Spatial and temporal dynamics of visual search tasks distinguish subtypes of unilateral spatial neglect: Comparison of two cases with viewer-centered and stimulus-centered neglect.

Neuropsychological Rehabilitation An International Journal

ISSN: 0960-2011 (Print) 1464-0694 (Online) Journal homepage: http://www.tandfonline.com/loi/pnrh20

Spatial and temporal dynamics of visual search tasks distinguish subtypes of unilateral spatial neglect: Comparison of two cases with viewercentered and stimulus-centered neglect Katsuhiro Mizuno, Kenji Kato, Tetsuya Tsuji, Keiichiro Shindo, Yukiko Kobayashi & Meigen Liu To cite this article: Katsuhiro Mizuno, Kenji Kato, Tetsuya Tsuji, Keiichiro Shindo, Yukiko Kobayashi & Meigen Liu (2015): Spatial and temporal dynamics of visual search tasks distinguish subtypes of unilateral spatial neglect: Comparison of two cases with viewercentered and stimulus-centered neglect, Neuropsychological Rehabilitation, DOI: 10.1080/09602011.2015.1051547 To link to this article: http://dx.doi.org/10.1080/09602011.2015.1051547

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Neuropsychological Rehabilitation, 2015 http://dx.doi.org/10.1080/09602011.2015.1051547

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Spatial and temporal dynamics of visual search tasks distinguish subtypes of unilateral spatial neglect: Comparison of two cases with viewer-centered and stimulus-centered neglect Katsuhiro Mizuno1,2,3, Kenji Kato4, Tetsuya Tsuji1, Keiichiro Shindo1,3, Yukiko Kobayashi1,5, and Meigen Liu1 1

Department of Rehabilitation Medicine, Keio University School of Medicine, Tokyo, Japan 2 Department of Rehabilitation Medicine, National Sanatorium Tama Zenshoen, Tokyo, Japan 3 Department of Rehabilitation Medicine, Tokyo Metropolitan Rehabilitation Hospital, Tokyo, Japan 4 Department of Biosciences and Informatics, Keio University, Kanagawa, Japan 5 Department of Rehabilitation Medicine, Ichikawa City Rehabilitation Hospital, Chiba, Japan (Received 28 October 2014; accepted 11 May 2015)

We developed a computerised test to evaluate unilateral spatial neglect (USN) using a touchscreen display, and estimated the spatial and temporal patterns of visual search in USN patients. The results between a viewer-centered USN patient and a stimulus-centered USN patient were compared. Two rightbrain-damaged patients with USN, a patient without USN, and 16 healthy subjects performed a simple cancellation test, the circle test, a visuomotor search test, and a visual search test. According to the results of the circle test, one USN Correspondence should be addressed to Katsuhiro Mizuno, Department of Rehabilitation Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 1608582, Japan. Email: [email protected] The authors would like to give special thanks to the patients and their families for their time and cooperation, and to the anonymous reviewers for their helpful suggestions. No potential conflict of interest was reported by the authors. This study was partially supported by funds from the Tokyo Metropolitan Rehabilitation Hospital and Toyota Tsusho Corporation. # 2015 Taylor & Francis


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patient had stimulus-centered neglect and a one had viewer-centered neglect. The spatial and temporal patterns of these two USN patients were compared. The spatial and temporal patterns of cancellation were different in the stimulus-centered USN patient and the viewer-centered USN patient. The viewercentered USN patient completed the simple cancellation task, but paused when transferring from the right side to the left side of the display. Unexpectedly, this patient did not exhibit rightward attention bias on the visuomotor and visual search tests, but the stimulus-centered USN patient did. The computerbased assessment system provided information on the dynamic visual search strategy of patients with USN. The spatial and temporal pattern of cancellation and visual search were different across the two patients with different subtypes of neglect. Keywords: Hemi-neglect; Spatial reference frame; Allocentric neglect; Egocentric neglect; Visual attention.

INTRODUCTION Unilateral spatial neglect (USN) is a failure to explore and respond to stimuli in the contralateral space of a brain lesion (Heilman, Watson, & Valenstein, 1993). USN is among the strongest predictors of poor functional recovery in stroke patients because it can disrupt rehabilitation and recovery of functional disabilities (Gillen, Tennen, & McKee, 2005). Although there have been many studies on USN, the lesions, mechanisms, and treatments are still unknown. One of the most complicated problems is that USN is a heterogeneous disorder. Various subtypes of USN have been identified according to the spatial and representational cognitive processing deficits, including near and far space neglect, attentional and intentional neglect, visual, tactile and motor neglect, personal and peripersonal neglect, and viewer-centered and stimulus-centered neglect (Arene & Hillis, 2007; Heilman et al., 1993). Most patients have a combination of deficits from different subtypes. As such, it is difficult to find a common index that represents the characteristics and severity of neglect in all patients with USN. From a neuroanatomical perspective, brain lesions in a variety of regions have been emphasised as critical for USN (Bartolomeo, Thiebaut de Schotten, & Doricchi, 2007; Mesulam, 1999; Karnath, Ferber, & Himmelbach, 2001; Thiebaut de Schotten et al., 2005), and there is a controversy as to the critical brain region. Several studies have suggested that lesions to the right inferior parietal lobe might be critical for USN (Mesulam, 1999), but another study found that lesions to the right superior temporal lobe were most common in USN patients (Karnath et al., 2001). Other studies have emphasised the role of fronto-parietal white matter disconnection in USN (Bartolomeo


SPATIAL AND TEMPORAL DYNAMICS OF USN

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et al., 2007; Thiebaut de Schotten et al., 2005). Recent studies (Committeri et al., 2007; Hillis, Newhart, Heidler, Barker, & Herskovits, 2005; Verdon, Schwartz, Lovblad, Hauert, & Vuilleumier, 2010; Yue, Song, Huo, & Wang, 2012) have reported a relation between the clinical features of USN and the location of the brain lesion, highlighting the need to consider the different subtypes of USN when investigating the relation between lesion location and clinical characteristics. It has been suggested that the symptoms of USN might be affected by nonspatially lateralised deficits of attention, and that these spatially non-lateralised deficits may exacerbate lateralised deficits (Husain & Rorden, 2003). For instance, it is suggested that global/local attention bias is involved in USN. Previous studies have reported that some patients with USN had hyperattention to local details of a hierarchical scene and difficulty perceiving and switching to a global structure (Bultitude, Rafal, & List, 2009; Dorricchi & Incoccia, 1998; Marshall & Halligan, 1995). Bultitude et al. (2009) reported that patients with temporo-parietal junction (TPJ) lesions had such local bias. Marshall and Halligan (1995) reported that patients who experienced neglect following cerebral infarction in the frontal and parietal cortices could identify a global form of hierarchical figures, but crossed out only the local objects on the right side when asked to cross out all local elements (Marshall & Halligan, 1995). Dorricchi and Incoccia (1998) reported the opposite behavioural dissociation. They reported a patient with a large right hemisphere lesion that included the occipital, parietal and temporal lobes who crossed out all local targets but did not identify the left side of the global shape. Brain regions associated with such global/local attention deficits are common to regions considered critical for USN (Husain & Rorden, 2003). Robertson, Lamb, and Knight (1988) reported that patients with a left superior temporal gyrus (STG) lesion had difficulty switching attention from a global target to a local target, whereas patients with a right temporo-parietal lesion showed opposite results. A positron emission tomography study of healthy persons revealed that switching attention between global and local levels activated the left STG and right TPJ (Fink et al., 1996). In addition, Yamaguchi, Yamagata, and Kobayashi (2000) used event-related brain potentials to show an asymmetrical neural basis for switching attention between global and local levels. They reported that the right temporo-parietal area was activated by an attention shift from the local to the global level, and the left posterior temporal area was activated by an attention shift from the global to the local level (Yamaguchi et al., 2000). Therefore, a lesion in the right TPJ might cause engagement in local details of the target, and a lesion in the right STG might cause hyperattention to local details as a result of lack of interhemispheric inhibition to the “intact” left STG. Visual exploratory tests, such as cancellation tests, are often used to evaluate USN. However, paper-and-pencil visual exploratory tests often fail to


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demonstrate spatial deficits in patients with mild USN because of compensation or repetition effect, and some patients with USN show normal results in visual exploratory tests even though they show severe abnormalities in other types of tests, such as line bisection, copying, and drawing. In addition, it is difficult to discriminate different subtypes of neglect using the results of simple visual exploratory tests. With a computer and a touchscreen device, the latency of the response to each target and the position of the target can be precisely recorded. The spatial and temporal patterns of responses can also be analysed. Computerised versions of the cancellation test have been developed (Donnelly et al., 1999; Potter et al., 2000; Rabuffetti et al., 2002, 2012) to investigate this task in more detail. However, because USN is a heterogeneous syndrome, it is difficult to detect all types of neglect with only one type of cancellation test. Therefore, it might be better to combine several types of visual search task. A detailed profile of the spatial and temporal pattern of visual search in an individual patient might provide more information on both the lateralised and non-lateralised mechanisms driving the various types of neglect syndrome. Several types of task have been developed to dissociate viewer-centered and stimulus-centered neglect (Gainotti & Ciaraffa, 2013; Ota, Fujii, Suzuki, Fukatsu, & Yamadori, 2001; Savazzi, Mancini, Veronesi, & Posteraro, 2009). However, recent studies (Rorden et al., 2012; Yue et al., 2012) raised a question about dissociation between these subtypes, i.e., proposed that stimulus-centered neglect was associated with viewer-centered neglect both clinically and anatomically. On the other hand, Gainotti and Ciaraffa (2013) claimed that spatial location would influence the severity of stimulus-centered neglect only in complex tasks that required thorough exploration, and they suggested that viewer-centered and stimulus-centered neglect could be dissociated with a simple test such as copying a multi-object scene (Gainotti & Ciaraffa, 2013) and other specific clinical tests (Chechlacz et al., 2010; Ota et al., 2001). Previous studies demonstrated that some USN patients have difficulty initiating limb movements in the leftward direction, even if they can perceive stimuli to the left (Chiba, Yamaguchi, & Eto, 2005; Heilman, Bowers, Coslett, Whelan, & Watson, 1985; Mattingley, Husain, Rorden, Kennard, & Driver, 1998; Tegne´r & Levander, 1991). To evaluate both perceptual (visual) and intentional (motor) components of neglect, we designed visual and visuomotor search tasks and compared reaction time between the two tasks in each individual patient. In this study, we developed a programme to evaluate both perceptual (visual) and intentional (motor) components of neglect. The programme used a computer and a touch screen display, and included two types of cancellation test and a visuomotor and visual search test. We quantified the spatial and temporal pattern of visual search in the cancellation tasks and the reaction


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time in the visuomotor and visual search tests, and compared them among two patients with USN, a patient without USN, and healthy controls.

MATERIAL AND METHODS


Participants Three right-brain-damaged patients were tested. Two patients exhibited behaviours of left unilateral neglect in clinical assessment and the third patient had no USN (control patient). The clinical characteristics of the patients are described below. Sixteen right-handed, healthy subjects at least 40 years old (mean age 57.3 + 10.7 years, 11 males and 5 females) were recruited as control subjects.

Case description Patient 1 (P1) was a 69-year-old, right-handed man who sustained a right hemisphere stroke on 7 October 2008. Magnetic resonance imaging (MRI) revealed an extensive right anterior and middle cerebral artery infarct, which involved primarily right frontal and parietal cortices without evidence

Figure 1. (A) T1-weighted magnetic resonance images from the patient with viewer-centered neglect (P1). (B) T1-weighted magnetic resonance images from the patient with stimulus-centered neglect (P2).


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of any left hemisphere or subcortical involvement (Figure 1A). On admission to Ichikawa Rehabilitation Hospital (Ichikawa city, Japan) 6 weeks after the stroke, P1 had severe left hemiplegia and moderate left hemianaesthesia. Full ocular movements were possible in all directions. There was no evidence of hemianopia on clinical assessment. He exhibited symptoms of USN. His Mini-Mental State Examination (MMSE) score was 14/30. Patient 2 (P2) was a 56-year-old, right-handed woman who sustained a right hemisphere stroke on 30 March 2008. MRI revealed an extensive right putaminal haemorrhage, which involved the right temporal lobe and at the TPJ without evidence of any left hemisphere or subcortical involvement (Figure 1B). On admission to Ichikawa Rehabilitation Hospital 8 weeks after stroke, P2 had severe left hemiplegia and moderate left hemianaesthesia. Full ocular movements were possible in all directions. There was no evidence of hemianopia with clinical assessment. She exhibited symptoms of USN. Her MMSE score was 28/30. The control patient (CP) was a 73-year-old, right-handed man who sustained a right hemisphere stroke on 15 July 2008. Computed tomography revealed a right middle cerebral artery infarct, which primarily involved white matter of the frontal lobe without evidence of any left hemisphere or subcortical involvement. On admission to Tokyo Metropolitan Rehabilitation Hospital (Tokyo, Japan) 4 weeks after stroke, CP had moderate left hemiparesis and mild left hemianaesthesia. Full ocular movements were possible in all directions. There was no evidence of hemianopia with clinical assessment. He did not exhibit any symptoms of USN or other cognitive disorders.

Assessments Conventional Behavioural Inattention Test (BIT-C)

All patients completed the BIT-C, a battery that is commonly used to assess USN (Wilson, Cockburn, & Halligan, 1987). The BIT-C consists of conventional and behavioural tests, has six items, and cut-off scores have been determined for each item and for the total BIT-C score. Computerised cancellation tests

Participants were seated at a desk on which a 32-inch liquid crystal touchscreen display (TouchUbiCom; Assist co., Ltd., Tokyo, Japan) was placed 45 cm from their eyes (Figure 2). Four tests of visual exploration were performed using the touchscreen: The simple cancellation test, the circle test (Ota et al., 2001), a visuomotor search test and a visual search test. For all tests, participants were asked to touch the object on the display or to push a button on the desk with their right hand.



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Figure 2. The experimental setting. Participants were sitting in front of a 32-inch touchscreen display. The distance between the patient and the display was 45 cm. Participants touched targets on the display with the tip of their right index finger.

Simple cancellation test: For the simple cancellation test the participant touched the “start” button on the display and then 18 red stars appeared (Figure 3A). Participants were asked to cancel all the stars by touching them. When the participant touched the display at the location of a star, it disappeared. The test continued until all the stars had disappeared or the participant said that it was over. The timing and order of cancellation were recorded, along with the number of stars remaining on the whole display at the end of the test (omissions) and the time from the start to the end of the test (total cancellation time). Circle test: The circle test was performed as described by Ota et al. (2001). Participants were instructed to select complete circles from complete and incomplete (left- or right-chipped) circles on the display (Figure 3B). Black circles were selected by touching the display, and turned red when selected. The number of omitted complete circles (egocentric error) and selected chipped circles (allocentric error) were recorded to distinguish viewer-centered and stimulus-centered neglect. The timing and order of cancellation were recorded automatically with a computer programme (MATLAB 7.7: The MathWork Inc., Massachusetts, USA). Patients with viewer-centered neglect omit circles on the left side of the display and patients with left stimulus-centered neglect identify left-chipped circles as complete circles. To estimate the severity of viewer-centered neglect, we calculated the centre of cancellation (CoC) score (Rorden & Karnath, 2010) using a computer programme developed by Rorden and Karnath (www.mricro.com/cancel/). This score indicates the centre of neglected items (range from 21 to 1). If subjects identify all targets, the CoC score is 0. A score of 1 indicates severe left USN. The time from the start to the end of the test (total cancellation time) was also quantified.

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Figure 3. The tests. (A) The display for the simple cancellation test. Participants were instructed to touch red stars in any order. When they touched a star it disappeared from the display. The test was finished when the participant had touched all the stars or declared that they had finished. O indicates the midpoint of the screen. (B) The display for the circle test. The targets (complete circles) and the distracters (left- or right chipped circles) were distributed on the display. Participants were instructed to touch complete circles. The targets and distracters turned red when they were touched. O indicates the midpoint of the screen. (C) The sequence of events in the visuomotor and visual search tests. After the start button was pressed a red star appeared in a random position on the display. Participants were asked to touch the star (visuomotor test) or push a button in front of their right hand (visual test) as soon as possible after seeing the star. The target disappeared when it was touched or the button was pressed. The next target appeared 500 ms later. The results were analysed according to the column in which the star appeared (left, middle, or right). Dashed lines were not visible in the tests.



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Visuomotor search test: For the visuomotor search test, participants touched the “start” button on the display to start the test. They were instructed to touch a star that appeared in a random position on the display (Figure 3C). The star disappeared when it was touched, and the next star appeared 500 ms later. If a participant did not touch a target for more than 3 min, the test was discontinued. The display area was divided in three columns (left, middle, and right) and in a single trial, six stars appeared in each area. The position of each star and the reaction time of the subject to touch it were recorded with a computer programme (MATLAB 7.7: The MathWork Inc., Massachusetts, USA). Reaction time was defined as the time from when a star appeared to when it was touched. Visual search test: For the visual search test, participants touched the “start” button on the display to start the test. The test was identical to the visuomotor search test, except participants pushed a button in front of their right hand instead of touching the display when a star appeared.

Analysis Performance in the simple cancellation test and the circle test was quantified using the average cancellation time and the average cancellation distance. Average cancellation time was calculated for each participant by dividing the total cancellation time by the number of cancelled (touched) objects. Average cancellation distance was calculated as the average point-to-point distance of each cancellation. We hypothesised that a participant would tend to choose the object nearest to the last object that was cancelled if he/ she intended to perform the cancellation test efficiently. Therefore, average cancellation time and average cancellation distance indicate the efficacy of the visual exploratory strategy, with smaller average cancellation time and average cancellation distance indicating a more efficient strategy. These indexes may provide additional information for qualitative evaluation of cancellation tests. Performance in the visuomotor and visual search tests was quantified using reaction time. In control subjects, average reaction time was compared across the three columns using analysis of variance (ANOVA) and post hoc analysis with Bonferroni correction (p , .05). In each patient, reaction times were compared between left column and right column using the Revised Standardized Difference Test (RSDT; Crawford & Garthwaite, 2005) (p , .05). We expected reaction time for stars in the left column to be longer than reaction time for stars in the right column in patients with USN. To estimate the motor component of neglect, average reaction time in the visuomotor search test was compared to average reaction time in the visual search test. The spatial and temporal patterns of cancellation and visual search were quantified and compared among the three patients (P1, P2, and CP). To


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evaluate the qualitative aspect of the search strategy, we compared the temporal and spatial patterns of the cancellation tests among these three patients. The time and number of each cancellation were plotted on a graph to evaluate the temporal pattern of cancellation for simple cancellation. This graph indicates the time course of cancellation. If patients temporarily lose the next target and then continue the cancellation, a long interval is observed in the graph. The position and order of the cancelled objects was recorded. Then, the cancelled objects were connected in order of cancellation with straight lines on the display. The spatial pattern, i.e., trajectory, indicates the strategy and efficacy of visual search. We also compared reaction time for the visuomotor and visual search tests in the three patients. The brain lesions of P1 and P2 were evaluated using MRI. All data collection and analysis, except for the RSDT, software was written with MATLAB 7.7 (The MathWork Inc., Massachusetts, USA). The RSDT analysis was performed with the software developed by Crawford and colleagues (http://homepages.abdn.ac.uk/j.crawford/pages/dept/SingleCaseMet hodology.htm).

RESULTS BIT-C The results of the BIT-C are shown in Table 1. P1 and P2 showed omissions in the BIT-C cancellation tests and had scores under cutoff for all other items (copy, bisection, and draw). However, P1 showed more omissions than P2, whereas P1 showed more severe deviation in the bisection test. CP achieved a perfect score in all the tests in the BIT-C.

Simple cancellation test Ten control subjects (6 males and 4 females, mean age 57.8 + 9.6 years) performed the simple cancellation test. No control subject had any omissions. TABLE 1 BIT-C scores for the patients

Patient

Line cancellation a

P1 P2 CP

32 36 36 a

Letter cancellation

Star cancellation

a

15 29a 38

under cutoff. BIT-C: conventional test of BIT.

a

27 44a 53

Copy a

1 1a 4

Bisection a

5 0a 9

Draw a

0 2a 3

Total 80a 112a 146


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TABLE 2 The number of errors in the simple cancellation and circle test for the patients Circle test Egocentric error Patient

Simple cancellation

Left

Right

CoC

Left

Right

0 1 0

9 4 0

3 2 1

0.505 0.083 20.031

0 9 0

0 1 0

P1 P2 CP


Allocentric error

Egocentric error ¼ number of omitted complete circles. CoC ¼ Centre of cancellation. Allocentric error ¼ number of selected chipped circles.

The number of omissions made by patients with USN is shown in Table 2, and the average cancellation time and average cancellation distance of the three patients and the controls are shown in Figure 4 and Table 3. Both P1 and P2 had longer average cancellation time than controls. The average cancellation time of P2 was more than two standard deviations (SDs) above the mean of the controls. The average cancellation time of CP was within the normal range of that of controls (Figure 4A). The average cancellation distance of P2 was more than 2 SD above the mean of the controls, whereas the average cancellation distance of P1 was slightly smaller than that of the controls. The average cancellation distance of CP was within normal range of that of the controls (Figure 4B).

Circle test Sixteen control subjects (mean age 57.3 + 10.7 years, 11 males and 5 females) performed the circle test. No control subject had any egocentric or allocentric errors. The number of allocentric and egocentric errors made by patients with USN is shown in Table 2, and the average cancellation time and average cancellation distance of the three patients and the controls are shown in Figure 4 and Table 3. The CoC score was 0.505 for P1, 0.083 for P2, and 20.031 for CP. The average cancellation time of P1 and P2 was more than 2 SD above the mean of the controls. The average cancellation distance of CP was within normal range of that of the controls (Figure 4A). The average cancellation distance of P1 was more than 2 SD below the mean of the controls, whereas the average cancellation distance of P2 and CP was slightly smaller than that of the controls (Figure 4B).

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Figure 4. Average cancellation time (ACT) and average cancellation distance (ACD) for each patient (P1, P2, and CP) and normal controls in the cancellation tests. (A) ACT of the three patients and normal controls. Error bars indicate standard deviation of normal controls. (B) ACD of the three patients and normal controls. Error bars indicate standard deviation of normal controls.


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TABLE 3 The average cancellation time and distance in a patient without USN (CP), a patient with viewer-centered neglect (P1), a patient with stimulus-centered neglect (P2), and normal controls

Simple cancellation


Circle test

ACT ACD ACT ACD

Normal controls

Viewer-centered neglect (P1)

Stimuluscentered neglect (P2)

Without USN (CP)

Average

SD

1.0 10.8 3.9a 6.3a

1.4a 14.9a 3.8a 10.9

0.6 11.5 1.2 9.4

0.6 11.6 1.3 13.8

0.2 1.1 0.4 2.7

ACT ¼ average cancellation time (seconds), ACD ¼ average cancellation distance (cm), SD ¼ standard deviation. a a figure out of range of Average + 2 SD of normal controls.

Visuomotor and visual search tests Eleven control subjects (8 males and 3 females, mean age 57.4 + 12.1 years) performed the visuomotor search test, and six control subjects (4 males and 2 females, mean age 60.0 + 12.9 years) performed the visual search test. Average reaction time for each of three columns (left, middle, and right) in each patient and the controls is shown in Figure 5 and Table 4. In the controls, there was a significant difference in average reaction time across the three columns in the visuomotor search test, ANOVA F(2, 20) ¼ 9.32, p , .01 (Figure 5A), but not in visual search test (Figure 5B). Post hoc analysis with Bonferroni correction demonstrated that the average reaction time was smaller in the middle column than in the left column and in the right column (left vs. middle: p , .01; right vs. middle: p , .05); however, the difference was small in magnitude (left: 1.3 s, middle: 1.2 s, right: 1.3 s). The average reaction time of P1 was more than 2 SD above the mean of the control in all three columns in the visuomotor search test and in the left column in the visual search test. There was no significant difference in reaction times between the left column and the right column in both the visuomotor search test and the visual search test (RSDT, p . .05; Figure 5). The average reaction time of P2 was more than 2 SD above the mean of the control in all three columns in the visuomotor search test and in the left and middle columns in the visual search test. Reaction time in the left column was significantly longer than that in the right column in both the visuomotor search test and the visual search test (RSDT, p , .01; Figure 5). The average reaction time of CP was within the normal range in both the visuomotor search test and the visual search test. There was no

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Figure 5. Reaction time in the visual and visuomotor search tests for each patient (P1, P2, and CP) and normal controls. The graphs indicate average reaction time for stars in each column (left, middle, and right) in each patient and normal controls in the visuomotor search test (A) and the visual search test (B). Error bars indicate standard deviation. ∗ and ∗∗ indicates significant difference (∗ p , .05, ∗∗ p , .01). Post hoc analysis with Bonferroni correction followed analysis of variance (ANOVA) in controls and the Revised Standardized Difference Test (RSDT) in each patient.


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TABLE 4 Reaction times (in seconds) in visuomotor and visual search tasks in a patient without USN (CP), a patient with viewer-centered neglect (P1), a patient with stimulus-centered neglect (P2), and normal controls


Normal controls

Visuomotor search column Left Middle Right Visual search column Left Middle Right a

Viewer-centered neglect (P1)

Stimulus-centered neglect (P2)

Without USN (CP)

Average

SD

2.1a 1.7a 2.2a

14.0a 1.7a 2.5a

1.6 1.3 1.4

1.3 1.2 1.3

0.2 0.2 0.2

1.5a 1.3 1.4

11.0a 1.8a 0.6

0.6 0.4 0.5

0.6 0.6 0.7

0.4 0.4 0.4

SD ¼ standard deviation. out of range of Average + 2 SD of normal controls.

significant difference in reaction times between in the left column and in the right column in CP in either the visuomotor or the visual cancellation test (RSDT, p . .05; Figure 5).

Comparison among the three patients in temporal and spatial patterns of cancellation and visual search tests Figure 6 shows the temporal patterns of cancellation in the simple cancellation test for the three patients. Both P1 and P2 paused for a few seconds between the 11th and 12th cancellation in the simple cancellation test (Figure 6). However, their trajectories were quite different (Figure 7). P1 cancelled the stars from top right to bottom left in sequential order, like reading the display of a vertical text. The 11th star was located in the centre of the display, and the patient paused before searching on the left side of the display. By contrast, the trajectory of P2 was non-sequential and crossed previous search paths many times during the test. When P2 reached the 11th star, which was located at the left edge of the display, she paused for a few seconds before moving to the 12th star on the right side of the display. The temporal pattern of CP indicated that he paused for a few seconds between the 17th and 18th cancellation (Figure 6). The trajectory indicates that he temporarily lost the last star, which was located on the top left of the display, but finally found it (Figure 7). Figure 8 shows the trajectory of cancellation in the circle test for each of the three patients. P1 revisited four complete circles placed at the right edge of


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Figure 6. The number and time of cancellations in the simple cancellation test for each patient. Both P1 and P2 paused a few seconds between the 11th and 12th cancellation. CP paused for a few seconds between 17th and 18th (final) cancellation.

the display and omitted almost all targets on the left side of the display (Figure 8; Husain et al., 2001). P2 did not show such revisits. However, the trajectory of P2 crossed previous search paths many times during cancellation (Figure 8). The trajectory of CP showed no revisits or crossing (Figure 8).

DISCUSSION In this study, we developed a computer-based system to assess USN using a touchscreen display. With this system we analysed the spatial and temporal patterns of visual exploration in three right-brain-damaged patients. Our data provide information about a visual search strategy that is not revealed by paper-and-pencil tests. We compared performance on our computer-



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Figure 7. The trajectory of cancellation in the simple cancellation test for each patient. The numbers indicate the order of cancellation. O indicates the midpoint of the screen.

based tests between two patients with different types of neglect and found that the spatial and temporal patterns of visual exploration differed between them, suggesting that they might differ across subtypes of neglect. Furthermore, the differences may correspond to the location of the brain lesion. The profiles of the BIT-C suggested that P1 and P2 had different subtypes of USN. P1 showed a number of omission errors on the left side of the paper in the cancellation tests, but showed milder deviation in the line located on the left side than that located on the right side of the paper (Table 1). In addition, P1 showed many egocentric errors and no allocentric errors in the circle test (Table 2; Ota et al., 2001). These results indicate that P1 had viewer-centered neglect. On the other hand, P2 showed fewer omissions than P1, and severe deviation regardless of line locations (Table 1). In the circle test, P2 showed many allocentric errors (Table 2). This indicates that P2 had stimulus-centered neglect. There was no evidence that CP had USN from the results of the BIT-C, because he achieved a perfect score in all the tests


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Figure 8. The trajectory of cancellation in the circle test for each patient. The numbers indicate the order of cancellation. O indicates the midpoint of the screen.

(Table 1). Although the proper criteria for the CoC index in the circle test have not been determined, Rorden and Karnath (2010) reported that CoC score greater than 0.081 on the Bells Test or greater than 0.083 on the Letter Cancellation Task were related to neglect behaviour. Therefore, the score of P1 (0.505) is considered moderate to severe viewer-centered neglect, and that of P2 (0.083) is considered borderline. With the computerised system, we were able easily and precisely to record the time and position of cancellations and target identifications in the cancellation and visual search tests. These data can provide information about dynamic processes such as average cancellation time, average cancellation distance, reaction time, and trajectory as well static outcomes such as omission errors (Donnelly et al., 1999; Potter et al., 2000; Rabuffetti et al., 2002, 2012). USN is a heterogeneous disorder (Arene & Hillis, 2007), and the diversity makes it difficult to find one common measure that represents all its subtypes. Donnelly et al. (1999) reported that only 14 out of 28 USN



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patients were identified by omission errors on their computerised cancellation test, but additional information about the time and trajectory increased the sensitivity to 25 out of 28. Recent studies suggest that computerised tests could detect spatial disorder in patients who are not clinically diagnosed with USN using paper-and-pencil tests (Bonato, Priftis, Marenzi, Umilta`, & Zorzi, 2010; Bonato, Priftis, Umilta`, & Zorzi, 2013; Rabuffetti et al., 2012). However, previous studies did not consider the relation between dynamic processes and neglect subtypes. In this study, we compared the temporal and spatial dynamics of cancellation and searching between a patient with viewer-centered neglect and a patient with stimulus-centered neglect, and our results suggested that these patients used a different strategy during visual exploration. These findings support the hypothesis that the underlying mechanisms of neglect differ according to the subtype. In addition, mild attention deficits were diagnosed by our computerised tests in the patient without USN (CP). These results suggest that our computerised tests may be more sensitive than the BIT-C. Hemispatial neglect can be categorised according to the reference frame (Hillis et al., 2005; Marsh & Hillis, 2008; Ota et al., 2001). Stimulus-centered neglect has been related to temporal lobe (including middle temporal gyrus and/or STG) lesions (Hillis et al., 2005, Verdon et al., 2010; Yue et al., 2012) and viewer-centered neglect has been related to parietal lobe (especially angular gyrus; Hillis et al., 2005) and inferior and middle frontal lobe lesions (Verdon et al., 2010). Some studies of healthy human subjects have revealed egocentric (viewer-centered) coordination activated bilaterally, mainly through the right fronto-parietal network (Galati et al., 2000; Vallar et al., 1999). Vallar et al. (1999) reported that the network between the posterior parietal lobe and the lateral premotor cortex was related to an egocentric reference frame. In this study, we identified a viewer-centered neglect patient (P1) and a stimulus-centered neglect patient (P2) from the results of the BIT-C and the circle test. In the circle test, P1 missed circles in the left half of the display, whereas P2 selected many left-chipped circles. To investigate the underlying mechanisms of these different responses, we compared the spatial and temporal patterns of simple cancellation and the reaction time of the search tests of these two patients (P1 and P2), a patient without apparent USN (CP), and normal controls. In the simple cancellation test and circle test, both P1 and P2 showed a longer average cancellation time than normal controls and CP (Table 3, Figure 4A). It is suggested that patients with USN take longer to make a cancellation than normal. In the three patients, average cancellation distance was different in the simple cancellation test and in the circle test. In the simple cancellation test, P2 showed a longer average cancellation distance than P1, CP and normal controls (Table 3, Figure 4B). It is suggested that the


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search strategy of P2 was less efficient than that of the other patients and normal controls, at least in the simple cancellation test. On the other hand, P1 showed a smaller average cancellation distance than P2, CP and normal controls in the circle test. One possible explanation for this result is that P1 searched for targets within a close range of the previous target because he found it difficult to disengage attention from the previous focus (Bartolomeo & Chokron, 1999; D’Erme, Robertson, Bartolomeo, Daniele, & Gainotti, 1992). P1 showed a rightward bias in the circle test but not in the simple cancellation test. This may be because the circle test required the participant to direct attention to local objects in order to identify true circles, whereas the other tests did not require any judgement of local objects. This local attention bias might have disturbed the global attention paid to the whole display. In addition, circles turned red and remained on the display after being selected, but in the other tests, the star disappeared when touched. Therefore, selected (red) circles might have engaged attention in the right side of the display (Bartolomeo & Chokron, 1999; D’Erme et al., 1992). P1 cancelled stars in sequential order in the simple cancellation test and appeared to recognise stars in the left side of the display even though his attention might have been biased to the right. It has been suggested that patients with viewer-centered neglect can see the forest but cut only half the trees, like the patient reported by Marshall and Halligan (1995). P2 showed a different temporal pattern and trajectory of cancellation. In the simple cancellation and circle tests, P2 cancelled objects in the left side of the display, although some were omitted, and the trajectory of cancellation was not sequential. In the circle test, P2 selected nine left-chipped circles and one right-chipped circle. These observations indicate the presence of both rightward attention bias and narrowing of attention towards local visual details. The patient reported by Dorricchi and Incoccia (1998) showed similar behaviours. She selected both “3”s and “B”s when asked to select only “3”s from an array of “3”s and “B”s, indicating that she searched for a critical detail in small items, such as “two little humps”. This is indicative of object-centered neglect. The cancellation trajectories of P2 are consistent with a narrowing of attention frame. The objects might have been cancelled in non-sequential order because the patient could not recognise their global distribution. In addition, P2 jumped from the top left of the display (object No. 11) to the right side of the display (object No. 12) after an interval of a few seconds, even though an object (No. 17) was near object No. 11. A wider attention frame may have enabled the patient to notice the nearest object. Spatial working memory might also be an important factor in USN (Behrmann, Watt, Black, & Barton, 1997; Husain et al., 2001; Husain & Rorden, 2003). When patients with left USN performed a cancellation task, some



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repeatedly reselected right-side targets they had already selected (Behrmann et al., 1997). Husain et al. developed a task to probe memory for previously inspected spatial locations during visual search (Husain et al., 2001). Patients were asked to find targets (Ts) among distracters (Ls) and to push the button only when they found a new target. During this task, many patients with USN mistook targets they had previously identified for new targets, indicating that they did not remember the targets previously identified (Husain et al., 2001; Husain & Rorden, 2003). Previous studies have reported that deficits of spatial working memory are related to lesions in the posterior parietal cortex and frontal lobe (Heide, Blankenburg, Zimmermann, & Ko¨mpf, 1995; Husain & Rorden, 2003). Functional imaging studies in healthy persons have also revealed that the posterior and/or inferior parietal cortex is activated when visual space is updated (Medendorp, Goltz, Vilis, & Crawford, 2003; Merriam, Genovese, & Colby, 2003). In our study, P1 revisited previously selected circles during the circle test, but P2 did not. These results suggest that deficits of spatial working memory affected the symptoms of viewer-centered neglect. Patients with viewer-centered neglect might engage with targets on the right side, and revisits to these targets might interfere with moving attention to the left side. The results of visual and visuomotor search tests were opposite to what we would have predicted from the results of circle test; i.e., the patient with viewer-centered neglect (P1) showed no laterality in reaction time on the visual and visuomotor search tests, whereas the patient with object-centered neglect (P2) showed a strong rightward bias (Figure 5). P1 had a longer reaction time than normal controls regardless of the egocentric position of targets, but reaction time was not significantly different between the left column and the right column, indicating that patients with viewer-centered neglect may not show rightward attention bias. Previous studies have suggested that USN patients are impaired at disengaging attention from the right side to orient it leftward (Bartolomeo & Chokron, 1999; Bartolomeo, Sie´roff, Decaix, & Chokron, 2001; D’Erme et al., 1992; Smania et al., 1998). However, Rastelli, Funes, Lupia´n˜ez, Duret, and Bartolomeo (2008) reported that disengagement deficit disappeared if cues disappeared before targets appeared. In this study, the target disappeared before the next target appeared. Therefore, patients might not have been affected by disengagement of attention. However, the results of P2 suggest that stimulus-centered neglect is affected by egocentric position (Karnath, Mandler, & Clavagnier, 2011). The patient with viewer-centered neglect (P1) had a lesion in the parietal and frontal lobes, including the TPJ, posterior parietal cortex and premotor area, and the patient with stimulus-centered neglect (P2) had a lesion in the STG and TPJ. These findings are consistent with previous studies in USN patients (Hillis et al., 2005; Mizuno et al., 2013; Verdon et al., 2010; Yue et al., 2012) and healthy human subjects (Galati et al., 2000; Vallar et al., 1999).


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With regard to non-lateralised deficits, P1 had difficulty switching attention from local details to global structures and exhibited deficits of visual working memory, whereas P2 had hyperattention to local details and narrowing of attention frame. Local processing bias might be caused by the TPJ lesion (present in both patients) and STG lesion (present in P2; Fink et al., 1996; Robertson et al., 1988; Yamaguchi et al., 2000). The lesion location in P1 was compatible with deficits of spatial working memory (Heide et al., 1995; Husain & Rorden, 2003; Medendorp et al., 2003; Merriam et al., 2003). Regions related to narrowing of attention frame are unclear. There is a report of a patient with narrowing of attention frame and a large lesion that spanned temporal, parietal and occipital lobes (Dorricchi & Incoccia, 1998) and a report of a patient who could recognise global structure and had a lesion in the frontal and parietal lobes (Marshall & Halligan, 1995). In this study, P2, who had narrowing of attention frame, had a lesion in the STG and TPJ, and P1 had a lesion in the frontal and parietal lobes (including the TPJ). Comparison of these cases suggests that damage to both the STG and the TPJ induces stronger local processing bias than damage to only the TPJ, and that strong local processing bias might cause narrowing of the attention frame. A few limitations of this study warrant consideration. First, because we tested only two USN patients, the difference we found may be explained not only as differences between subtypes of neglect, but also as inter-individual differences. Therefore, it is too early to conclude that our computerised test can precisely distinguish neglect subtypes. Secondly, P1 had a low score on the MMSE (14/30). Although she could understand and execute our test without any difficulty, a general cognitive impairment might have affected the result. Thirdly, although we developed visuomotor and visual search tests to distinguish motor components of neglect, there were no differences between the two tests in the patients that we tested in this study. Fourthly, we recruited healthy subjects at least 40 years old as controls. However, the mean age of the controls was slightly younger than that of the patients and sample size was small. Future studies with larger sample sizes are needed to demonstrate the validity of our test.

CONCLUSION In this study, we developed a computer-based programme to evaluate USN and compared temporal and spatial dynamics between a viewer-centered and a stimulus-centered neglect patient. The computer-based system provided information about the temporal and spatial dynamics of visual search strategy in patients with USN. Despite some limitations, our findings suggest that the combination of spatially lateralised and non-lateralised symptoms affected


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not only severity but also subtype of neglect syndrome. Furthermore, these neglect subtypes and combined non-lateralised deficits might be related to particular brain lesions. Further studies are necessary to elucidate the relation between neglect subtype and non-lateralised deficit.


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