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Purpose Myopia is a complex eye disorder. The X-linked form of complete congenital stationary night blindness (CSNB1A) is usually associated with moderate to high myopia, and is caused by mutations in the NYX gene. We explored if NYX mutations could be associated with high myopia, but not CSNB1A. Methods The coding regions of the NYX gene were sequenced for 204 Chinese males with high myopia (−8.00 dioptres or worse for both eyes). The frequencies of any sequence variations identified were determined in 200 Chinese males without myopia. Electro-oculography, electroretinography and standard cone function tests were performed on a male high myope carrying a mutation. Results A missense mutation (c.529_530GC>AT or p.Ala177Met) was identified in one male subject with high myopia, but not in 200 male emmetropes. Neither was this variant found in any of the 529 male and 567 female subjects of various ethnic backgrounds whose genome sequences are documented in the 1000 Genomes Project database. The mutation was predicted to affect the protein function. From ocular electrophysiological tests, the proband was found to have normal rod function, but mildly abnormal cone function and inner retina function. He did not seem to suffer from CSNB1A. Conclusions One novel missense NYX mutation was identified in an adult male presented with high myopia, but without the major electrophysiological features normally associated with CSNB1A. NYX gene mutations may be considered as one of the rare genetic risk factors for high myopia without key features of CSNB1A.

Purpose This study investigated the retinal adaptive mechanism in inner retinal dysfunction using the slow double-stimulation multifocal electroretinogram (mfERG) paradigm. Methods Slow double-stimulation mfERG responses were recorded from 15 eyes of 15 4-month-old Mongolian gerbils in control conditions and after suppression of inner retinal responses with injections of tetrodotoxin (TTX) and N -methyl-d-aspartic acid (NMDA). The stimulation consisted of five video frames: the two initial frames with multifocal flashes were triggered by two independent m-sequences, followed by three dark video frames. The results were compared with findings in humans: 7 subjects with glaucoma and 31 age-matched normal subjects were measured using the same mfERG protocol. Results The stimulation generates two responses (M 1 and M 2 ) from the two independent multifocal frames. The M 1 :M 2 ratio showed a significant reduction after administration of TTX+NMDA in the animal study. This matched with the human glaucoma findings. Glaucoma subjects generally have a reduced M 1 :M 2 ratio; this ratio showed a sensitivity of 86%, with a specificity of 84% for differentiating normal eyes from glaucomatous eyes. Conclusion This stimulation paradigm provides a method of measuring temporal visual characteristics. The M 1 :M 2 ratio acts as an indirect functional indicator of retinal adaptation, which may be abnormal in the diseased retina. Further development of this method may help to describe the functional variation in the diseased retina and to predict the occurrence of a range of retinopathies.

Glaucoma is one of the most important eye diseases resulting in blindness worldwide. It affects the inner retina and is without signs and symptoms in the early stages, making early detection of glaucoma important for eye care professionals. Electroretinography (ERG) is an objective technique used to measure retinal electrical responses, which directly reflect retinal function. The multifocal electroretinogram (mfERG) is a relatively new tool in this area. Various modifications of the mfERG stimulation paradigms such as fast flicker, low contrast, slow sequence, global flash and luminance-modulation have been developed in recent years. Using these techniques and a better understanding of the mfERG characteristics has resulted in greater effectiveness of the mfERG in the diagnosis of glaucoma. It is likely that sensitive clinical mfERG measurement protocols for early detection of glaucomatous damage will be possible in the near future.

Purpose: The present study investigated retinal adaptive responses in concert with the modulation of forward and backward adaptation induced by periodic global flashes using the global flash multifocal electroretinogram (mfERG). Methods: Six normal subjects were recruited for global flash mfERG measurements, which consisted of 103 scaled hexagonal elements followed by a global flash frame. In experiments I and II, with constant luminance maintained in both local and global flash frames, the number of dark frames was independently varied and these frames were either inserted prior to or following the global flash frame to investigate the forward or backward adaptive effect of the global flash on the mfERG. In experiment III, the number of dark frames was fixed but the luminance of the global flash frame was varied with constant luminance of the focal flash. This was used to demonstrate that the adaptive effect related not to time but to variation of luminance. Results: All the central, para-central and peripheral direct component amplitudes were found to be significantly influenced by variation of the number of dark frames (p < 0.01). Reducing the forward adaptive effect of the global flash enhanced the direct component response and it became steady after five dark frames were inserted following the global flash. Reducing the backward adaptive effect of the global flash also enhanced the direct component response but it started reducing after four dark frames were inserted prior to the global flash frame. These changes were different with luminance modulation of the global flash intensity with fixed dark frames, while the direct component amplitude grew approximately linearly with decreasing mean luminance of the global flash stimulation. Conclusion: The retina plays a major role in visual adaptation. Both forward and backward adaptive effects of the global flash on the direct component have been illustrated in this study. The results show that the forward and backward adaptive phenomena in the global flash mfERG are different and demonstrate that backward adaptation is found at the retinal level.

Multifocal ERG (mfERG) and multifocal VEP (mfVEP) have been used widely in the investigation of pathological changes or functional variations in the visual system. Altitudinal hemifield loss is a visual field defect that is usually found in patients with ischaemic optic neuropathy (ION). Anterior ischaemic optic neuropathy (AION) is a complex multi-factorial disease and it is difficult to diagnose according to clinical symptoms and signs alone. AION is believed to be caused by an infarction of the optic nerve due to the occlusion of the posterior ciliary arteries. The current report presents a patient diagnosed with non-arteritic AION. In this report, the mfERG findings did not match the results of the visual field test but those of the mfVEP did. After consideration of the visual electrophysiological and visual field results, the defect arises from neither the retina nor the visual pathway behind the optic chiasma. Hence, the optic nerve is the most likely location of the lesion, causing the superior altitudinal hemi-field loss. This report shows that the mfERG and mfVEP techniques can be used for objective visual field assessment to supplement the conventional visual field testing.

The electrical response of the retina was examined as a function of retinal region, using stimuli of various spatial frequencies in the first experiment. In the second experiment, the regional response of the retina to defocus at high and low spatial frequencies was investigated. Twenty three subjects were recruited for global flash multifocal electroretinogram (mfERG) in experiment 1. Black and white gratings (printed on plastic transparent sheets) of four spatial frequencies (SF), 0.24, 1.2, 2.4 and 4.8 cycle per degree were presented in front of the mfERG stimulation. The amplitudes and implicit times of the direct (DC) and induced (IC) components of mfERG responses were pooled into six concentric rings for analysis. There was low amplitude DC at low SF, which increased with increasing SF, and which decreased with increasing eccentricity. The IC was high in amplitude at all SF and reduced in amplitude with increasing eccentricity. Our findings suggested that outer and inner retina had different characteristics in processing spatial details. In experiment 2, Twenty-three young adults were recruited for mfERG measurement. The retinal electrical responses for low (0.24cpd) and high (4.8cpd) SF under fully corrected conditions of short-term negative defocus (-2D) and short term positive defocus (+2D) conditions were measured. There was a sign-dependent response to defocus in the DC response, mainly in peripheral regions. The sign dependent response at low SF was more obvious than that at high SF, and was located more peripherally. The IC response showed no clear trends for either defocus condition. The human retina seems to have a decoding system for optical defocus, which was tuned for low spatial frequency, and was located in the retinal near periphery.

Lycium Barbarum Polysaccharides (LBP) are the active components of Wolfberry (a traditional Chinese medicine) which has long been used for improving visual function. This study aims to investigate localized changes of retinal function in a partial optic nerve transection (PONT) model, and effects of LBP on visual function. The multifocal electroretinograms (mfERG) were obtained from 30 eyes of 30 Sprague-Dawley rats. The rats were divided into 6 groups (five treatment groups and one control group). Starting from the first day of the experiment, the rats in the (PONT+LBP) group and the (LBP) group were dosed with LBP; rats in the (PONT+PBS (phosphate buffered saline)) group and the (PBS) group were dosed with PBS via nasogastric tube every day until euthanized. The dorsal part of the optic nerve was transected in the (PONT), (PONT+LBP) and (PONT+PBS) groups at the end of week 1 (day 7 after LBP or PBS feeding began). The mfERG was measured at three time points: week 2, week 3 and week 5. Significant reduction of P1 and PhNR amplitudes of the mfERG were observed in all retinal regions a week after PONT. Feeding with LBP prior to PONT preserved retinal function. All mfERG responses returned to the normal range in the superior retina, which corresponds to the transected dorsal region of the optic nerve, while most of the inferior retinal responses were significantly increased at week 4 after PONT. The ventral part of the retina had secondary degeneration which was not only limited to the ganglion cell layer, but is a widespread effect affecting the outer retina. LBP altered the functional reduction caused by PONT by regulating the signal from the outer retina.

Introduction: Adaptation is one of the key characteristic of our vision which can maximize the visual function. It applies to both spatial and temporal characteristics. The fast flickering stimulation characteristics of the multifocal electroretinogram (mfERG) can be applied to analyze retinal interactions between flashes and to investigate retinal temporal processing mechanism. Besides, its localized stimulus pattern can also be used as a tool for investigation of retinal spatial interaction. Methods: The mfERG recordings were obtained from 13 eyes of 9, normal, six-week-old Yorkshire pigs. The control mfERG was measured using the pattern consisting of 103 nonscaled hexagons, where each hexagon will follow a pre-set m-sequence. Nine isolated hexagons from the 103 nonscaled pattern were chosen in the masking mfERG stimulation, where the remaining hexagons were kept at constant luminance. First-order and the second-order kernel responses were analyzed, which represent the outer and inner retinal responses, respectively. Results: The second-order kernel response amplitude from the visual streak region showed a significant enhancement under the masking stimulation. Conclusions: The enhancement found under the masking condition indicates that the retinal signal will be suppressed under surrounding flicker stimulation, and this spatial inhibitory mechanism may originate from the inner retina.

To investigate the association of the luminance-modulation global flash multifocal electroretinogram (mfERG) and other clinical assessments of vision in subsets of subjects at high risk of developing glaucomatous damage. Eighteen subjects (28 eyes) with asymmetric glaucoma and ocular hypertension were measured in this longitudinal study of visual field, OCT, and multifocal electroretinogram (mfERG). Five ophthalmic examinations were scheduled, once every 12 months over a 4-year period. The mfERG was assessed using a luminance-modulated global flash stimulation paradigm. The adaptive index which we have reported previously was calculated. There was a significant thinning of the peripapillary retinal nerve fiber layer over the course of the study for eyes with ocular hypertension, or for fellow eyes with asymmetric glaucoma which initially had an abnormal adaptive index; such eyes showed a thinning rate of −3.59 and −3.69 μm/year, respectively. However, no significant thinning was found for eyes which initially had a normal adaptive index. Two subjects were shown to have glaucomatous damage, confirmed by abnormal thinning of the retinal nerve fiber layer and visual field loss respectively at the last visit. However, these patients had shown an abnormal adaptive index in the mfERG measurement at the first visit. The adaptive index calculated from the measurement of luminance-modulated global flash mfERG is useful for predicting progression of signs related to glaucoma, especially in high-risk groups. The abnormal adaptive index reflects the change in fast-adaptive mechanisms in the retina and indicates the risk of developing glaucoma.

Aim Diabetes mellitus (DM) is a systemic disease with insufficient secretion of insulin or poor response to insulin. This typically causes poor control of blood glucose level leading to a range of complications. Early detection of the retinal function alteration in DM is needed. Methods A newly modified paradigm-slow double-stimulation multifocal electroretinogram (mfERG)-was introduced to measure early changes of retinal function in DM and to investigate changes in the adaptation mechanisms in the diabetic retina. The mfERG was measured by using a slow double-stimulation mfERG paradigm (M(1)M(2)OOO). Results The m1 amplitude of M(1) stimulation from diabetic subjects was significantly reduced in ring 1 in contrast to that of a control group. The m2 amplitude of M(2) stimulation from diabetic subjects was also significantly reduced in ring 1 and 2 as compared with those of the control group. The m1/m2 ratio which minimises intersubject variation shows a reasonable differentiation between the control and diabetic groups. There was a significant increase in the amplitude ratio from diabetic subjects in ring 2 and 3 as compared with those of the control group. Conclusions The present findings suggest that the new mfERG paradigm is a fast and sensitive test for the detection of early functional changes in the diabetic retina.

Previous studies have proposed that the inner retina is affected in myopes. This study aimed to investigate the changes in adaptive circuitry of the inner retina in myopia, using the global flash multifocal electroretinogram (global flash mfERG) with different levels of contrast (luminance modulation). Fifty-four myopes had global flash mfERG recorded with different contrasts. The direct component (DC) and the induced component (IC) of the mfERG response were pooled into six regions for analysis. The response amplitudes and implicit times at different contrasts were also analysed. Results showed that myopes had significant reduction in the paracentral DC amplitude for the 29% and 49% contrasts and in the paracentral IC amplitude at all contrasts measured. The peripheral IC amplitude for the 49% contrast was also reduced. No significant change was found in implicit time for either DC or IC response. Refractive error explained about 14% of the variance in DC and 16% of the variance in IC amplitude respectively; axial length could not account for additional variance in either paracentral DC or IC amplitudes in the hierarchical regression models used. We concluded that the paracentral retinal region in myopes showed signs of impaired retinal adaptation, suggesting a functional loss at the inner retinal layer. In addition, functions attributed to the outer retinal layer showed only small changes due to myopia.

Purpose The aim of this study was to obtain a better understanding of the cellular contributions to the porcine global flash mfERG by using a pharmacologic dissection method, together with the method using variation of stimulus contrast which has been used to demonstrate mfERG changes in human glaucoma. Methods Global flash mfERGs with different stimulus-contrast settings (99%, 65%, 49% or 29%) were recorded from 14 eyes of ten 6-week-old Yorkshire pigs in control conditions and after suppression of inner retinal responses with inhalation of isoflurance (ISO), and injections of tetrodotoxin (TTX) and N -methyl- d -aspartic acid (NMDA). ON- and OFF-pathway responses were isolated by injection of 2-amino-4-phosphonobutyric acid (APB) and cis-2,3-piperidinedicarboylic acid (PDA). Results The porcine global flash mfERG consisted of an early direct component (DC) and a late induced component (IC). ISO and TTX removed inner retinal contributions to the IC; NMDA application further abolished the oscillatory wavelets in the DC and removed the residual IC waveform. The inner retina contributed regular oscillation-like wavelets (W1, W2 and W3) to the DC and shaped the IC. After removing the inner retinal contributions, the porcine global flash mfERG waveform becomes comparable to that obtained with conventional mfERG stimulation. The remaining waveform (smoothed DC) was mainly contributed by the ON- and OFF-bipolar cells as revealed after APB or PDA injection. Photoreceptors contributed a small signal to the leading edge of N1. The characteristic of contrast response function of DC was demonstrated to be contributed by the inner retinal oscillation-like wavelets. Conclusion We believe that the DC of the porcine global flash mfERG is mainly composed of contributions from photoreceptors, and ON- and OFF-bipolar cells, where inner retinal activity partially shaped the DC with superimposed regular wavelets. However, the IC is dominated by inner retinal activity. The contrast response functions of DC consisted of both outer retinal response and oscillation-like wavelets of the inner retinal response. Both contain different characteristics during contrast modulation of the stimulus, where the changes of W2 of the inner retinal response seem independent of contrast modulation. The DC contrast response feature depends mainly on the relative contribution of inner retinal activities; the loss of inner retinal cells may alter the DC contrast response function, making it tend toward linearity.

PURPOSE. To use the global flash multifocal electroretinogram (mfERG) in patients with asymmetric glaucoma to determine whether retinal function is affected in fellow eyes that have no glaucomatous visual field defects. METHODS. Forty normal subjects and 12 patients with asymmetric glaucoma were recruited for visual field and mfERG measurement. The mfERG was assessed by using a global-flash stimulation paradigm with four video frames: 103 scaled hexagonal elements followed by a dark frame, a global-flash frame, and a dark frame. The localized luminance difference was set at 96%, 65%, 49%, and 29% display contrast during the four different test conditions, respectively. The first-order kernel response was measured, and the "adaptive index" which has been used previously was calculated. RESULTS. In fellow eyes with normal visual fields, the amplitude of the induced component (IC) was significantly reduced, and the adaptive index was reduced by a factor of almost 10 (P < 0.0001), as it was in the glaucomatous eyes. Although the adaptive index in the better (fellow) eye of the patients with glaucoma was slightly higher than in the eyes with diagnosed glaucoma, these differences were not statistically significant. CONCLUSIONS. The significant reduction of the adaptive index in the better eyes in subjects with asymmetric glaucoma shows that the fast adaptive mechanism(s) were reduced in these eyes. This implies that eyes that have functionally normal visual acuity and visual fields have abnormal fast-adaptive mechanisms.

Multifocal electroretinograms (mfERG) from isoflurane anesthetized pigs were recorded and sequential application of TTX, NMDA, APB and PDA were used to identify contributions to the mfERG from inner retinal neurons, ON-pathway, OFF-pathway and photoreceptors. The cellular origins of the first-order kernel (K1) and the first slice of the second-order kernel (K2.1) porcine mfERG are contributed from both inner and outer retina. For the K1 waveform, the n1 involved responses of cone photoreceptors and OFF-bipolar cells. The leading edge of p1 is dominated by ON-bipolar cell depolarization. The rear edge of p1, n2 and p2 are dominated by ON-bipolar activities and shaped by the activities of OFF-bipolar cells and retinal cells with NMDAr and voltage-gated sodium channels other than ganglion cells. The p3 is mainly inner retinal activities. For the K2.1 waveform, the p1 and n1 are the summation of activities of ON-, OFF-bipolar cells and retinal cells rich in NMDAr and voltage-gated sodium channels other than ganglion cells. The p2 seems to be related to the ganglion cells. Better understanding of the cellular origins of the normal porcine mfERG will be useful for comparing and defining the functional changes that may occur in diseased retinas.

Purpose - To investigate the variation of retinal electrophysiological function in glaucoma by using the global flash multifocal electroretinogram (mfERG) stimulation with altered differences in the stimulus luminance of the multifocal flashes, in an attempt to alter the levels of inner retinal contributions. Methods - The mfERG was assessed with a visual stimulus in steps of four video frames, which consisted of 103 scaled hexagonal elements followed by a dark frame, global flash, and dark frame. The localized luminance difference was set at 96%, 65%, 49%, or 29% stimulus contrast. Thirty subjects with glaucoma and 30 age-matched normal subjects were recruited for visual field and mfERG measurements. Results - This stimulus induces complex local first-order responses with an early direct component (DC) and a later induced component (IC). The luminance-modulated response functions of the DC and IC responses showed markedly different behavior. The peripheral IC showed a linear dependence on luminance difference, whereas the peripheral DC was saturated for higher luminance differences. This saturation became less obvious in subjects with glaucoma, mostly because of greater reduction of the response amplitude in the mid luminance-difference level. An “adaptive index” was calculated from the luminance-difference dependence of the peripheral DC, and it showed a sensitivity of 93%, with a specificity of 95% for differentiating normal from glaucomatous eyes, and also had a significant correlation (r = 0.58) with the glaucomatous visual field defect. Conclusions - The peripheral DC luminance-modulated response function is altered by the adaptive mechanism that is induced by the global flash; the reduction of the adaptive index may thus relate to an abnormal adaptive mechanism, presumably due to inner retinal damage. Glaucoma appears to produce large reductions of the adaptive index which correlate with field defects.

To investigate the effect of unsteady fixation on the multifocal electroretinogram (mfERG) measurement in normal subjects.The mfERGs of 20 subjects with normal vision (mean age=23.5 years) were recorded with different levels of voluntary eye movements made to mimic unsteady fixation. Subjects were required to move their fixation regularly every 2 s between the center and the ends of a fixation cross, so that 51.2% of the time fixation was at the center and 12.2% of the time it was at each end of the fixation cross. Four different conditions were performed: central fixation (without voluntary eye movements) and with 2 degrees, 4 degrees and 6 degrees magnitude of unsteady fixation. First-order kernel mfERG findings are presented.Analysis of the ring responses indicated that the central mfERG amplitude was most affected by unsteady fixation. There was significantly reduced amplitude for 4 degrees unsteady fixation and as expected, this reduction became larger with 6 degrees unstable fixation. However, there was no significant effect on the center hexagon amplitude for 2 degrees unsteady fixation. The amplitudes of the ring-2 responses were only affected in the 6 degrees unsteady fixation condition. No significant change in implicit time was found for any level of unsteady fixation.These results suggest that mfERG amplitude is not substantially affected if fixation is maintained within the central stimulus hexagon. We conclude that, for patients with poor fixation, the accuracy of mfERG results may be difficult to interpret and the use of a fixation-monitoring system is desirable for ideal measurement. The depth of depression at the blind spot area may be another useful parameter to interpret the accuracy of mfERG results in patients with poor fixation.

Purpose: The aim of this study was to obtain a better understanding of the cellular contributions to the chick global flash mfERG by using a pharmacological dissection method. Method: Global flash mfERGs were recorded from 11 white leghorn chicks (Gallus gallus). The inner retinal response was suppressed by injection of tetrodotoxin (TTX) and N-methyl-D-aspartic acid (NMDA). Responses from ON- and OFF-pathway were isolated by further injection of 2-amino-4-phosphonobutyric acid (APB). Results: The global flash mfERG of white leghorn chicks consist of a direct component (DC) originated from outer retina and a late induced component (IC) originated from the inner retina which are comparable to the global flash mfERG responses from primate, porcine and human. The ON- and OFF- responses found in chicks are also similar to that of porcine and primate with the N1 component is mainly from OFF-bipolar responses and the ON-response contributes mainly in the P1 component. Conclusion: Because of the similarities for the global flash mfERG found in chick to other species, this makes the possibility of using chick retina as a potential animal model for eye research in the area of mfERG.

Neural ectopic rewiring in retinal degeneration such as retinitis pigmentosa (RP) may form functional synapses between cones and rod bipolar cells that cause atypical signal processing. In this study, the multifocal electroretinograms (mfERGs) of a large animal model of RP, the rhodopsin P347L transgenic (Tg) pig, were measured to examine the sources and nature of altered signal processing.mfERG responses from a 6-week-old Tg pig were recorded before and after sequential application of tetrodotoxin (TTX), N-methyl-D-aspartate (NMDA), 2-amino-4-phosphonobutyric acid (APB), and cis-2,3-piperidinedicarboylic acid (PDA), to identify contributions to the retinal signal from inner retinal neurons, the ON-pathway, the OFF-pathway, and photoreceptors. The mfERG response contributions from different retinal components of in the Tg eyes were estimated and compared with control data from eyes of age-matched wild-type (WT) pigs.There was a prominent difference in the estimates of the inner retinal response and ON-bipolar cell pathway contribution between the Tg and WT mfERG responses. In particular, the early components of the inner retinal contribution were obviously altered in the Tg mfERG. The inner retinal components at approximately 24 and 40 ms appeared to be inverted. Differences in the estimates of OFF-bipolar cell pathway contributions were minimal. There was no change in cone cell responses in the Tg mfERG.In Tg retinas, ectopic synapses formed between cones and rod bipolar cells probably altered signal processing of the ON-bipolar cell pathway. In response to the altered visual signal input from the outer retina, signal processing in inner retinal neurons was also modified.