Amnesia, Anesthesia, Pain
Conditions
Keywords
midazolam, dexmedetomidine, memory, ketamine
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.
Interventions
DRUGDexmedetomidine
Selected subjects received this drug during a portion of the study
DRUGMidazolam
Selected subjects received this drug during a portion of the study
DEVICEPeripheral nerve stimulation
Experimental acute pain stimulus was delivered using a nerve stimulator. These painful shocks were paired randomly with some of the auditory experimental cues.
DRUGKetamine
Selected subjects received this drug during a portion of the study
Sponsors
Foundation for Anesthesia Education and Research
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 39 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Memory Testing | At memory testing 1 day later | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dexmedetomidine Only All subjects received saline (control) followed by dexmedetomidine infusion while performing memory task and receiving intermittent painful electric nerve stimulation. | 7 |
| Midazolam Only All subjects received saline (control) followed by midazolam infusion while performing memory task and receiving intermittent painful electric nerve stimulation. | 4 |
| Ketamine Only All subjects received saline (control) followed by ketamine infusion while performing memory task and receiving intermittent painful electric nerve stimulation. | 5 |
| Drug Order A All subjects received saline (control) followed by midazolam infusion while performing memory task and receiving intermittent painful electric nerve stimulation on their first experimental visit.
For another experimental session, all subjects received saline (control) followed by ketamine infusion while performing memory task and receiving intermittent painful electric nerve stimulation. | 8 |
| Drug Order B All subjects received saline (control) followed by ketamine infusion while performing memory task and receiving intermittent painful electric nerve stimulation on their first experimental visit.
For another experimental session, all subjects received saline (control) followed by midazolam infusion while performing memory task and receiving intermittent painful electric nerve stimulation. | 8 |
| Total | 32 |
Baseline characteristics
| Characteristic | Total | Midazolam Only | Ketamine Only | Drug Order A | Dexmedetomidine Only | Drug Order B |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 4 Participants | 5 Participants | 8 Participants | 7 Participants | 8 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — | — | — |
| Region of Enrollment United States | 32 participants | 4 participants | 5 participants | 8 participants | 7 participants | 8 participants |
| Sex: Female, Male Female | 14 Participants | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 18 Participants | 2 Participants | 4 Participants | 5 Participants | 4 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 4 | 0 / 5 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 7 | 0 / 4 | 1 / 5 | 1 / 8 | 1 / 8 |
| serious Total, serious adverse events | 0 / 7 | 0 / 4 | 0 / 5 | 0 / 8 | 0 / 8 |
Outcome results
Primary
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.
Time frame: At memory testing 1 day later
Population: The overall number analyzed for each drug condition represents the number of observations for that drug, which doesn't directly correspond to study arms. All participants received a saline control condition with their drug condition. Therefore, there were 48 saline observations (saline d' scores) which includes observations from all 5 study arms.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dexmedetomidine | Memory Testing | All Conditions | 1.20 d' score | Standard Error 0.27 |
| Dexmedetomidine | Memory Testing | Pain Condition | 1.28 d' score | Standard Error 0.43 |
| Dexmedetomidine | Memory Testing | No Pain Condition | 1.12 d' score | Standard Error 0.35 |
| Midazolam | Memory Testing | All Conditions | .56 d' score | Standard Error 0.05 |
| Midazolam | Memory Testing | Pain Condition | .57 d' score | Standard Error 0.06 |
| Midazolam | Memory Testing | No Pain Condition | .55 d' score | Standard Error 0.06 |
| Ketamine | Memory Testing | No Pain Condition | .85 d' score | Standard Error 0.11 |
| Ketamine | Memory Testing | All Conditions | .82 d' score | Standard Error 0.07 |
| Ketamine | Memory Testing | Pain Condition | .78 d' score | Standard Error 0.1 |
| Saline | Memory Testing | All Conditions | 1.18 d' score | Standard Error 0.07 |
| Saline | Memory Testing | Pain Condition | 1.10 d' score | Standard Error 0.1 |
| Saline | Memory Testing | No Pain Condition | 1.18 d' score | Standard Error 0.1 |