Long-term exposure to high glucose up-regulates VCAM-induced endothelial cell adhesiveness to PBMC.

BACKGROUND: The changes induced on endothelial cells by a long-term exposure to high glucose, a situation that mimics the hyperglycemia of diabetics, have not yet been determined. We compared short- and long-term effects of elevated glucose on macrovascular and microvascular endothelial cells. METHODS: Endothelial cells were grown in high-glucose media for 24 hours and for 8 weeks. Cell proliferation was evaluated by cell counting, apoptosis and expression of adhesion molecules by flow cytometry; nitric oxide (NO) by measuring the concentration of nitrite/nitrate in the cell supernatant; alpha 2(IV) collagen mRNA and protein by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The adhesion of peripheral blood mononuclear cells (PBMCs) to endothelial cells was evaluated by adhesion assay. In some experiments, endothelial cells were preincubated with anti-vascular cell adhesion molecule-1 (VCAM-1) and anti-receptor for advanced glycation end product (RAGE) blocking antibodies. RESULTS: At 24 hours, but not at 8 weeks, high glucose increased endothelial cell proliferation and apoptosis. High glucose did not modify NO synthesis at 24 hours and 8 weeks. Collagen production and expression were increased only after eight weeks. VCAM-1 but not intercellular adhesion molecule-1 was up-regulated after 8 weeks, a change not observed after 24 hours. The adhesion of PBMCs was significantly increased at eight weeks and was completely abrogated by anti--VCAM-1 and by anti-RAGE antibodies. After 24 hours, there was a modest increase of PBMC adhesion that was not blunted by anti-RAGE antibodies. CONCLUSIONS: Increased adhesion of PBMCs, caused by up-regulation of VCAM-1 with a mechanism involving advanced glycation end product (AGE) adducts, and augmented collagen deposition are critical effects of long-term high glucose on endothelial cells, and may eventually promote the atherosclerotic process.

Illusory contour strength does not depend on the dynamics or relative phase of the inducers.

We use a new objective measure of illusory contour strength, threshold reduction for aspect ratio discrimination, to examine the effect of dynamics and relative phase on the Kanizsa illusion. We found no dependence of illusory contour strength on the relative phase of flickering inducers (in phase, antiphase, or in quadrature phase) either for the standard Kanizsa square, or for modifications that facilitated or interfered with amodal completion. Comparison with a vernier acuity task indicates that the distance between the inducers, rather than the nature of the task, accounts for the insensitivity to relative phase.

Visual function and brain organization in non-decussating retinal-fugal fibre syndrome.

Functional neuroimaging, psychophysical and electrophysiological investigations were performed in a patient with non-decussating retinal-fugal fibre syndrome, an inborn achiasmatic state in which the retinal projections of each eye map entirely to the ipsilateral primary visual cortex. Functional magnetic resonance imaging (fMRI) studies showed that for monocularly presented simple visual stimuli, only the ipsilateral striate cortex was activated. Within each hemisphere's striate cortex, the representation of the two hemifields overlapped extensively. Despite this gross miswiring, visual functions that require precise geometrical information (such as vernier acuity) were normal, and there was no evidence for the confounding of visual information between the overlapping ipsi-lateral and contralateral representations. Contrast sensitivity and velocity judgments were abnormal, but their dependence on the orientation and velocity of the targets suggests that this deficit was due to ocular instabilities, rather than the miswiring per se. There were no asymmetries in performance observed in visual search, visual naming or illusory contour perception. fMRI analysis of the latter two tasks under monocular viewing conditions indicated extensive bilateral activation of striate and prestriate areas. Thus, the remarkably normal visual behavior achieved by this patient is a result of both the plasticity of visual pathways, and efficient transfer of information between the hemispheres.

Two-frequency analysis of interactions elicited by Vernier stimuli.

In five subjects, we measured visual evoked potentials (VEPs) elicited by Vernier targets in which the contrast of the two components of the stimuli were modulated by sinusoids at distinct frequencies fl and f2. This approach allows for the extraction of VEP signatures of spatial interactions, namely, responses at intermodulation frequencies n1f1 + n2f2, without the need to introduce motion into the stimulus. The most prominent interactions were at the sum frequency f1 + f2, and, for frequency pairs that were sufficiently separated, the difference frequency f1- f2. These responses had a systematic dependence on the temporal parameters of the stimulus, corresponding to an effective latency of 145 to 165 ms. Fourth-order interactions were also detected, particularly at the frequencies 2f1 +/- 2f2. These VEP signatures of interaction were similar to interactions seen for colinear line segments separated by a gap. Thus, for Vernier stimuli devoid of motion, VEP signatures of interaction are readily detected but are not specific to hyperacuity displacements. The distribution of interactions across harmonic orders is consistent with local rectification preceding the spatial interactions. Their effective latencies and dependence on spatial parameters are consistent with interactions within V1 receptive fields or mediated by horizontal connections between cells with a similar orientation tuning within V1.

Short-range vernier acuity: interactions of temporal frequency, temporal phase, and stimulus polarity.

We examined how vernier thresholds for flickering bars depend on the temporal frequency and relative temporal phase of the bars. The largest effect of relative phase (up to a fivefold increase in displacement thresholds) was seen at 2 Hz, and for most subjects, relative phase had little effect at 16 Hz and above. The effect of relative phase was essentially independent of contrast and trial duration. Thresholds were elevated by the greatest amount when bars were presented in antiphase, but at 1 and 4 Hz, quadrature phase offsets also led to substantial elevations in displacement thresholds. An experiment designed to examine the interaction of the vernier judgment with apparent motion failed to identify a role for mechanisms sensitive to apparent motion in threshold elevation. Another experiment in which the bars were modulated with sawtooth waveforms indicated that temporal correlation between the bars, rather than the ON versus OFF distinction, underlies the phase sensitivity. A simple dynamical model that posits partial rectification prior to a cross-correlation-like interaction accounts for the observed results.

Chromatic and luminance interactions in spatial contrast signals.

We report VEP studies which delineate interactions between chromatic and luminance contrast signals. We examined responses to sinusoidal luminance gratings undergoing 4-Hz square-wave contrast reversal, upon which standing gratings with various admixtures of luminance and chromatic contrast were alternately superimposed and withdrawn. The presence of the standing grating induced a VEP component at the fundamental frequency of the contrast-reversal grating. This VEP component appeared without any appreciable lag, and did not vary in amplitude over the 4 s during which the standing grating was present. The observed fundamental response differed from the fundamental component that would be expected from the known interaction between the luminance component of the standing grating with the modulated grating (Bodis-Wollner et al., 1972; Bobak et al., 1988), in three ways: (1) The fundamental response was not nulled for standing gratings that were isoluminant or near-isoluminant. (2) The chromatic dependence of the fundamental response implied an S-cone input to the interaction. (3) No single mechanism (driven by a linear combination of cone signals) could account quantitatively for the size of this response, particularly when the standing grating strongly modulated two cones in phase.

Nonlinear preprocessing in short-range motion.

The phenomenon of non-Fourier motion (visually perceived motion that cannot be explained simply on the basis of the autocorrelation structure of the visual stimulus) is well recognized, and is generally considered to be due to nonlinear preprocessing of the visual stimulus prior to a stage of standard motion analysis. We devised a sequence of novel visual stimuli in which the availability of a motion stimulus depends on the nature of the nonlinear preprocessing: an nth order stimulus Pn will generate a perception of motion if it is preprocessed by a nonlinearity of polynomial order n or greater, but not if preprocessed by a nonlinearity of polynomial order less than n. We found that unambiguous motion direction was perceived for P2, P3, and P4, but not for higher-order stimuli, and we measured the contrast thresholds for direction discrimination with superimposed noise. We found that an asymmetric compressive nonlinearity can, in a unified fashion, account for these results, while a purely quadratic nonlinearity or a rectification of the form T(p) = magnitude of p cannot. We compared velocity discrimination judgements for second-order non-Fourier stimuli (P2) with standard drifting gratings. Although velocity comparisons were veridical, uncertainties were greater for the non-Fourier stimuli. This could be reproduced by substituting a Fourier grating with superimposed noise for the non-Fourier grating. These findings are consistent with a single pathway which processes both Fourier and non-Fourier short-range motion, and are discussed in the context of other investigations which have been interpreted as demonstrating separate pathways.

Dynamic shifts of the contrast-response function.

We recorded visual evoked potentials in response to square-wave contrast-reversal checkerboards undergoing a transition in the mean contrast level. Checkerboards were modulated at 4.22 Hz (8.45-Hz reversal rate). After each set of 16 cycles of reversals, stimulus contrast abruptly switched between a "high" contrast level (0.06 to 1.0) to a "low" contrast level (0.03 to 0.5). Higher contrasts attenuated responses to lower contrasts by up to a factor of 2 during the period immediately following the contrast change. Contrast-response functions derived from the initial second following a conditioning contrast shifted by a factor of 2-4 along the contrast axis. For low-contrast stimuli, response phase was an advancing function of the contrast level in the immediately preceding second. For high-contrast stimuli, response phase was independent of the prior contrast history. Steady stimulation for periods as long as 1 min produced only minor effects on response amplitude, and no detectable effects on response phase. These observations delineate the dynamics of a contrast gain control in human vision.

The role of high-order phase correlations in texture processing.

Isodipole textures are pairs of texture ensembles whose autocorrelations, and hence power spectra, are equal. Examples of readily discriminable isodipole textures are well known. Such discriminations appear to require feature extraction, since the isodipole condition eliminates ensemble differences in spatial frequency content. We studied the effects of phase decorrelation on VEP indices of discrimination of isodipole texture pairs. Phase decorrelation, which ranged from 0.125 pi radians (slight randomization) to pi radians (complete randomization), was introduced in two ways: by independent jittering of each spatial Fourier component, and by a product method, which preserved correlations among certain quadruples of spatial Fourier components, despite pairwise decorrelation. For the even/random isodipole texture pair, independent phase decorrelation greater than 0.5 pi radians markedly reduced VEP indices of texture discrimination for all check sizes, and eliminated them entirely for check sizes of 8 min or greater. However, the product method preserved texture discrimination signals even with complete pairwise randomization of spatial phases. For the triangle/random isodipole texture pair, both kinds of phase decorrelation eliminated VEP indices of texture discrimination. These results imply that isodipole texture discrimination is based on fundamentally local processing, and not on global Fourier amplitudes-since the phase manipulations which eliminate texture discrimination preserve the Fourier amplitudes. The dependence of the antisymmetric response component (the odd harmonics) on phase decorrelation and texture type is consistent with a previously proposed model for feature extraction, and leads to constraints on how texture processing is modulated by contrast. The limited contribution of global spectral characteristics for small checks is consistent with a previously identified breakdown in scale-invariant processing.

Investigation of a patient with severely impaired direction discrimination: evidence against the intersection-of-constraints model.

A man with presumed posterior cortical atrophy had a markedly elevated threshold for orientation discrimination (approx. 25 deg) and selective impairment of "pop-out" tasks based on orientation. Direction discrimination for moving plaids was superior to direction discrimination for their component gratings. The superior performance for plaids disappeared when the spatial frequencies of the component gratings were altered to eliminate coherence. This finding implies that extraction of plaid motion is not dependent on pre-processing within narrow spatial frequency bands. It is inconsistent with simulations based on the "intersection of constraints" model, which predict that the error rate for plaids would be larger than the error rate for gratings, particularly for the plaids composed of gratings moving at nearly opposing angles. It is consistent with models such as the Heeger [(1987) Journal of the Optical Society of America A, 4, 1455-1471] model, which extract direction from the pattern of activity across broadly-tuned spatiotemporal filters.

Visual evoked potentials in dyslexics and normals: failure to find a difference in transient or steady-state responses.

We measured transient and steady-state checkerboard contrast-reversal visual evoked potentials (VEPs) in ten dyslexics, five patient controls, and 11 normals over a range of contrasts and luminances. Latency, amplitude, and phase measurements failed to distinguish the responses of dyslexics from those of normals or patient controls. Decreases in luminance or contrast resulted in an increased latency of the transient VEP in all groups, but these changes also did not distinguish the responses of dyslexics from those of the controls. Response variability was similar in dyslexics and normals, but was increased in subjects with attention deficit-hyperactivity disorder (ADHD). Performance on standardized psychometric testing did differentiate the dyslexics from controls, but did not correlate with VEP responses.

Stimulus orientation and contrast constancy.

The human visual system requires less contrast to detect patterns oriented vertically or horizontally than those oriented obliquely. We investigated whether this orientational anisotropy persists at suprathreshold contrasts. Using a contrast-matching technique, we found that it disappears at contrasts just above threshold, given the stimulus conditions employed. These results suggest that a neural mechanism, at suprathreshold, adjusts the gain of orientational subsystems to compensate for the lower sensitivity of the visual system to oblique patterns. A similar suprathreshold effect, referred to as contrast constancy, has been observed in studies employing grating patterns varying in spatial and temporal frequency. We argue, based on previous electrophysiological findings, that this neural compensation results from antagonism between excitatory and inhibitory processes in the visual cortex.

Coherence and transparency of moving plaids composed of Fourier and non-Fourier gratings.

We examined the perceptual coherence of two-component moving plaids. The gratings that constituted the plaids were either standard Fourier gratings (F), in which luminance was determined by a drifting sinusoid, or non-Fourier gratings (NF), in which the contrast of a random background was modulated by a drifting sinusoid. These NF gratings are examples of stimuli that generate a compelling percept of motion, even though they fail to elicit a motion signal from motion analyzers based on standard cross-correlation (Chubb & Sperling, 1988). Naive observers viewed three types of stimuli consisting of superpositions of these two components: (1) two standard drifting gratings (F/F), (2) two non-Fourier drifting gratings (NF/NF), and (3) one standard and one non-Fourier drifting grating (F/NF). As expected, the F/F stimulus yielded a compelling percept of coherent motion. The dominant percept of all the observers for the NF/NF stimulus was one of coherent motion, provided that both gratings were visible and of approximately equal contrast. None of the observers reported a dominant percept of coherent motion for the F/NF condition, over a wide range of contrasts for the two grating components and across two varieties of NF gratings. In view of the results of Albright (1992) and Albright and Chaudhuri (1989), that show that single cells in macaque V1 and MT respond to both F and NF motion, one cannot interpret our findings as evidence that F and NF motion are processed independently. Alternative, "higher level" interpretations based on the intrinsically ambiguous nature of the stimuli and physical laws governing the appearance of transparent objects are discussed.

Evoked potential and psychophysical analysis of Fourier and non-Fourier motion mechanisms.

Some visual stimuli produce a strong percept of motion, even though they fail to excite motion detectors based on Fourier energy or cross correlation. Models which suffice to explain the motion percept in these non-Fourier motion (NFM) stimuli include linear spatiotemporal filtering, followed by rectification, followed by standard motion analysis (Chubb & Sperling 1988). We used the human "motion-onset" evoked potential, which has been assigned to area 17 on the basis of work in the macaque (van Dijk et al., 1986; van Dijk & Spekreijse, 1989), to investigate the neural substrate of the processing stages postulated in the above models. Motion-onset VEPs elicited by FM and NFM matched for spatial and temporal characteristics were indistinguishable in temporal characteristics and scalp topography at a transverse chain of electrodes. Addition of textural cues (granularity and higher-order form) did not influence the response dynamics or scalp topography of NFM responses. However, comparison of responses to NFM stimuli and related stimuli without coherent motion but similar spatial and temporal properties showed that the motion-onset responses were distinct from responses to the onset of fixed flicker-defined contours not undergoing coherent motion. We discuss the implications of these results for computational models of motion analysis.

Spatial organization of nonlinear interactions in form perception.

We examined the perception of structure in a family of visual textures whose second-order correlation structure is flat. These textures were generated by two-dimensional recursion rules, in a manner which extends the construction of Julesz, Gilbert and Victor (1978; Biological Cybernetics, 31, 137-140). Textures generated by some recursion rules elicited a visually salient percept of structure, while textures generated by other recursion rules did not. Textures whose statistical structure was visually salient produced evoked responses which differed from the response evoked by completely random textures. The size of this VEP difference correlated well with psychophysical measures. Since the textures were constructed to have identical global spatial frequency spectra, models for the extraction of visual structure must be essentially nonlinear. Models based on symmetry, information content, or simple spatial extent (but not pattern) of correlation fail to explain the observed results. Models based on the cooperative interaction of pairs of nonlinear subunits provide a reasonable qualitative account of the findings. The critical model features are (i) the presence of multiple nonlinear subunits, and (ii) a second nonlinearity, such as a threshold, at the stage of combination of subunit signals.

Motion mechanisms have only limited access to form information.

We investigate the roles of spatial frequency content, flicker and higher-order elements of form ("features") in the generation of motion percepts. These cues are separated through the use of dynamic visual stimuli based on stochastic textures. Flicker alone and spatial frequency content alone suffice to generate a strong motion percept, but higher-order elements of form alone generate a much weaker motion percept. Thus, even for achromatic stimuli, all pattern information is not equally available for motion processing. Furthermore, higher-order form information, which by itself does not provide a strong cue to motion, is shown to interact with other visual information to facilitate determination of direction of motion.

Cortical interactions in texture processing: scale and dynamics.

We investigate the neural computations underlying pattern processing with stimuli based on textures balanced for spatial frequency content (and second-order correlations) but not for higher-order correlations (Julesz et al. 1978). Interchange between two such isodipole textures produces a robust human visual evoked potential (VEP). The difference in population activity driven by two isodipole textures is quantified by the antisymmetric component of the VEP. Statistical properties of the textures eliminate contributions from linear mechanisms to the antisymmetric VEP. The dependence of the antisymmetric VEP on check size and fourth-order correlation statistics is used to test nonlinear models for the underlying neural computations. Linear summation, followed by a simple nonlinearity (such as rectification, saturation, or threshold), is inconsistent with the data. More elaborate models, in which a second nonlinear stage combines the output of local nonlinear mechanisms, are consistent with the data, provided that an appropriate spatial scale is chosen for the second stage of processing. For checks 4 min or smaller, the deduced interaction length is 10-15 min. For checks larger than 4 min, the interaction length is proportional to check size.