Monitoring retinal function in neovascular maculopathy using multifocal electroretinography - early and long-term correlation with clinical findings.

PURPOSE: To objectively investigate and longitudinally monitor retinal function in patients with choroidal neovascularization (CNV) due to exudative age-related macular degeneration (AMD) and myopia using multifocal electroretinography (mfERG). METHODS: Patients with classic and occult subfoveal CNV secondary either to AMD or to myopia were enrolled in the study. The mfERGs were performed at the beginning of the study and every 3 months subsequently during a follow-up period of 15 months. In addition, standardized visual acuity testing, ophthalmologic examinations, color fundus photographs and fluorescein angiography were performed. The mfERG records were derived with the VERIS-System (Electro-Diagnostic Imaging, San Mateo, Calif., USA); 103 locations within the central 50 degrees in diameter were stimulated concurrently by means of the m-sequence technique. Fixation stability was monitored throughout the recording session with an infrared eye monitoring system (VERIS Refractor/Camera unit). The first-order response component was extracted for each stimulated retinal location. The response densities of the first-order kernel were evaluated as a function of eccentricity from the center (ring 1) to the periphery of the stimulated area (ring 6). The results were compared to those derived from age-matched normal control groups. For each patient mfERG responses measured on follow-up visits were compared to each other to evaluate and monitor changes in retinal function. These changes were tested for correlation with those observed in other clinical and electroretinographic findings. Statistical analysis was performed using the Pearson coefficient. RESULTS: Subfoveal neovascular maculopathy was associated with a reduction in response density most prominent within the central 5 degrees over the area affected by CNV detected either at the beginning of the study or at the follow-up recordings. During the follow-up period patients 1 and 4 showed stabilization or a slight increase in response densities over the neovascular lesion-complex and a corresponding stabilization or slight increase in visual acuity accompanied by a decrease in the activity of the neovascular lesion as determined by fluorescein angiography. Patient 2 revealed an increase in response density correlating with an increase in visual acuity and decrease in lesion size. In the contralateral eye of this patient the response density dropped in the area of new subfoveal CNV. In patient 3 continuous progression of the disease was documented by fluorescein angiography and visual acuity. It correlated well with a continuous decrease in retinal response densities during the follow-up. CONCLUSIONS: Objective monitoring of retinal function and correlation with morphological and psychophysical findings was at least in part possible in patients suffering from AMD and myopia. In all of four patients whose subfoveal CNV was documented by fluorescein angiography. Response densities were reduced particularly in the central 5 degrees and in visual acuity. The mfERG data showed a moderate to high statistical correlation with visual function as measured by visual acuity. On the other hand, the greatest linear dimension of the lesion size showed only a weak to moderate statistical correlation with both the response densities of the mfERG and the visual acuity. We conclude that the size of the CNV complex does not represent an accurate measure of retinal function in neovascular maculopathy. The good correlation of the mfERG data with visual acuity suggests that it may serve for objective assessment of retinal function, of the areas overlying the CNV. It shows potential as a valuable tool for longitudinal monitoring of AMD patients.

Electrophysiological estimate of human cortical magnification.

OBJECTIVE: The cortical magnification factor characterizes the area of human primary visual cortex activated by a stimulus as a function of angular distance from an observer's line of sight. This study estimates human cortical magnification using an electrophysiological method with excellent temporal resolution: visual evoked potential (VEP) dipole source localization. METHODS: For each of 60 independently modulated checkerboard patches within the central 18 deg of the visual field, location, orientation, magnitude, and time-course of the dipole current source that best described the VEP distribution across a multi-electrode array was obtained. At numerous eccentricities, cortical magnification was determined using two different techniques: (1) the distance between each pair of adjacent stimulus patches was matched to the corresponding distance between adjacent cortical sources; and (2) the area of each stimulus patch was matched to the magnitude of the corresponding cortical source (which was assumed to be proportional to cortical area). RESULTS: The estimates of human cortical magnification using our electrophysiological method were similar to previous estimates from psychophysics, cortical stimulation, and functional magnetic resonance imaging. CONCLUSIONS: The concordance of results provided by these disparate technologies, with differing spatial and temporal limitations, supports their combination in studying the spatio-temporal dynamics of human brain function.

The optic nerve head component of the monkey's (Macaca mulatta) multifocal electroretinogram (mERG).

To search for an optic nerve head component (ONHC) in the monkey's (Macaca mulatta) multifocal electroretinogram (mERG), mERGs from three animals were recorded with different electrode configurations. A component with a latency that varied with distance from the optic nerve head was easily identified by eye in recordings from the speculum of a Burian-Allen electrode referenced to a DTL on the unstimulated eye. This component was reasonably well isolated by subtracting a weighted version of a Burian-Allen bipolar recording or by employing the extraction algorithm of Sutter and Bearse (1999, Vision Research, 39, 419-436). The waveform of this component resembles the ONHC reported for the human mERG.

Imaging visual function with the multifocal m-sequence technique.

The multifocal m-sequence technique is a versatile set of tools for visual electrophysiology designed to provide access to the complex dynamic interplay of converging signals in the central nervous system. Here, a number of uses for the technique are demonstrated, with examples from human electroretinography. A simple relationship between the binary kernels extracted from a single experiment permits us to distinguish local from lateral interactions in the retina. Transformation of the series of binary kernels into response sequences provides new insight into unexpected fast dynamic properties of retinal responses and facilitates future modeling of the signals as well as identification of the signal sources.

Assessment of early retinal changes in diabetes using a new multifocal ERG protocol.

AIMS: To assess early functional retinal changes in diabetics without retinopathy, a new multifocal stimulus paradigm was used that emphasises fast adaptive response contributions. METHODS: 25 normal control subjects (25 eyes) and 11 diabetics without retinopathy (22 eyes) served as subjects. Stimulation and analysis were performed with Veris Science 4.0. A stimulation protocol was used that combines regular multifocal flicker stimulation with a periodic "global" flash inserted between the multifocal stimuli. The multifocal stimuli were presented four video frames apart. The global flash covered the entire screen in the third frame of the four frame interval. The remaining two frames were dark. The periodic global flashes could only contribute to the focal responses if they were affected by the multifocal stimulation. A non-linear component induced by the interaction of the focal and global flashes was observed. The differences between control subjects and diabetics were assessed in both the multifocal responses and their induced effect on the following global flashes. RESULTS: The responses to focal flashes were reduced significantly in diabetics matched in age to the control subjects. The induced components showed large intersubject variability in controls and patients, and did not differ significantly between the two groups. CONCLUSION: The periodic global flashes produce a greater multifocal response reduction in diabetics than in normals, indicating impairment in the rate or magnitude of recovery from the bright preceding stimulus. The new stimulation protocol reveals early changes in retinal function of diabetics.

Distribution of oscillatory components in the central retina.

This study examines the characteristics and the naso-temporal asymmetries of the higher-order oscillatory components of the multifocal electroretinogram (mERG). The magnitude of the mERG asymmetry and the mechanisms which produce it have not been studied previously. We recorded the mERG from seven normal observers using slow multifocal flicker and response filtering of 10-300 Hz. This permitted, without additional filtering, examination of the dominant first order component and the oscillation-rich components in the first and second order kernels. The oscillatory components in the two kernels had multiple peaks separated by about 6.8 ms, similar to those of conventional oscillatory potentials. Naso-temporal asymmetry of the three response components was analyzed in three groups (concentric rings around the fovea) spanning 1.5-10 deg of retinal eccentricity. The oscillation-rich components were, on average, approximately 14% larger in amplitude in the temporal retina than in corresponding nasal locations (p < 0.05) while the dominant first order component was not asymmetrically distributed. We tested the hypothesis that the asymmetry could be modeled as a combination of a retinal component (RC) and an optic nerve head component (ONHC) which varies in latency as a function of distance from the optic disc. We found that both oscillatory components and the dominant first order response could be decomposed into RCs and ONHCs that are symmetrically distributed. Thus, it appears that the naso-temporal asymmetries of the oscillation-rich components are produced primarily by the relative alignment and enhancement of RC and ONHC wavelets in the temporal retina, and misalignment and partial cancellation in the nasal retina.

Das multifokale elektroretinogramm in der diagnostik und verlaufskontrolle lokalisierter Netzhautfunktionsstörungen: fallbericht eines patienten mit chorioretinopathia centralis serosa.

The role of multifocal electroretinography (MF-ERG) in the diagnosis and follow-up of localized areas of retinal dysfunction is discussed. A 42-year-old male with the preliminary diagnosis of optic neuritis in his left eye was referred for evaluation with the MF-ERG. Simultaneous cone ERGs were obtained from 103 locations within the central 50 degrees of the retina. During an 8-month follow-up four MF-ERGs were obtained. Bilaterally reduced paracentral response amplitudes contradicted the preliminary diagnosis. Subsequently central serous chorioretinopathy was diagnosed. Follow-up showed normalization of the MF-ERG responses in the left eye while retinal function in the right eye showed initial worsening. The noninvasive MF-ERG lends itself to follow-up in patients with central serous chorioretinopathy.

Topography of cone electrophysiology in the enhanced S cone syndrome.

PURPOSE: To investigate the topography of cone electroretinographic (ERG) responses in the enhanced S cone syndrome (ESCS). METHODS: A 19-year-old female with ESCS who was one of the original cases defining the syndrome was studied. Full-field, focal (Maculoscope) and multifocal (VERIS) ERGs were performed using white light. Multifocal ERG responses were also generated with red and blue stimuli and with a slow m-sequence to elicit off-responses. Results were analyzed by averaging data in rings at increasing eccentricity from the fovea and compared to data recorded identically from a normal subject. RESULTS: The full-field ERG from this patient showed typ ical large slow photopic waveforms and was unchanged from recordings made 9 years earlier. The focal ERG showed signals of borderline low amplitude from the fovea with the multifocal ERG, the ESCS responses from the central macula had a relatively normal waveform, and those 9 degrees to 20 degrees from fixation showed the prolonged wave-form that characterizes the full-field ERG. Responses were larger to blue light than red light in ESCS in both center and periphery. The central ESCS responses were relatively normal in timing to both red and blue light, whereas the peripheral ESCS responses were markedly delayed to both. Off-responses were seen in ESCS only near the foveal center. CONCLUSIONS: The marked differences between central and peripheral ERG responses in ESCS suggest that there are different distributions of S, L, and M cones in these regions and that S cones may feed into different neural pathways in the center and periphery. It was postulated that in ESCS, S cones may partially replace L and M cones centrally and feed into the usual S cone pathways. In the periphery, however, there is little L and M cone b-wave activity in ESCS, and S cones may usurp both the space and neural pathways of the rods.

The optic nerve head component of the human ERG.

The local responses of the multifocal ERG reveal continuous changes in the second order waveforms from the nasal to the temporal retina. Scrutiny of these changes suggests the presence of an additive component whose latency increases with the distance of the stimulus from the optic nerve head. This observation led to the hypothesis of a contributing source in the vicinity of the optic nerve head whose signal is delayed in proportion to the fiber length from the stimulated retinal patch to the nerve head. The hypothesis was tested with two independent methods. In Method 1, a set of different local response waveforms was approximated by two fixed components whose relative latency was allowed to vary and the fit of this two component model was evaluated. In Method 2, two signals were derived simultaneously using different placements for the reference electrode. The placements were selected to produce a different ratio of the signal contributions from the retina and the nerve head in the two recording channels. The signals were then combined at a ratio that canceled the retinal component. Method 1 yielded an excellent fit of the two component model. Waveforms and latencies of the hypothetical optic nerve head component derived from the two methods agree well with each other. The local latencies also agree with the propagation delays measured in the nerve fiber layer of the monkey retina. In combination, these findings provide strong evidence for a signal source near the optic nerve head.

[Multifocal electroretinogram (MF-ERG) in diagnosis of macular changes. Example: senile macular degeneration]. / Multifokales Elekroretinogramm (MF-ERG) in der Diagnostik von Makulaveränderungen. Beispiel: Altersabhängige Makuladegeneration (AMD).

PURPOSE: Small areas of retinal pathology may pose diagnostic difficulties. The noninvasive multifocal electroretinogram (MF-ERG) provides a topographical mapping of retinal function. Its role in the diagnosis of macular diseases is examined in age-related macular degeneration (AMD). AMD is a main cause of central visual loss in the elderly population, affecting the second eye in 75%. METHODS: MF-ERG recordings of three patients with AMD were compared to the findings of fundus photography and fluorescein angiography. During the MF-ERG recordings the central 50 degrees of the retina was stimulated. The visual stimulus consisted of 241 hexagons that alternated, independently and pseudorandomly, between black and white according to a special predetermined binary sequence. Local retinal response components were extracted using the Fast m-Transform Algorithm. RESULTS: Three of six eyes had undergone cataract surgery with implantation of a posterior chamber lens (PCL). In accordance with an increase in light transmission through PCLs, these eyes showed an increase in the MF-ERG responses. MF-ERG allowed accurate topographic mapping of focal areas of retinal dysfunction in all patients tested. There was good correspondence to anatomical changes detected by fluorescein angiography. CONCLUSION: The high resolution of the MF-ERG enables detection of small areas of retinal pathology. It thus presents a clinically useful, noninvasive method in the early diagnosis and follow-up of macular disease.

Lack of lateral inhibitory interactions in visual cortex of monocularly deprived cats.

To gain new insight into the effects of monocular deprivation, we studied the visual cortex of adult cats deprived of vision in one eye. Local field potentials were recorded in response to contrast reversal of square-wave gratings modulated in time either by pseudorandom, m-sequences or periodically. We have found that: (1) stimulation of the retinotopic locus of the recording site elicits responses with abnormal waveforms and long latencies from the deprived eye; (2) stimulation of a remote, non-retinotopic locus elicits responses from the non-deprived eye but not from the deprived eye; (3) the monocularly deprived cortex lacks lateral inhibitory interactions which are characteristic of the normal cortex; and (4) steady-state responses showed little difference in spatial-frequency tuning and contrast sensitivity between the deprived and non-deprived eye, mostly conforming to earlier field-potential data in monocular deprivation. Functional lateral interactions appear to be greatly reduced in monocularly deprived cortex.

Assessment of local retinal function in patients with retinitis pigmentosa using the multi-focal ERG technique.

To assess local retinal function in patients with retinitis pigmentosa (RP), multi-focal ERGs and local thresholds (static visual fields) were obtained on eight RP patients with visual acuities of 20/25 or better. All eight patients showed multi-focal responses with normal timing within the central 5 deg. However, there were few responses with normal timing in the areas outside the central 7.5 deg, except in the case of the only patient with a 30 Hz full-field response with normal timing. Since full-field ERGs are dominated by responses from the periphery, this finding supplies a foundation for the commonly observed delays in the full-field cone ERGs of patients with RP. With respect to amplitude, only two patients showed multi-focal responses with near normal amplitudes anywhere in the field. The loss of amplitude at any point was not a good predictor of visual sensitivity in the Humphrey visual field. On the other hand, all areas with normal timing had near normal sensitivity. Timing changes appear to be an early indication of local retinal damage to the cone system. Nearly all areas with sensitivity losses greater than 0.5 log unit, and some areas with near normal sensitivity, showed significantly delayed multi-focal ERGs. Finally areas with extreme sensitivity loss show multi-focal responses with a wide range of amplitudes and implicit times across patients, suggesting different mechanisms of disease action in different patients.

Mapping of retinal function in diabetic retinopathy using the multifocal electroretinogram.

PURPOSE: To investigate focal abnormalities in the electroretinogram (ERG) signal in diabetic patients, with and without retinopathy, using a multifocal ERG. METHODS: Sixteen patients with diabetes mellitus, 8 of whom had diabetic retinopathy (mean duration of diabetes: 18.5 years) and 19 approximately age-matched healthy volunteers underwent multifocal ERG testing. One hundred three retinal locations within the central 50 degrees were stimulated concurrently, according to a pseudorandom m-sequence. Response components were extracted for each stimulated retinal location. RESULTS: In diabetic patients with retinopathy, the overall amplitudes were reduced (P < 0.01), and peak implicit times were increased (P < 0.01) in the first-order component (mean flash response) and in the first slice of the second-order component (local two flash interaction). In addition, local reductions of amplitude could be seen in the first- and second-order components. In patients without retinopathy, only amplitudes of the second-order component were reduced (P < 0.01). Another salient difference was observed in a special feature of the second-order component that was reduced in diabetic patients, with and without retinopathy (P < 0.05). CONCLUSIONS: Second-order components depend on nonlinear dynamics. Thus our findings indicate changes in the nonlinear dynamics of a fast-gain control in diabetic patients, presumably located in the inner retina. This suggests that early functional changes of the inner retina are evident in diabetic patients before impairment of the outer retina is observed. Multifocal nonlinear analysis permits the detection of subclinical diabetic retinopathy and offers the advantage of topographic mapping of retinal dysfunction.

M and P components of the VEP and their visual field distribution.

To study components related to parallel processing of information across the visual field, multi-focal pattern reversal visual evoked potentials (VEPs) were recorded using binary m-sequences. Contrast, chromatic, spatial and temporal characteristics of the stimuli were varied in order to favor contributions from either M or P pathways. Responses were decomposed into two additive components whose behavior was consistent with that of M and P mechanisms. The results suggest that contributions to the VEP from the M pathway precede those from the P pathway, and that the ratio of P/M contributions decreases with eccentricity.

Imaging localized retinal dysfunction with the multifocal electroretinogram.

Conventional electroretinographic techniques do not permit efficient mapping of retinal responsiveness for the detection of small dysfunctional areas. This study explores the application of a new technique that makes such mapping possible. It utilizes a multifocal electroretinogram technique based on binary m sequences that simultaneously tests a large number of small retinal areas by multiplexing their responses onto a single signal derived from the human cornea. The focal responses are subsequently extracted for the derivation of high-resolution maps that characterize retinal responsiveness. The required recording times are short enough to make such testing feasible in the clinic. In this study we demonstrate the high sensitivity of the technique by mapping a small area that has been partially bleached by a strobe flash in a normal retina and by mapping dysfunctional areas in three patients with different, well-documented retinal pathologies. The results suggest that the multifocal electroretinogram has the potential to become a valuable clinical tool.

A topographic study of oscillatory potentials in man.

The purpose of this study was to evaluate the use of slow multifocal m-sequence stimulation in analyzing the topographic distribution and underlying mechanisms (including nonlinearities) of the retinal oscillatory potentials (OPs). In giving us access to the response topography and the nonlinear characteristics of the OPs, the m-sequence technique provides us with two important means for the identification and characterization of the signal sources. In this study, we analyzed the OPs into the first- and second-order components and investigated their topographies and luminance dependence. The distribution of both the first- and second-order OP components differed significantly from that of the flicker ERG investigated by Sutter and Tran (1992). At eccentricities and luminance levels favoring activity by both rods and cones, the second-order OPs were particularly prominent, showing the most clear-defined and complex waveform. The topographic distribution of the second-order OPs showed combined features of both rod and cone distributions. On a strong rod-bleaching background, the second-order OPs were eliminated and the first-order OPs showed a reduced amplitude and a shifted latency. These results are consistent with the notion that the second-order component of the OPs is dominated by contributions from rod-cone interactions.

Spatially distributed responses induced by contrast reversal in cat visual cortex.

Field potentials were recorded from cat striate cortex, either between an epidural screw electrode and a cannula-electrode inserted deep in the gray matter (transcortical recording) or with a pair of metal microelectrodes. Electrodes were placed bilaterally near the cortical projection of the area centralis. The horizontal separation of the recording tips was approximately 2 mm and approximately 300 microns, respectively. The area of the visual field providing input to the recording site (receptive field) was determined by measuring the field potentials generated by contrast reversal of high-contrast, achromatic bar gratings. Five-degree-diameter grating patches were presented individually over a large area of the visual field. The gratings were contrast-reversed at 4, 6 or 10 Hz, while also being swept in spatial frequency between 0.56 and 5.24 c/deg. The receptive fields were approximately 20 deg across or more, substantially larger than expected on the basis of cortical retinotopy. Responses were also elicited by stimulation of the hemi-field contralateral to that contributing to the classical receptive field, implicating the presence of a callosal projection. The large, spatially distributed receptive fields consisted of patches of high and low sensitivity. Continuous cortical infusion of either 100 microM tetrodotoxin or 10 mM muscimol at the recording site totally suppressed the transcortically recorded field potentials, proving that the local field potentials were generated postsynaptically. The present findings suggest that a cluster of cortical cells near the projection site of the area centralis receives input from remote cortical regions to an extent that is comparable with that of anatomically demonstrated long-range lateral connections.

Retinotopic and nonretinotopic field potentials in cat visual cortex.

Two types of field potentials were identified in cat visual cortex using contrast reversal of oriented bar gratings: a short-latency fast-local component with a retinotopic organization similar to that seen with single-unit discharges at the same cortical site, and a slow, nonretinotopic component with a longer peak latency. The slow-distributed component had an extensive receptive field mapped by measuring the amplitude of binary kernels and showed strong inhibitory interactions within the receptive field. The peak latency of the slow-local component increased with distance from the retinotopic center, suggesting a possible conduction delay. Both components showed some orientation bias depending on the laminar location, but the bias could be independent of the orientation preferred by single units in the immediate vicinity. The present findings indicate that locally generated field potentials reflect cortical mechanisms for nonlinear integration over wide areas of the visual field.

The topography of visual evoked response properties across the visual field.

Visual evoked potentials (VEPs) to luminance and pattern reversal stimulation were derived for a large number of small areas throughout the central visual field. In one study, the field was tested with a stimulus array consisting of 64 equal-area patches. Local response components were extracted by independent m-sequence modulation of the patches. Field topographies were compared between and within subjects using different electrode placements. The subject-dependent local variability observed in response characteristics is attributed to contributions from two or more cortical representations of the visual field and to inter-subject variations in gross cortical anatomy. The second study used luminance modulation of 56 patches across a 15 degrees field, scaled to activate approximately equal cortical areas in area V1. This produced many robust signals at all eccentricities. Bipolar and double differential ("1-dimensional Laplacian") signals were compared. The double differencing reduced contributions from distant or distributed sources, enhancing nearby current source activity, and greatly improved S/N for many stimulus locations. The high-resolution visual field maps demonstrated that clinical field testing using the VEP is not feasible because of effects of cortical convolutions on responses. However, the vast improvement in data quality and quantity make it a useful tool for VEP source localization and identification.

The field topography of ERG components in man--I. The photopic luminance response.

A technique of multi-input systems analysis is used to explore the field topography of ERG responses to local luminance modulation. Variations in amplitude and wave form are studied within the central 23 degrees. Outside the fovea, the amplitude appears to follow a simple power law rx as a function of eccentricity r where x is approximately -2/3. The largest inter-subject variability is found in the fovea. Some nasal-temporal asymmetry is observed in all subjects with higher response densities in the temporal field outside the blind spot. The topography of the luminance response shares all these properties with the density of retinal cones.