Memory & Conditioning Under Anesthesia

Study Overview
=================
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.

Official Title
-----------------
Modulation of Memory and Conditioning by Pain During Sedation With Anesthetics

Conditions
-----------------
Anesthesia, Pain

Intervention / Treatment
-----------------
* Drug: Dexmedetomidine
* Drug: Propofol
* Drug: Fentanyl
* Device: Peripheral Nerve Stimulation
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults, age 18-39, who are native English speakers with at least a high school education have normal hearing and memory be of normal body-weight be generally healthy (free from significant chronic disease) have none of the specific exclusion criteria have a valid email address and valid phone number throughout the study anticipate ability to participate in all visits required for the phase of the study in which they are enrolled Exclusion Criteria: Pregnancy Body mass index > 35 (obese) or < 18 (underweight) Use of psychotropic medications, including anti-epileptics, anti-psychotics, anxiolytics, anti-depressants, stimulants, sleep-aids, anti-histamines, or analgesics History of adverse reaction to OR abuse of: dexmedetomidine (Precedex), propofol (Diprivan) or the opioids class of medications (fentanyl, morphine, hydromorphone, etc) History of clinically significant memory or hearing loss History of obstructive sleep apnea History of neurologic or psychiatric disease, including benign tremor History of significant cardiac disease, including high blood pressure or arrhythmia History of significant pulmonary disease History of diabetes or neuropathy History of chronic pain, or other pain processing disorder Have an implanted medical electronic device Have indwelling or implanted metal in their body that is not MRI-compatible Have claustrophobia Have a history of drug abuse

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo-controlled, within-subject
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine<br>Subjects in this group will receive dexmedetomidine during the drug portion of the experiment. | Drug: Dexmedetomidine<br>* 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.<br>* Other names: Precedex;Device: Peripheral Nerve Stimulation<br>* Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired randomly with some of the experimental cues.<br>* Other names: Electric Nerve Stimulation;Drug: Placebo<br>* Crystalloid IV solution will be infused, with no active drug.<br>* Other names: saline, IV fluid;|
| Experimental: Propofol<br>Subjects in this group will receive propofol during the drug portion of the experiment. | Drug: Propofol<br>* 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.<br>* Other names: Diprivan;Device: Peripheral Nerve Stimulation<br>* Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired randomly with some of the experimental cues.<br>* Other names: Electric Nerve Stimulation;Drug: Placebo<br>* Crystalloid IV solution will be infused, with no active drug.<br>* Other names: saline, IV fluid;|
| Experimental: Fentanyl<br>Subjects in this group will receive fentanyl during the drug portion of the experiment. | Drug: Fentanyl<br>* 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.<br>* Other names: fentanyl citrate;Device: Peripheral Nerve Stimulation<br>* Experimental acute pain stimulus will be delivered using a nerve stimulator. These painful shocks will be paired randomly with some of the experimental cues.<br>* Other names: Electric Nerve Stimulation;Drug: Placebo<br>* Crystalloid IV solution will be infused, with no active drug.<br>* Other names: saline, IV fluid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Explicit memory performance | Recognition memory testing, using the Remember-Know procedure, in which subjects indicate whether they recognize previously experienced experimental items among novel items (not previously in the experiment). This allows calculation of interdependent measures of recollection & familiarity using the signal detection statistic, d'. d' is calculated as the cumulative Gaussian distribution of false positive responses subtracted from the cumulative Gaussian distribution of correctly identified previously-experienced items. d' is on a (theoretically infinite) scale of standard deviation units, with negative values representing performance worse than chance guessing and positive values representing stand deviations of performance above chance. | 24-hrs post-experiment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain activity in hippocampus and amygdala | Blood-oxygen level dependent (BOLD) weighted MRI images of the brain will be obtained every 1 second during the drug+pain experimental procedure. Local changes in blood flow, which correlate to increased neuronal activity, can be detected that correlate in time to experimental events. This will allow drug vs. placebo comparisons for brain activity for successful vs unsuccessful memory encoding. The output data will include anatomical localization of brain activity differences, along with the statistical intensity (z-score) of such differences. | Immediately after each experimental item | 
| Heart rate response | Heart rate changes (measured by electrocardiogram, EKG) will be determined following experimental stimuli that delivered as part of the experiment. A 1-6 second window of physiologic data will be analyzed for changes in the peak of the EKG response (R-wave), allowing calculation of instantaneous heart rate. Increases in heart rate are well-known to correlate to sympathetic nervous system activity increases. | Immediately after each experimental item | 
| Skin response | Electrodermal activity (galvanic skin) response will be determined following experimental stimuli that delivered as part of the experiment. A 1-6 second window of physiologic data will be analyzed for changes in electrodermal activity, measured from the palm of subjects' hand. this well-established measure indicates sweat gland activity and is correlated to sympathetic nervous system activity increases. | Immediately after each experimental item | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
propofol, dexmedetomidine, fentanyl, functional MRI, electric nerve stimulation, sedation, functional connectivity