Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers

TLDR

Schizophrenia patients exhibit reduced mismatch negativity (MMN) and increased context‑dependent errors on the AX‑CPT, suggesting impaired transient memory formation linked to NMDAR dysfunction. This study examined whether NMDAR antagonism by ketamine would diminish MMN and impair AX‑CPT performance in healthy volunteers. Twenty healthy participants received a single‑blind, placebo‑controlled subanesthetic ketamine infusion while MMN to pitch and duration deviants were recorded during AX‑CPT task performance. Ketamine lowered MMN amplitudes by 27 % and 21 % and caused poorer AX‑CPT hit rates with heightened BX errors, demonstrating that NMDAR activity is essential for MMN generation and transient memory use.

Abstract

<h3>Background</h3> In patients with schizophrenia, deficient generation of mismatch negativity (MMN)—an event-related potential (ERP) indexing auditory sensory ("echoic") memory—and a selective increase of "context dependent" ("BX") errors in the "A-X" version of the Continuous Performance Test (AX-CPT) indicate an impaired ability to form and use transient memory traces. Animal and human studies implicate deficient<i>N</i>-methyl-D-aspartate receptor (NMDAR) functioning in such abnormalities. In this study, effects of the NMDAR antagonists ketamine on MMN generation and AX-CPT performance were investigated in healthy volunteers to test the hypothesis that NMDARs are critically involved in human MMN generation, and to assess the nature of ketamine-induced deficits in AX-CPT performance. <h3>Methods</h3> In a single-blind placebo-controlled study, 20 healthy volunteers underwent an infusion with subanesthetic doses of ketamine. The MMN-to-pitch and MMN-to-duration deviants were obtained while subjects performed an AX-CPT. <h3>Results</h3> Ketamine significantly decreased the peak amplitudes of the MMN-to-pitch and MMN-to-duration deviants by 27% and 21%, respectively. It induced performance deficits in the AX-CPT characterized by decreased hit rates and specific increases of errors (BX errors), reflecting a failure to form and use transient memory traces of task relevant information. <h3>Conclusions</h3> The NMDARs are critically involved in human MMN generation. Deficient MMN in schizophrenia thus suggests deficits in NMDAR-related neurotransmission.<i>N</i>-methyl-D-aspartate receptor dysfunction may also contribute to the impairment of patients with schizophrenia in forming and using transient memory traces in more complex tasks, such as the AX-CPT. Thus, NMDAR-related dysfunction may underlie deficits in transient memory at different levels of information processing in schizophrenia.