- Email: [email protected]
System-wide repercussions of damage to the immature visual cortex
Acknowledgements This work was supported by the MRCandihe We//come Trust.
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System-wide repercussions of damage to the immature visual cottex Bet-tram R. Payne and Paul Cornwell Be&am R. Payne is at the Dept of Anatomy and Neurobiology, Boston University School of Medicine, 80 EastConcord
Street, Boston, MA 02118,USA, and Paul Cornwellisatthe Dept of Psychology 130 Moore Building, The Pennsylvania State Univefsity, UniversQ Park, PA 16802, USA.
Damage of the primary visual cortex in mammals, including humans, severely disrupts vision @ disconnecting much of the cognitive-processing machinery of extrastriate cortex from its source of visual signals in the retina. Studies of’the anatomical consequences of damage to the immature primary visual cortex in cats reveal system-wide r@ercussions on neural circuitry that includes the retina, thalamus, midbrain and extrastriate cortex. The repercussions modify circuits that support relatively normal s&nal processing and the sparing of certain visually guided behaviors such as aspects of complex-pattern recognition and orienting to novel stimuli introduced into the visual field. These studies have implications for understanding the consequences of damage to the visual cortex in infant monkeys and humans, and for devising therapeutic strategies to attenuate defects in vision induced by cortical lesions. In humans, monkeys and cats, the primary visual cortex is the largest cerebral cortical area, and it is the major gateway to the cortical visual system. It has long been recognized that damage of the primary
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visual cortex severely disrupts vision, although it is now clear that certain functions such as flux and crude-pattern recognition remain after the damage’-5. The severity of the deficits are understandable because a lesion in the primary visual cortex disconnects the cognitive-processing machinery of extrastriate cortex and the parietal and temporal regions from the vast majority of visual signals ascending from the eye through the lateral geniculate nucleus (LGN). This can be seen by comparing Figs 1A and lB, which show the layout of the visual system in intact cats, and following the ablation of the primary visual cortical areas 17 and 18 in adulthood. However, there are alternative routes for visual signals to reach extrastriate cortex, which bypass the primary visual areas. One of these routes is minor and comprises a weak projection from the C complex of the LGN directly to parts of extrastriate cortex6. The major alternative pathway involves relays through the midbrain (superior colliculus and pretectum), and the lateral posterior (LP), pulvinar and lateral geniculate nuclei of the thalamu&‘. Visual signals passing along these alternative routes can alone activate neurons in TINS
at least some extrastriate areas ~° and they are probably responsible for the limited visual abilities that remain in the absence of the primary visual cortex. In contrast, following the lesions of areas 17 and 18 early in postnatal life (Fig. 1C), the visual system develops differently and the functional consequences of the lesions are much less disruptive to behavior 1H5. These differences include the expansion of pathways leading into and out of extrastriate cortex, and some of the changes are likely to contribute to the expression of the less disrupted behaviors. These outcomes of early lesions in cats have implications for understanding the consequences of early visual cortical damage in primates, including humans species for which detailed information is extremely limited. This transfer of knowledge is feasible because of the broad similarity between cats and primates in (1) the organization and function of the visual system in visually guided behavior 16, and (2) the components and execution of the developmental program, albeit that the primate program is extended over a longer timescale 17'1s. Moreover, the knowledge might be useful in a general way for understanding the effects of damage elsewhere in the immature cerebrum on neural function, and for developing therapeutic strategies to ameliorate cortical lesion-induced deficits.
Anatomicalrepercussions ofearlylesions
The anatomical repercussions of lesions of immature primary visual cortex in cats are numerous and widespread, and include regressive and progressive modifications (Fig. 1C). They encompass selective death of neurons within circuits dedicated to signal processing in areas 17 and 18, as well as expansions of pathways that bypass these two areas and that lead either into or out of extrastriate cortex. Neuron degeneration. Neurons forming major components in ascending circuits are particularly sensitive to damage incurred in infancy of their target areas 17 and 18. In the immature LGN, large numbers of neurons in layers A and A1, which normally project exclusively to areas 17 and 18 (Ref. 17), die as a result of the lesion 19, and that portion of the nucleus all but disintegrates (Fig. 2A). However, a number of neurons in the C complex, which normally form a more direct pathway for visual signals to reach extrastriate cortex 17, are unaffected by the lesion and survive 19. Moreover, the overwhelming majority of immature [~ retinal ganglion cells, which project exclusively to the severely degenerated layers A and A1 of the LGN (Ref. 20), die 21-23 (Figs 3A and 3B), whereas all o~ and y ganglion cells, which send substantial projections to targets outside of layers A and A1 (Ref. 20), survive ~1-22 (Figs 3A and 3B). A similar age-dependent sensitivity to damage of the primary visual cortex is exhibited by neurons in extrastriate visual cortex 25. For example, immature neurons in layers III and VI of the middle suprasylvian cortex die when they are axotomized (or deprived of target neurons, or both) by the removal of areas 17 and 18. This differential laminar vulnerability reflects the origin of efferent axons in extrastriate cortex that project to primary visual cortex in mature cats 25. Like mature [3 retinal ganglion cells, mature neurons in extrastriate cortex are resistant to damage of areas 17 and 18. TINS, Vol. 17, No. 3, 1994
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Fig. 1. Ascending and descending visual pathways associated with extrastriate cortex in the cat. (A) Intact cats. (B) Following ablation of primary visual cortical areas 17 and 18 in mature cats. (C) Following ablation of the primary visual cortex in newborn cats. Neurons in layers A and A1 project solely to primary visual cortical areas 17 and 18, whereas neurons in the C complex send weak projections to areas 17 and 18 and to the numerous areas comprising extrastriate cortex. The width of the arrows reflects the size of projections within a single processing tier. The greater size of projections might be because more neurons participate in the pathway or because axons in the pathway branch. In either case, there is a greater traffic in visual signals. Also, in (A) note the progressive amplification (not shown to scale) in the pathways through the lateral geniculate nucleus (LGN) and the primary visual cortex to extrastriate cortex. Abbreviations: A and A 1, layers A and A 1; C, C complex comprising layers C, C1-3; SC, superior colliculus; Pt, pretectum; LP, lateral posterior nucleus; Pul, Pulvinar nucleus; SGS, stratum griseum superficiale; SO, stratum opticum; I and D, intermediate and deep layers.
Pathway expansions. In several cases, pathways associated with extrastriate cortex expand following lesions of immature areas 17 and 18. As summarized in Fig. 1C, retinal projections to the C complex ~9'21 (Fig. 2C) and the wing 26 of the LGN increase in density, and novel projections to the LP complex might develop 27. In addition, the normally weak C-complex projections to extrastriate cortex increase 127
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Fig. 2. (A) and (B) Lightfield photomicrographs of the lateral geniculate nucleus (LGN) in an adult cat following unilateral ablation of primary visual cortical areas 17and 18 on the day of birth. (A) The LGN ipsilateral to cortical ablation. (B) The LGN ipsilateral to intact cortex. (C) and (D) Darkfield photomicrographs of the same sections shown in A and B to show the distribution of tritiated amino acids injected into the eye. (C) Ipsilateral projections. (D) Contralateral projections, Layers A and A 1, and the C complex are indicated. Note some large surviving neurons in the partially degenerated C complex (c; arrow), and reduced retinal inputs to degenerated layers A and A 1 and the increased density of inputs to the partially degenerated C complex. Abbreviations: d, severely degenerated layers A and A 1; n, normal tail of LGN that is connected to an intact, caudal portion of areas 17 and 18. Modified and reproduced with the permission of the Royal Society.
several fold and a normally ephemeral projection from the layers A and A1 is permanently established 2~'29. Furthermore, an increased fraction of neurons in the collicular recipient part of the LP nucleus projects to extrastriate cortex 2'. Moreover, descending extrastriate projections into the stratum opticum of the superior coUiculus expand and heavily innervate the superficial grey layer of the superior colliculus:~°. Lastly, transcortical projections from the posterior suprasylvian cortex to the middle suprasylvian region also expand following damage of immature areas 17 and 18 (Ref. 31). (For simplicity, this latter pathway is not illustrated in Fig. 1.) All of these pathway expansions increase the carrying capacity for visual signals to extrastriate cortex and to the superior colliculus, and, since the superior colliculus sends substantial projections to the LP nucleus, descending cortical signals reaching the superior colliculus can re-enter extrastriate cortex and contribute further to visual processing. It is important to note that equivalent expansions do not accompany damage of the mature areas 17 and 18 (Fig. 1B).
Behavioral and physiological repercussions Behavioral and electrophysiological studies implicate extrastriate cortex in the spared visual capacities following damage of primary visual cortex in immature cats. Bilateral removal of the primary visual cortex from mature cats induces moderate to severe deficits in pattern discrimination, depth perception, optokinetic nystagmus and visual orienting, whereas equivalent damage incurred shortly after birth pro128
duces substantially less severe deficits on these same tasks u-15. When the bilateral lesions include most of the contiguous areas comprising extrastriate visual cortex, in addition to the primary visual cortex, lesions incurred in infancy and at maturity are equally and profoundly debilitating 14. Moreover, following early lesions of the primary visual cortex, neurons in extrastriate cortex have receptive-field properties very similar to those of neurons in intact cats, and neuronal responsiveness is high :32':~:~.We believe that the expansion of projections from the C complex of the LGN and from LP nuclei into extrastriate cortex, described earlier, contribute to spared neuronal operations in extrastriate cortex. In contrast, damage of mature primary visual cortex lowers neuronal responsiveness and reduces or eliminates the directional and binocular specificity normally evident in receptive fields of extrastriate neurons 32':~:~. Similar age-dependent changes in the levels of neuronal responsiveness are evident in the superficial grey layer of the superior colliculus34, and they are accompanied by an expansion of projections from extrastriate cortex into the superficial grey layer. We also conclude that the spared neuronal operations evident in extrastriate cortex and the superior colliculus are related to the sparing of orienting abilities that accompany damage of the primary visual cortex in infancy. This is supported by four observations. (1) At least for the binocular visual field, the performance of cats with bilateral lesions of the primary visual cortex incurred in infancy approaches that of intact cats at orienting to novel stimuli 14. (2) Orienting performance is poor even in the binocular field if the lesions of the primary visual cortex are incurred in adulthood 14. (3) Orienting performance is even poorer if the lesions include extrastriate cortex in addition to the primary areas, and this is regardless of maturational status at the time the lesion is incurred u. (4) Both extrastriate cortex and the superior colliculus make substantial contributions to orienting behavior in cats with an intact primary visual cortex :~5':~6. It is likely that the robust neural operations in extrastriate cortex, and particularly in the superior colliculus, contribute greatly to the relatively accurate orienting performance in cats that incurred damage of the primary visual cortex in infancy. Comparable adjustments might occur elsewhere in the cortex and in other subcortical structures, and they are likely to be linked to the sparing of other visually guided behaviors mentioned earlier. In future studies, it will be important to ascertain the specific contributions the different extrastriate and subcortical regions make to the spared behaviors.
Comparisons with other mammals including primates Information on the anatomical, physiological and behavioral repercussions of damage to the immature primary visual cortex in a variety of other mammals, including primates, is fragmentary but consistent with the observations made for the cat. For example, removal of immature primary visual cortex from rats, hamsters, rabbits and ferrets causes the almost complete collapse of the LGN (Refs 37-41). However, only in ferrets is there evidence for degeneration of TINS, Vol. 17, No. 3, 1994
retinal ganglion cells as a consequence of neuron death in the LGN (Ref. 41). In this species, like cats, there are [3 ganglion cells that LGN ~ SC/Pt form a pathway dedicated to the ~ ~ transmission of signals to the cortex 4~ and presumably it is the 6 (i) ganglion cells that die following the early lesion. In rats and rabbits, there are no dedicated pathways to the cortex 43'44 and all retinal (ii) ganglion cells survive early lesions 9O% 10% of visual cortex 45'46. These ganglion cells have many features in com43% 57% mon with the o~and y ganglion cells 100% that survive early lesions of the (iii) primary visual cortex in cats 2t. \ I ~. As in cats, damage of visual cortex in immature ferrets and hamsters induces some retinal axons to innervate targets in the thalamus outside of the degenerated LGN (Refs 1:~ 41, 47 and 48), and induces some LP neurons to innervate new targets in the cortex 39, but only if there is additional damage to the immature midbrain. Descending projections from extrastriate cortex to the superior colliculus also expand following damage of the primary visual cortex early in life49-51 in rodents, as well as in cats. Following lesions of the primary visual cortex in adulthood, rats and rabbits retain some proficiency at recognizing patterns 52-5a, and it is known that in rats the proficiency is greater following equivalent lesions early in life52'5:~. In addition, extension of the lesions to encompass the entire set of rat Fig. 3. (A) Normal projections of classes of retinal ganglion cells. (i) Patterns of projections of o:, fi cortical visual areas results in pro- and ? cells to the lateral geniculate nucleus (LGN) and to the superior colliculus and pretectum; (ii) found defects in pattern vision, morphology of m [3 and 7 cells (modified from Ref. 24); and (iii) as ~, /3 and 7 cells appear following regardless of the age at which the application of HRP to the LGN. (B) Retinal ganglion cells in intact cats and after removal of areas 17 lesions are incurred 56'57. These and 18. Drawings of retina/ganglion cells identified to project into the LGN in intact cats and observations imply that the sparing following damage of areas 17and 18. Part B modified and reproduced with the permission of the of vision that follows infant lesions Royal Society. of the primary visual cortex, involves adjacent visual cortical areas, a conclusion also quite accurately with arm movements if the velocity reached from similar studies in cats. was rapid enougha, and he could discriminate between Much less is known about the consequences of opposite directions of movement and between targets early visual-cortex lesions in primates, but what is moving at different speeds 63. As in cats, extrastriate known is consistent with the information obtained cortex is likely to contribute to these abilities befrom cats. For example, removal of the primary visual cause the behaviors are superior to those in patients cortex from infant monkeys and humans causes who have undergone removal of all cortical visual massive death of neurons of the LGN, and selective areas 64-66. These findings suggest that similar trans-synaptic retrograde degeneration of large anatomical adjustments to those described for the cat numbers of ~ retinal ganglion cells 5s-60. Nevertheless, and other species occur in the monkey and human the infant-operated monkey shows impressive visual following early damage of visual cortex. capacities 61"62 - a level of competence substantially higher than that seen in monkeys with comparable Therapeutic strategies lesions incurred in adulthood5,6~. Limited evidence Studies of restricted cortical lesions in other also suggests that sparing of visual functions in cortical systems also point to widespread anatomical humans is greater following early lesions of the visual and behavioral repercussions. They suggest that cortex 3'63. For example, patient G.Y., who sustained several factors, including age at the time the lesion damage to the striate cortex when he was eight years is incurred, subsequent experience, and gender, old 63, was able to follow the path of a moving spot might play substantial roles in modifying the final
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consequences of the lesion 67. Moreover, they indicate that multiple therapeutic strategies might need to be adopted to attenuate defects. Potentially useful strategies include special behavioral training programs, as well as pharmacological or biological treatments. For example, in humans, practice at localizing stimuli within the scotoma improves accuracy68'69; in cats with lesions of the visual cortex, treatment with amphetamine attenuates the defects in depth discriminationT°; and following visual cortical lesions in rats, transplants of embryonic visual cortex or of extracts of embryonic visual cortex can slow the retrograde degeneration of LGN neurons 71'72. Moreover, instances in which the cortex might need to be removed surgically could benefit from procedures carried out in two or more stages. Multistage procedures afford a greater level of functional sparing compared with removals made in one stage 12, presumably by allowing the tissue remaining at each stage to contribute to compensatory adjustments that are not possible following large, single-stage removals. We hope that similar strategies can be used to enhance the modification of pathways, slow the degeneration of neurons and boost the faculties spared subsequent to lesions of the immature visual cortex. Successful strategies might also yield information valuable to the treatment of early damage incurred by any of the numerous other cortical systems in human infants.
Selected references
Acknowledgements Theauthors'research work wassupported by grants from the National Institutes of Health and the National Institute of Mental Health. We thank the TINS reviewers for their he/pfu/ commentson earlier versionsof the manuscnpt, We also thank Claire5ethares for her assistancewith the figures. 130
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System-wide repercussions of damage to the immature visual cottex Bet-tram R. Payne and Paul Cornwell Be&am R. Payne is at the Dept of Anatomy and Neurobiology, Boston University School of Medicine, 80 EastConcord
Street, Boston, MA 02118,USA, and Paul Cornwellisatthe Dept of Psychology 130 Moore Building, The Pennsylvania State Univefsity, UniversQ Park, PA 16802, USA.
Damage of the primary visual cortex in mammals, including humans, severely disrupts vision @ disconnecting much of the cognitive-processing machinery of extrastriate cortex from its source of visual signals in the retina. Studies of’the anatomical consequences of damage to the immature primary visual cortex in cats reveal system-wide r@ercussions on neural circuitry that includes the retina, thalamus, midbrain and extrastriate cortex. The repercussions modify circuits that support relatively normal s&nal processing and the sparing of certain visually guided behaviors such as aspects of complex-pattern recognition and orienting to novel stimuli introduced into the visual field. These studies have implications for understanding the consequences of damage to the visual cortex in infant monkeys and humans, and for devising therapeutic strategies to attenuate defects in vision induced by cortical lesions. In humans, monkeys and cats, the primary visual cortex is the largest cerebral cortical area, and it is the major gateway to the cortical visual system. It has long been recognized that damage of the primary
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visual cortex severely disrupts vision, although it is now clear that certain functions such as flux and crude-pattern recognition remain after the damage’-5. The severity of the deficits are understandable because a lesion in the primary visual cortex disconnects the cognitive-processing machinery of extrastriate cortex and the parietal and temporal regions from the vast majority of visual signals ascending from the eye through the lateral geniculate nucleus (LGN). This can be seen by comparing Figs 1A and lB, which show the layout of the visual system in intact cats, and following the ablation of the primary visual cortical areas 17 and 18 in adulthood. However, there are alternative routes for visual signals to reach extrastriate cortex, which bypass the primary visual areas. One of these routes is minor and comprises a weak projection from the C complex of the LGN directly to parts of extrastriate cortex6. The major alternative pathway involves relays through the midbrain (superior colliculus and pretectum), and the lateral posterior (LP), pulvinar and lateral geniculate nuclei of the thalamu&‘. Visual signals passing along these alternative routes can alone activate neurons in TINS
at least some extrastriate areas ~° and they are probably responsible for the limited visual abilities that remain in the absence of the primary visual cortex. In contrast, following the lesions of areas 17 and 18 early in postnatal life (Fig. 1C), the visual system develops differently and the functional consequences of the lesions are much less disruptive to behavior 1H5. These differences include the expansion of pathways leading into and out of extrastriate cortex, and some of the changes are likely to contribute to the expression of the less disrupted behaviors. These outcomes of early lesions in cats have implications for understanding the consequences of early visual cortical damage in primates, including humans species for which detailed information is extremely limited. This transfer of knowledge is feasible because of the broad similarity between cats and primates in (1) the organization and function of the visual system in visually guided behavior 16, and (2) the components and execution of the developmental program, albeit that the primate program is extended over a longer timescale 17'1s. Moreover, the knowledge might be useful in a general way for understanding the effects of damage elsewhere in the immature cerebrum on neural function, and for developing therapeutic strategies to ameliorate cortical lesion-induced deficits.
Anatomicalrepercussions ofearlylesions
The anatomical repercussions of lesions of immature primary visual cortex in cats are numerous and widespread, and include regressive and progressive modifications (Fig. 1C). They encompass selective death of neurons within circuits dedicated to signal processing in areas 17 and 18, as well as expansions of pathways that bypass these two areas and that lead either into or out of extrastriate cortex. Neuron degeneration. Neurons forming major components in ascending circuits are particularly sensitive to damage incurred in infancy of their target areas 17 and 18. In the immature LGN, large numbers of neurons in layers A and A1, which normally project exclusively to areas 17 and 18 (Ref. 17), die as a result of the lesion 19, and that portion of the nucleus all but disintegrates (Fig. 2A). However, a number of neurons in the C complex, which normally form a more direct pathway for visual signals to reach extrastriate cortex 17, are unaffected by the lesion and survive 19. Moreover, the overwhelming majority of immature [~ retinal ganglion cells, which project exclusively to the severely degenerated layers A and A1 of the LGN (Ref. 20), die 21-23 (Figs 3A and 3B), whereas all o~ and y ganglion cells, which send substantial projections to targets outside of layers A and A1 (Ref. 20), survive ~1-22 (Figs 3A and 3B). A similar age-dependent sensitivity to damage of the primary visual cortex is exhibited by neurons in extrastriate visual cortex 25. For example, immature neurons in layers III and VI of the middle suprasylvian cortex die when they are axotomized (or deprived of target neurons, or both) by the removal of areas 17 and 18. This differential laminar vulnerability reflects the origin of efferent axons in extrastriate cortex that project to primary visual cortex in mature cats 25. Like mature [3 retinal ganglion cells, mature neurons in extrastriate cortex are resistant to damage of areas 17 and 18. TINS, Vol. 17, No. 3, 1994
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Fig. 1. Ascending and descending visual pathways associated with extrastriate cortex in the cat. (A) Intact cats. (B) Following ablation of primary visual cortical areas 17 and 18 in mature cats. (C) Following ablation of the primary visual cortex in newborn cats. Neurons in layers A and A1 project solely to primary visual cortical areas 17 and 18, whereas neurons in the C complex send weak projections to areas 17 and 18 and to the numerous areas comprising extrastriate cortex. The width of the arrows reflects the size of projections within a single processing tier. The greater size of projections might be because more neurons participate in the pathway or because axons in the pathway branch. In either case, there is a greater traffic in visual signals. Also, in (A) note the progressive amplification (not shown to scale) in the pathways through the lateral geniculate nucleus (LGN) and the primary visual cortex to extrastriate cortex. Abbreviations: A and A 1, layers A and A 1; C, C complex comprising layers C, C1-3; SC, superior colliculus; Pt, pretectum; LP, lateral posterior nucleus; Pul, Pulvinar nucleus; SGS, stratum griseum superficiale; SO, stratum opticum; I and D, intermediate and deep layers.
Pathway expansions. In several cases, pathways associated with extrastriate cortex expand following lesions of immature areas 17 and 18. As summarized in Fig. 1C, retinal projections to the C complex ~9'21 (Fig. 2C) and the wing 26 of the LGN increase in density, and novel projections to the LP complex might develop 27. In addition, the normally weak C-complex projections to extrastriate cortex increase 127
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Fig. 2. (A) and (B) Lightfield photomicrographs of the lateral geniculate nucleus (LGN) in an adult cat following unilateral ablation of primary visual cortical areas 17and 18 on the day of birth. (A) The LGN ipsilateral to cortical ablation. (B) The LGN ipsilateral to intact cortex. (C) and (D) Darkfield photomicrographs of the same sections shown in A and B to show the distribution of tritiated amino acids injected into the eye. (C) Ipsilateral projections. (D) Contralateral projections, Layers A and A 1, and the C complex are indicated. Note some large surviving neurons in the partially degenerated C complex (c; arrow), and reduced retinal inputs to degenerated layers A and A 1 and the increased density of inputs to the partially degenerated C complex. Abbreviations: d, severely degenerated layers A and A 1; n, normal tail of LGN that is connected to an intact, caudal portion of areas 17 and 18. Modified and reproduced with the permission of the Royal Society.
several fold and a normally ephemeral projection from the layers A and A1 is permanently established 2~'29. Furthermore, an increased fraction of neurons in the collicular recipient part of the LP nucleus projects to extrastriate cortex 2'. Moreover, descending extrastriate projections into the stratum opticum of the superior coUiculus expand and heavily innervate the superficial grey layer of the superior colliculus:~°. Lastly, transcortical projections from the posterior suprasylvian cortex to the middle suprasylvian region also expand following damage of immature areas 17 and 18 (Ref. 31). (For simplicity, this latter pathway is not illustrated in Fig. 1.) All of these pathway expansions increase the carrying capacity for visual signals to extrastriate cortex and to the superior colliculus, and, since the superior colliculus sends substantial projections to the LP nucleus, descending cortical signals reaching the superior colliculus can re-enter extrastriate cortex and contribute further to visual processing. It is important to note that equivalent expansions do not accompany damage of the mature areas 17 and 18 (Fig. 1B).
Behavioral and physiological repercussions Behavioral and electrophysiological studies implicate extrastriate cortex in the spared visual capacities following damage of primary visual cortex in immature cats. Bilateral removal of the primary visual cortex from mature cats induces moderate to severe deficits in pattern discrimination, depth perception, optokinetic nystagmus and visual orienting, whereas equivalent damage incurred shortly after birth pro128
duces substantially less severe deficits on these same tasks u-15. When the bilateral lesions include most of the contiguous areas comprising extrastriate visual cortex, in addition to the primary visual cortex, lesions incurred in infancy and at maturity are equally and profoundly debilitating 14. Moreover, following early lesions of the primary visual cortex, neurons in extrastriate cortex have receptive-field properties very similar to those of neurons in intact cats, and neuronal responsiveness is high :32':~:~.We believe that the expansion of projections from the C complex of the LGN and from LP nuclei into extrastriate cortex, described earlier, contribute to spared neuronal operations in extrastriate cortex. In contrast, damage of mature primary visual cortex lowers neuronal responsiveness and reduces or eliminates the directional and binocular specificity normally evident in receptive fields of extrastriate neurons 32':~:~. Similar age-dependent changes in the levels of neuronal responsiveness are evident in the superficial grey layer of the superior colliculus34, and they are accompanied by an expansion of projections from extrastriate cortex into the superficial grey layer. We also conclude that the spared neuronal operations evident in extrastriate cortex and the superior colliculus are related to the sparing of orienting abilities that accompany damage of the primary visual cortex in infancy. This is supported by four observations. (1) At least for the binocular visual field, the performance of cats with bilateral lesions of the primary visual cortex incurred in infancy approaches that of intact cats at orienting to novel stimuli 14. (2) Orienting performance is poor even in the binocular field if the lesions of the primary visual cortex are incurred in adulthood 14. (3) Orienting performance is even poorer if the lesions include extrastriate cortex in addition to the primary areas, and this is regardless of maturational status at the time the lesion is incurred u. (4) Both extrastriate cortex and the superior colliculus make substantial contributions to orienting behavior in cats with an intact primary visual cortex :~5':~6. It is likely that the robust neural operations in extrastriate cortex, and particularly in the superior colliculus, contribute greatly to the relatively accurate orienting performance in cats that incurred damage of the primary visual cortex in infancy. Comparable adjustments might occur elsewhere in the cortex and in other subcortical structures, and they are likely to be linked to the sparing of other visually guided behaviors mentioned earlier. In future studies, it will be important to ascertain the specific contributions the different extrastriate and subcortical regions make to the spared behaviors.
Comparisons with other mammals including primates Information on the anatomical, physiological and behavioral repercussions of damage to the immature primary visual cortex in a variety of other mammals, including primates, is fragmentary but consistent with the observations made for the cat. For example, removal of immature primary visual cortex from rats, hamsters, rabbits and ferrets causes the almost complete collapse of the LGN (Refs 37-41). However, only in ferrets is there evidence for degeneration of TINS, Vol. 17, No. 3, 1994
retinal ganglion cells as a consequence of neuron death in the LGN (Ref. 41). In this species, like cats, there are [3 ganglion cells that LGN ~ SC/Pt form a pathway dedicated to the ~ ~ transmission of signals to the cortex 4~ and presumably it is the 6 (i) ganglion cells that die following the early lesion. In rats and rabbits, there are no dedicated pathways to the cortex 43'44 and all retinal (ii) ganglion cells survive early lesions 9O% 10% of visual cortex 45'46. These ganglion cells have many features in com43% 57% mon with the o~and y ganglion cells 100% that survive early lesions of the (iii) primary visual cortex in cats 2t. \ I ~. As in cats, damage of visual cortex in immature ferrets and hamsters induces some retinal axons to innervate targets in the thalamus outside of the degenerated LGN (Refs 1:~ 41, 47 and 48), and induces some LP neurons to innervate new targets in the cortex 39, but only if there is additional damage to the immature midbrain. Descending projections from extrastriate cortex to the superior colliculus also expand following damage of the primary visual cortex early in life49-51 in rodents, as well as in cats. Following lesions of the primary visual cortex in adulthood, rats and rabbits retain some proficiency at recognizing patterns 52-5a, and it is known that in rats the proficiency is greater following equivalent lesions early in life52'5:~. In addition, extension of the lesions to encompass the entire set of rat Fig. 3. (A) Normal projections of classes of retinal ganglion cells. (i) Patterns of projections of o:, fi cortical visual areas results in pro- and ? cells to the lateral geniculate nucleus (LGN) and to the superior colliculus and pretectum; (ii) found defects in pattern vision, morphology of m [3 and 7 cells (modified from Ref. 24); and (iii) as ~, /3 and 7 cells appear following regardless of the age at which the application of HRP to the LGN. (B) Retinal ganglion cells in intact cats and after removal of areas 17 lesions are incurred 56'57. These and 18. Drawings of retina/ganglion cells identified to project into the LGN in intact cats and observations imply that the sparing following damage of areas 17and 18. Part B modified and reproduced with the permission of the of vision that follows infant lesions Royal Society. of the primary visual cortex, involves adjacent visual cortical areas, a conclusion also quite accurately with arm movements if the velocity reached from similar studies in cats. was rapid enougha, and he could discriminate between Much less is known about the consequences of opposite directions of movement and between targets early visual-cortex lesions in primates, but what is moving at different speeds 63. As in cats, extrastriate known is consistent with the information obtained cortex is likely to contribute to these abilities befrom cats. For example, removal of the primary visual cause the behaviors are superior to those in patients cortex from infant monkeys and humans causes who have undergone removal of all cortical visual massive death of neurons of the LGN, and selective areas 64-66. These findings suggest that similar trans-synaptic retrograde degeneration of large anatomical adjustments to those described for the cat numbers of ~ retinal ganglion cells 5s-60. Nevertheless, and other species occur in the monkey and human the infant-operated monkey shows impressive visual following early damage of visual cortex. capacities 61"62 - a level of competence substantially higher than that seen in monkeys with comparable Therapeutic strategies lesions incurred in adulthood5,6~. Limited evidence Studies of restricted cortical lesions in other also suggests that sparing of visual functions in cortical systems also point to widespread anatomical humans is greater following early lesions of the visual and behavioral repercussions. They suggest that cortex 3'63. For example, patient G.Y., who sustained several factors, including age at the time the lesion damage to the striate cortex when he was eight years is incurred, subsequent experience, and gender, old 63, was able to follow the path of a moving spot might play substantial roles in modifying the final
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consequences of the lesion 67. Moreover, they indicate that multiple therapeutic strategies might need to be adopted to attenuate defects. Potentially useful strategies include special behavioral training programs, as well as pharmacological or biological treatments. For example, in humans, practice at localizing stimuli within the scotoma improves accuracy68'69; in cats with lesions of the visual cortex, treatment with amphetamine attenuates the defects in depth discriminationT°; and following visual cortical lesions in rats, transplants of embryonic visual cortex or of extracts of embryonic visual cortex can slow the retrograde degeneration of LGN neurons 71'72. Moreover, instances in which the cortex might need to be removed surgically could benefit from procedures carried out in two or more stages. Multistage procedures afford a greater level of functional sparing compared with removals made in one stage 12, presumably by allowing the tissue remaining at each stage to contribute to compensatory adjustments that are not possible following large, single-stage removals. We hope that similar strategies can be used to enhance the modification of pathways, slow the degeneration of neurons and boost the faculties spared subsequent to lesions of the immature visual cortex. Successful strategies might also yield information valuable to the treatment of early damage incurred by any of the numerous other cortical systems in human infants.
Selected references
Acknowledgements Theauthors'research work wassupported by grants from the National Institutes of Health and the National Institute of Mental Health. We thank the TINS reviewers for their he/pfu/ commentson earlier versionsof the manuscnpt, We also thank Claire5ethares for her assistancewith the figures. 130
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