Nonhuman primate model of schizophrenia using a noninvasive EEG method

Abstract

There is growing evidence that impaired sensory-processing significantly contributes to the cognitive deficits found in schizophrenia. For example, the mismatch negativity (MMN) and P3a event-related potentials (ERPs), neurophysiological indices of sensory and cognitive function, are reduced in schizophrenia patients and may be used as biomarkers of the disease. In agreement with glutamatergic theories of schizophrenia, NMDA antagonists, such as ketamine, elicit many symptoms of schizophrenia when administered to normal subjects, including reductions in the MMN and the P3a. We sought to develop a nonhuman primate (NHP) model of schizophrenia based on NMDA-receptor blockade using subanesthetic administration of ketamine. This provided neurophysiological measures of sensory and cognitive function that were directly comparable to those recorded from humans. We first developed methods that allowed recording of ERPs from humans and rhesus macaques and found homologous MMN and P3a ERPs during an auditory oddball paradigm. We then investigated the effect of ketamine on these ERPs in macaques. As found in humans with schizophrenia, as well as in normal subjects given ketamine, we observed a significant decrease in amplitude of both ERPs. Our findings suggest the potential of a pharmacologically induced model of schizophrenia in NHPs that can pave the way for EEG-guided investigations into cellular mechanisms and therapies. Furthermore, given the established link between these ERPs, the glutamatergic system, and deficits in other neuropsychiatric disorders, our model can be used to investigate a wide range of pathologies.

Keywords: brain; medicine; monkey; neurology; psychiatry.

Fig. 1.

MMN in humans and NHPs. Left graphs show ERP plots of grand average from a central electrode (Cz) of five humans (A) and two NHP subjects (C). These graphs depict waveforms (averaged across low and high tones) from standard (blue line) and deviant (red line) conditions, as well as difference wave (black line). The blue shaded area identifies duration of the MMN [human: 56–190 m (peak amplitude, −1.83 μV at 104 ms; *P < 0.001); NHP: 48–120 ms (peak amplitude, −1.62 μV at 88 ms; *P < 0.001]. Human and monkey head icons identify species for results presented (they do not represent precise electrode placement or density). (B and D) Upper right images show scalp-voltage topographic maps, which reveal central negativity found in the difference wave for both species [human: time interval 56–188 ms (B); NHP: time interval 48–120 ms (D)] corresponding to the MMN [white arrow indicates MMN (negative, blue) central-scalp distribution]. Three-dimensional reconstruction of topographic maps [front-top view; Montreal Neurological Institute (MNI) human head template; rhesus macaque MRI] averaged over the entire time interval is shown at left. Three 2D top views, shown at right, represent snapshots along this time interval. Lower right images show source localization (LORETA inverse solution) for the entire time intervals corresponding to MMN in each species. (B) Three-dimensional reconstruction of template human brain (MNI) (side view) shown at left indicates location of MRI coronal sections depicted at right. Coronal sections illustrate locations of temporal [STG (I)] and frontal [inferior temporal gyrus (II)] areas identified as the main generators of this neurophysiological signal in humans. In D, the 3D reconstruction (NHP MRI; side view) shown at left indicates location of MRI coronal sections depicted at right. These coronal sections illustrate temporal [STG (I)] and frontal [RG (II)] areas identified as main generators of this neurophysiological signal in NHPs. A, anterior; L, left; P, posterior; R, right.

Fig. 2.

P3a ERP component in human and nonhuman primates. The left graphs show ERP plots of grand average from a central electrode (Cz) of five human subjects (A) and two NHP subjects (C). Depicted are waveforms (average of low and high tones) of the deviant (red line) condition. The blue shaded area identifies the duration of the P3a component [human: 208–256 ms (peak amplitude, 0.72 μV at 228 ms; *P < 0.01); NHP: 104–248 ms (peak amplitude, 3.5 μV at 196 ms; *P < 0.01)]. Upper right images show scalp-voltage topographic maps, which reveal maximal central positivity for P3a in both species [human: time interval, 208–256 ms (B); NHP: time interval, 104–248 ms (D); white arrow indicates P3a (positive, red) central-scalp distribution]. Three-dimensional reconstruction of topographic maps (back-top view; MNI human head template; NHP MRI) averaged over the entire time interval is shown at left. Three 2D top views, shown at right, represent snapshots along this time interval. Lower right images show source localization (LORETA inverse solution) for the entire time intervals corresponding to P3a ERP component in each species. (B) Three-dimensional reconstruction of template human brain (MNI) (side view) shown at left indicates location of MRI coronal sections depicted at right. These coronal sections illustrate dorsal parietal, visual cortex, and cerebellum (I), temporal [STG (II)], and frontal [IFG, SFG) (III)] areas identified as the main generators of this neurophysiological signal in humans. (D) Three-dimensional reconstruction (NHP MRI) (side view) shown at left indicates location of MRI coronal sections depicted at right. Coronal sections illustrate dorsal parietal (I), temporal [STG (II)], and frontal [RG and ACG (III)] areas identified as generators of this neurophysiological signal in NHPs. A, anterior; L, left; P, posterior; R, right.

Fig. 3.

Acute subanesthetic ketamine effect on the MMN in NHPs. (A) Scalp-voltage topographic maps (2D top view) illustrating MMN effect under three conditions (Materials and Methods): ketamine, saline, and 5 h postketamine for the time interval of maximum MMN amplitude (72–96 ms). White arrow indicates MMN (negative, blue) central-scalp distributions. (B) ERP plot of grand average for difference waves (MMN) from a central electrode (Cz) of two NHPs. Data are plotted separately for three conditions: ketamine, brown curve (60–116 ms; peak amplitude, −0.94 μV at 88 ms); saline, green curve (68–136 ms; peak amplitude, −2.79 μV at 84 ms); and 5 h postketamine, orange curve (60–128 ms; peak amplitude, −2.62 μV at 84 ms). Topographic maps and ERP plots reveal marked and highly significant reduction of MMN magnitude under ketamine, relative to saline (ketamine vs. saline: P < 0.001). The ketamine effect reversed after 5 h of recovery (ketamine vs. 5 h postketamine: P < 0.001). The MMN magnitude for saline does not differ from that seen following ketamine washout (5 h postketamine vs. saline: P > 0.05).

Fig. 4.

Acute subanesthetic ketamine effect on the P3a in NHPs. (A) Scalp-voltage topographic maps (2D top view) illustrating P3a component under three conditions: ketamine, saline, and 5 h postketamine for the time interval of maximum P3a amplitude (152–200 ms). The white arrow indicates P3a (positive, red) central-scalp distributions. (B) ERP plot of grand average for deviant condition from a central electrode (Cz) of two NHPs. Data are plotted separately for three conditions: ketamine, brown line (108–232 ms; peak amplitude, 1.55 μV at 168 ms); saline, green line (108–244 ms; peak amplitude, 3.04 μV at 200 ms); and 5 h postketamine, orange line (120–268 ms; peak amplitude, 2.78 μV at 192 ms). Topographic maps and ERP plots reveal marked and highly significant reduction of P3a magnitude under the ketamine, relative to saline (ketamine vs. saline: P < 0.001). The ketamine effect reversed after 5 h of recovery (ketamine vs. 5 h postketamine: P < 0.001). P3a magnitude for saline does not differ from that seen following ketamine washout (5 h postketamine vs. saline: P > 0.05). mP3a indicates monkey P3.