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Gil-da-Costa R, Stoner GR, Fung R, Albright TD. Nonhuman primate model of schizophrenia using a noninvasive EEG method. Proc Natl Acad Sci U S A. 2013 Sep 17 ; 110(38):15425-30. Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Dan Javitt, SRF Advisor
Submitted 30 September 2013
Posted 30 September 2013

This is an important paper that confirms the role of NMDA receptors in the generation of mismatch negativity (MMN) and, by extension, the potential role of NMDA receptors in the pathophysiology of schizophrenia. As in prior studies with MMN in monkeys, the latency of MMN in monkeys appears to obey the 2/3 rule, which allows cross-species scaling of sensory ERP.

Since our initial report of PCP effects on MMN in monkeys in the late 1990s (Javitt et al., 1996) and subsequent reports on ketamine effects on MMN in humans shortly thereafter (Umbricht et al., 2000), the findings have been extensively replicated in humans. This, however, is the first replication in monkeys and the first to use primarily surface electrodes, and so opens the door to more widespread investigation. In particular, studies in humans are limited to acute administration. However, acute administration of NMDA receptor antagonists only captures a portion of the syndrome. In monkeys, chronic administration of NMDA receptor antagonists is possible and is associated with progressive development of negative-like symptoms (Linn et al., 2007).

As in our earlier report, ketamine treatment reduced MMN-related activity but did not affect responses to rapidly presented, repetitive, standard stimuli, reproducing the pattern of deficit observed in schizophrenia. In this initial study, no other classes of compounds were tested. However, establishment of this model permits testing of a wide range of compounds, including pharmacological probes for other classes of glutamate receptors, or from other transmitter systems (e.g., dopaminergic, cholinergic, GABAergic) that have also been implicated in schizophrenia. Especially during subchronic treatment, the ability to reverse MMN deficits may be an important screening model for potentially psychotherapeutic compounds in schizophrenia and other NMDA receptor-related disorders.

Another important issue that can be addressed using monkey models is the nature and identity of the "frontal generator." It is clear from both MEG and intracranial recording studies that primary generators for MMN are in auditory regions of the superior temporal cortex. Additional, frontal generators are also sometimes reported based upon source analysis. However, unless constrained through physiological means, source localizations can easily produce spurious results. This study uses LORETTA, a common source-localization approach, and identifies sources in frontal and anterior cingulate cortices (ACC), as well as in auditory cortex.

Generators in ACC are unlikely in humans, because they should be detectable by MEG. Nevertheless, an obvious follow-up of this study is to implant intracranial electrodes in those regions detected using LORETTA. If local generators are found, it will give renewed understanding about the relationship between auditory and frontal interaction during MMN generation. If local generators are not found, it will permit refinement of the LORETTA approach and reduction in "false positive" localizations that may, of themselves, complicate understanding of disorders such as schizophrenia.

Finally, a goal of biomarker research is the development of measures that can be implemented in relatively simple species, such as rodents. For complex disorders such as schizophrenia, however, it could be that more complex, primate models are required. As opposed to most primate paradigms, MMN can be obtained even in untrained animals, permitting a development path from rodents through primates and into humans.

References:

Javitt DC, Steinschneider M, Schroeder CE, Arezzo JC. Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia. Proc Natl Acad Sci U S A. 1996;93(21):11962-7. Abstract

Umbricht D, Schmid L, Koller R, Vollenweider FX, Hell D, Javitt DC. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry. 2000;57(12):1139-47. Abstract

Linn GS, O'Keeffe RT, Lifshitz K, Schroeder C, Javitt DC. Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine. Psychopharmacology (Berl). 2007;192(1):27-38. Abstract

Javitt DC, Spencer KM, Thaker GK, Winterer G, Hajos M. Neurophysiological biomarkers for drug development in schizophrenia. Nature reviews. 2008;7(1):68-83. Abstract

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