A new model of strabismic amblyopia: Loss of spatial acuity due to increased temporal dispersion of geniculate X-cell afferents on to cortical neurons.

Although the neural locus of strabismic amblyopia has been shown to lie at the first site of binocular integration, first in cat and then in primate, an adequate mechanism is still lacking. Here we hypothesise that increased temporal dispersion of LGN X-cell afferents driven by the deviating eye onto single cortical neurons may provide a neural mechanism for strabismic amblyopia. This idea was investigated via single cell extracellular recordings of 93 X and 50 Y type LGN neurons from strabismic and normal cats. Both X and Y neurons driven by the non-deviating eye showed shorter latencies than those driven by either the strabismic or normal eyes. Also the mean latency difference between X and Y neurons was much greater for the strabismic cells compared with the other two groups. The incidence of lagged X-cells driven by the deviating eye of the strabismic cats was higher than that of LGN X-cells from normal animals. Remarkably, none of the cells recorded from the laminae driven by the non-deviating eye were of the lagged class. A simple computational model was constructed in which a mixture of lagged and non-lagged afferents converge on to single cortical neurons. Model cut-off spatial frequencies to a moving grating stimulus were sensitive to the temporal dispersion of the geniculate afferents. Thus strabismic amblyopia could be viewed as a lack of developmental tuning of geniculate lags for neurons driven by the amblyopic eye. Monocular control of fixation by the non-deviating eye is associated with reduced incidence of lagged neurons, suggesting that in normal vision, lagged neurons might play a role in maintaining binocular connections for cortical neurons.

The advantage in being magnocellular: a few more remarks on attention and the magnocellular system.

We have recently proposed a model of visual processing in which object recognition through the ventral stream into inferotemporal cortex is facilitated by an initial rapid feedforward sweep through the dorsal stream activating parietal and frontal regions prior to subsequent feedback to primary visual cortex (V1). Modulation of inferotemporal cortex also requires feedback from frontal regions, and horizontal connections from the dorsal stream. Aspects of this model, however, have been called into question-in particular the timing advantage of magnocellular over parvocellular arrivals in V1 (the 'magnocellular advantage'), the link between attention and the magnocellular system, and also the role of MT in smooth pursuit and saccadic eye movements. These criticisms are each rebutted in detail here, and the basis for a model derived from the magnocellular advantage is reaffirmed.

A role for the 'magnocellular advantage' in visual impairments in neurodevelopmental and psychiatric disorders.

Evidence exists implicating abnormal visual information processing and visually driven attention in a number of neurodevelopmental and psychiatric disorders, suggesting that research into such disorders may benefit from a better understanding of more recent advances in visual system processing. A new integrated model of visual processing based on primate single cell and human electrophysiology may provide a framework, to understand how the visual system is involved, by implicating the magnocellular pathway's role in driving attentional mechanisms in higher-order cortical regions, what we term the 'magnocellular advantage'. Evidence is also presented demonstrating visual processing occurs considerably faster than previously assumed, and emphasising the importance of top-down feedback signals into primary visual cortex, as well as considering the possibility of lateral connections from dorsal to ventral visual areas. Such organisation is argued to be important for future research highlighting visual aspects of impairment in disorders as diverse as schizophrenia and autism.

Inhibition of retinal ON/OFF systems differentially affects refractive compensation to defocus.

Hatchling chicks reared with defocusing spectacle lenses compensate for the applied defocus, both refractively and through changes in eye growth, in about 1 week. In this experiment, we show that pharmacological inhibition of the retinal ON or OFF responses to light stimulation with isomers of alpha-aminoadipic acid results in a sign-dependent pattern of interference with the refractive compensation mechanism. An intravitreal injection of 2.5 microM L-alpha-aminoadipic acid inhibited the ERG ON response and inhibited refractive compensation to negative lens defocus, but not to positive or zero power lens defocus. D-alpha-aminoadipic acid in the same dose reduced the retinal OFF response and inhibited refractive compensation to positive lens defocus, but not to negative or zero power lenses. Thus the pharmacological manipulation of induced refractive change suggests that the retinal ON and OFF subsystems play independent roles in the emmetropization process.

Refractive compensation to optical defocus depends on the temporal profile of luminance modulation of the environment.

The refractive state of hatchling chicks rapidly compensates to applied optical defocus through alteration in eye growth. The mechanism is capable of sensing whether the plane of focus lies in front of or behind the photoreceptors, however, its nature and site of action within the retina are unknown. We attempted to create an imbalance in the adaptation of the retinal ON and OFF mechanisms previously implicated in refractive control through pharmacological interventions, by rearing chicks from 4 to 9 days of age with a monocular +10 D, 0 D or -10 D lens, in an environment illuminated by a moving or stationary plaid of luminance gradients. When the plaid moved in one direction a local Fast-ON sawtooth luminance modulation was produced, while plaid motion in the other direction resulted in a Fast-OFF sawtooth modulation. Significantly reduced refractive compensation accompanied +10 D lens/Fast-OFF and -10 D lens/Fast-ON rearing, but not for the other conditions. Thus the refractive compensation mechanism depends on the nature of the temporal contrast of the environment, suggesting a relationship between the sign of defocus and the state of adaptation of the retinal ON and OFF subsystems.

Altered expression of alternatively spliced isoforms of the mRNA NMDAR1 receptor in the visual cortex of strabismic cats.

PURPOSE: Although much has been written about the role of the NMDA receptor's role in experience dependent visual plasticity, the function of the NMDAR1 receptor subunit in the post-plasticity stage of development is still not well understood. However, in the well studied model of strabismic amblyopia where binocularity is reduced, but where most primary visual cortex neurons can be driven by one or other eye, the density of expression of NMDAR1 receptor protein is significantly reduced, compared to normals. This study aims to identify which of eight isoforms of the spliced heterogeneous variants of the NMDAR1 mRNA receptor gene are associated with this decrease in expression as a means of elucidating possible function. METHODS: A series of digoxygenin-labelled oligonucleotide probes based on the human gene sequence have been used for in situ hybridization (ISH) of sections from the striate cortex of four adult cats. The probes were used to uniquely detect the expression of alternatively spliced mRNA variants in 66,487 cells from sections from the area centralis projection of two normal cats and two cats made esotropic as kittens by tenotomy at two weeks of age. RESULTS: As expected, total NMDAR1 mRNA isoform expression was significantly lower in the striate cortex of strabismic compared to normal cats. The proportion of cortical cells expressing the R1-a, R1-b, and R1-1 isoforms in strabismic animals was decreased while the proportion expressing R1-3 was increased, especially in layers V and VI. No significant difference in expression of the R1-2 and R1-4 isoforms was seen comparing strabismic and normal cats. CONCLUSIONS: These results confirm our previous findings and suggest that transcriptional inhibition of specific isoforms of NMDAR1 mRNA may underlie the change in receptor expression. This preferential reduction in the proportion of neurons bearing particular NMDAR1 isoforms, i.e. isoforms R1-a and b, and R1-1 with partial compensation through the expression of the R1-3 isoform, is more likely related to lowered proportion of binocularly activated neurons in the strabismic cat than to changes in eye dominance or the presence of amblyopia in one eye.

Effects of a non-steroidal (ketorolac tromethamine) and a steroidal (dexamethasone) anti-inflammatory drug on refractive state and ocular growth.

Topical steroidal anti-inflammatory drugs (SAID) and non-steroidal anti-inflammatory drugs (NSAID) are known to affect fluid balance. The effects of twice daily topical applications of Maxidex (dexamethasone, a SAID), Acular (ketorolac, a NSAID), and saline were examined biometrically on the development of refractive errors and eye growth in chicks raised from days 3-12 wearing either a monocular +10 D, 0 D, or -10 D lens. Biometric analysis showed that neither SAID nor NSAID nor saline affected refractive error compensation but that the anti-inflammatory drugs affected eye growth. In chicks reared with a +10 D lens, dexamethasone induced a decrease in axial length (AL), vitreous chamber (VC) and anterior chamber (AC) depth, while ketorolac only induced a decrease in AC. In -10 D lens chicks dexamethasone again induced a decrease in AL and VC, but did not affect AC depth, whereas ketorolac only induced an increase in AC depth. Taken together, these results suggest that anti-inflammatory drugs can induce changes in ocular size without affecting refractive state and, as such, have implications for the management of progressive myopia.

Comparison of refractive state and circumferential morphology of retina, choroid, and sclera in chick models of experimentally induced ametropia.

PURPOSE: Simultaneous comparisons of the circumferential morphological tissue profiles and final refractions from form-deprivation myopia (FDM), defocus-induced myopia (DIM), and defocus-induced hyperopia (DIH) models of ametropia have been made to test the hypothesis that changes in the thickness profiles of the three coats of the eye, and particularly that of the choroid, can be predicted from the degree of induced refractive error. METHODS: Hatchling chickens (n = 23) were raised for 2 weeks wearing either a monocular translucent diffuser (FDM, n = 8), monocular -10.00 D lens goggle (DIM, n = 7), monocular +10.00 D lens goggle (DIH, n = 7), or nothing (Norm, n = 1). All animals were refracted using retinoscopy and were then sacrificed, and whole eyes were processed for scanning electron microscopy. Retinal, choroidal, and cartilaginous sclera (CS) thickness measurements were made from photographic collages of the entire circumference of the globe. Of the 23 chickens, complete morphological profile data were available for both eyes of 10 animals (nine treated and one normal). The contralateral fellow eyes (FEyes) of all nine experimental chickens were used as experimental controls as paired comparisons for statistical analyses. RESULTS: Morphological profiles of control and experimental eyes revealed significant systematic regional variations in tissue thickness. This variation was related to nasal or temporal eccentricity with the nasal side generally thinner than the temporal. Retinal, choroidal, and CS tissue from FDM and DIM eyes showed very similar anatomical responses despite significantly different degrees of refractive change. DIH eyes showed significant increases in choroidal thickness but none in retinal or CS thickness. Analysis of fellow control eyes indicated that in both myopia models (FDM and DIM), significant changes in all tissues of the untreated fellow eyes occur whereas only the choroid of the fellow eye was affected in the hyperopic (DIH) model. CONCLUSIONS: The morphological similarity observed in the circumferential profiles of the retina, choroid, and cartilaginous sclera of the FDM and DIM eyes despite approximately 20 D difference in final refraction suggests that choroidal thickness is not a good predictor of final refractive error across models. Similarly, the final refractive difference of approximately 20 D between the DIM and the DIH eyes did not receive a major contribution from the final difference in choroidal thickness (with its implied effect on vitreous chamber length).

A role for choroidal lymphatics during recovery from form deprivation myopia?

BACKGROUND: The choroid of the chick swells markedly during recovery from experimentally induced myopia. It has been demonstrated previously that the lymphatic sinusoids of the choroid contribute most to the expansion. This raises important questions about the particular ultrastructural changes occurring in choroidal lymphatics as a means of understanding the role these vessels might play in emmetropization. METHODS: Thirteen hatchling chicks were monocularly occluded for 2 weeks to induce myopia and then allowed normal visual experiences during recovery for periods of 0 to 72 h before sacrifice. RESULTS: Electron microscopic analysis detailed the temporal progression of vascular changes and provides qualitative evidence for edema in the extravascular space. Quantitative analysis showed that the frequency of open junctions between lymphatic endothelial cells (an indicator of passive fluid transfer) increased over the 3 days of recovery. Lymphatic fenestrations (an indicator of active fluid transfer) were rare in both nondeprived eyes and in form-deprived eyes at the time of occluder removal, but increased in density significantly over the first 24 h of recovery before returning to control levels by 72 h. The number of lymphatic endothelial caveolae did not change significantly during recovery, nor did the number of fenestrations along the walls of choriocapillaris vessels. CONCLUSIONS: The walls of the lymphatics of the chick choroid open to allow greater fluid transfer during re-emmetropization than normal; the lymphatics may play an important role in the maintenance of chorioretinal fluid balance and homeostasis.

A technique for in vivo measurement of photoreceptor orientation in the chicken retina.

The aim of the current study was to develop a method for simultaneously assessing central and peripheral photoreceptor alignment in vivo in animal models. The stimulus apparatus consisted of nine light-emitting diodes (LED) positioned 7.5 degrees apart around an arc. The stimulus was viewed through a pinhole imaged into the entrance pupil of the eye using a telecentric lens system. Photodiodes placed over an array of the VERIS imaging system stimulated the electroretinogram. Data were obtained by positioning the pinhole at 0.25-mm intervals across the pupil and recording (Volk Optical, Mentor, OH, USA) at each location. Orientation assessed in normal chickens demonstrates that photoreceptors orientate towards a locus near the centre of the pupil and that there is a systematic change in peak location with eccentricity. This technique provides a valuable method for determining photoreceptor orientation properties in vivo and can be applied to animal models of pathology.

X-ray elemental analysis differentiates blood vessels and lymphatic vessels in the chick choroid.

PURPOSE: Chick choroidal lymphatics swell rapidly during recovery from form-deprivation occlusion, leading to the question of functional significance. To date, analysis of lymph in initial lymphatics has been problematic because of the difficulties of access. However, elemental composition can be determined using scanning electron microscope (SEM) X-ray microanalysis. This study investigated whether cryo-fixation would permit vascular fluids to be analysed in situ. METHODS: Two chicks were raised normally and seven were raised with monocular occlusion for 12 days before varying periods of normal visual experience. The eyes were rapidly frozen, fractured and X-ray spectra obtained from the lumina of lymphatic and blood vessels in a Cambridge S360 SEM. RESULTS: The elemental signatures of Na/Cl/K/P/S distinguished the two vessel types. CONCLUSIONS: These results suggest this bulk-frozen tissue technique can quantify relative changes in elemental species present in various ocular compartments in response to light-induced changes in the retina.

Temporal limitations of information processing in global and local attention: the effect of information content.

PURPOSE: The refractory period during which detection or identification of a probe is degraded, following the successful visual identification of a target, is referred to as the attentional blink (AB). Previous work in this laboratory using global/local letter forms has shown that the degree of complexity of information influences the length of time between successful visual identifications, as does the attentional modality required of the subject. In the standard rapid serial visual presentation (RSVP) task, a gap following the first target is reported to destroy the AB. The current study examines the effect on the AB duration of inserting a gap in the stream of local orthographic information while not interrupting the stream of global information. It was hypothesized that masking of the local elements of the item immediately following the target (the +1 item) would lead to a decreased AB duration for local identification. METHODS: Twenty-one adult participants, experienced in the experimental paradigm, viewed sequences of compound letter stimuli and were required to identify a global or local red letter (target) and detect the presence of a global or local X (probe) in the sequence following. RESULTS: In one-half of the trials the local letter identity of the +1 global/local form was obscured, leaving only a global form. Neither the attentional condition nor local +1 masking significantly influenced the slope of recovery from the AB. Furthermore, no difference was observed in the AB duration for global or local probe detection between control and crystallized trials. CONCLUSIONS: The results suggest that the visual image of the item is accepted nto VSTM and processed for target candidature.

Cone receptor sensitivity is altered in form deprivation myopia in the chicken.

PURPOSE: The effect of form deprivation myopia (FDM) on cone photoreceptor function was investigated. METHODS: Photopic electroretinogram (ERG) a-waves were recorded from control and form-deprived eyes of chickens. Cone-generated P3 responses were derived from the leading edge of ERG a-waves using an analytical expression derived from a quantitative model of phototransduction. The parameters obtained were the maximum cone P3 response (RmaxP3), sensitivity (S), and delay (t(d)). RESULTS: P3 response sensitivity is significantly higher in form-deprived eyes, at lower retinal irradiances. At higher flash intensities, in form-deprived eyes, P3 response sensitivity declines at a significantly greater rate, per unit increase in retinal irradiance, than in control eyes. Visual deprivation does not significantly affect RmaxP3 or t(d). CONCLUSIONS: Hypotheses to explain the altered cone photoreceptor sensitivity in form-deprived eyes are proposed. Changes in the biochemistry of phototransduction, or intrinsic geometric and physical attributes of photoreceptors or their waveguide modal properties, could account for the findings.

Anomalies of genetic development as predictors of oculo-visual abnormalities in velo-cardio-facial syndrome.

BACKGROUND: Subjects with velo-cardio-facial syndrome (VCFS) were assessed to determine whether the learning disabilities (LDs) characterizing the syndrome are compounded by visual function deficits, which would be predicted on the basis of the proposed embryonic derivation of the genetic anomaly. METHODS: Twelve subjects diagnosed with VCFS underwent a vision screening with emphasis on binocular function. RESULTS: Subjects exhibited deficits in accommodation (N = 5), convergence (N = 7), fusional reserves (N = 9), and stereopsis (N = 10). Three patients were strabismic at near. No patient was in the clinically normal range for all tests of binocular function. CONCLUSIONS: Individuals with VCFS have a chromosome 22 deficit thought to alter the migration of neural crest (NC) cells, which are the embryonic precursors of the autonomic innervation of the smooth muscle components of the eye and of cranial nerves III, IV, and VI. It was predicted that VCFS patients would demonstrate reduced accommodation and convergence flexibility, which would reduce visual comfort for near work. The pathological etiology of the visual anomalies suggests that if visual training is not successful, these patients should be provided with a suitable optical reading correction from an early age.

Temporal analysis of the topographic ERG: chromatic versus achromatic stimulation.

The topographic electroretinogram evoked by multi-focal exchange of black and white or red and green stimuli was analysed into linear and non-linear Wiener kernels. The first-order (temporally linear) response showed a biphasic waveform which inverted as the luminance ratio of the exchanged colours passed through unity (established both psychophysically and photometrically). A short latency non-linearity which was dependant on luminance contrast was observed in both chromatic and achromatic ERG. However, in the chromatic second-order response, a long-latency non-linearity, foveally prominent, with a distinct skew in power towards the nasal retina, appeared around the isoluminant point, between the points of silent substitution for the L and M-cone types. Modelling of the second-order responses showed that over a wide range of luminance ratios, the chromatic ERG is well described by a linear combination of the achromatic (contrast-dependent) component and the response at isoluminance. The difference in second-order response between coloured and black and white stimulation, at the same luminance contrast, showed that the long-latency non-linearity is recorded when the red and green cone types are operating out of phase and peaks in amplitude at a green/red luminance ratio of 0.8. This interpretation was confirmed by the lack of the long-latency non-linearity in colour-anomalous subjects (whether deficient in the L or the M-cone type). A marked similarity exists between the properties of the long-latency non-linearity and the frequency-doubled response generated in the ganglion cells of the magnocellular pathway.

Anatomical correlates of experimentally induced myopia.

PURPOSE: The present study compares morphological changes associated with optical defocus-induced myopia (ODM) with those from form deprivation myopia (FDM), as it is yet to be determined whether the latter is a consequence of visual deprivation or active myopic eye growth. METHODS: Hatchling chicks were reared for 2 weeks wearing a monocular translucent occluder or -10.00 D lens, with the other eye used as a control. After enucleation, eyes were processed for scanning electron microscopy. RESULTS: Anatomical profiles of control eyes revealed significant variations in tissue thickness as a function of nasotemporal location. Both FDM and ODM eyes demonstrated similar morphological profiles of retinal thinning, cartilaginous scleral thickening, enlarged photoreceptor inner segments and decreased photoreceptor cell density towards the ora serrata. A graded differential orientation of photoreceptors existed in all eyes. CONCLUSION: The comparable morphological changes in FDM and ODM suggest that the response to altered visual experience is similar in both paradigms.

Attentional blink in global versus local attentional modes.

PURPOSE: Brain imaging studies have shown that global and local attention activate different areas of the brain, with implication for dependence of perception on attentional state. The aim of the present experiment was to investigate the duration of the attentional blink in global versus local attention. METHODS: Rapid Serial Visual Presentation (RSVP) sequences of global/local stimuli were presented to 34 adult subjects who had to identify a target red figure followed by a determination of whether a certain probe letter, 'X' (specified to be either the global or local form), was present in the subsequent string of letters. RESULTS: Attentional blinks were longer than any previously reported (1.67 s global; 2.97 s local) and were significantly different.Thus, the length of the attentional blink is dependent on the attentional state of the subject. CONCLUSION: This pattern of results is consistent with the hypothesis that global attention mechanisms receive predominantly M-pathway input.

Motion perception in global versus local attentional modes.

PURPOSE: Global and local attention are two forms of selective visual attention which activate different areas of the cortex. The purpose of this experiment was to test subjects' motion coherence thresholds under conditions of global or local attention. It was hypothesized that thresholds in global attention would be lower than in local attention. METHODS: Eleven adult subjects participated in this study. Subjects were required to identify direction of motion at variable coherence levels, while simultaneously identifying either the global or local letter. Three velocities were used for coherent motion (3, 6 and 18 degrees/s). RESULTS: The results showed that letter identification (global or local) did not significantly affect motion coherence thresholds; however, thresholds were significantly higher at 18 degrees/s than in the lower velocities. CONCLUSIONS: These results highlight the attentional limitations of visual information shown by increased motion coherence thresholds when two objects must be identified simultaneously in a brief display.