Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions

Abstract

Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.

Multistage drug effects of ketamine in the treatment of major depression

“…In general, however, the sustainability effect of ketamine remains poorly understood. A recent study reported enhanced memory reconsolidation 24 h after ketamine infusion [91]. Enhanced memory consolidation and reconsolidation were also found 24 h after memantine-an NMDA receptor antagonist-administration in day-old chicks [92].…”

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“…24 By creating new associations, reactivating them under ketamine, and then testing their strength, we observed that ketamine-reactivated associations were strengthened. 87 In humans, this effect correlated with ketamine-induced psychosis and PE brain signal. 87 …”

“…Likewise, when delusions are questioned, bringing them to mind may actually serve to reinforce rather than to disrupt the memory. 8,27,87 The idea here is that re-evocation of an association may strengthen a memory even when it is not formally reinforced. 27 We have modeled this process in humans and rats with ketamine.…”

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