Inappropriate rightward saccades after right hemisphere damage: Oculomotor analysis and anatomical correlates

Neuropsychologia 73 (2015) 1–11

Contents lists available at ScienceDirect

Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia

Inappropriate rightward saccades after right hemisphere damage: Oculomotor analysis and anatomical correlates Alexia Bourgeois a,b,n, Ana B. Chica c,d, Raffaella Migliaccio a,e, Dimitri J. Bayle a,f, Christophe Duret g, Pascale Pradat-Diehl h, Marine Lunven a, Pierre Pouget a, Paolo Bartolomeo a,b,i a INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Epinière (ICM) et Université Pierre et Marie Curie (UPMC), Groupe Hospitalier Pitié-Salpêtrière, Paris, France b Neuroscience Department, Laboratory for Behavioral Neurology and Imaging of Cognition, University of Geneva, Geneva, Switzerland c Department of Experimental Psychology, University of Granada, Spain d Brain, Mind, and Behaviour research center, Granada, Spain e AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Fédération de Neurologie, Paris, France f Centre de Recherche sur le Sport et le Mouvement (CeRSM, EA 2931), Université Paris Ouest-La Défense, Nanterre, France g Service de Neurorééducation, Clinique Les Trois Soleils, Boissise le Roi, France h ER 06, UPMC, service de MPR, groupe hospitalier Pitié-Salpêtrière, AP-HP, 75013 Paris, France i Department of Psychology, Catholic University, Milan, Italy

art ic l e i nf o

a b s t r a c t

Article history: Received 7 October 2014 Received in revised form 10 April 2015 Accepted 15 April 2015 Available online 27 April 2015

Patients with right hemisphere damage and visual neglect have severe problems to orient attention towards left-sided objects, often associated with the tendency to produce inappropriate rightward saccades. In its most severe form, this tendency can assume the compulsive character of a rightward deviation of gaze as soon as the visual scene deploys (so-called “magnetic attraction of gaze”). However, little is known about the exact nature of inappropriate rightward saccades, their relation with impaired conscious perception of left-sided stimuli, and their lesional correlates. To explore these issues, we studied three groups of patients with right brain damage: patients with signs of left visual neglect associated to left homonymous hemianopia, neglect patients without hemianopia, and patients without neglect or hemianopia. Participants searched for a gap missing within a target, presented among distractors. Manual responses for target detection were required, while participants were encouraged to move their eyes during search. Endogenous attention could be summoned to the target location by a central cue. All the three groups of patients produced inappropriate rightward saccades, which could not be completely overcome by the endogenous orienting of attention induced by the cues. Anatomical analysis indicated a specific implication of damage to the right frontal eye field and to a long-range white matter tract, the fronto-parietal superior longitudinal fasciculus. Fronto-parietal networks in the right hemisphere appear thus to be essential to integrate covert and overt orienting of attention, and to thoroughly explore space in order to become aware of the multiple competing objects around us. & 2015 Elsevier Ltd. All rights reserved.

Keywords: Magnetic gaze attraction Attentional orienting Saccadic orienting Visual neglect Right hemisphere damage Fronto-parietal networks

1. Introduction Patients with right brain damage and left spatial neglect are impaired in orienting attention towards left-sided events, and in consciously detecting them (Bartolomeo, 2014). Neglect patients may also exhibit striking disorders of oculomotor behavior. For n Corresponding author at: Alexia Bourgeois, INSERM UMRS 1127, Brain and Spine Institute, Hôpital de la Salpêtrière. 47 Bd de l’Hôpital. 75651 Paris Cedex 13, France. E-mail address: [email protected] (A. Bourgeois).

http://dx.doi.org/10.1016/j.neuropsychologia.2015.04.013 0028-3932/& 2015 Elsevier Ltd. All rights reserved.

instance, when presented with bilateral objects, some patients tend to immediately look at ipsilesional objects, as if these targets “magnetically” attracted patients’ gaze. In clinical settings, ipsilesional attraction of gaze typically occurs during visual field assessment with the confrontation method. Patients are required to fixate their gaze on the examiner’s nose and to detect finger movements performed by the examiner in the patients’ lateral visual fields. Magnetic gaze attraction occurs when, as soon as the examiner stretches his/her arms in the patients’ visual fields, patients lose central fixation and immediately make a saccade towards the hand ipsilateral to their lesion. Conjugate gaze deviation

2

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

towards ipsilesional objects was initially described by Cohn (1972) in patients with homonymous hemianopia. This phenomenon was further studied by Gainotti et al. (1991) in an unselected series of subacute patients with unilateral brain damage. Magnetic gaze attraction was present in 12 of 53 patients with right brain damage, but only in one of 33 patients with left hemisphere lesions, despite similar frequencies of visual field defects in either patient group. The severity of magnetic gaze attraction ranged from a brief saccade towards the ipsilesional stimulus, followed by spontaneous return to fixation, to an ipsilesional gaze deviation that occurred for each bilateral stimulus and required verbal command to regain fixation. Magnetic attraction was nearly always associated to signs of severe contralesional visual neglect and visual extinction. Gainotti et al. (1991) concluded that magnetic gaze attraction resulted from an early and severe orienting of attention towards ipsilesional stimuli, which occurs as soon as the visual scene unfolds, and precedes later attentional disengagement deficits from the same ipsilesional stimuli (Losier and Klein, 2001; Posner et al., 1984; Rastelli et al., 2008). In a second experiment, Gainotti et al. (1991) presented patients with lateralized overlapping figures and analyzed the temporal sequence of their identification. Right brain-damaged patients tended to identify first figures lying on the right side of the display, even when they could eventually identify all the figures presented (see also Azouvi et al., 2002). Thus, early ipsilesional orienting may occur even in patients with mild or no signs of neglect (D’Erme et al., 1992), and may persist as a residual sign of spatial bias when patients have compensated for neglect on paperand-pencil tests (Bartolomeo, 1997; Karnath, 1988; Mattingley et al., 1994). However, eye movements were not assessed in these studies. It is thereby uncertain whether these milder forms of spatial bias also entail directionally biased eye movements, which may suggest common neural mechanisms, or are confined to covert orienting of attention. Also, some neglect patients do make occasional saccades towards left-sided targets, although failing afterwards to acknowledge its presence, e.g. by a button press (Benson et al., 2012; Làdavas et al., 1997). This suggests that attention and saccade production are not always strictly coupled in neglect. All in all, these phenomena are broadly consistent with the hypothesis of dysfunctional attentional networks in the right hemisphere as an important contribution to neglect signs (Bartolomeo, 2014; Bartolomeo et al., 2007; Corbetta and Shulman, 2011; Doricchi et al., 2008). However, the precise relationships with attention processes and the exact anatomical correlates of inappropriate ipsilesional saccades remain currently unknown. Previous studies indicated that direction-specific deficits of saccadic production could underlie some neglect-related signs (Behrmann et al., 2001, 1997; Girotti et al., 1983; Harvey, Olk et al., 2002; Hornak, 1992; Natale et al., 2007; but see Niemeier et al., 2000; Van der Stigchel and Nijboer, 2010). For instance, Behrmann et al. (2001) demonstrated that saccadic impairments in neglect could be attributable to a deficit in the planning and initiation of saccades, rather than a deficit in their execution. Indeed, while saccadic latency towards left-sided targets was increased in neglect patients, the duration and velocity to reach the target were normal. However, most of these studies documented the temporal characteristics of saccades, without taking into account the quantification of the saccade trajectory itself. Here we aimed at obtaining a quantitative assessment of right brain-damaged patients’ tendency to produce inappropriate, rightdirected saccades during cued attentional tasks, and to identify the relevant lesional correlates in the grey and white matter. It would be problematic to address these issues in acute patients with clinically florid forms of magnetic gaze attraction, because by definition these patients cannot maintain fixation in attentional tasks; moreover, they are likely to suffer from temporary

phenomena of diaschisis in intact regions distant to the lesion (Carrera and Tononi, 2014; Feeney and Baron, 1986; Monakow, 1914), with consequent difficulties in mapping their deficits on the corresponding anatomical structures. Thus, we obtained detailed behavioral and anatomical evidence of inappropriate rightwards saccades in a group of patients with chronic, stable vascular lesions in the right hemisphere. In order to determine the relations between magnetic gaze attraction, visual field deficits (Cohn, 1972), visual neglect (Gainotti et al., 1991), and subclinical disorders of spatial attention, we explored spatial saccadic parameters in patients with or without neglect or hemianopia, combined with manual responses on different visual search tasks (pop-out or conjunction search). Before presentation of the search display, an endogenous attentional cue indicated the likely location of target appearance. Neglect patients’ performance was compared to matched groups of controls and right brain-damaged patients without neglect. Patients’ brain lesions were explored by using voxel-based lesion-symptom mapping (VLSM) analysis (Bates et al., 2003), combined with MRI-based diffusion tensor imaging (DTI) tractography to investigate long-range white-matter pathways.

2. Methods 2.1. Participants A total of 22 patients with unilateral right brain damage and ten age-matched healthy individuals participated in the study. Neglect was assessed by a paper-and-pencil neglect battery (Table 1), including tests of target cancellation, line bisection, and drawing. Patients with pathological performance on at least two tests of the battery were considered as showing signs of left neglect. Eight patients (mean age 54 years, range 26–69) with no visual field defects on confrontation met this criterion. Eight other patients (mean age 57 years, range 39–72) presented signs of left neglect associated with a visual field defect (left homonymous hemianopia or left quadrantanopia), attested by confrontation visual field testing and/or Goldmann perimetry, when available. The remaining six patients (mean age 55 years, range 54–66) had a right unilateral brain lesion without any signs of neglect or visual field defects. All patients were tested in the chronic phase of a vascular stroke (mean time post-onset, 258 days, range 57–745). One-tailed t tests indicated no significant differences between the three groups of patients concerning the time between stroke onset and testing (all ps 4.14). As it is often observed, there were differences in lesion volume between the neglect patients with hemianopia group and the non-neglect patients, as well as between the neglect patients with hemianopia group and the neglect patients without hemianopia (p ¼.005, and p ¼.004, respectively). To control for the effect of lesion volume, it was added as a regressor in the lesion analysis (see the Results section below). Neglect signs, as measured through laterality scores (Bartolomeo and Chokron, 1999), only showed a statistical tendency (p¼ .080) towards being more severe in the patients with hemianopia. Table 1 presents patients’ demographical and clinical data, as well as their performance on the neglect battery. Controls (mean age 58 years, range 37–73), matched for age and education to the patients (to1 for both comparisons), had no neurological or psychiatric history. All participants reported having normal or corrected-to-normal vision. This study was reviewed by the INSERM ethical committee and received the approval of an Institutional Review Board (CPP Ile de France 1).

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

3

Table 1 Demographical and clinical characteristics of non-neglect patients and neglect patients with or without hemianopia, with their performance on visuo-spatial tests. Bold characters with asterisks denote pathological performance compared to normative data (see cut-off scores below). For line bisection, positive values indicate rightward deviations, and negative values indicate leftward deviations. Scores for the landscape drawing (Gainotti et al., 1986) indicate the number of omitted left-sided details. I, ischemic; H, hemorrhagic; NA, not available. Extinction was present in 3 of the 6 patients without neglect, and in 3 of the 8 neglect patients without hemianopia. Patient Sex/age/ Onset education of Illness (days)

Etiology Lesion volume (cm3)

Bells cancellation (Left/right hits, max ¼ 15/ 15)

Letter cancellation (Left/right hits, max ¼30/ 30)

Albert cancellation (Left/right hits, max¼ 30/ 30)

Line bisection (mm Landscape drawing of rightward descore (/6) viation for 200 mm)

Reading (Left/right hits, max ¼ 61/ 55)

Non-neglect patients (without hemianopia)

PJ VE GT EM TP KJ

M/54/17 F/59/15 F/54/8 M/62/17 M/35/8 F/66/14

79 70 85 144 371 264

I I I I I I

0.56 44.56 0.06 NA 57.09 41.51

15/15 13/14 14/13 14/15 14/15 13/15

30/30 29/30 NA NA 28/30 NA

30/30 30/30 NA 30/30 NA 28/30

2 7 4.5  0.1 0.5 0.5

0 0 NA 0 0 0

61/55 61/55 61/55 61/55 NA 61/55

Neglect patients without hemianopia

LA PAM VG DS DY PZ CH BT

M/69/17 F/68/10 M/48/9 M/66/9 F/54/10 M/59/9 F/26/17 M/45/11

115 210 431 395 415 239 57 745

I I I I H H I H

16.77 4.77 21.74 143.22 47.06 66.44 NA 34.61

12/15* 0/7* 14/14 12/15* 14/13 10/13* 12/14* 09/15*

25/30* NA 23/28* 24/28* 30/29 NA NA 30/30

30/30 NA NA 19/30* 28/30 NA NA 30/30

5.5 5.5 16* 0.1 12.5* 9.5* 10* 9.5*

0 3* 0 3* 5* 0 0 0

61/55 0/12* 61/55 59/55* 61/55 58/55* 61/55 61/55

Neglect patients with hemianopia

GD TD LDA BC LP PR BGi TJP

F/63/8 M/59/9 F/39/17 F/62 /11 M/46/16 F/53/8 M/58/16 M/72/17

190 700 132 89 106 253 264 313

I I H/I I I I I I

251.95 292.12 284.74 NA 7.39 187.24 214.44 NA

12/15* 15/14 0/12* 1/11* 12/15* 0/6* 04/10* 09/15*

20/30* 25/25 0/21* 6/26* 28/29 NA NA NA

30/30 19/30* 20/30* 24/28* 28/30 NA NA NA

6 4 50* 53.5* 0.2 38.5* 21* 10*

0 0 3* 4* 0 4* 1* 1*

46/55* 55/55* 25/54* 2/35* 59/55* 0/37* 57/55* 56/55*

Cut-off scores: Bells cancellation, difference between left and right omissions 42 (Azouvi et al., 2006); Letter cancellation, one target in each field can rest undetected (Mesulam, 1985); Albert cancellation, difference between left and right omissions 42 (Albert, 1973); Line bisection,  7.3 mm for leftward deviation, 6.5 mm for rightward deviation (Azouvi et al., 2006); Landscape drawing, scores 40 (Azouvi et al., 2006); Reading, difference between left and right omissions 4oro 0 (Azouvi et al., 2006).

2.2. Apparatus, stimuli and procedure A PC Dell Latitude D600 running Eprime software (Schneider et al., 2002) controlled presentation of stimuli, timing operations, and data collection. Stimuli were presented on an eye-tracker screen (Tobii TX300, 1024  768, 16 bit), used to monitor and record the direction of gaze at a sampling rate of 300 Hz. Participants sat at approximately 57 cm from the monitor, with their head positioned on a chin rest. Each trial began with the presentation of a cue during 3000 ms. The cue was presented in a central white circle (8° of visual angle), displayed against a black background. The circle was imaginarily subdivided in four quadrants; at the beginning of each trial, one of these quadrants could be filled in white, serving as an attentional cue, which indicated the most likely location of target appearance. Eight peripheral grey circles, placed at equal distance, surrounded the central cue circle. The diameter of each peripheral circle subtended 1.3° of visual angle; their outline was located at 6.5° from the central circle. The target was then presented until a response was made, or for 6000 ms in case of no response. The target was created by eliminating either the upper or the lower part (0.4° of visual angle) of one of the eight peripheral circles (see Fig. 1). The cue correctly indicated the target location on 73% of the trials (valid trials). On 18% of the trials, the target appeared in one of the three uncued quadrants (invalid trials). On the remaining 9% of the trials, the target was not presented (catch trials) and participants had to refrain from responding. Catch trials were included in the design to invite participants to respond to targets, without guesses or anticipations.

Participants were instructed to maintain their gaze on the central fixation during the presentation of the cue, and were explicitly asked to freely move their eyes as soon as the cue disappeared, in order to find the target. They held a joystick with their right, non-paretic hand, and were asked to move it upward when the upper part of the circle was missing, or downward when the lower part was missing, as fast and as accurately as possible. It was stressed that most cues would indicate the location of the target. There were a pop-out condition and a visual search condition. In the pop-out condition, the target was always red and presented among blue distractors, therefore inducing a colorbased exogenous attentional capture to the target location. In the visual search condition, the color of each target and distractor changed randomly in each trial (blue, orange, red, and green), thus inducing a serial, more demanding search. Each condition consisted of a total of 176 trials. At the beginning of each block, the nature of the task (pop out or visual search) was explained to participants. In order to assess cue-induced effects on performance, two further control conditions without cues were presented (pop out and visual search). Each control condition consisted of 36 trials and was identical to the corresponding experimental condition, except that no cue was presented. For the control conditions, participants were asked to fixate a central empty circle, presented during 3000 ms before the presentation of the target (see Fig. 1). They were instructed to freely move their eyes to discriminate the target when presented. Participants performed the four conditions either in a single session or in two sessions, depending on their fatigability. All conditions were counter-balanced between participants.

4

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

2.5. Lesion analysis

Fig. 1. Sequence of events in a given trial. An endogenous cue (white quarter of the central circle) precede the target display (left upper panel). In the pop-out condition, the target (a circle missing either the upper or lower part) was always red, and was presented among blue distractors. In the visual search condition, the color of each target and distractor changed randomly in each trial (blue, orange, red, and green). In the control condition, no attentional cue was presented; instead an empty circle was displayed for the same duration as the cue (3000 ms) (right upper panel). Participants were instructed to maintain their gaze on the central circle. When the central circle disappeared, they were allowed to freely move their eyes. Their task was to produce an upward movement of the joystick for upper gaps and a downward movement for lower gaps, as fast and as accurately as possible.

2.3. Behavioral analyses 2.3.1. Manual response times In order to make the effect sizes comparable across our study populations, ANOVAs were performed on proportional mean RTs: The mean RT for each experimental condition and participant was divided by the mean overall RT for that participant see (Lupiáñez et al., 2004). Planned comparisons assessed attentional benefits (mean proportional RTs on uncued trials minus valid trials), as well as attentional costs (mean proportional RTs on uncued trials minus invalid trials). 2.3.2. Ocular saccades Saccade onsets were detected with a velocity threshold of 30 deg/s. Only saccades with amplitude larger than 3 degrees of visual angle were quantified and used for the analysis. Central gaze fixation at the beginning of each trial was verified off-line within a 2  2 degree window around fixation at the time of target presentation. We then checked that the number of saccades assumed a normal distribution for the pop-out and visual search conditions (Shapiro and Wilk, 1965), and conducted a repeated-measures ANOVA on the mean number of saccades from target onset until a correct manual response was produced. One control participant was discarded from the analysis because of technical problems during eye-movement recording. 2.4. MR acquisition Brain MRI scans were acquired within 3 months from behavioral testing. They included 3D T1 (IR-PSPGR; field of view¼250 mm2; acquisition matrix¼ 288  256; voxel resolution¼ 0.5  0.5  1.2 mm3; slice thickness¼1.2 mm; space between slices¼1.2 mm), T2 propeller, fluid attenuated inversion recovery, and diffusion sequences. Images were obtained with standard parameters on a 3 T General Electric scanner with a standard head coil for signal reception. For Diffusion Tensor (DT) MRI, we employed single-shot spin-echo echo-planar images (EPI) with 50 directions (b¼1000 s/mm2; field of view¼240 mm2; matrix¼128  128; voxel size¼ 2  2  2 mm3; slice thickness¼3 mm).

2.5.1. Study of the grey matter Lesions were assessed by an expert neurologist (RM) and a clinical neuropsychologist (AB), trained to read brain scans. Both were blind to patients’ clinical diagnosis and cognitive performance. First, lesion extent was determined for each patient by manually drawing the lesion borders directly onto the original 3D T1 MRI, by using the MRIcro software (Rorden and Brett, 2000, www.mricro.com) and a graphics tablet (WACOM Intuos A6, Vancouver, Washington, USA). Then, the 3D brain scans and lesion volumes were normalized to the standard Montreal Neurological Institute (MNI) brain template in Statistical Parametric Mapping-5 (http://www.fil.ion.ucl.ac.uk/spm) running under Matlab 7.5, (http://www.mathworks.com). In detail, to reduce lesion-induced registration errors, spatial normalization was performed using a mask that excluded the damaged areas of the brains, thereby preventing these areas from biasing the transformation (Brett et al., 2001). After normalization, the brain lesion was segmented, and its borders were redefined in the normalized brain. In order to study the anatomical correlates of attentional and saccadic orienting system, voxel-based symptom lesion mapping (VLSM) (Bates et al., 2003) was performed, consisting on a voxel-by-voxel regression on continuous measures, derived from the behavioral performance of the three groups of patients. 2.5.2. Study of the white matter Diffusion Tensor Imaging (DTI) tractography was used to study long-range of subcortical white matter pathways. DTI preprocessing was performed using FSL software (http://www.fmrib.ox.ac.uk/fsl/) in order to remove eddy-current-induced distortions. We used a wholebrain voxel-wise analysis of the fractional anisotropy data carried out with TBSS (Bates et al., 2003), as included in the FSL software package (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FSL, Smith et al., 2006). All fractional anisotropy maps were aligned to an averaged fractional anisotropy template into 1  1  1 mm3 MNI-152 standard space using a nonlinear registration. Correct registration was visually checked for each patient. Next, an average fractional anisotropy map was created and a skeleton map representing the center of the white matter (fractional anisotropy 40.2) common to all patients, computed. Finally, the patient’s registered fractional anisotropy maps were projected into the skeleton. We extracted the mean fractional anisotropy values of the three branches of the superior longitudinal fasciculus (SLF), the cingulum, and the inferior fronto-occipital fasciculus (IFOF) in the right hemisphere. These tracts were chosen on the basis of their implication in attention networks (Ossandon et al., 2012) and in visual neglect (Bartolomeo, Thiebaut de Schotten, & Doricchi, 2007; Urbanski, et al., 2008). Following common procedures (Scanlon et al., 2013; Thiebaut de Schotten et al., 2014), the percentages of tract presence derived from the atlases were thresholded at a probability superior to 50% (see Thiebaut de Schotten et al., 2011 for the atlas).

3. Results 3.1. Behavioral results 3.1.1. Manual response times Trials in which participants failed to respond, incorrect responses, as well as response times (RTs) inferior to 150 ms, were discarded from the analysis (0.07% of the trials for controls, 0.32% for non-neglect patients, 0.34% for patients with neglect, and 0.38% for patients with neglect and hemianopia).1 Proportional 1

The very low rate of omissions is likely to result from mild-to-moderate

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

mean RTs were entered in a repeated-measures analysis of variance (ANOVA) with the inter-participant factor of group (healthy controls, non-neglect patients, neglect patients, and patients with neglect and hemianopia), and the intra-participants factors of task (pop-out, visual search)2, target-side (left, right), and validity (invalid, valid, uncued trials)3. The ANOVA demonstrated an interaction between task, side, validity, and group, F(6,56) ¼ 3.24, MSE ¼0.0081, p ¼.008. To follow up this result, we performed separate ANOVAs for controls and brain-damaged patients, with the same intra-group factors. Controls showed attentional benefits and costs for the visual search task (Table 2 and Fig. 2). For the pop-out task, there was no attentional benefit or cost, presumably as a consequence of the bottom-up attentional capture exerted from the pop-out targets. This pattern of results was reflected in an interaction between task and validity, F(2,18) ¼10.47, MSE ¼0.0107, p¼ .001. The analysis performed on patients’ mean RTs revealed an interaction between task, side, validity, and group, F(4,38) ¼3.65, MSE ¼0.0091, p ¼.013. In order to follow up these results, and because of the asymmetry of spatial processing typically observed after right brain damage, we performed separate ANOVAs for each target side (left or right), with the within-group factors of task (pop-out, visual search), and validity (invalid, valid, uncued trials), and a between-group factor (non-neglect patients, neglect patients, and patients with neglect and hemianopia). For patients’ manual RTs to right-sided targets, there was an interaction between task and validity, F(2,38)¼5.07, MSE¼0.028, p¼.011, as well as a marginally significant interaction between task, validity, and group, F(4,38)¼2.26, MSE¼.0277, p¼ .081. Planned comparisons indicated that neglect patients with hemianopia presented larger benefits than non-neglect patients on the pop-out task (p¼ .046), and larger costs than neglect patients on the visual search task (p¼.017); there was a tendency in the same direction for neglect patients with hemianopia compared to non-neglect patients (p¼ .077). For left targets, there was an analogous interaction between task and validity, F(2,38)¼5.89, MSE¼.0281, p¼.006. The interaction between task, validity, and group did not reach significance (p¼ .306). Next, we compared attentional benefits and costs in each group of patients, for each task. The analysis demonstrated larger benefits for neglect patients with hemianopia as compared to neglect (footnote continued) degrees of neglect in our patients (patients with more severe forms of neglect would not have been able to perform the oculomotor test). Moreover, it is well known that central endogenous cues are often able to overcome neglect (see e.g. Làdavas et al., 1994; Losier and Klein, 2001), especially with targets presented not very far from the center, as in the present experiment. It is thus not surprising that patients’ performance was generally good, except for RTs in patients with neglect and hemianopia, who were particularly slow when searching the target in their blind and neglected field. 2 In a preliminary experiment, 12 healthy participants performed the two tasks (pop-out and visual search), with varying number of distractors in different blocks, consisting of the target plus 7, 11, or 15 distractors. An ANOVA on mean RTs with the within-group factors of task (pop-out and visual search), validity (invalid and valid trials), and number of distractors showed a significant interaction between task and number of distractors, F(2,22) ¼ 4.28, MSE ¼4682, p ¼ .027. RTs increased linearly with the number of distractors in the visual search task (670 ms, 715 ms, 763 ms, respectively), but not in the pop out task (560 ms, 581 ms, 574 ms). 3 To explore whether targets with upper or lower gaps induced differences in performance, we conducted an ANOVA on mean RTs with the inter-participant factor of group (non-neglect patients, neglect patients, and patients with neglect and hemianopia), and the intra-participants factors of gap position (upper, lower) and the target hemispace (left, right). There were main effects of side F(1,19)¼ 5.17, MSE¼ 66251, p¼ .001, and gap position, F(1,19) ¼4.94, MSE ¼30529, p¼ .038, as well as interactions between side and group, F(2,19) ¼14.82, MSE¼ 66251, p ¼ .001, and between side and gap position, F(2,19)¼ 9.91, MSE¼6824, p¼ .005. RTs were faster for left-sided targets for upper gaps than for lower gaps (p ¼.008), consistent with the proposed functional specialization of the upper visual field for the extrapersonal space in humans (Previc, 1990), and with the described increase of left neglect in the lower left part of space (Mark and Heilman, 1997).

5

patients and non-neglect patients in the visual search task (p¼.012, and p¼ .004, respectively). All the remaining effects or interactions did not reach significance (see Table 2 and Fig. 2). In summary, manual RT results demonstrated that patients were able to orient their endogenous attention to the location indicated by the cue. Neglect patients with hemianopia presented larger benefits and costs than neglect patients without hemianopia and non-neglect patients, especially on the more demanding visual search task. 3.1.2. Saccades The mean number of saccades was entered in a repeatedmeasures analysis of variance (ANOVA) with the between-participant factor of group (healthy controls, non-neglect patients, neglect patients, and patients with neglect and hemianopia) and the within-participant factors of task (pop-out, visual search), target-side (left, right), saccade congruency (congruent saccades, made towards the hemispace containing the target; incongruent saccades, made in the opposite direction to the target hemispace), and cue validity (invalid, valid, and uncued trials). There was a four-way interaction between the factors of task, side, saccade congruency, and group, F(3, 27) ¼4.50, MSE ¼.61, p ¼.011. To follow up this interaction, we performed separate ANOVAs for controls and for the three groups of patients, with the group variable added as a between participants factor in the analysis for patients. Controls made more saccades in the visual search task compared to the pop-out task, F(1, 8)¼ 38.62, MSE¼.46, p¼.001, and more saccades towards right-sided targets than to left-sided targets, F (1,8)¼7.17, MSE¼ .12, p¼.028. They also made more congruent saccades (i.e. to the target hemispace) than incongruent saccades (i.e. in the opposite direction to the target hemispace), F(1,8)¼ 98.99, MSE¼.62, p¼.001, especially in the visual search task (interaction task  congruency, F(1,8)¼6.05, MSE¼.086, p¼.039; Fisher’s LSD, pso.001), and when right-sided targets were presented (interaction side  congruency, F(1,8)¼ 24.88, MSE¼.041, p¼.001; Fisher’s LSD on left-sided vs. right-sided targets, pso.036). Finally, controls performed more saccades for invalid trials compared to valid and uncued trials, F(2,16)¼ 5.41, MSE¼.035, p¼.016; Fisher’s LSD, pso.05, especially in the visual search task (interaction tas  validity, F (2,16)¼5.52, MSE¼.169, p¼.015; Fisher’s LSD, pso.001). More incongruent saccades were made for invalid than for valid trials, indicating that participants made saccades to the location indicated by the cue, and therefore, if the target occurred at an invalid location, they had to perform more saccades to foveate the target (interaction congruency  validity, F(2,16)¼ 3.52, MSE¼.010, p¼.054; see Fig. 3A). Similar to controls, patients made more saccades in the visual search task compared to the pop-out task, F(1,19) ¼ 45.91, MSE¼ 1.68, p¼ .001. They performed more congruent than incongruent saccades, F(1,19) ¼92.91, MSE¼ .83, p ¼ .001, and more saccades for invalid trials compared uncued trials, F(2,38) ¼ 3.42, MSE¼ .65, Fisher’s LSD, p ¼.009. However, contrary to controls, patients made more saccades when left-sided targets were presented than when right-sided targets were presented, F(1,19) ¼ 9.29, MSE ¼.55, p ¼.007. Interestingly, the interactions between side and congruency, F (1,19) ¼13.14, MSE ¼1.74, p¼ .002, and between task, side, and congruency, F(1,19) ¼16.23, MSE ¼.79, p ¼.001, were also significant. At sharp variance with controls, all patients performed a comparable number of congruent and incongruent saccades when left-sided targets were presented in the visual search task, thus revealing an abnormal saccadic exploration behavior. Thus, the more demanding visual search task induced an overexploration of the right hemispace, consistent with the magnetic attraction of gaze exerted by right-sided targets in patients with neglect (Gainotti et al., 1991) (see Fig. 3B).

6

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

Table 2 Proportional mean manual response times (mean RT in ms for each experimental condition and participant divided by the mean overall RT for that participant, see Lupiáñez, et al., 2004) for controls and for the three groups of patients (non-neglect patients, neglect patients, and neglect patients with hemianopia). Standard errors are reported in parentheses. Left targets

Right targets

Valid

Invalid

Uncued

Valid

Invalid

Uncued

Pop-out Controls Non-neglect patients (without hemianopia) Neglect patients without hemianopia Neglect patients with hemianopia

.872 .903 .779 .683

.927 .895 .855 .987

.869 .842 .854 .945

.884 .891 .784 .630

.941 (.035) .906 (.045) .812 (.039) .817 (.039)

.821 .809 .801 .771

Visual search Controls Non-neglect patients (without hemianopia) Neglect patients without hemianopia Neglect patients with hemianopia

.985 (.044) 1.143 (.057) 1.100 (.049) .863 (.049)

1.233 (.062) 1.123 (.080) 1.166 (.069) 1.417 (.069)

1.133 (.067) 1.069 (.087) 1.215 (.075) .995 (.075)

(.035) (.046) (.040) (.040)

(.057) (.074) (.064) (.064)

1.217 (.062) 1.220 (.080) 1.317 (.069) 1.580 (.069)

(.056) (.073) (.063) (.063)

1.134 (.063) 1.217 (.082) 1.296 (.071) 1.517 (.071)

(.032) (.041) (.035) (.035)

.984 (.047) .982 (.060) 1.020 (.052) .794 (.052)

(.038) (.049) (.043) (.043)

Fig. 2. Attentional benefits (values above 0) and costs (values below 0) for left-sided and for right-sided targets in the pop-out task, and in the visual search task. Error bars represent standard errors. Asterisks denote significant results in comparison with the control group, p o .05.

In order to further test this result, we extracted the proportion of first saccades produced in the visual search task, when right and left-sided targets were presented. The analysis indicated a significant interaction between side and congruency, F(1,19) ¼8.47, MSE ¼.018, p ¼.009. When right-sided targets were presented, the first saccade was more often performed towards the target hemispace (congruent saccade, M = .45), than towards the opposite hemispace (incongruent saccade, M = .32) (p ¼.003). However, when left-sided targets were presented, patients made a comparable number of first saccades towards the target hemispace (.38) than toward the opposite hemispace (.42) (p¼ .47), thus performing a substantial number of inappropriate, rightward saccades as soon as the target display appeared, consistent with the phenomenon of magnetic attraction of gaze. In order to exclude potential confounds in our results, we performed another ANOVA on the mean amplitudes of saccades, with the intra-participants factors of task (pop-out, visual search), target-side (left, right), and the inter-participant factor of group (controls, non-neglect patients, neglect patients, and patients with neglect and hemianopia). The analysis did not reveal any

significant effects or interactions (all ps4.16), suggesting that inappropriate saccades towards the right hemispace could not be explained by the production of hypometric saccades. Finally, some of the oculomotor deficits correlated with neglect severity, as estimated by neglect scores for the bells test (Azouvi et al., 2006): increasing severity of neglect increased the number of incongruent saccades for invalidly cued left-sided targets in the pop-out condition (r ¼.44, p ¼.043), and decreased the number of congruent saccades for invalidly cued left-sided targets on the visual search task (r ¼.  43, p¼ .048), consistent with an early capture of attention by right-sided cues (D’Erme et al., 1992; Gainotti et al., 1991) and a disengagement deficit from these same cues (Posner et al., 1984; Rastelli, 2008). 3.2. Anatomical analysis 3.2.1. Study of the grey matter The analysis performed on the mean number of saccades revealed that patients presented impaired saccadic behavior in the more demanding visual search task, when left-sided targets were

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

7

Fig. 3. Mean number of congruent saccades (made in the same direction of the target hemispace) and incongruent saccades (made in the opposite direction), in controls (A) and in the three groups of patients (non-neglect patients, neglect patients, and neglect patients with hemianopia) (B) for left and right-sided targets in the pop-out and visual search task. At sharp variance with controls, all patients performed a comparable number of congruent and incongruent saccades when left-sided targets were presented in the visual search task, thus revealing an abnormal saccadic exploration behavior. Error bars represent standard errors. Asterisks denote significant results, p o .05.

8

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

There was a significant negative correlation between the index of congruency and FA values obtained for the right SLF II (r ¼  .48, p¼ .044) (see Fig. 5, left panel). The more the right SLF was damaged, the more patients tended to produce incongruent, rightdirected saccades after the occurrence of a left-sided target (see the right-sided panel of Fig. 5 for an illustration of two representative patients), presumably because their gaze was captured by right-sided distractors (Bartolomeo et al., 2004; Gainotti et al., 1991). The correlation analysis performed for the others tracts did not reach significance (all ps 4 .088, rs o  .155).

4. Discussion

Fig. 4. (A) Lesion distribution in all patients, on which voxel-based lesion-symptom mapping was performed. (B) Voxel-based lesion-symptom mapping study. Representative slices from VLSM maps computed on the congruency index (mean number of incongruent minus congruent saccades divided by the mean number of incongruent plus congruent saccades), for visual search left-sided targets. Only significant voxels at p o .05 were considered. VLSM revealed a significant implication of right precentral gyrus, middle frontal gyrus, frontal eye fields, putamen, and pallidum. R, right.

presented. To assess the lesional basis of this abnormal saccadic behavior, we calculated a corresponding congruency index (mean number of incongruent minus congruent saccades divided by the mean number of total saccades)4, and performed a VLSM analysis (Bates et al., 2003) on all patients’ MRI scans, except for one neglect patient (CH), two neglect patients with hemianopia (BC, TJP), and one non-neglect patient (EM), for whom 3D MRI was not available. The maximum overlap (10 patients) was in the putamen, the rolandic operculum, the superior temporal pole and the subcortical white matter, in a location consistent with the trajectory of the fronto-parietal superior longitudinal fasciculus (SLF) (Fig. 4A). For the VLSM, only significant voxels at p o.05 were considered (non-corrected for multiple comparisons). We used the nonparametric Brunner–Munzel test with 1000 permutations thresholding, which corrects for the number of independent comparisons in a volume, without making assumptions about the spatial structure of the data (Kimberg et al., 2007). The lesion size of each patient was added as a regressor. VLSM revealed a significant implication of the precentral gyrus (MNI coordinates, x y z, 51, 1, 34), the middle frontal gyrus (33, 6, 62), the Frontal Eye Fields (FEF; 39,  4, 54), the putamen (18,  6, 8), and the border of the pallidum adjacent to the putamen (21,  2, 2) (Fig. 4B). These regions were therefore associated to the magnetic gaze attraction observed in the patients (comparable number of congruent and incongruent saccades when left-sided targets were presented in the visual search task). 3.2.2. Study of the white matter We performed a Pearson correlation between the saccadic congruency index for left-sided targets in visual search and the fractional anisotropy (FA), obtained for each tract. 4 We performed further ANOVAs on the computed indexes of congruency, with the intra-participants factor of task (pop-out, visual search), target-side (left, right), and validity (invalid, valid, uncued trials), and group as a between-participant factor (non-neglect patients, neglect patients, and patients with neglect and hemianopia). There was a significant interaction between task and side, F(1,19) ¼ 6.91, p ¼ .016. T-tests against zero demonstrated significant effects in all conditions (all ps o.001), except for left-sided targets on the visual search task (p ¼.43), in good agreement with the results presented in the main text.

We investigated the occurrence of inappropriate rightward saccades produced by patients with right hemisphere damage, after visual endogenous cues and on different attentional conditions (pop-out and visual search). The use of these two different tasks allowed us to vary the degree of bottom-up target selection, together with the top-down orienting of attention provided by the cue, with the purpose of studying how attentional and saccadic orienting to the left hemispace can be modulated by the lesioninduced bias for right-sided locations in neglect. In order to gain insight into the neural substrates of inappropriate rightward saccades, patients’ brain lesions were analyzed by taking into account both damage to the grey matter (VLSM) and to the white matter (DTI). Endogenous cues were able to speed up manual responses to targets, especially during the more difficult visual search task.5 While non-neglect patients and controls showed no significant cue effects in the pop-out task, neglect patients with hemianopia did present cue-associated benefits. They also had larger benefits than the other groups for left-sided targets in the visual search task. This result suggests an abnormal over-use of cue information in patients with neglect and hemianopia. On the other hand, these patients also suffered from a huge cost when the same left-directing cue was followed by a right-sided target in visual search, probably as a consequence of non-lateralized attentional problems, such as an abnormal narrowing of the attentional focus (Barrett et al., 1998). Altogether, our results confirm and extend to the study of eye movements previous evidence obtained with covert orienting paradigms (Bartolomeo et al., 2001; D’Erme et al., 1992; Làdavas et al., 1994; Rastelli et al., 2008; Sieroff et al., 2007). All these previous covert attention studies demonstrated that severe attentional orienting impairments in left neglect concern first and foremost exogenous orienting, with relative sparing of endogenous orienting (Bartolomeo, 2014; Bartolomeo and Chokron, 2002 for a review; Bartolomeo et al., 2001). A novel finding reported here is that even if patients processed the information provided by the endogenous attentional cue, their saccadic exploration patterns were nonetheless dysfunctional. This result is consistent with behavioral evidence stressing that endogenous attention mechanisms are not always able to compensate for visual neglect (Seron et al., 1989; Sieroff et al., 2007). We demonstrated here that when left-sided targets were presented, saccades were equally likely to be performed towards the left side or towards the right side. Thus, the use of endogenous mechanisms may not be sufficient to counteract the patients’ 5 One might wonder whether neglect patients correctly perceived the left-directed cues. Although we did not ask patients to verbally report cues, RTs analyses demonstrated that neglect patients were able to benefit from left-sided cues, which suggests that they did perceive them. None of the patients presented an objectcentered neglect on the paper and pencil tests used. Thus, we did not expect the left quadrant of the cue presented at the center of the screen to be neglected.

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

rightward bias, and to efficiently explore the visual environment, because right-sided distractors remain able to occasionally capture patients’ attention (Bartolomeo et al., 2004). Importantly, in the more demanding visual search condition, inappropriate right-directed saccades after left-sided endogenous cues were performed not only by neglect patients, but also by right brain-damaged patients without neglect on paper-and-pencil tests. Thus, pathological production of eye movements can be considered as a subtle manifestation of visuospatial disorders. In good agreement with our results, previous studies (Cazzoli et al., 2011; Gainotti et al., 2009; Muri et al., 2009; Olk et al., 2002; Pflugshaupt et al., 2004) have shown that the direction of the first saccade during visual search/exploration is sensitive to the presence of neglect (even recovered and residual), with more ipsilesional than contralesional first saccades (but see Niemeier and Karnath, 2000; Ro et al., 2001; for discrepant results). It is certainly possible that at least some of our non-neglect patients had learned to compensate for neglect, which might have not been clinically evident in the acute phase of their stroke. Although there was no mention of neglect in the clinical records concerning these patients, we cannot exclude this possibility. Also, three of our non-neglect patients had signs of left visual extinction, and thus demonstrated some degree of spatial bias. Be that as it may, our findings are consistent with studies showing that attentionally demanding tasks can trigger emergence of lateralized signs of spatial bias in patients who are otherwise capable of compensating their deficits during easier paper-and-pencil tests without time constraints (Bartolomeo, 1997, 2000; Bonato, 2012; Bonato et al., 2010). Concerning the anatomy of our patients’ capacity (or lack thereof) to produce congruent, cue-directed saccades, VLSM indicated a specific involvement of the basal ganglia (putamen, and pallidum), and of frontal areas (precentral gyrus, middle frontal gyrus, and FEF). The middle frontal gyrus is part of the ventral attentional network described by Corbetta et al. (2002), and its damage has been associated with neglect signs (Husain and Kennard, 1997; Ringman et al., 2004). Neglect has also been associated

9

to damage to the basal ganglia (Karnath et al., 2002; Vallar and Perani, 1986). As it is often the case in patient studies, our sample was relatively small. To deal with this problem, we applied permutation testing in the VLSM analysis, which corrected for the number of independent comparisons in a volume, without making assumptions about the spatial structure of the data (Kimberg et al. 2007). Moreover, we used the Brunner–Munzel test, which computes permutations rather than relying on a normal distribution, and remains thus accurate for small sample sizes (Rorden et al., 2007). It is also well established that the FEF plays a key role in saccadic production, in concert with others connected brain regions, such as the superior colliculi (Schall, 2002; Schall and Hanes, 1993), through the putamen (Munoz and Everling, 2004; Neggers et al., 2012). The FEF contains salience maps representing potential targets and subsequent saccade goals (Schall, 2002; Walker et al., 2009). An influential model of attentional orienting based on fMRI data (Corbetta and Shulman, 2002) indicates the FEF as part of a bilateral dorsal attentional network, connected to key parietal regions such as the intra-parietal sulcus through the dorsal branch of the SLF (Doricchi et al., 2008; Thiebaut de Schotten, Dell’Acqua et al., 2011). Consistent with these findings reported in normal participants, the present DTI results on brain-damaged patients demonstrate a negative correlation between the tendency of patients’ gaze to be captured by right-sided targets (as indexed by their production of inappropriate saccades to these targets) and the integrity of the right SLF II. Thus, SLF II disconnection in the right hemisphere may be a lesional correlate of biased oculomotor behavior such as the “magnetic” capture of patients’ gaze (Gainotti et al., 1991) and attention (D’Erme et al., 1992; Rastelli, et al., 2008) by right-sided stimuli. There is now abundant evidence of a causal link between SLF dysfunction and signs of neglect (Bartolomeo et al., 2007; Ciaraffa et al., , 2012; Doricchi and Tomaiuolo, 2003; Shinoura, et al., 2009; Thiebaut de Schotten, et al., 2005). The present results add to this evidence by suggesting a role for frontoparietal networks linked by the SLF in neglect-related oculomotor

Fig. 5. Left panel: negative Pearson correlation between fractional anisotropy of the right SLF II (x axis) and the behavioral index of saccadic congruency obtained in the more demanding visual search task (y axis). The more the right SLF II was damaged, the more patients tended to produce incongruent, right-directed saccades after the occurrence of a left-sided target. All the indexes relative to saccade congruency and to fractional anisotropy were found to be within 2.5 SD of their respective group means, which argues against the presence of outliers. Right panel: color map, right right SLF, and vascular 3D lesion (in blue) of two representative patients. Upper panel, patient without neglect (TP), with preserved FEF and SLF; lower panel, patient with left neglect (BT), with damaged FEF and SLF tract. Fractional anisotropy scale varied from 0 (blue, preserved) to 1 (red, damaged). R, right. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

10

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

disturbances, which in their most severe instances can take the form of a tonic (De Renzi, et al., 1982) or phasic (Gainotti et al., 1991) gaze deviation towards the right side. Damage of the right FEF, combined with a disconnection of white matter pathway linking frontal regions with parietal attentional areas, may thus interfere with the effects of attention on saccadic behavior, leading to the production of inappropriate rightward saccades for left-sided targets in conditions of high attentional load (visual search) in our patients. Finally, if on the one hand the present results indicate the existence of common processes between covert and overt orienting (Rizzolatti et al., 1994), on the other hand they also suggest dissociations between these two forms of orienting, perhaps resulting from dysfunctional communication within and between the fronto-parietal networks of attention (Bartolomeo, 2006, 2014; Bartolomeo et al., 2012; Lunven et al., 2015). These disconnections might decouple eye and hand action in brain-damaged patients. To conclude, this study revealed that after damage to frontoparietal networks in the right hemisphere, demanding search tasks can bias patients’ overt spatial exploration towards rightsided objects, with the consequent production of inappropriate right-directed eye movements, despite the presence of left-directed endogenous cues. Fronto-parietal networks in the right hemisphere appear thus to be essential to integrate covert and overt orienting of attention, and to thoroughly explore our environment in order to become aware of the multiple competing objects around us.

Acknowledgements We would like to thank Bastien Oliveiro for programming the experiment, Pierre Daye and Hadrien Caron for their help in data analyses. This research was supported by a doctoral grant from the French Ministry of Research to AB, by EU FP6 and ANR project eraNET-NEURON BEYONDVIS to PB, by a Translational Research grant from the Assistance Publique-Hôpitaux de Paris (AP-HP) to PB, by postdoctoral grants from the Neuropôle de Recherche Francilen (NeRF), Marie Curie Intra-European Program (FP7), and Ramón y Cajal fellowship (RYC-2011-09320) Spanish Ministry of Education and Science to ABC, and by funding from the program “Investissements d’avenir” ANR-10-IAIHU-06.

References Albert, M.L., 1973. A simple test of visual neglect. Neurology 23, 658–664. Azouvi, P., Bartolomeo, P., Beis, J.M., Perennou, D., Pradat-Diehl, P., Rousseaux, M., 2006. A battery of tests for the quantitative assessment of unilateral neglect. Restor. Neurol. Neurosci. 24, 273–285. Azouvi, P., Samuel, C., Louis-Dreyfus, A., Bernati, T., Bartolomeo, P., Beis, J.-M., Chokron, S., Leclercq, M., Marchal, F., Martin, Y., de Montety, G., Olivier, S., Perennou, D., Pradat-Diehl, P., Prairial, C., Rode, G., Sieroff, E., Wiart, L., Rousseaux, M., 2002. Sensitivity of clinical and behavioural tests of spatial neglect after right hemisphere stroke. J. Neurol. Neurosurg. Psychiatry 73, 160–166. Barrett, A.M., Beversdorf, D.Q., Crucian, G.P., Heilman, K.M., 1998. Neglect after right hemisphere stroke: a smaller floodlight for distributed attentio. Neurology 51, 972–978. Bartolomeo, P., 1997. The novelty effect in recovered hemineglect. Cortex 33, 323–332. Bartolomeo, P., 2000. Inhibitory processes and compensation for spatial bias after right hemisphere damage. Neuropsychol. Rehabil. 10, 511–526. Bartolomeo, P., 2006. A parietofrontal network for spatial awareness in the right hemisphere of the human brain. Arch. Neurol. 63, 1238–1241. Bartolomeo, P., 2014. Attention Disorders After Right Brain Damage: Living in Halved Worlds. Springer-Verlag, London. Bartolomeo, P., Chokron, S., 1999. Egocentric frame of reference: Its role in spatial bias after right hemisphere lesions. Neuropsychologia 37, 881–894. Bartolomeo, P., Chokron, S., 2002. Orienting of attention in left unilateral neglect. Neurosci. Biobehav. Rev. 26, 217–234.

Bartolomeo, P., Sieroff, E., Decaix, C., Chokron, S., 2001. Modulating the attentional bias in unilateral neglect: the effects of the strategic set. Exp. Brain Res. 137, 432–444. Bartolomeo, P., Thiebaut de Schotten, M., Chica, A.B., 2012. Brain networks of visuospatial attention and their disruption in visual neglect. Front. Hum. Neurosci. 6, 110. Bartolomeo, P., Thiebaut de Schotten, M., Doricchi, F., 2007. Left unilateral neglect as a disconnection syndrome. Cereb. Cortex 17, 2479–2490. Bartolomeo, P., Urbanski, M., Chokron, S., Chainay, H., Moroni, C., Siéroff, E., Belin, C., Halligan, P., 2004. Neglected attention in apparent spatial compression. Neuropsychologia 42, 49–61. Bates, E., Wilson, S.M., Saygin, A.P., Dick, F., Sereno, M.I., Knight, R.T., Dronkers, N.F., 2003. Voxel-based lesion-symptom mapping. Nat. Neurosci. 6, 448–450. Behrmann, M., Ghiselli-Crippa, T., Dimatteo, I., 2001. Impaired initiation but not execution of contralesional saccades in hemispatial neglect. Behav. Neurol. 13, 39–60. Behrmann, M., Watt, S., Black, S.E., Barton, J.J., 1997. Impaired visual search in patients with unilateral neglect: an oculographic analysis. Neuropsychologia 35, 1445–1458. Benson, V., Ietswaart, M., Milner, D., 2012. Eye movements and verbal report in a single case of visual neglect. PLoS One 7, e43743. Bonato, M., 2012. Neglect and extinction depend greatly on task demands: a review. Front. Hum. Neurosci. 6, 195. Bonato, M., Priftis, K., Marenzi, R., Umilta, C., Zorzi, M., 2010. Increased attentional demands impair contralesional space awareness following stroke. Neuropsychologia 48, 3934–3940. Brett, M., Leff, A.P., Rorden, C., Ashburner, J., 2001. Spatial normalization of brain images with focal lesions using cost function masking. Neuroimage 14, 486–500. Carrera, E., Tononi, G., 2014. Diaschisis: past, present future. Brain 137, 2408–2422. Cazzoli, D., Nyffeler, T., Hess, C.W., Muri, R.M., 2011. Vertical bias in neglect: a question of time? Neuropsychologia 49, 2369–2374. Ciaraffa, F., Castelli, G., Parati, E.A., Bartolomeo, P., Bizzi, A., 2012. Visual neglect as a disconnection syndrome? A confirmatory case report. Neurocase. Cohn, R., 1972. Eyeball movements in homonymous hemianopia following simultaneous bitemporal object presentation. Neurology 22, 12–14. Corbetta, M., Shulman, G.L., 2002. Control of goal-directed and stimulus-driven attention in the brain. Nat. Rev. Neurosci. 3, 201–215. Corbetta, M., Shulman, G.L., 2011. Spatial neglect and attention networks. Annu. Rev. Neurosci. 34, 569–599. D’Erme, P., Robertson, I., Bartolomeo, P., Daniele, A., Gainotti, G., 1992. Early rightwards orienting of attention on simple reaction time performance in patients with left-sided neglect. Neuropsychologia 30, 989–1000. De Renzi, E., Colombo, A., Faglioni, P., Gibertoni, M., 1982. Conjugate gaze paresis in stroke patients with unilateral damage: an unexpected instance of hemispheric asymmetry. Arch. Neurol. 39, 482–486. Doricchi, F., Thiebaut de Schotten, M., Tomaiuolo, F., Bartolomeo, P., 2008. White matter (dis)connections and gray matter (dys)functions in visual neglect: gaining insights into the brain networks of spatial awareness. Cortex 44, 983–995. Doricchi, F., Tomaiuolo, F., 2003. The anatomy of neglect without hemianopia: a key role for parietal-frontal disconnection? Neuroreport 14, 2239–2243. Feeney, D.M., Baron, J.C., 1986. Diaschisis. Stroke 17, 817–830. Gainotti, G., D’Erme, P., Bartolomeo, P., 1991. Early orientation of attention toward the half space ipsilateral to the lesion in patients with unilateral brain damage. J. Neurol. Neurosurg. Psychiatry 54, 1082–1089. Gainotti, G., D’Erme, P., Monteleone, D., Silveri, M.C., 1986. Mechanisms of unilateral spatial neglect in relation to laterality of cerebral lesions. Brain 109, 599–612. Gainotti, G., De Luca, L., Figliozzi, F., Doricchi, F., 2009. The influence of distracters, stimulus duration and hemianopia on first saccade in patients with unilateral neglect. Cortex 45, 506–516. Girotti, F., Casazza, M., Musicco, M., Avanzini, G., 1983. Oculomotor disorders in cortical lesions in man: the role of unilateral neglect. Neuropsychologia 21, 543–553. Harvey, M., Olk, B., Muir, K., Gilchrist, I.D., 2002. Manual responses and saccades in chronic and recovered hemispatial neglect: a study using visual search. Neuropsychologia 40, 705–717. Hornak, J., 1992. Ocular exploration in the dark by patients with visual neglect. Neuropsychologia 30, 547–552. Husain, M., Kennard, C., 1997. Distractor-dependent frontal neglect. Neuropsychologia 35, 829–841. Karnath, H.-O., 1988. Deficits of attention in acute and recovered hemi-neglect. Neuropsychologia 20, 27–45. Karnath, H.O., Himmelbach, M., Rorden, C., 2002. The subcortical anatomy of human spatial neglect: putamen, caudate nucleus and pulvinar. Brain 125, 350–360. Kimberg, D.Y., Coslett, H.B., Schwartz, M.F., 2007. Power in Voxel-based lesionsymptom mapping. J. Cogn. Neurosci. 19, 1067–1080. Làdavas, E., Carletti, M., Gori, G., 1994. Automatic and voluntary orienting of attention in patients with visual neglect: horizontal and vertical dimensions. Neuropsychologia 32, 1195–1208. Làdavas, E., Zeloni, G., Zaccara, G., Gangemi, P., 1997. Eye movements and orienting of attention in patients with visual neglect. J. Cognit. Neurosci. 9, 67–74. Losier, B.J., Klein, R.M., 2001. A review of the evidence for a disengage deficit following parietal lobe damage. Neurosci. Biobehav. Rev. 25, 1–13.

A. Bourgeois et al. / Neuropsychologia 73 (2015) 1–11

Lunven, M., Thiebaut De Schotten, M., Bourlon, C., Duret, C., Migliaccio, R., Rode, G., Bartolomeo, P., 2015. White matter lesional predictors of chronic visual neglect: a longitudinal study. Brain 138, 746–760. Lupiáñez, J., Decaix, C., Sieroff, E., Chokron, S., Milliken, B., Bartolomeo, P., 2004. Independent effects of endogenous and exogenous spatial cueing: Inhibition of return at endogenously attended target locations. Experimental Brain Research 159, 447–457. Mark, V.W., Heilman, K.M., 1997. Diagonal neglect on cancellation. Neuropsychologia 35, 1425–1436. Mattingley, J.B., Bradshaw, J.L., Bradshaw, J.A., Nettleton, N.C., 1994. Residual rightward attentional bias after apparent recovery from right hemisphere damage: Implications for a multicomponent model of neglect. J. Neurol. Neurosurg. Psychiatry 57, 597–604. Mesulam, M.M., 1985. Principles of Behavioral Neurology. F.A. Davis, Philadelphia (PA). Monakow, C. v, 1914. Die Lokalisation im Grosshirn und der Abbau der Funktion durch kortikale Herde. J. F. Bergmann. Munoz, D.P., Everling, S., 2004. Look away: the anti-saccade task and the voluntary control of eye movement. Nat. Rev. Neurosci. 5, 218–228. Muri, R.M., Cazzoli, D., Nyffeler, T., Pflugshaupt, T., 2009. Visual exploration pattern in hemineglect. Psychol. Res. 73, 147–157. Natale, E., Marzi, C.A., Bricolo, E., Johannsen, L., Karnath, H.O., 2007. Abnormally speeded saccades to ipsilesional targets in patients with spatial neglect. Neuropsychologia 45, 263–272. Neggers, S.F., Diepen, R.M., Zandbelt, B.B., Vink, M., Mandl, R.C., Gutteling, T.P., 2012. A functional and structural investigation of the human fronto-basal volitional saccade network. PLoS One 7, e29517. Niemeier, M., Karnath, H.O., 2000. Exploratory saccades show no direction-specific deficit in neglect. Neurology 54, 515–518. Olk, B., Harvey, M., Gilchrist, I.D., 2002. First saccades reveal biases in recovered neglect. Neurocase 8, 306–313. Ossandon, T., Vidal, J.R., Ciumas, C., Jerbi, K., Hamame, C.M., Dalal, S.S., Bertrand, O., Minotti, L., Kahane, P., Lachaux, J.P., 2012. Efficient “pop-out” visual search elicits sustained broadband gamma activity in the dorsal attention network. J. Neurosci. 32, 3414–3421. Pflugshaupt, T., Bopp, S.A., Heinemann, D., Mosimann, U.P., von Wartburg, R., Nyffeler, T., Hess, C.W., Muri, R.M., 2004. Residual oculomotor and exploratory deficits in patients with recovered hemineglect. Neuropsychologia 42, 1203–1211. Posner, M.I., Walker, J.A., Friedrich, F.J., Rafal, R.D., 1984. Effects of parietal injury on covert orienting of attention. J. Neurosci. 4, 1863–1874. Previc, F.H., 1990. Functional specialization in the lower and upper visual fields in humans: Its ecological origins and neurophysiological implications. Behav. Brain Sci. 13, 519–542. Rastelli, F., Funes, M.J., Lupiáñez, J., Duret, C., Bartolomeo, P., 2008. Left neglect: Is the disengage deficit space- or object-based? Exp. Brain Res. 187, 439–446. Ringman, J.M., Saver, J.L., Woolson, R.F., Clarke, W.R., Adams, H.P., 2004. Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort. Neurology 63, 468–474. Rizzolatti, G., Riggio, L., Sheliga, B.M., 1994. Space and selective attention. In: Umiltà, C., Moscovitch, M. (Eds.), Attention and Performance XV: Conscious and Nonconscious Information Processing. Cambridge, MA: The MIT Press, pp. 231–265. Ro, T., Rorden, C., Driver, J., Rafal, R., 2001. Ipsilesional biases in saccades but not perception after lesions of the human inferior parietal lobule. J. Cognit. Neurosci. 13, 920–929.

11

Rorden, C., Brett, M., 2000. Stereotaxic display of brain lesions. Behav. Neurol. 12, 191–200. Rorden, C., Karnath, H.O., Bonilha, L., 2007. Improving lesion-symptom mapping. J. Cogn. Neurosci. 19, 1081–1088. Scanlon, C., Mueller, S.G., Cheong, I., Hartig, M., Weiner, M.W., Laxer, K.D., 2013. Grey and white matter abnormalities in temporal lobe epilepsy with and without mesial temporal sclerosis. J. Neurol. 260, 2320–2329. Schall, J.D., 2002. The neural selection and control of saccades by the frontal eye field. Philos. Trans. R. Soc. Lond. B Biol. Sci. 357, 1073–1082. Schall, J.D., Hanes, D.P., 1993. Neural basis of saccade target selection in frontal eye field during visual search. Nature 366, 467–469. Schneider, W., Eschman, A., Zuccolotto, A., 2002. E-prime User’s Guide. Psychology Software Tools Inc, Pittsburg. Seron, X., Deloche, G., Coyette, F., 1989. A Retrospective Analysis of a Single Case Neglect Therapy: A Point of Theory. In: Seron, X., Deloche, G. (Eds.), Cognitive Approaches in Neuropsychological Rehabilitation. Lawrence Erlbaum Associates, Hillsdale (USA), pp. 289–316. Shapiro, S.S., Wilk, M.B., 1965. Analysis of variance test for normality (complete samples). Biometrika, 591–611. Shinoura, N., Suzuki, Y., Yamada, R., Tabei, Y., Saito, K., Yagi, K., 2009. Damage to the right superior longitudinal fasciculus in the inferior parietal lobe plays a role in spatial neglect. Neuropsychologia 47, 2600–2603. Sieroff, E., Decaix, C., Chokron, S., Bartolomeo, P., 2007. Impaired orienting of attention in left unilateral neglect: a componential analysis. Neuropsychology 21, 94–113. Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C. E., Watkins, K.E., Ciccarelli, O., Cader, M.Z., Matthews, P.M., Behrens, T.E., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487–1505. Thiebaut de Schotten, M., Dell’Acqua, F., Forkel, S.J., Simmons, A., Vergani, F., Murphy, D.G., Catani, M., 2011. A lateralized brain network for visuospatial attention. Nat. Neurosci. 14, 1245–1246. Thiebaut de Schotten, M., Ffytche, D.H., Bizzi, A., Dell’Acqua, F., Allin, M., Walshe, M., Murray, R., Williams, S.C., Murphy, D.G., Catani, M., 2011. Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography. Neuroimage 54, 49–59. Thiebaut de Schotten, M., Tomaiuolo, F., Aiello, M., Merola, S., Silvetti, M., Lecce, F., Bartolomeo, P., Doricchi, F., 2014. Damage to white matter pathways in subacute and chronic spatial neglect: a group study and 2 single-case studies with complete virtual “in vivo” tractography dissection. Cereb. Cortex 24, 691–706. Thiebaut de Schotten, M., Urbanski, M., Duffau, H., Volle, E., Lévy, R., Dubois, B., Bartolomeo, P., 2005. Direct evidence for a parietal-frontal pathway subserving spatial awareness in humans. Science 5744, 2226–2228. Urbanski, M., Thiebaut de Schotten, M., Rodrigo, S., Catani, M., Oppenheim, C., Touze, E., Chokron, S., Meder, J.F., Levy, R., Dubois, B., Bartolomeo, P., 2008. Brain networks of spatial awareness: evidence from diffusion tensor imaging tractography. J. Neurol. Neurosurg. Psychiatry 79, 598–601. Vallar, G., Perani, D., 1986. The anatomy of unilateral neglect after right-hemisphere stroke lesions. A clinical/CT-scan correlation study in man. Neuropsychologia 24, 609–622. Van der Stigchel, S., Nijboer, T.C., 2010. The imbalance of oculomotor capture in unilateral visual neglect. Conscious. Cognit. 19, 186–197. Walker, R., Techawachirakul, P., Haggard, P., 2009. Frontal eye field stimulation modulates the balance of salience between target and distractors. Brain Res. 1270, 54–63.