Patricia Apkarian

A decisive electrophysiological test for human albinism

Abstract Abnormal decussation of temporal retinogeniculostriate projections associated with albinism is reflected in the potential distribution of the visual evoked potential (VEP). Following monocular stimulation misrouted optic pathway projections produce VEP asymmetry across the occipital left and right hemispheres. With recordings from 5 electrodes positioned at equal spaces of 3 cm in a horizontal row across the scalp, VEP asymmetry in 78 albino probands and 34 non-albino controls was assessed by two methods. The first method which was qualitative consisted of visual inspection of the potential distribution across the scalp within an early time period of the response. As an adjunct to visual inspection, the reverse in sign of a difference potential from a left minus right hemispheric response following both left eye and right eye stimulation was also used. The second method which was quantitative included analysis that was based on estimation of the peak of the potential distribution across the electrode array at every time instant of the response. For this latter method the midline derivation was excluded. Several experimental parameters (e.g. mode of stimulus presentation, pattern size, field size) were investigated to determine the optimum stimulus and recording parameters for detecting albino misrouting. Under optimum test conditions, evidence of misrouting by visual inspection was found in all of the 78 albino probands tested. The quantitative analysis which provides an indication of both the presence and the degree of VEP asymmetry was used to establish population norms for various test conditions. Results of the quantitative analysis provided evidence that the degree of asymmetry in a sample of non-albino controls (including heterozygote family members) was not significant. The degree of asymmetry for albinos, however, was highly significant and was primarily restricted to a narrow time window of the response between about 80 and 110 msec following the appearance of a checkerboard pattern with elements subtending 55′ of arc. The early time course of the asymmetry and the effects of pattern size and defocus suggest that albino misrouting is reflected in the CI component of the pattern appearance response. As the CI component is thought to be generated by dipoles lying within cortical area 17, we can assume that the reflected misrouting is of a similar origin. The 100% detection rate of VEP asymmetry in albinos and 0 false positives in normal controls, heterozygote family members and non-albino patients with comparable albino symptoms (e.g. nystagmus, reduced acuity, retinal hypopigmentation), indicates that VEP asymmetry is a decisive clinical measure for the diagnosis of albinism and for differential diagnosis. The protocol for electrophysiological diagnosis and the results of its application in several atypical patients is also presented.

Multiple spatial-frequency tuning of electrical responses from human visual cortex.

SummaryHuman occipital potentials evoked by stimulation with a counterphase flickering grating were recorded by a digital narrowband filter technique. The data showed a surprising degree of narrow tuning to particular spatial frequencies in addition to the expected narrow temporal frequency tuning. At each temporal frequency, there could be two or more peaks of response to different spatial frequencies, each distinct from the whole field flicker response. Variations in this multiple spatial frequency tuning were investigated as a function of luminance, electrode location, and temporal frequency for several observers. The results are interpreted in terms of many stimulus-specific resonant neural circuits within the brain, and suggest that it is possible to make a highly detailed exploration of the responses of neural circuits to visual stimulation.

Binocularity in the human visual evoked potential: facilitation, summation and suppression.

The electrophysiology of normal binocular function was investigated by studying the binocular interactions from monocular and binocular visual evoked potentials (VEPs) recorded under a range of stimulus conditions. The amplitude and phase of the steady-state VEPs, which were obtained with sinusoidal gratings temporally modulated in counterphase, were measured with synchronous narrow-band filtering techniques. Binocular interactions were investigated as functions of spatial frequency, temporal frequency and contrast. Detailed sampling and testing within each stimulus domain revealed an unprecedented degree of VEP specificity in the extent of binocular interaction, which varied from zero summation to pronounced facilitation. Binocular facilitation was explored in terms of its relation to the neural mechanisms subserving binocular function. VEP correlates of rivalry, fusion and stereopsis were obtained. The facilitatory binocular interactions, revealed by careful spatial and temporal stimulus manipulations, were akin more to the neurophysiological responses of single neurons than to previously reported evoked potential work. The relationship between the specificity and narrow tuning of the binocular interactions recorded with VEP techniques and those recorded with single unit techniques is discussed.

Effects of contrast, orientation and binocularity in the pattern evoked potential.

Monocular and binocular visual evoked potentials were studied as a function of modulation depth (contrast) of a counterphase sinusoidal grating stimulus. A range of spatial and temporal frequencies of stimulation were used. The contrast functions showed many different forms, and were in some cases nonmonotonic. The binocular response usually had a steeper slope than the monocular response. Extrapolating the slope to the zero intercept gave electrophysiological thresholds which did not correspond with psychophysical threshold at any spatial or temporal frequency used. The binocular response was reduced to the monocular level when the orientation difference between the two eyes exceeded about 20 degrees. The data show that the pattern evoked potential is highly specific to many stimulus variables.

Component specificity in albino VEP asymmetry: Maturation of the visual pathway anomaly

SummaryThe existence of an isolated albino asymmetry component was investigated in the visual evoked potential (pattern appearance/disappearance response) of 96 albinos ranging in age from 3 months to 65 years. Misrouted optic pathway projections in albinism produce VEP asymmetry across the left and right occiput upon monocular whole field stimulation of a checkerboard pattern (element size, 55′). Our results indicate that the asymmetry which reflects the albino feature is contralateral and is restricted to an early period of the appearance response corresponding to the latency of the CI component. Further support for CI component specificity in albino asymmetry is provided by half-field stimulation in nonalbino controls and by the results of a component maturation study in children under 6 years of age.

The use of a system analysis approach to electrodiagnostic (ERG and VEP) assessment

To evaluate the integrity of a biological system and its constituent functional units, a systematic study of input-output relations adopted from engineering has proven appropriate. With such an approach, sequential analysis can be implemented to probe the various parameter extractions along, for example, the visual system. The a priori assumption in this approach is that the visual world is processed along functionally separate pathways yielding distinct percepts such as contrast and motion. This so-called channel approach has proven useful not only to basic vision research but also for clinical application. The present overview shows that on the basis of the ERG or VEP, a type of functional anatomy can be performed with the biological system of interest remaining intact. Finally, it will be demonstrated that electrophysiological output parameters of the visual system can also serve as a non-invasive entry to investigate general systemic disorders.

Global stereopsis in human albinos

The presence of global stereopsis was examined in 18 clinically diagnosed albinos; four non-albino controls were also tested including two observers with congenital nystagmus. Stereopsis was evaluated with standard clinical stereo tests and with TV generated random dot stereograms. The latter test involved electrophysiological measures of vertical eye movement tracking in response to a stimulus target. For either test procedure, global stereopsis could be demonstrated in a significant number of albinos across varying phenotypes. These results are of interest in view of electrophysiological investigations in albino animal models which indicate a paucity of binocularly driven cortical neurons in visual areas 17, 18 and 19. While stereopsis may be mediated in our albinos via residual appropriately projecting retino-geniculo-cortical fibres, we suggest that inter and intra cortical communication via corpus callosal connections may play a primary role in providing the adequate neural substrate for albino binocularity.

Detection and maturation of VEP albino asymmetry : an overview and a longitudinal study from birth to 54 weeks

The genetic anomaly in albinism prevents adequate melanin metabolism within the fetal eye cup and stalk. This results in severe disruption of pre- and postnatal retinal development and the condition of abnormal temporal retinal projections. The obligate misrouting of retinal-geniculate-cortical projections in albinism can be detected in the topographical representation across the occiput of the visual evoked potential (VEP). Age-dependent misrouting detection methods are described which yield 100% detection rates with zero false positives across the life span. By combining appropriate state-defined neonatal recording procedures with the albino infant VEP test paradigm, the presence of aberrant optic pathway projections was observed in a 5-day-old full-term infant. Maximum asymmetry was observed within a long-latency window of the response which shifted during the postpartum period to shorter latencies. Longitudinal studies show two specific latency regions of significant VEP asymmetry. The first occurs within 40-70 ms after stimulus onset and remains constant across the age range. The second, more robust, cluster of asymmetry occurs within a longer latency window and shows an age-related shift towards shorter latencies. The decreasing latency of this asymmetry is concomitant with normal maturational changes of the evoked response. These results show that VEP misrouting can be extended to reliable albino diagnosis within the neonatal period and to the assessment of visual maturation.

PROPERTIES OF LOCALIZED PATTERN EVOKED POTENTIALS

The synchronous pattern evoked potential has been shown to have tremendous specificity to a number of stimulus parameters.’,* For example, changes in spatial or temporal frequency by as little as 10% can sometimes affect response amplitude by a factor of two or more, even when no corresponding change occurs in the psychophysical threshold function. A similar specificity may be used as a tool to study the properties of localized responses from small, homogeneous regions of cortex. The question of localization has usually been approached by attempting to compute the position in the brain corresponding to the source of the scalp potential by means of large numbers of electrodes on the scalp. The most extensive effort in this direction has been made by D. H. Fender and his group at California Institute of Technology, but they have not so far used highly localized stimulation condition^.^

Visual evoked potentials in Prader-Willi syndrome.

Oculocutaneous, electrophysiological, and cytogenetic factors were evaluated in 14 patients with Prader-Willi syndrome and in three controls, two albinos and a normal observer. In a substantial number of PW patients chromosomal anomalies, particularly deletions of the long arm of chromosome 15 as well as hypopigmentation of hair, skin, and eye have been identified. In the genetic condition of albinism, hypopigmentation related to neural ectoderm derivatives is associated with reduced visual acuity, foveal hypoplasia, and aberrant retinogeniculocortical projections. The latter can be observed by visual evoked potential (VEP) assessment of hemispheric response symmetry. To determine the possible neural ectodermal origin of hypopigmentation and its involvement in ocular development and optic pathway integrity, the potential distributions of the pattern onset/offset VEP were examined. Our results show hypopigmentation in 13 of our 14 PW patients and a chromosome abnormality in 6; no correlation between these two features was found. None of the PW patients showed the characteristic contralateral hemispheric asymmetry seen in albinism. On the other hand their VEP profiles were found to be atypical, rendering waveform and cortical topography difficult to interpret. Analysis suggests that in the absence of VEP evidence for optic pathway misprojection, PW hypopigmentation is probably of neural crest origin.