Visual electrophysiology and "the potential of the potentials"

Abstract

Visual electrophysiology affords direct, quantitative, objective assessment of visual pathway function at different levels, and thus yields information complementary to, and not necessarily obtainable from, imaging or psychophysical testing. The tests available, and their indications, have evolved, with many advances, both in technology and in our understanding of the neural basis of the waveforms, now facilitating more precise evaluation of physiology and pathophysiology. After summarising the visual pathway and current standard clinical testing methods, this review discusses, non-exhaustively, several developments, focusing particularly on human electroretinogram recordings. These include new devices (portable, non-mydiatric, multimodal), novel testing protocols (including those aiming to separate rod-driven and cone-driven responses, and to monitor retinal adaptation), and developments in methods of analysis, including use of modelling and machine learning. It is likely that several tests will become more accessible and useful in both clinical and research settings. In future, these methods will further aid our understanding of common and rare eye disease, will help in assessing novel therapies, and will potentially yield information relevant to neurological and neuro-psychiatric conditions.

Fig. 1. ERG responses to white flashes delivered in the dark-adapted and light-adapted state.

Traces show ERG responses (averaged from several flash presentation) recorded from a healthy individual to strong flashes (10 photopic cd s m⁻², corresponding to the DA10 of the ISCEV standard) delivered in the dark following dark adaptation (lefthand panels) and to standard flashes (3 photopic cd s m⁻², corresponding to the LA3 of the ISCEV standard) delivered on a standard white background (30 photopic cd m⁻²) in the light-adapted state (righthand panels). Labels in the upper panels highlight the quantitative parameters usually reported (a-wave and b-wave amplitudes and peak times); the oscillatory potentials (OPs) on the rising limb of the b-wave may be qualitatively evaluated or quantified with additional filtering. The lower panels highlight several components in the waveforms and the underlying retinal processes or neuronal origins that could potentially be interrogated quantitatively with more sophisticated analyses (including mathematical modelling or machine learning techniques).

Fig. 2. A portable nonmydriatic stimulus and recording system (RETeval, LKC Technologies).

A Demonstration of positioning of device over the eye from which recordings are being taken. The electrodes being used are the “Sensor Strip” skin electrodes (LKC Technologies), but the device can also be used in conjunction with other electrode types. B Example ERG responses recorded with this technique in response to a stimulus equivalent to the standard light-adapted flash (each trace is the average of approximately 30 flash presentations; the green and orange traces are from two successive series of flashes). C View of device screen prior to initiation of nonmydriatic recordings. The device has an inbuilt video camera, so the subject’s eye is visible. The device also detects the pupil (highlighted by blue circle) and will adjust stimulus strength to deliver the retinal illuminance equivalent to that delivered by standard stimuli through a dilated pupil. D Responses to a stimulus equivalent to the standard light-adapted 30 Hz flicker.

Fig. 3. Examples of non-standard stimulus protocols to interrogate specific aspects of retinal function.

A, B Upper panels show a method to separate rod and cone-driven contributions to dark-adapted flash responses. A Blue traces show ERG responses to blue flashes of a range of strengths delivered in the dark-adapted state (each trace averaged from multiple flash presentations). These responses contain contributions from rod and cone systems. The red traces show responses to the same flashes, but delivered on a blue background. The background strength was 2.9 photopic cd m⁻² and 34 scotopic cd m⁻². Delivered through a dilated pupil, the background illuminance (approximately 1500 to 1700 scotopic trolands) is likely to be sufficient to saturate the rods (which are thought to be largely saturated by backgrounds in excess of 1000 scotopic trolands), but minimally adapt the cones. Thus, the flash responses recorded are cone-driven with no rod-driven components. B Traces plotted are the result of mathematical subtraction of the red traces from the blue traces in panel A. These traces represent the estimated isolated rod-driven component (with the a-waves largely reflecting current flows in the rod photoreceptors). C, D Lower panels show an ERG method of tracking recovery of rod system sensitivity in the dark following a bright light exposure. C ERG responses to dim flashes of fixed strength (0.02 scotopic cd m⁻²) delivered at different times in the dark after steady state exposure to a standard white background (30 photopic cd m⁻²). The smaller amplitude responses were recorded at earlier times following extinction of the background, whilst the larger amplitude responses were recorded at later times. D Amplitudes of responses in C plotted as a function of post-bleach time. Amplitudes have been normalised to the estimated final dark-adapted level (denoted by the horizontal dashed line).

Fig. 4. Illustration of mathematical models fitted to rod-driven a-wave response to strong flash.

A Derived dark-adapted rod-driven response to strong blue flash from a healthy individual; this is the largest amplitude trace from Fig. 3B. This trace is also reproduced in panels B and C. B The red dashed curve shows a fit based on the model of Lamb & Pugh, developed for the outer segment photocurrent. The curve was fitted with the assumption that the photoreceptor response is truncated as a result of the encroaching of post-receptoral signals giving rise to the b-wave (not accounted for in the model), and hence the curve continues downward past the a-wave trough. C Red dashed curve shows a fit based on the later model of Robson & Frishman. This model explicitly takes into account current flows in other parts of the photoreceptor layer, showing that the a-wave trough region in the bright-flash ERG is consistent with arising from current flows proximal to the photoreceptor outer segments.