Left neglect dyslexia: Perseveration and reading error types

Author’s Accepted Manuscript LEFT NEGLECT DYSLEXIA: perseveration and rEading error types Roberta Ronchi, Lorella Algeri, Laura Chiapella, Marcello Gallucci, Maria Simonetta Spada, Giuseppe Vallar www.elsevier.com/locate/neuropsychologia

PII: DOI: Reference:

S0028-3932(16)30266-4 http://dx.doi.org/10.1016/j.neuropsychologia.2016.07.023 NSY6076

To appear in: Neuropsychologia Received date: 28 August 2015 Revised date: 15 April 2016 Accepted date: 19 July 2016 Cite this article as: Roberta Ronchi, Lorella Algeri, Laura Chiapella, Marcello Gallucci, Maria Simonetta Spada and Giuseppe Vallar, LEFT NEGLECT DYSLEXIA: perseveration and rEading error types, Neuropsychologia, http://dx.doi.org/10.1016/j.neuropsychologia.2016.07.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

LEFT NEGLECT DYSLEXIA: PERSEVERATION AND READING ERROR TYPES Roberta Ronchi1,2*, Lorella Algeri3, Laura Chiapella3, Marcello Gallucci4, Maria Simonetta Spada3, Giuseppe Vallar2,4* 1

Laboratory of Cognitive Neuroscience, Brain Mind Institute, School of Life Sciences, Ecole

Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; 2

Neuropsychological Laboratory, S. Luca Hospital, IRCCS Istituto Auxologico Italiano, Via

Mercalli 32, 20122-Milano, Italy; 3

Unità di Psicologia Clinica, Ospedale Papa Giovanni XXIII, Piazza OMS 1, 24127-Bergamo, Italy;

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Department of Psychology and Milan Centre for Neuroscience, University of Milano-Bicocca,

Piazza dell’Ateneo Nuovo 1, 20126-Milano, Italy; [email protected] [email protected] *

Corresponding authors: Roberta Ronchi, PhD, Laboratory of Cognitive Neuroscience, Brain

Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Station 19, CH-1015, Lausanne, Switzerland. *

Corresponding authors. Giuseppe Vallar, MD, Department of Psychology, University of Milano-

Bicocca, Piazza dell’Ateneo Nuovo 1, 20126-Milano, Italy.

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ABSTRACT Right-brain-damaged patients may show a reading disorder termed neglect dyslexia. Patients with left neglect dyslexia omit letters on the left-hand-side (the beginning, when reading left-toright) part of the letter string, substitute them with other letters, and add letters to the left of the string. The aim of this study was to investigate the pattern of association, if any, between error types in patients with left neglect dyslexia and recurrent perseveration (a productive visuo-motor deficit characterized by addition of marks) in target cancellation. Specifically, we aimed at assessing whether different productive symptoms (relative to the reading and the visuo-motor domains) could be associated in patients with left spatial neglect. Fifty-four right-brain-damaged patients took part in the study: 50 out of the 54 patients showed left spatial neglect, with 27 of them also exhibiting left neglect dyslexia. Neglect dyslexic patients who showed perseveration produced mainly substitution neglect errors in reading. Conversely, omissions were the prevailing reading error pattern in neglect dyslexic patients without perseveration. Addition reading errors were much infrequent. Different functional pathological mechanisms may underlie omission and substitution reading errors committed by right-brain-damaged patients with left neglect dyslexia. One such mechanism, involving the defective stopping of inappropriate responses, may contribute to both recurrent perseveration in target cancellation, and substitution errors in reading. Productive pathological phenomena, together with deficits of spatial attention to events taking place on the lefthand-side of space, shape the manifestations of neglect dyslexia, and, more generally, of spatial neglect.

KEYWORDS: Right-brain-damaged patients; Left unilateral spatial neglect; Recurrent perseveration; Neglect Dyslexia; Omission and Substitution reading errors.

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1. Introduction Right-brain-damaged patients may have difficulty in reading tasks, making errors on the side of the letter string contralateral to the side of the lesion (contralesional) (Kinsbourne & Warrington, 1962). Neglect dyslexia is a manifestation of the syndrome of unilateral spatial neglect (Arduino, Burani, & Vallar, 2002; Làdavas, Shallice, & Zanella, 1997; Stenneken, van Eimeren, Keller, Jacobs, & Kerkhoff, 2008; Vallar, Burani, & Arduino, 2010). Right-brain-damaged patients can exhibit both left neglect dyslexia, and other manifestations of left spatial neglect, such as a rightward bias in line bisection, and left-sided omissions in target cancellation. However, neglect dyslexia and these other manifestations of left neglect may also occur independently of one another (Costello & Warrington, 1987; Haywood & Coltheart, 2001; Lee et al., 2009), and there is evidence for a double-dissociation between these two neglect-related deficits (Bisiach, Meregalli, & Berti, 1990; see also Friedmann & Nachman-Katz, 2004 for a case of developmental neglect dyslexia in a child without unilateral spatial neglect). Neglect dyslexia shares the hemispheric asymmetry of unilateral spatial neglect (Heilman, Watson, & Valenstein, 2003; Vallar & Bolognini, 2014; Vallar et al., 2010). In patients reading from left to right, as in Italian, English, French, and German, neglect dyslexia involves more frequently the left hand-side of the stimulus, namely the beginning of the letter string. Neglect dyslexia is an heterogeneous syndrome, with different patients showing different reading patterns due to the damage of discrete levels of representation of the verbal stimulus (i.e., centred on the viewer, on the stimulus, on the word; see Caramazza & Hillis, 1990; Haywood & Coltheart, 2001; Vallar et al., 2010 for discussion). In the taxonomy of reading disorders caused by brain damage, neglect dyslexia is defined as “peripheral”, since it is caused by a disorder of visuo-spatial attention, with the more “central” phonological, and lexical-semantic, processes being spared, and not primarily responsible for the disorder (Vallar et al., 2010). Reading neglect errors have been distinguished from other types of paralexias through the identification of a “neglect point” (Ellis, Flude, & Young, 1987). Based on this criterion, reading errors are defined as

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neglect-related only if “target and error words are identical to the right of an identifiable neglect point, but share no letters in common to the left of the neglect point” (p. 445). Applying this principle, errors due to left neglect dyslexia can be classified into three categories (Ellis et al., 1987): omissions, when patients omit reading one or more contralesional letters in the string; substitutions, when patients substitute one or more contralesional letters; additions, when patients add one or more letters in the contralesional section of the string. The proportion of neglect errors varies across patients, with omissions and substitutions being the most frequent errors (Vallar et al., 2010). These two error types have been ascribed to a diverse severity of the deficit of contralesional spatial attention: omission errors may reflect the patients’ inability to encode even the presence of a letter, due to a more severe spatial bias; substitutions errors may occur when patients are able to encode the position, but not the identity, of the misread letters, due to a less severe spatial deficit (Ellis et al., 1987). According to this view, patients producing substitutions might be more sensitive to lexical effects because the substituted letters, even if not explicitly identified, are implicitly processed. However, this is not always the case: evidence both in support of this hypothesis (Arduino et al., 2002), and against it (Riddoch, Humphreys, Cleton, & Fery, 1990), is on record. Moreover, in contrast with the encoding theory, a study of oculomotor performance by patients with neglect dyslexia suggests that the position of misread contralesional letters during reading performance is not always registered (Behrmann, Black, McKeeff, & Barton, 2002). Therefore, the precise altered mechanisms underlying the production of omission and substitution reading errors by neglect dyslexic patients are still unclear. Finally, additions are the most infrequent error type in neglect dyslexia, and have been ascribed to productive or confabulatory responses (Chatterjee, 1995; Vallar, Zilli, Gandola, & Bottini, 2006). Some studies investigated the presence, the frequency, and the type of reading neglect errors in patients with left neglect dyslexia, examining their association with other classical manifestations of unilateral spatial neglect. In short, left neglect dyslexia, and certain “negative” symptoms of left spatial neglect (i.e., the absence of specific behaviours expected and required, given the task’s 4

demands: for example, the copy of a drawing with missing elements on the left side of the sheet), can occur independently of one another (neglect dyslexia vs. left spatial neglect, as assessed by bisection, cancellation, drawing tasks, see Vallar et al., 2010). However, no study has investigated so far the relationship between different productive or “positive” symptoms (i.e., additional behaviours not relevant to the task performed; see Vallar, 2001) in patients with unilateral spatial neglect and neglect dyslexia. Specifically, addition errors in left neglect dyslexia can be considered as productive manifestations (Vallar et al., 2006), characterised by the addition of letters not present in the string shown, without any request from the examiner. On the contrary, omissions may be regarded as “negative”, or defective, reading errors, in which patients omit to read a part of the stimulus. The status of substitution reading errors with respect to the defective/productive dichotomy is not well defined. Right-brain-damaged patients with left spatial neglect can show productive signs, such as the so-called perseveration, when they execute visuo-motor tasks. Different types of perseverative behaviours by neglect patients have been described, including repetitive marks to cross out the same target, the production of inkblots on the target without interrupting the pen-to-paper contact, and even the addition of irrelevant drawings on the paper sheet (Gandola et al., 2013; Rusconi, Maravita, Bottini, & Vallar, 2002; Vallar et al., 2006). One of these productive signs is characterized by the presence of additional (repetitive) marks on the same targets in cancellation tasks, and it is called recurrent perseveration. Recurrent perseveration is a high-level order deficit, independent from the presence of left-sided motor deficits caused by the right hemispheric lesion: therefore, in all studies investigating perseveration in visuo-motor target cancellation tasks, patients use their unaffected hand, ipsilateral to the side of the hemispheric lesion, namely in right-braindamaged patients the right hand (Na et al., 1999; Nys, van Zandvoort, van der Worp, Kappelle, & de Haan, 2006; Ronchi, Algeri, Chiapella, Spada, & Vallar, 2012; Rusconi et al., 2002). Furthermore, right-brain-damaged patients with left spatial neglect and perseveration may show or not show left-sided motor deficits (see Rusconi et al., 2002, Table 3). 5

In patients with left spatial neglect, perseveration has been extensively investigated, but usually apart from other “positive” neglect phenomena (Na et al., 1999; Nys et al., 2006; Ronchi et al., 2012; Rusconi et al., 2002). The present study aimed at assessing the relationships between different productive signs in neglect, to analyse if the potential co-occurrence of various forms of productive behaviours can be traced back to the disruption of shared functional mechanisms. We focussed our investigation on the more frequent type of perseveration in spatial neglect (i.e., recurrent perseveration, see Na et al., 1999; Rusconi et al., 2002), and we explored the incidence of various reading errors in right-brain-damaged patients with left spatial neglect, who exhibited or not recurrent perseveration in target cancellation tests. Finally, we also verified whether the presence of left neglect dyslexia was associated to a more severe left spatial neglect in conventional tests, since the available evidence is not definite on this point (Behrmann et al., 2002; Lee et al., 2009).

2. Materials and methods 2.1. Participants Fifty-four right-handed patients (30 males; mean age: 67.8 years, SD: 13.4, range: 27-97; mean education: 10.7 years, SD: 5.1 years, range: 2-18) with right hemispheric lesions participated in the study. The aetiology of the focal lesion was vascular in all patients (41 ischemic, 13 haemorrhagic). Lesion site was assessed by CT or MRI scans. All vascular patients included were assessed at least 1 week after stroke onset, in a late-sub-acute-to-chronic phase, according to a standard neurological classification of the phases of stroke (Bahn, Oser, & Cross, 1996; Di Pino et al., 2014). The mean duration of disease of stroke patients was 3.69 months (SD: 5.9, range: 0.328.5). None of the participants had a history or evidence of previous neurological or psychiatric diseases. Table I shows the demographic and neurological information of patients.

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Fifty right-handed neurologically unimpaired participants (27 males), matched for age (mean: 66 years, SD: 12.9), and years of education (10.9 years, SD: 4.8), took part in the study as the control (C) group.

2.2. Materials The presence of left unilateral spatial neglect was assessed by the following conventional clinical tests: Line Bisection, Letter Cancellation (Diller & Weinberg, 1977), and Star Cancellation (Wilson, Cockburn, & Halligan, 1987). The details about these tasks are described in Appendix I. Neglect dyslexia was assessed by two reading tests, including one baseline (WR) and one experimental (EWR) list: 1. Word reading test (WR; range: 0-35). Each participant was shown a series of real words, from 4 to 12 letters in length (mean length: 7.7; SD: 2.3), printed individually in black uppercase letters (Arial, pt.18) in a horizontal position in the centre of an A4 sheet. The stimuli were selected from the list of words of Vallar et al. (1996); their mean written frequency was 54.4 (SD: 72.4 range: 3-369) (Laudanna, Thornton, Brown, Burani, & Marconi, 1995). This list was considered as the baseline task to evaluate the presence of neglect reading disorders, and it was not chosen to elicit a specific neglect reading response. C participants made no neglect errors, and a mean of other reading errors of 0.36 (SD: 0.8; range: 0-4) (see paragraph 2.3 here below for details). 2. Experimental word reading test (EWR; range: 0-35). The stimuli were words from which it was possible to create new words by adding a single letter to the left side of the first letter of the stimulus. For example, “cultura” (culture) became “scultura” (sculpture), by the addition of the letter “s” on the left extremity of the word. The alternative strings had a completely different meaning but a comparable written frequency. The stimuli had an average written frequency of 466.7 (SD: 643.4; range: 304-98498), and the alternative words an average written frequency of 318.7 (SD: 680.2; 7

range: 7-3336) (Laudanna, Thornton, Brown, Burani, & Marconi, 1995). As in the WR, each word was printed horizontally in the centre of an A4 sheet in black uppercase letters (Arial, pt.18), and presented individually to participants. The length of each stimulus varied from 4 to 9 letters (mean length: 5.6; SD: 1.4). C participants made no neglect errors and a mean of other reading errors of 0.16 (SD: 0.37; range: 0-1) (see paragraph 2.3 here below for details). The full list of stimuli of the WR and EWR tasks is reported in Appendix II.

2.3. Procedure Patients were classified as showing left spatial neglect (N+) if they presented with defective spatial scores in at least one cancellation task (Star and Letter), or in the Line Bisection test (see Appendix I for the cut-off scores). For all patients classified as affected by left spatial neglect, an omission percent score [(number of omissions/number of targets)*100] was calculated in each cancellation test. Moreover, for all patients the Center of Cancellation (CoC) (Rorden & Karnath, 2010) (see http://www.mccauslandcenter.sc.edu/CRNL/tools/cancel) was computed in each cancellation test. The CoC index ranged from -1 to +1, with patients who identified all targets scoring zero, patients who only identified the leftmost items near -1, and patients who only identified the rightmost items near +1. This score reflected the pattern of exploration along the horizontal left-right axis; therefore, it took into consideration also the performance of patients producing omissions not lateralized on the leftward part of the sheet. The presence of recurrent perseveration in target cancellation tasks was also assessed. In the cancellation tests participants were asked to cross all targets with a single mark, and the examiner noted the presence and the number of recurrent perseverations, namely: the number of additional marks (Na et al., 1999; Ronchi, Posteraro, Fortis, Bricolo, & Vallar, 2009; Vallar et al., 2006). C participants did not make any extraneous cancellation marks in target cancellation: therefore, right-

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brain-damaged patients who showed one or more recurrent cancellation marks, in at least one of the two (Star and Letter) cancellation tests, were classified as perseverant (P+). The following perseveration index (Ronchi et al., 2009) was computed for each cancellation test: [(number of cancellation single marks + number of added cancellation marks) / number of cancelled targets]. Patients who did not show perseveration behaviour (P-) were assigned a perseveration index score of “1”, whereas P+ patients were assigned a perseveration index greater than “1” (Ronchi et al., 2012, 2009). In the reading tests, participants were requested to read each letter string, with no time limit. They were allowed to move their head and eyes. The examiner took note of the first verbal response, but did not give any feedback about its correctness. Errors were classified as “neglect” if it was possible to identify a neglect point, namely if the target and the response were identical to the right of this point, but completely different to the left of it (Ellis et al., 1987 for details). This conservative measure guaranteed that errors were likely to be a manifestation of left spatial neglect. Applying this principle, neglect reading errors were classified into three categories: 1) omissions: patients did not read one or more contralesional letters [e.g., “famiglia” (family) misread as “miglia” (mile)]; 2) substitutions: patients substituted one or more contralesional letters [e.g., “famiglia” read as “camiglia” (a nonword in Italian)]; 3) additions: patients added one or more letters in the contralesional section of the string [e.g., “famiglia” read as “sfamiglia” (a nonword in Italian)]. For the classification of a combination of two types of errors, see Appendix I. Misreadings not classifiable as neglect errors were recorded as “other” errors. Each reading test was divided into two sub-lists of 17 and 18 words at random, the order of administration being WR1-EWR1-EWR2WR2. As C participants made no neglect errors, patients were classified as affected by neglect dyslexia (ND+) if they produced at least one neglect error in the baseline list (WR); accordingly, patients not producing neglect errors in the WR list were considered as not showing neglect dyslexia (ND-).

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2.4. Lesion localisation The patients’ lesions were drawn on a standard MRI template with a 1 mm slice distance (voxels of 1 mm3), using the MRIcro software (Rorden and Brett, 2000; www.mricro.com). This procedure required the rotation of the standard template, in order to adapt it to each CT/MRI patient’s orientation. Subsequently, each lesion was manually drawn on the correspondent adapted template. Finally, the obtained lesion map was translated to return to the parameters of the original MRI template. Lesion mapping was performed by RR and checked by GV.

2.5. Statistical analyses Parametric analyses were performed on line bisection scores, and on CoC and percent omission errors in target cancellation tasks. Because the omission scores in cancellation tests were not normally distributed, percent scores were converted into the arcsin of the square root of the raw values. Because of the small variability of the recurrent perseveration scores, non-parametric tests were performed (Siegel & Castellan, 1988). To compare the frequency of reading errors produced by perseverant and non-perseverant neglect patients, a Poisson generalized linear model was used (Agresti, 2002). Due to the repeated-measure design, the Poisson model parameters and the associated inferential tests were obtained with Generalized Estimating Equation (GEE) methodology. For those models an exchangeable working correlation matrix was used to model the correlation between the repeated measures (Zeger & Liang, 1986). Post-hoc analyses on individual patients’ data were performed applying binomial statistical tests. The relationships between visuomotor and reading scores in ND+ were explored using Pearson’s correlations. Mean lesion volumes of ND+ and ND- neglect patients were compared using parametric analyses. To compare the lesion correlates of ND+ patients with and without perseveration, a Liebermeister test was performed using the Non-Parametric-Mapping software (Rorden, Karnath, & Bonilha, 2007).

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3. Results 3.1 Visuo-motor spatial neglect and recurrent perseveration severity Based on their performances in the Star and Letter Cancellation, and in the Line Bisection tests, 50 out of 54 right-brain-damaged patients (P5-P54) were classified as N+, and four (P1-P4) as non-neglect (N-). Four out of 50 N+ (8%) showed neglect only in Line Bisection, 12 out of 50 N+ (24%) only in target cancellation, and 34 out of 50 N+ (68%) in both tasks. N+ patients were classified as follows, based on the neglect errors produced in the WR list: 27 out of 50 patients (54%) as ND+ and 23 (46%) as ND-. With respect to reading performance, all four N- patients made no neglect reading error. Table I shows the classification of patients in sub-groups and Table II reports the scores of the neuropsychological assessment of visuo-spatial neglect in the Star and Letter Cancellation and Line Bisection tasks for each N+ patient. The two subgroups of patients with and without ND were comparable with respect to age (mean age ND+ = 68.5 years, SD±14.5; ND- = 66.4±13.2; t(48)= 0.53, p= 0.600) and education (mean years of schooling ND+ = 11.1±5.1; ND- = 10.8±5.2; t(48)= 0.23, p= 0.822). Severity of spatial neglect in ND+ and ND- patients was compared. Independent-group t-tests revealed that neglect was more severe in ND+ patients in Line Bisection (mean deviation ND+ = +23.4±22.4; ND- = +6.3±8.3; t(47)= 3.40, p= 0.001) (data from one ND- patient, who did not perform the Line Bisection test, were excluded from the correspondent analysis). The severity of neglect in target cancellation tasks resulted statistically greater for ND+ vs. ND- patients, considering both the omission percent scores (Star mean omission score ND+ = 61%±30.1; ND- = 16.5%±20.6; t(48)= 5.72, p< 0.001. Letter ND+ = 61.9%±35.8; ND- = 19.9%±25.3; t(48)= 4.8, p< 0.001), and the CoC indexes (Star mean CoC ND+ = +0.66±0.35; ND- = +0.14±0.21; t(48)= 6.08, p< 0.001. Letter ND+ = +0.57±0.38; ND- = +0.15±0.22; t(48)= 4.7, p< 0.001).

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With respect to perseverative behaviours in target cancellation, 25 out of 50 N+ patients (50%) were classified as perseverant (N+P+), and 25 patients (50%) as non-perseverant (N+P-). No N- patient produced perseveration. A Wilcoxon signed ranks test with two dependent variables (perseveration indexes in Star and Letter) was computed to compare perseveration between the two cancellation tasks (see Ronchi et al., 2009): a significant difference was found (T= 1; z= 4.26; p< 0.001), indicating that N+P+ patients produced more perseveration in Star than in Letter cancellation (mean perseveration index Star = 1.18±0.15; Letter = 1.01±0.04), confirming previous data from the literature (Ronchi et al., 2012). With respect to the spatial distribution of perseveration, a Wilcoxon signed ranks test with two dependent variables (Star perseveration indexes on the right- vs. left-hand side) revealed that the most perseverative behaviours were produced in the right-hand side, ipsilateral to the side of the lesion (ipsilesional) (M= 1.19±0.15), as compared with the contralesional left-hand side (M= 1.06±0.10; T= 48.5; z= 3.07; p= 0.002). In the ND+ group (N= 27), 15 out of 27 (55.6%) patients showed perseveration in target cancellation (P+ND+), while 12 out of 27 (44.4%) did not (P-ND+). Neglect severity of perseverant and non-perseverant ND+ patients was compared. P-ND+ and P+ND+ groups had comparable omission percent scores in target cancellation (Star mean omission score P-ND+ = 71.8%±22; P+ND+ = 52.3%±33.5; independent sample t-test: t(25)= 1.79, p= 0.085. Letter P-ND+ = 74.8%±27.9; P+ND+ = 51.5%±38.9; t(25)= 1.76, p= 0.091). When the CoC index was taken into consideration, no significant differences for the Star (mean CoC P-ND+ = +0.76±0.28; P+ND+ = +0.57±0.39; t(25)= 1.45, p= 0.159), and the Letter (P-ND+ = +0.72±0.31; mean omission score P+ND+ = +0.45±0.40; t(25)= 1.92, p= 0.066) cancellation tests were found, although P-ND+ patients produced omissions more lateralized leftward vs. rightward on the latter paper test. A significant difference was found for Line Bisection (mean deviation P-ND+ = +33.4±24.6; P+ND+ = +15.4±17.5; t(25)= 2.22, p= 0.036), with non-perseverant patients showing a greater rightward bias. Finally, in the P+ND+ group the amount of perseverative responses was greater in the Star vs. Letter Cancellation test (mean perseveration indexes Star = 1.22±0.18; Letter = 1.01±0.04; T= 1; z= 12

3.35; p< 0.001), and with more recurrent perseveration on the right hand-side (M right = 1.23±0.11 vs. M left = 1.04±0.11) of the Star cancellation sheet (right vs. left hand-side: T= 8; z= 2.95; p= 0.003). In sum, left spatial neglect was more severe in ND+ than in ND- neglect patients. In the ND+ subgroup, P-ND+ patients had a left spatial neglect more severe than P+ND+ patients in the Line Bisection test.

3.2 Reading errors Figure 1 shows the mean reading performance of neglect dyslexic patients in the WR and EWR lists, and table III reports the number of neglect and other errors produced by each ND+ patient in the two lists. Within the WR list, a Poisson GEE model with Error (three levels: omissions, substitutions, additions), as the within-subjects factor, and Group (two levels: P-ND+ and P+ND+) as the between-subjects factor was performed on the counts of errors. The main factor Error (c2(2)= 40.1; p< 0.001) was significant: multiple comparisons with Bonferroni’s correction revealed that, independently of the group considered, patients produced less addition (M = 0.4) than substitution (M = 3.1; p< 0.001), and omissions (M= 2.9; p= 0.006) errors. A further Poisson GEE analysis was then performed on the two more frequent error types: substitutions and omissions. The main factor Error was not significant (c2(1)= 2.66; p= 0.103), while the main factor Group was significant (c2(1)= 7.94; p= 0.005), indicating that, on average, non-perseverant patients produced more neglect reading errors than perseverant ones (mean reading errors P-ND+ = 2.9; P+ND+ = 1.6). Also the interaction Error by Group was significant (c2(1)= 23.18; p< 0.001). A simple effect analysis was performed to examine the difference within groups in the two reading errors: for the nonperseverant group, the contrast was significant, showing a greater average production of omission (M = 5.8±7.8) vs. substitution (M = 2.5±2.4) errors (c2(1)= 4.47; p= 0.034); the opposite result was 13

found in the perseverant patients, with a major amount of substitution (M = 3.6±2.6) vs. omission (M = 0.7±0.8) errors (c2(1)= 23.96; p< 0.001). A second simple effect analysis was performed to examine the difference between groups for each reading error: even if there was on average a greater number of substitutions produced by perseverant patients, this comparison between P-ND+ and P+ND+ was not significant (c2(1)= 1.27; p= 0.260); by contrast, P-ND+ and P+ND+ patients significantly differed for the production of omission errors (c2(1)= 19.87; p< 0.001). Further analyses were performed on the neglect errors’ count of each patient. Table III shows that six out of 12 P-ND+ patients produced more omissions, and 15 out of 15 P+ND+ patients produced more substitutions. Binomial tests were run on the number of omission and substitution errors of each patient, in order to assess whether the distribution of one of these two error types was significantly greater than chance (50%), with reference to the total number of these errors. The occurrence of omissions was greater than chance for P-ND+ patient P7 (p< 0.001); P-ND+ P25 showed a trend (p= 0.055). The occurrence of substitutions was greater than chance for P+ND+ patients P43 (p< 0.05) and P51 (p< 0.001); P+ND+ patient P38 showed a trend (p= 0.063). In all other patients no significant difference was found. Importantly, this analysis of the performance of individual patients showed that no P-ND+ produced substitution errors, and no P+ND+ omission errors, with a greater than chance probability. To assess whether the EWR condition modulated the production of addition reading errors, the comparison between errors produced in the WR vs. EWR lists was performed separately for each group. Two Poisson GEE models were estimated with Error (three levels: omissions, substitutions, additions) and List (two levels: WR and EWR) as within-subjects factors. For P-ND+ participants, the main factor Error was significant (c2(2)= 36.2; p< 0.001), indicating that nonperseverant patients produced more omission (M = 4.7) than substitution (M = 2.9, post hoc with Bonferroni’s correction p= 0.006), and addition (M = 1.4, p< 0.001) errors, and also a greater number of substitution than addition errors (p< 0.001). Also the main factor List was significant 14

(c2(1)= 8.80; p= 0.003), revealing that the EWR elicited more neglect reading errors than the WR list (mean EWR = 3.1, mean WR = 2.9). Importantly, the Error by List interaction was significant (c2(2)= 20.93; p< 0.001): a simple effect analysis showed that the number of additions increased (EWR M = 2.5, WR M = 0.3; c2(1)= 14.33; p< 0.001), while the number of omissions decreased (EWR M = 3.7, WR M = 5.8; c2(1)= 5.4; p= 0.020) in the EWR list, with no modification of the amount of substitutions between WR and EWR lists (EWR M = 3.3; WR M = 2.5; c2(1)= 1.17; p= 0.280). For P+ND+ participants, the Poisson model comparing the errors produced in WR vs. EWR lists revealed a significant effect of the main factor Error (c2(2)= 39.30; p< 0.001). P+ND+ participants produced more substitution (M = 2.7) than omission (M = 0.6, p< 0.001), and addition (M = 1.2, p< 0.001) errors. The effect of the main factor List was not significant (c2(1)= 0.38; p= 0.538), while the Error by List interaction was significant (c2(2)= 17.71; p< 0.001): a simple effect analysis showed that the number of additions increased (EWR M = 1.9, WR M = 0.5; c2(1)= 10.4; p= 0.001), and the number of substitutions decreased (EWR M = 1.9, WR M = 3.6; c2(1)= 7.95; p= 0.005) significantly in the EWR list, with no change in the frequency of omission errors between WR and EWR lists (EWR M = 0.5, WR M = 0.7; c2(1)= 0.22; p= 0.638). Examples of neglect reading errors made by patients are shown in Table IV. In both lists, the frequency of other, non-neglect, errors was also compared. A Poisson GEE model with List (two levels: WR and EWR), as the within-subjects factor, and Group (two levels: P-ND+ and P+ND+) as the between-subjects factor only revealed a significant effect of the main factor List (c2(1)= 28.89; p< 0.001), with a greater production of other errors in the WR list (EWR M = 1.4, WR M = 3.9). Binomial analyses were run on the results of the WR baseline list to check if the proportion of neglect vs. other errors was higher than chance (50%): results showed that five patients (P7, P19, P20, P25 and P52) produced more neglect errors, with no patients showing the opposite significant pattern.

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In sum, non-perseverant patients made more omission than substitution errors, while perseverant patients showed an opposite pattern, in both the WR and the EWR lists. Other nonneglect errors were comparable in P+ND+ vs. P-ND+ patients. The EWR list brought about a global increase of addition errors, without altering the pattern of relationships between the presence/absence of perseveration in target cancellation, on the one hand, and the distribution of substitution/omission reading errors, on the other hand.

3.3 Relationship between performances in visuo-motor and reading tasks The relationship between the reading errors produced in the baseline WR list and the patients’ scores in the Letter and Star Cancellation (omission percent score, CoC), and Line Bisection, tasks was assessed by Pearson’s correlation analyses. In the whole ND+ group (N = 27), the sum of the most frequent neglect reading errors (omissions plus substitutions) positively correlated with the omission percent score of the Letter test (r= 0.44; p= 0.024), the CoC indexes in both target cancellation tasks (Star: r= 0.41, p= 0.033; Letter: r= 0.46, p= 0.016), and the deviation error in the Line Bisection task (r= 0.67, p< 0.001); no correlation between the global neglect reading errors and the omission percent score of the Star Cancellation test was found (r= 0.34, p= 0.081). Correlation analyses between the omission reading errors and the measures of neglect in visuo-motor tasks were also computed. Omissions correlated with the bias in the Line Bisection task (r= 0.64, p< 0.001), and with the CoC in the Letter test (r= 0.40, p= 0.040). No significant correlations were found for the other measures considered: omission percent scores (Star: r= 0.30, p= 0.125; Letter: r= 0.37, p= 0.059), and CoC (Star: r= 0.35, p= 0.076). No significant correlations were found between the substitution reading errors and the measures of neglect in target cancellation tasks: omission percent scores (Star: r= 0.18, p= 0.369; Letter: r= 0.26; p= 0.185), and CoC (Star: r= 0.26, p= 0.199; Letter: r= 0.26, p= 0.184). Also the correlation between the substitution reading errors and Line Bisection was not significant (r= 0.25, p= 0.210). 16

3.4 Anatomical correlates The cerebral regions damaged in ND+ patients, comparing the lesions size of ND+ vs. NDpatients, were analysed. Lesion images were available for mapping for 26 ND+, and for 15 NDpatients, based on TC (N = 35) and MRI (N= 6) scans. Average lesion volumes were greater in ND+ patients: 124.71 cm3 (±81.1, range 33.1-307.2) for ND+, and 73.99 cm3 (±59.5, range 2.7209) for ND– patients (significant statistical difference: t(39)= 2.11, p= 0.041). Figure 2-A shows the overlap of the lesion maps of ND+ patients: the maximum lesion overlap was on the right white matter under the inferior frontal and post-central regions, as well as on the right insula and the right basal ganglia. Previous lesion-analysis studies (Lee et al., 2009; Ptak, Di Pietro, & Schnider, 2012) reported a damage more posterior than this result, but they included patients producing a greater number of omission vs. substitution reading errors (Lee et al., 2009). Moreover, a recent study found as neural correlate of neglect dyslexia a network including the superior temporal gyrus, the insular cortex, and the basal ganglia, using a prose reading task (Beschin, Cisari, Cubelli, & Della Sala, 2014). Within the ND+ group, the lesion pattern of P-ND+ vs. P+ND+ patients was analysed. A Liebermeister test was performed to compare the lesions of patients classified as showing (0), or not showing (1) perseveration, analysing only voxels damaged in at least 30% of patients (see Ronchi et al., 2012 for the same type of analysis). We used a mask based on cortical (frontal, parietal, temporal, occipital and insular cortices), and subcortical (basal ganglia) regions associated with neglect dyslexia and perseverative symptoms in the neglect syndrome. The Liebermeister analysis indicated the following anatomical correlates specific for P+ND+ vs. P-ND+ patients: the right insula (middle and posterior portions), the right putamen and caudate, the white matter underlying the insula, the inferior frontal and the temporo-parietal regions, at a statistical threshold of p= 0.05 (z with FDR correction= 1.83) (see Figure 2-B).

17

4. Discussion This study investigated the putative association between different productive manifestations of left spatial neglect, in the discrete domains of written language and spatial exploration. The main result is an association between two behaviours exhibited by neglect patients: recurrent motor perseveration in target cancellation tasks, and substitution errors in a word reading test, with perseverant patients producing more substitution reading errors than omissions and additions. Addition errors, also considered as a productive symptom of neglect dyslexia (Chatterjee, 1995; Vallar et al., 2006), are less frequent, and not associated with other (productive or defective) manifestations of spatial neglect. What are the mechanisms underlying these different types of reading errors? The suggestion has been made that a substitution error corresponds to a paralexia produced by neglect patients with a less severe spatial deficit, namely: a defective encoding of the identity of contralesional letters, the processing of their presence and position in the letter string being comparatively preserved (Ellis et al., 1987). This hypothesis has not been confirmed by some studies, however: Riddoch and collaborators (1990) found preserved lexical effects in two patients, one making omission, and the other substitution errors. Moreover, another right-brain-damaged neglect patient producing mainly omissions was able to implicitly process letter strings that had been read incorrectly (Vallar et al., 1996). An alternative explanation postulated that a visuo-spatial attentional deficit may be responsible for omissions, while a perceptual deficit, such as a disproportionate pathological crowding of the letters, may account for the presence of substitution errors (Martelli, Arduino, & Daini, 2011). However, while some experimental manipulations confirm that omission and substitution reading errors rely, at least in part, on independent mechanisms (Daini et al., 2013; Martelli et al., 2011), the crowding effect does not appear to be the main dysfunction accounting for substitutions (Martelli et al., 2011). The present study highlights an alternative interpretation: we 18

found that the most frequent reading error in patients showing productive behaviour (i.e. recurrent perseveration) is substitution. This may reflect the association between two disorders, whose shared feature is to be “productive”, namely: a visuo-motor repetitive activity (i.e., recurrent perseveration), and the active re-elaboration of the contralesional portion of the verbal target (i.e., substitution). We also notice that, although the non-perseverant group produced more omission than substitution reading errors, the amount of the latter ones did not statistically differ between perseverant and non-perseverant dyslexic patients. This suggests that the presence of substitutions per se is not an unambiguous sign for the presence of productive manifestations, with the proportion between omission vs. substitution reading errors being a more relevant parameter. We hypothesize that right-brain-damaged patients with left spatial neglect, who show productive visuo-motor behaviours, are more susceptible to exhibit productive signs also in other domains, for example in reading tasks, with a consequent reduction of the frequency of pure defective (omissions) reading errors. This could be interpreted in terms of a defective inhibition of specific motor responses in the visuo-spatial domain, using the upper hand effector for cancellation, and the verbal-articulatory effector for reading. In the reading domain, the result is that patients modify the left (misread) part of the letter string, inserting some letters not present in the original stimulus, and not relevant for the task’s demands. Addition is an infrequent paralexia (Arduino et al., 2002; Ellis et al., 1987), rarely produced by patients reading a standard list of words, such as the present baseline; addition errors increase with stimuli specifically devised to elicit them. In a single case study, a similar manipulation elicits only one addition in one right-brain-damaged patient producing mainly substitutions (Ellis et al., 1987). Both perseverant and non-perseverant dyslexic patients appear susceptible to a left-side letter addition phenomenon during a reading task designed to elicit this behaviour, while this manipulation does not influence reading performance in control participants. Addition errors are “positive” manifestations that, like other productive signs (Rusconi et al., 2002), may be found in

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right-brain-damaged patients with spatial neglect; however they are rare, unless the task does not specifically trigger that behaviour. The dissociation between the pathological mechanisms bringing about different error types in left neglect dyslexia is in line with evidence concerning the double dissociation between productive and defective behaviours, exhibited by right-brain-damaged patients in visuo-motor tests used to assess unilateral spatial neglect. Perseveration and omissions in cancellation tasks are two independent disorders; this conclusion is supported by two sources of evidence: on the one hand, the lack of correlation between the two error types (Mark, Woods, Ball, Roth, & Mennemeier, 2004; Pia, Folegatti, Guagliardo, Genero, & Gindri, 2009; Ronchi et al., 2009; Rusconi et al., 2002), with some features of the cancellation tasks (such as target type, and spatial disposition, see Ronchi et al., 2012) differently modulating the two pathological manifestations; on the other hand, the discrete neural correlates of the two disorders. In the study of Ronchi et al. (2012) damage to the right insula, and, marginally, to the right inferior frontal region, is a neuroanatomical correlate specific for neglect patients with perseverating behavior; conversely, damage to the right inferior parietal lobule, and partially to the inferior, middle and precentral frontal areas is a correlate of omissions (namely, left spatial neglect) without perseveration. Sensorimotor adaptation to optical prisms that displace rightward the visual scene, which improves left neglect (Chokron, Dupierrix, Tabert, & Bartolomeo, 2007; Kerkhoff, 2003; Vallar, Guariglia, & Rusconi, 1997), reduces omissions in cancellation tasks, but is not effective on perseveration (Nys, Seurinck, & Dijkerman, 2008). In another study (Vallar et al., 2006), prism adaptation proved to be effective in reducing omissions and perseverations in target cancellation tasks, but the two error types loaded on two different factors in a factor analysis, again suggesting their independence. Also in the reading domain, substitutions and omissions seem to rely on two different factors (Daini et al., 2013; Martelli et al., 2011), and the present study proposes a possible functional mechanism triggering for the presence of substitutions.

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With respect to the relationship between unilateral spatial neglect and neglect dyslexia, the greater severity of neglect in dyslexic patients has been confirmed, in line with a previous group study (Lee et al., 2009). Moreover, the severity of left visuo-spatial neglect is comparable in patients with neglect dyslexia producing vs. non-producing recurrent motor perseveration (P+ND+ vs. P-ND+) in target cancellation tasks, but P-ND+ patients exhibit a greater rightward bias in line bisection than P+ND+ ones. Using a paragraph reading task, Reinhart and colleagues (2013) found a positive correlation between the size of the rightward error in line bisection, and the number of left-sided omitted or substituted letters; conversely, cancellation scores resulted unrelated to such errors. In the present sample, the severity of neglect dyslexia overall, as well as omission reading errors alone, correlate with the other measures of spatial neglect, and particularly with the rightward bias in line bisection. The presence of an association between the extent of the rightward bias in line bisection and the greater production of reading omissions may reflect the sharing of some general mechanisms contributing to the processing of horizontal stimuli, such as lines and letter strings. This finding further supports the independence of the mechanisms whose disruption brings about omission, on the one hand, and substitution errors, on the other hand. Defective errors in reading (i.e., omissions) are associated with the rightward bias in line bisection, and this association may be mainly related to a defective perceptual component of visuospatial neglect (see Verdon, Schwartz, Lovblad, Hauert, & Vuilleumier, 2010). Substitutions, on the other hand, rely on a different pathological mechanism, and may involve a defective inhibition of response, responsible also for the occurring of recurrent perseveration. The lesion correlates of recurrent perseveration may support this association of productive symptoms. The lesion analyses of perseverant vs. non-perseverant dyslexic patients show lesions involving the right insula, the right basal ganglia, as well as the white matter underlying the right insular and frontal cortices: these results are in line with previous lesion data about recurrent perseveration in patients with left neglect, which has been associated with damage to the right frontal/inferior frontal, basal ganglia and insular regions (Na et al., 1999; Nys et al., 2006; Pia et al., 2009; Rusconi et al., 2002; Ronchi 21

et al., 2012). Perseveration in cancellation and substitutions in reading can be traced back to an output deficit of response inhibition, and lesion data provide neuro-pathological support to this account: frontal and insular regions are part of a network concerned with the intentional stopping of action, and error awareness (Ronchi et al., 2012; Brass and Haggard, 2010; Ullsperger et al., 2010), with the inferior frontal regions involved in the control of response inhibition (Aron, Robbins, & Poldrack, 2014). To conclude, we show a behavioural association between productive symptoms in the visuomotor and reading domains in right-brain-damaged patients with left spatial neglect, which could be accounted for in terms of a shared pathological mechanism, namely a defective response inhibition for recurrent perseveration in target cancellation tasks, and substitution paralexic errors committed by patients with left neglect dyslexia.

Acknowledgements and Funding. This work has been supported in part by Ricerca Corrente Grants from the Istituto Auxologico Italiano and FAR Grants to Giuseppe Vallar.

Appendix I 2.2 Materials and Methods: The following tasks were used to assess the presence of unilateral spatial neglect: 1.

Line Bisection. Participants were asked to mark the mid-point of six horizontal black lines (2 mm in width; length: two 10 cm, two 15 cm, and two 25 cm). The score was the mean deviation of the participants’ mark from the objective midpoint (measured to the nearest mm). A positive score denoted a rightward bias, a negative score a leftward bias. The mean bisection error of the C group was -0.84 mm (SD: 2.1, range: -6.5/+2.7).

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Letter Cancellation (Diller & Weinberg, 1977). Participants were given an A3 sheet with

2.

104 letter Hs (53 in the left-hand side, and 51 in the right-hand-side) arranged in six rows and mixed with other letters, and were instructed to mark each of the Hs once. Previous data on the performance of a group of neurologically unimpaired participants showed that the maximum difference between omission errors on the two sides of the sheet (leftsided minus right-sided omissions) was two targets (mean left-right omission: 0.10; SD: 0.31; range: 0/2) (Vallar, Rusconi, Fontana, & Musicco, 1994). Star Cancellation (Wilson et al., 1987). Participants were given an A4 sheet with 56

3.

small black stars (30 in the left-hand, 26 in the right-hand-side), mixed with distracters (big stars, letters, and English words), and were instructed to mark each of the stars once. The stimuli were disposed scattered on the sheet. In the C group, the maximum difference between the number of omission errors in the two sides of the sheet (left-sided minus right-sided omissions) was two targets (mean left-right omission: 0; SD: 0.73; range: -2/2).

2.3 Procedure The following cut-off scores were applied to classify patients as affected by left unilateral spatial neglect: -

Line Bisection: mean deviation score greater than “+3.36 mm”, that is, greater than 2 SDs added to the C group’s mean.

-

Target Cancellation: a difference in target omissions between the two sides of the sheet (omission Left – omissions Right) greater than “2” for the Letter (Vallar et al., 1994) and the Star tests, that is, greater than the maximum omission error score obtained by control participants in these tasks.

With respect to neglect reading errors, a misreading resulting in a combination of two types of errors was classified according to the following definitions: 1) omission + substitution: it was 23

considered as substitution [e.g., the target “criminale” (criminal) was read “fanale” (lamp), with the correct reading of the string “nale”, the omission of the first three letters “cri” and the substitution of the other two letters “mi” with “fa”]; 2) substitution + addition: it was considered as addition [e.g., the target “arto” (limb) was read “porto” (seaport), with the correct reading of the string “rto”, the substitution of the letter “a” with “o”, and the addition of the letter “p” at the left end of the word].

Appendix II List WR 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

ARTO MELA VOTO CONO COCCO PIUMA SUOLO PUGNO SIGLA MATITA VISONE RUVIDO PILOTA FLUIDO VACANZA BASTONE GIRAFFA EREMITA MISSILE OROLOGIO MARCHESE CARCIOFO MARTELLO COLTELLO SINDACATO CRIMINALE BRILLANTE POLMONITE PASTICCIO CATECHISMO PARROCCHIA TAFFERUGLIO VIOLONCELLO ARTIGLIERIA TRADIZIONALE

List EWR (in brackets the new word which can be created by adding a letter to the left side of the stimulus) 1.

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MANO

(UMANO)

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

AUTO UOMO MARE ARTE ANNO UOVO ASTA ARCO CENA RETE PALLA RESTO VOLTA VENTO GENTE LOTTA MAGGIO MOTIVO ERRORE CALARE SOLARE ATTIVO ALZARE SEGUIRE SALTARE CULTURA INVIARE RENDERE LETTORE LEZIONE OFFRIRE APPELLO REAZIONE RESIDENTE

(CAUTO) (DUOMO) (AMARE) (PARTE) (DANNO) (NUOVO) (PASTA) (PARCO) (SCENA) (PRETE) (SPALLA) (PRESTO) (SVOLTA) (EVENTO) (AGENTE) (FLOTTA) (OMAGGIO) (EMOTIVO) (TERRORE) (SCALARE) (ISOLARE) (CATTIVO) (BALZARE) (ESEGUIRE) (ESALTARE) (SCULTURA) (RINVIARE) (PRENDERE) (ELETTORE) (ELEZIONE) (SOFFRIRE) (CAPPELLO) (CREAZIONE) (PRESIDENTE)

Figure 1 Mean frequency (SEM) of the omission, substitution and addition reading errors produced by ND+ patients, divided in two subgroups: ND+ making (P+, right-side), and not making (P-, leftside) perseveration in target cancellation tasks. WR (full plots) and EWR (stripe plots) lists are shown. Figure 2 A) Lesion maps of ND+ patients. Bottom row: frequencies of overlapping lesions, from dark violet (n = 1) to red (n = maximum number of maps). B) Liebermeister analysis comparing lesion sites of P+ND+ vs. P-ND+ patients, at a p< 0.05 statistical threshold. False-discovery-rate (FDR) corrections are applied. Montreal Neurological Institute (MNI) Z-coordinates of each transverse section are shown. R: right hemisphere; L: left hemisphere.

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Table I

P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P28 P29 P30 P31 P32 P33

NNNNN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+P+ N+P+ N+P+ N+P+

+ + + + + + + + + + + + + -

M F F F M M M M M M M F F F M M M M M M M F M M F M M M F M M F M

63 72 79 68 60 53 59 60 68 34 75 71 79 37 70 65 54 61 64 60 83 50 60 77 74 74 27 75 69 50 76 68 57

13 5 5 5 8 8 5 5 4 9 17 13 4 8 17 17 18 5 18 13 13 13 8 13 8 13 13 6 8 13 17 2 18

I/Th I/P-O-ic I/scort H/Bg-ic H/Th-ic I/F-T-P I-H/F-T-P I/F-In-Bg I/T-P H/T-P-Bg I/F-T-P-O-In-Bg I/F-T-P-Bg I/Sylvian region H/F-Bg I/T-P-O I/T-P I/ Sylvian region I/T-O H/F-T H/P-O I/F-scort + I-H/In-Bg I/T-P-O-Th H/P-Bg H/F I/F-O-Bg-crb I-H/F-T-P-In I/Bg-wm I-H/ Sylvian region H/F-T-P I/F-T-P I/F-T-P-In I-H/F-T-Bg

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+ + e + + + + + + + + + + + + e + + + e + + + + -

+ + + + + + + e + + + + + + + + + + + e n.a. + + + -

+V +V +V + SS +M + SS +M + SS + SS-V + M-SS-V + SS-V + M-SS-V + SS-V + SS-V + M-SS -

-

-

-

-

-

-

-

-

+

+ + + + + -

ND Sex Age Education Aetiology/ Neurological deficit Associated deficit (years) (years) Lesion site M SS V AN PN SP ___________________________________________________________________________________________________

Group

Table I. Demographic and neurological data of the 54 right-brain-damaged patients ___________________________________________________________________________________________________

N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+

+ + + + + + + + + + + + + + -

M F M F F F F M M F M M F F F F M F F F F

85 53 62 83 71 76 82 87 65 78 61 71 57 97 73 70 73 82 79 82 81

18 8 17 13 5 8 13 18 5 5 18 18 8 17 5 13 5 10 5 17 8

I/T-P-O-crb I/F-T-P-O-In-Bg I/T-P-In-Bg I/Sylvian region I/T-P-bg-ic I/Bg-Th-wm I/Bg I/F-P-scort I/Bg-wm I-H / Sylvian region H/F-scort I/Sylvian region H/F-P-In-Bg I-H/F-P H/F-Bg H/T-P I/F-T-P-In I/F-P-In I/F-P I/P I-H/T-Bg

+ + + + + + + + + + + + + + + + + + + + +

+ + + + + e + e + + + + + + + + + n.a.

+ + + + e e e + e + e + + + e + n.a. + e

+ SS-V + SS-V + M-SS + M-SS + SS + SS + SS + M-SS-V + SS-V + M-SS-V + SS-V + SS -

+ -

-

-

+ + + +

-

N: left unilateral spatial neglect; P: recurrent perseveration; M/F: male/female. H/I: hemorrhagic/ischemic lesion. F: frontal; P: parietal; T: temporal; O: occipital; In: insula; ic: internal capsule; Bg: basal ganglia; Th: thalamus; scort: sub-cortical; crb: cerebellum; wm: white matter. M/SS/V: left motor/somatosensory/visual half-field deficit; e: left-sided extinction to double simultaneous stimulation; AN: anosognosia; PN: left-sided personal neglect; SP: leftsided somatoparaphrenia. +/-: presence/absence of deficit. n.a.: not assessed.

_____________________________________________________________________________________________________

P34 P35 P36 P37 P38 P39 P40 P41 P42 P43 P44 P45 P46 P47 P48 P49 P50 P51 P52 P53 P54

Table II

P5 P6 P7 P8 P9 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P28 P29 P30 P31 P32 P33 P34 P35 P36 P37

N+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+PN+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+

+ + + + + + + + + + + + + + + +

+5.5* --1.5 +69.3* +8* +16.2* +9.3* +11.7* +9.5* -8.2 +8.2* +14.5* -7.8 +39.5* +8.3* +56.2* +58.3* +4* -2 +56.5* +7.67* +44* +3.3 +4.2* +7.7* +40* n.a. -2.6 +2.8 +10.3* +19.3* +7.7* +9.8* +7*

0 0 86%* 20%* 46%* 68%* 89%* 71%* 29%* 38%* 32%* 9%* 88%* 0 73%* 86%* 45%* 18%* 78%* 0 85%* 18%* 0 5%* 82%* 27%* 7%* 5%* 0 27%* 77%* 27%* 82%*

0 11%* 94%* 0 68%* 87%* 86%* 55%* 9%* 15%* 24%* 0 96%* 0 92%* 89%* 13%* 37%* 52%* 0 99%* 0 14%* 0 96%* 13%* 23%* 11%* 18%* 13%* 66%* 9%* 88%*

0 0 0.97 0.12 0.44 0.70 0.89 0.60 0.10 0.28 0.30 0.08 0.98 0.02 0.77 0.97 0.37 0.19 0.84 0 0.99 0.14 0 0.04 0.98 0.10 0.03 0.04 0 0.15 0.85 0.15 0.88

0.01 0.03 0.95 -0.01 0.67 0.88 0.84 0.36 0.02 0.12 0.22 -0.01 0.96 0 0.91 0.83 0.08 0.35 0.47 0 1 0.01 0.09 -0.02 0.98 0.04 0.22 0.05 0.14 0.05 0.65 0.06 0.33

1.02 1.04 1.04 1.21 1.1 1.08 1.07 1.3

1.02 1 1 1 1 1.11 1 1

Omission percent score Center of Cancellation Perseveration index Star Letter Star Letter Star Letter ____________________________________________________________________________________________________________

Patient Group ND Line Bisection

Table II. Neuropsychological assessment of visuo-spatial neglect of the 50 right-brain-damaged patients classified as N+. ____________________________________________________________________________________________________________

N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+ N+P+

+ + + + + + + + + + + -

+8.3* -1.67 +9* +8.7* +23.7* +20.5* -1.7 +0.8 +5.7* +11.2* +11.2* +69.3* +13.5* +31.3* +1.5 +30.2* +11.5*

0 0 0 79%* 0 83%* 0 45%* 19%* 89%* 27%* 86%* 67%* 80%* 37%* 15%* 82%*

7%* 42%* 4%* 73%* 0 98%* 29%* 30%* 84%* 98%* 11%* 96%* 70%* 91%* 9%* 35%* 77%*

0.02 0 0 0.87 0.01 0.90 0 0.55 0.29 0.97 0.28 0.97 0.77 0.97 0.31 0.15 0.93

0.03 0.42 0.03 0.71 0 0.88 0.13 0.12 0.48 1 0.06 0.98 0.79 0.91 0.07 0.31 0.72

1.08 1.13 1.07 1.42 1.18 1.1 1.21 1.04 1.14 1.14 1.34 1.63 1.38 1.38 1.06 1.15 1.14

1 1 1 1 1 1 1.12 1 1 1 1 1 1 1.11 1 1 1

N: left unilateral spatial neglect; P: recurrent perseveration; ND: neglect dyslexia. Line Bisection: mean deviation of the participants’ mark from the objective midpoint (positive score: rightward bias; negative score: leftward bias). Omission percent score: score computed for patients with a defective performance in that task, indicating left N+ [(number of omissions/number of targets)*100]. Center of Cancellation: measure of the centre of mass of the cancelled items (value close to -1: patients who only identified the leftmost items; value close to +1: patients who only identified the rightmost items). Perseveration index: [(number of cancellation single marks + number of added cancellation marks) / number of cancelled targets]; score= 1 indicates absence of recurrent perseveration, score> 1 indicates the presence of recurrent perseveration. +/-: presence/absence of deficit; n.a.: not assessed; *: defective spatial score, indicating left N+.

___________________________________________________________________________________________________________

P38 P39 P40 P41 P42 P43 P44 P45 P46 P47 P48 P49 P50 P51 P52 P53 P54

Table III

Table III. Number of neglect reading errors by type (omission, substitution, addition), and of other reading errors, committed by each ND+ patient in the WR and EWR lists.

Patient

Omission

Substitution

Addition

Other

Omission

Substitution

Addition

Other

LIST EWR: Error type ________________________________________________

P7 P10 P11 P12 P14 P17 P19 P20 P22 P23 P25 P29

25§ 0 0 0 2 1 6 11 1 0 14 9

0 1 0 1 2 4 4 6 0 1 7 4

0 0 1 0 0 0 2 1 0 0 0 0

1 0 1 1 4 5 5 9 2 3 10 11

18 0 0 0 2 0 1 5 0 0 15 3

3 0 0 0 3 2 4 4 1 2 15 5

0 2 3 0 4 6 2 4 0 5 1 3

0 0 0 0 0 2 4 3 0 1 1 2

P31 P34 P35 P37 P38 P41 P42 P43 P45 P47 P48 P49 P50 P51 P52

0 0 0 1 0 0 2 0 0 1 1 2 2 0 1

1 3 2 4 4 1 4 6* 1 2 2 3 6 11§ 4

0 1 0 0 0 0 0 0 0 1 0 1 0 3 2

1 0 1 7 4 1 5 8 0 3 2 2 4 13 1

0 0 0 2 0 0 2 1 0 1 0 0 0 1 1

0 2 2 1 1 0 1 3 0 3 0 3 4 5 3

0 3 4 0 0 1 4 2 0 3 1 6 1 2 2

0 0 0 3 1 0 3 3 0 3 0 1 3 8 0

N: left unilateral spatial neglect; P: recurrent perseveration; ND: neglect dyslexia. Binomial test on neglect reading errors: § p< 0.001, * p< 0.05

____________________________________________________________________________________________________________________________

N+P+

____________________________________________________________________________________________________________________________

N+P-

____________________________________________________________________________________________________________________________

Group

LIST WR: Error type _______________________________________________

____________________________________________________________________________________________________________________________

Table IV

Substitutions

Additions

Italics: letters read correctly to the right of the neglect point. Bold: letters substituted, extraneous to the target. Underlined: letters added to the left of the neglect point, exceeding the length of the target.

POLMONITE NITE PARROCCHIA VECCHIA ASTA CASTA MISSILE SILE MANO SANO ERRORE TERRORE VOTO OTO INVIARE AVVIARE APPELLO CAPPELLO EREMITA ITA VIOLONCELLO CANCELLO LETTORE DIRETTORE VISONE SONE FLUIDO GUIDO EREMITA NEREMITA MATITA TITA RUVIDO LIVIDO RENDERE ATTENDERE SINDACATO DACATO VISONE BISONE CALARE REALARE _____________________________________________________________________________________

Patient’s Target Patient’s Target Patient’s reading reading reading _____________________________________________________________________________________

Target

Omissions

Table IV. Examples of reading errors in right-brain-damaged patients with left neglect dyslexia. _____________________________________________________________________________________

Highlights · Neglect dyslexic patients with perseveration make more substitutions than omissions · Patients with no recurrent perseveration make more omission reading errors · Response inhibition deficits may underlie perseveration and substitution errors · Omission and substitution neglect paralexias are two independent disorders

31