Evidence for greater sight in blindsight following damage of primary visual cortex early in life

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Pergamon

0028 3932(95)00161 1

Neuropsychologia,Vol. 34, No. 8, pp. 741 774, 1996 Copyright ~' 1996 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0028--3932/96 $15.00+0.00

Perspective Evidence for greater sight in blindsight following damage of primary visual cortex early in life BERTRAM R. PAYNE,* STEPHEN G. LOMBER, MARGARET A. MACNEIL and PAUL CORNWELL~ Laboratory of Visual Perception and Cognition, Center for Advanced Biomedical Research, Boston University School of Medicine, 700 Albany Street, Boston MA 02118, U.S.A.; talso at Department of Psychology, 130 Moore Building, The Pennsylvania State University, University Park, Pennsylvania, 16802, U.S.A. (Receired 16 June 1995; accepted 7 October 1995)

Abstract--This review compares the behavioral, physiological and anatomical repercussions of lesions of primary visual cortex incurred by developing and mature humans, monkey and cats. Comparison of the data on the repercussions following lesions incurred earlier or later in life suggests that earlier, but not later, damage unmasks a latent flexibility of the brain to compensate partially for functions normally attributed to the damaged cortex. The compensations are best documented in the cat and they can be linked to system-wide repercussions that include selected pathway expansions and neuron degenerations, and functional adjustments in neuronal activity. Even though evidence from humans and monkeys is extremely limited, it is argued on the basis of known repercussions and similarity of visual system organization and developmental sequence, that broadly equivalent repercussions most likely occur in humans and monkeys following early lesions of primary visual cortex. The extant data suggest potentially useful directions for future investigations on functional anatomical aspects of visual capacities spared in human patients and monkeys following'early damage of primary visual cortex. Such research is likely to have a substantial impact on increasing our understanding of the repercussions that result from damage elsewhere in the developing cerebral cortex and it is likely to contribute to our understanding of the remarkable ability of the human brain to adapt to insults. Copyright © 1996 Elsevier Science Ltd. Key Words: brain damage; rewiring; degeneration; functional compensations; human; monkey; cat.

Introduction

flux [10]; detection of stationary targets [263], motion [8]; detection and discrimination of velocity [11, 193], direction of motion [10, 193, 199, 309], apparent motion [29], optic flow [155], spatial orientation and the resolution of spatial structure [10, 306-308, 316]; low grade stereopsis [215]; completion of illusory shapes [305]; tilt after-effect [203]; semantic priming and cognition [150, 152, 239]; spatial and temporal summation and inhibition, between seeing and 'blind' hemifields [51, 152, 212, 261, 280]; and sensitivity to chromatic signals [35, 258, 262, 264~266]. Moreover, saccades can be made to loci within the scotomas, but they are somewhat inaccurate [197, 205, 316, 328, 329], although they can improve with practice [36, 328, 330, 331]. Despite this long list of visual capacities, the patients are clearly unaware and mute about what their visual systems are apparently capable of processing. Furthermore, the accuracy and sensitivity mediated by their residual circuits is well below that of an intact visual system. Under similar testing situations, both monkeys and

'Blindsight' is a wonderful oxymoron that accurately describes the visual defects and residual capacities of humans who have incurred destruction of primary visual cortex [316]. The residual capacities are based on the remaining visual pathways and include extrastriate cortex and they may be substantially greater if striate damage occurs early in life. The defect is characterized by no conscious experience and the residual capacities can only be revealed by forced-choice testing methods that require eye or hand movements to signal responses. Under these testing conditions, cortically blind patients are highly proficient at a wide variety of visual tasks: detection and localization of flashes and flickering lights [197, 199] and *Address for correspondence: Laboratory of Visual Perception and Cognition, Center for Advanced Biomedical Research, Boston University School of Medicine, Boston, MA 02118, U.S.A.; Fax: 617-638-4102. 741

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cats with damage to primary visual cortex also show residual visual capacities 1 [monkey: e.g. 71, 74, 81, 112114, 121,122, 138, 158, 178-181,232, 245, 304, 312, 313; cat:e.g. 18, 19,52 54,56,60,77, 110, 176, 177, 182, 183, 289]. Moreover, specific tests for blindsight in monkeys have yielded positive results [63, 167]. We will use this similarity to draw on knowledge gained primarily from cats and monkeys to describe the pathways most likely contributing to blindsight and to show that damage of primary visual cortex induces repercussions that reverberate throughout the visual system. We will review the data on cats and show that damage of primary visual cortex early in life results in a broad rewiring of the visual system, which results in neuronal compensations and in the sparing of certain classes of visually guided behaviors that do not occur following equivalent damage sustained in adulthood. We will also review the more limited data on monkeys and humans and suggest that damage to primary visual cortex in infancy or childhood may result in broadly similar adjustments to those identified in cats. The implication is that patients who incur damage early in life, when the brain is still developing and maturing, may have greater visual capacities than patients who incur equivalent damage in adulthood, when the brain is mature. Thus, patients who incurred their damage early in life may have more 'sight' in their 'blindsight' than patients who sustain similar damage later. Moreover, this 'sight' may have a perceptual or conscious component that can be linked to the strengthening of certain pathways. Following on from Weiskrantz et al. [311] and for convenience, we divide the visual capacities after lesions of primary visual cortex (or other brain regions for that matter) into three main categories: (a) Residual vision describes the visual capacities that remain after lesions. (b) Recovered vision describes the visual capacities that remain after lesions if these capacities emerged from and are superior to residual vision. Recovery is rarely complete. (c) Spared vision describes the visual capacities that are present after lesions incurred in the earlier part of life before faculties have fully matured. Spared vision is always greater than both residual and recovered vision and results from altered development of the visual system. Implicit in spared vision is the notion of altered central nervous system (CNS) connections. These alterations may include one or more of the following: (i) redirection of pathways to novel targets; (ii) expansion of existing pathways; (iii) retention of ephemeral pathways; and (iv) increased number and/or efficacy of synapses. Commensurate with these increases, and possibly an important component of the sparing, is the elimination of

~From a historical perspective it should be noted that much of the monkey work preceeded the modern human work on the consequences of striate lesions on visual capacities. Moreover, the methods used by Humphrey [112-114] on monkeys were instrumental in revealing many of the characteristics of human blindsight.

poorly connected neurons. All three types of vision after lesions may utilize pathways little used in the normal brain. 2 As will be seen, extrastriate cortex in adult humans, monkeys and cats plays a substantial role in blindsight 3 and other visual capacities that remain following damage of primary visual cortex. Moreover, extrastriate cortex contributes significantly to the visually-guided behaviors of cats that are spared following damage of primary visual cortex early in the postnatal life of the cat. Thus, we start the review by implicating extrastriate cortex in human blindsight, and supporting that implication with anatomical and electrophysiological data obtained from monkeys. However, it will become apparent that not all human patients experience similar degrees of blindsight; some have more 'sight' than others and we will proffer that the differences in visual function can be linked in an important way to the age at which the damage of primary visual cortex was sustained. Of course, we acknowledge that variable direct or indirect involvement ofextrastriate visual regions may also contribute to the variation in residual and spared capacities. But when all other factors are equated, we suggest that maturational status is an important factor determining an individual's response to cortical damage and that damage sustained early in life unmasks a latent flexibility of the human brain to compensate partially for functions normally attributed to the damaged cortex. Similar conclusions have been reached from studies on cats, where much more substantive 2Relatively speaking, residual vision is straightforward to understand: it depends on residual pathways. Blindsight falls within this category when residual vision is unconscious and results from lesions incurred in adulthood. The basis for recovered vision is more obscure, particularly when it occurs spontaneously many years after the damage was incurred (e.g. patient D.B. spontaneously regained vision in much of his upper left quadrant after 3 years of a dense hemianopsia following removal of all, or a major part, of his right striate cortex [306]). In some instances training or use contributes to recovery [328, 331]. The basis of spared vision is also poorly understood, but what is known forms the basis for much of the current review. Depending upon the age at which the damage was incurred, the three types of vision contribute to the final visual capacities in different ways and different amounts. However, in general terms, it is likely that within limits, spared vision is the dominant form following early visual cortical damage; recovered vision with little sparing characterizes the outcome of lesions incurred during middle years; and residual vision most likely characterizes the outcome of lesions in later years, when practice is likely to have less of an impact and recovery is likely to be limited. Following lesions of striate cortex, residual and recovered vision is without awareness, whereas spared vision may have both conscious and subconscious components in humans. 3It should be acknowledged that Fendrich et al. [83] provide evidence that residual vision in humans may be related to residual fragments of striate cortex. This is an important point that needs to be considered in any examination of patients with damage of striate cortex. Stoerig [260] and Weiskrantz [310] acknowledge the importance of accurate assessments of lesions. However, they reason that such fragments cannot account for residual vision in all patients that have been studied, especially those whose brains have been imaged at high resolution.

B. R. Payne et al./Early brain damage behavioral, anatomical and physiological data are available. Towards the end of the article, we discuss the few known repercussions of late and early cortical damage in monkeys and humans, that parallel the sequelae identified in cats. From there it may be possible to speculate on useful future directions that will contribute substantially to our understanding of the aftermath of early damage of primary visual cortex in the immature visual system of humans. Such research is likely to have a substantial impact on increasing our understanding of the repercussions that result from damage elsewhere in the developing cerebral cortex and more specifically, the adjustments immature neurons are able to make and the remarkable ability of the human brain to adapt to insults.

1. Role of extrastriate cortex and visual pathways in blindsight

Extrastriate cortical regions that remain following lesions of primary visual cortices contribute greatly to the residual visual capacities of humans. The primary evidence for this is derived from a comparison of patients with acquired lesions of primary visual cortex and patients who have undergone surgical hemidecortication or hemispherectomy [294]. Both groups of patients suffer from a dense hemianopia, but patients with lesions largely restricted to primary visual cortex are sensitive to wavelength and are able, within limits, to detect, localize or discriminate high contrast, flashed or flickering stationary stimuli or a variety of moving stimuli (see Introduction) whereas hemidecorticated and hemispherectomized patients cannot [131, 196,207,208, 259]. Moreover, visual evoked potentials can be evoked from the extrastriate cortex of patients with primary visual cortex lesions [49, 239]. Even in the light of these data, it is important to acknowledge that a component of the substantial deficits induced by hemidecortication or hemispherectomy may be the massive anterograde and retrograde degeneration induced in the thalamus, midbrain and elsewhere [285], which is much less severe following damage of primary visual cortex alone [e.g. 103, 204, 290-292]. Lesions in monkeys, which extend beyond primary visual cortex into extrastriate cortex, also degrade visual capacities below those remaining following lesions of area VI alone [71, 179]. Supporting evidence for a role of extrastriate cortex in mediating aspects of blindsight is provided by pathway tracing experiments carried out on monkeys. These studies demonstrate pathways that bypass either visual area V1 or dorsal lateral geniculate nucleus (dLGN) and transfer visual signals to numerous parts of extrastriate cortex. These pathways include: (a) A relay of retinal signals directly from dLGN to cortical areas V2, V4, TEO, TE and to the V3 and V5 areal complexes. These projections arise primarily from the

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interlaminar zones and 'S' layers of dLGN [17, 41, 90, 109a, 123, 146, 251,301,323]; (b) A direct relay of retinal signals via the retinal recipient part of the pulvinar to extrastriate [64, 116, 162, 163, t73]; (c) An indirect relay of retinal signals through the midbrain and either the interlaminar zones and 'S' layers of dLGN or more medial parts of the thalamus to extrastriate cortex [7, 16, 31,251,300]. All three pathways are likely to contribute to residual extrastriate function in one way or another. Moreover, at least one, and possibly all three, pathways are present in the human brain and there is evidence that one or more of these pathways can transmit motion signals to area V5 at the same time or in advance of signals transmitted through area VI [15, 85, 86] as they do in the monkey [213]. We suspect that the most likely candidate for this fast pathway to area V5 involves the magnocellular layers of dLGN. In normal vision, this pathway may play a priming role. It is perhaps the interaction of the priming signal with signals arriving over other routes which fosters conscious experience. Moreover, the pathway involving area V5 may be capable of triggering eye movements [234]. We will return to the pathway later in this paper to discuss its possible role in spared human vision. The importance of the combined bypass pathways has been demonstrated in monkeys by electrophysiological techniques which show that during either temporary or permanent inactivation of primary visual cortex, significant numbers of neurons in extrastriate cortex remain visually active [40, 231]. So far, the strongest residual activity has been identified in visual areas V3A and V5 and in superior temporal polysensory area (STP): areas where substantial numbers of neurons remain active, although the levels of activity and stimulus selectivity are less than normal [37, 40, 94, 97, 221,222]. Moreover, it is likely that nearby areas MST, FST, POa and PGc remain visually active because they have rich connections with areas V5 and STP [2, 6, 32, 48, 169, 287]. These areas comprise part of the occipitoparietal visual system and contribute strongly to analyses of motion, spatial vision and action [12, 73, 159, 288,326,327]. The residual activity in area V3A may be linked to the preserved orientation and form discrimination [74, 179, 232, 307] and the residual activity in area V5 may be linked to the residual movement detection and discrimination abilities [11, 12, 29, 306, 316] identified in monkeys and humans with damaged primary visual cortex. Both the direct projection from dLGN and the transcollicular routes to extrastriate cortex are essential for the residual activity in extrastriate cortex of monkeys following damage of primary visual cortex. The evidence is provided by combined lesions of both the superior colliculus and primary visual cortex which abolish the activity in areas V5 and STP [37, 97, 222]. Moreover, the same combination of lesions prevents saccades to visual targets presented in the cortical scotoma [164] and the localization of objects [245]. In addition, the pathway through dLGN to extrastriate cortex also transmits sig-

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nals critical for saccadic eye movements because monkeys with dLGN lesions involving all layers are unable to saccade to near threshold stimuli presented within field defects even though primary visual cortex and superior colliculus are intact and collicular receptive fields are still present [237]. This result implies that the pathways from dLGN to extrastriate cortex also contributes in important ways to the residual capacities in the absence of primary visual cortex. The importance of the direct dLGN projections to extrastriate cortex may have been underestimated. For example, blockade of activity in the magnocellular layers of dLGN can silence neurons in area V5 on its own [84, 153]. This is surprising because lesions or cooling inactivation of area V1 leave the majority" of V5 neurons responsive [95, 221]. Since the major output of the magnocellular layers reaches area V5 via area V1, how are these different results explained? One possibility is that the blockade of the magnocellular layers, in addition to suppressing neuronal responses in area V1 [149, 174] also interferes with the transmission of signals from the superior colliculus via dLGN to area V5. This occurs either directly or via spread of the blocking agents to the interlaminar zone neurons and to the underlying 'S' layers of dLGN, which are the major participants in the colliculo-geniculo-extrastriate projection [17, 90, 106]. An equally likely interpretation, based upon the early activation of V5 neurons [213], is that the magnocellular blockade eliminates a priming input to area V5, which is essential for the activation of V5 neurons by signals arriving along other pathways. It is evident in humans and monkeys, that the residual signals reaching extrastriate visual cortex traverse parietal cortices to reach frontal cortices and the voluntary motor system. These circuits are likely to guide hand and eye movements and may explain why pointing and eye movement methods of reporting are methods for demonstrating residual vision in the absence of conscious experience [159, 205, 306, 316]. These regions most likely contribute little to conscious experience and we hypothesize that the absence of conscious experience in most blindsight patients stems from the visual cortical lesion disrupting the normal functioning of important regions in the temporal visual system. Despite the presence of direct pathways that transmit sufficient visual signals to activate neurons in areas V3A, V5 and STP in the absence of area V1, neurons in areas V2, V3, V4, TEO and TE, in the anesthetized monkey, remain largely silent following inactivation of area V1 [92-94, 97, 219, 236]. Areas V4, TEO and TE comprise the occipitotemporal visual system which is associated primarily with color vision and form recognition and has close links to the signals transmitted through the parvocellular layers of dLGN [73, 84, 233,235,286, 324, 325, 327]. Silencing the temporal regions may also occur in humans and it may be linked to the absence of awareness and an inability in humans to experience and verbally characterize the visual signals that are processed by

other signal streams traversing regions of parietal and frontal cortices. Nevertheless, it is important to recognize that there is substantial variation in the blindsight abilities and that a subgroup of patients reveal awareness of visual stimuli while most blindsight patients do not [311]. This variation and the presence or absence of awareness can be linked to the age at which the primary visual cortex was damaged.

2. Age at lesion Despite broadly similar types of lesions, not all blindsight patients are equal in their residual capacities. Besides the visual capacities described earlier for patients with genuine blindsight, some patients have an aware mode [229, 306, 311]. This aware mode is best exemplified by one of the most important blindsight patients, G.Y. He has participated in about one-third of the 30 or so studies carried out on blindsight in patients with circumscribed damage of cerebral cortex, and is of great interest because he has many residual capacities that are shared by few other blindsight patients [306, 309]. Moreover, the additional capacities of G.Y. cannot be accounted for by the residual fragments of striate cortex of the kind identified by Fendrich et al. [83]. This assertion can be made quite forcefully because G.Y. demonstrates blindsight throughout much of his blind hemifield and there are no 'islands' in the visual field (except his macular sparing) where visual capacities are markedly better than the remainder of the field, a feature that characterizes the study of Fendrich et al. [83]. Like other blindsight patients in the unaware mode, G.Y. can make saccadic eye movements into the blind hemifield, he is able to follow the path of a moving spot with arm movements, and he can discriminate between opposite directions of movement and between targets moving at different speeds even though he is not conscious of the presence of the stimulus [9, 11, 309]. However, under certain circumstances he switches to an aware mode where he is conscious of the presence of stimuli and can verbally report on stimulus position, aspects of spectral content, as well as the direction and velocity of stimulus movement providing that the size, contrast, displacement and velocity are high enough [11, 35, 229, 311,314]. Moreover, some of these observations in G.Y. are supported by regional cerebral blood flow studies which show that following stimulus presentation to his blind hemifield, the V3 and V5 areal complexes (as well as Brodmann's area 7) are very active, suggesting that the signals reaching extrastriate regions along the bypass pathways are sufficient in themselves for visual discriminations, conscious awareness and ability to report verbally at least some stimulus attributes [12]. In these respects, the term 'blindsight' does not accurately describe G.Y.'s residual capacities [12] which may be more appropriately termed 'spared vision' when he is in the aware mode. It is these spared visual capacities that set G.Y. apart from the other blindsight patients who

B. R. Payne et al./Early brain damage have no conscious awareness and who are mute about visual stimuli. 4 Moreover, it is these same residual capacities which make studying G.Y. easier than the other blindsight patients [Weiskrantz, personal communication]. An important factor distinguishing G.Y. from the other blindsight patients is that he incurred destruction of primary visual cortex when he was 8 years old, an age which is much earlier than other patients, who incurred their damage in adulthood, Based on the data on the cat reviewed in Section 4, we speculate that following the earlier lesion in G.Y. the bypass pathways to, as well as the pathways within, extrastriate cortex may have been strengthened. When these pathways in G.Y. transmit strong signals from sufficiently salient stimuli (fast movement, large displacement, or suddenness of onset for stationary stimuli) they reliably activate the perceptual and verbal commentary systems. It may be that the priming pathway from d L G N to extrastriate cortex, mentioned in Section 1, may have been elevated to a perceptual pathway, albeit a crude one, following the lesion of striate cortex during G.Y.'s childhood. Other pathways, such as those linking occipitoparietal and occipitotemporal regions [169], may also have been strengthened. Corroborating data are available from other blindsight patients (H.W. and R.L.), who also incurred damage to primary visual cortex in childhood (ages one and eight, respectively; see Ref. 30]. They both perform almost as well as G.Y. on a localization task [30] setting them apart from 20 other patients included in the same study, who incurred their damage later in life. Unfortunately, there are no published data on whether or not patients H.W. and R.L. can report conscious awareness of stimuli in their defective fields. In a fourth blindsight patient (D.B.) the age of onset of the neural defect is less clear. D.B. like G.Y., has been the focus of intensive studies and many of the studies on D.B. have been central to defining the characteristics of blindsight [306]. However, under certain conditions, fast movements and steep transients for stationary stimuli, patient D.B. also functions in the aware mode and senses aspects of the stimuli, although for orientation and detection with slow onset only the unaware (genuine blindsight) mode functions [306]. In D.B., these sensations may also be linked to early problems with striate cortex. D.B.'s visual problems were not reported until he was 14 years and his surgery was not carried out until he was 33 years. However, it has been suggested that the angioma that was removed in adulthood may have been present 4Other patients, described earlier in the century by Poppelreuter [206] and Riddoch [216], also have some residual perceptual awareness of moving stimuli. Such patients are usually not considered as having blindsight on the grounds that they probably have a grossly malfunctioning rather than an absent primary visual cortex. The presence of a primary visual cortex, albeit a malfunctioning one, sets these patients apart from the subjects described in the present review who have documented destruction of all or parts of primary visual cortex.

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from birth or earlier [306] and interfered with the normal development of striate cortex. The last patient is the focus of a remarkable report. Damasio et al. [67] examined a 34-year-old woman who suffered closed-head injury at age 5 and a right hemispherectomy at age 20. There is no report of the likely visual field defects following the initial trauma, but immediately after hemispherectomy surgery the left eye was blind and the visual field of the right eye was markedly constricted. Fourteen years later, and after repeated testing by different examiners, the left eye remained blind but there was 'almost normal vision' through the right eye and there was no evidence of hemianopia. These observations suggest that neural adaptations occurred following the initial brain damage, but that they were masked by the damaged hemisphere. After the damaged hemisphere was removed, and after a period of use, the adaptations became manifest) These greater levels of performance and the perceptual awareness these patients experience following early damage suggest that the immature human visual system has a latent flexibility to compensate partially for the deficits induced by the damage of primary visual cortex, providing the damage is incurred early in life, a possibility that has been explored in greater detail using cats.

3. Cat model of latent flexibility of immature brains A profound, latent flexibility of the visual system to respond to early damage of primary visual cortex has been demonstrated in cats and these studies may be significant for understanding the flexibility of the immature human brain to adjust to early damage. So far, studies on cats have shown a substantial sparing of visuallyguided behaviors subsequent to an early lesion of primary visual cortex that has a substantial base in rewired visual pathways into and out of extrastriate cortex and in substantial neuronal compensations in extrastriate cortex and the superior colliculus [186]. All together, these behavioral, anatomical and physiological adjustments reveal a remarkable flexibility of the immature brain to adjust to damage and to compensate for substantial deficits that accompany similar lesions in the mature brain. Since there are substantial parallels in the organization, function, behaviors and development of cat and monkey and. by extension, human visual systems, we believe the knowledge gained from cats can be used to guide investigations into the visual capacities of monkeys and humans following damage of primary visual cortex. These similarities include visual areas in cats and primates that: (a) have an equivalent layout of the visual field; (b)

5Some caution needs to be exercised in accepting these data because modern methods to minimize 'cheating' by the subject during the visual field examination were not applied in this study which was carried out some years prior to 1975.

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have similar patterns of connections; (c) contain neurons with similar sensitivities to visual stimuli; and (d) contribute to similar types of behaviors [184]. Moreover, the execution of the developmental programs in cats, monkeys and humans have many parallels [70, 124, 190, 214, 320], although the pace of development in cats is more rapid, and they reach maturity well in advance of monkeys and humans. This is an enormous advantage for investigators because it means that the outcome of scientifically induced lesions of primary visual cortex sustained by cats early in life can be studied over a period of years rather than over a period of decades that it currently takes to understand the consequences of similar early lesions in monkeys or therapeutic or natural lesions in human infants and children. Consequently, studies in the cat are likely to continue at a pace substantially faster than those of either monkeys or humans, and cats are likely to remain the best 'test bed' for devising effective future studies of the sequelae of early visual cortex damage than the more slowly developing monkeys and humans. As background to understanding the sequelae of primary visual cortex damage, the essential features of the cat's visual system will be described in the next section.

4. Cat visual system and its response to primary visual cortex damage (I) Organization of the cat's visual system

Except for the processing of spectral signals [104], the overall structure and organization of the visual system in cats resembles that of monkeys and humans (Fig. IA; see Payne [184]). The major portion of the optic pathway terminates in the dLGN, with lesser projections to the superior colliculus and additional minor projections to a number of lesser, non-cortically projecting structures including the pretectum. The vast majority of visual signals are relayed through the magnocellular layers A, A1 and C 6 of d L G N to primary visual areas 17 and 18. 7 From there, signals are relayed laterally to numerous

6The reader should be aware that the terms 'magno-' and 'parvo-cellular' in cat and monkey are both anatomical terms that describe the sizes of constituent neurons. The two terms are not meant to imply that the magno- and parvo-cellular layers of the cat are identical to the magno- and parvo-cellular layers of the monkey, in terms of detailed patterns of connections and relay of signals. In the cat it is likely that neurons in the magnocellular layers A, A1 and C are largely equivalent to the neurons in the monkey magno- and parvo-cellular layers, except that there is little processing of spectral signals. In hodological terms, the neurons comprising layers C1-3 in cat dLGN appear to be identical to the monkey dLGN interlaminar and 'S' layer neurons [46, 47]. 7In cats, both areas 17 and 18 are considered primary visual cortex because both receive substantial projections from the magnocellular layers A, A1 and C of dLGN [233,240].

extrastriate areas of the middle and posterior suprasylvian gyri and then onto the remaining extrastriate areas [35, 73, 223,240]. The middle and posterior suprasylvian gyri are known to process motion and form and mnemonic aspects of vision, respectively (see review by Payne [184]). In addition, lesser numbers of visual signals are relayed through parvocellular layers C 1-36 of d L G N and the medial interlaminar nucleus (MIN) and via the retinal recipient zone of the pulvinar directly to several regions of extrastriate cortex [Fig. 1A; Refs. 39, 79, 147, 223, 240]. Some of the neurons projecting to extrastriate cortex have axon collaterals that also innervate areas 17 and 18, although their numbers appear to be small [25, 42, 278]. The transgeniculate pathway transmits and amplifies the number of visual signals reaching primary visual cortex [202]. The specific signals transmitted along this pathway differ depending upon whether the relay is via the magnocellular layers or the parvocellular layers of dLGN or MIN. Signals relayed through the magnocellular layers to primary visual cortex are derived primarily from c~and fl retinal ganglion cells [14] and are classified physiologically as Y and X cells, respectively [91,147, 230, 252, 253, 298]. These signals are transmitted by d L G N type I (Y) and types II and IIIs (X) neurons [88, 89, 147]. Signals relayed through the parvocellular layers C1 and C2 to primary and extrastriate cortex are derived largely from 7 retinal ganglion cells [141] and they are classified physiologically as a rather heterogeneous group of W cells [267]. W signals are transmitted by d L G N type IV neurons 8 [147, 254, 255]. The dominant signals relayed through MIN to primary and extrastriate cortex are derived from c~ (Y) retinal ganglion cells, although there is a minor number of ? ganglion cells that project to MIN [227]. These signals are transmitted by types I and IV neurons in MIN [147, 211]. Signals relayed through the retinal recipient zone of the pulvinar originate from E ganglion cells [140, 210] which transmit W, or Q, signals [210, 281[. For ease of illustration in Fig. 1, we have included them with the 7 ganglion cell group and consider them a subgroup of W cells [267]. The relay of Y signals directly from d L G N to extrastriate regions is particularly interesting because under the appropriate conditions Y signals are some of the first signals generated by retinal ganglion cells and they are the most rapidly transmitted to the brain [267]. Since the middle suprasylvian (MS) region is closer to d L G N than either areas 17 or 18, the implication is that under certain circumstances MS cortex may be activated at the same time or in advance of areas 17 and 18, a situation already noted for the equivalent regions in monkeys and humans [15, 85,213]. Such activity may be fed forward onto areas 17 and 18 or it may provide a priming effect on MS neurons that temporarily facilitate the processing of like or similar signals arriving from areas 17 and 18 or other visual structures. SNeurons typed by Guillery [102].

B. R. Payne et al./Early brain damage The major alternate route for visual signals to reach the cortex is via the midbrain. The larger of these pathways is the transcollicular pathway which continues through layer C3 6 in the parvocellular layers of d L G N and the medial part of the lateral posterior nucleus (LP) to extrastriate cortex [1, 24, 106]. The signals transmitted along this pathway originate primarily from 7 and y retinal ganglion cells [141] and thus the pathway transmits primarily Y and W signals to extrastriate cortex. The numerically smaller transpretectal pathway transmits signals to the pulvinar nucleus for relay to extrastriate cortex [23, 96]. This pathway also transmits primarily Y and W signals derived from ~ and 7 ganglion cells [133, 141]. So far, the transpretectal pathway has not been implicated in the modified visual system circuitry. Consequently, for ease of presenting the other pathways, we have excluded it from Fig. 1. Lastly, there are substantial descending projections from primary and extrastriate visual cortices to the superior colliculus; those from primary cortex terminate in stratum griseum superficiale (SGS) whereas those from extrastriate areas terminate most densely in stratum opticum (SO) and stratum griseum intermediale [SGI; Ref. 107]. This corticocollicular pathway transmits signals derived from ~ (Y) and 7 (W) ganglion cells [22, 50, 87], although some/3 (X) signals may be mixed with Y and W signals and reach the superior colliculus from area 17. The ~ (Y), p (X) and 7 (W) retinal ganglion cells contribute to vision in different ways [218, 238, 241, 298]. Alpha retinal ganglion cells have large receptive fields, poor sensitivity to low contrasts and extend visual capabilities into the high temporal domain; they are implicated in coarse and more global aspects of spatial vision. Beta cells have smaller receptive fields and high sensitivity to low contrasts that extend visual capabilities in the low contrast and fine spatial domains. These capacities most likely contribute to dynamic range of contrast sensitivity and explain high-frequency cut-offand visual acuity. Beta cells are implicated in local aspects of vision. Both ~ and /3 cells give brisk responses, and up to the limit of 7 cell acuity, ~ cell activity dominates/3 cell activity and ~ cells are superior to /~ cells at stimulus detection [111, 129, 298]. Gamma cells are a rather sluggish and heterogeneous group primarily concerned with peripheral

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ambient vision and have rather poorly defined functions [228, 267]. Consequently, under most circumstances and under high spatial-contrast conditions, ~ cells generate the dominant signals in the visual system whereas/3 cells add acuity. Under low spatial-contrast conditions/3 cells are the major source of signals. As can be seen from Fig. 1B, ablation of primary areas 17 and 18 in the mature cat disconnects all of extrastraite cortex from all visual signals relayed through the magnocellular layers, including the substantial X pathway. However, there are residual transcollicular and transgeniculate pathways to extrastriate cortex that include the parvocellular layers of d L G N , which relay primarily W and Y visual signals. Furthermore, SGS in the superior colliculus is disconnected from signals relayed through areas 17 and 18 and there is massive degeneration of relay neurons in the magnocellular layers of dLGN. Despite the loss of the substantial X pathway, there remain a variety of visually guided behaviors supported by the bypass pathways through the parvocellular layers of d L G N and the superior colliculus. However, performance on many of these residual behaviors is impaired compared to intact cats.

(II) Residual vision in the absence of primary visual cortex In the absence of primary visual cortex, cats retain many aspects of both learned and reflexive visually guided behaviors but performance is moderately to severely impaired compared to performance of the intact cat. These behaviors include acuity [19, 110, 137], lineorientation discrimination [19, 176, 177, 289], certain types of form and motion stimuli [182, 183], depth perception [53, 54, 242], stereopsis [120, 209], detection of patterns in the presence of textures or noise [72, 110, 134, 135], learning of complex pattern discriminations [Fig. 2; Refs. 52, 53, 56, 78, 249, 250], orienting to novel stimuli introduced into the periphery of the visual field [Fig. 3 left; Ref. 242] and optokinetic nystagmus [OKN; Ref. 242]. Many of the residual capacities depend upon the integ-

)

Fig. 1. Diagrams to summarize the major visual circuits in intact cats (A) and changes in connections of MS cortex induced by damage of primary visual cortical areas 17 and 18 incurred in adulthood (B), at 1 month of age (C), or on the day of birth (D). Width of arrows indicates relative magnitude of projections. Blue = normal connections, red = increased connections, green = no information on pathway changes available (primarily circuits related to superior colliculus). Y, X and W = types of signals generated by ~,//and 7 ganglion cells, respectively; dLGN = dorsal lateral geniculate nucleus; M = magnocellular layers ofdLGN (A, A1 and C); P = parvocellular layers of dLGN (C 1-3); MIN = medial interlaminar nucleus; Pul = pulvinar nucleus; SC = superior colliculus; LP = lateral posterior nucleus, with medial (m) and lateral (1) divisions; 17/18 = areas 17 and 18; MS = middle suprasylvian visual cortex; dPS = dorsal part of the posterior suprasylvian gyrus; vPS = ventral part of the posterior suprasylvian gyrus. For clarity, several pathways have been omitted from the figure. These pathways include those involving the pretectum and many extrastriate regions other than MS, dPS and vPS cortices that either do not change following lesions of areas 17 and 18, or for which no information is available. Also note that dPS and vPS cortices receive substantial projections from visual thalamic nuclei and either directly or indirectly, from areas 17 and 18. These latter connections are not well understood even in the intact brain. They have been omitted in the interests of simplicity of the presentation of known lesion-induced repercussions and major pathways.

B) ADULTABLATION

Part A: 1. Note progressive amplification of visual signals transmitted through d L G N to primary visual cortex. 2. X and Y signals reach extrastriate cortex via the magnocellular layers of d L G N and primary visual cortex. 3. Y signals also reach extrastriate cortex via M I N and via the superior colliculus and the lateral posterior complex. 4. W signals reach extrastriate cortex via the parvocellular layers of dLGN, MIN and via the superior colliculus and the lateral posterior complex. 5. W, X and Y signals reach the superior colliculus either directly or via primary and extrastriate cortex. 6. Visual signals also reach MS cortex via dPS and vPS cortices which receive substantial visual inputs via LP nucleus (connections not shown). Part B: 1. Partial shrinkage of magnocellular layers due to death of neurons. Dense retinal projection maintained to all of dLGN. 2. Following the damage of primary visual cortex, X signal transmission to extrastriate cortex is interrupted and Y signal transmission is reduced. 3. In some cats, direct retinal projections to LP nucleus appear following lesions of areas 17 and 18 incurred early in adult life. 4. No X signals reach the superior colliculus and no Y signals are relayed to the superior colliculus through primary visual cortex. 5. W and Y signal transmission to the superior colliculus and through MIN to extrastriate cortex is unaffected by the lesion. The one caveat to this statement is that signal transmission through the connected layers of d L G N and superior colliculus may be severely compromised by the absence of facilitatory signals descending from areas 17 and 18.

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Part C: 1. Retention of substantial retinal projections to dLGN, even though magnocellular layers of dLGN have partially degenerated. 2. Expansion of retinal projections into LP. 3. Massive expansion of projections from the parvocellular layers of d L G N to MS cortex and the rescue and recruitment of neurons in magnocellular layers of d L G N to the projection. 4. Expansion of MS cortical projections to the superior colliculus. Part D: 1. Note virtually complete elimination of X signals .due to death of massive numbers of fl retinal ganglion cells. 2. Very few neurons survive in the magnocellular layers of dLGN. 3. Amplification of W and Y signal transmission to extrastriate cortex and superior colliculus via expansions of the ascending pathways through both d L G N and LPm to MS cortex and descending projections to the superior colliculus. 4. Massive amplification in projections from vPS cortex to MS cortex. These pathways transmit signals derived from ~ (Y) and 7 (W) retinal ganglion cells.

B.R. Payne et al./Early brain damage

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Fig. 2. Summary of visual capacities and defects for learned pattern discriminations. Relative performance of intact cats and cats which sustained lesions of areas 17 and 18 in adulthood or within a few days of birth. Simple stimuli: all cats can learn simple pattern discriminations and do not require the presence of primary visual cortex. Even so, the ease of learning by the cats with damage incurred in adulthood is less than for intact cats, or cats with early damage. Complex stimuli: adult-damaged cats have great difficulty learning the simple pattern discrimination when the patterns are either obscured by grid masks or surrounded by a peripheral border. Infant-damaged cats have less difficulty learning the same discrimination providing the level of masking is increased gradually or when lesions are incurred in two stages. Data drawn from Cornwell et al. [52] and Cornwell and Payne [57].

rity of more lateral regions of cortex. 9 For example, extension of the lesion laterally to include area 19 impairs discrimination of partially hidden figures [53, 56] and the detection of figures on noisy backgrounds when the figures, background or both move [134] and for the retention of simple and complex pattern discriminations [3, 20, 77, 105, 247, 249]. Moreover, when the lesion extends even further laterally to include the suprasylvian region, the performance on visuospatial, depth, O K N and retention and relearning of pattern and form discriminations is substantially more degraded than that induced by lesions of areas 17 and 18 alone [e.g. Fig. 3 right; Ref. 242]. These further degradations following progressively more extrastriate damage bear strong similarities to the progressive degradation of visual capacities as lesions of striate cortex expand to include progressively more of extrastriate cortex in monkeys [179] or that follow hemispherectomy in humans [131]. Even though there are numerous and at times substantial impairments, what is surprising is that cats have 9Similar conclusions have been reached for other species [rats: 14, 27, 273, 274; tree shrews: 127, 128, 243, 244, 297; rabbits: 165, 170; and bushbabies: 4, 43, 126, 151, 321]. However, a detailed discussion of the findings in these other species is beyond the scope of the present review.

patent residual cortically-mediated visual capacities in the absence of inputs from areas 17 and 18. These capacities are linked to the bypass pathways and the remaining regions of extrastriate cortex, such as area 19 and the middle (MS) and posterior suprasylvian (PS) cortices which remain visually active [55, 98, 99, 101, 130, 156, 246]. However, for the most part, residual activity evoked by the bypass pathways in extrastriate cortex is abnormal. Activity of neurons in MS and the dorsal part of PS cortex (dPS or areas 21) is depressed and receptive field properties are less sophisticated following removal of inputs from areas 17 and 18 [156, 246]. In addition, there is one report that even combined removal of primary visual cortical areas and the superior colliculus fails to alter neuronal activity in these lateral areas [98]. If validated, these data will show that even the limited inputs from d L G N directly to MS cortex have substantial influences and are capable of activating cortical neurons. Whether validated or not, what is not in dispute is that many neurons in a large swathe of suprasylvian cortex remain visually active following the silencing of inputs from areas 17 and 18. These observations demonstrate the importance of the bypass pathways in the activation of suprasylvian cortical neurons. Moreover, this residual neural activity and the behaviors are based on signals derived largely from c~(Y) and y (W) ganglion cells. These observations on circuitry have an important bearing on the types of visually guided behaviors that are partially spared by lesions of primary visual cortex incurred within a few days of birth, when the cortex is still very immature. These behaviors are summarized in the next section. Subsequently, we link these spared behaviors to the expansion of these same circuits to extrastriate cortex that bypass either d L G N or areas 17 and 18 and that transmit Y and W signals.

(lII) Age dependent sparing of visually guided behaviors On many visually guided tasks, the behaviors of cats with lesions incurred within a few days of birth are superior to the behaviors of cats with similar lesions incurred in adulthood.I° This higher level of performance is termed 'sparing' and it has been demonstrated for both learned and natural, or reflexive, visually guided behaviors. For example, cats with early lesions of areas 17 and 18 learn to discriminate a solid T shape from a solid 'O' shape in substantially fewer trial errors than do cats with late lesions. In addition, under some conditions, cats with early lesions of areas 17 and 18 are able to learn complex-pattern discriminations involving a simple shape overlain with a grid masking pattern, as readily J°Broadly similar conclusions have been reached on the consequences of earlier versus later lesions of visual cortex in rats [14, 27, 28, 273, 174] and rabbits [172, 257]. However, full discussion of the studies using these other species is outside the scope of the present review.

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Fig. 3. Performance of intact cats and cats which incurred damage of visual cortex, either during infancy or adulthood, on a visual detection and orienting task. Binocular viewing condition. In this task the cat attends to a low incentive stimulus introduced at 0" azimuth and a second high incentive stimulus is introduced at one of the peripheral locations. If the cat orients promptly to the second stimulus the trial is scored as correct. For intact cats, performance is virtually perfect +_60° either side of the midline (light stipple). Towards the periphery performance falls off and reaches 50% at an azimuth of 90°. Left: following damage of areas 17 and 18 incurred in adulthood, perIbrmance is poor at all locations (dense stipple). Equivalent damage incurred in infancy results in substantial sparing of orienting behavior (medium stipple). Right: same data from intact cats and data from cats which sustained removal of all continguous visual areas of the middle and posterior suprasylvian regions in addition to areas 17 to 18. Removals made either in adulthood or in infancy. Same stipple conventions apply. Note markedly inferior performance of both adult and infant damaged cats compared to left figure. Differences between figures on left and right reveal the contribution extrastriate cortex makes to residual and spared behaviors. Data drawn from Shupert et al. [242]. as intact cats, and much more adeptly than cats with equivalent lesions incurred in adulthood (Fig. 2). One condition which allows complete, or almost complete, sparing on this task employs a procedure of increasing the complexity of the masking in a series of small steps, ensuring that at each step the animal has mastered that level before progressing to the next [52]. The performance of cats with lesions incurred in adulthood benefits from this ascending staircase procedure, but even with this assistance cats with lesions made in adulthood fail to acquire the series of discriminations as readily as the controls or the cats with lesions incurred in infancy. Sparing on this set of pattern discriminations with overlain grids is also complete, or almost complete, if the lesions incurred in infancy are made in two stages with 3 days between operations [57]. No special behavioral shaping procedures are needed to reveal the sparing if the lesions are made in two stages during the first 2 weeks of life. Unfortunately, no information is available on the ability of pattern discrimination tasks of cats with two-stage lesions made in adulthood but it seems unlikely that allowing as little as 3 days between operations would reveal complete sparing on this complex pattern discrimination with overlain masking. Clearly, not all complex-pattern discrimination learning is spared after lesions of areas 17 and 18 incurred in infancy, at least if the lesions are made in one stage. When a simple shape is surrounded by a peripheral mask, cats with early lesions of areas 17 and 18 perform as poorly as cats with later lesions [Fig. 2; Refs. 52, 57]. No information is available on whether or not a method of increasing the peripheral masks in gradual steps would occasion relatively more sparing by cats with lesions made in infancy than by those with similar damage incurred in adulthood. It is clear, however, that cats with lesions incurred in two stages during infancy perform as well as unoperated cats on these complex discriminations

and that an interoperative interval of only 3 days is sufficient to allow such complete sparing [57]. In addition to learned visually guided behaviors, reflexive behaviors, modulated by the cerebral cortex, are partially spared by early lesions of primary visual cortex. These behaviors include orienting to novel stimuli introduced into the periphery of the visual field, monocular optokinetic nystagmus and depth judgments as assessed on the visual cliff [242]. For example, in intact cats, orienting to novel stimuli is almost perfect in the binocular portion of the visual field (Fig. 3, left) and it drops off towards the periphery, whereas lesions of areas 17 and 18 incurred in adulthood severely impair performance, even in the central parts of the visual field and orienting performance is reduced to 65% or less. In contrast, performance of cats with early lesions is far superior and approaches normal performance towards the center of the visual field [Fig. 3A; Ref. 242]. Extrastriate cortex plays a prominent role in the spared behaviors, because extension of the cortical lesion beyond areas 17 and 18 to include area 19 and the middle and posterior suprasylvian gyri reduces visually guided behaviors almost to levels determined for cats with equivalent lesions incurred in adulthood [242]. This can be seen clearly when cats are tested for their ability to orient to novel stimuli (Fig. 3, right). We suspect that the sparing of behavioral capacities are importantly related to the pathway expansions we have identified into and out of thalamus, extrastriate cortex and midbrain that characterize the response of the brain to early lesions of areas 17 and 18 (see Section 4V, below).

( I V ) Neuronal degenerations

Paradoxically, the sparing of visual capacities occurs despite massive, but specific, death of neurons that elim-

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inate entire visual pathways that under normal circumstances are heavily connected with primary visual cortex [136, 185, 189, 191, 282]. Immature neurons are particularly sensitive to lesions and this sensitivity is linked closely to patterns of connections. In dLGN, lesions of areas 17 and 18 incurred shortly after birth induce a very rapid response and all but a small number of type I neurons in the magnocellular layers are eliminated within days [Fig. 4A; Refs. 136, 147]. In contrast, many type IV neurons in the parvocellular layers survive, as do several types I and IV neurons in the medial interlaminar nucleus [MIN; Fig. 4A; Refs. 142, 144, 147, 189]. The vulnerable neurons have sole or substantial projections to the damaged region, whereas surviving neurons in all d L G N compartments have substantial, sole, or collateralized, projections to extrastriate cortex [38, 58, 125, 147,277]. These latter neurons are largely unaffected by the lesion of areas 17 and 18 [119, 142]. There may also be a small fraction

of the neurons, which normally project axons exclusively to areas 17 and 18, but when faced with the damage, they manage to extend and maintain axonal projections into MS or other cortical regions [119, 142]. A subgroup of surviving type IV neurons have cell bodies that hypertrophy and dendritic fields that are larger and more complex than normal [Fig. 4A; Refs. 142, 147, 171], and the overwhelming majority of surviving d L G N neurons transmit Y and W signals [147, 282]. The sensitivity of neurons to visual cortex damage in young cats is not confined to d L G N but extends transsynaptically out to the eye [Fig. 1D; Ref. 192] where the majority of/~ and a small number of 7, retinal ganglion cells also die [Fig. 5; Refs. 189, 266, 279]. As in dLGN, the selective loss and survival of ganglion cells is linked to patterns of connections established with the mature brain. Normally, the vast majority of/~ cells send massive projections to layers A and A1 of d L G N [Fig. 1A; Refs. 33, 141, 269, 272] and when these target neurons dis-

Fig. 4. A and B. Light field photomicrographs of dLGN in an adult cat after unilateral ablation of primary visual cortical areas 17 and 18 on the day of birth. A. dLGN ipsilateral to cortical ablation. B. dLGN 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 which had been injected into the eye. C. Ipsilateral pl'ojections. D. Contralateral projections. Layers A and A1 and the C complex are indicated. In the intact dLGN note dominant retinal projections to layer A1 and very weak retinal projections to the C complex. In the degenerated dLGN note greatly reduced projections to the severely degenerated layers and a massive increase in projections to the residual neurons in the C complex. Note that residual C neurons (C, arrow) are large and hypertrophied; d = severely degenerated layers A and A1; n = normal tail of dLGN that is connected to an intact, caudal portion of areas 17 and 18. From Payne et al. [189]. Modified and reproduced with the permission of the Royal Society and Elsevier.

B. R. Payne et al./Early brain damage

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Fig. 5. Drawing of ganglion cells in contralateral nasal retina labeled by injection of horseradish peroxidase into an intact dLGN (left) and a dLGN of an adult cat which sustained a complete lesion of areas 17 and 18 shortly after birth (right). Top row: ~,/3 and 7 cells. Middle row: ~ and 7 cells. Bottom row:/~ cells. Note: (1) After the early lesion ~90% of/~ cells have been eliminated, yet all and 7 cells remain; (2) some ~ cells are smaller than normal and some 7 cells are larger than normal. From Payne et al. [189]. Reproduced with the permission of the Royal Society. appear quickly following lesions of areas 17 and 18 incurred shortly after birth [136], the majority of/3 ganglion cells also succumb (Fig. 5). On the other hand, c~ and 7 retinal ganglion cells survive in large numbers because they have substantial projections to neurons in the parvocellular layers of d L G N , MIN, superior colliculus, pretectum and/or the accessory optic system [Fig. ID; Refs. 33, 141, 269, 272], where large numbers of healthy target neurons reside. The degeneration of/3 retinal ganglion cells is matched by a massive withdrawal of retinal fibers from the degenerated magnocellular layers o f d L G N [Figs ID and 4C; Refs. 144, 189]. This degener-

ation of the /3 (X) cell pathway explains the defect of cats with lesions incurred on P1 to detect high spatial frequencies [160] and suggests that such cats have difficulty with tasks requiring analysis of fine details when presented under low-contrast conditions. Presumably, what behaviors are spared by the early lesions are based primarily on signals derived from ~ (Y) and 7 (W) ganglion cells. Immature neurons in extrastriate cortex also die, but only those normally destined to form strong links with the damaged areas 17 and 18. For example, subpopulations of neurons in layers III and VI of MS cortex,

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Fig. 6. Photomicrographs to show the thickness and lamination of MS cortex in: A. An intact cat; B. an adult cat that sustained a complete lesion of areas 17 and 18 in adulthood; C. an adult cat that sustained a complete lesion of areas 17, 18 and 19 shortly after birth. The marked strip is 200 #m wide and indicates the layers and the location of neuron counts reported in Ref. 185. In C, note the shrinkage of layers III and IV. Reproduced with permission of Oxford University Press.

which normally send substantial projections to primary areas 17 and 18, perish following the lesion [Fig. 6; Ref. 185]. Like ~ and ~ retinal ganglion cells and the types I and IV d L G N neurons, the survival of remaining MS cortical neurons is linked to connections with surviving populations of neurons in cortex and subcortical structures [185]. Maturational status is also a factor linked to neuron survival or death following damage of primary visual cortex. For example, there is evidence of little neuron death in retina and extrastriate cortex following lesions of primary visual cortex sustained in adulthood [Figs 1B and 6; Refs. 117, 185, 191]. Also, following similar lesions incurred at 1-month of age the majority of retinal/~ (X) ganglion cells also survive [Fig. 1C; Refs. 44, 191], even though the long term appearance of d L G N is shrunken and in many respects indistinguishable from that following lesions of area 17 and 18 incurred within days of birth [144]. In accordance with the large scale survival of /~ (X) retinal ganglion cells, retinal projections to the degenerated layers are retained at about normal densities [Fig. 1C; Ref. 144]. The survival of/~ (X) cells and the retention of substantial projections to d L G N following damage sustained at 1 month of age suggest that some/~ (X) signals are transmitted to cortex. Evidence supporting this proposition is provided by Mitchell [160] who reports that cats which incurred lesions of primary visual cortex at 1 month of age are able to us/~ (X) signals and detect high spatial frequencies. This result is just one example illustrating the differential, age dependent effects of equivalent lesions incurred at two different stages in

development. We will discuss further the differential, age dependent pathway expansions evoked by early lesions ~ of areas 17 and 18 in the next section.

( V) Expansion of specific pathways There is substantial expansion of a number of visual pathways following early lesions of areas 17 and 18, but the magnitude and the structures involved differ depending whether the lesions are incurred at the beginning or end of the first postnatal month (Figs IC and D). These expansions include intraretinal circuits, retinal projections to the thalamus, ascending thalamic projections to cortex, transcortical projections and descending cortical projections to the superior colliculus. These expansions are likely to be adaptive and contribute to the neuronal compensations (see Section 4VI) and to the sparing of certain perceptual and cognitive functions (see Section 4II) following early lesions of primary visual cortex. The pathway expansions induced by lesions of primary visual cortex on the day of birth (P1) are summarized below and include all three pathways bypassing d L G N and primary visual cortex (Fig. I D).

~In this review, early refers specifically to the first month of postnatal month in the cat. However, we suspect that many connections in the cat's brain retain some flexibility for 6 months or more [66], although whatever flexibility remains at 6 months it is markedly attenuated and cannot easily be detected using current pathway tracing techniques.

B. R. Payne et al./Early brain damage (i) Lesions of primary visual cortex shortly after birth result in a thickening of the inner plexiform layer of the retina [224] which suggests an expansion of synaptic neuropil involving the bipolar and amacrine cells of the inner nuclear layer and the amacrine cells and whatever ganglion cells remain in the ganglion cell layer. In central retina, the increased neuropil is accounted for, in part, by the hypertrophy of some ~ ganglion cells [5] and in the periphery by the hypertrophy of 7 cells [189]. However, in the periphery there is a concomitant shrinkage of some c~ cells [5, 189], which give rise to axons that conduct action potentials more slowly than normal [225]. (ii) Following the primary visual cortex lesions incurred on the day of birth (PI), retinal projections into the remnants of the parvocellular layers ofdLGN and retinal recipient zone of the pulvinar increase [Figs 1D and 4; Refs. 118, 136, 144, 189] and, in some cats, a novel projection into the lateral posterior (LP) nucleus is also established [187]. The expansion in the parvocellular layers is most likely brought about by a redeployment of substantial numbers of Y (e) axon boutons from the degenerated magnocellular layers to the parvocellular layers [189, 299], although the redeployment may be incomplete because of axon's retinal cell bodies shrink [5, 189]; an indicator of reduced numbers of axon boutons. In contrast, W (),) axon arbors may expand in the C complex to match the hypertrophy of their parent cell bodies in the retina [189]. At the moment it is not known if retinal projections into the superior colliculus or pretectum are modified by the cortical lesion, although it is known that lesions of primary visual cortex in adult monkeys modifies retinal projections to the pretectum [76]. (iii) Following lesions incurred on P1 there is a substantial expansion in the projections from thalamus to cortex. Many times the usual number of cells in the parvocellular layers of dLGN project to MS cortex and a number of neurons in the severely degenerated magnocellular layers survive and establish permanent projections to MS cortex [Figs ID and 7; Refs. 119, 142, 147]. Moreover, many of the type IV C layer neurons have hypertrophied cell bodies (Figs 4A and 7; Refs. 55, 77, 144, 147, 171, 189] which may be necessary to support both enlarged dendritic arbors [147] and enlarged axon arbors in MS cortex. These enlarged dendritic and axon arbors may form larger than normal numbers of input and output synapses and also contribute to the expansion of the pathway, by permitting greater convergence of signals at the input to the neuron and greater divergence at the output. Transneuronal labeling from MS cortex to the retina using retrograde tracers have identified that the expanded disynaptic retino-geniculato-extrastriate pathway originates almost entirely from ~ and 7 retinal ganglion cells [Fig. 8; Ref. 143] and anterograde tracers show that the expanded pathway terminates in layers III and IV in MS cortex [Fig. 9; Ref. 143]. The first effect of both these expansions is likely to be raised signal transmission levels in the transgeniculate pathway to MS

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cortex, which includes the fastest Y pathway. The second effect is to increase the size of receptive fields and decrease in retinotopic organization. Both of these features are characteristic of neurons that survive in dLGN following lesions of areas 17 and 18 incurred shortly after birth [171]. The third effect may be a mixing of Y and W signals, as well as signals from other sources such as the superior, colliculus, which converge on the hypertrophied type IV neurons and radically alter their properties. However, this last proposition has not so far been borne out of physiological studies, which show that in cats with early lesions it is straightforward to classify dLGN neurons into Y and W types with few having intermediate properties [282]. Even so, this does not eliminate the possibility that Y, W and collicular inputs converge on some neurons and the methods for assessing mixed signals are rather crude and the mixing has so far gone undetected. In addition to the modifications in the transgeniculate pathway to MS cortex, there is a doubling of the normally massive projection from the medial part of the lateral posterior nucleus [LP; Fig. ID; Ref. 142]. This is of considerable interest because the same part of LP receives substantial input from the superior colliculus [1, 24]. Thus, the residual circuits in both the transgeniculate and in the transcollicular pathways to MS cortex expand following damage of primary visual cortex on P l. As described earlier, pathways involving both the transgeniculate pathway through the parvocellular layers of dLGN and the transcollicular pathway originate from c~ and 1' retinal ganglion cells, which transmit Y and W visual signals. Together, these pathways substitute, at least in part, for the inputs to MS cortex eliminated by the lesion and both routes substantially increase the carrying capacity of visual signals to extrastriate cortex. The expansion of the retino-geniculo- and transcollicular pathways most likely contribute to neuronal compensations in MS cortex (see Section 4VI) and to the sparing of orienting behavior and optokinetic nystagmus (see section 4III). (iv) Pathways within extrastriate cortex also expand following lesions incurred on PI. For example, there is an overall increase in the numbers of neurons that project to MS cortex and most of these neurons are located in the ventral part of the posterior suprasylvian cortex (vPS) [Figs ID and 10; Ref. 148]. The projection from vPS cortex also contributes to the transfer of signals derived from ~ (Y) and I' (W) ganglion cells to MS cortex, because the major subcortical input to vPS is derived from the medial part of LP [223]. Moreover, since the majority of transcortical pathways are strongly reciprocal [82, 271], we might expect strong projections from MS cortex to vPS cortex also to exist. Such connections between parietal and temporal regions may contribute to the sparing of pattern vision following lesions incurred shortly after birth; for it is known that lesions ofvPS cortex (area 20) in otherwise intact cats disrupt discrimination of stationary patterns [45, 59, 110, 250].

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Fig. 7. Pattern of labeling in dLGN following injection of wheat germ agglutinin-horseradish peroxidase into MS cortex. A. Intact cat. Note only a small number of cells contain label and that they are confined to the C layers. This poor labeling demonstrates that the direct pathway from dLGN to MS cortex is extremely weak in the normal cat. Note size of largest neuron containing label. This neuron is shown in the inset; B. Adult cat which sustained complete removal of areas 17 and 18 1 month after birth. Note: (1) The recruitment of many additional neurons in the magno- and parvo-cellular C layers (CM and Cp) to the pathway; (2) the recruitment of neurons in layers A and A1 to the pathways; (3) quality of labeling differs from that shown in A. This difference reflects larger axon fields in MS cortex that permit pickup and transport of large amounts of label compared to the intact cat; (4) hypertrophy of many neurons that support a larger dendritic and axonal fields. Scale bar = 500/~m. From Lomber et al. [142]. Reproduced with permission of Oxford University Press.

(v) Pathways leading from extrastriate cortex to subcortical structures also expand following the lesion o f primary visual cortex on P1. These pathways include those to stratum opticum which expand into SGS o f the superior colliculus [Figs I D and 11; Ref. 268]. This

expansion physically substitutes for the projections normally arising from ablated areas ! 7 and 18 and restores the indirect geniculo-cortical p a t h w a y to stratum griseum superficiale. This expansion increases the transfer of signals derived from ~ (Y) and ~/ (W) ganglion cells and

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Fig. 8. Ganglion cells in contralateral nasal retina of an adult cat which sustained complete removal of areas 17 and 18 on the day of birth labeled by WGA-HRP injected into MS cortex. The label was transported retrogradely and trans-synaptically through the dLGN. Alpha cells and numerous ), cells contain label. Only the occasional/3 cell is labeled. Identical procedures carried out on intact cats or cats which sustained removal of areas 17 and 18 in adulthood result in no labeling in the retina, even though there is the normal pattern of labeling in the brain. The substantial retrograde transport of label via the C complex of dLGN to retina confirms the huge expansion of the transgeniculate pathway to MS cortex. Scale bar = 100 #m.

transmitted via cortex, to the superior colliculus [268] and may contribute to neural compensations determined for SGS (see Section 4VI) and to the sparing of orienting behavior (see Section 4III). (vi) As indicated earlier, the anatomical consequences of lesions incurred at the end of the first postnatal month differ from those incurred within days of birth (compare Figs 1C and 1D). For example, the expansion of the projection from d L G N to MS cortex is substantially greater following lesions incurred at 1 month of age compared to 1 day of age [142], yet the magnitude of the expanded MS cortical projection into SGS of the superior colliculus is more limited [268]. Lastly, expansions from the medial part of LP and vPS cortex to MS cortex evident following lesions incurred on the day of birth are not evident following lesions incurred at 1 month of age [142, 148]. Since electrophysiological and behavioral studies on cats which incurred lesions at I month of age are limited, we do not know what the functional expression of these expansions might be. We suspect that other subcortical and transcortical pathways also expand to innervate structures deafferented by the early lesions of primary visual cortex and that they may do so differentially following lesions incurred at

different stages in the development of the visual system. But these suspicions need to be confirmed in future studies. Even so, it is important to acknowledge that none of the adjustments in pathways described above accompanying equivalent lesions in fully mature cats [142-144, 148, 191,268,276].

(VI) Adjustments in neural activity and,/unetional compensations by neurons Following early lesions, pathways expand by the addition of extra neurons to the pathway and by the enlargement of dendritic arbors and axonal fields, all of which are likely to contribute in a substantial way to functional compensations. The addition of neurons to pathways increases the numbers of signals that are transmitted, while the enlargement of dendritic and axon arbors permits greater convergence of signals at the input to the neuron and greater divergence at the output. All three expansions most likely raise signal transmission and transfer throughout what remains of the visual system. This transfer is efficient and close to or even above normal levels in early lesioned animals, whereas it is markedly

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Fig. 9. Darkfield photomicrograph to show the distribution of label transported from the eye via dLGN to MS cortex in a cat which sustained a lesion of areas 17 and 18 on the day of birth. High density label corroborates the expanded retino-PMLS pathway and establishes the high degree of coupling in the retino-geniculo-MS cortex pathway. Arrows indicate labeled axons. Equivalent data have been collect from cats which incurred similar lesions at 1 month of age. No labeling is detected in MS cortex of intact cats or cats which sustained lesions of areas 17 and 18 in adulthood. Scale bar = 200/lm.

depressed or abnormal following equivalent lesions sustained in adulthood. This is true even though in both instances the bulk of visual signals originate from ~ (Y) and 7 (W) ganglion cells. These differential levels of activity have parallels in behavioral performances; cats with early lesions demonstrate more competent performance on a number of visually guided behaviors than cats with equivalent lesions incurred later in life. Evidence for functional compensation is provided by the near normal levels of metabolic activity in d L G N and MS cortex of early lesion cats as demonstrated by the cytochrome oxidase method [Fig. 12; Refs. 145, 188] and by direct electrophysiological measurements taken from d L G N [171,282], MS and vPS cortices [55, 77, 99-101] and the

superior colliculus [Fig. 13; Refs. 21, 154, 161,256]. These functional compensations reflect the amplifications of pathways bypassing the degenerated d L G N neurons and areas 17 and 18 and the elimination of circuits normally heavily connected with areas 17 and 18. It is straightforward to understand how pathway expansions are adaptive, but not the death of neurons and elimination of circuits. We interpret the deaths to purge the brain of poorly connected neurons, thereby eliminating unnecessary and inefficient computations, spurious signals, and erroneous damping of useful signals. The net outcome would be a more efficient and accurate processing of signals in the remaining circuits, which we speculate is a prerequisite for near normal neuronal processing and

B. R. Payne et al./Early brain damage

759

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Fig. 10. Adult cat which sustained a unilateral (right) removal, on the day of birth, of all of areas 17 and 18 and the rostral, lower field representation of area 19. Plots of coronal sections to show the position of neurons labeled by injection of identical amounts of rhodamine labeled latex microspheres at mirror symmetric loci in the two hemispheres. There was no cross-contamination between hemispheres because the corpus callosum was cut. Cross hatching represents the region exposed to tracers. Although not equal in the figure, planimetric measurements show that the total volume of the intact hemisphere exposed to the tracer was 13 mm 3, whereas it was 12 mm 3 in the damaged hemisphere. Note in the intact hemisphere that most labeled neurons are located in areas 17, 18, 19 and dPS. In the damaged hemisphere, most labeled neurons are located in dPS and vPS cortex, dPS corresponds broadly to areas 21a and 21 b and vPS corresponds to areas 20a, 20b and PS [283,288]. Top right: number of neurons labeled in the two hemispheres. Note that following the damage on P1 more neurons are labeled even though areas 17 and 18 and much of area 19 have been removed; Bottom right: lesion reconstruction; 7, 17, 18, 19 = areas 7, 17, 18 and 19; dPS = dorsal part of the posterior suprasylvian gyrus; ME, PE = middle and posterior ectosylvian cortices; LIM = limbic (peri and ento-rhinal) cortex. Other conventions as in Fig. 1. Scale bar = 5 mm. From MacNeil et al. [148]. Reproduced with permission of Oxford University Press.

accurate performance on a n u m b e r o f perceptual and cognitive functions by cats with early lesions [52, 57, 99, 100, 154, 242]. This speculation is borne out by the substantial functional compensations neurons in MS cortex undergo following the lesion o f areas 17 and 18 incurred on the day o f birth. In MS cortex neurons develop receptive field properties that are largely indistinguishable from those in MS cortex o f intact cats [99, 100, 248,276] and quite different from the a b n o r m a l properties in MS cortex o f cats which incurred lesions o f areas 17 and 18 in adulth o o d [101,246]. In both the earliest postnatal- and adult-

lesioned cats, the visual signals driving neurons and guiding behavior are derived primarily from ~ (Y) and ~ (W) ganglion cells and the heightened neuronal activities and spared behaviors simply reflect the expansion o f the bypass pathways into and out o f suprasylvian cortex. However, neurons in MS cortex o f cats which sustained lesions at one m o n t h of age, show the same full compensation based on ~ (Y) and 7 (W) ganglion cells and transgeniculate pathway expansions. But, in addition, a subpopulation o f the MS neurons demonstrate stimulus orientation selectivity, which is a property barely detected in MS cortex o f the intact cat [276] and emblematic of

760

B.R. Payne et al./Early brain damage

Fig. I 1. Label (wheat-germ agglutinin conjugated to horseradish peroxidase) transported from MS cortex to the superior colliculus in a cat which sustained a bilateral removal of areas 17 and 18 on the day of birth. Note dense label throughout both stratum griseum superficiale (SGS) and stratum opticum (SO). This pattern of label is unusual because MS cortex in normal cats projects most densely into SO and the deep one-third of SGS [107, 268]. This pattern of labeling shows that the MS projection has expanded to innervate the full thickness of SGS and physically substitute for the fibers from areas 17 and 18 that terminate in the upper two-thirds of SGS. Scale bar = 500/~m.

neurons in areas 17 and 18 [175]. This finding suggests that a subpopulation of MS neurons have acquired functions normally associated with areas 17 and 18. At this stage it is not known if this acquisition simply reflects the amplification of the Y and W conduit along the transgeniculate pathway [142] or whether it is linked to the survival of fl retinal ganglion cells and the transfer of at least some X signals to MS cortex along the same route. In any event, there is no doubt that Y and W signals are the dominant driving force in the parts of the visual system that remain visually active following early damage of primary visual cortex. However, a major point to consider is that the composition of the IPL in the retina is likely to be fundamentally different from that of normal cats [224]. The implication is that the visual signals sent to the brain differ fundamentally from those in normal cats and this difference is likely to have a substantial impact in the processing of visual signals in all visual centers in the brain.

5. Parallel sequelae of primary visual cortex damage in monkeys In monkeys, as in cats, patterns of connections influence the outcome of primary visual cortex damage. This is most evident in d L G N , where all neurons that project to primary visual cortex die following a complete lesion of primary visual cortex [62, 157], whereas neurons pro-

jecting to extrastriate cortex survive [62, 132, 323]. Moreover, there is substantial loss of the numerically dominant fl retinal ganglion cells [61, 65, 290, 291, 317, 318], of which 85% die and virtually eliminate all retinal projections from the fl recipient layers of d L G N [132, 317, 318]. In contrast, all e and 7 cells survive and at least the c~ cells retain substantial projections to their normal targets in d L G N [65, 132, 137, 318]. It is presumed that the 7 ganglion cell projections, which terminate mainly in the midbrain [200, 201,319], are largely unaffected by the cortical lesion. These results clearly match the loss of the majority of fi ganglion cells and the survival of c~ and 7 cells following damage of immature primary visual cortex in the cat [189]. Moreover, like the cat, age at which the lesion is sustained has a major impact on the rapidity and severity of the ganglion cell degeneration. Visual cortex lesions incurred earlier in life induce more rapid and severe degeneration than equivalently large, later lesions [75, 317]. For example, the earliest lesions, during the first postnatal weeks, are characterized by massive death of retinal ganglion cells and the virtually complete retraction of retinal projections from the parvocellular layers and even substantial retractions from the magnocellular layers. Lesions sustained sometime later during the first year are characterized by less degeneration of ganglion cells and the retention of substantial retinal projections to the magnocellular d L G N layers. Lesions sustained several years later are characterized by only limited gan-

B. R. Payne et al./Early brain damage

761

.6.

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Fig. 12. A. Coronal section of the thalamus to show relative levels ofcytochrome oxidase activity in a cat which sustained a unilateral (right) removal of areas 17 and 18 at one month of age P28. Note that level of cytochrome oxidase activity is high in the C complex Ccx of dLGN, which contain neurons that reroute projections to extrastriate cortex (see Fig. 7). This high level of activity indicates that metabolic and neural activity is high and almost comparable to that of the layers A and AI of the intact dLGN on the opposite side. Thus, the C complex has undergone a metabolic compensation that parallels the rerouting and expansion of signal transfer to MS cortex. Activity in the degenerated layers A and Al are severely reduced compared to the high activity in the intact tail of dLGN (A*) and in the opposite dLGN. This decreased activity reflects the degeneration of dLGN neurons and the removal of neuropil. OT = Optic tract; ps = partial sparing due to incomplete removal of the parts of areas 17 and 18 representing the monocular segment of the visual field; A* = intact tail of dLGN, which is connected to the portion of areas 17 and 18 representing the uppermost visual field. On the right side, these parts of areas 17 and 18 were also spared by the lesion. As expected because of the normal or near normal neuropil in the spared portions of dLGN metabolic and hence neural, activity is much higher than in the degenerated A complex. Scale bar = 4 mm. B and C. Enlargements of the intact (B) and degenerated (C) dLGNs. Scale bar = 2 mm. From Payne and Lomber [Ref. 188]. Copyright ~) 1996 Cambridge University Press. Reproduced with permission of Cambridge University Press.

glion cell death and limited retraction of projections even from the parvocellular d L G N layers [75, 317]. There is no doubt that the most vulnerable group of ganglion cells are/3 cells [65], but their sensitivity is graded in an agedependent way characterized by a marked attenuation in later years. It is not known if the greatest ganglion cell loss following the earliest postnatal lesions includes c~ ganglion cells. The partial retraction of retinal projections from the magnocellular layers might support the idea, but it could be that the lesions induce withdrawal of some or all axon arbors, some of which may be redeployed in another visual structure. In any event, both the general pattern and scale of ganglion cell degeneration and withdrawal of retinal projections from d L G N induced by the primary visual cortex lesion are similar to those described in the cat. The one

major difference between cats and monkeys is the length of the period ganglion cells remain vulnerable to the visual cortical damage, the susceptible period in cats extends to the first postnatal month or slightly longer, whereas in monkeys it extends for several years, but in a highly attenuated form. However, an extended period of sensitivity of cat/~ retinal ganglion cells to target removal has been revealed by the use of neurotoxins to induce rapid degeneration of mature d L G N neurons [193-195]. These results suggest that the slowed response of d L G N neurons to visual cortex damage in the mature cat is an important factor contributing to the survival of mature /~ retinal ganglion cells. It is important to acknowledge that the extended period of vulnerability in the monkey has parallels with the period in which the monkey visual system is capable of

762

B. R. Payne et al./Early brain damage g

o~ ~J

,M C)

Intact

Adult Ablation

Neonatal Ablation

Fig. 13. Mean levels of visually evoked neuronal activity in stratum griseum superficiale and stratum opticum for intact cats and cats which sustained bilateral removals of areas 17 and 18 either in adulthood or on the day of birth. Activity = number of action potentials per stimulus presentation with spontaneous activity subtracted. Note that following damage of areas 17 and 18 in the neonate, level of neuronal activity in SGS is comparable to that of neurons in SGS of the intact cat. In contrast, damage to areas 17 and 18 in adulthood markedly depresses neuronal activity in SGS. From Mendola and Payne [154]. Copyright © 1993 Cambridge University Press. Reproduced with permission of Cambridge University Press.

making rapid adjustments in metabolic and physiological activity following blockade or reduction of signals emanating from the eye [26, 139, 270, 284, 322]. As for the cat, this plasticity and the neuron degenerations may both contribute to the emergence of visual capacities. Moreover, following visual cortex damage incurred in adulthood, the emergence of visual capacities may take months to become evident [74, 114, 115, 232, 315]. Almost no information is available on the expansion of pathways following early lesions of primary visual cortex in monkeys. The only relevant data has been provided by Hendrickson and Dineen [109] who showed that, like the cat, the residual neurons in d L G N of monkey hypertrophy following damage to primary visual cortex sustained in infancy suggesting that the neurons expand their dendritic arbors in d L G N and their axon arbors in extrastriate cortex. However, it is not known if, following early damage, additional neurons are also recruited to increase the direct projection to extrastriate cortex numerically. Such an expansion is a distinct possibility because it is known that some d L G N neurons project transiently to parts of extrastriate cortex early in life [229], and such neurons may be able to establish permanent projections in the absence of primary visual cortex, as they do in the cat [119, 142]. Moreover, there are transitory transcortical projections within the visual system of young monkeys [13,220, 302] and some become stabilized following early lesions [303], suggesting that parallel stabilizations might occur to those described in the cat for transcortical projections following early lesions of primary visual cortex [148]. Following early lesions of primary visual cortex in mon-

keys, the expanded pathways are likely to transmit signals derived from both a (Y) and 7 (W) ganglion cells and they are likely to contribute greatly to a monkey's ability to navigate and retrieve and manipulate objects [112, 114, I 15]. Expanded pathways may also contribute to the increased ability of monkeys with early lesions to detect and make accurate eye movements to visual stimuli presented in the scotoma compared to later lesions of primary visual cortex [166]. Moreover, such pathways may also contribute to the ability of monkeys with early lesions to discriminate between different directions of motion (168), a capacity not shared by monkeys with equivalent lesions sustained in adulthood (168). However, these adaptations are counterbalanced by the large loss of fl retinal ganglion cells and the X signals derived from them, which greatly attenuate other types of functions, such as discrimination of fine details and reduced contrast sensitivity [152] and chromatic signals [232], in monkeys that sustained damage to primary visual cortex in adulthood.

6. Parallel sequelae of primary visual cortex damage in humans To our knowledge, there is no information on differences in the structure of the visual system of human patients who incurred damage to primary visual cortex early in life compared to later in life. However, the patterns of degeneration induced by lesions incurred in adulthood resemble closely those identified following damage in monkeys of equivalent maturational status, and by extension, the cat [103, 290, 291, 296]. The degeneration of these and other poorly connected neurons which occurs at a slow pace in the mature brain, may contribute to the substantial delayed appearance of residual visual capacities [306]. There is virtually no systematic data comparing the visual functions in patients with earlier versus later damage of primary visual cortex, although there are some suggestions that visual capacities may be greater following earlier lesions or early hemidecortication. For example, a patient who sustained bilateral damage to visual cortex at birth could avoid obstacles while navigating new ground [217] and, in broad terms, his visual capacities resemble those of the monkey with early bilateral lesion of striate cortex studied by Humphrey [112-114]. Moreover, the patient could detect motion and make moderately accurate saccades. It is also important to recognize the contribution of Teuber [275] who provided data on the greater ability of the younger brain to recover from occipital cortex wounds. He studied several groups of soldiers who sustained gunshot wounds to occipital cortex at different ages. In a long-term follow up study he showed that the induced scotoma shrank: (a) in the majority of soldiers who incurred wounds in their late teens; (b) in somewhat fewer soldiers who incurred wounds in their early twenties; and (c) in substantially fewer soldiers who incurred wounds when 26 years of age or older. Part of this recov-

B. R. Payne et al./Early brain damage ery in the younger brains may be linked to the more efficient and rapid clearance of neurons normally heavily connected with striate cortex and the greater potential adjustments that occur in the visual pathways [75, 76, 317]. In the absence of more systematic data on early versus late lesions of visual cortex we must look to data obtained from patients who underwent hemispherectomy between the ages of 6 and 17 for additional evidence of sparing of visual functions. This group is small. Even so, perimetry shows that, as expected, such hemispherectomy patients have a dense hemianopia. However, results show a good statistical relationship between pointing and target positions on a spatial localization task carried out in the hemianopic field [198] and performance on a line orientation and pattern discrimination tasks are reliably above chance [198]. But of most importance for the present review is the link to age at time of surgery on these tasks. The two patients with operations at 7 years of age or younger showed much greater visual capacities compared to the patient who underwent surgery at 17 years of age [108]. These observations are supported by those made in two patients who underwent hemidecortication during the first year of life and who could subsequently saccade and fixate conspicuous targets in the 'blind' hemifield [34]. While these data on hemidecorticated patients support the thesis of the present review, it is important to acknowledge the recent results of King et al. [131], cited in Section 1, who obtained no evidence on a large battery of tasks for residual vision in the hemianopic field of hemispherectomized patients. King et al. [131] suggest that the visual capacities identified in the cited studies were due to scatter of light into the seeing hemifield. Even with these caveats undermining the usefulness of the data, there is no doubt that substantial functional capacities remain in other systems following hemidecortication and that they are substantially greater following earlier compared to later hemidecortications [293,295]. These latter observations are important because they demonstrate a general latent capacity of the human brain to attempt to compensate for damage acquired early in life, which may parallel that documented more fully for the cat following early lesions of areas 17 and 18.

7. Epilogue and future directions We recognize that it is risky to speculate about the details of the human brain and its response to injury based on work carried out on the cat. However, we think it appropriate to speculate in broad terms because, as outlined earlier, there are broad and substantial similarities in the organization and function of the visual system of cats and monkeys and, by extension, humans. Also, the developmental program in cats, monkeys and humans follow a largely similar sequence. Moreover, there are enough strong similarities in the system-wide anatomical repercussions that result from primary visual

763

cortex damage in young and adult cats and monkeys that we are secure in our prediction that commensurate system-wide repercussions follow primary visual cortex damage in infant and adult humans. Furthermore, we suspect that the repercussions will spare similar classes of behavior to those already described for the cat. Indeed, studies carried out so far support this idea, for we know that visuospatial tasks are performed more adroitly by patients with early than with late lesions of primary visual cortex [29]. Our suspicions are borne out by results obtained from patient G.Y. who shows strong neural activity, as revealed by regional cerebral blood flow measurements, in both the V3 and V5 complexes of areas. In cats, the homologue of the V5 complex is considered to be MS cortex [184] and this cortex is a major site for pathway rewiring and substantial neuronal compensations and the same may be true of the homologue of the V3 complex [area 19 and adjoining cortices; Ref. 184]. Indeed, the V3 complex of areas is thought to play a major role in pattern vision [184, 326] and some aspects of complex pattern vision are spared by early lesions of primary visual cortex in cats [52, 55, 57]. It may be that visual pathways reaching these regions expand, or are at least strengthened, following lesions of primary visual cortex incurred shortly after birth or during childhood as they are in the cat following early lesions of primary visual cortex. Moreover, increased connections and transfer of signals from occipitoparietal into the occipitotemporal cortices may lead to awareness and experience of stimuli. Such expanded connections may also be a prerequisite for verbal responses. Where to from here'? The evidence is strong that early damage of areas 17 and 18 in cats leads to widespread physiological and anatomical changes which extend even to the retinal inner plexiform layer [224]. Many of these changes are likely to occur in humans and other primates following early damage of primary visual cortex and the techniques are now available to examine some of these changes. For instance, activity changes in area V5 can be examined non-invasively in monkeys or humans with early or late lesions of the visual cortex using evoked potentials or functional magnetic resonance imaging (fMRI). In humans such analyses may provide evidence of differences between blindsight in the more normal unconscious mode and that in the rarer conscious mode. Methods are also available for studying, with intracellular injection, the possibility of detailed anatomical changes in fixed postmortem tissue as it becomes available from cases of early or late damage of the visual cortex [80, 147]. Another extremely important avenue to pursue is the role extant islands of striate cortex play in residual visual abilities following striate damage in adulthood. There is no doubt that when such islands are large they contribute greatly, and vision, in an equivalent part of the visual field, is normal, or nearly so. But what is the vision like when the islands are small? Some-in-roads have been

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made into this area by Fendrich et al. [83] but a link between the locus of spared vision and imaged function of the spared island is needed. Whatever links are established, such islands are likely to have an even greater role following early damage of primary visual cortex. Based on our knowledge of the flexibility of the immature brain to alter connections radically (present review) and for cortical axons in the mature cortex to sprout [68, 69], it is relatively straightforward to imagine: (a) substantial rewiring or compression of dLGN inputs onto residual fragments of area 17, and (b) expansion of projections from fragments into functionally silenced and/or structurally deafferented territories in extrastriate cortex. Both of these modifications are likely to contribute greatly to spared vision. A third extremely important avenue to pursue is the differences in visual capacities of people and monkeys who incurred lesions of primary visual cortex at different ages. Particularly important are patients who sustained lesions earlier in life than G.Y. to ascertain whether their visual capacities are greater, or of a different type, from those presented by G.Y. If the sparing is greater or of a different type, it will be a potent example, of how experimental investigations on laboratory animals can guide investigations of the human brain. But more significantly, it will show that the sight in blindsight is greater following earlier lesions of primary visual cortex. This conclusion can be expected to have considerable impact on our understanding of the consequences of lesions in other regions of the developing neocortex and it will epitomize the remarkable ability of the developing human neocortex to adjust to insults.

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Acknowledgements--We would like to thank John Barbur, Giovanni Berlucchi,Jean Bullier, Gillian Einstein, Hillary Rodman, Petra Stoerig and Lawrence Weiskrantz and the anonymous reviewers of Neuropsychologia for their excellent and in some cases, detailed comments on an earlier version of the manuscript. Some of the comments provoked much thought. We thank them for their efforts in keeping us on the straight and narrow and for the resulting improvements to the manuscript. Also, we thank John Barbur and colleaguesand Hillary Rodman and colleagues for giving us access to manuscripts prior to publication. Their generosity is greatly appreciated. The research work in the authors' laboratory is supported by grants from the National Institute for Neurological Diseases and Stroke and the National Institute of Mental Health. These awards are gratefully acknowledge.

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