Electoretinographic evidence of retinal ganglion cell-dependent function in schizophrenia

Abstract

Schizophrenia is a complex disorder that is diagnosed mainly with clinical observation and evaluation. Recent studies suggest that many people with schizophrenia have abnormalities in the function of the N-methyl-d-aspartate receptor (NMDAR). The retina is part of the central nervous system and expresses the NMDAR, raising the possibility of the early detection of NMDAR-related schizophrenia by detecting differences in retinal function. As a first-step, we used two non-invasive outpatient tests of retinal function, the photopic negative response (PhNR) of the light-adapted flash-electroretinogram (PhNR-fERG) and the pattern ERG (PERG), to test individuals with schizophrenia and controls to determine if there were measurable differences between the two populations. The PhNR-fERG showed that males with schizophrenia had a significant increase in the variability of the overall response, which was not seen in the females with schizophrenia. Additionally at the brightest flash strength, there were significant increases in the PhNR amplitude in people with schizophrenia that were maximal in controls. Our results show measurable dysfunction of retinal ganglion cells (RGCs) in schizophrenia using the PhNR-fERG, with a good deal of variability in the retinal responses of people with schizophrenia. The PhNR-fERG holds promise as a method to identify individuals more at risk for developing schizophrenia, and may help understand heterogeneity in etiology and response to treatment.

Keywords: Biomarker; Electroretinogram; NMDA receptor; Pattern ERG; PhNR; Retina; Retinal ganglion cells; Schizophrenia.

Conflict of interest statement

Declaration of competing interest The authors declare no conflicts of interest.

Copyright © 2019. Published by Elsevier B.V.

Figures

Fig. 1.

Individual PhNR-fERG waveform for a single subject at a single flash (1 cd s/m2) intensity from a A) female control, (B) female with schizophrenia, (C) male control, and (D) male with schizophrenia with time from stimulus onset in milliseconds (ms) on the x-axis and amplitude (Amp.) in microvolts (μV) on the y-axis. Arrows indicate the a-wave, bwave, i-wave, and PhNR components of the PhNR-fERG.

Fig. 2.

Filtered PhNR-fERGs at the brightest flash strength of 10 cd$s/m2 from (A) female controls, (B) females with schizophrenia, (C) male controls, and (D) males with schizophrenia. Each colour represents the PhNR-fERG from a single individual and black line represents the mean of each group. Time from stimulus onset in milliseconds (ms) is on the xaxis and amplitude in microvolts (mV) on the y-axis.

Fig. 3.

Graphs represent the (A) PhNR trough amplitude, (B) PhNR implicit time, and (C) negativity of the PhNR deflection at 72 ms (N72) averaged for all subjects at each flash strength. Black represents the controls, dotted lines represent the people with schizophrenia, gray dotted lines represent all people with schizophrenia, blue represents the male people with schizophrenia, and red represents the females with schizophrenia. Ampl is amplitude. Impl. is implicit time. Cd s/m2 represents candelas per second per meters squared, a measure of constant luminance. Bars indicate standard error. HC is healthy controls; Scz is people with schizophrenia. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4.

Graphs summarize the power analysis of the oscillatory potentials. (A–C) Mean total power of all oscillatory potentials between 75 and 300 Hz in microVolts (μV), (D–F) mean total power of oscillatory potentials between 75 and 100 Hz in mV, and (G-I) mean total power of oscillatory potentials between 100 and 300 Hz in mV. Cd·s/m2 represents candelas per second per meters squared, a measure of constant luminance. Bars represent standard error. HC is healthy controls; Scz is people with schizophrenia.

Fig. 5.

Graphs of all PERG traces from the (A) healthy control female subjects examined with the CRT display (HC); (B) females with schizophrenia (Scz) examined with the CRT display; (C) control male subjects (HC) examined with the CRT display; (D) males with schizophrenia (Scz) examined with the CRT display; (E) control female subjects examined with the LED display (HC); (F) females with schizophrenia (Scz) examined with the LED display; (G) control male subjects (HC) examined with the LED display; (H) males with schizophrenia (Scz) examined with the LED display. Black lines depict the mean of the PERG response, thick red lines depict the mean of the PERG response for female subjects, and thick blue lines represent the mean of the PERG response for male subjects. X-axis shows time (ms) from pattern reversal. Amp is amplitude in microVolts (μV). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6.

Analysis of the PERG using the LED and CRT displays. (A) N35 amplitude (Amp.) and (B) N35 implicit (Imp.) time; (C) P50 amplitude (Amp.) and (D) implicit (Imp.) time; and (E) N95 amplitude (Amp.) and (F) implicit (Imp.) time. Black open circles are control (HC) males subjects and blue open circles are males with schizophrenia (Scz). Black asterisks are control (HC) females and red asterisks are females with schizophrenia (Scz). Bars indicate standard error. Amplitude is in microVolts (μV) and implicit time is in milliseconds (ms). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)