRB #:   PRO14050609 
 
 
************************************************************************************************************************** 
 
VOLUNTARY CONSENT 
 
The above information has been explained to me and all of my current questions have been answered.  I understand 
that I am encouraged to ask questions about any aspect of this research study during the course of this study, and 
that such future questions will be answered by a qualified individual or by the investigator(s) listed on the first page of 
this consent document at the telephone number(s) given. I understand that I may always request that my questions, 
concerns or complaints be addressed by a listed investigator.   
 
I understand that I may contact the Human Subjects Protection Advocate of the IRB Office, University of Pittsburgh 
(1-866-212-2668) to discuss problems, concerns, and questions; obtain information; offer input; or discuss situations 
that have occurred during my participation.  By signing this form, I agree to participate in this research study.  A copy 
of this consent form will be given to me. 
 
____________________________  
____________________________  
____________ 
Participant’s Signature 
 
 
Printed Name of Participant 
 
Date 
 
 
 
 
CERTIFICATION of INFORMED CONSENT 
 
I certify that I have explained the nature and purpose of this research study to the above-named individual(s), and I 
have discussed the potential benefits and possible risks of study participation.  Any questions the individual(s) have 
about this study have been answered, and we will always be available to address future questions as they arise. 
 
I further certify that no research component of this protocol was begun until after this consent form was signed. 
 
 
 
___________________________________  
________________________ 
Printed Name of Person Obtaining Consent  
Role in Research Study 
 
 
_________________________________ 
 
____________ 
Signature of Person Obtaining Consent 
 
Date  
 

Prot_002.pdf: 
 
 
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.   
 
 


 
 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_000.pdf: 
 
 
April 24, 2020 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
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 
 
 
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