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Visual representation of space in congenital and acquired strabismus
Behavioural Brain Research 101 (1999) 29 – 36
Research report
Visual representation of space in congenital and acquired strabismus Piero Paolo Battaglini a,*, Maurizio Battaglia Parodi b, Isabella Tiacci a, Giuseppe Ravalico b, Amir Muzur c a
Department of Physiology and Pathology, Uni6ersity of Trieste, 6ia Fleming 22, 34127 Trieste, Italy b Eye Clinic, c/o Ospedale Maggiore, Trieste, Italy c Cogniti6e Neuroscience Sector, International School for Ad6anced Studies, Trieste, Italy
Received 20 March 1998; received in revised form 9 September 1998; accepted 9 September 1998
Abstract The aim of the present work was to readdress the problem of altered spatial localization in strabismic subjects and to assess whether and how spatial representation is affected by the degree of plasticity of the brain. We therefore compared targeting performance in adult subjects affected by acquired strabismus versus children affected by congenital strabismus. Our data confirm the correlation between deviation of the eye and targeting errors, but they also show that this correlation is not present when strabismus occurs early in life. We suggest that the neuronal machinery involved in the building of an internal representation of space reaches its full maturity several years after birth and that this might explain the limited differences observed in targeting errors between normal and strabismic children. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Strabismus; Representation of space; Development
1. Introduction It is current opinion that, in order to evaluate the position of objects in space, the visual system must take into account changes in gaze direction so as to compensate for the image displacements which these produce on the retina and to allow a stable perception of visual space [9]. Hence, it is reasonable to postulate the existence of a central representation of space in the brain, where objects maintain their location irrespective of where their image falls on the retina as a consequence of eye movements, and that this central representation is used for both perceptual and motor purposes ( see [5,16,19], for review). On the basis of this assumption, a number of studies have been carried out in order to find out how this map is built up and to determine what its main features are. * Corresponding author. Tel.: + 39 40 572088; fax: + 39 40 567862.
The matter has been recently approached by studying the accuracy in locating a position in space where a target had previously appeared [2,7,11]. When pastpointing was used and the subjects operated in dim light, there was found to be a vertical asymmetry of space representation, characterized by a correct estimation of upward positions and an overestimation of downward positions [2,7]. Opposite results were obtained by Gnadt et al. [11], who monitored eye movements instead of past-pointing. They found that, compared to eye movements towards visible targets, those directed to targets which had already disappeared were spatially distorted. Spatial distortion had a constant component, characterized by overestimation of upper locations and underestimation of lower locations. This distortion was considerably evident in the dark but reduced in dim light or when the target was presented against a structured background. The different kind of distortion found by Gnadt et al. is, however, not sur-
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prising, given that upward nystagmus is a common finding when working in the dark [17] and this may easily account for the perceptual distortion of upward locations. It appears that in healthy subjects the internal representation of space is spatially distorted along the vertical meridian and, in normal conditions (to which total darkness is an exception) the magnitude of the lower quadrants of the visual field is overestimated with respect to the upper ones. In the above-mentioned work, Gnadt et al. [11] also studied the role played by the oculomotor input in building an egocentric representation of space. They presented the first target in locations other than the straight ahead direction or asked their subjects to fix their gaze on it with different head orientations and found a clear influence of eye position in the orbit on the accuracy of target localization. In other words, the direction of gaze affected the accuracy of the central representation of space. These findings had already been anticipated by several studies devoted to the role played by extraretinal inputs in building a central representation of space. Helmholtz [13] noted that patients affected by acute paralysis of the lateral rectus overestimated the position of objects located laterally in the paretic side of the visual field. Later, Perenin et al. [20] studied the accuracy of space perception in subjects affected by paralysis of one or more oculomotor nerves. When subjects fixated with their strabismic eye, the position of the previously seen target was markedly overestimated by their hand (past-pointing). In addition, whilst past-pointing errors made by non-operated strabismic subjects did not seem to change considerably in time, those of operated patients returned to the pre-operative level within a few days of surgery ([4]; see also the discussion on the importance of the tendon-organ afference in [22]). This may depend on the fact that the brain not only builds an internal representation of the visual space by using information on the position of the eye in the orbit, but also maintains the ability to do this over very long periods in time: when the information changes, the representation changes accordingly, but it soon returns to its previous state. In other words, the brain does not seem not to have enough plasticity to permanently adapt to new changes in sensorimotor information concerning the direction of gaze. Alternatively, it might need a longer time after an injury than that afforded by the test to rearrange the new sensorymotor input, by continuously updating the new information and finally disregarding the old state. These hypotheses led us to study the ability of normal adults and children to position a visible pointer precisely on the location of a previously appeared target and to compare their precision with that of patients affected by one of two forms of strictly horizontal deviation of the eye: congenital or acquired strabismus.
From the physiopathological point of view these two types of strabismus differ dramatically. In congenital strabismus the defect arises when the visual system is not yet completely mature, and this leads to the development of typical sensorial ‘defence’ mechanisms (i.e. abnormal retinal correspondence and suppression). The origin of infantile natural strabismus has been the object of several different theories. According to the most widely accepted one, the primary defect might be maldevelopment of the visual pathways which mediate eye movements and motion [14]. Although the cause of maldevelopment is still rather unclear and in spite of the fact that in patients with congenital strabismus the brain appears to be altered in many different areas [6], it seems clear that the cerebral cortex is strongly involved [12], either in the genesis of the strabismus itself or in the mechanisms adopted to compensate for the abnormal situation. In acquired strabismus, on the other hand, the defect arises at a later stage; it is commonly due to paralysis of one or more extraocular muscles and the lesion accounting for it may cause different alterations, evident in both visual perception (diplopia) and motor performance (past pointing). Part of the present data has already been presented in abstract form [1].
2. Methods A rigorous selection was carried out among the strabismic patients who came under observation over a period of one year. In order to have samples as homogeneous as possible, the criteria adopted for patients to be included in the experimental schedule were that: (a) strabismus had to be strictly horizontal; (b) the affected eye had to be deviated always in the same direction. Since esotropia (eye nasally deviated) was more frequently observed than exotropia (eye temporally deviated), only patients with esotropia were selected; (c) strabismus had to have appeared late in life or had to have been already present in early life (congenital). Diagnosis of acquired and congenital strabismus was obtained from complete clinical ophthalmological examinations carried out by specialized staff according to standard criteria [18]. Experiments were carried out on 32 volunteers, subdivided into two groups. The first group consisted of six adult patients affected by paralytic strabismus and six healthy subjects, age and sex matched. Mean age was 249 6 years, range: 19–35. The mean angle of eye deviation of the strabismic patients was 169 6 cm/m (prismatic dioptres). In five subjects, strabismus was the consequence of a head injury, while in one subject it was due to multiple sclerosis. All patients presented esotropia of the left eye and complained of diplopia.
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The second group consisted of ten children affected by essential infantile esotropia (five of the left eye and five of the right eye) and ten healthy children, age and sex matched. Mean age was 993 years, range: 5–14. The mean angle of deviation of the strabismic children was 18 9 14 cm/m (prismatic dioptres). All the patients had been affected by amblyopia and had undergone occlusion treatment. At the time of the experiments, visual acuity (natural or corrected) was 1 and anomalous correspondence was present. All subjects (and their parents, in the case of children) were informed of the purpose of the research and gave their consent to the experiments, which had previously been approved by a local committee. Subjects were invited to perform the tests with the greatest possible accuracy and without time limits. Experiments were always carried out monocularly, after a complete ophthalmological examination. When needed, correction with an optical lens was allowed; apart from such correction, all subjects had normal vision and normal visual fields. Before starting the experiment, subjects were allowed to familiarize themselves with the experimental procedures. Familiarization ranged from just a few to 20–30 trials, depending on the subject. During the experiments, which were carried out in a dimly lit room, subjects were seated in front of, and 57 cm from, a 27¦ Philips TV monitor connected to a personal computer (Amiga 500) used to generate visual stimuli. The screen borders were covered by a large square of cardboard with a hole of 30° in diameter at its centre to prevent them from being seen. Each subject was asked to use a computer trackball, with their preferred hand, to move a pointer (a small cross, 0.2° in size) on the screen, and to position it on a small white square (0.2° in size) in the centre of the screen. When this task was completed, the square changed into two vertical bars of the same size (the vertical sides of the square) and a second, peripheral target stimulus (a circle 0.2° in diameter) appeared on the screen for 150 ms. Two seconds after the second target had disappeared, the first one changed into two horizontal bars (the horizontal sides of the square), and this was the signal for the subject to move the pointer to the location where the second target had previously appeared. The light intensity of the visual stimuli was subjectively adjusted in such a way that they were barely but still visible when the room was dimly illuminated. This, together with the short time of appearance of the target and the long delay prior to the instruction to move the pointer, ensured that the residual lightening of the phosphors illuminated by the targets had completely disappeared at least 1 sec prior to the instruction to move the pointer. The target stimulus was presented in one of eight different positions, equidistant from each other at 8° from the center of the screen and 7° from the edge of the cut-out in the cardboard. Its site of
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appearance was made less predictable by randomly presenting 30% of the trials in a different location, i.e. 2° radially distant from the standard positions. The data derived from these trials were not included in the statistical analysis. The pattern of stimulation is schematically shown in Fig. 1A, while Fig. 1B reproduces the reconstruction of pointings performed by a representative subject of the control group.
Fig. 1. Schematic representation of the pattern of stimulation (A) and example of collected data (B). (A) The central square represents the fixation target, while the circles indicate the different positions where the target stimulus was presented. Empty circles indicate the non valid positions where the target stimulus randomly appeared (in 30% of the cases). (B) Data from a representative subject of the normal adult group. The main central cross indicates the horizontal and vertical meridians passing through the center of the screen, where the fixation target appeared; scale bars = 1°. Circles represent the positions where the valid target stimuli appeared; crosses indicate the final positions of the pointer. In both A and B, circles and crosses are not scaled for the sake of clarity: their actual size was 0.2°.
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Fig. 2. Graphical representation of data obtained from representative subjects. The location of the eight target stimuli have been overimposed at the intersection of the grey lines, irrespectively of their actual location on the screen. Circles indicate the location of the final pointer, the coordinates of which have been centered on the targets. Scale is in degrees of visual angle. (A) Data from a control test, where the target was always present on the screen, referring to a strabismic subject looking with his deviated eye. (B) Data from a healthy adult subject. (C) Data from a strabismic adult patient whose left eye was nasally deviated by 17°; the subject looked with his non-deviated eye. (D) Same as in C, but this time the subject looked with his deviated eye.
Each subject performed three tests. The first was a control test, in which the target stimulus did not disappear and the subject simply had to position the pointer on it. This test was made binocularly and it had two purposes: (a) to allow the subject to become familiar with the experimental apparatus, and (b) to collect data on the most accurate positionings of the pointer, in order to use them in the off-line analysis to detect possible mistakes in the procedures of data acquisition, graphical reconstruction and statistical analysis. If in this test the distance between the target and the final position of the pointer (hereafter referred to as TE, targeting error) had turned out to be greater than 0.4° (sum of target and pointer sizes), all the data collected after the last correct control test would have been discarded. This never occurred. In the remaining two tests, which were carried out monocularly, the stimulus target disappeared as previously described; they differed from each other only with respect to the eye used by the subject to perform the test. Valid trials were repeated 40 – 64 times (5–8 times for each position); the com-
puter collected the X and Y coordinates of the target stimuli and of the final position of the pointer, calculated the distance between them and computed the means and standard deviations of targeting errors for each position. Rough and computed data were then transferred to a Macintosh CI computer for statistical analysis. Since the data were not normally distributed, statistical analysis was performed with non-parametric MannWhitney rank and unpaired t-test, which are nonparametric tests. Both tests were applied to the same groups of data, and, in order to minimize statistical errors of types I and II, the difference between measurements was assumed to be significant when the P value was less than 0.01.
3. Results Fig. 2 reports the data obtained from some representative observations, according to different methods
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Fig. 3. Summary of data obtained from all adult subjects. (A) The cross indicates the horizontal and vertical meridians of the visual field when the subjects were looking at the central fixation point; scale bars = 1°. The large circle marks the peripheral 8° where the valid targets appeared (at the intersection of the circle with the cross and the short diagonal lines). Different symbols, explained in the figure itself, indicate the mean locations where the pointer was positioned relatively to the eight target locations. For each location, data where obtained from 72 repetitions in the case of control subjects and from 32 repetitions in the case of each one of the two groups of strabismic subjects. Two statistical analyses have been carried out to look for significant differences: in the first analysis, data from normal subjects have been compared to those obtained from strabismics looking with their non-deviated eye; in the second analysis, the latter have been compared to TE performed by the same strabismic subjects when looking with their deviated eye. When significant differences were found, the respective P values have been reported inside the circle for the first analysis and outside the circle for the second one. (B) Correlation between targeting errors and ocular deviation in the group of six strabismic subjects (all esotropic with the left eye) looking with their deviated eye. Crosses indicate the mean values of the X component of TE in each of the eight target locations. Black circles represent mean values of the crosses and have been used to plot the regression line (heavy line) and to compute the square of the regression coefficient, which is reported in the figure together with the equation of the regression line itself.
than that used in Fig. 1B. The final positions of the pointer have been reproduced with respect to target locations, irrespective of the location of the target on the screen. Fig. 2A shows an example of the control test, in which the subject had to position the pointer on the visible target. The mean distance from the target was 0.2 90.18° in all subjects; it was less than the target and pointer size, thus suggesting a good level of accuracy in data collection and analysis. Fig. 2B shows the performance of a healthy subject: the great majority of targeting errors is clearly shifted towards the inferior quadrants. This kind of performance was mainly due to overestimation of targets located in the lower hemifield. Fig. 2C and D show data from a strabismic adult subject. It is evident that the majority of TE, besides being in the lower hemifield, are also lateralized according to the eye deviation. This phenomenon was fre-
quently observed, mainly in adult patients, but it was not the rule for all of them. For further analyses, data referring to adults and children were examined separately and then compared.
3.1. Adults Normal subjects performed almost in the same way when looking with one eye or the other (the comparison of TE relating to each target location never gave a P value lower than 0.3), thus the data referred the left and the right eye were grouped together for further analysis. Fig. 3 illustrates the main data collectively obtained from the adult group. Different symbols (squares, empty and black circles) indicate the mean locations of TE exhibited in each of the eight positions by normal
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Fig. 4. Summary of the data obtained from the children groups. Explanations as in Fig. 3A. For each symbol, data were computed from 72 observations in the case of normal children, 31 in the case of strabismic children with esotropic left eye and 22 for children with esotropic right eye. Contrary to Fig. 3A, no P values are shown outside the circle, because TE performed by strabismic subjects looking with their non-deviated eye as opposed to those looking with their deviated eye did not show any significant difference between the two groups.
subjects, by strabismics looking with the non deviated eye and by strabismics looking with the deviated eye, respectively. TE differed significantly in positions towards the right and bottom of the screen. They were bigger in the strabismic subjects than in the normal ones and, on average, even larger when strabismics looked with the deviated eye. Significant TE were only present in the direction of the deviated eye and downward along the vertical meridian. In Fig. 3B, the mean value of the X component of TE obtained from strabismic subjects looking with the deviated eye has been plotted against the degree of ocular deviation. The regression coefficient computed for TE in all target positions (black circles in the figure) was close to 1, suggesting a good linear correlation between the two variables. When the same calculation was carried out for strabismic subjects looking with the non-deviated eye, no correlation was found (R 2 =0.49). 3.2. Children As in the group of normal adults, in normal children there was no statistical difference in TE between the two eyes, hence the data obtained from both eyes were pooled for analysis. This was carried out in the same way as for the adult group. The only exception was that we had two groups of squinting children (one with esotropic left eye and the other with the esotropic right eye) whose data were analysed separately.
Fig. 4A reports the data obtained from normal children and strabismic children with esotropic left eye. Differences in TE were confined to only one target position, and only when normal children were compared to strabismic children looking with their non-deviated eye. No differences in TE were found between the non-deviated and deviated eyes of strabismic children, and the difference between them and normal children was on the whole very small. Fig. 4B shows the results of this analysis on strabismic children with esotropic right eyes. Significant differences in TE were found among normal children and strabismic children looking with the non-deviated eye, but not when strabismic children looked with one versus the other eye. Generally, both normal and strabismic children displayed an overestimation of almost all target locations, irrespective of which eye was deviated. The overestimation was more pronounced in the lower hemifield along the vertical meridian, again with virtually no differences between strabismic children looking with either eye and control children.
3.3. Adults 6ersus children Fig. 5 compares the data obtained from the esotropic left eyes of adults and children with those obtained from normal subjects. Compared to strabismic adults,
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strabismic children showed, on average, significantly larger TEs (0.7° versus 0.5°, respectively, P B 0.001), irrespective of target locations. In strabismic subjects, TEs were greater in the inferior hemifield and their vertical component was significantly larger in children than in adults. Another difference between squinting adults and squinting children was that the former performed worst when looking with the deviated eye (see Fig. 3A), whilst in the latter no significant differences in TE between the two eyes were found (see Fig. 4A, B).
4. Discussion We found that strabismic adults make more targeting errors when looking with the deviated eye than with the non-deviated one, and that there is a direct correlation between the direction of the deviated eye and the direction of targeting errors. This finding confirms the results obtained from past-pointing experiments carried out in both natural [3,13] and experimental strabismus [10].
Fig. 5. Comparison of targeting errors performed by adults and children, both normal and strabismics. Explanations as in Fig. 3A. The plot is a re-drawing of some of the data presented in Figs. 3 and 4. Note how the great majority of significantly different targeting errors are made in the inferior quadrants, along the vertical axis.
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More interesting and unexpected data were instead obtained for strabismic children. These subjects did not show significant interocular differences in targeting errors, nor was there a clear correlation between the direction of the deviated eye and the targeting errors. Finally, the previously described overestimation of target locations in the inferior quadrants [2,23], which was significantly greater in strabismic adults than in healthy adults, was even greater in children, irrespectively of their being strabismic or not. These novel findings raise complex questions: Why does horizontal strabismus not affect the horizontal representation of space in the congenital group? If the overestimation of target positions in the lower hemifield is larger in strabismic than in normal adults, why don’t strabismic versus normal children display such difference? We do not have an answer to these questions, nevertheless a hypothesis may be tentatively advanced. The great similarity of data obtained in strabismic and normal children and the clear differences these display when compared to adults, may be an age-related effect due to strabismus onset time. In other terms, these findings might be due to the fact that the internal representation of space reaches its full maturity several years after birth. If this were the case, also the absence of a direct correlation between the direction of eye deviation and that of targeting errors observed in strabismic children could be accounted for. It is well known, in fact, that injuries or pathological conditions affecting a developing brain are more easily compensated for than in a fully mature brain. Therefore, strabismus probably somehow affects the building of the internal representation of space, but this does not lead to the clear signs observed in adults, i.e. pastpointing, when it affects very young individuals. In this case, in fact, the brain is still developing, hence it has more plasticity than in adults, and is still able to compensate for the visual field asymmetries induced by strabismus. Previous data reported in the literature may support this interpretation. Studying strabismic amblyopes, for example, Sireteanu et al. [21] proposed that in these subjects the cortical maps of visual space are disorganized, with altered metric and mapping precision. A determinant role of the cerebral cortex has been proposed also by studies on behaving monkeys, which suggest that important steps in generating an internal representation of visual space take place in the cerebral cortex [8,9]. As a measure of cortical development, quantitative counts of synapses in humans are available for the striate cortex [15]. It has been shown that a rapid increase in synaptic density takes place within the first 8 months from birth; synaptic density then decreases, and the adult level is reached at about 11 years of age [15]. Our children’s mean age was lower than this. These data, therefore, suggest that the cerebral
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cortex, i.e. the possible site of space representation, may not be fully mature around the age of our normal and squinting children and certainly was not mature in their previous life span, when strabismus developed.
[10]
[11]
Acknowledgements
[12]
This work has been supported by EC grant CHRXCT93-0267 (DG 12 COMA) and by grants from MURST and CNR, Italy. Authors are also grateful to the C. and D. Callerio Foundation, Trieste, for generously providing facilities.
[13]
[14] [15]
References [1] Battaglini PP, Battaglia Parodi M, Tiacci I, Ravalico G. Pointing performance in young and adult strabismic subjects. Eur J Physiol 1994;69:R182. [2] Battaglini PP, Galletti C, Fattori P. Inaccuracy of pointing to remembered locations in the bi-dimensional space. Neurosci Lett 1990;Suppl 39:S19. [3] Bielschowsky A. Lectures on Motor Anomalies. Hanover: College Publications, 1956. [4] Bock O, Kommerell G. Visual localization after strabismus surgery is compatible with the ‘outflow’ theory. Vis Res 1986;26:1825 – 9. [5] Carpenter RHS. Movements of the Eyes. London: Pion, 1977. [6] Day SH, Norcia AM. Infantile esotropia and the developing visual system. Pediat Ophthalmol 1990;3:281–7. [7] Fattori P, Tiacci I, Battaglini PP. Visuomotor reconstruction of visual space. J Biol Res Boll Soc Ital Biol Sper 1993;69:85 – 92. [8] Fogassi L, Gallese V, Di Pellegrino G, Fadiga L, Gentilucci M, Luppino G, Matelli M, Pedotti A, Rizzolatti G. Space coding by premotor cortex. Exp Brain Res 1992;89:686–90. [9] Galletti C, Battaglini PP, Fattori P. Parietal neurons encoding
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spatial locations in craniotopic coordinates. Exp Brain Res 1993;96:221 – 9. Gauthier GM, Nommay D, Vercher JL. The role of ocular muscle proprioception in visual localization of targets. Science 1990;249:58 – 61. Gnadt JW, Bracewell RM, Andersen RA. Sensorimotor transformation during eye movements to remembered visual targets. Vis Res 1991;31:693 – 715. Hamer RD, Norcia AM, Orel-Bixler D, Hoyt CS. Cortical responses in nasalward and temporalward motion are asymmetric in early but not late onset strabismus. Invest Ophthal Vis Sci 1990;31:289. von Helmholtz H. Handbuch der physiologischen Optik [Southall JPS, Trans.]. Optical Society of America, 1924. Original work published Hamburg: Voss, 1909. Hoyt C, Good W. Infantile strabismus: what is it? where is it? Br J Ophtalmol 1994;78:325 – 6. Huttenlocher PR, de Courten C, Garey LJ, van der Loos J. Synaptogenesis in human visual cortex: evidence for synapse elimination during normal development. Neurosci Lett 1982;33:247 – 52. MacKay DM. Visual stability and voluntary eye movements. In: Jung R. editor. Handbook of Sensory Physiology, vol. VII/3: Central Processing of Visual Information. Part A. Integrative Functions and Comparative Data. Berlin: Springer, 1973:307– 332. Maldonado H, Schlag-Rey M. Head and eye contribution to gaze drift on monkey in darkness. Soc Neurosci Abstr 1982;8:290. von Noorden GK. Binocular Vision and Ocular Motility. New York: Mosby, 1990. Paillard J. Brain and Space. Oxford: Oxford Science, 1991. Perenin MT, Jeannerod M, Prablanc C. Spatial localization with paralyzed eye muscle. Ophthalmologica 1977;175:206 – 14. Sireteanu R, Lagreze WD, Constantinescu DH. Distortions in two-dimensional visual space perception in strabismic observers. Vis Res 1993;33:677 – 90. Steinbach MJ, Smith DR. Spatial localization after strabismus surgery: evidence for inflow. Science 1981;213:1407– 8. Tiacci I, Battaglini PP, Galletti C, Fattori P. Visually guided pointing to remembered locations and subjective representation of space. J Biol Res Boll Soc Ital Biol Sper 1994;70:43 – 9.
Research report
Visual representation of space in congenital and acquired strabismus Piero Paolo Battaglini a,*, Maurizio Battaglia Parodi b, Isabella Tiacci a, Giuseppe Ravalico b, Amir Muzur c a
Department of Physiology and Pathology, Uni6ersity of Trieste, 6ia Fleming 22, 34127 Trieste, Italy b Eye Clinic, c/o Ospedale Maggiore, Trieste, Italy c Cogniti6e Neuroscience Sector, International School for Ad6anced Studies, Trieste, Italy
Received 20 March 1998; received in revised form 9 September 1998; accepted 9 September 1998
Abstract The aim of the present work was to readdress the problem of altered spatial localization in strabismic subjects and to assess whether and how spatial representation is affected by the degree of plasticity of the brain. We therefore compared targeting performance in adult subjects affected by acquired strabismus versus children affected by congenital strabismus. Our data confirm the correlation between deviation of the eye and targeting errors, but they also show that this correlation is not present when strabismus occurs early in life. We suggest that the neuronal machinery involved in the building of an internal representation of space reaches its full maturity several years after birth and that this might explain the limited differences observed in targeting errors between normal and strabismic children. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Strabismus; Representation of space; Development
1. Introduction It is current opinion that, in order to evaluate the position of objects in space, the visual system must take into account changes in gaze direction so as to compensate for the image displacements which these produce on the retina and to allow a stable perception of visual space [9]. Hence, it is reasonable to postulate the existence of a central representation of space in the brain, where objects maintain their location irrespective of where their image falls on the retina as a consequence of eye movements, and that this central representation is used for both perceptual and motor purposes ( see [5,16,19], for review). On the basis of this assumption, a number of studies have been carried out in order to find out how this map is built up and to determine what its main features are. * Corresponding author. Tel.: + 39 40 572088; fax: + 39 40 567862.
The matter has been recently approached by studying the accuracy in locating a position in space where a target had previously appeared [2,7,11]. When pastpointing was used and the subjects operated in dim light, there was found to be a vertical asymmetry of space representation, characterized by a correct estimation of upward positions and an overestimation of downward positions [2,7]. Opposite results were obtained by Gnadt et al. [11], who monitored eye movements instead of past-pointing. They found that, compared to eye movements towards visible targets, those directed to targets which had already disappeared were spatially distorted. Spatial distortion had a constant component, characterized by overestimation of upper locations and underestimation of lower locations. This distortion was considerably evident in the dark but reduced in dim light or when the target was presented against a structured background. The different kind of distortion found by Gnadt et al. is, however, not sur-
0166-4328/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S0166-4328(98)00136-3
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prising, given that upward nystagmus is a common finding when working in the dark [17] and this may easily account for the perceptual distortion of upward locations. It appears that in healthy subjects the internal representation of space is spatially distorted along the vertical meridian and, in normal conditions (to which total darkness is an exception) the magnitude of the lower quadrants of the visual field is overestimated with respect to the upper ones. In the above-mentioned work, Gnadt et al. [11] also studied the role played by the oculomotor input in building an egocentric representation of space. They presented the first target in locations other than the straight ahead direction or asked their subjects to fix their gaze on it with different head orientations and found a clear influence of eye position in the orbit on the accuracy of target localization. In other words, the direction of gaze affected the accuracy of the central representation of space. These findings had already been anticipated by several studies devoted to the role played by extraretinal inputs in building a central representation of space. Helmholtz [13] noted that patients affected by acute paralysis of the lateral rectus overestimated the position of objects located laterally in the paretic side of the visual field. Later, Perenin et al. [20] studied the accuracy of space perception in subjects affected by paralysis of one or more oculomotor nerves. When subjects fixated with their strabismic eye, the position of the previously seen target was markedly overestimated by their hand (past-pointing). In addition, whilst past-pointing errors made by non-operated strabismic subjects did not seem to change considerably in time, those of operated patients returned to the pre-operative level within a few days of surgery ([4]; see also the discussion on the importance of the tendon-organ afference in [22]). This may depend on the fact that the brain not only builds an internal representation of the visual space by using information on the position of the eye in the orbit, but also maintains the ability to do this over very long periods in time: when the information changes, the representation changes accordingly, but it soon returns to its previous state. In other words, the brain does not seem not to have enough plasticity to permanently adapt to new changes in sensorimotor information concerning the direction of gaze. Alternatively, it might need a longer time after an injury than that afforded by the test to rearrange the new sensorymotor input, by continuously updating the new information and finally disregarding the old state. These hypotheses led us to study the ability of normal adults and children to position a visible pointer precisely on the location of a previously appeared target and to compare their precision with that of patients affected by one of two forms of strictly horizontal deviation of the eye: congenital or acquired strabismus.
From the physiopathological point of view these two types of strabismus differ dramatically. In congenital strabismus the defect arises when the visual system is not yet completely mature, and this leads to the development of typical sensorial ‘defence’ mechanisms (i.e. abnormal retinal correspondence and suppression). The origin of infantile natural strabismus has been the object of several different theories. According to the most widely accepted one, the primary defect might be maldevelopment of the visual pathways which mediate eye movements and motion [14]. Although the cause of maldevelopment is still rather unclear and in spite of the fact that in patients with congenital strabismus the brain appears to be altered in many different areas [6], it seems clear that the cerebral cortex is strongly involved [12], either in the genesis of the strabismus itself or in the mechanisms adopted to compensate for the abnormal situation. In acquired strabismus, on the other hand, the defect arises at a later stage; it is commonly due to paralysis of one or more extraocular muscles and the lesion accounting for it may cause different alterations, evident in both visual perception (diplopia) and motor performance (past pointing). Part of the present data has already been presented in abstract form [1].
2. Methods A rigorous selection was carried out among the strabismic patients who came under observation over a period of one year. In order to have samples as homogeneous as possible, the criteria adopted for patients to be included in the experimental schedule were that: (a) strabismus had to be strictly horizontal; (b) the affected eye had to be deviated always in the same direction. Since esotropia (eye nasally deviated) was more frequently observed than exotropia (eye temporally deviated), only patients with esotropia were selected; (c) strabismus had to have appeared late in life or had to have been already present in early life (congenital). Diagnosis of acquired and congenital strabismus was obtained from complete clinical ophthalmological examinations carried out by specialized staff according to standard criteria [18]. Experiments were carried out on 32 volunteers, subdivided into two groups. The first group consisted of six adult patients affected by paralytic strabismus and six healthy subjects, age and sex matched. Mean age was 249 6 years, range: 19–35. The mean angle of eye deviation of the strabismic patients was 169 6 cm/m (prismatic dioptres). In five subjects, strabismus was the consequence of a head injury, while in one subject it was due to multiple sclerosis. All patients presented esotropia of the left eye and complained of diplopia.
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The second group consisted of ten children affected by essential infantile esotropia (five of the left eye and five of the right eye) and ten healthy children, age and sex matched. Mean age was 993 years, range: 5–14. The mean angle of deviation of the strabismic children was 18 9 14 cm/m (prismatic dioptres). All the patients had been affected by amblyopia and had undergone occlusion treatment. At the time of the experiments, visual acuity (natural or corrected) was 1 and anomalous correspondence was present. All subjects (and their parents, in the case of children) were informed of the purpose of the research and gave their consent to the experiments, which had previously been approved by a local committee. Subjects were invited to perform the tests with the greatest possible accuracy and without time limits. Experiments were always carried out monocularly, after a complete ophthalmological examination. When needed, correction with an optical lens was allowed; apart from such correction, all subjects had normal vision and normal visual fields. Before starting the experiment, subjects were allowed to familiarize themselves with the experimental procedures. Familiarization ranged from just a few to 20–30 trials, depending on the subject. During the experiments, which were carried out in a dimly lit room, subjects were seated in front of, and 57 cm from, a 27¦ Philips TV monitor connected to a personal computer (Amiga 500) used to generate visual stimuli. The screen borders were covered by a large square of cardboard with a hole of 30° in diameter at its centre to prevent them from being seen. Each subject was asked to use a computer trackball, with their preferred hand, to move a pointer (a small cross, 0.2° in size) on the screen, and to position it on a small white square (0.2° in size) in the centre of the screen. When this task was completed, the square changed into two vertical bars of the same size (the vertical sides of the square) and a second, peripheral target stimulus (a circle 0.2° in diameter) appeared on the screen for 150 ms. Two seconds after the second target had disappeared, the first one changed into two horizontal bars (the horizontal sides of the square), and this was the signal for the subject to move the pointer to the location where the second target had previously appeared. The light intensity of the visual stimuli was subjectively adjusted in such a way that they were barely but still visible when the room was dimly illuminated. This, together with the short time of appearance of the target and the long delay prior to the instruction to move the pointer, ensured that the residual lightening of the phosphors illuminated by the targets had completely disappeared at least 1 sec prior to the instruction to move the pointer. The target stimulus was presented in one of eight different positions, equidistant from each other at 8° from the center of the screen and 7° from the edge of the cut-out in the cardboard. Its site of
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appearance was made less predictable by randomly presenting 30% of the trials in a different location, i.e. 2° radially distant from the standard positions. The data derived from these trials were not included in the statistical analysis. The pattern of stimulation is schematically shown in Fig. 1A, while Fig. 1B reproduces the reconstruction of pointings performed by a representative subject of the control group.
Fig. 1. Schematic representation of the pattern of stimulation (A) and example of collected data (B). (A) The central square represents the fixation target, while the circles indicate the different positions where the target stimulus was presented. Empty circles indicate the non valid positions where the target stimulus randomly appeared (in 30% of the cases). (B) Data from a representative subject of the normal adult group. The main central cross indicates the horizontal and vertical meridians passing through the center of the screen, where the fixation target appeared; scale bars = 1°. Circles represent the positions where the valid target stimuli appeared; crosses indicate the final positions of the pointer. In both A and B, circles and crosses are not scaled for the sake of clarity: their actual size was 0.2°.
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Fig. 2. Graphical representation of data obtained from representative subjects. The location of the eight target stimuli have been overimposed at the intersection of the grey lines, irrespectively of their actual location on the screen. Circles indicate the location of the final pointer, the coordinates of which have been centered on the targets. Scale is in degrees of visual angle. (A) Data from a control test, where the target was always present on the screen, referring to a strabismic subject looking with his deviated eye. (B) Data from a healthy adult subject. (C) Data from a strabismic adult patient whose left eye was nasally deviated by 17°; the subject looked with his non-deviated eye. (D) Same as in C, but this time the subject looked with his deviated eye.
Each subject performed three tests. The first was a control test, in which the target stimulus did not disappear and the subject simply had to position the pointer on it. This test was made binocularly and it had two purposes: (a) to allow the subject to become familiar with the experimental apparatus, and (b) to collect data on the most accurate positionings of the pointer, in order to use them in the off-line analysis to detect possible mistakes in the procedures of data acquisition, graphical reconstruction and statistical analysis. If in this test the distance between the target and the final position of the pointer (hereafter referred to as TE, targeting error) had turned out to be greater than 0.4° (sum of target and pointer sizes), all the data collected after the last correct control test would have been discarded. This never occurred. In the remaining two tests, which were carried out monocularly, the stimulus target disappeared as previously described; they differed from each other only with respect to the eye used by the subject to perform the test. Valid trials were repeated 40 – 64 times (5–8 times for each position); the com-
puter collected the X and Y coordinates of the target stimuli and of the final position of the pointer, calculated the distance between them and computed the means and standard deviations of targeting errors for each position. Rough and computed data were then transferred to a Macintosh CI computer for statistical analysis. Since the data were not normally distributed, statistical analysis was performed with non-parametric MannWhitney rank and unpaired t-test, which are nonparametric tests. Both tests were applied to the same groups of data, and, in order to minimize statistical errors of types I and II, the difference between measurements was assumed to be significant when the P value was less than 0.01.
3. Results Fig. 2 reports the data obtained from some representative observations, according to different methods
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Fig. 3. Summary of data obtained from all adult subjects. (A) The cross indicates the horizontal and vertical meridians of the visual field when the subjects were looking at the central fixation point; scale bars = 1°. The large circle marks the peripheral 8° where the valid targets appeared (at the intersection of the circle with the cross and the short diagonal lines). Different symbols, explained in the figure itself, indicate the mean locations where the pointer was positioned relatively to the eight target locations. For each location, data where obtained from 72 repetitions in the case of control subjects and from 32 repetitions in the case of each one of the two groups of strabismic subjects. Two statistical analyses have been carried out to look for significant differences: in the first analysis, data from normal subjects have been compared to those obtained from strabismics looking with their non-deviated eye; in the second analysis, the latter have been compared to TE performed by the same strabismic subjects when looking with their deviated eye. When significant differences were found, the respective P values have been reported inside the circle for the first analysis and outside the circle for the second one. (B) Correlation between targeting errors and ocular deviation in the group of six strabismic subjects (all esotropic with the left eye) looking with their deviated eye. Crosses indicate the mean values of the X component of TE in each of the eight target locations. Black circles represent mean values of the crosses and have been used to plot the regression line (heavy line) and to compute the square of the regression coefficient, which is reported in the figure together with the equation of the regression line itself.
than that used in Fig. 1B. The final positions of the pointer have been reproduced with respect to target locations, irrespective of the location of the target on the screen. Fig. 2A shows an example of the control test, in which the subject had to position the pointer on the visible target. The mean distance from the target was 0.2 90.18° in all subjects; it was less than the target and pointer size, thus suggesting a good level of accuracy in data collection and analysis. Fig. 2B shows the performance of a healthy subject: the great majority of targeting errors is clearly shifted towards the inferior quadrants. This kind of performance was mainly due to overestimation of targets located in the lower hemifield. Fig. 2C and D show data from a strabismic adult subject. It is evident that the majority of TE, besides being in the lower hemifield, are also lateralized according to the eye deviation. This phenomenon was fre-
quently observed, mainly in adult patients, but it was not the rule for all of them. For further analyses, data referring to adults and children were examined separately and then compared.
3.1. Adults Normal subjects performed almost in the same way when looking with one eye or the other (the comparison of TE relating to each target location never gave a P value lower than 0.3), thus the data referred the left and the right eye were grouped together for further analysis. Fig. 3 illustrates the main data collectively obtained from the adult group. Different symbols (squares, empty and black circles) indicate the mean locations of TE exhibited in each of the eight positions by normal
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Fig. 4. Summary of the data obtained from the children groups. Explanations as in Fig. 3A. For each symbol, data were computed from 72 observations in the case of normal children, 31 in the case of strabismic children with esotropic left eye and 22 for children with esotropic right eye. Contrary to Fig. 3A, no P values are shown outside the circle, because TE performed by strabismic subjects looking with their non-deviated eye as opposed to those looking with their deviated eye did not show any significant difference between the two groups.
subjects, by strabismics looking with the non deviated eye and by strabismics looking with the deviated eye, respectively. TE differed significantly in positions towards the right and bottom of the screen. They were bigger in the strabismic subjects than in the normal ones and, on average, even larger when strabismics looked with the deviated eye. Significant TE were only present in the direction of the deviated eye and downward along the vertical meridian. In Fig. 3B, the mean value of the X component of TE obtained from strabismic subjects looking with the deviated eye has been plotted against the degree of ocular deviation. The regression coefficient computed for TE in all target positions (black circles in the figure) was close to 1, suggesting a good linear correlation between the two variables. When the same calculation was carried out for strabismic subjects looking with the non-deviated eye, no correlation was found (R 2 =0.49). 3.2. Children As in the group of normal adults, in normal children there was no statistical difference in TE between the two eyes, hence the data obtained from both eyes were pooled for analysis. This was carried out in the same way as for the adult group. The only exception was that we had two groups of squinting children (one with esotropic left eye and the other with the esotropic right eye) whose data were analysed separately.
Fig. 4A reports the data obtained from normal children and strabismic children with esotropic left eye. Differences in TE were confined to only one target position, and only when normal children were compared to strabismic children looking with their non-deviated eye. No differences in TE were found between the non-deviated and deviated eyes of strabismic children, and the difference between them and normal children was on the whole very small. Fig. 4B shows the results of this analysis on strabismic children with esotropic right eyes. Significant differences in TE were found among normal children and strabismic children looking with the non-deviated eye, but not when strabismic children looked with one versus the other eye. Generally, both normal and strabismic children displayed an overestimation of almost all target locations, irrespective of which eye was deviated. The overestimation was more pronounced in the lower hemifield along the vertical meridian, again with virtually no differences between strabismic children looking with either eye and control children.
3.3. Adults 6ersus children Fig. 5 compares the data obtained from the esotropic left eyes of adults and children with those obtained from normal subjects. Compared to strabismic adults,
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strabismic children showed, on average, significantly larger TEs (0.7° versus 0.5°, respectively, P B 0.001), irrespective of target locations. In strabismic subjects, TEs were greater in the inferior hemifield and their vertical component was significantly larger in children than in adults. Another difference between squinting adults and squinting children was that the former performed worst when looking with the deviated eye (see Fig. 3A), whilst in the latter no significant differences in TE between the two eyes were found (see Fig. 4A, B).
4. Discussion We found that strabismic adults make more targeting errors when looking with the deviated eye than with the non-deviated one, and that there is a direct correlation between the direction of the deviated eye and the direction of targeting errors. This finding confirms the results obtained from past-pointing experiments carried out in both natural [3,13] and experimental strabismus [10].
Fig. 5. Comparison of targeting errors performed by adults and children, both normal and strabismics. Explanations as in Fig. 3A. The plot is a re-drawing of some of the data presented in Figs. 3 and 4. Note how the great majority of significantly different targeting errors are made in the inferior quadrants, along the vertical axis.
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More interesting and unexpected data were instead obtained for strabismic children. These subjects did not show significant interocular differences in targeting errors, nor was there a clear correlation between the direction of the deviated eye and the targeting errors. Finally, the previously described overestimation of target locations in the inferior quadrants [2,23], which was significantly greater in strabismic adults than in healthy adults, was even greater in children, irrespectively of their being strabismic or not. These novel findings raise complex questions: Why does horizontal strabismus not affect the horizontal representation of space in the congenital group? If the overestimation of target positions in the lower hemifield is larger in strabismic than in normal adults, why don’t strabismic versus normal children display such difference? We do not have an answer to these questions, nevertheless a hypothesis may be tentatively advanced. The great similarity of data obtained in strabismic and normal children and the clear differences these display when compared to adults, may be an age-related effect due to strabismus onset time. In other terms, these findings might be due to the fact that the internal representation of space reaches its full maturity several years after birth. If this were the case, also the absence of a direct correlation between the direction of eye deviation and that of targeting errors observed in strabismic children could be accounted for. It is well known, in fact, that injuries or pathological conditions affecting a developing brain are more easily compensated for than in a fully mature brain. Therefore, strabismus probably somehow affects the building of the internal representation of space, but this does not lead to the clear signs observed in adults, i.e. pastpointing, when it affects very young individuals. In this case, in fact, the brain is still developing, hence it has more plasticity than in adults, and is still able to compensate for the visual field asymmetries induced by strabismus. Previous data reported in the literature may support this interpretation. Studying strabismic amblyopes, for example, Sireteanu et al. [21] proposed that in these subjects the cortical maps of visual space are disorganized, with altered metric and mapping precision. A determinant role of the cerebral cortex has been proposed also by studies on behaving monkeys, which suggest that important steps in generating an internal representation of visual space take place in the cerebral cortex [8,9]. As a measure of cortical development, quantitative counts of synapses in humans are available for the striate cortex [15]. It has been shown that a rapid increase in synaptic density takes place within the first 8 months from birth; synaptic density then decreases, and the adult level is reached at about 11 years of age [15]. Our children’s mean age was lower than this. These data, therefore, suggest that the cerebral
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cortex, i.e. the possible site of space representation, may not be fully mature around the age of our normal and squinting children and certainly was not mature in their previous life span, when strabismus developed.
[10]
[11]
Acknowledgements
[12]
This work has been supported by EC grant CHRXCT93-0267 (DG 12 COMA) and by grants from MURST and CNR, Italy. Authors are also grateful to the C. and D. Callerio Foundation, Trieste, for generously providing facilities.
[13]
[14] [15]
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