Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study - PubMed (original) (raw)

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Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study

G D Honey et al. Cereb Cortex. 2005 Jun.

Abstract

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance.

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Figures

Figure 1

Figure 1. Diagrammatic representation of experimental protocol.

The period of drug exposure, shown in red, included the retrieval of the first study list, and encoding of the second study list.

Figure 2

Figure 2. Activation associated with episodic encoding during placebo treatment.

The maximum intensity projections or ‘glass brain’ figures (viewed from the right, from behind and from above, thresholded at P < 0.005, uncorrected) show activations associated with the deep versus shallow (A) and difference due to subsequent memory (Dm) (B) contrasts. Details of the activations are given in Table 3.

Figure 3

Figure 3. Dose-dependent increase in a region of left prefrontal cortex for deep compared to shallowly encoded items under ketamine compared to placebo.

Figure 4

Figure 4. Increased activation of right prefrontal cortex during encoding under ketamine compared to placebo, associated with items which were subsequently correctly identified, compared to incorrectly identified items.

Activation was reduced for the 50 ng/ml condition.

Figure 5

Figure 5. Activation associated with episodic retrieval during placebo treatment.

Glass brain images (threshold at P < 0.005, uncorrected). (A) Activation associated with retrieval of deep, compared to shallowly encoded items. (B) Activation associated with items which were incorrectly identified at test compared to correct responses. (C) Activation associated with items which had not been presented at encoding, compared to items previously encountered.

Figure 6

Figure 6. Dose-dependent decrease of left frontal activation for deep compared to shallowly encoded items under ketamine compared to placebo.

Figure 7

Figure 7. Regions demonstrating increased activation for correct compared to incorrectly identified items under ketamine compared to placebo.

Figure 8

Figure 8. Regions demonstrating increased activation for old compared to new items under ketamine compared to placebo.

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