Non-lateralised deficits in anti-saccade performance in patients with hemispatial neglect

Neuropsychologia 47 (2009) 2488–2495

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Non-lateralised deficits in anti-saccade performance in patients with hemispatial neglect Stephen H. Butler a , Stephanie Rossit b , Iain D. Gilchrist c , Casimir J.H. Ludwig c , Bettina Olk d , Keith Muir e , Ian Reeves f , Monika Harvey b,∗ a

Department of Psychology, University of Strathclyde, Glasgow, UK Department of Psychology, University of Glasgow, 58 Hillhead Street, Glasgow G12 8QB, Scotland, UK Department of Experimental Psychology, University of Bristol, Bristol, UK d School of Humanities and Social Sciences, Jacobs-University, Bremen, Germany e Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK f Care of the Elderly, Southern General Hospital, Glasgow, UK b c

a r t i c l e

i n f o

Article history: Received 19 November 2008 Received in revised form 12 March 2009 Accepted 24 April 2009 Available online 3 May 2009 Keywords: Stroke Pro-saccades Voluntary control Oculomotor control Inhibition Action

a b s t r a c t We tested patients suffering from hemispatial neglect on the anti-saccade paradigm to assess voluntary control of saccades. In this task participants are required to saccade away from an abrupt onset target. As has been previously reported, in the pro-saccade condition neglect patients showed increased latencies towards targets presented on the left and their accuracy was reduced as a result of greater undershoot. To our surprise though, in the anti-saccade condition, we found strong bilateral effects: the neglect patients produced large numbers of erroneous pro-saccades to both left and right stimuli. This deficit in voluntary control was present even in patients whose lesions spared the frontal lobes. These results suggest that the voluntary control of action is supported by an integrated network of cortical regions, including more posterior areas. Damage to one or more components within this network may result in impaired voluntary control. Crown Copyright © 2009 Published by Elsevier Ltd. All rights reserved.

1. Introduction Neuropsychological evidence has so far supported the idea that automatic and voluntary control is dissociable in terms of their underlying neural pathways (Gaymard, Ploner, Rivaud, Vermersch, & Pierrot-Deseilligny, 1998; Guitton, Butchel, & Douglas, 1985). One classic paradigm to assess voluntary control over stimulus input is the anti-saccade paradigm. In this task participants are required to saccade away from an abrupt onset target. In order to perform this task participants have to inhibit the stimulus-driven orienting response to the target, and instead generate a voluntary orienting response in the opposite direction (Connolly, Goodale, Desouza, Menon, & Vilis, 2000; Hallett, 1978). In their seminal paper Guitton et al. (1985) demonstrated that patients with frontal lobe damage show increased error rates in the anti-saccade task whereas the ability to simply look towards a visual target is unimpaired in such patients. In a similar vein Pierrot-Deseilligny, Rivaud, Gaymard, and Agid (1991) compared the performance of patients with either posterior pari-

∗ Corresponding author. Tel.: +44 141 330 6174; fax: +44 141 330 4606. E-mail address: [email protected] (M. Harvey).

etal or dorsolateral prefrontal lesions in both pro-saccade and anti-saccade tasks. They reported bilateral increases in saccadic latency for pro-saccades in patients with right posterior parietal cortex lesions, and a small increase for just contralesional saccades for those with left sided lesions in this area. Patients with lesions to prefrontal cortex demonstrated a higher error rate in the anti-saccade task. Further studies have provided evidence for the involvement of the frontal eye field (FEF) in the generation of anti-saccades (Machado & Rafal, 2004; Olk, Chang, Kingstone, & Ro, 2006). Machado and Rafal (2004) showed that patients with chronic, unilateral frontal lesions involving the FEF made more erroneous pro-saccades towards contralesional targets and that this was not the case for patients with frontal lesions in whom the FEF was spared. Olk et al. (2006) tested healthy participants with the anti-saccade task whilst applying transcranial magnetic stimulation (TMS) over the FEF of the right hemisphere. They observed that stimulation significantly delayed anti-saccades into the right hemifield, a result that was best explained by a modulation of saccade inhibition to the stimulus presented on the left side. Based on these diverging findings, a prevalent assumption has been that posterior brain regions (perhaps in the form of a parietotectal route) are sufficient for the generation of stimulus-triggered

0028-3932/$ – see front matter. Crown Copyright © 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2009.04.022

S.H. Butler et al. / Neuropsychologia 47 (2009) 2488–2495

saccades. Voluntary control, however, is thought to depend on the frontal lobes, or some substructure within the frontal lobes (Everling & Fischer, 1998; Munoz & Everling, 2004). We have recently reported data on the oculomotor capture behaviour of a patient with a right temporo-parietal lesion that challenges this view (Butler, Gilchrist, Ludwig, Muir, & Harvey, 2006). The patient was asked to search for a target among distractors and signal its location with a saccade. On some trials, a task-irrelevant, additional distractor appeared with an abrupt onset. Compared to controls, the patient showed a greatly elevated level of oculomotor capture by the irrelevant onset. What is interesting is that he had no damage to frontal structures but was still unable to appropriately inhibit saccades to the task irrelevant distractors. These results suggest an additional role for temporo-parietal areas in voluntary control functions. Several other researchers have implicated the involvement of inferior and superior parietal areas, as well as the intraparietal sulcus in the successful completion of the anti-saccade task. In a recent review, Rafal (2006) points out that both the frontal and parietal lobes have oculomotor regions, which are connected to each other as well as to the colliculi. He proposes that the frontal cortex is vital for the generation of voluntary saccades and the parietal cortex for providing the required sensorimotor transformations. Connolly et al. (2000) used fMRI to show that a region in the posterior superior parietal cortex was more active in an anti-saccade compared to a pro-saccade task whilst the middle inferior parietal region was active only in the anti-saccade task. DeSouza, Menon, and Everling (2003) also reported evidence that intraparietal sulcus (IPS) regions showed higher activity for anti-saccade preparation. More specifically, using delayed anti-saccades Zhang and Barash (2000, 2004) demonstrated that stimulus direction is re-mapped in monkey LIP (the monkey equivalent of human IPS) to code the direction for the saccade, thus implicating this area in vector inversion. More converging evidence comes from Medendorp, Goltz, and Vilis (2005) who used an event-related fMRI design tracking signal changes in IPS whilst subjects were instructed to remember and execute either a pro or anti-saccade. They showed that the saccade goal is presented more strongly in the activation of IPS than the memory for the visual stimulus. Additionally though, Anderson, Husain, and Sumner (2008) implicated the right IPS in ‘reactive inhibition’ which they refer to as the process that suppresses the emerging reflex in order to resolve competition in favour of the desired antisaccade. In summary, there is little doubt that lesions to the frontal lobe result in deficits in the anti-saccade task. In addition, there is some evidence that more posterior areas are involved. In the current study, we wanted to test patients who suffered from hemispatial neglect, who had a common lesion site that was more posterior, using this classic paradigm to assess voluntary oculomotor control. We hypothesised that such patients, who show an inability to respond to events in the left half of their subjective space (Pierce & Buxbaum, 2002), and whose lesions have been shown to be critically centred either in the right inferior parietal (Mort et al., 2003) or superior temporal lobe (Karnath, Ferber, & Himmelbach, 2001; Karnath, Fruhmann Berger, Kueker, & Rorden, 2004) would show an impairment in this task. In particular we expected these patients to demonstrate the greatest impairment in making anti-saccades away from a right stimulus as it has been shown that such patients: (1) demonstrate abnormally short latencies of saccades to ispilesional targets (Natale, Marzi, Bricolo, Johannsen, & Karnath, 2007); (2) are slow to disengage from a right-sided stimulus when having to orient to the left (Friedrich, Egly, Rafal, & Beck, 1998; see also Losier & Klein, 2004 for a review). To our surprise we found strong bilateral effects in that patients with hemispatial neglect produced large numbers of erroneous pro-saccades to both left and right stimuli.

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2. Methods 2.1. Subjects Thirteen patients who suffered from hemispatial neglect, after right-brain damage (mean age 64.8, SD 6.4), and 12 age-matched healthy subjects (mean age 73.2, SD 5.1) were included in the study. All participants were right-handed (Annett, 1967). Hemispatial neglect was initially assessed with the behavioural inattention test (BIT, Wilson, Cockburn, & Halligan, 1987). If a patient scored above the cut-off on the BIT, the line bisection task (Harvey, Milner, & Roberts, 1995) and the Balloons Test (Edgeworth, Robertson, & McMillan, 1998) were also administered. On these occasions, patients were considered to have hemispatial neglect if they presented a significant rightward bisection error (Halligan, Manning, & Marshall, 1990) or were impaired in a lateralised manner on the sub-test B of the Balloons Test (see Table 1 for the patients’ clinical details). Patient MMG, albeit not showing neglect on paper and pencil tests, was included as she presented strongly lateralised symptoms of the disorder as reported both by her family and the medical staff (e.g., bumping into items on the left, failure to dress the left body half as well as failing to eat items on the left of her plate). Computerized perimetry testing was performed on all patients. The two patients with the strongest neglect (JQ and JM) failed to respond to any of the stimuli displayed for 100 ms, so no score could be generated. Of the remaining 11 patients, 5 showed no evidence of a visual field deficit. For the other patients it is difficult to determine whether their failure to detect the target was the result of hemianopia or hemispatial neglect. Indeed, these two disorders are notoriously difficult to disentangle (Walker, Findlay, Young, & Welch, 1991). In any case we found that performance on the visual field test failed to predict any of the outcome measures in both the pro- and the anti-saccade tasks. Moreover, the patients’ performance on the pro-saccade task reported below clearly shows that all patients were able to orient to contralesional visual targets. The lesions of the patients were mapped onto Damasio templates (Damasio & Damasio, 1989; see Fig. 1). The study was conducted in accordance with the ethical guidelines of the South Glasgow University Hospitals NHS trust and the Declaration of Helsinki. All participants gave their informed consent prior to the study and were reimbursed for their travel expenses. 2.2. Apparatus and stimuli A centrally presented white circle with a diameter of 0.6◦ on a black background served as a fixation circle. Stimuli consisted of a single white square, 0.6◦ in size, which would appear peripherally in each trial at one of two possible locations on the horizontal meridian, either 7.3◦ to the left or right of the centre of the screen. Displays were presented on a 17 SVGA monitor with 800 × 600 pixel resolution and 74 Hz refresh rate. The monitor was located at 57 cm from the chinrest. A second PC was used to record eye position data on-line. Eye movements were monitored with the SMI EyeLink System (SensoMotoric Instruments GmbH, Teltow, Germany). The system uses the centre of the pupil and the corneal reflection technique to define pupil position. Eye movements were recorded at 250 Hz, with an operational spatial resolution of about 0.3◦ . Saccade onset was defined as a change in eye position with a minimum velocity of 35◦ /s or a minimum acceleration of 9500◦ /s2 . 2.3. Procedure Each of the two blocks of trials started with a nine-point grid calibration and validation procedure. Participants were asked to saccade to a grey, circular disk (identical to the fixation point) that appeared sequentially (but unpredictably) in a 3 × 3 grid. After a satisfactory validation had been obtained, a block of trials was run. In all conditions subjects were instructed to begin each trial by fixating on the central circle on the screen. In the pro-saccade condition participants were instructed to make a saccade towards the single white box, which appeared peripherally on the right or left of the screen, as quickly as possible. Conversely, in the anti-saccade condition, participants were instructed to maintain central fixation until they detected the single white box, and then look to the same place on the opposite side of the screen away from the white box as quickly as possible, without looking at the stimulus. In between trials a central fixation disk was displayed. When the experimenter was confident that fixation was on this disk and stable, the space bar on the control PC was pressed to initiate the trial. This procedure also allowed for a trial-by-trial drift correction to be carried out on the eye tracking calibration. An experimental trial consisted of the continued presence of the central fixation circle for a random duration of 500–1500 ms (to reduce anticipatory responses) followed by the onset of the stimulus to one side of the screen (thus the central fixation circle remained on the screen throughout the trial). The stimulus remained on the screen for 1000 ms, the offset of which signified the end of the trial. Prior to each block participants were shown a 10 trial demonstration of the task to illustrate the task and to ensure that the patients understood what they were required to do. Each block consisted of 40 leftward and 40 rightward peripheral stimuli trials, randomly intermixed. The order of blocks was counterbalanced between subjects.

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Table 1 Demographic and clinical data of the right brain-damaged patients with hemispatial neglect. Patient

Gender

Age

Scan

Etiology

Lesion location

TO

VFD

BIT

Line bisection

Balloons

JS JH JMO JCA AM MJA MMG NF DS MMO JQ JM TH

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

74 57 56 63 63 59 63 68 65 72 59 67 76

MRI MRI MRI MRI CT CT CT MRI MRI MRI MRI MRI CT

Infarct Infarct Infarct Infarct Infarct Infarct Infarct Infarct Infarct Infarct Haematoma Infarct Infarct

Temporal, insular cortex and periventricular white matter Fronto-temporo-parietal Fronto-parietal Superior post-central gyrus (parietal lobe) and occipital Fronto-temporo-parietal-insular Fronto-temporo-parietal-occipital Dorsal frontal, parietal, corona radiata Fronto-temporo-parietal Fronto-temporo-occipital Fronto-temporo-insular Basal ganglia Frontal, basal ganglia Temporo-parietal

6 28 15 3 17 8 3 11 3 6 3 38 31

Yes Yes No No Yes Yes No Yes Yes No (-) (-) No

117 139 117 93 134 122 143 143 91 128 35 61 126

(-) 11.8 (-) (-) 19 (-) 3.1 5.5 (-) (-) (-) (-) (-)

(-) 69 (-) (-) 50 (-) 59 29 (-) (-) (-) (-) (-)

TO = time since injury onset (months); VFD = visual field defect; BIT = behavioural inattention test conventional sub-tests score (cut-off = 129); line bisection represents the average error (in mm) obtained with 20 lines (200 mm length), no sign is equivalent to a rightward error and a negative sign is equivalent to a leftward error (cut-off = 6 mm, Halligan, Manning, & Marshall, 1990); Balloons represents the lateralised index score in sub-test B (patient is impaired when this index is lower than 45%); (-) = data absent.

2.4. Data processing Firstly, we assessed the number of trials in which participants failed to initiate an eye movement (pro- or anti-saccade). In the pro-saccade condition none of the controls failed to initiate a saccade (and did so in less than 1% of the anti-saccade trials). The patients also only failed in less than 1% of trials in both pro- and antisaccade trials. In addition, trials were excluded if (1) participants anticipated the stimulus appearance by making a saccade with a latency (saccadic reaction time) shorter than 80 ms; (2) they improperly fixated the central stimulus (deviation larger than 1◦ ); (3) the amplitude of the eye movement was less than 1◦ (cf. Machado & Rafal, 2000). In the pro-saccade condition, this resulted in the exclusion of 10.5% of the controls’ trials and 38.5% of the neglect patients’ trials. In the anti-saccade condition, 9.6% of trials collected from the age-matched controls and 47.9% from the patients’ trials were excluded. Despite these exclusions 640 trials of the patients’ pro-saccades and 540 of their anti-saccades could be analysed. However, as a much greater number of patients’ rather than control subjects’ trials were excluded, we looked at each of these criteria in more detail in case a neglect bias itself might be driving these initial exclusions. Patients anticipated on 14.7% (left target, range = 7.5–30%) and 19.4% (right target, range = 0–35%) of pro-saccade trials and healthy controls on 4.4% (right target) and 6.9% (left target). In the anti-saccade condition, the anticipation criteria resulted in the exclusion of 13.6% and 14.9% of trials in the patient group for left and right hand targets, respectively (range left target = 0–37.5%; range right target = 0–30%) (healthy controls mean for left target = 3.1%, and right target = 6.7%). In the pro-saccade condition 19.1% (left target range = 5–37.5%) and 17.3% (right target range = 0–42.5%) of trials were excluded from the patient group due to improper fixation (healthy controls mean for left = 4.0%, and right = 2.9%). In the anti-saccade condition, the patients improperly fixated in 19.3% and 20.7% of left and rightward target trials (range left = 5–42%, and right = 0–43%), whilst healthy controls only made this error in 1.7% (left target) and 3.1% (right target) of trials. Finally, for pro-saccades smaller than 1 degree 9.7% of left and 1.3% of right target trials were excluded in the patient group whilst in healthy controls only 0.8% (left target) and 1.5% (right target) of trials were excluded. In the anti-saccade condition, this amplitude criterion resulted in the exclusion of 7.7% (left target) and 1.9% (right target) and 2.1% and 1.0% in healthy controls in response to the leftward and rightward stimulus, respectively. Only this final exclusion criteria gave any indication of a lateral bias in the patients and this bias was indeed mirrored in the saccadic accuracy data presented in Section 3. 2.5. Analyses For both pro-saccade and anti-saccade conditions, we analysed the saccadic reaction time (SRT), the absolute error (i.e., the unsigned angular error in the x-axis with respect to the target or the position opposite, for the anti-saccade condition) and assessed the signed error (i.e., the signed angular error (with right (+) and leftward (−) deviations) in the x axis with respect to the target or the position opposite, for the anti-saccade condition). Saccadic amplitude and variable saccadic amplitude (i.e., the standard deviation of the amplitude) were also analysed, yet for brevity and as the results mirrored the angular error data, they will not be reported here. For the anti-saccade condition, the principal measure of performance was the error rate, which is the mean proportion of erroneous pro-saccades made. In addition, for successful anti-saccades only, the following parameters were analysed: SRT, absolute and signed error, amplitude and variable amplitude (which again mirrored the angular error data and will not be reported). We further examined whether corrective saccades were made following an erroneous pro-saccade, as this shows that the subject understood the task and executed the vector inversion. So whenever an erroneous pro-saccade was made, the saccade following this was

examined and considered corrective if it ended on the side of the display opposite the stimulus. Finally we also investigated the SRTs and accuracy of the erroneous pro-saccades. Means for each participant were computed per condition per variable and target position. Statistical analysis consisted of 2 × 2 mixed ANOVAs (group and side) for each variable separately for each condition. Post hoc comparisons were made with the Bonferroni method, p < 0.05.

3. Results 3.1. Pro-saccade condition Analysis of the SRTs revealed a main effect of side [F(1,23) = 21.77, p < 0.001], in that all participants showed longer latencies for left compared to right stimuli. However, this was qualified by the significant side by group interaction [F(1,23) = 32.51, p < 0.001] with pairwise comparisons revealing that, compared to controls, neglect patients had significantly slower pro-saccades to left targets (neglect mean left = 279 ms, range = 184–375 ms; controls mean left = 214 ms, range = 120–312 ms; mean difference = 65 ms, p < 0.01). In addition, it looked like the neglect patients had abnormally fast pro-saccades to the right targets compared to the age-matched controls (neglect mean right = 190 ms, range = 115–302 ms; controls mean right = 223 ms, range = 140–355 ms; mean difference = −33ms) but this difference was not significant. Moreover, healthy participants were as fast to pro-saccade to left and right targets (mean difference = −9 ms), whereas the neglect patients presented a significant asymmetry in the SRT of their pro-saccades (mean difference = 89 ms, p < 0.001), with slower responses to the left target. We also analysed how accurate the eye movements were in respect to the target position. Analysis of the absolute error confirmed that the pro-saccades of neglect patients were less accurate than the ones of the healthy controls [F(1,23) = 25.24, p < 0.001]. Again there was an effect of side [F(1,23) = 14.91, p = 0.001] which was qualified by the significant group by side interaction [F(1,23) = 18.38, p < 0.001]. Pairwise comparisons showed that although neglect patients were inaccurate in response to both target positions when compared to healthy controls (mean difference for left target = 4.18, p < 0.001; mean difference for right target = 0.64, p = 0.001), there was a significant asymmetry in the neglect group. Neglect patients were less accurate when performing pro-saccades towards the left compared to the right target (mean left = 4.74, range = 0.8–10.9; mean right = 1.37, range = 0.9–2.9, p < 0.001), whereas healthy participants presented similar errors across both sides of space (mean left = 0.55, range = 0.3–0.9, mean right 0.73, range = 0.4–1.0). Inspection of the sign of these errors revealed that neglect patients demonstrated undershoots to both targets (mean left = 4.35, range = 0.1–10.9; mean right = −1.04, range = −1.9 to

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Fig. 1. Maps of damaged areas of right hemisphere lesioned patients with hemispatial neglect. Templates were taken from Damasio and Damasio (1989) (for MMG the scan has been untraceable).

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−0.4). Control participants also undershot (controls mean left = 0.35, range = −0.1 to 0.9; controls mean right = −0.44, range = −1.0 to 0.5) but as for absolute errors there was a spatial asymmetry in the patients. 3.2. Anti-saccade condition Fig. 2 shows the proportion of pro-saccade errors in response to left and right visual targets, separately for controls and patients. The error bars around the control data indicate the 95% within-subject confidence intervals. The thin lines connect the error proportions for left and right targets for each individual patient. It is clear that the group as a whole showed a marked increase in error rates (70% vs. 13%, respectively, F(1,23) = 55.79, p < 0.001) and that this pattern was highly representative of that of individual patients. Surprisingly, there was no effect of target location, nor did these two factors interact. The absence of a lateral bias in error rates was found for almost all individual patients. If anything a subset of patients (Table 2) showed greater errors rate to the leftward rather than rightward targets (against our original prediction). Although almost all neglect patients failed to perform an antisaccade as their first saccade, patients corrected their errors (Table 3) providing important evidence that they understood the task instructions. Nonetheless, analysis of the corrective saccades showed that healthy controls produced more corrections than the neglect patients [F(1,21) = 19.25, p < 0.001]. There was also a main effect of side, in that more corrective saccades were made in response to the right target when compared to the leftward one [F(1,21) = 20.36, p < 0.001]. This was qualified by the significant group by side interaction [F(1,21) = 7.47, p < 0.05]. Pairwise comparisons revealed that neglect patients made fewer corrective saccades than healthy controls for both target positions (mean difference for left target = −42%, p < 0.001; mean difference for right target = −20%, p < 0.01), but there was also a greater asymmetry in the neglect group. The patients made significantly fewer corrective saccades in response to the left compared to the right target (mean difference = −29%, p < 0.001), whereas the

Table 2 Means and standard deviations (in parenthesis) for percentage of erroneous prosaccades for the anti-saccade condition per stimulus position. Group

Healthy controls Neglect patients JS JH JMO JCA AM MJA MMG NF DS MMO JQ JM TH

Target position Left

Right

11.88 (10.64) 74.75 (22.64) 71.43 90.00 70.73 38.10 84.78 74.19 98.57 95.35 69.57 79.17 93.62 85.71 20.59

14.15 (12.69) 64.49 (31.78) 82.35 88.24 81.94 9.38 92.50 77.46 100.00 60.78 27.43 91.25 86.00 92.86 13.16

Data is presented firstly for each group separately and then individually for each neglect patient.

controls’s correction rate was similar for both targets (mean difference = −7%). Unlike the SRTs for the pro-saccades, analysis of the correct anti-saccade SRTs showed no effects of group or side nor an interaction, although there was some suggestion that the neglect group had longer latencies for making saccades away from a right target (neglect mean left target = 338 ms; range = 96–655 ms; neglect mean right target = 412 ms; range = 80–570 ms; controls mean left target = 359; range = 204–479 ms; controls mean right target = 369; range = 289–480 ms). To further examine the accuracy of these correct anti-saccades we performed an analysis of variance on the absolute error. This confirmed that neglect patients presented significantly higher errors in their correct anti-saccades [F(1,22) = 24.66, p < 0.001], but again (and different from the pro-saccades) there were no effects of side nor an interaction with side (neglect mean left target = 4.95 and range = 1.5–7.8; neglect mean right target = 4.11 and range = 1.8–6.5; controls mean left target = 2.39, range = 1.2–3.3; controls mean right target = 2.04 and range = 1.1–3.4). As for the sign of these errors, saccades undershot the anti-target position and all participants presented larger errors in response to the left sided stimulus (rightward anti-saccade) when compared to the rightward one.

Table 3 Means and standard deviations (in parenthesis) for percentage of corrective saccades for the anti-saccade condition per stimulus position. Group

Fig. 2. Mean proportion of pro-saccade errors in the anti-saccade task for agematched controls (N = 12) and neglect patients (N = 13). Error bars around the control means are 95% confidence intervals. Individual patient data is shown by the grey circles and thin grey lines connect the data from left and right targets for each individual patient.

Healthy controls Neglect patients JS JH JMO JCA AM MJA MMG NF DS MMO JQ JM TH

Target position Left

Right

82.10 (18.34) 42.00 (24.93) 32.00 11.11 31.03 50.00 33.33 30.43 37.68 31.71 43.75 68.42 68.18 8.33 100.00

87.07 (15.81) 71.03 (17.99) 57.14 33.33 83.05 66.67 56.76 63.64 70.51 58.06 83.87 78.08 95.35 76.92 100.00

Data is presented firstly for each group separately and then individually for each neglect patient.

S.H. Butler et al. / Neuropsychologia 47 (2009) 2488–2495

The latencies (SRTs) of the erroneous pro-saccades were very similar to the ones obtained in the pro-saccade condition (neglect mean left target = 274 ms and range = 137–350 ms; neglect mean right target = 186 ms and range = 120–303 ms; controls mean left target = 229 ms, range = 122–373 ms; controls mean right target = 196 ms, range = 107–359 ms). Although this time there was no main effect of group, the effect of side was still significant in that all participants had faster erroneous pro-saccades to the right stimulus [F(1,21) = 27.70, p < 0.001]. The interaction between side and group was again significant [F(1,21) = 5.87, p < 0.05]. Pairwise comparisons revealed that although neglect patients were not significantly slower than healthy controls for either target position, they had a greater asymmetry in their SRTs. They were significantly slower in their leftward erroneous pro-saccades, compared to rightward ones (mean difference = 88 ms, p < 0.001) whereas the healthy controls performed similarly for both target positions (mean difference = 32 ms). We also examined the accuracy of these erroneous pro-saccades. In terms of absolute error the ANOVA revealed a significant main effect of side [F(1,21) = 14.22, p = 0.001], in that all participants were less accurate in their erroneous pro-saccade towards the left target. The main effect of group was not significant, but there was a significant group by side interaction [F(1,21) = 8.00, p = 0.01]. Pairwise comparisons revealed that compared to the control group, neglect patients were significantly more inaccurate in their leftward erroneous pro-saccades only (neglect mean left target = 3.51, range = 0.1–6.0; neglect mean right target = 1.34, range = 0.6–2.7, controls mean left target = 2.04, range = 0.4–5.2; controls mean right target = 1.73, range = 0.3–2.9, p < 0.05). Healthy controls where as accurate for both their leftward and rightward erroneous prosaccades, whereas neglect patients had bigger errors in their leftward erroneous pro-saccades. Finally, we compared the accuracy of the erroneous prosaccades in the anti-saccade condition with the accuracy of correct pro-saccades in the pro-saccade condition in terms of absolute error. Only the interaction between condition and group was significant [F(1,21) = 9.37, p < 0.01]. Post hoc tests revealed that neglect patients were only inaccurate, compared to healthy controls, in the pro-saccade condition (p < 0.001). Furthermore, although healthy subjects were less accurate in their erroneous pro-saccades in the anti-saccade condition when compared to their correct prosaccades (p = 0.01), neglect patients’ saccades did not differ in this way. 4. Discussion In the pro-saccade condition, neglect patients showed abnormally increased latencies towards leftwardly presented targets and their accuracy was reduced in terms of a greater undershoot for stimuli presented on the left side of space, although they did not fail to respond to the left stimulus. To our surprise though, performance in the anti-saccade task showed a very different pattern: the neglect patients showed bilateral impairments. All patients had great difficulty in suppressing incorrect pro-saccades to both sides of space. In the few cases for which correct anti-saccades were performed, saccades were less accurate but again for both sides of space. Also, fewer corrective saccades were made away from the left stimulus rather than away from the right stimulus. The following discussion will focus in more detail on these key findings. 4.1. Pro-saccade performance A number of studies have already shown that patients with hemispatial neglect are impaired in their eye movement patterns

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generally, in that such patients demonstrate a rightward deviation of exploratory gaze (Hornak, 1992; Karnath & Fetter, 1995; Karnath, Niemeier, & Dichgans, 1998), start their exploration in right hemispace and, compared to healthy participants, spend relatively less time exploring the left (Behrmann, Watt, Black, & Barton, 1997; Chedru, Leblanc, & Lhermitte, 1973). More specifically leftward saccades are characterised by prolonged saccade latencies and hypometric amplitudes (Girotti, Casazza, Musicco, & Avanzini, 1983; Ishiai, Furukawa, & Tsukagoshi, 1987; Walker, Findlay, Young, & Lincoln, 1996) which is exactly what we have replicated here. Like Natale et al. (2007) we also found that neglect patients produced faster pro-saccades than the healthy control subjects although here these differences were not significant. The neglect patients did not fail to execute leftward saccades, a finding we have previously reported in two isolated cases (Harvey, Olk, Muir, & Gilchrist, 2002, but see also Natale et al., 2007 for contrary findings) yet particular task demands may come into play here. Patients knew that a target would appear either to the right or the left of the screen, so if no target appeared on the right, a leftward eye movement might be made resulting in the saccade indeed being executed, yet with an increased latency, reduced amplitude and accuracy. This strategy would dramatically fail (and has been shown to do so) in more complex search situations for example when distractors are included (Harvey et al., 2002; Behrmann et al., 1997). However, we think that neglect patients are relatively less impaired in performing a direct on-line action (such as an immediate reach or indeed a stimulus triggered eye-movement) than a more complex off-line action or visual search. Indeed Milner and colleagues (Milner & Goodale, 2006; Milner & Harvey, 2006) have repeatedly argued that on-line reaches to both left and right targets are relatively unimpaired in hemispatial neglect (see also Himmelbach & Karnath, 2003). In a very recent study (Rossit et al., 2009), we found that neglect patients virtually never failed to execute a left reach, in line with the finding here that neglect patients did not fail to execute a leftward saccade. This could suggest that simple stimulus triggered saccades are relatively spared in such patients even towards leftward targets. Corroborating this interpretation is the finding that the erroneous pro-saccades in the anti-saccade task were also stimulus-triggered as their latencies and accuracies mirrored the pro-saccade pattern. Admittedly in this study though, patients showed impairments in latency and accuracy for left proas well as erroneous pro-saccades in the anti-saccade task, something we did not find for the immediate reaches (Rossit et al., 2009). As a minor point, we found that the pro-saccade impairments were unrelated to the presence or absence of hemianopia. This data agrees with our previous studies that have failed to find differences in the performance of neglect patients with and without hemianopia (Harvey, Kramer, & Gilchrist, 2001; Harvey, Olk, Muir, & Gilchrist, 2003), yet others such as Dorrichi and colleagues (Doricchi & Angelelli, 1999; Doricchi, Onida, & Guariglia, 2002) have reported such differential effects. 4.2. Anti-saccade performance The most remarkable finding, and in stark contrast to the more or less expected pro-saccade data, was that our neglect patients produced a great number of incorrect pro-saccades both to the left (75%) and right (65%) target stimuli when asked to perform antisaccades away from them. In fact the size of the effect, compared to the controls (12% left, 14% right) seems suggestive of disinhibition. Indeed the reported inability of our neglect patients to suppress erroneous pro-saccades is comparable to the behaviour of the patient in the study by Butler et al. (2006). This patient, who suffered from a temporo-parietal lesion, was unable to appropriately inhibit saccades to the task irrelevant distractors. However, in his case the performance was spatially modulated: when the target

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was ipsilesional and the distractor contralesional the extent of capture shown by the patient was dramatically reduced. This was not the case for the data presented here, in fact four patients showed greater numbers of erroneous pro-saccades to the left stimulus. What generates these bilateral impairments? To succeed at the anti-saccade task participants have to inhibit the stimulus-driven orienting response to the target, and generate a voluntary orienting response in the opposite direction. One possibility is that neglect patients, due to the lateral bias in their behaviour fail to perform anti-saccades on both sides but for different reasons: with a right stimulus, as we expected (see also Losier & Klein, 2004), the patients code the location accurately, but fail to suppress the right prosaccade in favour of the leftward anti-saccade. Although this can be done, it is effortful and results in incorrect rightward orienting as well as impaired anti-saccade accuracy in the few cases in which a correct anti-saccade is generated. For the left target it may be that the target location is not coded accurately in the first place (even pro-saccades fall short of the target) thus precluding vector inversion. This may also explain the finding that fewer (second) corrective saccades were made away from the left stimulus. Moreover, the bilateral impairment fits with the results of Medendorp et al. (2005) who reported bilateral activation of the IPS during their anti-saccade task demonstrating that dynamic exchange of activity occurs when the location of a visual stimulus must be reversed to specify the goal for a saccade. Obviously a unilateral lesion would impair this exchange and result in bilateral deficits. We therefore propose that frontal structures that have more traditionally been associated with the voluntary control of action are instead working within a more closely integrated network that includes posterior regions of the cortex, including those implicated in neglect. Damage to these posterior regions can in and of themselves lead to deficits in voluntary control (see Peers et al., 2005). Two important caveats have to be made here. First, although virtually all our patients had posterior lesions, 9/13 also showed signs of some frontal damage and it is distinctly possible that the bilateral impairments we report are simply related to the inability in these patients to suppress the pre-potent response. Although we cannot refute this possibility, it should be noted that 4/13 patients were without frontal involvement and these patients showed performance patterns on both tasks that could not be distinguished from the remaining patients (Table 2). A second limitation of the current study is that we did not have a ‘fixation’ or ‘no go’ control condition. We had indeed planned to include such a control condition yet the patients were simply not able to cope with the extra task demands and since, at the time, we expected neglect type lateral biases in the behaviour pattern (erroneous pro-saccades to right but not leftward targets) we did not foresee the constraints this would impose on our interpretation. We are currently running experiments looking at potential ‘no-go, fixation’ failures in these patients. Finally, the neglect group reported here has diverse lesions. The focus of this paper is to report the surprising bilateral impairments in patients with hemispatial neglect with typical lesions. However, it is clear that we cannot make strong claims about the underlying neuroanatomy driving these impairments. To do this we need to associate anti-saccade error rates with critical lesion sites across impaired and unimpaired right hemisphere lesioned patients for example using the Bruner-Munzel rank order test (Rorden, Karnath, & Bonilha, 2007). This should allow us to make more specific claims regarding the critical lesion site associated with voluntary oculomotor control yet at present, as pointed out by Rorden and Karnath (2004), anatomical conclusions drawn without a comparison to a control group of patients who also suffer from a right brain lesion but do not show the pathological behaviour may simply reflect vulnerability of that area to vascular injury.

With these points in mind, we would nonetheless argue that our findings agree with recent investigations that implicate the parietal lobe in anti-saccade tasks: Connolly et al. (2000) showed that the middle inferior parietal region was selectively active in an anti-saccade task and DeSouza et al. (2003) reported evidence for intraparietal sulcus involvement in anti-saccade preparation. Doricchi et al. (1997) proposed that the inferior parietal lobule activation observed in their anti-saccade task was linked to sensory-motor activation related both to attentional disengagement from the initial cue and the recomputation of the new saccadic vector for the anti-saccade which also fits with the neurophysiological and fMRi results described earlier (Zhang & Barash, 2000; Zhang & Barash, 2004). Finally and very interestingly apart from implicating parietal areas in vector inversion, Anderson et al. (2008) have implicated the right IPS in ‘reactive inhibition’. Using fMRI they demonstrated that this area appears to index the degree of competition between stimulus triggered and voluntary saccades plans, showing that the IPS gives an activity pattern predicted for an area involved in suppressing the saccade reflex. This finding implicates posterior brain areas in inhibition and fits well with the data presented here. To conclude, it has recently become increasingly recognised that the symptoms of patients with hemispatial neglect can be exacerbated by deficits that may not be spatially lateralised such as deficits in: sustained attention (Robertson, Mattingley, Rorden, & Driver, 1998); the ability to ignore central distractors (Ptak, Schnider, Golay, & Mueri, 2007); spatial working memory (Malhorta et al., 2005) and vigilance (Malhorta, Paton, Greenwood, & Husain, 2006). Here, we report bilateral impairments in the voluntary control of saccades. We argue (within the constraints outlined above) that the control of action is supported by an integrated network of cortical regions, including more posterior areas. Damage to one or more components anywhere within this network may result in impaired voluntary control. Acknowledgements The authors wish to thank all the patients and healthy participants for their patience and willingness and the anonymous reviewers for most constructive comments on an earlier version of this manuscript. In addition, we would like to thank Katrina Livingstone, Hazel Clark, Pauline Castle and Caroline Hogg for help with patient recruitment and Gemma Learmonth for help with clinical information. This work was supported by grants from the Royal Society (2005/R3-JP) to M. Harvey and B. Olk, the Royal Society of Edinburgh/Lloyds TSB Foundation to S. Butler and the Foundation for Science and Technology (FCT, Portugal (SFRH/BD/23230/2005)) to S. Rossit. References Anderson, E. J., Husain, M., & Sumner, P. (2008). Human intraparietal sulcus (IPS) and competition between exogenous and endogenous saccade plans. NeuroImage, 40, 838–851. Annett, M. (1967). The binomial distribution of right, mixed and left handedness. The Quarterly Journal of Experimental Psychology, 19, 327–333. Behrmann, M., Watt, S., Black, S. E., & Barton, J. J. S. (1997). Impaired visual search in patients with unilateral neglect: An oculographic analysis. Neuropsychologia, 35, 1445–1458. Butler, S. H., Gilchrist, I. D., Ludwig, J. C. H., Muir, K., & Harvey, M. (2006). Impairments of oculomotor control in a patient with a right temporo-parietal lesion. Cognitive Neuropsychology, 23, 990–999. Chedru, F., Leblanc, M., & Lhermitte, F. (1973). Visual searching in normal and braindamaged subjects: Contribution to the study of unilateral inattention. Cortex, 9, 94–111. Connolly, J. D., Goodale, M. A., Desouza, J. F. X., Menon, R. S., & Vilis, T. (2000). A comparison of frontoparietal fMRI activation during anti-saccades and anti-pointing. Journal of Neurophysiology, 84, 1645–1655. Damasio, H., & Damasio, A. R. (1989). Lesion analysis in neuropsychology. Oxford University Press.

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