Translatability of Scalp EEG Recordings of Duration-Deviant Mismatch Negativity Between Macaques and Humans: A Pilot Study

Abstract

Mismatch negativity (MMN) is a negative deflection of the auditory event-related potential (ERP) elicited by an abrupt change in a sound presented repeatedly. In patients with schizophrenia, MMN is consistently reduced, which makes it a promising biomarker. A non-human primate (NHP) model of MMN based on scalp electroencephalogram (EEG) recordings can provide a useful translational tool, given the high structural homology of the prefrontal and auditory cortices between NHPs, such as macaques, and humans. However, in previous MMN studies, the NHP models used did not allow for comparison with humans because of differences in task settings. Moreover, duration-deviant MMN (dMMN), whose reduction is larger than that in the frequency-deviant MMN (fMMN) in patients with schizophrenia, has never been demonstrated in NHP models. In this study, we determined whether dMMN can be observed in macaque scalp EEG recordings. EEGs were recorded from frontal electrodes (Fz) in two Japanese macaques. Consistent with clinical settings, auditory stimuli consisted of two pure tones, a standard and a deviant tone, in an oddball paradigm. The deviant and standard tones differed in duration (50 and 100 ms for the standard and deviant tones, respectively). A robust dMMN with a latency of around 200 ms, comparable to that in humans, was observed in both monkeys. A comparison with fMMN showed that the dMMN latency was the longer of the two. By bridging the gap between basic and clinical research, our results will contribute to the development of innovative therapeutic strategies for schizophrenia.

Keywords: animal model; electroencephalogram (EEG); macaque; mismatch negativity; schizophrenia.

Figure 1

Electrode location. The EEG signal was recorded from an electrode positioned in the frontal area (Fz). The reference electrode (Ref) was placed in front of the ear.

Figure 2

dMMN and fMMN in macaque monkeys. (A), Grand average waveforms in the duration-deviant experiment conducted on two macaque monkeys. The electrical potential is plotted as a function of the time from tone onset. The black line shows the responses to the standard stimulus, the blue line the responses to the deviant stimulus, and the red line the differential waveform. The stimulus duration (indicated at the bottom of the graph) was 50 ms for the standard stimulus (black) and 100 ms for the deviant stimulus (blue). The stimulus frequency was 1,000 Hz for both the standard and deviant stimuli. Red dots on the top of the graph denote the times at which the responses to the standard and deviant stimuli were statistically different (two-sample t test, p < 0.05, FDR corrected). (B), Grand average waveforms in the frequency-deviant experiment conducted on two macaque monkeys. The stimulus frequency (shown at the bottom of the graph) was 50 ms for both the standard (black) and deviant (blue) stimuli. The stimulus frequency was 1,000 Hz for the standard stimulus and 1,200 Hz for the deviant stimulus. There were no statistical differences between the responses to the standard and deviant stimuli. The figure conventions are the same as in A.

Figure 3

Waveform characteristics of ERP. Responses to the standard (black) and deviant (blue) stimuli, and the differential waveform (red), are shown for the duration-deviant (A, C, E, G) and frequency-deviant (B, D, F, H) experiments conducted on monkey F (A–D) and monkey N (E–H). Conventions are the same as in . The yellow shaded area denotes the time window of the dMMN (C, G) and fMMN (D, H) in Nagai et al. (13).

Figure 4

Responses to 100-ms-duration stimuli in different contexts. (A), Response by one macaque monkey (monkey F) to 100-ms stimuli in a standard context (standard condition in the “flip-flop” paradigm: black) and a deviant context (deviant condition in the original oddball paradigm: blue). (B), Comparison of differential waveforms using ERPs to the standard stimulus in the original oddball paradigm (thin line: same as ) and ERPs to the standard stimulus in the flip-flop paradigm (thick line).

Figure 5

dMMN in macaque monkeys and in a human. (A), Waveforms in the duration-deviant experiment from one macaque monkey (monkey F). (B), Waveforms in the duration-deviant experiment from one human. Conventions are the same as in.