Memory Modulation by Pain During Anesthesia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Modulation of Long-term Memory by the Experience of Pain During Sedation With Anesthetics

Conditions
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Amnesia, Pain, Anesthesia

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Midazolam
* Device: Peripheral nerve stimulation
* Drug: Ketamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult volunteers, with normal memory and hearing, whose native language is English Exclusion Criteria: pregnancy significant memory or hearing loss sleep apnea chronic pain metal or electronic implants claustrophobia Currently taking: antidepressants, anti-psychotics, antihistamines, anti-anxiety medication, stimulants, sleep-aids, or pain medication

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: There are 3 single drug arms completed by a few participants. The majority of participants participated in a crossover design with two drugs, midazolam & ketamine.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine Only<br>All subjects receive saline (control), followed by a dexmedetomidine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. | Drug: Dexmedetomidine<br>* Selected subjects received this drug during a portion of the study<br>* Other names: Precedex;Device: Peripheral nerve stimulation<br>* Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.<br>* Other names: electric nerve stimulation;|
| Experimental: Midazolam Only<br>Subjects receive saline (control), followed by midazolam infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. | Drug: Midazolam<br>* Selected subjects received this drug during a portion of the study<br>* Other names: Versed;Device: Peripheral nerve stimulation<br>* Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.<br>* Other names: electric nerve stimulation;|
| Experimental: Ketamine Only<br>All subjects receive saline (control), followed by ketamine infusion. They also experience intermittent experimental pain delivered by peripheral nerve stimulation. | Device: Peripheral nerve stimulation<br>* Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.<br>* Other names: electric nerve stimulation;Drug: Ketamine<br>* Selected subjects received this drug during a portion of the study<br>* Other names: Ketalar;|
| Experimental: Saline/Midazolam/Saline/Ketamine<br>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. | Drug: Midazolam<br>* Selected subjects received this drug during a portion of the study<br>* Other names: Versed;Device: Peripheral nerve stimulation<br>* Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.<br>* Other names: electric nerve stimulation;Drug: Ketamine<br>* Selected subjects received this drug during a portion of the study<br>* Other names: Ketalar;|
| Experimental: Saline/Ketamine/Saline/Midazolam<br>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. | Drug: Midazolam<br>* Selected subjects received this drug during a portion of the study<br>* Other names: Versed;Device: Peripheral nerve stimulation<br>* Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.<br>* Other names: electric nerve stimulation;Drug: Ketamine<br>* Selected subjects received this drug during a portion of the study<br>* Other names: Ketalar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Memory Testing | Subjects completed the Remember, Know, New (RKN) task during next day testing. Their d' memory score was calculated based on their ability to discriminate between previously heard words and new words. A higher d' score indicates stronger recollection. D' scores were compared across the control condition (saline) and the drug conditions dexmedetomidine, midazolam, and ketamine. Performance was also calculated according to words associated with Pain and No Pain conditions. | At memory testing 1 day later | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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midazolam, dexmedetomidine, memory, ketamine