|Year : 1996 | Volume
| Issue : 2 | Page : 69-76
Neuronal basis of amblyopia: A review
John Grigg1, Ravi Thomas2, Frank Billson1
1 Department of Clinical Ophthalmology and Save Sight Institute, University of Sydney, Australia
2 Department of Ophthalmology, Christian Medical College, Schell Eye Hospital, Vellore, India
Department of Clinical Ophthalmology and Save Sight Institute, University of Sydney P.O.Box 493 Darlinghurst, NSW 2010, Australia
Source of Support: None, Conflict of Interest: None
Amblyopia is an acquired defect in vision due to an abnormal visual experience during a sensitive period of visual development. The neuronal basis of amblyopia is the study of the effects of "abnormal" environmental influences on the genetically programmed development of the visual processing system. Visual pathway development commences with ganglion cells forming the optic nerve. The process that guides these neurones initially to the lateral geniculate nucleus (LGN) and then onto the visual cortex is genetically programmed. Initially this process is influenced by spontaneously generated impulses and neurotrophic factors. Following birth, visual stimuli modify and refine the genetically programmed process.
Exposure to the visual environment includes the risk of abnormal inputs. Abnormal stimuli disrupt the formation of patterned inputs allowing alteration of visual cortical wiring with reduction in ocular dominance columns driven by the abnormal eye.
Correction of the abnormal visual input and penalisation of the "normal" input is the mainstay of therapy for amblyopia. Further understanding of the mechanisms involved in the development of a normal visual processing system will allow trialing therapies for amblyopia not responding to occlusion therapy. Levodopa is one agent providing insights into recovery of visual function for short periods in apparently mature visual systems.
Keywords: Amblyopia - Neuronal basis - Treatment.
|How to cite this article:|
Grigg J, Thomas R, Billson F. Neuronal basis of amblyopia: A review. Indian J Ophthalmol 1996;44:69-76
Amblyopia refers to an acquired defect in vision that is due to an abnormal visual experience during a sensitive period of visual development. The neuronal basis of amblyopia is the study of the effects of "abnormal" environmental influences on the genetically programmed development of the visual processing system. Therefore to study the neuronal basis of amblyopia requires the investigation of the normal anatomy and physiology of the visual processing system and most importantly an understanding of the factors regulating the development of visual system during both intrauterine and postnatal periods.
| Visual Processing - The Genetically Programmed Substrate|| |
Vision is a process for making inferences about the three-dimensional structure and composition of the external physical world, based upon information contained in two-dimensional retinal images. The net result is a seemingly unified visual perception. Interruption or alteration to the functioning of the image processing pathways results in abnormal image formation and one such consequence is amblyopia. Important structures in visual processing are summarised below.
| Structure and Function of the Striate Cortex: An Overview|| |
The neocortex has 6 fundamental cellular laminae arranged parallel to the pial surface. Distinguished by the density, types, and arrangements of their cells.Heterotypical cortex is the term given to areas of the neocortex in which there is enlargement of one laminae compared to the other layers. This is characteristic of neocortex in primary sensory areas. Laminae in heterotypical visual cortex form pial surface inwards [Table - 1].
The primary visual cortex (V1 also termed area 17 in Brodmann's classification) is also termed the Striate Cortex due to the presence of a macroscopic band in layer IVB known as the Stria of Gennari. V1 is organised as a retinotopic map of the visual field with adjacent points on the retina projecting to adjacent points in V1. The representation of the visual field in V1 is magnified compared with the retina.
The afferent fibres to Area 17 primarily arise from the lateral geniculate nucleus (LGN) of the thalamus. Information to the LGN is already divided along functional lines and then segregated into different laminae. The two subdivisions of the visual pathway are referred to as "magno" and "parvo" pathways. These divisions differ physiologically in four major ways: colour, acuity, speed and contrast sensitivity. The parvo system is colour selective, and has high spatial resolution, whereas the magno system is movement selective and has high contrast sensitivity.
The different divisions maintain discrete anatomical pathways with the parvocellular fibres terminating in layer IVCβ & IVA (absent in humans). The magnocellular fibres terminate in layer IVα.
Efferent fibres from Area 17 have two major destinations either subcortical (LGN, Superior colliculus, or the pulvinar) or cortico-cortical connections (layers II & III, provide the pyramidal cells that project to extrastriate visual regions).
| Striate Cortex Physiology: An Overview|| |
| Columnar Organisation|| |
The visual cortex has a columnar organisation superimposed on it to form a three dimensional unit. The columns group different features of the image together. These include orientation, and ocular dominance. In addition, there are areas which stain with cytochrome oxidase (indicating metabolically active areas) superimposed on the three dimensional structure [Figure - 1].
Columnar organisation of cortex is present from the beginning of cortical development. When neurones migrate from the ventricular zone to the cortical plate, they do so in ontogenic columns, developing neuronal inter-connections and passing through waiting thalamic afferent terminations en route.
| Orientation columns|| |
Orientation columns have their receptive fields of a particular orientation grouped together. Adjacent orientation columns differ slightly (approximately 10°) and in a systematic way in their orientation specificity. The columns are slabs or sheets with irregular, undulating configurations.
| Ocular Dominance Columns|| |
Axon terminals from right and left eye geniculate laminae are not randomly distributed in layer IVC of the striate cortex, but rather, they are segregated into a system of alternating parallel stripes called ocular dominance columns., The alternating bands are about 0.5 mm wide, representing ipsi- & contra-lateral eyes.About as many cells prefer stimulation of the left eye as prefer stimulation of the right. They form a system of irregular parallel stripes orientated at right angles to the surface of the striate cortex.
Inputs from the 2 eyes often do not have identical influence on the cortical cell, the cells outside layer IV are usually binocular, although they still tend to respond more strongly to stimulation of one eye than the other. Dominant input produces a greater response to a given stimulus than the input from the other eye.
| Cytochrome Oxidase Blobs|| |
Cytochrome oxidase stains metabolically active areas. In the striate cortex its use demonstrates that some areas appear to be more metabolically active than surrounding regions. The regions are called blobs because of their appearance on tangential section. The blobs are most distinct in layers II & III and are located within the centre of the ocular dominance columns.
Within cortical areas V1 and V2, a tripartite organisational pattern emerges that is closely related to the pattern of lamination and to the tangential distribution of staining for cytochrome oxidase (CO). The connections are summarised in [Table - 2].
The visual cortex continues the theme of being divided into 2 parallel processing pathways, each of which begins in the primary visual cortex and transmits information through parts of the extrastriate visual cortex. The pathways can be defined functionally as well as anatomically. One appears to be specialised for processing visual motion and the other for processing form and colour [Table - 3].
| Intrauterine Development of the Visual System|| |
Much of the basic anatomical structure of the visual pathway is constructed before birth. A wave of maturation sweeps through the system, from the eye to the visual cortex. The correct formation of connections depending on the precisely timed interactions between axons and their targets. Competition between growing axons (apparently dependent on spontaneous impulse activity in those axons), cell death (partly influenced by competition between those cells' axons), axon withdrawal, trophic interactions and other mechanisms play a part in constructing the visual pathway and laying down basic "maps" of the visual field before birth.
| Optic Nerve Development|| |
Most of the ganglion cells are generated between the eighth and fifteenth weeks of gestation. The ganglion cell population reaches a plateau of 2.2 to 2.5 million by week 18 and remains at that level until the thirtieth week gestation. After week 30, the ganglion cell population falls drastically during a, period of rapid cell death that lasts for about 6 to 8 weeks. Thereafter cell death continues at a low rate through birth into the first few postnatal months. The ganglion cell count is reduced to about 1 million. Recent evidence suggests that spontaneous impulses propagating along the fibres of the optic nerve regulate the process of competition between their terminals. If these impulses are blocked by using tetrodotoxin arborizations of the optic nerve axons within the LGN fail to become restricted to their normal laminar pattern. [13,14]
| Lateral Geniculate Connections|| |
LGN neurones appear in the macaque monkey between embryonic (E) days E36 to E43. This would correspond to human weeks 8 to 11. The first retinal ganglion cell fibres reach the LGN at 10 weeks. The segregation of ocular inputs occurs in the same time frame with the development of lamination. In humans the lamination occurs between weeks 22 to 25.
| Projections from Thalamus to Cortex|| |
Cells destined for striate cortex arise in the macaque monkey between E43 and E102 corresponding to weeks 10 to 25 in the human foetus.
In macaques the geniculate afferents begin to innervate striate cortex by E110, a time equivalent to gestational week 26 in humans. The segregation into ocular dominance columns transpires during the last few weeks of pregnancy and is almost complete at birth.
The maturation of the ocular dominance columns requires thousands of left eye and right eye geniculate afferents to gradually disentangle their overlapping axon terminals in striate cortex. The individual geniculate fibres remodel their terminal arbors to generate the ocular dominance columns in layer IV.
They do this by withdrawing modest branches from inappropriate territory and growing extensive terminal arbors within appropriate territory. Ocular dominance columns in layer 4 form from extensively intermixed LGN inputs representing the two eyes, presumably also by a process of axonal remodelling and synapse elimination.
| Impulse Activity and the Patterning of Connections during CNS Development|| |
The observation that the wiring of LGN axons and the eye preference of cortical neurones can be influenced by early visual experience set the stage for the idea that use of the visual system is required for its normal development and the maintenance of its connections, at least during the "critical period".
| Abnormal use such as Monocular Occlusion|| |
An explanation for the profound changes in connectivity at the level of the visual cortex is that a use dependent synaptic competition between LGN axons serving the two eyes for layer 4 neurones normally drives the formation of the ocular dominance columns during the critical period. Evidence supporting this is that binocular deprivation leaves the ocular dominance of cortical neurones unaltered.
| Role of Patterned Neural Activity in Competitive Interactions|| |
Signalling by neurones is via action potentials and synaptic transmission; hence the effects of visual experience on cortical organisation must be a consequence of alterations in either the level or the patterning of neural activity within the visual pathways. Evidence for the role of neuronal patterning in the development of the visual pathway is supported by experimental work using intraocular injections of tetrodotoxin (TTX), a sodium channel blocker. TTX silences the entire visual pathway from retina to cortex. Segregation of LGN axons into patches is prevented entirely, and neurones in layer 4, normally monocularly driven, are instead driven binocularly, reminiscent of the initial period of normal postnatal development.
Stryker and Strickland examined the synchronicity of neural activity. In their work they first blocked all retinal activity with TTX, but then experimentally controlled by electrical stimulation the optic nerves either synchronously or asynchronously. Synchronous stimulation of the two nerves prevented the formation of ocular dominance columns, whereas asynchronous stimulation permitted them to form. The only difference between the two experiments was the timing of the stimulation, thereby demonstrating directly that patterning of neural activity provides sufficient information for ocular segregation to occur, at least at the primary visual cortex level.,
Stryker and Strickland's experimental work explains why ocular dominance columns can develop even when animals are reared in the dark or are binocularly deprived during the critical period. In the absence of visual stimulation, ganglion cells in the mammalian retina of adults, and even in foetal animals fire action potentials spontaneously. Such spontaneous firing supplies activity-dependent cues, provided that the ganglion cell firing in the two eyes is asynchronous to allow development of ocular dominance columns.
The finding that synchronous activation of afferents prevents them from segregating, while asynchronous activation promotes segregation, indicates that the timing of presynaptic activity is crucial to the processof visual system development.
| Cellular Correlates of Activity-dependent Competition|| |
Postsynaptic activity is also crucial to the process of segregation., The requirement for the participation of both pre- and postsynaptic partners in activity-dependent re-arrangements and the fact that coincident activation can strengthen coactivated inputs are consistent with a Hebb rule governing the process of synapse rearrangements during ocular dominance column development in mammals. (Hebb suggested that when pre- and post-synaptic neurones are coactivated, their synaptic connections are strengthened, whereas connections are weakened with lack of coincident activation.)
| Role for Neurotrophic Factors|| |
In addition to the fundamental role of neural activity the interaction between neural and neurotrophic activities needs to be considered. It is known that target cells provide limited amounts of specific neurotrophic molecules to innervating neurones; each axonal terminal must acquire sufficient neurotrophic factor for its maintenance, otherwise it is eliminated. It can, therefore be hypothesised that geniculocortical afferents from the two eyes are in competition, perhaps for a neurotrophic factor.
Carmignoto et al tested this hypothesis by examining the amblyopic effects of monocular deprivation in the cat and whether the effects could be prevented by nerve growth factor (NGF) treatment. The NGF was administered intraventricularly by means of a cannula-minipump system. They found that administration of NGF during the critical period of monocular deprivation (MD) reduces the amblyopic effects of MD and that following the initial period of MD the subsequent administration of NGF promotes the functional recovery of the deprived eye. An interpretation of this data is that NGF preserves the functional input from the deprived eye to the visual cortex.
| Possible Role of NGF on Visual Cortical Plasticity|| |
It is possible that NGF interacts directly with a specific neuronal population of the visual system. The hypothesis that the ocular dominance shift of area 17 neurones towards the open eye in monocularly deprived animals is due to competition between the afferents from the two eyes for NGF implies that geniculo-cortical axonal terminals express the NGF receptor. Evidence exists that the NGF receptor mRNA encoding for the low-affinity NGF receptor, and related protein is expressed in many visual system related nuclei of the rat, including the visual cortex.
Carmignoto et al obtained evidence that in the lateral geniculate nucleus of the rat the low-affinity NGF receptor is exclusively related to retinal ganglion cell axonal terminals and not to intrinsic projecting neurones. Neurotrophic factors could therefore modulate synaptic efficiency by regulating the expression of neurotransmitter receptors.,
| Environmental Influence on Neural Connections|| |
The continued development of visual function after birth is accompanied by major anatomic changes that occur simultaneously at all levels of the central visual pathways. Ocular segregation (similar to the competitive interaction that generates the layers of the LGN) takes place after birth. Initially the geniculate fibres from left and right eyes are intermingled. The terminals gradually rearrange their terminal distribution during the first two months of postnatal life in the cat and monkey.
In the visual cortex the density of dendritic spines and synapses reaches a peak at 8 months of age. Subsequently the level declines by 40% over a period of several years. Note that this corresponds to the most sensitive part of the critical period. Synaptic plasticity may permit cortical neurones to refine their processing capacities on the basis of information provided by the visual environment.
It is clear that the synaptic input to cortical cells is being regulated on the basis of activity reaching the cortex from the eyes. This sensitivity to visual stimulation is presumably of adaptive importance to the animal, perhaps being needed to refine the mechanisms for detection of fine detail in the image, for stereoscopic vision and for the identification of shape. However, this period of sensitivity also makes the cortex vulnerable to disturbances of visual experience, which can have permanent consequences for vision. The human critical period for susceptibility to deprivation appears to begin at about 4 months of age, reaching maximal sensitivity between 6 and 9 months. Sensitivity to deprivation then declines, but lasts to about age 8.
| Neuroanatomical and Neurophysiological Abnormalities in Amblyopia|| |
Foveal vision in amblyopia resembles peripheral vision in normals. This suggests that inappropriately large receptor fields (spatial summation) have developed in the foveal visual cortex. This hypothesis would explain the loss of contrast sensitivity at high spatial frequencies with preservation of low spatial frequencies. The phenomenon of spatial uncertainty, defects in judging line offset effects (vernier acuity) and the altered psychovisual performance when tested with crowded targets.
| Amblyogenic Mechanisms - Disuse versus Competition|| |
Two amblyogenic mechanisms have been proposed, and that these may be effective, individually or, in unison, in the various forms of amblyopia.
| Disuse|| |
A lack of adequate retinal stimulation during infancy, causing visual deprivation with arrest of development at a stage at which the interference began, or disuse atrophy of afferent connections that were already present at birth. This is not regarded as being a major factor in the development of strabismic amblyopia is now being disputed. Since the salient feature of strabismic amblyopia is not the lack of afference but the incompatibility of visual impressions received by both eyes.
| Competition|| |
This is based on the view that stimulation of corresponding retinal points with unequal images causes rivalry between the two eyes which is decided in favour of the fixating eye, the other eye becoming amblyopic.
Binocular deprivation and strabismus experiments support the notion that competition, rather than disuse is the main cause of the observed changes. The right circumstances must exist, however, for the competition to occur, since cells in the normal visual cortex tend to be dominated by one eye or the other, and the dominant eye does not take over the cell completely. It appears that the incompatibility of the visual input [Table - 4] received by the two eyes causes a decrease or even blockage of synaptic transmission of the afferent impulses originating from the nonfixing eye.
| Monocular Deprivation|| |
Evidence for competitive mechanisms has been found by studying the effects of visual deprivation on cats and monkeys. Measurement of geniculate cell sizes revealed that cells from the deprived eye were of a smaller size than the non-deprived eye.
Tangential electrode penetrations of visual cortex showed a clear segregation of the cells into unusually distinct ocular dominance columns, even outside layer IV. Furthermore pattern deprivation in the monkey produced by lid suture is not reversed if the eye is merely opened.
Competitive inhibition is orientation and spatial frequency specific. A monkey raised in an environment of vertical stripes with one eye closed, showed equal responsiveness to horizontal stripes but responses to vertical stripes only in the open eye.
In animal experiments with monocular deprivation most striate neurones respond from the sound eye, only a few, if any can be driven from the amblyopic eye and binocularly responsive neurones are virtually absent. These anomalous responses in monkeys are identical, regardless whether the amblyopia is caused by surgically induced strabismus, experimental anisometropia, or unilateral lid suture.
Tracer studies show that with monocular deprivation, the geniculate terminals with input from the nondeprived eye take over much of the space that would normally have been occupied by terminals from the deprived eye. The input from the deprived eye has shrunk down to occupy the small strips lying between the terminals of the input to the non-deprived eye.
| Neurophysiological Basis for Therapeutic Options in Amblyopia|| |
| Recovery from Deprivation - Occlusion Therapy|| |
Monocular closure during the entire critical period in cats and monkeys results in permanent blindness in that eye. Short periods of deprivation during the critical period if reversed during the critical period will result in gradual partial or complete normalisation of visual acuity.
Patching the 'good eye' leads to a complete switch in eye preference if done early in the critical period. The geniculate innervation of layer IVC also reverses so that the shrunken regions controlled by the initially closed eye expand at the expense of the other eye.
The initially deprived eye takes over much of the lower part of layer IVC (IVCβ), but fails to reverse the domination of the other eye in the upper part of layer IVC (IVCα), Layer IVCβ is innervated by the parvocellular layers of the LGN, whereas layer IVCα receives its input from the magnocellular layers of the LGN. Results from eye-reversal experiments indicate that the critical period is different for the two cell types.
Despite a "normalisation" of the ocular dominance histograms, there is an irreversible loss of binocular cells in the monkey, even after subsequent prolonged exposure to a normal visual environment. There is however no correlation between the loss of binocular striate cells and the loss of fusion. This loss of binocular cells correlates with the loss or absence of stereopsis. So the risk associated with unilateral patching or alternate patching is the loss of stereopsis but not fusion.
| Noradrenergic neurones, Levadopa and Amblyopia|| |
There is evidence that plasticity of the visual system during the sensitive period is dependent on input from noradrenergic neurones and is subject to pharmacological manipulation.
Gottlob and Stangler-Zuschrott found that a single dose of levodopa/benzerazide (200 mg/50 mg) temporarily improved contrast sensitivity and decreased scotoma size in the amblyopic eyes of 9 adults. Leguire et al. studied 5 amblyopic children, (between the ages of 7 and 12 years), and 2 normal adults who were given between 100 mg /25 mg and 400 mg /100 mg of levodopa/carbidopa, depending on body weight. One hour after drug ingestion, Snellen visual acuity temporarily improved from an average of 20/159 to 20/83 in the amblyopic eyes. Contrast sensitivity and pattern VERs (10 minute checks) temporarily improved in both dominant and amblyopic eyes, whereas visual function remained stable in normal eyes. The improvements in visual function started to decrease 5 hours after drug ingestion.
| Summary|| |
The normal visual pathway development commences with the first ganglion cells joining together to form the optic nerve at the proximal end of the optic fissure. The process that guides these neurones initially to the LGN and then onto the visual cortex is genetically programmed. Initially this process is influenced by spontaneously generated impulses and neurotrophic factors such as nerve growth factor. Following birth and exposure to visual stimuli, modification to the genetically programmed process occurs. This process is necessary for refinement of the visual processing system.
Exposure to the visual environment also places the development process at risk due to abnormal stimuli such as occur with optical defocus, strabismic ocular mal-alignment or deprivation. These stimuli disrupt the formation of patterned inputs allowing alteration of visual cortical wiring with reduction in ocular dominance columns driven by the abnormal eye.
Correction of the abnormal visual input and penalisation of the "normal" input is well established and is the main stay of therapy for amblyopia. Further understanding of the mechanisms involved in the development of a normal visual processing system will allow trialing therapies for amblyopia for situations not responding to occlusion therapy. Levodopa is one pharmacological agent which is providing such insights into recovery of visual function for short periods in apparently mature visual systems.
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[Figure - 1]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]