RESUMEN
Under certain circumstances, implicit, automatic learning may be attenuated by explicit memory processes. We explored the brain basis of this phenomenon in a functional magnetic resonance imaging (fMRI) study of motor sequence learning. Using a factorial design that crossed subjective intention to learn (explicit versus implicit) with sequence difficulty (a standard versus a more complex alternating sequence), we show that explicit attempts to learn the difficult sequence produce a failure of implicit learning and, in a follow-up behavioural experiment, that this failure represents a suppression of learning itself rather than of the expression of learning. This suppression is associated with sustained right frontal activation and attenuation of learning-related changes in the medial temporal lobe and the thalamus. Furthermore, this condition is characterized by a reversal of the fronto-thalamic connectivity observed with unimpaired implicit learning. The findings demonstrate a neural basis for a well-known behavioural effect: the deleterious impact of an explicit search upon implicit learning.
Asunto(s)
Encéfalo/fisiología , Imagen por Resonancia Magnética , Memoria/fisiología , Inhibición Neural/fisiología , Aprendizaje Seriado/fisiología , Adulto , Encéfalo/citología , Femenino , Lóbulo Frontal/citología , Lóbulo Frontal/fisiología , Humanos , Masculino , Vías Nerviosas , Lóbulo Temporal/citología , Lóbulo Temporal/fisiología , Tálamo/citología , Tálamo/fisiologíaRESUMEN
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.
Asunto(s)
Anestésicos Disociativos/administración & dosificación , Lóbulo Frontal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Ketamina/administración & dosificación , Memoria/efectos de los fármacos , Adolescente , Adulto , Anestésicos Disociativos/sangre , Femenino , Lóbulo Frontal/fisiología , Hipocampo/fisiología , Humanos , Inyecciones Intravenosas , Ketamina/sangre , Imagen por Resonancia Magnética , Masculino , Memoria/fisiología , Persona de Mediana Edad , Tiempo de Reacción/efectos de los fármacos , Esquizofrenia/fisiopatologíaRESUMEN
We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamine's effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.