Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia.

Javitt, Daniel C.; Steinschneider, Mitchell; Schroeder, Charles E.; Arezzo, Joseph C.

doi:10.1073/pnas.93.21.11962

Cited by 599 publications

(474 citation statements)

References 35 publications

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“…Our results would instead indicate that it was specifically MMN generation that was impairedFthat is the mechanism mediating the comparison between standard and deviant stimuli. This pattern of results is in solid agreement with those obtained following the infusion of the NMDA antagonist phencyclidine in non-human primates (Javitt et al, 1996) and administration of ketamine to healthy human volunteers (Umbricht et al, 2000). In these studies, MMN was reduced, despite intact sensory responses.…”

Section: Discussionsupporting

confidence: 88%

“…Moreover, GSH deficit in hippocampus slices leads to NMDA receptor hypofunction and inhibition of long-term potentiation (Steullet et al, 2006). In patients with low brain GSH, NAC could increase GSH levels, restoring normal GSH levels and thus improving NMDA reception functioning, which is thought to be reflected by the amplitude of the MMN (Javitt et al, 1996). Therefore, the present observation of an increase in MMN amplitude after NAC treatment is likely to reflect improved NMDA receptor function.…”

Section: Discussionmentioning

confidence: 71%

“…The MMN is an AEP component pre-attentively elicited by discriminable stimulus changes in an otherwise contiguous stream of events that typically peaks B150-200 ms post-stimulus onset (Näätänen et al, 1978). NMDA receptor antagonists block MMN generation in both primates (Javitt et al, 1996) and humans (Umbricht et al, 2000), suggesting that the MMN reflects current flow through NMDA channels. The amplitude of MMN is known to be decreased in schizophrenia (Catts et al, 1995;Javitt et al, 1993Javitt et al, , 1998Shelley et al, 1991;Shutara et al, 1996; for review see Turetsky et al, 2007), further implicating impaired NMDA function in such patients.…”

Section: Introductionmentioning

confidence: 99%

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Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Lavoie

Murray

Deppen

et al. 2007

Neuropsychopharmacol

325

220

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In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex-and age-matched healthy controls (p ¼ 0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p ¼ 0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Lavoie

Murray

Deppen

et al. 2007

Neuropsychopharmacol

325

220

View full text Add to dashboard Cite

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“…In nonhuman primates, NMDAR antagonists selectively abolish the generation of MMN without affecting sensory ERPs such as N1 (Javitt et al, 1992(Javitt et al, , 1994(Javitt et al, , 1996. Likewise, we recently demonstrated that the NMDAR antagonist ketamine induces a significant reduction of MMN, but not of N1, in healthy volunteers (Umbricht et al, 2000).…”

Section: Introductionmentioning

confidence: 79%

Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

Umbricht

Vollenweider

Schmid

et al. 2003

Neuropsychopharmacol

155

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Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)Fmeasures of auditory and visual context-dependent information processingFin a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT 2A receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT 2A agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT 2A and NMDAR-related neurotransmission.

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“…Javitt et al (1996) provided relevant intracortical local field potential data on the cortical origins of the MMN in primates. They showed in particular that the MMN mainly originates from supragranular layers of the cortex.…”

Section: Layer Distribution Of Current Sourcesmentioning

confidence: 99%

A Neuronal Model of Predictive Coding Accounting for the Mismatch Negativity

Wacongne¹,

Changeux²,

Dehaene³

2012

J. Neurosci.

461

395

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The mismatch negativity (MMN) is thought to index the activation of specialized neural networks for active prediction and deviance detection. However, a detailed neuronal model of the neurobiological mechanisms underlying the MMN is still lacking, and its computational foundations remain debated. We propose here a detailed neuronal model of auditory cortex, based on predictive coding, that accounts for the critical features of MMN. The model is entirely composed of spiking excitatory and inhibitory neurons interconnected in a layered cortical architecture with distinct input, predictive, and prediction error units. A spike-timing dependent learning rule, relying upon NMDA receptor synaptic transmission, allows the network to adjust its internal predictions and use a memory of the recent past inputs to anticipate on future stimuli based on transition statistics. We demonstrate that this simple architecture can account for the major empirical properties of the MMN. These include a frequency-dependent response to rare deviants, a response to unexpected repeats in alternating sequences (ABABAA. . . ), a lack of consideration of the global sequence context, a response to sound omission, and a sensitivity of the MMN to NMDA receptor antagonists. Novel predictions are presented, and a new magnetoencephalography experiment in healthy human subjects is presented that validates our key hypothesis: the MMN results from active cortical prediction rather than passive synaptic habituation.

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Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia.

Cited by 599 publications

References 35 publications

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

A Neuronal Model of Predictive Coding Accounting for the Mismatch Negativity

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