Conditions: Anesthesia Pain
Keywords: propofol dexmedetomidine fentanyl functional MRI electric nerve stimulation sedation functional connectivity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 92
Healthy volunteers: yes

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.

Arms:
arm 1: Subjects in this group will receive dexmedetomidine during the drug portion of the experiment. arm 2: Subjects in this group will receive propofol during the drug portion of the experiment. arm 3: Subjects in this group will receive fentanyl during the drug portion of the experiment.

Interventions: intervention 1: Dexmedetomidine intervention 2: Propofol intervention 3: Fentanyl intervention 4: Peripheral Nerve Stimulation intervention 5: Placebo
Intervention descriptions: intervention 1: 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 2: 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 3: 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 4: 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 5: Crystalloid IV solution will be infused, with no active drug.

Protocol document:
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STUDY consent form
KEY INFORMATION  
Study Title:  Modulation of memory and conditioning by pain during sedation with anesthetics
1. You are being offered the opportunity to participate in a research study.  One of the investigators 
will explain the study to you and will answer any questions you might have.  You should take your 
time to make your decision, which is completely voluntary. 
2A. Summary of the research
Purpose of the research: The purpose of this study is to better understand what factors allow or 
prevent memories to be formed in people receiving IV anesthesia and experiencing pain. 
Duration, number of study visits: There are four visits associated with participation in this study. The 
first visit will last approximately 3-4 hours.  The second visit must occur the next day and will last 
approximately 1 hour.  At least 5 days later, the third visit will occur, lasting 3-4 hours.  The fourth visit, 
which will occur the day after visit 3, will last approximately 1 hour. 
Overview of study procedures: 
•
urine pregnancy & drug screen
•
questionnaires about your sleep, stress, anxiety, depression, and pain
•
nerve stimulator calibration to a pain intensity of 5-7/10
•
brief physical exam including evaluation of the health of your lungs, heart, neck and mouth
•
questions about medical conditions, past surgeries, medications, allergies, substance (drug) 
use, and any symptoms that you have during physical activity
•
intravenous (IV) catheter placement (using a needle)
•
connection to monitor that measures your heart rate, blood pressure, and breathing
•
potential MRI scanning and MRI safety screening questions
•
enter the high magnetic field environment of the MRI scanner
•
connection to monitor that measures your heart rate, blood pressure, and breathing
•
placement inside the MRI scanner
•
listen to recordings, look at images while experiencing painful stimulation and being scanned 
by the MRI
•
next-day memory testing using a computer
•
additional questionnaires about sleep, stress, anxiety, depression, and pain
3. Reasonable, foreseeable risks or discomforts
Risks and side effects related to the MRI scanning include those which are: 
Likely: Discomfort from loud noise, positional discomfort
Rare but serious:  claustrophobia, risk of interaction with undetected/undisclosed metal in/on subject's 
body that could cause physical injury; hearing damage/loss 
UPMC |
University of Pittsburgh
Medical Center
Department of Anesthesiology & Perioperative Medicine


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Risks and side effects related to the collection & storage of personal health information include those 
which are: 
Rare but serious: Breach of confidentiality
Risks and side effects related to the electric nerve stimulation include those which are: 
Likely: Pain due to electric shock
Rare but serious: Theoretical risk of burns due to an interaction with MRI scanner
Risks and side effects related to the deep anesthesia include those which are: 
Likely: Residual sedation that will resolve over time
Rare but serious: Corneal abrasion, need for airway intervention leading to nasal, pharyngeal, or 
laryngeal soft tissue injury, need for resuscitative medication administration
Risks and side effects related to the fentanyl administration include those which are:
Likely: Itching, nausea, sedation
Less Likely: constipation
Rare but serious: Allergic reaction (rash, itching), low blood pressure, slow heart rate, shallow or 
absent breathing, addiction/dependence, abdominal pain, 
Risks and side effects related to the dexmedetomidine administration include those which are:
Likely: Sedation, low or high blood pressure, slow or fast heart rate, dry mouth
Rare but serious: Nausea and/or vomiting, difficulty breathing, dizziness/light-headedness, blurred 
vision/visual disturbance, allergic reaction (rash, itching), abdominal pain/diarrhea
Risks and side effects related to the propofol administration include those which are: 
Likely: Sedation, burning on injection, dizziness/light-headedness
Rare but serious: shallow or absent breathing, low blood pressure, allergic reaction
Risks and side effects related to IV access include those which are: 
Likely: Discomfort or pain, bleeding or bruising, skin sensitivity
Rare but serious: infection, thrombosis (blood clot), possibility of multiple needle punctures
Risks and side effects related to the psychometric questionnaires include those which are: 
Less Likely: Discomfort with disclosure of personal information
Risks and side effects related to the pre-visit restrictions include those which are: 
Less Likely: Discomfort from hunger or strong urge to urinate
4. Reasonable, expected benefits
There will be no direct benefit to you from participating in the study.  However, this study will help the 
researchers learn more about how the brain forms memories when under sedation and experiencing 
pain.  


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CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY
TITLE:  Modulation of memory and conditioning by pain during sedation with anesthetics
PRINCIPAL INVESTIGATOR:
CO-INVESTIGATOR:
Keith M. Vogt, MD, PhD
Anesthesiology & Perioperative Medicine
Montefiore Hospital, Suite 467
3459 Fifth Avenue, Pittsburgh, PA  15213
Telephone: 412-647-3147
SOURCES OF SUPPORT:
- Department of Anesthesiology & Perioperative Medicine, University of Pittsburgh, School of 
Medicine
- National Institute of General Medical Sciences
Why is this research being done?
You are being offered the opportunity to take part in a research study.  Research Studies include only 
people who choose to take part.  The study team members will explain the study to you and will 
answer any questions you might have.  You should take your time to make your decision. The 
purpose of this study is to better understand what factors allow or prevent memories to be formed in 
people receiving intravenous (IV) anesthesia and experiencing pain. We also want to understand how 
pain affects some of your body’s automatic responses, such as sweating or rapid heart beating.   
Knowing this may improve the ability to control pain and prevent unpleasant memories during medical 
procedures, using these types of drugs.
Who is being asked to take part in this research study?
Any adult who is 18-39 years of age, not pregnant, free from any serious chronic medical condition, 
has never had a history of psychological or neurological disease, and who has never had a reaction to 
or abused a drug similar to any of the study medications may be able to participate in this study.  To 
qualify to be a part of the study, you must also have completed the medical pre-screening and 
screening memory testing. 
To re-iterate, specific exclusion criteria include:
-
being pregnant or attempting to conceive
-
having a body mass index (BMI) > 35
-
having significant memory impairment or hearing loss
-
having sleep apnea
-
having chronic pain or other chronic medical problems
-
having neurologic or psychiatric disease, including benign tremor, anxiety, and depression
-
having significant cardiac disease or hypertension
-
having diabetes
-
having significant pulmonary disease
-
being claustrophobic
-
have metal implants or non-removable metal piercings
-
having a history of adverse reaction to anesthetics
-
have no history of illicit substance abuse
James W. Ibinson, MD, PhD
Anesthesiology & Perioperative Medicine
Montefiore Hospital, Suite 467
3459 Fifth Avenue, Pittsburgh, PA  15213


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-
taking: antiepileptics, antidepressants, anti-psychotics, antihistamines, anti-anxiety medication, 
stimulants, sleep-aids, or pain medication
We will recruit 150 people to participate. The total time for you to participate is 8-10 hours over 5 
visits, spaced over a few weeks.
What procedures will be performed for research purposes?
There are four visits associated with participation in this study. The first visit will last approximately 3-4 
hours, the second visits will last approximately 1 hour, the third visit will last approximately 3-4 hours, 
and the fourth visit will late approximately 1 hour. Each visit will occur on a separate day. The 
experimental procedures will take place either in a research testing room or MRI scanner.  Research 
testing facilities are within the UPMC Presbyterian/Montefiore hospital complex.  The MRI scanners 
that will be used for this project are located either within UPMC Presbyterian Hospital or the 
Biomedical Science Tower (a research facility connected by bridge to UPMC 
Presbyterian/Montefiore).  Subjects will be informed in advance which specific locations will be used 
for their experimental sessions, and the intended location will not change between enrollment and 
study completion.  Depending on experimental needs, different groups of subjects may undergo the 
different visits in the experiment under different conditions (in vs. out of an MRI scanner).
If you decide to take part in this research study, you will undergo the following procedures:
Experimental Procedures:
If you qualify to take part in this research study, you will undergo the experimental procedures 
listed below,  
1.
We will ask you to abstain from solid food and caffeine for 8 hours prior to your scheduled visit, 
consume only clear liquids until 1 hour prior to your scheduled arrival time, and not urinate in 
the hour before the visit.
2.
We will collect a urine sample to test for pregnancy in females and drugs of abuse screening in 
all subjects. 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 way to predict someone’s response to anesthetic medications. These 
will require about 15 minutes for you to complete.
3.
A nerve stimulator will be connected to one or two of your fingers with two small electrodes. A 
small electrical current will then be delivered. Starting at zero, the intensity will slowly be 
increased until you report a pain of 5 - 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 periodically for a few seconds 
at a time during the rest of the experiment. Unless you request an adjustment, the level of 
current delivered (pain intensity) will not be changed after adjustment to the level you rate as 
5-7 out of 10 pain. 
This study uses low doses of intravenous sedation drugs: dexmedetomidine, propofol, and 
fentanyl. These drugs are used routinely to medicate/sedate patients, for example before and 
during surgery. A physician anesthesiologist will interview you and do a brief physical exam to 
be sure you are safe to receive any of the study drugs. These will include (at least) questions 
about your medical conditions, past surgeries, medications, allergies, substance (drug) use, 
and any symptoms that you have during physical activity. The examination will consist of (at 


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least) looking in your mouth, feeling you neck, and listening to your heart and lungs with a 
stethoscope.
An intravenous needle (IV) will be placed, likely in your hand or arm. The needle is removed, 
and a small plastic catheter (tube) will remain in your arm throughout the study.  The IV will be 
used to give you 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, and breathing. 
These procedures will take between 15 and 60 minutes.
You will receive either saline (a saltwater solution) or one of the drugs at each visit.  Saline 
acts as a placebo, meaning it will have no effect on your brain or behavior. All subjects will 
receive one drug (or none) during this study visit. The drug that was used will not be disclosed 
to you until after your final session is complete. For this study, drugs are administered by a 
physician anesthesiologist (a doctor with specialized training in the administration of these 
medications). 
4.
Portions of the experiment may take place in an MRI scanner, and you will be informed in 
advance if you are in one of the subgroups that will undergo MRI scanning, and during which 
visits this will occur. If your recruitment occurs during the phase of the study in which MRI 
scanning is being performed, you would be asked additional screening questions to ensure 
that it is safe for you to undergo MRI scanning (no metal or electronic implants, etc). Prior to 
entering the MRI environment, you will be asked to remove any jewelry or glasses and be 
asked to change into a hospital gown if your clothes contain any metal.
5.
You will receive sedation medication or saline (placebo) through your IV, which will take 10-15 
minutes to reach effect. You will both listen to auditory cues (typically recorded words or tones) 
and view visual cues (images) that may require you to respond by pressing a button. A 
proportion of the cues will be paired with brief painful stimulation, as described above. A 
qualified anesthesia provider will monitor your response to the medication at all times. This 
part of the study will take about 30 minutes, after this you will have completed the experiment 
for this visit. 
6.
You will then be monitored while you recover from the effects of sedation. Towards the end of 
this time, you will do a few more paper-based questionnaires. Once it is safe to do so, you will 
be discharged, typically 1 - 2 hours later. You will be paid $175 for completing this first study 
visit, which will overall take 3 - 4 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 potentially involved drug administration.  
7.
You will return for the second study visit the next day, which will be approximately one hour 
long and consist of memory testing. You will again experience both auditory and visual cues.  
You may also experience some painful stimulations at the previously-determined level.  Your 
response may be required by pressing a button. You will also complete a few brief paper-
based questionnaires. You will be paid $50 for completing the procedures involved in this visit.  
8.
Study Visit 3 will occur at least 1 day after Study Visit 2 and will involve the procedures 
described in #1 - 6. This will overall take 3 - 4 hours, and you will be paid $175 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 #6 above). You will be paid $50 for completing this visit. 
At the end of this visit, you will also receive a bonus of $40 for completing all Study Visits. 
Thus, subjects will receive a total of $500 for completing all required study procedures, 
including the payments you already received for previous study visits.


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What are the possible risks, side effects, and discomforts of this research study?
Performing the experimental tasks pose no risks to subjects. Other aspects of the study involve some 
risk, which are described below.  
Known risks of the specific medications to be used
Receiving dexmedetomidine can cause the following effects:
Common side effects include
Sedation
Low or high blood pressure
Slow or fast heart rate
Dry mouth
Shallow breathing
Uncommon possible side effects include:
Nausea and/or vomiting
Difficulty breathing
Dizziness/light-headedness
Visual disturbance
Abnormal heart rhythm
Confusion/hallucination
Allergic reaction
Abdominal pain/diarrhea
Receiving fentanyl can cause the following effects:
Common side effects include:
Itching
Nausea
Sedation
Low blood pressure
Slow heart rate
Respiratory 
depression
Addiction/dependence
Uncommon possible side effects include:
Allergic reaction (rash, itching)
Abdominal pain
Constipation
Apnea
Receiving propofol can cause the following effects:
Common side effects include: 
Sedation
Burning on injection
Dizziness/light-headedness
Uncommon possible side effects include:
Respiratory depression
Low blood pressure
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 related to intravenous (IV) access
•
Discomfort will occur in all subjects with needle insertion. 
•
There is a risk of a small bruise or soreness at the IV site, that may last for several days after 
the study. 
•
Less than 1% risk of fainting (syncope), or nausea/vomiting with IV placement  
•
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. 
•
Extremely small risk of serious bleeding or infection related to IV placement. Study personnel 
who are trained in IV access will implement precautionary measures including ensuring your 


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physical comfort, proper disinfection of the needle insertion site, application of pressure after 
removal of the needle, and 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. 
•
Some individuals have veins that are unexpectedly difficult to access, and these subjects 
could experience multiple needle sticks in an attempt to obtain a functioning IV.  As IV access 
is required for the study procedures, inability to obtain IV access could result in involuntarily 
withdrawal from further participation in the study.
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 reduced or stopped and the study may 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 that is a routine part of anesthesia care can include insertion of 
tubes in your nose, mouth, or throat. Such interventions would only be undertaken if necessary, but 
can result in injury 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 injury or death. In the unlikely event 
that these were to occur, immediate emergency treatment would be administered by the physician 
(anesthesiologist) investigator, which could include the administration of IV medications like 
epinephrine or atropine.  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 of MRI scanning
•
You may feel nervous and/or 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 verbal contact with the investigators and operator of the MRI machine, 
and you can request that the experiment (and scanning) be stopped at any time, and you 
would be immediately removed from the scanner. 
•
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 long-lasting side effects from MRI scanning. 
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 
questionnaires or your responses.
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.


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With your permission, we will use text messaging and email to remind you of appointments and 
scheduling issues. No personal information will be transmitted; however, know that both email and 
text messages are NOT secure.
Risks of Pre-Visit Restrictions 
There is a small risk of discomfort from the pre-visit restrictions, such as hunger and strong urge to 
urinate. 
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 $500 for completing all visits and all associated experimental 
procedures in the study.  This payment will be processed on a reloadable debit card.  Since you are 
being compensated for your participation in this study, your name, address, date of birth, and social 
security number will be released to the Accounting Office. All compensation is taxable income to the 
participant regardless of the amount.  If you receive $600 or more in a calendar year from one 
organization, that organization is required by law to file a Form 1099 – Miscellaneous with the IRS and 
provide a copy to the taxpayer. Individuals who do not provide a social security number may still 
participate in the research, but the IRS requires that 24% of the payment be sent by the institution to 
the IRS for ‘backup withholding;’ thus you would only receive 76% of the expected payment. 
Commercialization statement
Your data from this research study may contribute to a new discovery or treatment. In some 
instances, these discoveries or treatments may be of commercial value and may be sold, patented, or 
licensed by the investigators and the University of Pittsburgh for use in other research or the 
development of new products. You will not retain any property rights nor will you share in any money 
that the investigators, the University of Pittsburgh, or their agents may realize.
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 


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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.  You waive no 
legal rights by signing this consent form.
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. Your permission to store this information last 
indefinitely. You may withdraw your authorization to store your private medical information by 
submitting it in writing with a date to the PI on page 1. You will be withdrawn from the study if you 
withdraw this authorization.
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 scientific information from this study, so that it may be combined 
with other 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 Office of Research Protections may review your research information. Additionally, an 
Independent Medical Monitor, Dr. Tetsuro Sakai, MD, PhD (who is a UPMC anesthesiologist not 
involved in conducting the study) will review the medical information (such as heart rate, blood 
pressure and reported adverse events) that are collected during the study. This data will be shared 
with the Independent Medical Monitor in de-identified format, such that your name and personal 
information is not linked to the medical information.
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. The 
researchers with this Certificate may not disclose or use information, documents, or biospecimens 
that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other 
action, suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, unless 
you have consented for this use. Information, documents, or biospecimens protected by this 
Certificate cannot be disclosed to anyone else who is not connected with the research except, if there 
is a federal, state, or local law that requires disclosure (such as to report child abuse or communicable 
diseases but not for federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings; if you have consented to the disclosure, including for your medical treatment; or if it is 
used for other scientific research, as allowed by federal regulations protecting research subjects.
When you are admitted to the CTRC for your study visit, a UPMC medical record will be created (or 
added to your existing records.) The study team will access your CTRC chart for study related data 
about the medication administered, your vital signs and information specific to being in the study 
needed to complete the research. It will be available to the research team indefinitely; this 


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authorization is valid until all study data needed is collected. You have the right to not give permission 
or to cancel your permission for the study team to collect this information. You must do so in writing to 
Dr. Vogt. If you cancel your permission, you will be withdrawn from the study.
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by US 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. Representatives from the National 
Institutes of Health will have access to identifiable private information for purposes of monitoring the 
study.
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 practical considerations or safety 
concerns arise that do not allow you to participate.
Will clinically relevant results be available to me?
Any clinically-relevant abnormalities would be disclosed to you, at the discretion of one of the study 
physician investigators.


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VOLUNTARY CONSENT
The above information has been explained to me and 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 and allow the use of my private health information. 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 

SAP_002.pdf: 
ClinicalTrials.gov Document cover page 
 
Official Title: Memory and Conditioning Under Anesthesia 
 
ClinicalTrials.gov ID (NCT number): NCT04062123 
 
Document Date: 4/2/2024 
 
 


Statistical Analysis 
Analysis of numerical behavioral data, including memory performance data, was carried out with R 
software (version 4.3.1, https://www.r-project.org/). Memory and 3-back task performance were 
evaluated by comparing dʹ scores. Data were first tested for normality with the Kolmogorov–
Smirnov test prior to application of two-tailed parametric statistical methods for analysis. Separate 
mixed models were fit for each outcome, with drug group as a fixed effect, and participant as a 
random effect. Interaction terms between time and drug group were fit and tested for significance 
and included in models if significant. P < 0.05 used as the threshold for significance, and values are 
reported both raw and Pa, indicating Bonferroni adjustment for the number of comparisons 
performed in the analysis.  
 
Functional MRI data analysis 
Functional MRI datasets were preprocessed using FSL 6 (https://fsl.fmrib.ox.ac.uk/) on several 
machines running MacOS (Apple Inc., Cupertino, CA). Subsequent acronyms are subroutines 
within the FSL software package. Correction for magnetic field distortion, using the acquired field 
maps, was performed on all functional data using TOPUP. Brain extraction was performed with BET 
and tissue segmentation with FAST. Based on the principle components of signal within the white 
matter and CSF in the functional time-series, the CompCor algorithm was used to reduce 
physiologic noise related to respiration and cardiac pulsatility. Motion parameters were included as 
a covariate of no interest in the first-level model, with censoring of any time point with root mean 
squared frame displacement motion over 0.9 mm. Spatial smoothing was performed with a 5 mm 
Gaussian kernel.  
 
Event-related task activation was calculated based on timing of events. For the memory and 
conditioning task data, three subject-level contrasts were included: items subsequently recognized 
correctly (with either a correct Remember or Know response at next day testing), items forgotten (a 
false negative response at next-day testing), and the timing of all electric nerve stimulations 
(regardless of memory performance for the corresponding word). In the pain task data, only shock 
timing was used as a first-level contrast. Average task activation and drug-condition difference 
maps were generated by grouping data from each drug condition in a group-level mixed effects 
model. Two hardware and one software upgrades to the scanner over the course of the study were 
accounted for at the group level as effects of no interest. Clusters were initially thresholded for 
significance at Z > 2, then an additional threshold was applied that adjusted the overall analysis-
level false discovery rate to p < 0.05. No statistical power calculation was possible for the imaging 
analyses; but overall sample size was based on general estimates suggesting that 24 subjects are 
adequate for task-based functional magnetic resonance imaging studies. 
 

Prot_001.pdf: 
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.