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.

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 efficacy of brief periods of reverse occlusion in promoting recovery from the physiological effects of mononuclear deprivation in kittens.

The relative effect of short daily periods of reverse occlusion in promoting recovery from the physiological effect of monocular deprivation in kittens were examined with a view to identifying a neurophysiological basis for the visual improvement observed with minimum occlusion therapy in amblyopia. Kittens were monocularly deprived from near birth until 5 weeks of age, at which time they were reverse-sutured and housed in total darkness. Each kitten received a short period of visual exposure through its initially deprived eye each day for either a fixed number of days or for a constant total visual exposure spread over a different number of exposure sessions. Electrophysiological recordings from single cells in the visual cortex were made the day after the last visual exposure. Kittens that received daily periods of reverse occlusion as brief as 30 min for 20 days showed a substantial degree of reversal of cortical ocular dominance. Other experiments indicated that 20 hr of reverse occlusion distributed over a number of brief daily sessions was far more effective in promoting physiological recovery than the same total period of exposure imposed in only two sessions. In general these results suggest that a given period of reverse occlusion may be more effective in promoting recovery with distributed than with massed periods of occlusion.

Effects of retinal image degradation on ocular growth in cats.

High-powered negative and positive contact lenses have been used to produce a state of continuous retinal defocus in the eyes of 11 kittens in an attempt to induce a predictable amount of axial lengthening and myopia. Another group of six kittens had one eye continuously atropinized and a third group of four animals had the lids of one eye sutured. The axial dimensions and refraction were measured using ultrasonography and retinoscopy respectively. Although the treated eyes of eight kittens tested behaviorally were shown to be amblyopic, no myopia appeared in any animal at any stage during development and only three cats showed a small axial length difference between the two eyes. These results differ from other retinal deprivation studies reported on kittens and no satisfactory explanation for this discrepancy can be offered. However, it is suggested that the lack of change may be associated with the gross anatomy of the cat's eye, and it is concluded that myopia cannot be induced reliably in kittens by retinal image degradation.

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.

Amblyopia and suppression in binocular cortical neurones of strabismic cat.

The neural mechanism of strabismic amblyopia was investigated by recording the spatio-temporal properties of striate cortical neurones of cats raised with a surgically induced esotropia. Multiple pseudo-random flashed or phase-alternating stimuli were used, and through cross-correlation, the Wiener kernels were extracted. This analysis has shown that in neurones which retain binocularity to adulthood, two different neural mechanisms of adaptation to ocular misalignment exist. Some of these neurones become amblyopic, such that the non-deviating eye dominates the response for high spatial frequencies while the strabismic eye dominates at low spatial frequencies. Other neurones adapt through active suppression of the monocular response to stimulation of the strabismic eye when the non-deviating eye is simultaneously stimulated.

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.

Distribution and localization of NMDA receptor subunit 1 in the visual cortex of strabismic and anisometropic amblyopic cats.

ACTIVATION of NMDA (N-methyl-D-aspartate) receptors has recently been proposed as a prerequisite for the induction of experience-dependent modification of visual cortical neurones seen during early postnatal development. A new monoclonal antibody to the NMDA receptor subunit 1 (NMDA-R1) has been used to localize and compare the distribution of the receptors in the primary visual cortex of normal cats and those raised with either amblyopia induced by monocular optical blur or monocular esotropic strabismus. Although all three groups showed densest labelling in layers II-III, a comparison of immunopositive cells at any depth below the cortical surface showed a significantly lower frequency in strabismic and anisometropic cats than in normal cats, but a greater frequency in anisometropic cats that in strabismic animals. There appears to be no direct relationship between the expression of NMDA-R1 receptors and the level of excitability, binocularity or neuronal acuity known to exist in either of these two cat models of amblyopia, thus raising further questions as to the precise nature of the role of NMDA receptors in the processes of visual cortical plasticity.

Visual acuity of the northern native cat (Dasyurus hallucatus)--behavioural and anatomical estimates.

Behavioural estimates of the visual acuity of the Northern Native Cat (or Northern Quoll)--Dasyurus hallucatus--were made using the Mitchell jumping stand technique. A value of 2.3-2.8 cycles per degree was obtained. This functional acuity compared well with predictions based on the peak ganglion cell density (2600 cells/mm2) determined from the retinal ganglion cell density map.

Partial interocular transfer of brightness and movement discrimination by split-brain cats.

Interhemispheric transfer of discriminations of brightness and direction of movement, two types of stimuli which may be processed by midbrain visual areas, was compared to transfer of control patterns in cats with sections of the optic chiasm and forebrain commissures. Transfer in these split-brain cats was further compared to transfer in partially split-brain cats with sparing of either the splenium of the corpus callosum or the anterior commissure. An intact splenium was necessary for high levels of interhemispheric transfer of all of the discriminations, which implies a prominant role for cortical mechanisms in such tasks. However, animals with complete section of the corpus callosum often showed partial interocular transfer of both brightness and movement discriminations, which may reflect a limited but selective participation of subcortical areas in visual perception. Cats in which the anterior commissure was spared did not show greater transfer on any of these tasks than did cats with section of both callosum and anterior commissure.

Afferent input for target survival in marsupial visual development.

The influence of afferent input on the survival of target neurons in mammals has been examined by the removal of one eye of pouch young of the marsupial native cat (Dasyurus hallucatus). The ages at eye removal spanned the period of neurogenesis of the ascending visual pathway, and were earlier than the time of maximal axon number in the optic nerve. Autoradiography following the injection of tritiated proline into the intact eye of adult animals shows that the lateral geniculate nucleus contralateral to the injected eye of the earliest enucleates retains its laminated structure, despite the total absence of binocular competition throughout development. However, we find a dramatic, age-related reduction in the volume of those parts of the lateral geniculate nucleus and superior colliculus which would normally receive a contralateral-only projection from the enucleated eye. The effects of the enucleation are not restricted to the primary termination sites of the optic axons but ramify throughout a large part of the neo- and archicortex.

Temporal analysis of the chromatic flash VEP--separate colour and luminance contrast components.

Temporal analysis of the chromatic flash visual evoked potential (VEP) was studied in human subjects with normal and anomalous colour vision using a deterministic pseudo-random binary stimulus (VERIS). Five experiments were carried out on four normal subjects investigating heterochromatic red-green exchange and single colour/achromatic (either red/grey or green/grey) exchange over a wide range of luminance ratios for the two stimuli, the effects of lowered mean luminance on the chromatic VEP and the effects of colour desaturation at constant mean luminance and constant luminance contrast. Finally, the performance of three dichromats, a protanope and two deuteranopes, on heterochromatic exchange VEP and on colour desaturation were investigated. In contrast to the chromatic electroretinogram, which shows great symmetry with respect to luminance ratio on opposite sides of the isoluminant point, the chromatic VEP demonstrated a distinct asymmetry when the colours exchanged included red. On the red side of isoluminance (red more luminant than green), a wave with longer latency and altered waveform became dominant. The effects of green stimulation were indistinguishable from those of achromatic stimulation at the same luminance contrast over the whole range of chromatic contrast and for all levels of desaturation studied. Desaturation of red with constant luminance contrast (desaturated red/grey stimulation) resulted in a systematic alteration in the evoked waveform. Subtraction of the achromatic first- and second-order responses from responses recorded in the red desaturation series resulted in remarkably uniform waveforms, with peak amplitudes growing linearly with saturation. The absence of interaction between achromatic and coloured components for all (including the most intense colour) stimulus parameters used suggests that the generators of these components are separate. Recordings from the dichromats showed that the contrast response minimum shifted from the point of photopic isoluminance to the point of zero cone contrast (at the silent substitution point) for the remaining cone type. The waveforms recorded with a series of luminance ratios were much simpler than those recorded from trichromats and symmetrical with respect to their isoluminant points. Despite the indication of the presence of L cones of apparently normal spectral sensitivity in the deuteranopes (on the basis of flicker photometry), there was no evidence for a red-sensitive component in the desaturation or heterochromatic stimulation series. The results are discussed in terms of the possibility of separate generation of chromatic and achromatic contributions to the VEP.

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.

Separate magnocellular and parvocellular contributions from temporal analysis of the multifocal VEP.

Temporal analysis of the multifocal cortical visual evoked potential (VEP) was studied using pseudo-random (m-sequence) achromatic stimulation. The effects of variation of luminance contrast on the first-order response were complex. At low to mid contrasts (< 60%), a wave doublet (P100-N115) predominated. A second wave complex (N100-P120-N160) dominated at high contrasts. The second-order responses, however, showed an extremely simple variation with luminance contrast. Intrinsic differences in the adaptation time of the generators of these two components caused a distinct separation in the slices of the second-order response. A rapidly adapting nonlinearity saturating at low contrasts was only observable when measuring the responses from two consecutive flashes. Its latency coincided with the contrast saturating first-order response component. By comparison, the nonlinearity derived from the responses to the stimuli with longer interstimulus intervals (second and third slices) yielded a much more linear contrast response function with lower contrast gain and latencies, which clearly corresponded to the longer latency component of the first-order response. Thus, the second-order responses show a first slice which is predominantly driven by neural elements that have a latency and contrast function that mimic those of the magnocellular neurons of the primate LGN and a second slice which is dominated by a generator whose properties resemble primate parvocellular function. This division into magno and parvocellular contribution to the VEP is based on function (interaction time) as distinct from other currently available analyses, with potential for neural analysis of visual disease.

The effect of various anaesthetics on the spatial tuning of two major wave peaks in the transient pattern electroretinogram of the cat: evidence for pattern and luminance components.

The main PERG component of the transient contrast reversal pattern electroretinogram (PERG) in cats was a negative wave (3.5 microV average, SD 1.7 microV) peaking at about 130 msec (N130) with a spatial resolution above 5.5 c/deg, close to behavioural estimates. The early positivity (P35) was more variable, smaller and had lower spatial resolution. Different anaesthetic protocols affected both the waveform and the amplitude by spatial frequency functions. Responses of urethane anaesthetised cats were like those reported previously for decerebrate cats or cats paralysed and ventilated with N2O/O2/CO2 (75%/24%/1%). P35 was evoked only by coarse stimuli and N130 amplitude decreased linearly as spatial frequency increased. When the luminance response amplitude, predicted from the optical transfer function of the eye, was subtracted, spatial tuning appeared. An anaesthetic mixture of ketamine hydrochloride and xylazine depressed both P35 and N130 at low spatial frequencies while enhancing them at high frequencies. In paralysed animals ventilated with N2O/O2 (67%/33%) P35 was larger and recordable to 1.6 c/deg. Peak times were reduced and the inter-peak time halved. Other anaesthetics depressed the ERGs. These effects suggest that cats are a good model for studying N130 in isolation or its interaction with P35 and that both PERG peaks include luminance and pattern components.

A role for photoreceptor outer segments in the induction of deprivation myopia.

An ultrastructural examination of the outer retina and choroid of hatchling chicks reared for periods of 1, 2 or 4 weeks with opaque occluders (MD) covering one eye, was instigated to elucidate the mechanism of deprivation myopia. Refractive myopia (approximately 20 D), retinal and choroidal thinning were induced in all deprived eyes. Electron microscopy showed significant changes in the MD eyes compared to normals. Cone inner segments were markedly thicker and outer segment lamellae more damaged. The rod outer segments were elongated and thicker than normal, such that their distal tips either directly apposed the basal lamina of the retinal pigment epithelium, or indented the cell nuclei. We hypothesize that this "rod-push" mechanism leads to thinning of the choroid in deprived eyes, and may directly contribute to axial myopia.

Formoguanamine-induced inhibition of deprivation myopia in chick is accompanied by choroidal thinning while retinal function is retained.

Twenty hatchling chickens were injected intravitreally every 4 days from day 2 to day 16 with dimethyl sulphoxide (DS) in one eye and DS or formoguanamine dissolved in DS (FG.DS) with or without occlusion in the other (FG.DS.MD, DS.MD, FG.DS). At day 16, the FG.DS.MD eyes failed to show the high refractive myopia and showed less axial elongation than that developed by the DS.MD eyes. Electroretinograms indicated that at the dosage used, FG.DS does not eliminate phototransduction. Light microscopy showed choroidal and retinal thinning in DS.MD and FG.DS.MD eyes but less than in FG.DS eyes, suggesting that change in choroidal thickness is unlikely to be the primary cause of form deprivation myopia.

Extended contact lens wear in the developing cynomolgus monkey eye. Recovery from adverse responses.

Soft extended wear contact lenses were designed for and fitted to 12 eyes of 11 infant semiwild cynomolgus monkeys. The lenses were satisfactorily worn over observation periods of up to 465 days, the longest continuous period of lens wear being 69 days. However, some of the corneas were subject to a pattern of complications analogous to that in human contact lens wear. Nine eyes showed adverse responses, and of these, the ocular complications were severe enough in four cases to cause abandonment of lens wear. The most remarkable feature of the complications was the rapid recovery of severe reactions to near normality in less than 24 h, indicating an impressive ability of the cornea to tolerate and survive insult. Another feature was the recurrent nature of mild complications in certain monkeys despite apparent resolution from previous episodes. There appeared to be no correlation between duration of lens wear and appearance of the first or recurrent episodes of corneal infiltration and vascularization.