Healthy
Conditions
Keywords
N/A healthy volunteers
Brief summary
This study involves 60 healthy volunteers aged between 18 and 50 recruited from the general community. It involves doing a set of simple memory tests while inside a fMRI machine. The subject is given a very low dose of an anesthetic drug intravenously while in the scanner. The subject then sees a sequence of pictures on a screen, and presses a button if they remember seeing the picture before. While this is happening, the scanner will be capturing images that tell us what parts of the brain are active. Hypothesis: patterns of hippocampal and amygdala activation during the encoding and retrieval of memory,as measured by fMRI, will be altered by intravenous anesthetics such that suppression of hippocampal and amygdala activities will be dissociable. This dissociation pattern will be different between the drugs propofol and thiopental.
Detailed description
Background: Subclinical doses of propofol produce anterograde amnesia, characterized by an early failure of memory consolidation. It is unknown how propofol affects the amygdala-dependent emotional memory system, which modulates consolidation in the hippocampus in response to emotional arousal and neurohumoral stress. We present an event-related functional magnetic resonance imaging study of the effects of propofol on the emotional memory system in human subjects. Methods: Sixty healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 μgml-1, thiopental, at an estimated brain concentration of 3.0 μgml-1, or placebo. During drug infusion, emotionally arousing and neutral images were presented in a continuous recognition task, while blood-oxygen-level-dependent activation responses were acquired. After a drug-free interval of 2 h, subsequent memory for successfully encoded items was assessed. Imaging analysis was performed using statistical parametric mapping and behavioural analysis using signal detection models.
Interventions
DRUGPlacebo
A low dose given intravenously one time for just under an hour while the subject is shown visually stimulating images in an MRI machine.
DRUGPropofol
A low dose of propofol 0.90 μgml-1, given intravenously while the subject is shown visually stimulating images in an MRI machine.
DRUGThiopental
A low dose of thiopental 3.0 μgml-1, given intravenously while the subject is shown visually stimulating images in an MRI machine.
Sponsors
National Institutes of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* age b/w 18 and 50 * right-handed * minimum of high school education * fluent in English * normal vocabulary
Exclusion criteria
* any significant medical/psychiatric comorbidity * deficit in vision or hearing that would impede the study * allergies to any of the study drugs, to soybeans, or eggs. * history of head trauma * family history of major psychiatric illness * body mass index \> 30 kg/m2 * claustrophobia * prior exposure to IAPS pictures * pregnancy * permanent metal objects anywhere in the body * a personal/family history of any porphyria
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood-oxygen-level-dependent Significant Activation Cluster | for 90 minutes after the drug/placebo was commenced | Three anatomical regions for which there was an a priori mechanistic hypothesis were assessed using standard small volume correction: (i) the amygdala, bilaterally; (ii) the hippocampus, bilaterally; and (iii) the parahippocampus, bilaterally. Using single-tailed t tests, a priori regions were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons in the hypothesized anatomical region. For non-hypothesized regions outside the medial temporal lobe, findings were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons across the whole brain. Clusters containing voxel maxima at these thresholds are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | for 90 minutes after the drug/placebo was commenced | Three anatomical regions for which there was an a priori mechanistic hypothesis were assessed using standard small volume correction: (i) the amygdala, bilaterally; (ii) the hippocampus, bilaterally; and (iii) the parahippocampus, bilaterally. Using single-tailed t tests, a priori regions were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons in the hypothesized anatomical region. For non-hypothesized regions outside the medial temporal lobe, findings were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons across the whole brain. Clusters containing voxel maxima at these thresholds are reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo given in low dose to gauge subject's responses to visual stimuli.
Placebo: A low dose given intravenously one time for just under an hour while the subject is shown visually stimulating images in an MRI machine. | 20 |
| Propofol Propofol given at 0.90 μgml-1 to gauge subject's responses to visual stimuli.
Propofol: A low dose of propofol 0.90 μgml-1, given intravenously while the subject is shown visually stimulating images in an MRI machine. | 21 |
| Thiopental Thiopental give at 3.0 μgml-1 to gauge subject's responses to visual stimuli.
Thiopental: A low dose of thiopental 3.0 μgml-1, given intravenously while the subject is shown visually stimulating images in an MRI machine. | 19 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | fMRI technical problems | 1 | 1 | 0 |
| Overall Study | Infusion technical problems | 0 | 1 | 0 |
| Overall Study | poor subject data | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Propofol | Thiopental | Total |
|---|---|---|---|---|
| Age, Continuous | 26 years | 25 years | 24 years | 25 years |
| Sex: Female, Male Female | 15 Participants | 14 Participants | 13 Participants | 42 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 6 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 | 0 / 19 |
| other Total, other adverse events | 0 / 20 | 0 / 21 | 0 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 | 0 / 19 |
Outcome results
Primary
Blood-oxygen-level-dependent Significant Activation Cluster
Three anatomical regions for which there was an a priori mechanistic hypothesis were assessed using standard small volume correction: (i) the amygdala, bilaterally; (ii) the hippocampus, bilaterally; and (iii) the parahippocampus, bilaterally. Using single-tailed t tests, a priori regions were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons in the hypothesized anatomical region. For non-hypothesized regions outside the medial temporal lobe, findings were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons across the whole brain. Clusters containing voxel maxima at these thresholds are reported.
Time frame: for 90 minutes after the drug/placebo was commenced
Population: Of the 20 placebo subjects recruited, 3 subjects' data was excluded due to technical problems or poor quality.~Of the 21 propofol subjects recruited, 3 subjects' data was excluded due to technical problems, poor quality, or subject withdrawal.~Of the 19 thiopental subjects recruited, no subjects' data was excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster | Right Amygdala | 1 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster | Left Amygdala | 1 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster | Right Hippocampus | 1 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster | Left Hippocampus | 1 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster | Right Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster | Left Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster | Left Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster | Right Amygdala | 1 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster | Left Hippocampus | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster | Right Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster | Left Amygdala | 1 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster | Right Hippocampus | 0 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster | Left Amygdala | 1 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster | Right Hippocampus | 0 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster | Left Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster | Left Hippocampus | 1 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster | Right Amygdala | 1 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster | Right Parahippocampal Cortex | 0 BOLD significantly activated clusters |
Secondary
Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory
Three anatomical regions for which there was an a priori mechanistic hypothesis were assessed using standard small volume correction: (i) the amygdala, bilaterally; (ii) the hippocampus, bilaterally; and (iii) the parahippocampus, bilaterally. Using single-tailed t tests, a priori regions were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons in the hypothesized anatomical region. For non-hypothesized regions outside the medial temporal lobe, findings were reported as significant if the initial uncorrected voxel-wise P value was \< 0.001, and then the P value was \< 0.05 after family-wise error correction for multiple comparisons across the whole brain. Clusters containing voxel maxima at these thresholds are reported.
Time frame: for 90 minutes after the drug/placebo was commenced
Population: Of the 20 placebo subjects recruited, 3 subjects' data was excluded due to technical problems or poor quality.~Of the 21 propofol subjects recruited, 3 subjects' data was excluded due to technical problems, poor quality, or subject withdrawal.~Of the 19 thiopental subjects recruited, no subjects' data was excluded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Amygdala | 0 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Amygdala | 1 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Hippocampus | 0 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Hippocampus | 1 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Placebo | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Amygdala | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Hippocampus | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Parahippocampal Cortex | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Amygdala | 0 BOLD significantly activated clusters |
| Propofol | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Hippocampus | 0 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Amygdala | 0 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Hippocampus | 1 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Parahippocampal Cortex | 1 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Left Hippocampus | 0 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Amygdala | 0 BOLD significantly activated clusters |
| Thiopental | Blood-oxygen-level-dependent Significant Activation Cluster for Positive Sequential Memory | Right Parahippocampal Cortex | 0 BOLD significantly activated clusters |