Listening to numbers affects visual and haptic bisection in healthy individuals and neglect patients

Neuropsychologia 50 (2012) 913–925

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Listening to numbers affects visual and haptic bisection in healthy individuals and neglect patients Zaira Cattaneo a,∗ , Micaela Fantino b , Flavia Mancini a , Flavia Mattioli c , Giuseppe Vallar a,d,∗∗ a

Department of Psychology, University of Milano-Bicocca, Piazza dell’Ateneo Nuovo 1, 20126 Milano, Italy Department of Psychology, University of Pavia, Piazza Botta, 6, 27100 Pavia, Italy Clinical Neuropsychology, Ospedali Civili of Brescia, V. Nikolajewka, 13, 25123 Brescia, Italy d Neuropsychological Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy b c

a r t i c l e

i n f o

Article history: Received 25 May 2011 Received in revised form 21 January 2012 Accepted 25 January 2012 Available online 2 February 2012 Keywords: Neglect Line bisection Visual Haptic Mental number line Priming Numerical cognition Crossmodal interaction

a b s t r a c t There is evidence that humans represent numbers in the form of a mental number line (MNL). Here we show that the MNL modulates the representation of visual and haptic space both in healthy individuals and right-brain-damaged patients, both with and without left unilateral spatial neglect (USN). Participants were asked to estimate the midpoint of visually or haptically explored rods while listening to task-irrelevant stimuli: a small digit (“2”), a large digit (“8”), or a non-numerical auditory stimulus (“blah”). In a control silent condition, the bisection error of USN patients was biased rightwards (namely, the marker of USN) only in the visual modality. Regardless of the direction of the bisection error committed in silent trials, listening to the small digit shifted the perceived midline leftwards, and listening to the large digit shifted the perceived midline rightwards, compared to a control condition in which a neutral syllable (“blah”) was presented. The shift induced by listening to numbers occurred independently of the modality of response (i.e., both in vision and haptics), and in every group of participants. Interestingly, the effect of auditory numbers processing on space estimation was overall larger for haptically than for visually explored space in all participants. In conclusion, the present data show that listening to irrelevant numbers affects space perception also in patients with left USN, indicating that the spatial representation and attention processes disrupted by USN are not involved in these numerical magnitude-spatial effects. © 2012 Elsevier Ltd. All rights reserved.

1. Introduction Numbers are typically represented in a spatial format that takes the form of a mental number line (MNL; see Dehaene, Bossini, & Giraux, 1993), that – in left-to-right reading cultures – appears to be left-to-right oriented. Accordingly, small numbers occupy the left side of the MNL, and large numbers the right side. There is evidence for similar biases in the way attention is allocated to physical space, and to the space of the MNL. In particular, neurologically unimpaired individuals tend to show a leftward directional bias – often referred to as “pseudoneglect” (for a review, see Jewell & McCourt, 2000) – both when bisecting physical lines and numerical intervals (Cattaneo, Fantino, Tinti, Silvanto, & Vecchi, 2010; Longo & Lourenco, 2007), although the mechanisms underlying

∗ Corresponding author. ∗∗ Corresponding author at: Department of Psychology, University of MilanoBicocca, Piazza dell’Ateneo Nuovo 1, 20126 Milano, Italy. E-mail addresses: [email protected] (Z. Cattaneo), [email protected] (G. Vallar). 0028-3932/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2012.01.031

pseudoneglect for numerical and physical lines bisection may not overlap completely (e.g., Ashkenazi & Henik, 2010). Importantly, the spatial representation of numbers and the perception of physical space affect each other (see Umiltà, Priftis, & Zorzi, 2009; Wood, Willmes, Nuerk, & Fischer, 2008, for reviews). For instance, visually presented small numbers bias attention toward the left side of physical space, and visually presented large numbers bias attention to the right side of it (Fischer, Castel, Dodd, & Pratt, 2003). Correspondingly, activating the representation of specific portions of space affects numerical processing (Cattaneo, Fantino, Silvanto, Vallar, & Vecchi, 2011; Stoianov, Kramer, Umiltà, & Zorzi, 2008). Such interaction can also occur across sensory modalities: in particular, listening to small and large magnitude numbers while haptically estimating the length of a rod shifts its perceived midline respectively to the left and to the right of the true midpoint in neurologically unimpaired participants (Cattaneo et al., 2010). Critically, whether space perception is affected by processing numerical magnitudes to a similar extent in different sensory modalities is not known so far. A recent study demonstrates that auditorily presented numbers affect length estimation of haptically

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perceived rods (Cattaneo et al., 2010), but whether this effect is also present and – if so – to a similar extent when the length of visually presented rods has to be judged has not been investigated yet. In fact, it could prove to be the case that the visual modality is more “resistant” against the attentional biases induced by the concurrent auditory presentation of numbers, being vision usually the most precise modality for judging spatial location and spatial extent (with the modality that “dominates” in a specific situation being the one that is more precise for the task being performed, see Ernst & Banks, 2002; Welch & Warren, 1986). Moreover, it has not been previously investigated whether auditorily presented numbers can affect the representation of space in patients affected by unilateral spatial neglect (USN). This is a deficit, typically brought about by right hemispheric lesions, whereby patients are not able to report stimuli presented in the portion of space contralateral to the side of the lesions (namely, the left-handside in right-brain-damaged patients), and to explore that side of space (Halligan, Fink, Marshall, & Vallar, 2003; Heilman, Watson, & Valenstein, 2003; Husain, 2008; Vallar, 1998, 2001). One task frequently used to assess USN – both for diagnostic and research purposes – is “line bisection”, where participants are required to mark the perceived mid-point of a line that, in order to assess lateral USN, is presented horizontally. Right-brain-damaged patients with left USN typically bisect the line to the right of the veridical midpoint, therefore underestimating its left portion (Bisiach, Bulgarelli, Sterzi, & Vallar, 1983; Bisiach, Capitani, Colombo, & Spinnler, 1976; Schenkenberg, Bradford, & Ajax, 1980; Vallar, Daini, & Antonucci, 2000). Notably, also the horizontal spatial representation of numbers is distorted in USN patients (despite a spared abstract knowledge of numerical quantities, see Pia, Corazzini, Folegatti, Gindri, & Cauda, 2009; Vuilleumier, Ortigue, & Brugger, 2004). In particular, right-brain-damaged patients with left USN may show a rightward bias in setting the mid-point of auditorily presented numerical intervals (Zamarian, Egger, & Delazer, 2007; Zorzi, Priftis, & Umiltà, 2002), and a representational neglect of the left portion of the MNL in other paradigms such as judging whether a given number represents the midpoint of a numerical interval (Hoeckner et al., 2008), or comparing numerical magnitudes (Vuilleumier et al., 2004). Interestingly, in a left-brain-damaged patient with right USN, an opposite pattern has been described (Pia et al., 2009). Other interactions between spatial and numerical representations, however, appear not to be prevented by USN: in particular, numbers presented visually at the extremities of a to-be-bisected visual line affect the bisection performance of right-brain-damaged patients with left USN (Bonato, Priftis, Marenzi, & Zorzi, 2008). Specifically, the bisection error is displaced leftward (i.e., contralaterally with respect to the side of the lesion) when a small digit is presented, and rightward (i.e., ipsilaterally to the side of the lesion) when a large digit is presented (for reviews on the relationship between spatial and numerical representations see de Hevia, Vallar, & Girelli, 2008; Umiltà et al., 2009). So far, no studies have ever investigated whether listening to task-irrelevant numbers affects spatial judgments in the visual and haptic modality in right-brain-damaged patients with USN, as assessed by line bisection. In this study, a group of neurologically unimpaired participants and a group of patients with right hemisphere lesions, with and without evidence of left USN, were required to bisect rods of different length in the visual and haptic modalities, while concurrently listening to numerical cues of a different magnitude. Were the attentional modulation induced by numbers processing the same across sensory modalities, putative shifts in the bisection bias should be comparable in the visual and in the haptic tasks. Moreover, finding evidence for an effective modulation by auditorily presented numbers on bisection performance in right-brain-damaged patients with left USN shall contribute to

shed light on the nature of the attentional deficits induced by USN, and on the neural circuits mediating numbers-space interactions in neurologically unimpaired individuals. 2. Methods 2.1. Participants Nineteen patients with right hemisphere brain lesions, confirmed by CT or MRI scan, participated in the study and were recruited from the inpatient population of the Neurorehabilitation Unit of the IRCCS Italian Auxological Institute, Milan, and of the Neuropsychological Unit, Ospedali Civili di Brescia, Brescia, Italy. Patients gave written informed consent to the study, that was approved by the Ethical Committee of the IRCCS Italian Auxological Institute, Milan, Italy. The patients’ demographic and neurological features are summarized in Table 1. All patients were right-handed, according to a standard interview (Oldfield, 1971), and had no history or evidence of previous neurological or psychiatric diseases. All patients had a normal or corrected-to-normal vision. Nine patients (N+ group) had left USN (4 males, mean age = 67.4, SD ± 10.4, mean years of education = 9.4), whereas 10 patients (6 males, mean age = 49.2, SD ± 9.2, mean years of education = 12.6) showed no USN (N− group). The presence of USN was assessed by a battery of standard tests (see Table 2): patients were assigned to the N+ group if they showed a rightward bias in line bisection, and evidence of left USN in at least one of the cancellation tests, and in one of the other screening tests (see below). Contralesional motor, somatosensory, and visual half-field deficits, including extinction to tactile and visual stimuli, were assessed by a standard neurological exam (Bisiach, Cappa, & Vallar, 1983). None of the patients showed a cognitive deficit, as evaluated by the Mini Mental State Evaluation (Grigoletto, Zappala, Anderson, & Lebowitz, 1999). Control data were provided by two groups of right-handed neurologically unimpaired participants, matched for gender, age, and education with the N+ and the N− groups. The C+ group (control for the N+ patients) consisted in 9 participants (4 males, mean age = 66.1, SD ± 10.6, mean years of education = 10.9), the C− (control for the N− patients) group consisted in 10 participants (6 males, mean age = 49.6, SD ± 9.2, mean years of education = 13.2). Each participant gave informed written consent to take part in the experiment. All participants were treated in accordance with the Declaration of Helsinki. Lesions were mapped for each right-brain-damaged patient using the MRIcro software (Rorden & Brett, 2000) and were drawn manually onto selected horizontal slices of a standard template brain. MNI z-coordinates of each transverse section are given. Fig. 1 shows the overlapped lesion maps of 18 of the 19 right-brain-damaged patients, subdivided into showing and not showing left USN, and the colour-coded relative frequency of damage in the N+ group after subtraction of the N− group. In N+ patients the maximum overlap involved the right putamen and the insula (8 patients); in N− patients a puntiform maximum overlap was observed over the posterior part of the right putamen (4 patients). The subtraction identified a region localised in the right insula and putamen as associated to the USN deficits. Overall, lesions were more extensive in the N+ group (mean volume of the lesion = 87.16 cc, SD ± 81.88) than in the N− group (mean volume of the lesion = 35.04 cc, SD ± 43.72), a result that is in line with previous evidence (e.g., Hier, Mondlock, & Caplan, 1983a,b; Leibovitch et al., 1998). Scan images were unavailable for N− patient #3; medical records for this patient reported ischemic lesions in the internal capsule, the thalamus and the cerebellum. 2.2. Baseline neuropsychological assessment The diagnostic battery assessing the presence of left unilateral neglect included: three visuomotor exploratory tasks [line (Albert, 1973), letter and bell cancellation (for the cut-off criteria of these two tests we referred to the normative data reported in Vallar, Rusconi, Fontana, & Musicco, 1994)], sentence reading (Pizzamiglio et al., 1992), line bisection (for the cut-off criteria of this test we referred to Fortis et al., 2010), and three drawing tasks (daisy copying, clock from memory and the fiveelement complex drawing copying test, Gainotti, Messerli, & Tissot, 1972; for cut-off criteria we referred to Fortis et al., 2010, and to normative unpublished data by Corbetta, 2008). Patients used their right unaffected hand to perform each cancellation, bisection, and drawing task. In each task, the centre of the sheet was aligned with the mid-sagittal plane of the trunk of the patients, who were free to move their head and eyes. 2.2.1. Line bisection The patients’ task was to mark with a pencil the midpoint of six horizontal black lines (two 10 cm, two 15 cm, and two 25 cm in length, all 2 mm in width), presented in a random-fixed order. Each line was printed in the centre of an A4 sheet, aligned with the mid-sagittal plane of the participant’s body. The length of the left-hand side of the line (i.e., from the left end of the line to the participant’s mark) was measured to the nearest mm. This measure was converted into a standardized score (percent deviation), namely: measured left half minus objective half/objective half × 100 (cf. Rode, Michel, Rossetti, Boisson, & Vallar, 2006). This transformation yields positive numbers for marks placed to the right of the physical centre, negative numbers for marks placed to the left of it (line bisection error: LBE). According to normative

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Table 1 Demographical and neurological data of 19 right-brain-damaged patients with (N+) and without (N−) neglect. F: female; M: male; I/H/N: ischemic, hemorrhagic, neoplastic. M/S/VHF: left motor, somatosensory, visual half-field deficit:+, ++, +++/−: presence and severity/absence of impairment; e: sensory extinction to double simultaneous stimulation. Patients

N+ patients 1 2 3 4 5 6 7 8 9 N− patients 1 2 3 4 5 6 7 8 9 10

Sex

Age

Education (years)

Duration of disease (months)

Etiology

Neurological deficit M

S

VHF

F M M M F F F F M

75 72 78 67 78 73 53 51 60

8 18 17 5 5 5 6 13 8

0.9 4.6 36.3 33.6 21.2 4.0 1.6 1.2 1.0

I I I–H I I H I I–H I

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

e ++ e ++ ++ ++ e ++ −

++ ++ ++ +++ +++ e − +++ +++

M M M F F M F M F M

39 38 47 42 41 55 52 64 61 53

13 13 16 13 13 13 8 5 13 19

24.5 13.8 0.8 8.6 0.9 2.2 1.2 6.0 13.6 1.3

I I I H N N I I I–H I

+ − ++ − + − ++ − − −

− − − − − − − − − −

− − − − − − − e − −

data referred to by Fortis et al. (2010), the mean percentage deviation score of 65 neurologically unimpaired participants (mean age = 72.2, SD ± 5.16, range 65–83; years of education (mean) = 9.5, SD ± 4.48, range 5–18) was −1.21% (SD ± 3.48, range −16.2% to +6.2%). In the current study, a positive LBE exceeding the upper range limit reported in the reference sample (i.e., ≥+6.2%) was considered as indicative of left USN.

2.2.2. Line cancellation (adapted from Albert, 1973) The patients’ task was to cross out all of 40 black 2.5 cm-long lines printed on an A4 sheet with no distracters. The score was the number of omissions in the leftand right-hand sides of the sheet. Normal participants perform this task without errors. The presence of one or more omissions in the left-hand side of the sheet was considered as indicative of spatial neglect.

Fig. 1. Panel A: Overlay lesion plot of nine N+ right-brain-damaged patients. Panel B: Overlay lesion plot of nine out of 10 N− right-brain-damaged patients. MNI coordinates for the shown axial slices are given. The number of overlapping lesions is illustrated by different colours coding increasing frequencies from violet (n = 1) to red (n = 9). Regions specifically damaged in USN patients mainly involved multiple puntiform regions in the right posterior insula (83.35%) and a wider region including the right putamen and the insula (66.68%). Panel C: Overlay plot of the subtracted superimposed lesions of the group of patients with USN minus the patients’ group without USN. Reddish colours indicate relative prevalence of damage in patients with USN (N+), shown in bins of 20% from dark red (1–20%) to white (80–100%). Bluish colours indicate prevalence of damage in the patients without USN (N−) from dark blue (1–20%) to light blue (80–100%). Purple (middle of the colour bar) designates regions where there is an identical percent of lesions in the N+ and the N− groups (=0%). The subtraction map shows, that in comparison to patients without neglect brain damage in neglect patients was more frequent in a region involving the right insula and putamen. MNI coordinates for the shown axial slices are given. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

916 Table 2 Baseline assessment. Line bisection: percent displacement (−/+ leftward/rightward). Target cancellation: number of omitted targets (left-right hand-sides), total percent omissions in round brackets. For the Letter and Bells cancellation tasks the CoC index is reported in square brackets (normative data for the CoC index are only available for the Bells cancellation task, see main text). Drawing tasks, Mini Mental State Examination (MMSE): raw scores. Sentence reading: number correct. Patient

N− 1 2 3 4 5 6 7 8 9 10 a

Cancellation tests

Drawing

Reading task

MMSE

Line

Letter

Bells

Daisy

Complex

Clock

+4.6 +2.4 +1.93 +42.89a +50.51a +9.4a +8a +6.2a +77.8a

0–0 (0%) 1–0 (2.5%)a 2–0 (5%)a 20–2 (55%)a 20–9 (72.5%)a 0–0 (0%) 0–0 (0%) 0–0 (0%) 19–0 (47.5%)a

1–0 (1.0%) [0.005] 42–8 (48.1%)a [0.423] 15–4 (18.3%)a [0.105] 53–31 (80.8%)a [0.819] 53–42 (91.3%)a [0.919] 19–12 (29.8%)a [0.076] 17–19 (34.6%)a [0.014] 51–7 (55.8%)a [0.545] 53–35 (84.6%)a [0.841]

6–0 (17.1%)a [0.161a ] 12–5 (48.6%)a [0.331a ] 8–0 (22.9%)a [0.236a ] 18–11 (82.9%)a [0.832a ] 18–13 (88.6%)a [0.878a ] 3–0 (8.6%) [0.081] 6–4 (28.6%)a [0.042] 1–0 (2.9%) [0.03] 18–14 (91.4%)a [0.929a ]

2 1.5a 1a 2 0.5a 1.5a 2 2 1a

10 5.5a 10 4a 1a 10 10 9a 4a

3a 12 12 12 1a 4a 6a 12 1a

4a 4a 6 1a 0a 6 6 6 0a

24 28 26 29 24 28 27 27 25

−2.62 −5.13 −1.4 −0.62 −1 −9 −4.2 −11.49 −0.77 −2

0–0 (0%) 0–0 (0%) 0–0 (0%) 0–0 (0%) 0–0 (0%) 0–0 (0%) 0–0 (0%) 0–0 (0%) 0–0 (0%) 0–0 (0%)

0–0 (0%) [0] 0–0 (0%) [0] 0–0 (0%) [0] 0–0 (0%) [0] 1–0 (1.0%) [0.004] 0–0 (0%) [0] 0–0(0%) [0] 2–0 (1.9%) [0.018] 0–0(0%) [0] 2–3 (4.8%)a [−0.003]

0–0 (0%) [0] 2–0 (5.7%) [0.061] 0–0 (0%) [0] 0–2 (5.7%) [−0.019] 1–3 (11.4%) [−0.055] 1–0 (2.9%) [0.022] 0–0 (0%) [0] 2–0 (5.7%) [0.04] 0–0 (0%) [0] 4–0 (11.4%) [0.101]

2 2 2 2 2 2 2 2 2 2

10 10 10 10 10 10 10 10 10 10

12 12 12 12 12 12 12 12 12 12

6 6 6 6 6 6 6 5 6 6

29 29 29 28 30 27 27 30 29 30

Defective performance, indicative of left USN, according to the adopted cut-off criteria, see main text.

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N+ 1 2 3 4 5 6 7 8 9

Line bisection

Z. Cattaneo et al. / Neuropsychologia 50 (2012) 913–925 2.2.3. Letter cancellation task (adapted from Diller & Weinberg, 1977) The patients’ task was to cross out all of 104 H letters (53 in the left-hand-side, and 51 in the right-hand-side of the sheet), printed on an A3 sheet, together with other letter distracters (the test differed from the original one for the larger size of the sheet we used, measuring 30 cm × 42 cm rather than 21.5 cm × 28 cm). We scored the number of omissions in the left and right sides of the sheet of paper. According to normative data reported in Vallar et al. (1994), a total number of omissions larger than 4 or a difference between left-sided and right-sided omissions larger than 2 is indicative of a pathological performance. The Center of Cancellation index (CoC) was also computed according to the software developed by Rorden and Karnath (2010); normative data are not available for the specific task we used, being only provided for the Letter Cancellation Task originally developed by Weintraub and Mesulam (1985) (with a CoC score greater than 0.083 in this task likely reflecting the presence of neglect, see Rorden & Karnath, 2010). 2.2.4. The Bells Test (adapted from Gauthier, Dehaut, & Joanette, 1989) The patients’ task was to cross out all of 35 bells (18 in the left-hand-side, and 17 in the right-hand-side of the sheet), printed on an A3 sheet, together with other 280 distracters (the test differed from the original one for the larger size of the sheet we used measuring 30 cm × 42 cm rather than 21.5 cm × 28 cm). We scored the number of omissions in the left and right sides of the sheet of paper. According to normative data reported in Vallar et al. (1994), a total number of omissions larger than 4 or a difference between left-sided and right-sided omissions larger than 4 is indicative of a pathological performance. The CoC index was also computed according to Rorden and Karnath (2010), with a CoC score greater than 0.081 likely reflecting the presence of spatial neglect (but notice that the normative data reported in Rorden & Karnath, 2010, refer to the standard version of the test presented on a A4 sheet). 2.2.5. Sentence reading (Pizzamiglio et al., 1992) Six sentences of different lengths were presented one at a time, printed centrally on an A4 sheet. The score was the number of incorrectly read sentences (range 0–6). Normal participants and patients with right brain damage without USN make no errors on this test. Patients with left USN make omission errors, substitution errors, or both, in the left half of the sentence. We considered the presence of one or more omissions or substitution errors in reading the left half of the sentence as indicative of left USN. 2.2.6. Drawing Patients were required to copy two figures [a daisy and a complex figure with two trees in the left-hand-side, two pine trees in the right-hand-side, and a house in the centre of an A4 sheet (Gainotti et al., 1972)], and to draw from memory the hours of a clock in a circular quadrant (diameter 12 cm), printed on an A4 sheet. Omission errors were calculated as follows: (a) Daisy (range 0–2): 2 (flawless copy); 1.5 (partial omission of the left-hand-side of the daisy); 1.0 (complete omission of the left-hand-side of the daisy); 0.5 (complete omission of the left-hand-side of the daisy, and partial omission of the right-hand-side of the daisy); 0 (no drawing, or no recognizable element). The mean number of omissions of 148 neurologically unimpaired participants (mean age = 61.89, SD ± 11.95, range 40–89) was 1.99 (SD ± 0.12, range 1–2) (Corbetta, 2008). Accordingly, the presence of a partial or complete omission of the lefthand side of the daisy (score of 1.5 or lower) was considered as indicative of left USN. (b) Five-element complex drawing (range 0–10): each element was scored 2 (flawless copy), 1.5 (partial omission of the left-hand side of an element), 1 (complete omission of the left-hand side of an element), 0.5 (complete omission of the lefthand side of an element, together with partial omission of the right-hand side of the same element), or 0 (no drawing, or no recognizable element). The horizontal ground line was not considered for scoring. The mean score of 148 neurologically unimpaired participants (mean age = 61.89, SD ± 11.95, range 40–89) was 9.89 (SD ± 0.23, range 9.5–10). Accordingly, a score lower than 9.5 indicated a defective performance. (c) Clock drawing by memory (range 0–12): 1 (for each element in the correct position); 0 (for each omission or left-to-right translocation of an hour from the left-hand-side quarters of the quadrant; the “12” and “6” hours were scored as translocated when displaced in the right-hand-side quadrants). The mean number of omissions of 148 neurologically unimpaired participants (mean age = 61.89, SD ± 11.95, range 40–89) was 0.45 (SD ± 1.17, range 0–6), with no translocations (Corbetta, 2008). Accordingly, a score lower than 9 indicated a defective performance. Also, neurologically unimpaired participants made no translocations. Since the experimental task involved numerical cognition, patients were also presented with a battery of tests adapted from Delazer and colleagues (Delazer, Girelli, Granà, & Domahs, 2003), measuring number comprehension and arithmetic abilities, and including a number comparison task (namely, deciding which of two presented numbers was larger), a parity judgment task, a task requiring to transcode from Arabic numerals to tokens, and arithmetic tests (addition, subtraction, multiplication). Overall, patients did not show any specific deficit in number comprehension or calculation capacity. In particular, the mean percentage scores of

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the N+ patients were 99% (SD ± 3) in the number comparison task, 96% (SD ± 11) in the parity judgment task, 97% (SD ± 6) in transcoding Arabic numerals to tokens, 96% (SD ± 5) in addition, 99% (SD ± 3) in subtraction, and 94% (SD ± 6) in multiplication. Mean percentage scores of the N− patients were 100% (SD ± 0) in the number comparison task, 100% (SD ± 0) in the parity judgment task, 99% (SD ± 3) in transcoding Arabic numerals to tokens, 99% (SD ± 2) in addition, 98% (SD ± 3) in subtraction, and 93% (SD ± 7) in multiplication. 2.3. Visual and haptic line bisection task The same stimuli were used in the visual and haptic conditions. Stimuli consisted of wooden rods of six different lengths (200, 250, 300, 350, 400, and 450 mm). The diameter of each rod was 14 mm. Rods were positioned centrally with respect to the midline of each participant. Each rod was fixed with Velcro strips (attached on the bottom of each rod) horizontally onto a wooden panel. The rods could thus be haptically explored without being moved and a constant alignment between the participants’ mid-sternum and the midpoint of the rod could be maintained. The distance between the subject’s mid-sternum and the midpoint of the rod was kept about 380 mm. At the start of the experiment, a vertical line (approximately 1 mm wide) was drawn with a pen in the middle of the tip of the participants’ right index finger. After each trial, the experimenter used this line to measure the difference between the participants’ perceived midpoint and the actual midpoint, within the nearest mm. The experimenter measured the bias by using a measuring tape whose left extremity was aligned with the left end of the rod; the bias was then recorded on a notebook: the measuring tape was positioned in such a way that numbers were visible to the experimenter only, thus preventing participants to possibly estimate their own level of performance in the visual condition. In the visual condition, participants were instructed to look at the rods and to indicate the estimated midpoint with their right index finger. Participants were given a maximum of 20 s to respond. In the haptic condition, participants were blindfolded throughout the entire experiment. Participants were instructed to explore the length of the rod in their preferred direction (left-to-right or right-to-left), using their right index finger only. At the beginning of each trial, the experimenter placed the palm of the participant’s right hand on the rod, such that it approximately covered the midpoint of the rod. This palm-based starting position could not be used as an accurate estimate of the rod’s midpoint, due to its approximate nature, and because at the start of each trial participants were asked to lift their palm off the rod, and to begin to explore it with their right index finger. This starting point for haptic exploration was used in order to control for systematic biases in scanning direction, that may influence bisection performance (see Cattaneo, Fantino, Tinti et al., 2011; Cattaneo et al., 2010, for a similar procedure). The exploration could last for a maximum of 20 s; within this time participants were allowed to scan the rod as many times as they wished. At the end of the trial they were asked to indicate the midpoint of the rod, using their right index finger. In each trial, the initial scanning direction (i.e., whether participants started moving the finger toward the left or the right end of the rod) was recorded by the experimenter. No instructions were given to patients as to the speed of movement of the index finger during the exploration. 2.4. Number presentation In both the visual and the haptic modalities, the line bisection task was performed in four different conditions: (a) Silent condition, in which no auditory stimuli were presented (this condition was included to provide a baseline measure for any effects observed in conditions in which an auditory stimulus was presented); (b) Control auditory condition: the non-word “Blah” was auditorily presented; (c) Small number condition: the number “2” was auditorily presented; (d) Large number condition: the number “8” was auditorily presented. The number “2” corresponded to the low (left-sided) end of the MNL, and the number “8” to its high (right-sided) end (cf. Fischer et al., 2003). In each trial, the same auditory stimulus was repeated 25 times with a frequency of one per sec. In both the visual and haptic modality, the presentation of the auditory stimuli started 5 s before the beginning of the exploration, and lasted throughout the entire exploration (to a maximum of 20 s from the starting of the exploration). In the visual condition, during the pre-cueing phase, participants were not allowed to look at the rod. Audio files were recorded using a specific sound program and were spoken by an Italian female voice, at a comfortable volume. 2.5. Procedure The experiment started with a practice session (not included in the analyses) in which participants were instructed to bisect each of the six lengths of rods within a 20 s time limit in both the haptic and the visual modality (with no concurrently auditory stimulation). Before starting the experiment, participants were presented with the three types of auditory stimuli (“Blah”, “2”, and “8”) and were informed that in some trials they would have been auditorily presented with these stimuli, their task being the same regardless the possible concurrent auditory stimulation. No specific instruction was given to participants about whether to pay attention or to ignore the auditory stimuli. In each test modality (visual and haptic), for each of the six lengths of the rods, there were three trials for each auditory condition (baseline silent; “Blah”, “2”, or “8”), for a total of 72 trials. Hence, the entire experiment consisted of a total of 144 trials. The auditory conditions, as well as the different lengths

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of the rods, were presented in four possible random orders, for each participant the order being the same in the visual and haptic conditions; unimpaired control participants performed the trials in the same order as the patients they were matched to. The order of presentation of the visual and the haptic condition was counterbalanced within each group and between groups. Participants were allowed to take short rests whenever they needed. The entire experiment lasted approximately 1 h and 45 min. 2.6. Scoring and statistical analyses Deviations from the objective midpoint were recorded to the nearest mm. As in previous studies (e.g., Cattaneo et al., 2010; Laeng, Buchtel, & Butter, 1996; Rode et al., 2006), deviations from the veridical centre were converted to signed percentage scores (positive if bisections were to the right, negative if to the left) by subtracting the true half-length of the rod from the measured distance of each setting from the left extremity of it, and then dividing this value by the true half-length and multiplying the quotient by 100. The data were analysed by analyses of variance, with the within-subjects variables Modality (visual vs. haptic) and Cue condition (silent, “Blah”, “2” or “8”), and the between-subjects variable group. A first analysis was carried out on the participants’ performance in the baseline silent condition, in order to get a measure of bisection biases in the visual and in the haptic modality in each group of participants. Hence, analyses were carried out to investigate the effect of the different auditory cues on the original bisection bias. Additional analyses were performed on individuals’ standard deviations (variable bisection error, VBE) as a measure of individuals’ response uncertainty (see Bonato et al., 2008; Cattaneo, Fantino, Tinti et al., 2011; Chieffi, Iavarone, & Carlomagno, 2008). All post hoc comparisons were corrected according to Bonferroni.

3. Results 3.1. Baseline (i.e., silent) condition Fig. 2 shows the mean LBE for the N+, N−, and the two control groups in the baseline visual and haptic bisection conditions. Unimpaired participants overall showed a leftward bisection bias both in the visual and in the haptic modality. A similar pattern was observed in the N− patients, also erring to the left in both modalities. Conversely, the N+ group showed a rightward bias in the visual modality and a leftward bias in the haptic modality. A repeated-measures analysis of variance (ANOVA) on the mean percent LBE in the baseline silent condition with Modality as within-subjects factor, and Group (N+, N−, C+, C−) as between-subjects factor showed significant main effects of Modality, F(1,34) = 19.24, p < .001, 2p = .36, and of Group, F(3,34) = 8.51, p < .001, 2p = .43. The Group by Modality interaction was not significant, F(3,34) = 2.12, p = .12, 2p = .16. The main effect of Modality was due to the magnitude of the bisection error being overall larger in the haptic than in the visual modality. The main effect of Group was due to N+ patients’ LBE being overall significantly different from that shown by the N− patients, t(17) = 4.53, p < .001, and by both C− and C+ participants, t(17) = 4.01, p = .001 and t(16) = 2.88,

p = .01. Conversely, no significant difference was found between the two Control groups, t(17) = .30, p = .77, or between the N− patients and either the C−, t(18) = .96, p = .35, or the C+, t(17) = .95, p = .36, participants. Although the interaction Group by Modality failed to reach significance, Fig. 2 suggests that the difference between the N+ patients and the other groups involved mainly the visual modality, in which patients with USN showed a consistent bias in the opposite direction (i.e., to the right), compared to that shown by the other three groups. N+ patients were significantly older than N− patients, t(17) = 4.05, p = .001 (with unilateral neglect being usually more severe and frequent in older patients, see Gottesman et al., 2008). Moreover, although lesion size did not significantly differ between the two groups, t(16) = 1.68, p = .11 (but note that data of one N− patient could not be considered since his scan images were unavailable), N+ patients tended to present overall larger brain lesions compared to N− patients (see Fig. 1). Therefore, in order to control for a possible effect of age and lesion size in determining the different bisection pattern in N+ and N− patients, we carried out an analysis of covariance (ANCOVA) on the patients’ mean LBE with Modality as within-subjects factor, Group (N+, N−) as betweensubjects factor, and Age and Lesion size as covariates (here and in following ANCOVAs, covariates were mean centred prior to the analyses). The main effects of the covariates Age, F(1,14) = .012, p = .92, 2p = .00, and Lesion size, F(1,14) = .11, p = .74, 2p = .01, failed to reach significance. Moreover, neither Age, F(1,14) = .21, p = .65, 2p = .02, nor Lesion size, F(1,14) = .02, p = .90, 2p = .00, significantly interacted with Modality. The main effect of Modality was significant, F(1,14) = 11.84, p = .004, 2p = .46. Importantly, the main effect of Group was still significant, F(1,14) = 19.17, p = .001, 2p = .58. Hence, the presence of USN affected the patients’ performance regardless of their age and lesion size. To verify whether the bisection biases shown in the haptic and in the visual modality by patients and control participants were significantly different from zero, one-sample t-tests were carried out, comparing the mean LBE with the null set (zero, that is, the objective midpoint) for each Group and for each Modality. The visual rightward bias of N+ patients was significant, t(8) = 3.03, p = .016; conversely, their leftward deviation in the haptic modality was not significant, t(8) = .83, p = .43. The leftward bias shown by N− patients was significant in the haptic modality, t(9) = 4.34, p = .002, but not in the visual one, t(9) = .51, p = .63. C− participants showed a significant leftward bias in the haptic modality, t(9) = 3.24, p = .010, and a close to significance leftward bias in the visual modality, t(9) = 2.23, p = .053; the leftward bias shown by C+ participants was evident in both modalities but failed to reach significance, t(8) = 1.45, p = .19 for the visual, and t(8) = 1.28, p = .24 for the haptic modality. 3.2. Effect of the auditory cues on the bisection bias

Fig. 2. Baseline silent bisection condition, collapsed across rod length. Mean line bisection bias (LBE) by Group (N+, n = 9; N−, n = 10; C+, n = 9; C−, n = 10), and by Modality (visual and haptic). Values are percentage deviation = (deviation from midpoint/half length of rod) × 100. Negative/positive values: leftward/rightward shift (error bars: ±1 SEM).

In order to look at the specific effect of the three different auditory cues (“Blah”, “2”, “8”) on the participants’ LBE, the original biases reported in the silent baseline condition were subtracted by each auditory condition (see Cattaneo et al., 2010, for a similar analysis), so that the resulting bias depended entirely on the “semantic” content of the auditory cue being presented, controlling for possible general effects of an auditory stimulation on the bisection task. Fig. 3 shows the modulation of the original bias induced by the three different auditory cues in the visual and haptic modality in each group of participants and Fig. 4 shows the same effect for each patient of the N+ and N− group. It is apparent that all four groups showed a modulation of their original bisection performance by the auditorily presented numbers, with the cue “2” causing a leftward bias, and the cue “8” a rightward bias; these directional biases were larger in the N+ group.

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Fig. 3. Mean (SEM) percent LBE by Group (N+, N−, C+, C−), Modality (visual and haptic), and auditory Cue (“Blah”, “2”, and “8”), adjusted for the average bias in the silent condition (i.e., for each modality, the mean percent LBE reported in the silent condition was subtracted by the mean percent LBE reported in each cued condition).

A repeated-measures ANOVA was carried out on the normalized mean LBE with Modality (visual vs. haptic) and auditory Cue (“Blah”, “2” and “8”) as within-subjects main factors, and Group (N+, N−, C+, C−) as between-subjects main factor. Neither the main effect of Modality, F(1,34) = .001, p = .97, 2p < .001, nor the main effect of Group, F(3,34) = .21, p = .89, 2p = .018, were significant. Conversely, the main effect of the auditory Cue was significant, F(2,68) = 117.98, p < .001, 2p = .78. The Cue by Group, F(6,68) = 7.71, p < .001, 2p = .41, Cue by Modality, F(2,68) = 35.36, p < .001, 2p = .51, and Cue by Modality by Group, F(6,68) = 4.18, p = .001, 2p = .27, interactions were significant. The Modality by Group interaction was not significant, F(3,34) = .40, p = .76, 2p = .034. The main effect of Cue was due to the “2” cue shifting overall the bisection bias significantly leftward compared to both the “Blah” cue, t(37) = 8.81, p < .001, and the “8” cue, t(37) = 9.11, p < .001. Conversely, the “8” cue shifted the original bisection bias to the right, compared to the “Blah” cue, t(37) = 6.77, p < .001. Four separate repeated-measures ANOVAs with Modality and Cue as within-subjects variables were carried out to explore the effects of Modality and Cue within each group of participants in light of the significant Cue by Modality by Group interaction. In the N+ group, the main effect of Cue was significant, F(2,16) = 32.47, p < .001, 2p = .80, with the cues “2” and “8” shifting the original bisection bias respectively leftward (p = .003) and rightward (p < .001) compared to the neutral “Blah” cue. The effect of Modality was not significant (p = .48); however, the analysis revealed a significant Modality by Cue interaction, F(2,16) = 11.47, p = .001, 2p = .59. Post hoc comparisons showed that the magnitude of the cueing effect was larger in the haptic than in the visual modality for both the “2” cue, t(8) = 2.73, p = .026, and the “8” cue, t(8) = 2.90, p = .020,

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whereas no modality-differences were observed for the “Blah” cue (p = .75). In the N− group, the ANOVA revealed again a significant effect of Cue, F(2,18) = 31.88, p < .001, 2p = .78, with the “2” cue shifting the bisection bias leftward (p < .001) and the “8” cue shifting the bias rightward (p = .011) compared to the “Blah” cue. No significant effect of Modality was observed (p = .99), whereas the interaction Modality by Cue was significant, F(2,18) = 8.05, p = .003, 2p = .47. Post hoc comparisons showed that the cueing effect was larger in the haptic than in the visual modality for the cue “2”, t(9) = 2.70, p = .024, whereas there were no modality differences in the cueing effects induced by the cue “8” (p = .21) and by the cue “Blah” (p = .43). In the Control C+ group the ANOVA again revealed no main significant effect of Modality (p = .66); conversely, the effect of Cue was significant, F(2,16) = 48.22, p < .001, 2p = .86, with the “2” and “8” cues shifting the bisection bias respectively to the left (p < .001) and to the right (p < .001) compared to the “Blah” cue. The interaction Modality by Cue was also significant, F(2,16) = 21.35, p < .001, 2p = .73. This interaction depended on the bias induced by the cue “2” tending to be overall larger in the haptic than in the visual modality, t(8) = 1.82, p = .11; whereas there was no modality-difference in the bias induced by the cue “8” (p = .32) and by the cue “Blah” (p = .83). In the Control C− group the ANOVA again revealed no effect of Modality (p = .93). The effect of Cue was significant, F(2,18) = 22.58, p < .001, 2p = .72, with the “2” and “8” cues shifting the bisection bias respectively to the left (p = .002) and to the right (p = .009) compared to the “Blah” cue. The interaction Modality by Cue failed to reach significance, F(2,18) = 2.08, p = .15. The significant interaction Cue by Modality by Group reported in the main ANOVA suggests that cueing effects in the visual and haptic modalities may have differed among the four groups. To investigate this, three repeated-measures ANOVAs on the mean LBE for each Cue condition, with Modality as within-subjects factor, and Group as between-subjects factor, were performed. For the “Blah” condition the main factor of Modality (p = .74) and of Group (p = .80), as well as the Modality by Group interaction (p = .95) were not significant. For the “2” cue condition, the main factor of Modality was significant, F(1,34) = 15.36, p < .001, 2p = .31, reflecting larger cueing effect in the haptic than in the visual modality. The main factor of Group was significant, F(3,34) = 3.69, p = .021, 2p = .25, whereas the Modality by Group interaction was not (p = .33). Post hoc tests revealed that the leftward shift was larger in N+ patients compared to N− patients, t(17) = 3.00, p = .008, and C− participants, t(17) = 3.49, p = .003, but not significantly different from that shown by the C+ group (p = .29). No significant differences were observed among the other groups (N−, C+, C−). For the “8” cue condition, the main factor of Modality was significant, F(1,34) = 10.93, p = .002, 2p = .24, with larger cueing effects in the haptic compared to the visual modality. The main factor of Group was significant, F(3,34) = 3.69, p = .021, 2p = .25, but this effect may have been modulated by Modality, as suggested by the Modality by Group interaction, F(3,34) = 2.49, p = .077, 2p = .18, which showed a trend towards significance. In fact, two one-way ANOVAs showed that the cueing effects induced by the number “8” were comparable across the four groups in the visual modality, F(3,34) = .75, p = .53, 2p = .06, but differed significantly in the haptic modality, F(3,34) = .3.15, p = .037, 2p = .22. Post hoc comparisons showed that the directional bias induced by the “8” cue in the haptic modality was overall larger in the N+ patients than in the N− patients, t(17) = 2.36, p = .030, and in C− participants, t(17) = 2.95, p = .009, and larger – although not to a significant effect – in N+ patients than in C+ participants, t(16) = 1.77, p = .096. No significant differences were observed among the other groups (N−, C+, C−). The previous analyses show an overall higher susceptibility of N+ compared to N− patients to the effects induced by the numerical cues (except for the effect of the cue “8” in the visual modality).

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Fig. 4. Individual adjusted (see caption of Fig. 3) mean percent LBE in bisecting rods in N+ patients (a, b) and in N− patients (c, d) induced by the presentation of the auditory cues “Blah”, “2”, and “8”, in each test Modality (visual and haptic).

However, age may have interacted with spatial neglect in leading to the larger numerical cueing effects observed in N+ compared to N− patients (also considering the lack of significant differences between N+ patients and their age-matched controls). To clarify this issue, an ANCOVA was carried out on the normalized mean LBE with Modality and Cue as within-subjects factors, Group (N+, N−) as between-subjects factor, and Age, and Lesion size as the covariates (data of the N− patient whose scan images were unavailable could not be included in this analysis). The covariate factors of Age, F(1,14) = .63, p = .44, 2p = .04, and Lesion size, F(1,14) = 1.03, p = .33, 2p = .07, were not significant. Age did not significantly interact with either Modality, F(1,14) = .00, p = .99, 2p = .00, or Cue, F(2,14) = .32, p = .74, 2p = .02; similarly, Lesion size did not significantly interact with either Modality, F(1,14) = .07, p = .80, 2p = .01, or Cue, F(2,14) = 1.13, p = .34, 2p = .08. Importantly, the main effect of Cue was significant, F(2,28) = 51.78, p < .001, 2p = .79; conversely, the main effects of Modality, F(1,14) = .21, p = .66, 2p = .02, and Group, F(1,14) = .02, p = .88, 2p = .00, were not significant. The interactions Cue by Group, F(2,28) = 8.90, p = .001, 2p = .39, and Modality by Cue by Group, F(2,28) = 5.06, p = .013, 2p = .27, were significant. The three-way interactions Modality by Cue by Lesion size, F(2,28) = .78, p = .47, 2p = .05, and Modality by Cue by Age, F(2,28) = .32, p = .73, 2p = .02, were not significant. 3.3. Analysis on variable bisection error (VBE) In this analysis of variance on the mean percent VBE, the Cue condition (Silent, Blah, “2” and “8”) and the Modality were the within-subjects main factors, and Group was the between-subjects main factor. The main factors of Modality, F(1,34) = 312.62, p < .001,

2p = .90, and of Group, F(3,34) = 14.25, p < .001, 2p = .56, were significant; whereas the main effect of Cue condition, F(3,102) = 2.45, p = .09, 2p = .06, was not significant. None of the interactions was significant: Modality by Cue, F(3,102) = 1.33, p = .27, 2p = .04; Modality by Group, F(3,34) = 2.24, p = .11, 2p = .17; Cue by Group, F(9,102) = .69, p = .71, 2p = .06, and Modality by Cue by Group, F(9,102) = .84, p = .58, 2p = .07. The significant main effect of Modality was due to variability being higher in the haptic (10.3%) than in the visual modality (3.2%). The significant main effect of Group was due to response variability being higher in the N+ group (10.2%), compared to the N− group (5.5%), t(17) = 3.71, p = .002, the C+ group (5.0%), t(16) = 3.70, p = .002, and the C− group (4.3%), t(17) = 4.58, p < .001. The VBE was also significantly higher in the N− group compared to the C− group, t(18) = 2.63, p = .017, whereas it was comparable between the N− patients and the C+ participants (p = .45), and between the two control groups (p = .21). To control for a possible effect of Age and Lesion size, the same analysis was performed on the patients’ groups including age, and lesion size as covariates. The covariate factors Age, F(1,14) = .54, p = .48, 2p = .04, and Lesion size, F(1,14) = .11, p = .75, 2p = .01, were not significant. Moreover, Age did not significantly interact with either Modality, F(1,14) = .38, p = .55, 2p = .03, or Cue condition, F(3,42) = .71, p = .55, 2p = .05; similarly, Lesion size did not significantly interact with either Modality, F(1,14) = 1.24, p = .28, 2p = .08, or Cue condition, F(3,42) = .71, p = .55, 2p = .05. The interactions Modality by Cue by Age, F(3,42) = .16, p = .92, 2p = .01, and Modality by Cue by Lesion size, F(3,42) = .26, p = .86, 2p = .02, were not significant. Critically, the effect of Group was significant, F(1,14) = 11.42, p = .004, 2p = .45. As for the within-subjects factors, the main effect of Modality, F(1,14) = 130.95, p < .001, 2p = .90, was significant. The

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main effect of Cue was not significant, F(3,42) = .59, p = .62, 2p = .04; similarly, the interactions Cue by Group, F(3,42) = .72, p = .55, 2p = .05, Modality by Cue, F(3,42) = .36, p = .78, 2p = .03, and Modality by Cue by Group, F(3,42) = .70, p = .56, 2p = .05, were not significant. 3.4. Effect of cueing and response variability It has been found that the effect of directional cues (like arrows) is more evident in patients with USN, and it has been suggested that this may be related to the higher variability of responses (indexed by standard deviations) often observed in these patients (Bonato et al., 2008). The analyses reported above have shown that the effect of numerical cueing was overall larger in patients with USN (with the exception of the bias induced by the cue “8” in the visual modality, that did not reach significance), and that variability of responses was also overall higher in N+ patients than in the other three groups. We therefore investigated whether there was a significant correlation between the effect exerted by numerical cueing and participants’ response variability in the baseline condition. In N+ patients, for the visual modality, the analysis showed a significant correlation between response variability (i.e., mean standard deviations) in the baseline condition and the leftward bias induced by the cue “2”, Pearson’s r(9) = −.79, p = .011: hence, the higher the variability of responses at baseline, the larger the leftward bias induced by the cue “2”. In contrast, the correlation between response variability and the bias induced by the cue “8” was not significant, Pearson’s r(9) = −.05, p = .91. In the haptic modality, the bias induced by the cue “2” did not significantly correlate with N+ patients’ response variability in the baseline condition, r(9) = .04, p = .91, whereas a weak trend toward a correlation was found between the bias induced by the cue “8” and N+ patients’ response variability in the baseline condition, r(9) = .60, p = .091. No significant correlation was found in patients with no USN and in unimpaired participants between the variability of their responses at baseline and the bias induced by the numerical cues in both the haptic (for the cue “2”: p = .39 in N− patients, p = .49 in C+, and p = .50 in C− participants; for the cue “8”: p = .98, p = .42, and p = .16), and the visual modality (for the cue “2”: p = .24 in N− patients, p = .85 in C+, and p = .17 in C− participants; for the cue “8”: p = .23, p = .33, and p = .37). 3.5. Effect of the auditory cues on the initial scanning direction in the haptic modality Nonparametric analyses were performed to assess whether the auditory cue affected the initial scanning direction in the haptic modality. Possible initial scanning directions were to the right (R) or to the left (L). Table 3 shows the percentage of the rightward scanning direction in each group of participants in the silent and cued conditions. Control healthy participants (both C+ and C− groups) showed a significant leftward preferential initial scanning direction in all the cue conditions (Binomial tests, all p ≤ .001). There were no significant differences in the preferential (leftward) initial scanning direction across the four experimental conditions in both the C+ group, 2 (df: 3, n = 366) = .06, p = .998, and the C− group, 2 (df: Table 3 Haptic condition. Percent of initial rightward direction scans in each experimental condition for each group of participants (number of trials = 162 for N+ patients and C+ participants, and 180 for N− patients and C− participants).

N− N+ C− C+

Silent

“Blah”

“2”

“8”

51.7% 60.5% 38.3% 42.6%

55.0% 66.7% 38.9% 43.8%

57.2% 68.5% 37.2% 44.4%

51.6% 63.6% 36.7% 43.2%

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3, n = 388) = .09, p = .993. N+ patients showed an opposite pattern by always preferentially scanning rightwards in all experimental conditions (Binomial test: p = .009 in the baseline silent condition, p ≤ .001 in all the other cue conditions). There were no significant differences in the preferential (rightward) initial scanning direction across the four experimental conditions, 2 (df: 3, n = 420) = .93, p = .82. N− patients did not show any overall preferential initial scanning direction in the four cue conditions (Binomial tests, all p < .05). There were no significant differences in the number of initial rightward scanning movements across the four experimental conditions, 2 (df: 3, n = 388) = .74, p = .86.

4. Discussion In this study, patients with right hemisphere damage (with and without USN) and neurologically unimpaired individuals are required to estimate the midpoint of a series of rods either visually or haptically explored while listening, in certain conditions, to either a number of different magnitude (“2” and “8”), or to a neutral syllable (“blah”). Performing the task while listening to task-irrelevant numbers affects performance in all participants. In particular, listening to a small digit (“2”) shifts the perceived midline significantly to the left, and listening to a large digit (“8”) shifts it to the right, compared to when a neutral auditory stimulus is presented. This pattern is consistently found in both the visual and haptic bisection tasks, and regardless of the initial directional bias shown in trials that are not accompanied by the simultaneous presentation of an auditory stimulus. According to previous evidence (Baek et al., 2002; Cattaneo, Fantino, Tinti et al., 2011; Cattaneo et al., 2010), when the task is performed without any concurrent auditory stimulation, neurologically unimpaired participants show a consistent leftward bias in both modalities, presumed to reflect a right-hemisphere-based spatial attentional bias directed leftwards, a phenomenon known as “pseudoneglect” (Jewell & McCourt, 2000). It is also worth noticing that such a leftward bias – although present – was not significant in the older control participants (C+ group). This result is in line with previous findings showing a reduction, or even a reversal, of the leftward bias in participants aged over 60 years in line bisection and landmark tasks (cf. Fujii, Fukatsu, Yamadori, & Kimura, 1995; Schmitz & Peigneux, 2011; but see Brooks, Della Sala, & Logie, 2011). This might be due to right hemispheric functional changes through physiological aging (for a review, see Dolcos, Rice, & Cabeza, 2002). Right-hemisphere-damaged patients with no USN also exhibit a leftward bias in the haptic modality, but no consistent directional bias in the visual modality (see also Hjaltason, Caneman, & Tegner, 1993, for similar data in patients with right hemisphere damage but no USN in the visual modality). Conversely, in patients with USN a consistent rightward bias is found in the visual, but not in the haptic condition. In the latter task USN patients, if anything, tend to bisect the rod to the left of the veridical midpoint, although this deviation is not significant (for a similar pattern, see Chokron et al., 2002). A number of previous studies have found such a difference between the bisection biases of USN patients in the visual and in the haptic modality, with no rightward, neglect-related, error in the latter (Chokron et al., 2002; Fujii, Fukatsu, Kimura, Saso, & Kogure, 1991; Hjaltason et al., 1993; Mancini, Bricolo, Mattioli, & Vallar, 2011). One interpretation for this difference between visual vs. haptic line bisection is that USN is primarily a visual phenomenon, with ipsilesional visual stimuli disproportionately drawing rightwards the patients’ attention (Chokron et al., 2002). Consistent with these conclusions, USN has been found to be more severe in exploratory tasks when vision is permitted to patients (Chedru, 1976; Gentilini, Barbieri, De Renzi, & Faglioni, 1989; see Schindler, Clavagnier, Karnath, Derex, & Perenin, 2006, for a greater rightward

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bias of the centre of exploration for visual than for tactile search; Villardita, 1987). The greater severity of USN when vision is available has been recently interpreted in terms of “the greater role that the automatic capture of attention by irrelevant ipsilesional stimuli seems to play in the visual modality” (Gainotti, 2010). These findings are consistent with the view that either USN is basically a visual phenomenon, or that vision, through mechanisms such as those suggested by Chokron et al. (2002), and by Gainotti (2010), increases the disproportionate ipsilesional bias. There is also evidence, however, that “visual” and “haptic” (or “tactile-kinesthetic”) USN, as assessed by motor exploratory tasks, may occur independently of each other, suggesting a double dissociation between visual and haptic spatial representations (Cubelli, Nichelli, Bonito, De Tanti, & Inzaghi, 1991, for a reanalysis of the data of Gentilini et al., 1989; Marsh & Hillis, 2008; Vallar, Rusconi, Geminiani, Berti, & Cappa, 1991). In sum, in the baseline bisection condition of the present experiment, USN appears to be primarily a visual phenomenon, absent in the haptic modality, as repeatedly found in previous studies (see above). As patients used their right unaffected hand in all conditions, and no rightward bias was found in the haptic task, it is unlikely that the pathological mechanism involves a premotor, exploratory component (Vallar & Mancini, 2010, for discussion), concerning instead visual vs. haptic representations of extent (see also Gainotti, 2010, for further discussion). It is also worth noting that the preserved haptic bisection performance by USN patients occurs in spite of some form of USN revealed by the preferential rightward direction of the initial scanning (see Table 3). This suggests that the lack of haptic USN in the present sample of right-brain-damaged patients was confined to the ability of setting the midpoint of the rod. Previous evidence has shown that digits simultaneously presented at the two extremities of a visual line can affect estimation of the length of a line in USN patients (Bonato et al., 2008). Accordingly, Priftis, Zorzi, Meneghello, Marenzi, and Umiltà (2006) reported that SNARC effects (i.e., faster left-hand responses for small numbers and faster right-hand responses for large numbers; cf. Dehaene et al., 1993) are spared in USN. The present data extend these findings by showing that USN patients are also susceptible to a modulation exerted by auditorily presented numbers on both haptic and visual space representations. Numbers modulate the performance of all participants (except one N− patient, P10, who does not show the effect in the haptic condition, see Fig. 4), despite being completely irrelevant for the bisection task (see also Bonato et al., 2008; de Hevia, Girelli, & Vallar, 2006). Although it has been previously suggested that numbers orient attention only via a top-down mechanism, requiring some explicit attentional involvement (Galfano, Rusconi, & Umiltà, 2006; Ristic, Wright, & Kingstone, 2006), our data indicate that listening to numbers may activate the representation of the MNL even when individuals are not specifically instructed to pay attention to them, and that this representation modulates judgments of estimation of lateral extent. Nonetheless, we cannot exclude that the activation of the MNL may be more likely to occur when numbers are presented during the execution of a spatial task, whereas a concurrent spatial representation may not be necessarily generated when numbers are presented during the execution of a non-spatial task. It is worth noting that these results, as those by Bonato et al. (2008), bear some resemblance with earlier findings by Vallar et al. (2000), and Daini, Angelelli, Antonucci, Cappa, and Vallar (2002), who found that USN patients are as sensitive as control participants to a visual illusion, namely the Brentano version of the Mueller–Lyer illusions, that expands a perceived extent leftward or rightward (according to the outward or inward orientation of the fins placed at the two ends of the shaft or in the centre of it). Taken together, these results shed light on the range of processes that may be preserved in USN patients despite the impairment in spatial attention and

representation mechanisms that characterizes USN (Bisiach & Vallar, 2000; Rizzolatti & Matelli, 2003; Vallar & Mancini, 2010). At the cortical level, the interaction between space representation and numerical magnitude is likely to occur in posterior parietal regions (Dehaene, Piazza, Pinel, & Cohen, 2003). In particular, the intraparietal sulcus (IPS) may play a central role in this interaction. On the one hand, the right posterior parietal cortex – including the IPS – plays a critical role in processing space (for reviews, see Bueti & Walsh, 2009; Hubbard, Piazza, Pinel, & Dehaene, 2005; Husain & Nachev, 2007). On the other hand, the bilateral horizontal segment of IPS subserves the representation of magnitude (Dehaene et al., 2003; Hubbard et al., 2005; Piazza, Izard, Pinel, Le Bihan, & Dehaene, 2004), and the IPS is automatically activated by passive listening to numbers, as compared to other stimuli, as letters, colour names or pseudowords (Eger, Sterzer, Russ, Giraud, & Kleinschmidt, 2003; Klein, Moeller, Nuerk, & Willmes, 2010). The USN patients participating in this study have extensive lesions showing a maximum overlap in the right putamen and insula (see Fig. 1), broadly in line with current knowledge about the neural correlates of the syndrome (Committeri et al., 2007; Husain, 2008; Vallar, 2001; Verdon, Schwartz, Lovblad, Hauert, & Vuilleumier, 2010). Nonetheless, regardless of lesion site, the modulation exerted by numbers on rod bisection is present in each USN patient, as shown in Fig. 4. This suggests that the interaction between space and the MNL may involve bilateral circuits, or that, in any case, it acts independent of the functional main mechanisms deranged in extra-personal USN, namely an aware perceptual representation of space (Bisiach & Vallar, 2000; Rizzolatti & Matelli, 2003; Vallar & Mancini, 2010). Critically, numerical cueing effects in our study are overall larger in the haptic than in the visual modality. In a previous study investigating numerical cueing effects on a line bisection task, Bonato et al. (2008) suggested that numerical cueing effects are stronger when variability in the bisection performance (reflecting response uncertainty) increases. Accordingly, in our study, response variability is overall larger in the haptic than in the visual modality in all groups of participants. Moreover, the weaker effect of numerical cueing in the visual modality, compared to the haptic one, may depend on vision being more robust against influences of other stimuli. In fact, vision is the sense humans usually rely on in localising and estimating the size of objects (although other sensory modalities may “dominate” over vision in other situations – but this issue is beyond the scope of this study – see Ernst & Banks, 2002; Welch & Warren, 1986). However, it is important to note that the present paradigm does not induce a lower-level competition between sensory modalities: although numbers are auditorily presented, it is not the auditory experience per se that modulates the allocation of spatial attention, but rather the semantic meaning of the information being processed (inducing the activation of a spatially oriented MNL, see Bonato et al., 2008; Dehaene et al., 1993). The fact that the modulation in the bisection bias induced by numbers processing does not depend upon the acoustic stimulation per se is further confirmed by the absence of any significant effects associated to the presentation of a neutral syllable on the bisection performance. Notably, the shift in the bisection bias induced by number magnitude processing tends overall to be larger in USN patients compared to patients with no USN, except for the effect induced by the large number in the visual condition (see below). One may hypothesize that the older age of USN patients compared to patients without USN contributed to this pattern of results, as also suggested by the lack of significant differences in numerical cueing effects between patients with USN and their age-matched controls (although a negative finding is to be treated with caution). Accordingly, previous evidence has shown that the SNARC effect, which reflects the association of numbers and space, tends to increase with age (see Wood et al., 2008, for a review). The larger SNARC effects reported in the elderly have been explained in terms of

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their stronger habit of associating numbers and space (with this association consolidating along the life span), and their diminished efficiency in suppressing task-irrelevant information. These factors likely lead to more interference on performance from the automatic association in the elderly, compared to younger adults (Wood et al., 2008). However, in our study the higher susceptibility of USN patients to numerical cueing effects remains clear even when differences in age (and lesion size) between patients with and without USN are controlled for by a covariance analysis. Therefore, in our study age is unlikely to be the critical factor in leading to the higher susceptibility to numerical cueing effects of patients with USN compared to patients without USN. Accordingly, cueing effects in our younger (C−) and older (C+) healthy participants are comparable. Furthermore, larger effects of numerical cueing on a line bisection task in USN patients have been observed also by Bonato et al. (2008) when comparing USN patients with age-matched brain-damaged patients without USN. Bonato et al. (2008) hypothesized that larger numerical cueing effects in patients with USN depend on an inconsistent perception of line length in USN patients, reflected by the increased variability in their bisection performance. In our study overall response variability is higher in USN patients than in brain-damaged patients without USN (even when the possible effects of age and lesion size on response variability are controlled for) and in healthy participants, in all experimental conditions. Interestingly, correlational analyses show that in patients with USN the higher is the level of uncertainty in estimating the rod’s length in the visual silent condition, the higher is the influence exerted by the small numerical cue in directing attention leftward. This seems to suggest that the effect of cueing indeed relates to response uncertainty, but only when such uncertainty is “pathological”, as in case of the rightward bisection error shown by patients with USN in the silent visual condition. Accordingly, the effect of cueing did not relate to response variability in either patients with no USN and in unimpaired participants; moreover, although also patients with no USN showed larger response variability compared to their age-matched unimpaired controls, their performance was not “pathological” in line bisection. In sum, the increased variability in the bisection performance observed in USN patients seems to account for the overall larger numerical cueing effects we found in patients with USN. Conversely, it is unlikely that age interacted directly with the participants’ response variability: there is evidence, based on larger sample sizes, that ageing is not accompanied by an increase in response variability in line bisection (Barrett & Craver-Lemley, 2008); also, differences in response variability between the two patients’ groups remained significant when age (and lesion size) were controlled for. Notably, the larger cueing effect in USN patients was particularly evident in the visual condition for the cue “2” (being not significant for the cue “8”) (see Fig. 3), suggesting that the numerical cue may be more effective when it operates “against” a strong pre-existing bias (i.e., the rightward bias reported in the baseline visual condition by N+ patients). In line with this interpretation, Daini et al. (2002, see their Figure 4) found that in USN right-brain-damaged patients sensitive to the Brentano illusion, the illusory effect on line bisection is greater leftwards (namely, in the direction opposite to the baseline rightward bias) than rightwards. It may thus be the case that the effect of the numerical cue is stronger in counteracting the pre-existing bias (than in enhancing it) when the estimation of lateral extent is more approximate. It is worth noting that patients with USN showed more frequently a visual half-field deficit, as compared to the other right-hemisphere damaged patients (see Table 1). This could be traced back, at least in part, to USN itself (i.e., “visual hemiinattention”, see Kooistra & Heilman, 1989), and we did not have

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electrophysiological evidence, in order to disentangle between it and hemianopia (Vallar, Sandroni, Rusconi, & Barbieri, 1991). However, a perusal of the performance of the individual patients in the bisection task during the auditory numerical stimulation (see Fig. 4) shows that USN patients P7 (with a preserved left visual half-field) and P6 (with extinction to double simultaneous stimulation, and no hemianopia) exhibit effects of the numerical auditory cues, both in the visual and the haptic condition, comparable to those shown by the other patients with left visual half-field deficits. These findings make unlikely the possibility that a visual half-field deficit may have modulated the effect of the auditory cues. We also investigated whether the presentation of numbers affected the initial scanning direction. Overall, we did not find an effect of numerical processing on the initial direction of scanning. In particular, control healthy participants start scanning preferentially to the left in all conditions (both silent and cued), as also reported in previous studies (see Baek et al., 2002; Cattaneo, Fantino, Tinti et al., 2011), with this preferential direction of exploration likely reflecting “pseudoneglect” (Jewell & McCourt, 2000). Conversely, USN right-brain-damaged patients start scanning always to the right, regardless the number presented, showing a starting rightward “position preference” (see Campbell & Oxbury, 1976; Costa, 1976, for related evidence). Right-hemisphere damaged patients without USN do not show any preferential initial scanning direction in either the baseline silent or in the cued conditions, confirming the overall absence of a specific imbalance in space representation (be it “pseudoneglect” or left USN), that appears to locate them in an intermediate position between neurologically unimpaired participants and USN patients. The finding that numbers’ magnitude does not affect the initial scanning bias may suggest that numbers need a certain time to activate the MNL (in our experiment, numbers were presented 5 s before the starting of the exploration and lasted then for the entire duration of it). A prolonged time may be needed to induce the number magnituderelated bias. More likely though, the scanning initial direction may be more robust against the influence exerted by magnitude, reflecting a (dichotomic) strategic factor, less susceptible to be modulated as compared to a more continuous variable (i.e., the bisection error). Be as it may, the rightward preferential direction of the initial scanning by USN patients in the haptic task, in which they do not show the rightward error diagnostic of left USN, seems to suggest a dissociation between the preserved ability to compute lateral extent in the haptic bisection task, and an initial exploratory bias. In sum, the present study shows preserved interactions in patients with USN between auditory information about numerical magnitude and the ability to compute horizontal spatial extent. Future research may further explore the functional features and the neural underpinnings of this number-space interaction. Acknowledgments GV has been supported by a FAR Grant 2011 from the University of Milano-Bicocca, and by a Ricerca Corrente Grant from the Italian Auxological Institute, Milan, Italy. We are grateful to Marcello Gallucci and Marco Perugini for their statistical advice and to the patients that took part in the study for their forbearance. References Albert, M. L. (1973). A simple test of visual neglect. Neurology, 23, 658–664. Ashkenazi, S., & Henik, A. (2010). A dissociation between physical and mental number bisection in developmental dyscalculia. Neuropsychologia, 48, 2861–2868. Baek, M. J., Lee, B. H., Kwon, J. C., Park, J. M., Kang, S. J., Chin, J., et al. (2002). Influence of final search direction on tactile line bisection in normal subjects. Neurology, 58, 1833–1838. Barrett, A. M., & Craver-Lemley, C. E. (2008). Is it what you see, or how you say it? Spatial bias in young and aged subjects. Journal of the International Neuropsychological Society, 14, 562–570.

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