EEG using electrodes resting on the surface of the brain has found an MMN-equivalent in monkeys (Javitt et al., 1992), but the new work tests non-invasive EEG electrodes placed on the scalp instead.
First author Ricardo Gil-da-Costa and colleagues studied the EEG responses of five humans and two macaque monkeys during an auditory processing task that taps into attention. The humans or monkeys listened to a series of identical tones that were occasionally interrupted by an “oddball” tone louder or quieter than the rest. In human brains, the oddball stimulus evokes a larger than usual voltage signal compared to the standard stimuli. The difference between the deviant and the standard stimuli is the MMN, which indicates the brain’s detection of the deviant stimulus. The P3a signal appears only during an oddball stimulus, after the MMN signals, and is thought to reflect reorienting one’s attention to the oddball tone.
The researchers reported similar MMNs between humans and monkeys. In the humans, a 64-electrode array measured a standard-looking MMN at 56-188 milliseconds after stimulus onset, peaking at -1.83 μV. In the monkeys, a 22-electrode array picked up an MMN-like signal 48-120 milliseconds after stimulus onset, peaking at -1.62 μV. The P3a signal that followed was also similar across species. The high density of scalp electrodes allowed the researchers to infer where the MMN and P3a signals were coming from, and these analyses pointed to the superior temporal gyrus and homologous frontal regions in both species.
A sub-anesthetic dose of ketamine given to the monkeys reduced their MMN and P3a signals compared to saline infusions. The signals returned to normal after five hours, when ketamine had dropped to low levels.
The researchers propose that this model could be used to screen drugs for schizophrenia and get a better picture of their action in the brain. And as MMN and P3a are widely studied, monkey EEG may well prove useful in testing treatments for other brain disorders.—Michele Solis.
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):15425-3. 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