Area-Specific Amblyopic Effects in Human Occipitotemporal Object Representations

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Neuron, Vol. 40, 1023–1029, December 4, 2003, Copyright 2003 by Cell Press

Area-Specific Amblyopic Effects in Human Occipitotemporal Object Representations Y. Lerner,1,6 P. Pianka,2,6 B. Azmon,3 H. Leiba,4 C. Stolovitch,2,5 A. Loewenstein,2,5 M. Harel,1 T. Hendler,2,5 and R. Malach1,* 1 Weizmann Institute of Science Rehovot, 76100 2 Sourasky Medical Center Tel Aviv, 64239 3 Notal Vision Co. Tel Aviv, 63143 4 Kaplan Medical Center Rehovot, 76100 5 Tel Aviv University Tel Aviv, 69978 Israel

Summary The role of early visual experience in the establishment of human high-order visual areas is poorly understood. Here we investigated this issue using human amblyopia—a developmental visual disorder, which manifests a central vision (acuity) deficit. Previous fMRI studies of amblyopes have described abnormal functional activations in early retinotopic areas. Here we report the surprising finding of a selective object-related abnormality in high-order occipitotemporal cortex. Specifically, we found that face-related cortical areas show a severe disconnection from the amblyopic eye, while building-related regions remain essentially normal. The selectivity of the deficit highlights the differential computations performed in the different objectrelated areas and is compatible with the suggested association of face regions with analysis of fine detail. Introduction To what extent does normal visual experience during childhood play a role in the proper development of human visual areas? This fundamental question has been debated extensively, but little relevant functional data is presently available to address it. A particularly striking example of the role of early visual experience on the human visual system is presented through the case of developmental amblyopia—a condition of reduced visual acuity and contrast sensitivity, usually in one eye, which is commonly associated either with abnormal ocular alignment (strabismus) or unequal refractive error between the two eyes (anisometropia) in early childhood (Hess et al., 1978; von Noorden, 1988; Hess et al., 1990; Levi and Carkeet, 1993; Kiorpes and Movshon, 1996; Movshon et al., 1996). Such abnormal visual experience leads to malfunction in cortical circuits, while retinal and thalamic functions appear normal (Hubel and Wiesel, 1965). The nature of the cortical abnormalities is under *Correspondence: [email protected] 6 These authors contributed equally to this work.

debate, but the acuity loss is suggestive of a deficit of central visual field processing. We have recently found, in normal subjects, that certain object images, particularly faces and buildings, appear to show differential association with central and peripheral visual field representations (Levy et al., 2001; Hasson et al., 2002). Such association may suggest that amblyopia could differentially affect representation of face images compared to building images. Here we examined this possibility with fMRI to map brain activation in amblyopic subjects using images of faces and buildings. Our results reveal a strikingly specific deficit in objectrelated regions. Thus, face images presented through the amblyopic eyes failed to activate the face-related fusiform (pFs) (Kanwisher et al., 1997; McCarthy et al., 1997; Haxby et al., 2000) gyrus and a face-related part of LO (the lateral occipital region) located in the inferioroccipital gyrus (IOG). In contrast, building images presented through the amblyopic eye produced normal activations in the building- and scene-related collateral (CoS) (Aguirre et al., 1998; Epstein and Kanwisher, 1998; Ishai et al., 1999) and transverse-occipital (TOS) sulci. These results show a preferential dependence of facerelated regions on normal visual experience. Furthermore, they highlight the highly differentiated nature of cortical processes associated with different objectrelated areas. Results To explore the impact of amblyopia on high-order visual areas, we compared the fMRI activations for images of faces and buildings, presented separately to the sound and amblyopic eyes using red-green glasses (Figure 1, see Experimental Procedures). The experiment was conducted in 14 amblyopic subjects (version I and version II). A detailed list of the patients and their amblyopic conditions is provided in Table 1. Figures 2 and 3 show the results of this experiment averaged across 13 subjects (version I) and an example of a single subject, respectively. As can be seen, when presented through the sound eye (Figure 2A), a typical pattern of facerelated (filled arrows, red) (Kanwisher et al., 1997; Tong et al., 2000; Haxby et al., 2000, 2001; Levy et al., 2001) and building-related (open arrows, green) (Aguirre et al., 1998; Epstein and Kanwisher, 1998; Ishai et al., 1999) activation was found. In contrast, when the amblyopic eye was tested, a profound deficit in face-related regions was found (filled arrows, Figure 2B), while the building-related regions remained relatively normal (open arrows, Figure 2B). Compatible with these maps, when the activation for both face and building images presented through the sound eye was compared to the activation through the amblyopic eye, a consistently stronger activation for the sound eye was found in the posterior fusiform and inferior-occipital gyri face-related regions (filled arrows, Figure 2C) (pFs: left, x, y, z: ⫺37 ⫾ 6, ⫺53 ⫾ 7, ⫺13 ⫾

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4A. A significant amblyopic-related activation reduction was found for face images in the face-related pFs and IOG (percent signal change: IOG: 1.3 ⫾ 0.2 versus 0.5 ⫾ 0.1; one-tailed paired t test: p ⬍ 0.004; pFs: 1.26 ⫾ 0.2 versus 0.45 ⫾ 0.08; p ⬍ 0.0009; n ⫽ 13). Interestingly, the reduction was face specific and did not appear to generalize to the building images (percent signal change: IOG: 0.5 ⫾ 0.08 versus 0.45 ⫾ 0.1; one-tailed paired t test: p ⫽ 0.3; pFs: 0.39 ⫾ 0.06 versus 0.4 ⫾ 0.1; p ⫽ 0.5). In contrast, no significant activation reduction was found for visual stimuli in the building-related CoS and TOS. Here, similar activation for both eyes was found for both face and building images (CoS, p ⫽ 0.3; TOS, p ⫽ 0.2). To examine to what extent the deprivation effect was secondary to disruption in early retinotopic areas, we sampled the activation in these regions. To that end, regions of interest in the mid-central and peripheral visual field representations were externally defined using a separate experiment in which small and large object images were compared (see Experimental Procedures). The boundaries of early retinotopic cortex were delineated using meridian mapping through the sound eye (see Experimental Procedures). In contrast to the findings in high-order visual areas, the results in early visual cortex revealed that the activation degradation for the amblyopic eye was milder and did not show the face-selective deprivation effect. Thus, in the peripheral region of interest, activation by the sound eye for faces and houses was 0.59% ⫾ 0.09% and 0.6% ⫾ 0.1%, respectively, while for the amblyopic eye, activation was reduced to 0.48% ⫾ 0.06% for faces and 0.48% ⫾ 0.08% for houses. For the mid-central ROI, the activation for the sound eye was 0.84% ⫾ 0.16% for faces and 0.84% ⫾ 0.17% for houses, with the amblyopic eye activation showing a reduction for faces to 0.67% ⫾ 0.17% and houses to 0.58% ⫾ 0.09%, this difference was not statistically significant (one-tailed paired t test, p ⫽ 0.18). Could the amblyopic deficit in high-order occipitotemporal cortex be explained by a simple deficit in low-

Figure 1. Visual Stimuli Example of stimuli used in the experiment to map the face- and building-related areas in amblyopic and control subjects. For separate stimulation to the amblyopic and sound eye, stimuli were colored in red and green, and red-green glasses were used to view the images. An interleaved short epoch design was used (see Experimental Procedures).

3; right, x, y, z: 34 ⫾ 6, ⫺52 ⫾ 4, ⫺12 ⫾ 3; IOG: left, x, y, z: ⫺42 ⫾ 3, ⫺69 ⫾ 5, ⫺6 ⫾ 4; right, x, y, z: 41 ⫾ 4, ⫺67 ⫾ 3, ⫺6 ⫾ 3). The building-related collateral sulcus as well as dorsal transverse-occipital sulcus (CoS: left, x, y, z: ⫺27 ⫾ 1, ⫺40 ⫾ 6, ⫺9 ⫾ 3; right, x, y, z: 25 ⫾ 3, ⫺40 ⫾ 6, ⫺8 ⫾ 2; TOS; left, x, y, z: ⫺34 ⫾ 4, ⫺75 ⫾ 2, 13 ⫾ 2; right, x, y, z: 34 ⫾ 4, ⫺73 ⫾ 5, 12 ⫾ 3) did not manifest any enhanced activation for sound-eye stimulation (open arrows, Figure 2C). The phenomenon was quite consistent. Of 14 amblyopic patients studied in the two experimental versions (analysis was done independently for each subject, see Data Analysis), ten showed drastically reduced activity in the face-related IOG and pFs but not in the building-related CoS (see a representative subject in Figure 3). No significant difference was observed between the two experimental versions. To obtain a more quantitative estimate of the effect, we analyzed the percent signal change in the face- and building-related regions of interest (open and filled arrows in Figure 2A). The results are shown in Figure

Table 1. Details of the Amblyopic Subjects and Their Visual Examination Subject

Type

Amblyopic Eye

Age/Sex

VA/RE

VA/LE

Ref RE

Ref LE

BB BT SU BMa ELa PTa BP FE QJa,b FN FPa GC ZT ZL IKb WAb JOb

An Str Str Str Str Str Str Str Str An Str Str Str Str Str An Str

LE LE LE LE LE LE LE LE LE LE LE RE RE RE LE RE LE

27/F 25/F 35/M 16/F 21/M 22/M 72/M 50/F 36/F 14/F 27/F 39/M 43/F 15/M 27/F 56/F 34/M

6/6 6/6 6/10 6/6 6/6 6/7.5 6/30 6/8.5 6/6 6/6.5 6/6 1/24 6/30 6/6 6/6 6/20 6/6

6/30 6/40 6/15 6/30 6/30 6/30 6/60 6/60 6/60 6/30 1/24 6/9 6/6 6/60 6/12 6/6 6/15

⫹0.25 ⫺0.25 ⫹0.5 ⫺0.5 ⫺0.25 ⫹0.5 ⫹2.0 ⫹3.0 ⫹2.75⫹1.25*90 ⫹1.75⫹0.5*80 ⫺0.5 ⫹0.5⫹1.0*90 ⫺2.5⫹1.0*70 ⫺0.75 ⫺2.0 ⫺2.0 ⫺0.75

⫹0.5⫹3.5*80 ⫺0.5⫹0.75*90 ⫹0.5 ⫺0.5*90 ⫺0.5 ⫹1.0⫹0.5*90 ⫹2.0 ⫹3.0 ⫹1.5⫹0.5*90 ⫹2.0⫹2.5*120 ⫺1.25⫹0.25*70 ⫹1.5 ⫺0.5 ⫺1.0 ⫺2.0⫺0.5*90 ⫺9.0 ⫺0.5

An, anisometropia; Str, strabismus; VA, optometric (line chart) visual acuity test. Note that visual acuity is given after best optical correction was prescribed. Ref, optical refractive correction. a The subjects from which the MTF function for the control experiment 1 was derived. b The subjects took part in the control experiment 2.

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Figure 3. Object-Related Areas—Single-Subject Maps (A) An example of face- and building-related regions mapped through the sound eye in a single subject (version I). (B) Sound eye versus amblyopic eye. Presentation format and statistical tests as in Figure 2. Borders of visual retinotopic areas are denoted by dotted lines.

Figure 2. Object-Related Areas—Multisubject Maps—Version I (A) Sound eye stimulation. Preferential activation for faces (red, filled arrows) versus buildings (green, open arrows) presented on unfolded hemispheres. R, right; L, left. A, anterior; P, posterior. Dotted lines, anterior border of retinotopic areas. IOG, inferior occipital gyrus; pFs, posterior fusiform gyrus; CoS, collateral sulcus; TOS, transverse-occipital sulcus. (B) Same as (A), but stimuli presented through amblyopic eye. Note selective deficit in face-related regions. (C) Maps showing preferential activation to sound (red) versus amblyopic (blue) eyes. Note again the sound eye advantage in facebut not building-related regions.

level sensory mechanisms such as loss of contrast sensitivity to high spatial frequencies? To examine this possibility, we simulated the amblyopic condition by measuring the contrast sensitivity function of the amblyopic eyes and adjusted the face and house images used in the original experiment by an equivalent degree of blur (see Experimental Procedures for details). We then compared the activation of the original images and the blurred images in a group of six control healthy subjects. This comparison demonstrated a reduction in the overall visual activation in occipitotemporal cortex for the blur condition (albeit not statistically significant; faces: IOG,

p ⫽ 0.1; pFs, p ⫽ 0.1; buildings: CoS, p ⫽ 0.2, TOS, p ⫽ 0.3; one-tailed paired t test). However, in clear contrast to the amblyopic condition, blur by itself did not induce any selective deficit in face-related regions. Comparison of the pattern of activation of the original and blurred images (Figure 5) revealed an almost identical pattern in face- and building-related regions during stimulation by normal (Figure 5A) and blurred (Figure 5B) images. Could the amblyopic deficit be mimicked by introducing simple blur to the nonamblyopic eye? To explore this point, we repeated the control experiment, but this time the amblyopic conditions were simulated on the sound eye of the amblyopic subjects (n ⫽ 4, see Experimental Procedures). We compared the activation of the sound eyes obtained by the blurred images and the activation of the amblyopic eyes obtained by the original stimuli. The results of such a comparison revealed that, in contrast to the real amblyopic effect and similar to normal subjects, simulated blur did not produce a faceselective deficit in the sound eye of the amblyopic patients (percent signal change: IOG: 0.9 ⫾ 0.1 for “simulated blur” versus 0.4 ⫾ 0.1 for amblyopic; one-tailed paired t test: p ⬍ 0.008; pFs: 0.8 ⫾ 0.1 for “simulated blur” versus 0.27 ⫾ 0.03 for amblyopic; p ⬍ 0.006). How does the amblyopic fMRI deficit relate to the behavioral performance of the patients? To begin answering this question, we conducted, outside the magnet, a recognition test using images of famous and unfamiliar buildings and faces (version II). Furthermore, the faces had different expressions (smiling, sad, or neutral).

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Figure 4. Activation Profiles and Psychophysical Performance (A) Average percent signal change (13 subjects, version I). Left panel, face-related voxels; right panel, building-related voxels (ROI defined independently by sound eye stimulation). The y axis represents fMRI activation. Error bars, SEM. Abbreviations as in Figure 2. Note striking reduction of face activation for the amblyopic eye. (B) Psychophysical performance for amblyopic relative to sound eye stimulation (seven subjects, version II). Two tasks for each stimuli type: faces, naming famous faces and facial expressions, in red and orange, respectively; houses, naming famous buildings and category, in dark and light green, respectively. Note the pronounced reduction for facial expressions compared to identity recognition.

The task of the subjects was to identify the famous faces or buildings as well as the facial expressions and building category (private, e.g., single family home, or public). The results of this experiment are shown in Figure 4B. In parallel with the fMRI deficit (these results in version II were identical to previous ones in version I), viewing images through the amblyopic eye resulted in a significant reduction of face recognition compared to building recognition (one-tailed paired t test, p ⬍ 0.00002). Interestingly, the impact of amblyopia was more severe on recognizing facial expression compared to face identity (one-tailed paired t test, p ⬍ 0.00005). Discussion The present study demonstrates that disruption of normal visual experience leads to specific and consistent deprivation effects in human high-order object areas. Thus, amblyopia produces a striking deficit, which for the stimuli used in the present study was particularly accentuated in human occipitotemporal cortex. The deficit was not uniform but rather showed a consistent preferential impact on face-related compared to building-related cortical regions. The amblyopic deficit is likely to result from a highlevel focus, but the present results cannot completely rule out the possibility of some disruption of signals from earlier areas. The fact that the activation pattern in early cortex revealed a milder and far less object-

selective deficit supports the notion of a high-order disruption. However, it should be noted that recent studies did report disruptions and weaker activations in early visual cortex (e.g., Barnes et al., 2001). Thus, the weak deprivation effect we found in retinotopic cortex might be due to the use of rather large (visual angle 7⬚ ⫻ 7⬚) images. We are currently examining the deprivation effects using objects of different size. Alternatively, the difference with earlier studies may be due to the choice of object stimuli, which were less effective in activating early visual cortex compared to visual patterns rich in local visual details, which reveal consistent amblyopic effects in early cortex (Demer et al., 1997; Goodyear et al., 2000; Barnes et al., 2001; Algaze et al., 2002). Finally, the occipitotemporal disruption could not be attributed to a simple low-level deficit in the contrast sensitivity of the amblyopic eye since simulating the contrast sensitivity loss either in normal subjects or in the sound eye of amblyopic patients produced a much milder deficit with no indication of a face-selective loss (compare Figure 5 and Figure 2). The selective nature of the high-order deficit further supports the hypothesis that building- and face-related regions in human occipitotemporal cortex subserve qualitatively different computations. More specifically, the present findings are compatible with the notion that face processing depends on fine-detail analysis (Levy et al., 2001; Hasson et al., 2002), while building-related processes involve large-scale feature integration. Thus, it is tempting to speculate that recognition processes, which appear to depend on fine-detail analysis, could be severely disrupted by the eye misalignments during early childhood (the source of the amblyopic condition in our patient population) leading to the cortex’s selective functional disconnection from the amblyopic eye found in regions specializing in such processes. In contrast, building-related regions, which we hypothesized to be involved in more global integrative processes such as surface and texture detection as well as scene and layout orientation (Malach et al., 2002), should be less affected by the image doubling induced by ocular misalignments. Compatible with this notion, it is interesting to note that one of the defining deficits in amblyopia is a severe impairment in word and letter recognition. We have recently shown that word and letter representations manifest a preferential central-field bias, similar to that found for faces (Hasson et al., 2002). The present findings also point to the impact of early visual experience on the layout of high-order facerelated representations. This impact was shown to extend even to brief periods of early visual deprivation (Le Grand et al., 2001) as well as adult learning effects (Gauthier et al., 1999). It will be interesting to see if other developmental abnormalities (such as an early abnormality of peripheral vision) may affect the buildingrelated collateral sulcus regions in a similar fashion. The fact that essentially normal visual inputs remained in high-order building-related regions also has important and interesting implications. First, the presence of these normal inputs argues against the notion that amblyopia involves a global functional disconnection of the entire thalamocortical pathway. This conclusion against a lowlevel source for the amblyopic deficit is supported also by the control experiments using blurred images both

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Figure 5. Object-Related Areas in Control Experiment 1 and Activation Profiles (A) Simulation of the “sound” eye performance: stimulation by the original face and house images. Preferential activation for faces (red, filled arrows) versus buildings (green, open arrows) presented on unfolded hemispheres of control subjects (n ⫽ 6). Dotted lines, anterior border of retinotopic areas. Abbreviations as in Figure 2. (B) Simulation of the “amblyopic” eye: same as (A), but here the original images were filtered to quantitatively mimic the amblyopic contrast sensitivity function (see Experimental Procedures for details). Note remarkable similarity in activation of face-related regions by both the original and blurred images. (C) Comparing average percent signal change of original and blurred images. Top panel, face-related voxels; bottom panel, building-related voxels (ROI defined independently by sound eye stimulation). The y axis represents fMRI activation. Error bars, SEM. Note global activation reduction both for faces in face-related regions and for buildings in building-related regions in striking contrast to the purely face-selective deficit in true amblyopia.

in normal controls and in the sound eye of amblyopic patients, which failed to mimic the amblyopic effect. If the amblyopic deficit indeed occurred at high-order locus, then the present results imply that up to this disconnection site the visual inputs must have remained monocularly segregated to some extent—otherwise, no selective monocular deprivation effect would be possible. Indeed, such a breakdown of binocularity in early visual cortex has been previously demonstrated in animal models of amblyopia (Hubel and Wiesel, 1965; Movshon and Kiorpes, 1990). It is interesting that the amblyopic effect depended on both object-category and cortical region. Thus, the face-related amblyopic effect was found only in facerelated and not in building-related regions. This might be explained trivially as a “floor” effect which prevents the deficit from being manifested in nonoptimal activations but could also reflect differential processing of faces in the two regions. Most of the amblyopia-related effects demonstrated in the present study were found in high-order object areas. The behavioral findings fit nicely with these fMRI results in that amblyopia was more detrimental for face recognition compared to recognition of buildings. Interestingly, the deficit was more severe for recognizing facial expressions compared to face identity, which may

hint to a critical role of the pFs and IOG regions in this particularly demanding face-related recognition process. Experimental Procedures Experimental Acquisition Subjects were scanned on a 1.5 T Signa Horizon LX 8.25 GE scanner equipped with a quadrature surface coil. BOLD contrast was acquired with gradient-echo echo-planar imaging (EPI) sequence (TR, 3000; TE, 55; flip angle, 90⬚; field of view, 24 ⫻ 24 cm2; matrix size, 80 ⫻ 80). The scan volume included 17 nearly axial slices, each 4 mm, and 1 mm gap. T1-weighted high-resolution (0.93 ⫻ 0.93 mm in-plane) anatomical images and 3D SPGR sequence (0.93 ⫻ 0.93 ⫻ 1.2 mm) were obtained. Subjects Seventeen amblyopic (fourteen of strabismic and three of anisometropic origin) and six control subjects (with normal or corrected-tonormal vision) participated in the study. No significant difference was found between strabismic and anisometropic amblyopes in the present study, so their data were combined. Each subject was examined by an ophthalmologist, was fitted with optimal correction, and signed a consent form approved by the Tel Aviv Sourasky Medical Centre. Table 1 summarizes the detailed medical examinations of the subjects. Visual Stimulation All visual stimuli were generated on a PC, presented via an LCD projector (Epson MP 7200) onto a translucent screen, and shown in a mirror positioned ⵑ45⬚ above the subject’s forehead.

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Experimental Design Activation maps to faces or buildings were obtained for the sound and amblyopic eye separately, using red-green glasses for monocular stimulation. Version I: Thirteen Amblyopic, Two of Them Anisometropic Subjects viewed the colored (red and green) line drawings of faces or buildings (32 images each, 7⬚ ⫻ 7⬚ visual angle), which were presented at 1 Hz (500 ms on and 500 ms blank) in pseudorandom ordered 9 s blocks alternated with 6 s blanks. One or two pictures were repeated in each block, and subjects were required to perform a one-back memory task. Version II: Six Amblyopic Same as version I, except that the face and building stimuli consisted of 50% famous and 50% nonfamous pictures of faces and buildings (red and green colored, visual angle 7⬚ ⫻ 7⬚). Faces had smiling, neutral, or sad expressions. During scan, subjects were asked to recognize the person or building when it was possible and, in addition, to recognize facial expression or private/public category for houses. In both versions, stimuli were identical in luminance and contrast levels for the two eyes. Moreover, the stimuli colors in the amblyopic eye were balanced across subjects (50% red and 50% green). Mapping Borders of Visual Areas The representation of vertical and horizontal visual field meridians was mapped in each subject for the sound eye to establish the location of retinotopic areas (Sereno et al., 1995; DeYoe et al., 1996; Tootell et al., 1996; Grill-Spector et al., 1998). Briefly, visual stimuli consisted of triangular wedges of object images that were presented either vertically (upper or lower) or horizontally (left or right). The visual stimuli were presented at 4 Hz in 18 s blocks alternated with 6 s blanks. Subjects were required to fixate on a small central dot. Center/Periphery Localizer To define regions of interest approximating center-mid and peripheral representations of early visual cortex, we have used separate experiments in which the subjects (n ⫽ 11) viewed common objects of different size (small, 1.5⬚; mid, 3.5⬚; large, 15⬚). By contrasting the activation patterns produced by the large versus small images presented to the sound eye, a fairly consistent ROI could be defined in early retinotopic cortex across subjects. Control Experiment 1 Six control subjects with normal or corrected-to-normal vision were tested. Stimuli in this experiment were either identical to the face and house images used for the amblyopic subjects (version I) or a blurred version of the same images in which the level of contrast sensitivity deficit of the amblyopic condition was simulated. To obtain a quantitative estimate of the contrast sensitivity loss, we measured the contrast sensitivity of amblyopic subjects (n ⫽ 5; Table 1, asterisks) which showed a robust cortical deprivation effect in the fMRI study. The contrast sensitivity was measured across a range of spatial frequencies (1.5, 3, 6, 12, 18 cycles per degree) using a standard Vision Contrast Test System (Vistech Consultants, Inc., 1990). From these measurements, the modulation transfer function (MTF) was derived. Specifically, we calculated the extent of contrast reduction, for each spatial frequency, in the amblyopic eye relative to the sound eye. The average MTF was used as a filter for the original images. This procedure blurred the input images in such a way that a normal eye would experience a contrast sensitivity loss identical to that found in the amblyopic condition. The blurred stimuli were shown to one eye of normal subjects to mimic the amblyopic condition, whereas the other eye was stimulated by the original, nonblurred, images. Again, these blurred images were alternated between left and right eyes of the control subjects. Control Experiment 2 Four amblyopic subjects were tested (one of them took part in the previous studies) (Table 1). The images and blurring procedure were the same as in control experiment 1. This time, in the blurred images, the level of contrast sensitivity deficit for each subject was simulated individually according to the subject’s contrast sensitivity measurements. The blurred images were presented to the sound eye of the subjects, whereas the amblyopic eye was stimulated by the original unblurred stimuli. Behavioral Experiment Psychophysical performance was performed for seven subjects outside the magnet, after the scan, for the sound and amblyopic eye

separately. Subjects were presented with the same images as in version II except that blanks were extended to 1500 ms to allow response time. Subjects were requested to recognize the smiling/ sad/neutral facial expression or private/public house category (32 images of each type) and name the famous persons or buildings (a subset of 16 images of each type). Percentage of correct naming for amblyopic eye relative to the correct naming for sound eye (measurements in each task were performed proportionally to the number of pictures) was used for the performance estimation. Data Analysis Single-Subject Analysis fMRI data were analyzed with the “BrainVoyager” software package (Brain Innovation, Masstricht, Netherlands). The cortical surface was reconstructed for each subject and unfolded. Preprocessing of functional scans included motion correction and high-frequency temporal filtering. The functional maps were Talairach transformed (Talairach and Tournoux, 1988) and superimposed on reconstructed surfaces. General Linear Model (GLM) (Friston et al., 1995) statistics were used. The analysis was done independently for the time course of each individual voxel for each subject. An average time course was calculated from all voxels within a priori defined regions of interest (ROI). Multisubject Analysis In addition to the single-subject analysis, data were also analyzed in a multisubject random effect statistics. For this purpose, the time series of images of all subjects were converted into Talairach space and z normalized. For each subject, the relative contributions of the predictors for each contrast were estimated separately and then from the obtained set of values the significance at the multisubject level (random effect) was computed. The multisubject functional maps were superimposed on the Talairach normalized brain of one subject. Calculation of significance values in the activation maps was based on the individual voxel significance and on the minimum cluster size of ten voxels (Forman et al., 1995). The probability of a false positive was determined from the frequency count of cluster sizes within the entire cortical surface, using a Monte Carlo simulation (AlphaSim by B. Douglas Ward, a software module in Cox, 1996). Statistical level ranged from p ⬍ 0.05 (the darker colors) up to at least p ⬍ 0.001 (the brighter colors) and was indicated by the color scales. Acknowledgments The authors thank E. Okon for technical assistance; Y. Assaf and I. Goldberg for assistance in running the experiments; I. Levy, U. Hasson, and S. Gilaie-Dotan for comments. The work was funded by ISF grant 77/00, Adams Super Center for brain studies, Tel Aviv University grant and Center of Excellence grant 8009. Received: March 3, 2003 Revised: September 15, 2003 Accepted: October 11, 2003 Published: December 3, 2003 References Aguirre, G., Zarahn, E., and D’Esposito, M. (1998). An area within human ventral cortex sensitive to “building” stimuli: evidence and implications. Neuron 21, 373–383. Algaze, A., Roberts, C., Leguire, L., Schmalbrock, P., and Rogers, G. (2002). Functional magnetic resonance imaging as a tool for investigating amblyopia in the human visual cortex: a pilot study. J. AAPOS 6, 300–308. Barnes, G., Hess, R., Dumoulin, S., Achtman, R., and Pike, G. (2001). The cortical deficit in humans with strabismic amblyopia. J. Physiol. 533, 281–297. Demer, J., Grafton, S., Marg, E., Mazziotta, J., and Nuwer, M. (1997). Positron-emission tomographic study of human amblyopia with use of defined visual stimuli. J. AAPOS 1, 158–171. DeYoe, E., Carman, G., Bandettini, P., Glickman, S., Wieser, J., Cox,

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