When left becomes right and vice versa: Mirrored vision after cerebral hypoxia

Neuropsychologia 45 (2007) 2078–2091

When left becomes right and vice versa: Mirrored vision after cerebral hypoxia Tobias Pflugshaupt a,b , Thomas Nyffeler a,b , Roman von Wartburg a,b , Pascal Wurtz a , Mathias L¨uthi a,b , Daniela Hubl c , Klemens Gutbrod b , Freimut D. Juengling d , Christian W. Hess a,b , Ren´e M. M¨uri a,b,∗ a

Perception & Eye Movement Laboratory, Departments of Neurology and Clinical Research, University Hospital, 3010 Bern, Switzerland b Unit of Neuropsychological Rehabilitation, Department of Neurology, University Hospital, 3010 Bern, Switzerland c University Hospital of Clinical Psychiatry, University of Bern, 3000 Bern, Switzerland d Department of Nuclear Medicine, University Hospital, 3010 Bern, Switzerland Received 17 August 2006; received in revised form 19 January 2007; accepted 24 January 2007 Available online 2 February 2007

Abstract The combination of acquired mirror writing and reading is an extremely rare neurological disorder. It is encountered when brain damaged patients prefer horizontally mirrored over normal script in writing and reading. Previous theories have related this pathology to a disinhibition of mirrored engrams in the non-dominant hemisphere, possibly accompanied by a reversal of the preferred scanning direction. Here, we report the experimental investigation of PR, a patient who developed pronounced mirror writing and reading following septic shock that caused hypoxic brain damage. A series of five oculomotor experiments revealed that the patient’s preferred scanning direction was indeed reversed. However, PR showed striking scanpath abnormalities and mirror reversals that cannot be explained by previous theories. Considered together with mirror phenomena she displayed in neuropsychological tasks and everyday activities, our findings suggest a horizontal reversal of visual information on a perceptual level. In addition, a systematic manipulation of visual variables within two further experiments had dramatic effects on her mirror phenomena. When confronted with moving, flickering or briefly presented stimuli, PR showed hardly any left-right reversals. Not only do these findings underline the perceptual nature of her disorder, but also allow interpretation of the pathology in terms of a dissociation between visual subsystems. We speculate that early visual cortices are crucially involved in this dissociation. More generally, her mirrored vision may represent an extreme clinical manifestation of the relative instability of the horizontal axis in spatial vision. © 2007 Elsevier Ltd. All rights reserved. Keywords: Human; Brain damage; Mirror writing; Mirror reading; Eye movements

1. Introduction Telling left from right can be a problem for young children or even adults. This instability of the horizontal axis in spatial perception is likely to become manifest in writing and reading, as the left–right orientation of our visual environment is particularly relevant when we generate or encode script. Support for this assumption comes from the phenomena of mirror writing and reading, which are characterised by a complete horizontal reversal of motor output or visual input. Mirror writing is the variety of

∗

Corresponding author at: Department of Neurology, Inselspital, 3010 Bern, Switzerland. Tel.: +41 31 632 30 81; fax: +41 31 632 97 70. E-mail address: [email protected] (R.M. M¨uri). 0028-3932/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2007.01.018

script that runs in a direction opposite to the normal, with individual letters also being reversed (Critchley, 1928). When children learn to write, mirror script can be observed as a common but usually short-lived developmental stage (Fuller, 1916). Mirror writing in healthy adults is very rare and may have a hereditary origin (Mathewson, 2004). Historically, the best known adult mirror writer was Leonardo da Vinci, who produced almost all of his vast literary output in mirror script (Schott, 1999). Contrasting these spontaneous forms, mirror writing can also appear as a consequence of brain damage. For example, it has been described in patients with essential tremor, Parkinson’s disease or spinocerebellar disorders (Tashiro, Matsumoto, Hamada, & Moriwaka, 1987). Moreover, acquired mirror writing may occur in 2–3% of hemiplegics as a transient phenomenon, commonly when right-handed individuals are forced to write with their left

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hand due to right hemiplegia (Paradowski & Ginzburg, 1971). The so-called motor centre hypothesis of mirror writing suggests that in these patients, damage to the writing-dominant left hemisphere may release mirror-reversed motor programs stored in the intact right hemisphere, which results in mirror writing with the left hand (Schott & Schott, 2004). Compared to mirror writing, the phenomenon of mirror reading, defined as the capability to read reversed script easily without the use of a mirror (Heilman, Howell, Valenstein, & Rothi, 1980), is less frequent. For healthy adults, it seems legitimate to assume that mirror writers such as Leonardo da Vinci are also trained mirror readers, ensuring efficient encoding and monitoring during the writing process. However, patients who produce mirror script often find their own handwriting difficult to read (Gottfried, Sancar, & Chatterjee, 2003), and the combination of acquired mirror writing and reading is extremely rare. In previous single case reports, the combined pathology has been observed after brain concussion (Jokel & Conn, 1999; Streifler & Hofman, 1976), in the course of a bilateral extrapyramidal motor system disorder (Heilman et al., 1980), after the removal of a left parietal meningeoma (Durwen & Linke, 1988), following a series of epileptic seizures of the grand mal type (Wade & Hart, 1991), in the course of progressive ischaemia particularly affecting the left basal ganglia and temporo-parietal region (Lambon-Ralph, Jarvis, & Ellis, 1997), after bilateral frontal hypoperfusion (Gottfried et al., 2003), and in migraine with accompanying sensory and perceptive disturbances (Nakano, Endo, & Tanaka, 2003). Beside aetiological and neuroanatomical heterogeneity, these patients also differ from each other with respect to symptom duration, ranging from less than 3 months (Heilman et al., 1980) to more than 8 years (Gottfried et al., 2003). Further variation between individual pathologies concerned the issues of: (a) whether mirror writing and reading was accompanied by mirror phenomena in non-verbal activities (e.g. Lambon-Ralph et al., 1997) or not (e.g. Durwen & Linke, 1988) and (b) whether mirror writing was shown with one hand (e.g. Nakano et al., 2003) or both (e.g. Gottfried et al., 2003). Since the combination of mirror writing and reading obviously cannot be explained by the release of reversed motor programmes alone, more general hypotheses have been put forward to interpret it. For example, the visual word-form hypothesis – originally postulated by Orton (1928) to explain mirror writing in dyslexic children – assumes that bilateral but mirror-reversed visual engrams are formed in opposite hemispheres due to homotopically organised commissural connections. During reading development, mirrored graphemes in the non-dominant (i.e. usually right) hemisphere are suppressed, but under pathological conditions might be disinhibited and become manifest as mirror writing or reading (Durwen & Linke, 1988). Empirical evidence for the visual word-form hypothesis comes from tachistoscopic experiments, which revealed a leftvisual-field superiority for mirrored words in healthy subjects (Tankle & Heilman, 1982) and in one of the patients mentioned above (Durwen & Linke, 1988). The results of another patient in picture-word matching and lexical decision tasks were also interpreted as evidence for easy access to reflected graphemic representations (Gottfried et al., 2003). Finally, a cross-sectional

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fMRI study in healthy subjects (age range: 6–22 years) showed that learning to read was associated with increased activity in left inferior frontal and middle temporal cortices as well as decreased activity in the right inferotemporal cortex. This agerelated increase in left-hemispheric control over the reading process was explicitly considered as support for Orton’s theory of reading development (Turkeltaub, Gareau, Flowers, Zeffiro, & Eden, 2003). Another hypothesis to explain acquired mirror writing and reading was proposed by Heilman et al. (1980). Akin to the visual word-form hypothesis, and based on findings from experimental psychology (e.g. Bradshaw, Nettleton, & Patterson, 1973), they assumed that mirrored engrams are available but overridden by veridical ones in healthy subjects. It was suggested that, in their patient with transient mirror writing and reading, the lefthemispheric lesion caused a reversal of the learned left-to-right scanning direction, which – together with the availability of mirrored engrams – may have induced mirror reading. The patient’s mirror writing was attributed to general spatial confusion that became manifest in non-verbal tasks as well. For example, he reversed the direction in which the bases have to be run during a baseball game or was inconsistent in deciding which side of the road one should drive on. Concerning the proposed reversal of the scanning direction, experimental findings from another patient with acquired mirror writing and reading provide empirical support (Lambon-Ralph et al., 1997). First, when scanning and naming lines of geometrical shapes, this patient was considerably quicker at solving the task from right to left than from left to right. Second, in a word reading task that allowed a direct comparison of the effects of letter orientation (normal versus mirrored) and scanning direction (leftwards versus rightwards), her reading accuracy was high for all experimental conditions. However, she preferred mirrored over normal letters as well as right-to-left over left-to-right scanning, as indicated by corresponding decreases in reading time. Here, we present a patient with particularly pronounced mirror writing and reading as well as mirror phenomena in nonverbal activities after diffuse cerebral hypoxia. Based on the results from a series of oculomotor and other behavioural examinations, we will show that her pathology cannot be sufficiently explained by previous theories, since our findings indicate a horizontal reversal of visual information on a perceptual level, rather than a disinhibition of internally stored, mirrored engrams. Moreover, manipulations of visual variables such as motion or exposure duration revealed that the patient’s mirrored vision can be interpreted within a framework of visual subsystems, as her horizontal reversals were nearly absent with moving, briefly presented, or flickering stimuli. 2. Case history PR, a right-handed 33-year-old female, suffered septic shock and coma in the course of pneumococcal pneumonia. Her initial symptoms were a left-sided sensory hemisyndrome, disorientation in time, retrograde amnesia, ataxia, alexia and difficulties in number processing. In addition, she displayed clinical signs of a left-sided hemineglect, simultanagnosia and colour blindness,

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but these three deficits disappeared within 2–3 weeks. Three months after the septic shock, PR was admitted to our outpatient clinic for neurological and neuropsychological evaluation. The letter of admission included a rather unusual description of her reading problems: although, she was still not able to read normal script, her son had discovered that PR could fluently read the very same text when it was held against a mirror. Our clinical examination revealed that her initial pathology had largely persisted, as the most prominent findings were a mild left-sided hemisyndrome and ataxia, anterograde amnesia with both verbal and non-verbal material, alexia, acalculia and difficulties in mental rotation. The patient also described various problems in her everyday life such as bumping into doors when opening them, burning her hands on hot cooker elements or losing her way in well-known environments. In addition to these deficits, PR displayed pronounced mirror phenomena during the clinical examination: when asked to write, either from dictation or spontaneously, the patient wrote from right to left with either hand and thereby mirrored individual letters as well as letter and word order. Comparison with a handwriting sample from a diary she had written prior to the septic shock revealed a nearly complete horizontal reversal of the script, including letter shape and slant (Fig. 1A). The patient was fully aware of her mirror writing and stated that it was mandatory so that she can read what she writes. While her ability to read normal text was restricted to common single words, she read mirror script fluently and with comparatively little effort. Besides mirror writing and reading, horizontal reversals were evident in non-language tasks. For example, she repeatedly misjudged the horizontal position of objects during manual reaching tasks (by initially orienting towards the mirror-reversed position), drew a mirror equivalent of the original when asked to copy simple objects (Fig. 1B) or displayed complete horizontal reversals on neuropsychological tasks such as the block design subtests of the Wechsler adult intelligence scale. With regard to hand preference (Oldfield, 1971), the patient reported a change from originally distinct right-handedness to partial left-handedness after the septic shock. Finally, and similar to previous patients with mirror writing and reading (e.g. Lambon-Ralph et al., 1997; Wade & Hart, 1991), she could identify right and left parts of

her own body but reversed left and right on the examiner’s body when disorientation of the personal and extrapersonal space was tested based on the procedure proposed by Semmes, Weinstein, Ghent, and Teuber (1963). To allow thorough medical examination of her pathology, PR was admitted to our clinic for a 3-week inpatient treatment. While MRI of the brain, EEG, lumbar puncture and visual field perimetry were all normal, a resting [(18)F]deoxyglucosePET scan showed pronounced hypometabolism in many brain areas, including the frontal, temporal and occipital cortex of both hemispheres (Fig. 2). This diffuse and wide distribution of hypometabolic areas was interpreted as hypoxic brain damage due to the septic shock. Apart from the medical examinations, a series of oculomotor experiments was conducted during these 3 weeks for a detailed analysis of her unusual behavioural deficits (experiments 1–5). Compared to previous case reports on mirror writing and reading, the present study’s focus on eye movement behaviour is new, and it offers at least one main advantage: reading is closely connected with oculomotor control (see Reichle, Rayner, & Pollatsek, 2003, for a review), and eye movement data have been very useful in the analysis of specific reading disorders such as hemianopic dyslexia (Zihl, 1995), neglect dyslexia (Behrmann, Black, McKeeff, & Barton, 2002) or pure alexia (Behrmann, Shomstein, Black, & Barton, 2001). 3. Experiment 1: Eye movement patterns during a sentence reading task The first experiment was an examination of PR’s eye movements while reading normal and mirrored sentences. Our intention was to investigate whether and how her almost complete inability to read normal script is reflected in oculomotor data. 3.1. Methods Eye movements were recorded with an infrared-based video tracking system (EyeLinkTM , SensoMotoric Instruments GmbH, Berlin, Germany) at a sampling rate of 250 Hz. This system provides spatial resolution of 0.01◦ and gaze-position accuracy relative to stimulus coordinates of 0.5–1.0◦ . A chin rest was used to ensure constant distance and minimise head movements. PR and 10 healthy

Fig. 1. Examples of mirror phenomena in PR’s handwriting and drawing. (A) Excerpt from a diary she wrote prior to the septic coma (top; English: step-by-step), the same words written during rehabilitation (middle), and an artificially flipped version of her mirrored script (bottom), which highlights the resemblance between pre- and post-incident writing style. (B) When the patient was instructed to copy simple objects such as a trumpet (top), she created a complete horizontal reversal in the copy (middle) as well as the delayed recall task (bottom; drawing performance 30 min after the presentation of the original).

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Fig. 2. PET analysis of PR’s brain. Red areas display significantly hypometabolic areas, relative to the results from a normative sample (Juengling, Kassubek, & Otte, 2000). PR’s data were mapped onto a reference brain (maximum intensity projections) from the Montreal Neurological Institute (Friston, Holmes, & Worsley, 1995). (A) Mid-sagittal view of the left hemisphere. (B) Mid-sagittal view of the right hemisphere. (C) Lateral view of the left hemisphere. (D) Lateral view of the right hemisphere. (E) Ventral view. (F) Dorsal view. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.) control subjects (mean age = 32.80 years, range: 28–39 years; all right-handed females) sat at a 70 cm distance from a 19-in. computer screen, resulting in a stimulus size of 29◦ × 22◦ of visual angle. During the sentence reading task, five single sentences were presented per condition (normal versus mirror script). All sentences were simple German main clauses in the present tense and consisted of seven words each. Before each sentence, a lateral point was shown to indicate the position of the first letter in the first word. The instruction was to read the sentence silently and then to stop the presentation with a keypress. Subsequently, participants had to say the sentence aloud. The quantitative offline analysis was based on the following variables: mean reading time per sentence, mean fixation duration, mean saccadic amplitude and the percentage of regressive saccades. In order to address the question of whether PR significantly differed from the control group for a given variable, we applied modified t-tests that were specifically designed for single-case studies (Crawford & Howell, 1998). Unless stated otherwise, the same statistical procedure, eye tracking system, and control group were used for experiments 1–5. Prior to the examination, which was carried out in accordance with the latest version of the Declaration of Helsinki and approved by the local ethics committee, all participants gave written informed consent.

In addition, reading normal script consistently evoked a peculiar scanning strategy in the patient. Beginning with a large rightward saccade to the last letter of a word, she then read it, sometimes repeatedly, from right to left in a letter-by-letter manner, before making another large rightward saccade to the last letter of the next word, and so on (Fig. 3). It appeared as if her gaze was automatically attracted by the rightmost letter in each word. Furthermore, she did not attempt to change her backward letter-by-letter strategy despite the enormous problems this imposed on reading comprehension. It was thus hardly surprising that the patient could name only a few single words of normal-script sentences when asked to say the silently read sentences aloud. This contrasts with her faultless performance in repeating mirrored sentences as well as with the repetition performance of the control subjects, who were able to repeat all sentences accurately, irrespective of script orientation.

3.2. Results

4. Experiment 2: Eye movement patterns during a clock reading task

Compared with the control subjects, PR showed significant deficits in terms of prolonged reading time per sentence, prolonged fixation duration, shorter saccadic amplitudes and a higher percentage of regressive saccades. However, these differences were only observed with normal script (Table 1).

The second experiment was an examination of PR’s eye movements while reading normal and mirrored clock faces. Previous case reports contain evidence that clock reading may be particularly difficult for patients with acquired mirror writing

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Table 1 Results of the sentence reading task Condition

Variable

PR mean

Control subjects mean (S.D.)

t (d.f. = 9)

p (two-tailed)

Normal sentences

Reading time per sentence (s) Fixation duration (ms) Saccadic amplitude (◦ ) Percentage of regressive saccades (%)

38.12 545 1.28 59.54

2.21 (1.03) 212 (17.67) 4.14 (0.80) 11.79 (7.64)

33.251 17.992 −3.409 5.959

<0.01 <0.01 <0.01 <0.01

Mirrored sentences

Reading time per sentence (s) Fixation duration (ms) Saccadic amplitude (◦ ) Percentage of regressive saccades (%)

3.96 232 2.02 10.79

5.34 (2.47) 261 (32.86) 2.49 (0.41) 15.91 (5.70)

−0.517 −0.834 −1.093 −0.856

0.617 0.426 0.303 0.414

Note: The variable ‘reading time per sentence’ was defined as the duration from stimulus onset to keypress. Regressive saccades were defined as saccades that are directed contrary to the script-specific reading direction (i.e. leftward saccades with normal script, rightward saccades with mirrored script). For the variable, ‘saccadic amplitude’, both normal and regressive saccades were included.

and reading: (a) the patient of Streifler and Hofman (1976) showed directional reversals (i.e. anti-clockwise instead of clockwise) when setting a clock, (b) the patient of LambonRalph et al. (1997) displayed consistent mirror reversals when reading clock faces without numerals (i.e. 13:15 instead of 10:45) and (c) the patient of Nakano et al. (2003) drew mirror reversed clock faces with the right hand. With reference to these findings, we expected that PR’s clock reading performance and oculomotor behaviour would strongly depend on whether she had to read normal or mirror-reversed clock faces. 4.1. Methods During the clock reading task, 10 clock faces with numerals were presented per condition (normal versus mirrored clocks) in random order. Prior to each

clock face, a central fixation point was shown that prompted participants to start visual exploration at a central location. They were instructed to read the displayed clock face silently and as fast as possible before stopping the presentation with a keypress and saying the indicated time aloud. Quantitative analyses were performed for mean reading time per clock, mean fixation duration and mean saccadic amplitude.

4.2. Results In general, the patient and 8 of the 10 control subjects were able to read all clocks correctly. Two control subjects misread one of the mirrored clocks. Table 2 shows that the quantitative analysis revealed only one significant difference between PR and the control group: when reading normal clocks, PR’s reading time was considerably prolonged.

Fig. 3. Typical eye movement patterns during the sentence reading task. Left column: An example of a sentence in normal script (e.g. Anna cannot pay for the blue dress). Right column: An example of a sentence in mirror script (e.g. One cannot find a ring in this place). In each panel, the temporal dimension is plotted on the y-axis, from top to bottom. Scanpaths (black lines) are based on unparsed data, so that fixations are represented by roughly vertical line segments.

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Table 2 Results of the clock reading task Condition

Variable

PR mean

Control subjects mean (S.D.)

t (d.f. = 9)

p (two-tailed)

Normal clocks

Reading time per clock (s) Fixation duration (ms) Saccadic amplitude (◦ )

11.23 311 3.40

2.16 (0.46) 248 (46) 4.51 (0.58)

18.800 1.306 −1.825

<0.01 0.224 0.100

Mirrored clocks

Reading time per clock (s) Fixation duration (ms) Saccadic amplitude (◦ )

2.65 238 3.87

5.54 (2.45) 280 (36) 3.97 (0.57)

−1.125 −1.112 −0.167

0.290 0.295 0.871

Note: The variable ‘reading time per clock’ was defined as the duration from stimulus onset to keypress.

The reason for this prolongation became obvious during a descriptive analysis of her scanning behaviour. With normal clocks, the patient consistently displayed a time-consuming, counting-like scanning strategy. A typical example is shown in the upper left panel of Fig. 4. In contrast, reading mirrored clock faces evoked an efficient scanning strategy that was focused on task-relevant image regions (i.e. clock hands and adjacent numerals), closely resembling the scanning strategy of control subjects when reading normal clocks. 5. Experiment 3: Eye movement patterns during a search task The aim of the third experiment was to investigate PR’s preferred scanning direction. According to Heilman et al. (1980), a pathological reversal of the learned left-to-right scanning preference is a crucial factor in the aetiology of mirror reading. Supporting empirical evidence has been presented by LambonRalph et al. (1997). Their patient was, for example, considerably faster in scanning and naming non-verbal arrays from right-to-

left than from left-to-right. However, while these authors applied tasks that allowed evaluating the preferred scanning direction on the basis of total naming times, a more direct approach was chosen for the present search task. In particular, we analysed scanning directions that were spontaneously chosen by the participants. 5.1. Methods Two types of non-verbal arrays were used, both of which included eight images with one target and 99 distractors per image. In one type of array (the chair search), the target was a chair surrounded by vases, brushes, candles and bobbins, whereas the second type of array (the elephant search) included an elephant as target, surrounded by giraffes, rhinoceroses, tigers and zebras. Overall, targets were evenly distributed over image quadrants, and the arrangement of objects within images was – relative to the original alignment in rows and columns – slightly distorted to increase task difficulty. Similar to the clock reading task, a central fixation point was shown prior to each image. Participants were instructed to choose one of the four image corners as soon as the central fixation point disappeared. From there, they should scan the arrays systematically in a row-by-row or column-by-column manner and thereby find and click the predefined target as soon as possible. For the quantitative analyses, we analysed whether PR differed from the control group concerning the following variables: mean search time per image, mean fixation duration and mean saccadic amplitude.

5.2. Results

Fig. 4. Typical eye movement patterns during the clock reading task. Scanpaths are shown in red: lines depict saccades, circles represent fixation locations, and circle diameters are proportional to fixation duration. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

Both PR and the control group were able to find and click all targets. However, Table 3 shows that the patient’s search time per image was significantly longer, while her mean fixation duration and saccadic amplitude did not differ from those of the control subjects. The descriptive scanpath analysis needed to test our hypothesis of a reversed scanning direction in PR revealed two main results: first, the starting point for systematic visual search was mirror-reversed in PR. In particular, she invariably chose the upper right corner, while all control subjects started searching the arrays in the upper left corner. Typical examples are shown in Fig. 5. Second, the patient consistently scanned from right-toleft and row-after-row, which included rightward return sweeps when moving to the next row. This scanning strategy was not shown by any of the control subjects. Instead, they generally scanned the arrays from left-to-right, either in a row-by-row or a column-by-column manner. Some of the control subjects displayed a particularly efficient scanning strategy, as they alternated between rightward and leftward scanning from row to row and thereby avoided return sweeps.

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Table 3 Results of the search task Variable

PR mean

Control subjects mean (S.D.)

t (d.f. = 9)

p (two-tailed)

Search time per image (s) Fixation duration (ms) Saccadic amplitude (◦ )

21.60 238 3.95

12.07 (2.69) 227 (16) 4.54 (0.94)

3.378 0.661 −0.598

<0.01 0.525 0.564

Note: The variable ‘search time per image’ was defined as the duration from stimulus onset to keypress.

6. Experiment 4: Eye movement patterns during a letter-reading task The fourth experiment was aimed at investigating the influence of grapheme orientation (normal versus mirrored) and scanning direction (leftwards versus rightwards) on the patient’s oculomotor behaviour. To this end, a letter-reading task was administered during which PR and the control subjects had to scan and read aloud single lines of letters and numbers. In contrast to a similar experiment by Lambon-Ralph et al. (1997), we chose a letter-reading task over a single-word reading task to ensure that word-form effects did not interfere with the influence of grapheme orientation and scanning direction. 6.1. Methods The experimental design included four types of stimulus lines: left-to-right with normal graphemes, left-to-right with mirrored graphemes, right-to-left with normal graphemes and right-to-left with mirrored graphemes. One practice trial and four test trials were presented per condition, and each trial was preceded by a central fixation point. The order of conditions was randomised on a trialby-trial basis. With regard to letters and numbers used for the stimulus lines, we only included graphemes whose normal and horizontally mirrored forms differed from each other in terms of visual input (e.g. Z, 9, s, R). Overall, the same graphemes were used across conditions to counterbalance task difficulty, but the order of graphemes within stimulus lines was condition-specific to pre-

vent learning effects (see upper panel of Fig. 6 for an example). PR and the control subjects were instructed to read each stimulus line aloud and in accordance with the lateral arrow indicating the starting point and scanning direction. Immediately after they had read the last grapheme of each line correctly, the experimenter stopped the presentation with a keypress. The quantitative analysis was exclusively based on mean reading times per stimulus line, defined as the duration from stimulus onset to keypress. For the analysis of possible dissociations between experimental conditions in PR’s performance, the Revised Standardized Difference Test (RSDT; Crawford & Garthwaite, 2005) and the formal criteria defined by Crawford, Garthwaite, and Gray (2003) were used.

6.2. Results The letter-reading task revealed two general findings: (a) both PR and the control subjects showed faultless performance and (b) the patient’s reading times were significantly prolonged in all experimental conditions (Table 4). However, this prolongation strongly depended on grapheme orientation and scanning direction. PR read mirrored graphemes faster than normal graphemes and right-to-left stimulus lines faster than left-to-right stimulus lines. Both differences fulfilled the formal criteria for a strong dissociation between conditions (normal versus mirrored graphemes: RSDT: t = 14.597, d.f. = 9, ptwo-tailed < 0.01; leftto-right versus right-to-left stimulus lines: RSDT: t = 10.360,

Fig. 5. Typical eye movement patterns during the search task. Scanpaths are shown in red: lines depict saccades, circles represent fixation locations and circle diameters are proportional to fixation duration. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of the article.)

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Similar to the sentence and clock reading tasks, descriptive oculomotor analysis of PR’s letter-reading behaviour revealed an unusual scanning strategy. After the stimulus-preceding central fixation point, she consistently made a large saccade away from the lateral arrow and fixated at a horizontally mirrored position instead. A typical example is depicted in the middle panel of Fig. 6. It appeared as if PR misperceived the lateral starting point and, as a consequence, needed some extra oculomotor work – including a large corrective saccade towards the true location of the arrow – to accomplish the task. This obvious misperception was not shown by any of the control subjects. 7. Experiment 5: Visually guided reflexive saccades Based on the observation of a horizontal reversal in PR’s visual perception of lateral stimuli, the aim of the fifth experiment was to investigate the patient’s reflexive saccade behaviour. To this end, we applied two basic oculomotor tasks, i.e. the gap and the overlap task, both of which required participants to perform visually guided saccades towards a lateral target appearing either left or right of a central fixation point. Given that PR suffered from horizontal reversals on a perceptual level, we speculated that she would demonstrate saccades away from the lateral target with latencies and accuracies comparable to those of control subjects when making reflexive saccades towards the lateral target. 7.1. Methods

Fig. 6. Stimulus examples for each experimental condition (top panel) and typical eye movement patterns during the letter-reading task. In the middle and lower panel, the temporal dimension is plotted on the y-axis, from top to bottom. Scanpaths (black lines) are based on unparsed data, so that fixations are represented by roughly vertical line segments.

d.f. = 9, ptwo-tailed < 0.01). In other words, the difference in PR’s reading time between, for example, right-to-left and left-to-right stimulus lines was significantly greater than corresponding differences in the control group. Descriptively, the influence of grapheme orientation was stronger than that of scanning direction: on average, the patient read off stimulus lines with mirrored graphemes 6 s faster than those with normal graphemes, whereas the corresponding difference between right-to-left and left-toright stimulus lines was approximately 3 s (Table 4).

During the gap task, a central fixation point (CF) was presented with pseudorandomised durations between 2000 and 3000 ms, followed by a lateral target (LT) that appeared 200 ms (i.e. the temporal gap) after the offset of the CF and was shown for 1000 ms. Target amplitude (range: 3.7–9.1◦ ) and direction were randomised in the horizontal plane. In the overlap task, stimulus parameters were identical except for the CF, which remained visible during the presentation of the LT (i.e. the temporal overlap). This prompted subjects to show a more active disengagement from the CF. The instruction for both tasks was to perform a saccade towards the LT as quickly and accurately as possible. Overall, 42 targets were shown per task. Quantitative analyses were performed for latencies and accuracies defined as gain ratios (i.e. observed amplitude/required amplitude).

7.2. Results While nearly all saccades displayed by the control subjects were reflexive and thus directed towards the LT (gap: mean = 98.6% of all saccades, S.D. = 2.4%; overlap: mean = 100%, S.D. = 0%), PR consistently made saccades away from the LT (gap: 95.2%; overlap: 100%). With regard to latency, these mirror-reflected saccades did not significantly differ from the reflexive saccades of the control group. However, PR dis-

Table 4 Results of the letter-reading task: reading time per line in seconds Condition

PR mean

Control subjects mean (S.D.)

t (d.f. = 9)

p (two-tailed)

Left-to-right, normal graphemes Left-to-right, mirrored graphemes Right-to-left, normal graphemes Right-to-left, mirrored graphemes

16.09 10.65 13.36 7.23

4.29 (0.74) 4.63 (0.88) 4.68 (0.77) 4.50 (0.75)

15.204 6.523 10.748 3.471

<0.01 <0.01 <0.01 <0.01

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Table 5 Results of the basic oculomotor tasks Task

Variable

PR mean

Control subjects mean (S.D.)

t (d.f. = 9)

p (two-tailed)

Gap

Latency (ms) Accuracy (gain ratio)

224 0.82

194 (35) 0.96 (0.05)

0.813 −2.670

0.437 0.026

Overlap

Latency (ms) Accuracy (gain ratio)

297 0.90

228 (33) 0.98 (0.03)

1.988 −2.543

0.078 0.032

Note: Since the patient consistently showed reflexive saccades away from the lateral target, the sign of her gain ratios had to be changed to allow a comparison with the gain ratios of the control group. All statistical analyses are based on comparisons between PR’s ‘mirrored’ reflexive saccades and the reflexive saccades of the control group.

played slight but significant hypometria in both tasks (Table 5). A comparison of leftward with rightward saccades in both PR and the control subjects revealed no significant differences. 8. Discussion of experiments 1–5 In general, experiments 1–5 provided strong evidence that PR’s mirror phenomena are not restricted to reading and writing but are also evident in non-verbal tasks such as clock reading (experiment 2) or visual search (experiment 3). In this respect, her behavioural deficits may be related to those of other patients with acquired mirror writing and reading, who showed additional mirror phenomena in non-verbal activities (Heilman et al., 1980; Lambon-Ralph et al., 1997; Nakano et al., 2003; Streifler & Hofman, 1976). Furthermore, and with regard to previous theories about mirror writing and reading, our results support the hypothesis of a pathologically reversed scanning direction (Heilman et al., 1980), as PR displayed a pronounced preference for right-to-left scanning. This was observed irrespective of whether the preferred scanning direction could be chosen spontaneously by the participants (experiment 3) or had to be inferred from the time needed to read single lines of letters and numbers (experiment 4). Her propensity to scan from right to left was even evident when reading normal script in terms of a reversed letter-by-letter reading strategy (experiment 1). However, neither the reversed scanning hypothesis nor the visual word-form hypothesis can explain why the patient, when confronted with lateral stimuli that had to be fixated after the disappearance of a central fixation point, consistently made saccades towards the opposite side (experiments 4 and 5). Together with the mirror phenomena in clock reading (experiment 2) and neuropsychological tests (e.g. drawing, pointing, block design), these findings suggest that PR suffers from mirrored vision, i.e. a horizontal reversal of visual information on a perceptual level. Such an assumption contrasts with the reversed scanning and visual word-form hypotheses, as these two theories relate mirror phenomena to the availability and disinhibition of internally stored mirrored engrams, while PR’s reversals appear to occur online when perceiving the spatial characteristics of her visual environment. Thus, the present study differs substantially from previous case reports on mirror writing and reading, as PR’s problems with normal script can be considered to be outcomes of a more general visuo-perceptive disorder that is characterised by a horizontal reversal at input level. It is important to note that our patient’s horizontal reversals in vision are also substantially different from problems with the

left-right orientation seen in other neurological disorders. For example, patients with Gerstmann’s syndrome typically show left-right confusion or disorientation (e.g. Mayer et al., 1999). In contrast, PR is not confused about where left and right are, but systematically misperceives them. Furthermore, several single case studies have reported pure agnosia for horizontal mirror images in patients with parietal brain damage (e.g. Davidoff & Warrington, 2001; Priftis, Rusconi, Umilt`a, & Zorzi, 2003). In contrast to PR’s general perceptual reversals, this deficit was highly task-specific, as it exclusively occurred when patients had to discriminate horizontal mirror images. With regard to perception-related mirror phenomena, McCloskey and co-workers (McCloskey, 2004; McCloskey & Rapp, 2000a, 2000b; McCloskey et al., 1995) described a well-educated young woman (AH) with no history of neurological injury or disease, who displayed a striking developmental deficit in determining the location of objects from vision. For example, AH showed both left-right and up-down reversals during copying or manual reaching tasks (McCloskey et al., 1995). Interestingly, manipulating visual variables such as motion, exposure duration, flicker, contrast or eccentricity affected her mirror phenomena. In particular, AH showed very few reversals when moving, briefly presented, flickering, low contrast or eccentric stimuli were presented, and this was interpreted as strong evidence for impairment in visual processing (McCloskey, 2004). In order to further substantiate our hypothesis of mirrored vision in PR, we performed similar manipulations of visual variables on the occasion of a follow-up examination 2 years after the onset of her pathology. Clinical tests revealed that the main symptoms such as mirror writing and reading or horizontal reversals in drawing or pointing tasks were unchanged. 9. Experiment 6: Influence of motion The aim of the sixth experiment was to determine if PR’s horizontal reversals in reflexive saccade behaviour depend on whether the lateral stimulus is stationary or moving. On the basis of clinical evidence, we expected that motion could reduce these reversals: (a) PR told us that in everyday situations, motion helps her to correctly localise objects. For instance, she was able to easily identify the position of a fly in space as long as the insect was moving, but failed to orient towards flies whenever they lingered motionless on a surface. (b) Confrontational tests revealed that PR still misperceived stationary objects during pointing and reaching tasks. However, when the experimenter was standing closely in front of her with an object in both of his hands and

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then randomly dropped one of the objects, the patient consistently made a reflexive arm and hand movement towards the true location of the falling – and thus quickly moving – object to catch it. 9.1. Methods and results Two variants of the so-called step-ramp paradigm (Rashbass, 1961) were applied, both of which required PR to make an initial saccade towards a lateral target (i.e. step), followed by smooth pursuit eye movements (i.e. ramp) to track the lateral target that started to move either immediately (step-ramp task) or 1000 ms after its onset (step-delayed ramp task). At the beginning of each trial, a central fixation point was shown for 2000 ms, immediately followed by the lateral target. The direction of steps (leftward versus rightward) and ramps (inward versus outward) was pseudo-randomised over a total of 20 trials per task. Several parameters were held constant throughout the experiment: when steps were followed by inward ramps, step amplitude was 10.8◦ , as opposed to 5.2◦ for steps followed by outward ramps. Ramp velocity was 5◦ s−1 , and every ramp was shown for 2000 ms. Eye movements were recorded with an infrared-based video tracking system (HiSpeedTM , SensoMotoric Instruments GmbH, Berlin, Germany) at a sampling rate of 240 Hz. Similar to the EyeLinkTM system, this eye tracker provides gaze-position accuracy relative to stimulus coordinates of 0.5–1.0◦ , largely depending on participants’ accuracy during the calibration procedure. PR sat at a distance of 72 cm from a 20-in. computer screen, resulting in a horizontal and vertical visual angle of 32◦ and 24◦ , respectively. The step-ramp trials were created and presented with E-PrimeTM (Psychology Software Tools Inc., Pittsburgh, PA, USA).

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A descriptive analysis of PR’s eye movement behaviour during the two step-ramp tasks clearly demonstrated a strong influence of motion on her mirrored vision: during all trials of the step-delayed ramp task, and as in the gap and overlap tasks (experiment 5), she consistently made an initial saccade away from the lateral target that remained stationary for 1 s. Shortly after the target had started to move, she re-oriented towards the true location of the target and thereafter tracked it with rather inaccurate pursuit eye movements including frequent corrective saccades. The upper right panel of Fig. 7 depicts a typical example. However, such initial misperceptions were very rare in the step-ramp task and occurred only in 3 of the 20 trials. During all other trials, PR’s initial saccade was directed towards the true location of the moving target, as illustrated in the upper left panel of Fig. 7. 10. Experiment 7: Influences of flicker and exposure duration The seventh experiment was aimed at investigating whether manipulation of flicker and exposure duration had an effect on PR’s mirrored vision. Our expectation that such an effect should be revealed was based on an experience the patient had had in her everyday life. During a rock concert in a bar under flickering lighting conditions, PR realised that she could easily read normal script. 10.1. Methods Both flicker and exposure duration were tested with a separate task: (a) during the flicker task, drawings of animals were presented for 1000 ms, either constantly or flickering at 10 Hz. The instruction was to press the left or right mouse button after the animal had disappeared, depending on whether the ani-

Fig. 7. Typical examples of oculomotor behaviour during the step-ramp tasks. Thick grey lines indicate the position of the stimulus, the value of zero on the temporal dimension (y-axis) denotes the moment when the lateral target appeared and started to move – either immediately (step-ramp task) or after a 1000 ms delay (step-delayed ramp task) – at a stable velocity of 5◦ s−1 . Scanpaths (black lines) are based on unparsed data.

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mal’s head was oriented towards the left or right side. For the stimuli, 40 animals from the “Snodgrass and Vanderwart-like” objects (Rossion & Pourtois, 2004) were selected and duplicated by flipping them along the horizontal axis, resulting in a total of 80 pictures. We exclusively used animals shown from a lateral view to ensure that their head could unambiguously be assigned to the left or right side. (b) During the mask task, the same animals were presented for varying durations within a ‘sandwich-mask’ to avoid stimulus-related retinal afterimages. A grid consisting of black X’s was used as pre- and postmask. After the postmask had disappeared, participants had to press the left or right mouse button in accordance with the location of the animal’s head. The exact time course of stimulus presentation in both tasks is illustrated in the upper row of Fig. 8. In general, 40 stimuli were randomly chosen and shown per experimental condition. Stimulus presentation and data acquisition was performed with E-PrimeTM (Psychology Software Tools Inc., Pittsburgh, PA, USA). While solving the tasks, PR and 10 healthy control subjects (mean age = 34 years, range: 27–41 years; all right-handed females) sat at a distance of 50 cm from a 17-in. computer screen with a spatial resolution of 1280 × 1024 pixels, and all animal pictures were 422 × 296 pixels in size. Prior to participation, both PR and the control subjects gave written informed consent in accordance with the latest version of the Declaration of Helsinki.

11. Discussion of experiments 6 and 7 In sum, the results of experiments 6 and 7 show that PR’s mirrored vision is virtually absent when moving, flickering or briefly presented stimuli are applied. The observation that manipulating visual variables had such dramatic effects on her pathology can be regarded as further evidence for a strong perceptual component in the disorder. Of particular interest is the finding of a threshold between 100 and 200 ms exposure duration, which denotes an abrupt transition from normal to mirrored vision in the patient. McCloskey et al. (1995) described a similar finding in AH: when manipulating exposure duration, they found a steep rise in the percentage of localisation errors from 8% to 48% between 80 and 250 ms. With longer exposure durations (i.e. 500 and 1000 ms), AH’s error rate did not increase further (see Fig. 4 in McCloskey et al., 1995). 12. Outpatient treatment

10.2. Results The manipulation of both flicker and exposure duration had dramatic effects on PR’s mirrored vision: in the flicker task, she correctly responded to all flickering stimuli, but did not give a single correct answer when animals were constantly shown (lower left panel of Fig. 8). The mask task revealed a similar dissociation: when exposure duration was 50 or 100 ms, PR performed virtually without error. With longer durations, however, her percentage of correct responses dropped to a level between 0% and 2.5% (lower right panel of Fig. 8). In the control group, mean percentages of correct responses exceeded 99% in all experimental conditions.

Apart from its striking scientific value, the evidence for mirrored vision in PR also had clinical implications. Since her visual problems could not be alleviated by behaviourally based interventions such as systematic left-to-right-scanning training, an important part of the outpatient treatment was to determine whether an optical flip of visual information along the horizontal axis would provide more positive results. To this end, a specific monocular vision aid (Fig. 9) was created by combining a 60◦ -Bauernfeind prism (Linos AG, G¨ottingen, Germany) with a 60◦ -isosceles prism (Fisba Optik, St. Gallen, Switzerland). On the occasion of another follow-up examination in our outpatient clinic, it was confirmed that her mirror phenomena

Fig. 8. Time course of stimulus presentation and results of the flicker and mask tasks. Error bars based on interindividual dispersion in the control group are not visible due to the minimal magnitude of corresponding standard deviations.

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Fig. 9. Monocular vision aid. Construction layout (left) and demonstration of its horizontally reversing effect (right).

in verbal and non-verbal activities had persisted. However, she could read newspaper articles in normal script fluently with the monocular vision aid, which provided further evidence for a strong perceptual component in her pathology. 13. General discussion To the best of our knowledge, the present case study is the first empirical demonstration that brain damage can provoke persistent mirrored vision, i.e. a reversal of visuo-perceptive information along the horizontal axis. Our evidence for mirrored vision in a patient (PR) with hypoxic brain damage can be grouped into four categories: (1) during a series of oculomotor tasks (experiments 1–5), PR consistently acted as if visual input was mirror-reversed. For example, she scanned normal words from right to left, read mirrored clocks much faster than normal clocks, or made saccades away from lateral stimuli when visually guided reflexive saccades were required. (2) Manipulating visual variables such as motion, flicker or exposure duration (experiments 6 and 7) had dramatic effects on PR’s mirror phenomena and thus provided further evidence for a deficit in perceptual processing. (3) Applying a monocular vision aid that optically flipped visual information along the horizontal axis eliminated her inability to read normal script. (4) In visuospatial tasks such as figure copying, pointing or block design, the patient consistently displayed left-right reversals. Moreover, the reported change from originally distinct right-handedness to partial left-handedness can also be regarded as evidence for mirrored vision, as the EEG of healthy subjects, when wearing left-right reversing goggles, shows a decrease in arm-related lateralisation (Berndt, Franz, Bulthoff, Gotz, & Wascher, 2005). With regard to possible mechanisms responsible for PR’s mirrored vision, the influence of visual variables such as motion or flicker is particularly important, as it allows the interpretation of PR’s pathology within a framework of visual subsystems. McCloskey (2004) proposed that the so-called sustained subsystem is most sensitive to static stimuli with relatively long durations, while its counterpart – the transient subsystem – predominantly processes rapidly changing stimuli. Supporting evidence for the assumption of two visual subsystems with different temporal resolutions comes from neurophysiology. For several decades, it has been known that retinal ganglion cells can be grouped into two main classes: (1) magnocellular neu-

rons with large cell bodies and dendritic arbours as well as thickly myelinated axons. Concerning physiological properties, these neurons show low spatial but high temporal resolution due to fast conduction velocity. (2) Parvocellular neurons with small cell bodies and compact dendritic arbours as well as relatively thin axons, providing higher spatial but lower temporal resolution than magnocellular neurons (Leventhal, Rodieck, & Dreher, 1981; Livingstone & Hubel, 1987; Rodieck, Binmoeller, & Dineen, 1985). Information from these two types of ganglion cells remains segregated along the visual pathways from the retina via the lateral geniculate nucleus of the thalamus to the primary visual cortex V1 in the occipital lobe (see Callaway, 2005, for a review). Theoretically, mirrored vision in PR under sustained visual stimulation could therefore be related to a dissociation between an unaffected magnocellular and an impaired parvocellular system. Further evidence for this assumption is her colour blindness during the first few weeks after the septic shock, as the perception of colour is predominantly, or perhaps exclusively, based on parvocellular processing (Merigan, 1989). The suggestion that a neuronal pathology specifically affects either the magnocellular or parvocellular system has also been put forward in the context of other diseases. For example, findings from neuroophthalmological research suggest such a dissociation for the pathway between the retina and V1 (see Bassi & Lehmkuhle, 1990, for an overview). A partial segregation between parvo- and magnocellular systems has also been postulated for visual processing in extrastriate cortical areas: Livingstone and Hubel (1987) assumed that from V1, magnoand parvocellular pathways primarily project to the parietal (i.e. the dorsal stream) and inferior temporal lobe (i.e. the ventral stream), respectively. It follows that circumscribed cortical brain damage may also provoke a dissociation between magno- and parvocellular processing. In this regard, cerebral achromatopsia, i.e. colour blindness in patients with cortical lesions that affect the ventral stream, is a classic example, being attributed to a selective disruption of the colour-sensitive parvocellular channel (e.g. Cowey & Heywood, 1995). However, the interpretation of disorders due to extrastriate cortical damage as either magno- or parvocellular deficits is challenged by recent physiological findings. It has been suggested that magno- and parvocellular channels are brought together and largely intermingled in V1 before visual information is transferred to extrastriate areas (Sincich & Horton, 2002, 2005).

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Based on this assumption, one can postulate that disturbed function in early visual cortices may interfere with the integration of magno- and parvocellular channels and eventually produce dissociations such as those observed in PR. Correspondingly, our PET analysis of the patient’s brain revealed highly significant hypometabolism in both rostro-medial occipital cortices. The possible role of early visual cortices in mirrored vision is further supported by a recent fMRI study: after a few days of wearing left-right reversing goggles, healthy subjects showed not only contra- but also ipsilateral V1-activity in response to unilateral checkerboard stimuli (Miyauchi et al., 2004). This bilateral activity was interpreted as evidence for large-scale functional reorganisation in occipital areas due to optical inducement of mirrored vision. Similarly, PR’s mirrored vision might result from functional reorganisation due to bilateral occipital hypometabolism. The question of why PR exclusively showed horizontal reversals can be related to previous theories about spatial vision, especially to theories about the visual perception of organisms and objects. It has been postulated that the left-right dimension is the least asymmetric (Ittelson, Mowafy, & Magid, 1991) or most arbitrary (Corballis, 2000) of the three spatial axes in the natural world. Humans and most animals show clear functional and structural differences along both the top-bottom and front-back axis, but are more or less symmetric with respect to the horizontal axis. Therefore, the evolutionary pressure to tell left from right seems to be of relatively lesser importance. This is reflected, for example, in the observation that young children often confuse left and right or produce mirror script when learning to write (Corballis & Beale, 1970, 1976). Moreover, microelectrode recordings in the inferior temporal cortex of monkeys have shown that horizontal mirror image confusion can even be found on the level of single neurons, as they responded similarly to horizontal but not to vertical mirror images (Rollenhagen & Olson, 2000) or figure-ground reversals (Baylis & Driver, 2001). Together with clinical reports of patients with a specific deficit in discriminating between horizontal mirror images after parietal brain damage (e.g. Davidoff & Warrington, 2001; Priftis et al., 2003), these findings highlight the relative instability of the left-right dimension in neuronal processing. Generally, mirrored vision can be regarded as an extreme clinical manifestation of this instability. Acknowledgements We thank PR, the control subjects, Helene Hofer, Giovanni Ferrieri, Heather Murray, Christian Kamm, Fritz Buser, Eveline Klimmeck and Doerthe Heinemann for their time and effort. This research was supported by a grant from the Haag-Streit Foundation. References Bassi, C. J., & Lehmkuhle, S. (1990). Clinical implications of parallel visual pathways. Journal of the American Optometric Association, 61, 98–110. Baylis, G. C., & Driver, J. (2001). Shape-coding in IT cells generalizes over contrast and mirror reversal, but not figure-ground reversal. Nature Neuroscience, 4, 937–942.

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