The electroretinogram b-wave amplitude: a differential physiological measure for Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder

Abstract

Background: Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent childhood neurodevelopmental disorder. It shares some genetic risk with Autism Spectrum Disorder (ASD), and the conditions often occur together. Both are potentially associated with abnormal glutamate and GABA neurotransmission, which can be modelled by measuring the synaptic activity in the retina with an electroretinogram (ERG). Reduction of retinal responses in ASD has been reported, but little is known about retinal activity in ADHD. In this study, we compared the light-adapted ERGs of individuals with ADHD, ASD and controls to investigate whether retinal responses differ between these neurodevelopmental conditions.

Methods: Full field light-adapted ERGs were recorded from 15 ADHD, 57 ASD (without ADHD) and 59 control participants, aged from 5.4 to 27.3 years old. A Troland protocol was used with a random series of nine flash strengths from -0.367 to 1.204 log photopic cd.s.m^-2. The time-to-peak and amplitude of the a- and b-waves and the parameters of the Photopic Negative Response (PhNR) were compared amongst the three groups of participants, using generalised estimating equations.

Results: Statistically significant elevations of the ERG b-wave amplitudes, PhNR responses and faster timings of the b-wave time-to-peak were found in those with ADHD compared with both the control and ASD groups. The greatest elevation in the b-wave amplitudes associated with ADHD were observed at 1.204 log phot cd.s.m^-2 flash strength (p < .0001), at which the b-wave amplitude in ASD was significantly lower than that in the controls. Using this measure, ADHD could be distinguished from ASD with an area under the curve of 0.88.

Conclusions: The ERG b-wave amplitude appears to be a distinctive differential feature for both ADHD and ASD, which produced a reversed pattern of b-wave responses. These findings imply imbalances between glutamate and GABA neurotransmission which primarily regulate the b-wave formation. Abnormalities in the b-wave amplitude could provisionally serve as a biomarker for both neurodevelopmental conditions.

Keywords: ADHD; ASD; Differentiation; Electroretinogram; GABA; Glutamate; Neurotransmission Imbalance; Physiological Marker.

Fig. 1

Schematic diagram of the retinal pathway generating the electroretinogram in response to light. The schematic diagram displays the cellular component of the retina and the retinal pathway in response to light generating the electroretinogram (ERG) waveform. Light passes through the transparent retinal layers before reaching the photoreceptor chromophores which absorb the photons. The cone photoreceptor outer segment subsequently hyperpolarises, shutting off glutamate release into the post photoreceptor synapse. This hyperpolarisation is recorded as the a-wave in the electroretinogram waveform. Glutamate has opposite effects on the ON- and OFF-bipolar cells. Decreased glutamate binding on the mGLUR6 receptor starts a cascade of signals that open the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) channel which depolarises the ON-bipolar cells and increases glutamate release to the ON-ganglion cell [31]. In contrast, the OFF-bipolar cell becomes hyperpolarised by the reduction of glutamate release from the cone cell binding on the iGLUR4 receptor, resulting in decreased glutamate release toward the OFF-ganglion cell. The b-wave amplitude is the summation of ON- and OFF-bipolar cell responses. The Photopic Negative Response (PhNR) is the summation of ON- and OFF-ganglion cell responses and contributions of Müller cell potassium currents. Glu, glutamate release; red arrow pointing down means reduced; mGLUR6, metabotropic glutamate receptor 6; iGLUR4, ionotropic glutamate receptor 4. Retinal layers: OS, Outer Segment; ON, Outer Nuclear; OP, Outer Plexiform; IN, Inner Nuclear; IP, Inner Plexiform; GC, Ganglion Cell

Fig. 2

Different parameters of the ERG waveform. The ERG response starts at time 0 followed by the a-wave, b-wave, and Photopic Negative Response (PhNR). Description of the ERG waveform parameters: a-amp, a-wave amplitude, an amplitude from the baseline to the a-wave trough; a-time, a-wave time-to-peak, from the light onset to a-wave trough; b-amp, b-wave amplitude, measured from a-wave trough to b-wave peak; b-time, b-wave time-to-peak, from the light onset to the time when the b-wave amplitude peaks; p72, PhNR amplitude from baseline to the waveform at 72 ms post-stimulus onset; PhNRmin, PhNR amplitude measured as the most negative point from the baseline within the time window of 55 and 95 ms following stimulus onset; Tmin, time of PhNR at a minimal amplitude occurred within the 55–95-ms window

Fig. 3

Comparison of the representative light-adapted ERG waveforms of one individual from each group. The ERG waveforms of each ADHD, control and ASD individual at the nine randomised flash strengths are displayed on the left panel. The right panel enlarges the image of the representative ERG waveforms produced by the 1.204 log phot cd.s.m⁻² flash strength, which showed the most significant differences amongst these individuals. The b-wave amplitudes of ADHD are all distinctively higher than both ASD and control individuals at all light strengths. The b-wave amplitudes of ASD are lower than the controls from 0.398 to 1.204 log phot cd.s.m^–2

Fig. 4

Comparison of the b-wave amplitudes of the ADHD, Control and ASD groups. For each flash strength, a set of three boxplots representing ASD, Control and ADHD (from left to right) are displayed. The medians and 95% CIs of each group are presented. The medians of ADHD are distinctively higher than those of the control and ASD groups at all flash strengths

Fig. 5

The photopic hill of the b-wave amplitudes of the ADHD, Control and ASD groups. The mean b-wave amplitudes with 95% CIs for each group are plotted at the nine flash strengths

Fig. 6

Boxplots showing the comparisons of the b-wave time-to-peak of the ADHD, ASD and Control groups. For each flash strength, a set of three boxplots representing ASD, Control and ADHD (from left to right) are displayed. The medians and 95% CIs of each group are presented

Fig. 7

The Photopic Negative Responses (PhNR) at t = 72 ms (p72). The amplitudes of PhNR, p72, of ADHD, Control and ASD groups are shown at all flash strengths. For each flash strength, a set of three boxplots representing ASD, Control and ADHD (from left to right) are displayed. The medians and 95% CIs of each group are presented