Effect of propofol on the medial temporal lobe emotional memory system: a functional magnetic resonance imaging study in human subjects

Abstract

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: Thirty-five healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 μg ml(-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.

Results: Propofol had no effect on the stereotypical amygdalar response to emotional arousal, but caused marked suppression of the hippocampal response. Propofol caused memory performance to become uncoupled from amygdalar activation, but it remained correlated with activation in the posterior hippocampus, which decreased in proportion to amnesia.

Conclusions: Propofol is relatively ineffective at suppressing amygdalar activation at sedative doses, but abolishes emotional modulation and causes amnesia via mechanisms that commonly involve hyporesponsiveness of the hippocampus. These findings raise the possibility that amygdala-dependent fear systems may remain intact even when a patient has diminished memory of events. This may be of clinical importance in the perioperative development of fear-based psychopathologies, such as post-traumatic stress disorder.

Clinical trial registration: NCT00504894.

Keywords: amnesia, chemically induced; amygdala; fMRI; hippocampus; memory, drug effects; propofol, pharmacology.

© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Fig 1

Experimental paradigm. The middle line of the figure depicts the experimental sequence, and the bottom line the timing of the drug infusion. The top section shows segments of the experimental tasks in fine detail. The encoding task was performed in the scanner during the drug infusion. A sequence of 160 IAPS pictures was presented in 8 blocks of 20 items (purple bars), with 40 negative—arousing and 40 neutral images each shown twice as part of an old/new continuous recognition task. The recognition task was performed 120 min later outside of the scanner. Here, the 80 images previously seen in the encoding task and 80 novel images were shown in a random sequence across two blocks (blue bars).

Fig 2

Exploratory assessment of whole-brain changes in the pattern of blood-oxygen-level-dependent (BOLD) activation. Whole-brain contrasts are shown at the exploratory visualization thresholds of uncorrected P<0.001 (column A), and uncorrected P<0.05 (column B). The contrast includes all stimuli and is undifferentiated with regard to the cognitive task. Regions in which propofol has a relative increase in BOLD signal are shown in orange, while regions with a relative decrease are shown in blue. The sagittal, coronal, and axial images represent plane views at Montreal Neurologic Institute co-ordinates x=0, y=0, and z=0.

Fig 3

Response to emotional dynamics. Contrast between exposure to negative—arousing items and neutral items. Three coronal slices through the hippocampus (y-co-ordinates −36, −33, −30) and amygdala (0, 3, 6) are selected. (a) is placebo, and (b) propofol. Propofol had no effect on the amygdala response to emotional arousal, but markedly attenuated the hippocampal response. The scale shows color rendering of the groupwise t values, with yellows positive and blues negative. The threshold for color rendering is |t| ≥3.37.

Fig 4

Hippocampal predictors of propofol amnesia. Rendering of a regression model correlating d′ with activation in the propofol condition. The analysis combines first and second image presentations. (a) Left parasagittal slice in the plane x=−12; (b) Right parasagittal slice in the plane x=18; (c) Coronal slice in the plane y=−36; (d) Relationship between d′ and the blood-oxygen-level-dependent (BOLD) signal extracted from the peak voxel in the left (blue) and right (red) hippocampus. Scale shows color rendering of the groupwise t values. The threshold for color rendering is |t| ≥3.37. Automated Anatomical Labeling masks for the hippocampus are indicated by the white line.