Russell D. Hamer

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.

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.

Vibrotacile masking of Pacinian and non‐Pacinian channels

Vibrotactile masking functions were determined using sinusoidal and noise maskers. Results were nearly identical within the Pacinian (P) and non-Pacinian (NP) channels. At low maskers SLs there was a substantial amount of negative masking which proved not be an artifact of stimulus definition. The critical parameters for successful prediction of the data were a peripheral threshold and internal Gaussian noise. Threshold shifts in cross-channel stimulation can be attributed to the masker exceeding the detection threshold of the signal channel.

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.

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.

Toward a unified model of vertebrate rod phototransduction.

Recently, we introduced a phototransduction model that was able to account for the reproducibility of vertebrate rod single-photon responses (SPRs) (Hamer et al., 2003). The model was able to reproduce SPR statistics by means of stochastic activation and inactivation of rhodopsin (R*), transducin (G alpha ), and phosphodiesterase (PDE). The features needed to capture the SPR statistics were (1) multiple steps of R* inactivation by means of multiple phosphorylations (followed by arrestin capping) and (2) phosphorylation dependence of the affinity between R* and the three molecules competing to bind with R* (G alpha, arrestin, and rhodopsin kinase). The model was also able to account for several other rod response features in the dim-flash regime, including SPRs obtained from rods in which various elements of the cascade have been genetically disabled or disrupted. However, the model was not tested under high light-level conditions. We sought to evaluate the extent to which the multiple phosphorylation model could simultaneously account for single-photon response behavior, as well as responses to high light levels causing complete response saturation and/or significant light adaptation (LA). To date no single model, with one set of parameters, has been able to do this. Dim-flash responses and statistics were simulated using a hybrid stochastic/deterministic model and Monte-Carlo methods as in Hamer et al. (2003). A dark-adapted flash series, and stimulus paradigms from the literature eliciting various degrees of light adaptation (LA), were simulated using a full differential equation version of the model that included the addition of Ca2+-feedback onto rhodopsin kinase via recoverin. With this model, using a single set of parameters, we attempted to account for (1) SPR waveforms and statistics (as in Hamer et al., 2003); (2) a full dark-adapted flash-response series, from dim flash to saturating, bright flash levels, from a toad rod; (3) steady-state LA responses, including LA circulating current (as in Koutalos et al., 1995) and LA flash sensitivity measured in rods from four species; (4) step responses from newt rods ( Forti et al., 1989) over a large dynamic range; (5) dynamic LA responses, such as the step-flash paradigm of Fain et al. (1989), and the two-flash paradigm of Murnick and Lamb (1996); and (6) the salient response features from four knockout rod preparations. The model was able to meet this stringent test, accounting for almost all the salient qualitative, and many quantitative features, of the responses across this broad array of stimulus conditions, including SPR reproducibility. The model promises to be useful in testing hypotheses regarding both normal and abnormal photoreceptor function, and is a good starting point for development of a full-range model of cone phototransduction. Informative limitations of the model are also discussed.

Analysis of visual modulation sensitivity. IV. Validity of the Ferry–Porter law

The maximum flicker frequency was determined over a 5+6-log-unit range of retinal illuminance for a stimulus configuration designed to isolate the linear response from long-wavelength (R) cones. For a particular retinal location, the data conformed to the Ferry-Porter law and departed significantly from the predictions of the diffusion equation. The slope of the function was an invariant characteristic and was unaffected by stimulus intensity or area, modulation waveform, or modulation amplitude. However, the slope varied substantially with retinal locus, increasing by more than a factor of 2 between the foveola and 35 degrees eccentricity. This increase shows that the time constant of the linear, unadapted visual response decreases with increasing eccentricity. The difference between foveola and periphery remained at high spatial frequencies, implying that it was not attributable to lateral inhibitory effects.

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.

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.

Analysis of visual modulation sensitivity. V. Faster visual response for G- than for R-cone pathway?

To determine the linear, unadapted responses of the cone pathways, we have measured the critical fusion frequency (CFF) for green (555-nm) and red (642-nm) flicker as a function of retinal illuminance. Both functions obeyed the Ferry-Porter law (CFF proportional to log illuminance) to high accuracy over a > or = 5-log-unit range. In both foveola and periphery the CFF/illuminance functions were significantly steeper for green light than for red light. The peripheral 555-nm function had an average slope 1.26 times the average slope of the 642-nm function. An additive model of flicker detection could not account for the observed differences in slope. A threshold independence model, in which detection is based on the most sensitive mechanism, accurately fits the data. Whichever model is assumed, the presence of different slopes for the two wavelength flicker conditions strongly implies that the R- and G-cone pathways have different temporal properties. The occurrence of steeper CFF/illuminance slopes in response to green light implies that the linear (near-CFF) response of the G-cone pathways in inherently faster than that of the R-cone pathways at both retinal loci. These differences in R- and G-cone-mediated temporal properties complicate the fundamental concept of luminance and invalidate it for precise application over the full illuminance range.