Psychophysical analysis of contrast processing segregated into magnocellular and parvocellular systems in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy.

We examined achromatic contrast discrimination in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy (LHON 18 controls) and 18 age-match were also tested. To evaluate magnocellular (MC) and Parvocellular (PC) contrast discrimination, we used a version of Pokorny and Smith's (1997) pulsed/steady-pedestal paradigms (PPP/SPP) thought to be detected via PC and MC pathways, respectively. A luminance pedestal (four 1 degree x 1 degree squares) was presented on a 12 cd/m2 surround. The luminance of one of the squares (trial square, TS) was randomly incremented for either 17 or 133 ms. Observers had to detect the TS, in a forced-choice task, at each duration, for three pedestal levels: 7, 12, 19 cd/m2. In the SPP, the pedestal was fixed, and the TS was modulated. For the PPP, all four pedestal squares pulsed for 17 or 133 ms, and the TS was simultaneously incremented or decremented. We found that contrast discrimination thresholds of LHON carriers were significantly higher than controls' in the condition with the highest luminance of both paradigms, implying impaired contrast processing with no evidence of differential sensitivity losses between the two systems. Carriers' thresholds manifested significantly longer temporal integration than controls in the SPP, consistent with slowed MC responses. The SPP and PPP paradigms can identify contrast and temporal processing deficits in asymptomatic LHON carriers, and thus provide an additional tool for early detection and characterization of the disease.

A proposed role for all-trans retinal in regulation of rhodopsin regeneration in human rods.

In order to account for the multi-phasic dynamics of photopigment regeneration in human rods, we developed a new model of the retinoid cycle. We first examined the relative roles of the classical and channeling mechanisms of metarhodopsin decay in establishing these dynamics. We showed that neither of these mechanisms alone, nor a linear combination of the two, can adequately account for the dynamics of rhodopsin regeneration at all bleach levels. Our new model adds novel inhibitory interactions in the cycle of regeneration of rhodopsin that are consistent with the 3D structure of rhodopsin. Our analyses show that the dynamics of human rod photopigment regeneration can be accounted for by end-product regulation of the channeling mechanism where all-trans retinal (tral) inhibits the binding of 11-cis retinal to the opsin.tral complex.

Multiple steps of phosphorylation of activated rhodopsin can account for the reproducibility of vertebrate rod single-photon responses.

Single-photon responses (SPRs) in vertebrate rods are considerably less variable than expected if isomerized rhodopsin (R*) inactivated in a single, memoryless step, and no other variability-reducing mechanisms were available. We present a new stochastic model, the core of which is the successive ratcheting down of R* activity, and a concomitant increase in the probability of quenching of R* by arrestin (Arr), with each phosphorylation of R* (Gibson, S.K., J.H. Parkes, and P.A. Liebman. 2000. Biochemistry. 39:5738-5749.). We evaluated the model by means of Monte-Carlo simulations of dim-flash responses, and compared the response statistics derived from them with those obtained from empirical dim-flash data (Whitlock, G.G., and T.D. Lamb. 1999. Neuron. 23:337-351.). The model accounts for four quantitative measures of SPR reproducibility. It also reproduces qualitative features of rod responses obtained with altered nucleotide levels, and thus contradicts the conclusion that such responses imply that phosphorylation cannot dominate R* inactivation (Rieke, F., and D.A. Baylor. 1998a. Biophys. J. 75:1836-1857; Field, G.D., and F. Rieke. 2002. Neuron. 35:733-747.). Moreover, the model is able to reproduce the salient qualitative features of SPRs obtained from mouse rods that had been genetically modified with specific pathways of R* inactivation or Ca2+ feedback disabled. We present a theoretical analysis showing that the variability of the area under the SPR estimates the variability of integrated R* activity, and can provide a valid gauge of the number of R* inactivation steps. We show that there is a heretofore unappreciated tradeoff between variability of SPR amplitude and SPR duration that depends critically on the kinetics of inactivation of R* relative to the net kinetics of the downstream reactions in the cascade. Because of this dependence, neither the variability of SPR amplitude nor duration provides a reliable estimate of the underlying variability of integrated R* activity, and cannot be used to estimate the minimum number of R* inactivation steps. We conclude that multiple phosphorylation-dependent decrements in R* activity (with Arr-quench) can confer the observed reproducibility of rod SPRs; there is no compelling need to invoke a long series of non-phosphorylation dependent state changes in R* (as in Rieke, F., and D.A. Baylor. 1998a. Biophys. J. 75:1836-1857; Field, G.D., and F. Rieke. 2002. Neuron. 35:733-747.). Our analyses, plus data and modeling of others (Rieke, F., and D.A. Baylor. 1998a. Biophys. J. 75:1836-1857; Field, G.D., and F. Rieke. 2002. Neuron. 35:733-747.), also argue strongly against either feedback (including Ca2+-feedback) or depletion of any molecular species downstream to R* as the dominant cause of SPR reproducibility.

Absolute thresholds in human infants exposed to continuous illumination.

Continuous illumination at low-to-moderate photopic levels can cause damage to the visual system in nonhuman species. Therefore, the authors sought to determine whether behaviorally measurable visual deficits occurred in young human infants who had been exposed to long-term, continuous illumination in a neonatal intensive care unit (NICU). Using the forced-choice, preferential-looking technique, the authors measured absolute thresholds for detection of a 502 nm stimulus in nine preterm infants who had been exposed to 13 to 46 days of continuous room illumination. Nine infants born at term, who had experienced less than or equal to 5 days of continuous illumination, served as controls. The thresholds for the light-exposed and control infants did not differ. In addition, the light-exposed infants did not differ from control infants in their performance on a rapid acuity screening under photopic conditions. Thus, the present data provide no evidence of functional damage to either rod or cone vision in infants who had been exposed to continuous illumination in an NICU. Some limitations to the generality of these conclusions are discussed.

High visual contrast sensitivity in the young human infant.

The visual evoked potential (VEP) was used to estimate photopic contrast sensitivity of 10-week-old infants over a wide range of spatial frequencies including the acuity limit. Adult and infant VEP contrast sensitivity was compared for sinusoidal luminance gratings reversed in contrast at 6 Hz. Space-average luminance was 220 cd/m2. Grating contrast was swept from well below the measured thresholds to well above them in 10 sec trials. Contrast thresholds were defined as the zero voltage intercept of the initial rising portion of the VEP amplitude versus contrast function. The VEP contrast sensitivity of 10-week-old infants was close to that of the adults for spatial frequencies below about 1 cycle (c)/deg.

Anomalous motion VEPs in infants and in infantile esotropia.

Visual evoked potentials (VEPs) were recorded monocularly in response to vertical gratings that underwent oscillatory apparent motion at a temporal frequency of 10 Hz. In normal infants 6 months or younger and in patients with a history of constant strabismus onset before 6 months of age, the oscillatory motion VEP contains a prominent first harmonic component that is temporally 180 degrees out of phase in the two eyes. This pattern is not seen in normal adults and is consistent with the presence of a nasalward/temporalward asymmetry of cortical responsiveness in infants and in patients with early onset strabismus.

Analysis of Ca++-dependent gain changes in PDE activation in vertebrate rod phototransduction.

PURPOSE: Recent biochemical and physiological data point to the existence of one or more Ca++-mediated feedback mechanisms modulating gain at stages early in the vertebrate phototransduction cascade, i.e., prior to activation of cGMP-phosphodiesterase (PDE). The present study is a computational analysis that combines quantitative optimization to key data with a qualitative evaluation of each candidate model's ability to capture "signature" features of representative rod responses obtained under a broad range of dark- (DA) and light-adapted (LA) conditions. The primary data motivating the analyses were the two-flash data of Murnick & Lamb. These data exhibited strikingly nonlinear behavior: the period of complete photocurrent saturation (Tsat) in response to a Test flash was reduced substantially when preceded by a less-intense saturating Pre-flash. Depending on the delay between Pre- and Test flashes, the change in Tsat (DTsat) could exceed the magnitude of the delay, and could be reduced by as much as approximately 50%, corresponding to a large reduction in gain by a factor of 10-15. The overall goal of the study was to evaluate what model structure(s) were commensurate with both the Murnick & Lamb data and the salient qualitative features of rod responses obtained under a broad range of DA and LA conditions. METHODS: Three candidate models were quantitatively optimized to the Murnick & Lamb saturated toad rod flash responses and, simultaneously, to a set of sub-saturated flash responses. Using the parameters from these optimizations, each candidate model was then used to simulate a suite of DA and LA responses. RESULTS: The analyses showed that: (1) Within the context of a model with Ca++ feedback onto rhodopsin (R*) lifetime (tR), the salient features of the Murnick & Lamb data can only be accounted for if the rate-limiting step is not the Ca++-sensitive step in the early cascade reactions, i.e., if PDE* lifetime, and not tR, is rate-limiting. (2) With tR rate-limiting, the model cannot account for DTsat exceeding the delay. (3) The Ca++-dependent reduction in tR required to effect the large gain is incommensurate with the empirical dynamics of dim-flash responses. (4) Regardless of which reaction is rate-limiting, a model using solely modulation of R* lifetime puts strong constraints on the domain of biochemical parameters commensurate with the large gain changes Murnick & Lamb observed. (5) The analyses show that, in principle, the Murnick & Lamb data can be accounted for when tR is both rate-limiting and Ca++-sensitive if, in addition to the feedback onto tR, there is an earlier, stronger Ca++ feedback that does not affect R* inactivation kinetics (e.g., gain at R* activation or transducin (T*) activation). (6) Ca++-modulation of R* activation or T* activation as the sole early gain mechanism can also account for the Murnick & Lamb data, but fails to predict the data of Matthews, and can thus be rejected along with any model of comparable form. CONCLUSIONS: The results imply that the Murnick & Lamb data per se are insufficient to rule out rate-limitation by (Ca++-sensitive) R* lifetime; evaluation of a broader set of responses is required. The analyses illustrate the importance of evaluating candidate models in relation to sets of data obtained under the broadest possible range of DA and LA conditions. The analyses are aided by the presence of reproducible signature, qualitative features in the data since these tend to constrain the domain of acceptable model structures and/or parameter sets. Some implications for vertebrate photoreceptor light-adaptation are discussed.

Spatial summation in dark-adapted human infants.

Behavioral measures of spatial summation in 4- and 11-week old human infants were obtained using the forced-choice preferential looking technique. Infants exhibit complete spatial summation over large areas (4 weeks: 8.9 degrees; 11 weeks: 5.5 degrees), much larger than those of adults tested in the same apparatus (2.6 degrees). Thus, infants' summation areas are larger than adults' by factors of 12 at 4 weeks and 4 at 11 weeks. It is argued that at most, one-half of this difference between the infant and adult data may be due to optical factors (e.g. defocus and small eye size). The remainder probably reflects differences in the neural organization of the immature and mature visual systems.

The development of motion sensitivity during the first year of life.

Using the sweep visual evoked potential (VEP), we have measured oscillatory displacement thresholds (OMTs) in 49 infants ranging in age from 7 to 54 weeks of age. The stimuli were high-contrast (80%), sine-wave gratings (1 c/deg) undergoing oscillatory displacements at 6 Hz. In addition to the motion thresholds, contrast thresholds for phase-reversing (6 Hz), 1 c/deg gratings were measured in the same session for 26 infants. In the main experiment, responses were recorded at the second harmonic (F2) of the stimulus frequency (12 Hz) under binocular viewing conditions. Our main finding is that, over the age range during which infants' peak contrast sensitivity (CS) first develops to within a factor of 2 of adult CS (9-12 weeks), infants' sensitivity to grating displacement is a factor of approximately 10 less than adults'. Moreover, infants' sensitivity to oscillatory motion undergoes relatively little development over the period between 2 and 15 months postnatal, gradually achieving a factor of 4.5 below adult values by 1 yr of age. Averaged over the entire age range tested, infants' OMTs were 167 sec arc, a factor of 6.4 times higher than the average OMT (26 sec arc) for 13 adults tested under identical conditions. In contrast, the infants' average CS for reversing gratings averaged only a factor of 2.5 less than the adults' average CS. In a second experiment, we took advantage of a developmental asymmetry in the monocular oscillatory motion VEP which allows for unambiguous identification of direction selective responses from very young infants. Monocular motion VEPs were measured in five infants (8-14 weeks) and their data analyzed at the fundamental frequency (F1). Responses at F1 were present in the monocular motion VEP from each infant and were 180 deg out of phase between the two eyes, identifying them as directional cortical responses with a nasalward/temporalward bias. These directional thresholds were equal to or lower than the symmetric (F2) thresholds. The presence of directional asymmetry in the motion VEP and the similarity of the monocular F1 and F2 OMTs support the notion that the OMTs measured in the main experiment were, in fact, derived from the responses of directionally selective cells in visual cortex. These data also imply that the OMTs are not derived from local contrast-reversal responses. Other models to explain infants' relative insensitivity to oscillatory motion are discussed.

Measurement of spatial contrast sensitivity with the swept contrast VEP.

Contrast response functions (CRFs) for the VEP were obtained with a Discrete Fourier Transform (DFT) technique employing swept contrast gratings. VEP CRFs in infants were found to have a form similar to those observed in adults, being linear functions of log contrast over a range of near-threshold contrasts. CRFs with low and high contrast lobes were present in infants, as they are in adults. Contrast thresholds were estimated by extrapolation of the CRF to zero microvolts. The effects of additive EEG noise and of the DFT data window on the shape of the measured CRF are considered. For large signals, the measured CRF is nearly independent of the additive noise, but at small signal values additive noise introduces a small bias towards larger amplitudes. The VEP signal-plus-noise distribution was modeled as a family of Rice distributions in order to evaluate the effects of bias on the estimates of threshold. The amount of bias depends inversely upon the slope of the CRF. The amount of bias introduced by a smoothing window also depends upon slope of the CRF as well as the sweep rate. The combined effects of additive noise and window bias were such that the total bias was nearly independent of CRF slope. Sweep VEP contrast thresholds were shown empirically to be unaffected by changes in the range of contrast swept.

Development of contrast sensitivity in the human infant.

Contrast sensitivity and grating acuity were measured using the sweep VEP method in a group of 48 infants from 2 to 40 weeks of age and in a group of 10 adults. Sinusoidal gratings were reversed in contrast at 12 alternations per sec at a space-average luminance of 220 cd/m2. During 10 sec trials, either the contrast or the spatial frequency was increased in a series of 19 steps. Thresholds were estimated by extrapolation of the VEP response functions to zero amplitude. The contrast threshold at low spatial frequencies developed rapidly from 7% contrast at 2-3 weeks to an asymptote of 0.5% at 9 weeks. For adults, maximum sensitivity at low spatial frequencies was 0.32-0.22%. The sweep VEP estimate of grating acuity showed a gradual increase in spatial frequency with age, starting at 5 c/deg during the first month and reaching 16.3 c/deg at 8 months. The mean adult acuity was 31.9 c/deg. There appeared to be two phases in the development of contrast sensitivity and acuity. Between 4 and 9 weeks overall contrast sensitivity increased by a factor of 4-5 at all spatial frequencies. Beyond 9 weeks, contrast sensitivity at low spatial frequencies remained constant, while sensitivity increased systematically at higher spatial frequencies.

The effect of light adaptation on scotopic spatial summation in 10-week-old infants.

Psychophysical area-intensity functions of individual 10-week-old human infants and adults were obtained in the dark adapted state, and in the presence of a steady background that elevated threshold 1 log unit above the dark adapted level. For dark adapted infants, the mean diameter for complete spatial summation (4.42 degrees; SD: 1.67 degrees) was significantly larger than that of adults (2.32 degrees; SD: 0.09 degrees). The background reduced the mean critical diameter to 2.67 degrees for infants (SD: 0.64 degrees) and to 1.16 degrees for adults (SD: 0.08 degrees). Spatial probability summation has similar effects on infant and adult thresholds, and, therefore, does not appear to account for the developmental decrease in critical diameters. Rather, decreases in receptive field size are suspected.

Rayleigh discriminations in young human infants.

The capacity of young infants to discriminate 3 x 3 degrees broadband red or 550 nm green squares from a 589 nm yellow surround was tested by means of the forced-choice preferential looking technique. All 3-month olds, about 3/4 of the 2-month olds, and just under half of the one-month-olds could make at least one of these discriminations. Taken together with other known properties of infant color vision, the failures of discrimination shown by the younger infants are more readily modeled as immaturities of neural processing than as an absence of anomaly of LWS or MWS cones.

Plasticity of human motion processing mechanisms following surgery for infantile esotropia.

Monocular oscillatory-motion visual evoked potentials (VEPs) were measured in prospective and retrospective groups of infantile esotropia patients who had been aligned surgically at different ages. A nasalward-temporal response bias that is present prior to surgery was reduced below pre-surgery levels in the prospective group. Patients in the retrospective group who had been aligned before 2 yr of age showed lower levels of response asymmetry than those who were aligned after age 2. The data imply that binocular motion processing mechanisms in infantile esotropia patients are capable of some degree of recovery, and that this plasticity is restricted to a critical period of visual development.

Area-threshold relations at controlled retinal locations in 1-month-old infants.

A fixation-and-flash technique has been developed to provide control over the retinal eccentricities of stimuli presented to infant subjects, to within a few degrees of visual angle. The technique is a variant of forced-choice preferential looking (FPL). An adult observer triggers presentation of the test stimulus when she judges that the infant is fixating a centrally located fixation target. The stimuli are short in relation to the infant's refixation latency. Auxiliary experiments confirmed that on most trials the stimuli fell within +/- 4 degrees of the designated eccentricity. Test fields of two sizes, 3.1 and 17 degrees, were presented to 1-month-old infants at one of four retinal locations, 9, 18, 27 and 36 degrees eccentric. The infants' data show a perfect area-intensity tradeoff at all four locations. Adult control subjects showed summation over areas of only 1-2 degrees. The results are discussed in relation to other evidence of coarse spatial processing in human infants and other immature mammalian systems.

Effect of monocular light exclusion on the Stiles-Crawford function.

Contrary to previously published studies, monocular light exclusion did not alter the shape of the Stiles-Crawford function in a substantial manner in four subjects who were patched in this laboratory for one full week. In order to rule out methodological differences, an experimenter from each of the two sets of experiments (current and prior) patched one eye for 1 week, then tested each other. For one subject, there was little effect of patching. For the other, patching had a measurable effect, but it was different from that originally reported. However, the much larger, symmetrical broadening of the Stiles-Crawford function reported in earlier studies was not replicated. A testable working hypothesis to explain the earlier results is discussed.

The development of monocular and binocular VEP acuity.

The development of monocular and binocular grating acuity was measured in 87 infants, 2-52 weeks of age, using the sweep VEP technique. Average monocular and binocular acuity growth functions were nearly identical, with a small (less than 0.2 octaves) binocular acuity superiority occurring only under 6 months. Interocular acuity differences were small (averaging less than 1/4 octave, unsigned, with a 95% confidence interval of less than +/- 0.6 octaves) and were not significant at any age. These characteristics make the sweep VEP technique a potentially sensitive tool for the detection of monocular visual losses in the early stages of amblyopia.

Postural stability and stereo-ambiguity in man-designed visual environments.

Our modern rectilinear visual environment contains visual stimuli for which evolution has not had time to optimally shape visual processing. One such stimulus, periodic stripes, is known to lead to visual depth ambiguity. In this paper we show that postural instability, as measured by the variance of fore and aft sway, is increased by viewing such stimuli. This instability may be the precursor of falls. Designers must evaluate the visual impressions conveyed by their systems in order to avoid postural instability due to visual ambiguity.

Preoperative alternate occlusion decreases motion processing abnormalities in infantile esotropia.

We have examined the effects of preoperative, full-time alternate occlusion on the development of visual motion processing mechanisms. Motion visual evoked potentials (MVEPs) were recorded longitudinally in 14 infantile esotropia patients during the course of standard preoperative occlusion therapy. The MVEP in these patients was initially asymmetric in a fashion consistent with a nasalward/temporalward response bias, with a motion asymmetry significantly higher than that of age-matched normals. The magnitude of the developmental motion asymmetry declined significantly after an average of 24 weeks of alternate occlusion. This result implies that the binocular motion-sensitive cells underlying the MVEP retain some degree of plasticity up to at least 1 year of age. Our data suggest further that the persistence of motion asymmetries in untreated infantile esotropia patients is maintained by an active process that can be disrupted by alternate occlusion. Alternate occlusion apparently eliminates a form of abnormal binocular interaction that supports the persistence of the motion asymmetry. We propose that one of the necessary pre-conditions for symmetricization of motion processing in infantile esotropia is the absence of abnormal competitive binocular interactions.

Polaroid photorefractive screening of infants.

We modified a Polaroid SE camera for use as a photoretinoscope. A total of 187 infants between 2 and 18 months of age were photographed using this device. About half of these infants (97) participated in a double blind study in which the results of photorefraction were compared with those of standard cycloplegic retinoscopy. Eighty-three infants were photographed without cycloplegia. Thirty-four infants were photographed while cyclopleged. Photographs were evaluated for significant refractive errors and other ocular abnormalities. The effectiveness of the camera system to screen for significant refractive errors without the use of cycloplegia was assessed. Infants were identified to be at risk by photorefraction if, in any photograph, a hyperopic bright crescent calculated to be greater than or equal to +1.25 D was present in the pupil. Clinically significant refractive errors were defined by the results of cycloplegic retinoscopy: "at-risk" infants had either 3.5 D or more hyperopia in either eye, or astigmatism in either eye greater than or equal to 2.5 D, or anisometropia greater than or equal to 1.5 D. With these clinical criteria and the above photographic screening criterion, the camera's sensitivity and specificity were 83% and 69%, respectively. The present system compares favorably with earlier, more sophisticated units in alerting practitioners to potentially significant refractive errors in infants. Additionally, as a screening tool, this device offers the benefits of being inexpensive and easy to use, and of providing immediate feedback.