 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.
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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