September 26, 2013. Monkeys under the influence of ketamine show brain signals reminiscent of schizophrenia, reports a study published online August 19 in the Proceedings of the National Academy of Sciences. Led by Thomas Albright at the Salk Institute for Biological Studies in La Jolla, California, the study developed non-invasive electroencephalography (EEG) that identified comparable brain signals from humans and monkeys. Two signals linked to impairments in cognitive and sensory processing found in schizophrenia—mismatch negativity (MMN) and P3a—were identified in macaque monkeys, and were reduced by ketamine, a blocker of the NMDA type of glutamate receptor that is thought to mimic the underactive glutamate systems in schizophrenia. A similar reduction is seen in people with schizophrenia, which suggests that monkeys can model aspects of the disorder.
The research comes at a time when drug development for psychiatric disorders has stalled, which some have blamed on a shortage of animal models (Hyman, 2012). With the rise of genomic research, most animal models these days include rodents carrying disease-related genetic glitches, but linking their various behaviors to psychiatric symptoms can be tenuous. The approach in the new study combines the complexity of the nonhuman primate brain with a pharmacological manipulation to simulate schizophrenia by using EEG signals as outcomes. Based on evidence of underactive NMDA receptor signaling in schizophrenia (see hypothesis by Bita Moghaddam) as well as the schizophrenia-like state the drug causes, ketamine has been used to mimic aspects of the disorder in healthy humans (see SRF related news story).
But tracking ketamine’s effects in the brains of nonhuman primates is complicated by the fact that their brains are shaped differently from human brains. This means that signals arising from, say, auditory cortex, could be located in a different place than in humans or combined with signals from another region. An invasive type of 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