Rightward exogenous attentional shifts impair perceptual memory of spatial locations in neglect patients
A. Saj1,2, J. Pierce3, A. Caroli3, Roberta Ronchi3, Marine Thomasson1, P. Vuilleumier1,3
1Neurology Department, University Hospital of Geneva, Geneva
2Department of Psychology, University of Montréal, Québec, Canada
3Neuroscience Department, Laboratory for Behavioral Neurology and Imaging of Cognition, University of Geneva, Geneva
Address for Correspondence: Dr. Arnaud Saj
Neuropsychology Unit, Department of Neurology, University Hospital of Geneva, rue Gabrielle-Perret-Gentil 4, CH-1211 GENEVA, Switzerland.
Email: arnaud.saj@unige.ch 1
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Abstract
Spatial remapping implies the updating and maintaining of the spatial position of objects in successive visual images across time, despite their displacement on the retina due to eye movements. In the parietal cortex, the representation of spatial locations appears to be partly centered on gaze direction, and thus modulated by current eye-gaze position. It has been suggested that short-term memory for spatial locations across delays might be impaired in right brain-injured patients with left spatial neglect, but more so after rightward than leftward gaze shifts – an asymmetry attributed to a loss of spatial representations normally transferred from left to right hemisphere during remapping. Because several studies point to a strong link between attentional and oculomotor circuits in the brain, we hypothesized that similar remapping effects might result from attentional displacements without overt eye movements.
We tested this hypothesis in right-brain damaged patients with and without left neglect in a visuo-spatial memory task. As predicted, neglect patients showed a selective deficit in location memory following an exogenous attentional shift caused by a brief flash in the periphery of their right (but not left) visual field. We conclude that an attentional displacement without eye movements is sufficient to remap spatial representations across hemifields, and that this process is impaired in neglect patients when a location has to be transferred to the neglected/left side relative to current gaze or attention focus. More generally, these results support the notion of neural overlap between oculomotor and attentional mechanisms, and confirm a role for impaired remapping in the neglect syndrome, wherein spatial representations of contralesional locations may fail to be maintained during active attentional behavior.
Keywords: Remapping; Spatial Neglect; Stroke; Attention 21
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1. Introduction
Neglect is a complex neuropsychological disorder, most often associated with right hemisphere damage, and characterized by an inability to perceive, orient, and respond to stimuli in the contralesional (left) side of space (Heilman & Valenstein, 1979; Rafal, 1994).
Besides directional deficits in the orienting of attention, other cognitive deficits may contribute to the heterogeneous collection of spatial neglect manifestations (Rafal & Posner, 1987; Rode et al., 2017). It is thought that these additional (perhaps non-lateralized) deficits could interact with the rightward directional biases in attention to determine the abnormal deployment of attention in space, and thus exacerbate left neglect symptoms.
Among the distinct components underlying neglect behavior, deficits in spatial working memory and remapping might constitute important factors, by preventing the brain from keeping track of spatial locations across eye movements. These deficits could contribute to spatial asymmetries in exploration toward the ipsilesional side of space, in combination with the classic impairment in exogenous attention thought to be at the core of neglect symptoms (Bartolomeo et al., 2012). Husain et al. (2001) were the first to provide evidence for impaired spatial working memory in neglect: in visual search tasks, patients often re-fixate targets that have already been detected, showing a defect in remembering these previous locations after only a few saccades. The neural substrates of spatial working memory deficits in patients (De Nigris et al., 2013) are generally attributed to widespread lesions in right fronto-parietal networks, partly overlapping with attentional systems (Toba et al., 2018;
Vuilleumier, 2013 for review). In addition, neglect patients are also impaired at remembering two locations presented vertically, although they show normal performance for letters or other visual stimuli (Malhotra et al., 2009). This phenomenon can have an impact on the rehabilitation of spatial neglect (Stiemer et al., 2013) and should be noted that such a deficit in spatial memory may be observed without full neglect and occur in other neuropsychological 46
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spatial syndromes, like constructional apraxia (Russell et al., 2010). Moreover, other non- spatial deficits (like vigilance or sustained attention) might interact with spatial working memory deficits and attentional biases to further exacerbate contralesional neglect.
An inability to update the spatial coordinates of visual locations during exploration of visual scenes (and/or attentional shifts), i.e. impaired remapping, is also considered to share with spatial neglect some common neural substrates within the posterior parietal cortex (PPC). Accordingly, Pisella and Mattingley (2004) put forward the idea that remapping deficits after parietal damage might play a key role in explaining unawareness for left space in neglect patients. Based on results from the double-step saccade task (DSST), these authors proposed a theoretical model attempting to account for revisiting behavior during search and other clinical neglect phenomena that remain poorly understood. In the DSST, two sequentially flashed visual targets (e.g. A on the left, and B on the right) have to be sequentially fixated by the subject, after starting from a central fixation point (FP), such that the subject makes two consecutive saccades: from FP to A, and then from A to B. Critically, while the first saccade is initiated, both targets disappear. This means that the subject has to integrate oculomotor information (the first-saccade vector) with the original spatial- retinotopic information about target B and calculate its new position relative to the new eye position. Remapping mechanisms are therefore required to correctly perform the second saccade toward the location of target B. Spatial neglect patients with damage to the right PPC may fail to execute a second rightward saccade toward target B when target A is flashed on the left (contralesional, neglected) hemifield. To account for this phenomenon, Pisella and Mattingley (2004) proposed that the position of a right target might be overwritten when another target in the neglected field is fixated. In other words, a saccade toward target B in the ipsilesional (right) hemifield is impaired by a failure of the remapping mechanism for this location (due to right parietal damage) when patients make a first saccade to target A in the 71
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contralesional (left) hemifield. Pisella and Mattingley (2004) hypothesized that, on the contrary, there should be no impairment when target A is on the right (ipsilesional) hemifield and a leftward saccade toward target B follows. In this case, a saccade toward the contralesional (neglected) hemifield can be correctly performed thanks to the intact remapping mechanism operating in the left PPC. Importantly, this model underscores the crucial role of a dynamic transfer of visual locations for spatial remapping across the two hemispheres, integrating information from both hemifields. However, the model of Pisella and Mattingley (2004) was mainly derived from theoretical assumptions concerning the neurophysiology of remapping and the neuropsychology of spatial neglect. More direct empirical evidence is still needed.
A related hypothesis was tested experimentally by Vuilleumier et al. (2007). The authors designed a new experimental paradigm to examine the role of spatial remapping on gaze-centric representations in spatial neglect. Rather than strictly focusing on oculomotor behavior (i.e. saccade accuracy), this study tested explicit spatial memory. It was hypothesized that right-injured neglect patients would show a deficit in maintaining spatial locations across saccades. This hypothesis was based on previous work by Umeno and Goldberg (2001) in the monkey, who showed that neurons in the frontal eye field (Umeno and Goldberg,2001)) could maintain activation evoked by a remembered visual target even after the stimulus had disappeared, if the location of that stimulus remained task-relevant. Notably, dynamic remapping was found to operate on this memory-related activation: when a saccade brings that location into the receptive field of another neuron, the latter will activate in response to the memory trace of that relevant location, even if it has never been directly stimulated. Using fMRI, Medendorp et al. (2003) reported a similar modulation in humans’
parietal and prefrontal cortex during saccades. Based on these findings, Vuilleumier et al.
proposed that for a location initially encoded at fixation, a rightward gaze-shift should remap 96
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this location leftward in gaze-centric terms, and so presumably into neuronal subpopulations of the contralateral right hemisphere. As anticipated, the latter remapping was found to be deficient in right-injured patients. Note, however, that the direction of these effects is opposite to the prediction of Pisella and Mattingley (2004), and contrasts with findings in the DSST, where deficits have been attributed to the loss of motor efference copy signals predicting the saccade’s direction. However, efference copy signals might not play a role in explicit spatial memory performance with longer delays, as tested in both the current and previous studies Vuilleumier et al., (2007), since different neural circuits are presumably recruited in this case (unlike those implicated in faster and automatic oculomotor reactions).
Asymmetries between the two hemispheres during spatial remapping has also been suggested by transient disruption of parietal cortex activity with transcranial magnetic stimulation (TMS). In particular, elegant work by Rafal and colleagues (van Koningsbruggen et al., 2010) showed that single-pulse TMS over the right anterior intraparietal cortex, but not the left, could eliminate the updating of the location of inhibition of return during an exogenous orienting paradigm (Rafal & Posner, 1987; Bartolomeo et al., 2012). The authors concluded that neuronal populations within the right anterior intraparietal cortex may constitute a neural substrate for maintaining a salience map across saccades, and not simply for propagating an efference copy of saccade commands (van Koningsbruggen et al., 2010).
Several issues, therefore, remain unresolved concerning the exact manifestation of spatial remapping impairments after right brain lesion, their link to particular areas in parietal cortex (vs. other brain regions), and their contribution to neglect symptoms in patients.
Remapping deficits might constitute a specific neglect component with relevance to those visual-spatial tasks that are most sensitive to parietal damage (i.e. those that require holding a stable spatial location in memory during saccades). This could explain why deficits in line 121
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lesions, compared to other (frontal or subcortical) lesions, as suggested by clinical neuropsychological studies (Verdon et al., 2010; Umarova et al, 2011; Saj et al., 2012;
Baumann & Mattingley, 2014), and why parietal but not frontal patients fail to return rapidly to a previously fixated location after intervening eye movements.
The aim of the current study was to investigate whether overt eye movements are necessary to observe spatial remapping deficits in neglect patients, or if an attentional shift alone (without eye movement) could induce the same phenomenon. In overt attention, an eye movement accompanies the attentional shift to foveate the focus of attention; gaze direction and attention direction correspond. In covert attention, an eye movement does not accompany the attentional shift. Ocular fixation is maintained while a displacement of the focus of attention takes place; gaze direction and attention direction do not correspond. There is abundant evidence for anatomical overlap of brain areas subserving eye movements and attentional processes in fronto-parietal cortices (Rizzolatti et al., 1987; Corbetta and Shulman, 2002; Steinmetz and Moore, 2012), suggesting that visual locations encoded for the control of overt saccades and covert attentional orienting might engage at least some common neuronal populations. We therefore hypothesized that visual cues triggering an attentional shift toward the (right or left) periphery of the visual field would recruit spatial remapping process in order to update and maintain the representation of a task-relevant location in explicit short-term memory, and that such spatial remapping processes would be impaired in right-injured patients with left neglect. In addition, we examined whether such deficits would be observed after leftward shifts in attention (in line with the model derived from the DSST by Pisella and Mattingley (2004) or after rightward shifts (in line with results of Vuilleumier et al., 2007) in a similar short-term spatial memory task).
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2. Methods 2.1. Participants
We recruited prospective patients from the stroke unit at Geneva University Hospital. Six patients (mean age=53; SD=11.4) with right-hemisphere lesions who presented left spatial neglect symptoms were included based on clinical criteria and their ability to maintain fixation in our task (additional patients with poor eye movement controls were also tested and showed similar behavioral findings but were not retained for final analyses). Neglect patients were compared to two control groups. The first was composed of six patients (mean age=60;
SD=11.7) with right-hemisphere lesions without spatial neglect symptoms, and the other was composed of six healthy elderly subjects (mean age=59; SD=5.7). No significant differences were observed between ages in the three groups (F(1, 18)=56.3 , p = .72). All subjects were right-handed. A further group of 4 neglect patients (mean age = 51.5; SD = 6.3) was also included in a different short-term memory task (with additional colors) that served as an auxiliary control experiment.
All patients had a focal right-hemisphere stroke, ischemic or hemorrhagic, demonstrated by MRI or CT scan (Figure 1). The presence and severity of spatial neglect was assessed using a standard clinical battery (Table 1) composed of the Bells test (Gauthier, Dehaut, & Joanette, 1989), Scene copy (Gainotti, Messerli, & Tissot, 1972), and Line bisection (Schenkenberg, Bradford, & Ajax, 1980). Patients with abnormal clinical score in at least two out of three tests were included in the neglect group. All patients were also examined with the Mini-Mental State Examination (Folstein, Folstein, & McHugh, 1975), a standardized clinical test used to exclude other major cognitive disorders and dementia (Table 1). All participants gave written informed consent according to the local Ethics Committee regulation of the University Hospital of Geneva.
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2.2. Material and procedure
Our main experimental task (location memory) aimed at inducing a transient orienting of covert attention toward the visual periphery, and then testing for any interference on a concurrent visual memory task as a function of the direction of attention shifts. Based on previous observations by Vuilleumier et al. (2007) for overt eye movements, the task was expected to show a modulation of neglect patients’ performance depending on covert attentional capture and laterality of the distractor. The task (see Figure 2) was programmed with the software E-Prime 1.
Subjects were placed at 50 cm from the computer screen (Asus VG 249HE 800*600 pixels, 24 inch, 16/9), on which a central fixation-cross appeared. Subjects were told to keep their eyes fixated on the cross at screen centre during all trials. After 500 ms, a first dot (red or green) could appear either on the left or the right side of the screen. All dots appeared on the middle of the vertical height of the screen, randomly jittered horizontally around the middle of the left (25%) or the right (75%) half of the screen, and remained visible for 1000 ms.
During a subsequent interval (1750 ms), before a second dot (target) appeared, either a blank screen was presented or a salient stimulus (flash) appeared in the left or right periphery of the screen. Subjects were told not to pay attention to the flash and to always keep their eyes on the fixation cross in the middle of the screen. The flash was expected to induce a transient displacement of covert exogenous attention (e.g. like in a standard Posner paradigm, see Sapir et al., 2004). After this interval, the target-dot (red or green) could appear randomly in one of three possible horizontal locations: the same as the first dot, slightly (10%) to its left, or slightly (10%) to its right. This means that the target-dot was always shown on the same side of the screen (left or right) as the first dot. There were in total six possible eccentricities where 193
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the target-dot could appear: 15%, 25%, or 35% from the left-most periphery when the first dot appeared on the left side; 65%, 75%, or 85% from the left periphery when the first dot appeared on the right. There was no variability of position along the vertical axis (dots always appearing in the middle of the screen’s height). The location and the color of the two dots could be either the same or different.
At the end of each trial, the questions ‘Color?’ and ‘Position?’ appeared on the screen.
Subjects had to press two different buttons to indicate whether the color or the position of the two dots, respectively, were the same or different. Once subjects had pressed the button, the next trial began. Healthy subjects pressed the buttons themselves, while patients indicated the answer verbally to the experimenter, who pressed the buttons for them, in order to simplify their task. The experimenter had no direct vision of the stimulus screen.
In conditions where the flash appeared in the memory retention interval, it was presented after a blank display (750 ms) for a duration of 250 ms, followed by another blank display (750 ms). The target-dot stayed on the screen for 1000 ms. The first question appeared and stayed on until the subject pressed the response button, after what the second question appeared. Once the subject pressed the response button for the second question, the next trial began. There were 72 trials, for a total duration of about 15 minutes.
An auxiliary control experiment was also run in a separate group of neglect patients (n=4) to verify that asymmetric memory performance was not due simply to memory task difficulty. In this experiment, patients were asked to memorize the target dot color but now the latter had more than only two possible options. Specifically, the dot color could be red, green, greenish blue, fuchsia pink, purple, and orangey red, preventing easy verbalization.
Other aspects of the task were identical, i.e., the dot was first presented to either the left or right hemifield, then briefly interrupted while a peripheral flash was presented on one or the 217
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other side, and finally reappeared with either the same or one of the six other colors, at either the same or slightly shifted location. Patients had to report whether the position and the color of the dot were identical or changed.
2.3. Eye-tracking
During the main experimental task, eye movements were measured with an eye-tracker (iView X Hi-Speed 2.4, Sensomotoric Instruments, sampling rate 100Hz) in all participants.
Head was kept fixed on a chin rest. Eye position was monitored continuously during task performance and data were recorded for subsequent offline analysis using custom Matlab scripts to ensure general adherence to the given instructions. All participants included in the final analysis were only those found to be able to maintain fixation reasonably well during online monitoring. However, in subsequent analysis, trials were also individually scored to compute the number of saccades across conditions (when a change in eye position exceeded 6° during a whole trial length), and to exclude such trials from the task analysis. To compute eye position during a trial, we determined a central square on the screen, and considered that central fixation was maintained if the average point of gaze did not fall outside of that square during the whole trial duration (from fixation onset until response). The square was centered on the fixation point coordinates with limits at a distance of 12.5% of the screen size along both the X and Y axes. Thus, as the laptop screen was setup at 800x600 pixels, the central rectangle was delimited from 325 to 475 pixels along the X axis, and from 225 to 375 on the Y axis. The center of the screen was at 400 pixels on the X axis and 300 on the Y axis. Trials were gaze was directed outside this central square for >250ms were then excluded from final analysis of task performance.
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2.4. Data analysis
Performance in the main task (location memory) was assessed by response accuracy only (not reaction times). We distinguished data into two categories: color responses and position responses. The color-discrimination question was used to make sure that subjects correctly perceived the two dots, and it was expected to be similarly easy for all subjects. In fact, Pisella, Berberovic, and Mattingley (2004) showed, using a change-detection task, that spatial neglect patients are specifically impaired in location memory, but not in color or shape memory. The position-discrimination task allowed measuring the effect of the transitory displacement of exogenous attention on spatial memory performance. The dependent variable was the number of correct responses (proportion) in both the color and the position tasks.
There were three independent factors: Group (neglect patients, non-neglect patients, control subjects), Flash position (interval without flash, flash in the left periphery, flash in the right periphery), and Visual field of the to-be-remembered dot (left half of the screen, right half of the screen). Two more factors were controlled by balanced trials, but not relevant to our analyses: the dots’ color (either red or green, and either the same or different between the two successive dots), and the second dot’s position (either the same, or 10% shifted to the right or to the left of the first dot). Our assumptions were that neglect patients’ performance in the spatial position task would be significantly impaired when the flash was presented on the right periphery (see Vuilleumier et al., 2007), as compared to non-neglect patients and control subjects, and that such impairment would arise independently of the visual field (left or right) where dots were presented. In addition, flashes in left periphery might or might not differentially affect spatial memory performance in both groups of patients.
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A repeated-measure ANOVA (2x3x3x2) on correct answer proportion was performed using the software Statistica (version 11.0.170.0). Analysis was performed using the four factors of Task (color or position response), Group (neglect, non-neglect, and controls), Flash condition (none, right, or left side), and Visual field of the target dot (right or left).
These differences were confirmed by direct pairwise comparisons between experimental conditions using the R software with RStudio Desktop (https://cran.r- project.org/; https://www.rstudio.com). We used the False Discovery Rate (FDR) controlling procedure of Benjamini and Hochberg (1995). This method allows for more robustness in the results and avoids overinterpretation of null results, particulary for the patients in the case of missing data and difference in variances. A dependent variable made a significant contribution to predicting the outcome variable when exceeding the 95% confidence interval.
3. Results
3.1. Eye-Tracker
Eye tracking data were recorded and compared across the different task conditions to ensure that subjects did not make inappropriate saccades that could influence remapping processes.
We computed the mean eye position (averaged x and y coordinates over trial duration) and number of saccades (displacement >6° regardless of direction) for each trial of each condition in all participants. Fixation center was located at screen coordinates (X=400; Y=300). Across all trials, the mean gaze coordinates was (339+57; 245+19) for neglect patients, (365+50;
280+20) for non-neglect patients, and (342+10; 262+7) for healthy control subjects. A direct comparison of these values found no significant differences between the three groups for X axis (F(2, 3)=0.059, p=0.943) and for Y axis (F(2, 3)=0.031, p=0.97). These data indicate that all participants, including those with neglect, showed globally similar oculomotor behavior 288
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and consistently maintained fixation throughout the task, without major asymmetries between groups.
In addition, we also compared the mean gaze position during the critical time interval between the two dots, as a function of the side of the peripheral flash. Importantly, we found again that the average direction of gaze never fell out of the central square area during this interval, independently of whether the flash appeared at the left periphery, the right periphery, or did not appear. This was true for each group. For neglect patients, the mean gaze position was (389+43; 272+14) in the presence of a right flash, (371+29; 270+17) in the presence of a left flash, and (356+36; 273+20) in the absence of flash. A one-way ANOVA on the X coordinates confirmed that these conditions did not significantly differ, (F(2, 3)=0.02, p=0.987). For non-neglect patients, the mean gaze position was (482+28; 315+10) with a right flash, (448+19; 374+20) with a left flash, and (460+31; 361+15) without flash; again no significant difference between conditions, (F(2, 3)=0.21, p=0.741). For control subjects, the mean gaze position was also well maintained, (389+10; 320+13), (396+10; 324+11), and (408+9; 318+10) for right, left, and no flash, respectively (F(2, 3)=0.15, p=0.954); no difference between conditions (F(2, 3)=0.13, p=0.88).
Finally, we computed the number of trials with eye movements away from central fixation across conditions and groups. Such saccades were found on 16.7% of trials among the neglect patients, 11.1% among non-neglect patients, and 8.3% among healthy controls. There were no differences between conditions in all three groups (all t < 2, p = n.s.). These trials were removed from analysis, leaving an average number of 62.3 trials (SD = 3.0) out of 72.
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3.2. Main Experimental Task
Accuracy results from our main task were analyzed using an ANOVA with the four factors of Task (color or position response), Group (neglect, non-neglect, and controls), Flash condition (none, right, or left side), and Visual field of the target dot (right or left). Results showed a main effect of Task (F(1, 16)=4.726, p=0.023), indicating better performance in color discrimination than position memory across all subjects and all conditions (as expected).
More importantly, there were two significant interactions, namely, for Task X Group (F(2, 16)=9.65, p<0.01) and Task X Flash condition X Group (F(4, 32)=4.284, p<0.01). There was no significant effect of the Visual field side (corresponding to the location of the target dot;
F(1, 16)=0.32, p=0.709), nor any interaction with this factor.
The Task X Group interaction indicated that difficulties in the position memory task were more important in the neglect patient group as compared with the two others groups: a significant difference between color and position discrimination accuracy (i.e. worse position memory than color memory) was observed only in the neglect (p=0.031), but not in non- neglect (p=0.734) patients and the healthy controls (p=0.943). Furthermore, neglect patients were significantly worse than non-neglect patients (p=0.029) and control subjects in position discrimination (p=0.022). In contrast, no significant difference was observed between non- neglect patients and control subjects in position discrimination (p=0.710).
The three-way interaction of Task X Flash condition X Group (F(4, 32)=5,390, p=0.023) indicated that such difficulty in the position discrimination task among neglect patients was particularly important when the peripheral flash appeared on the right side of the screen (see Figure 3). These differences were confirmed by direct pairwise comparisons between experimental conditions.
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Neglect patients’ performance in position discrimination after a right flash (see Figure 3, orange bars) was significantly worse compared to the same condition in non-neglect patients (t = 3.18, df = 6.7, p-value = 0.023; IC -0.042 to 0.525) and control subjects (t = 1.795, df = 5.79, p-value < 0.01; IC -0.231 to 0.635). The most interesting result in the light of our predictions is that performance in position discrimination after a right flash was significantly worse than when a left flash or no flash (p<0.031) was presented the neglect group. By contrast, no significant difference was found between the left flash and no flash conditions (p =0.356). Furthermore, no significant differences were observed in any other group (neither the non-neglect patients’ group, nor the control subjects’ group) in position discrimination as a function of the flash position. In particular, right and left flash led to similar performance in non-neglect patients (p=0.301) and control subjects (p=0.543).
Finally, we computed a differential remapping cost by comparing location memory accuracy as a function of the direction of attentional capture (flashL - flashR) and then tested for any correlation with a global neglect severity score (computed as sum of all tests).
However, we found no significant correlation when considering only the neglect group (p=0.74; r=0.45).
3.3. Control color memory task
A separate group of neglect patients (n=4) was tested in a control with greater memory load for the color of dots (six possible hues instead of two), in order to verify that asymmetric memory performance was not due simply to memory difficulty. Only behavioral data were acquired in this group. Critically, results were identical to the main experimental task. Color 357
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overall pattern of performance was unchanged, with asymmetric results for location responses after right compared to left peripheral flashes (mean = 65 vs 72% correct) but no such asymmetry for color responses (mean= 91 vs 93% correct, respectively, Figure S1).
4. Discussion
In the current study, we show that spatial remapping is impaired in right brain lesion patients with left neglect following an exogenous attentional shift toward the right side, without making overt eye movements. These findings mirror the results of a previous study on spatial remapping in neglect patients (Vuilleumier et al. 2007) where eye gaze shifts were made during a brief interval between encoding and remembering the position of a visual target. We conclude that the memory trace of a spatial location may be lost or degraded in neglect patients when it has to be remapped to the left within gaze-centric representations, which normally should be held by the right (but lesioned) hemisphere. Moreover, in both cases, the costs of transient rightward shifts were observed in neglect patients only, not in right-injured patients without left neglect. These results broadly accord with the theoretical model of Pisella and Mattingley (2004) that spatial remapping deficits play a critical role in spatial neglect symptoms, but contradict their assumption that leftward (rather than rightward) gaze- shifts should be selectively detrimental to performance in these patients. More generally, our new results add support to a functional overlap of spatial representations guiding shifts of attention and eye movements (Corbetta and Shulman, 2002; Steinmetz and Moore, 2012;
Vasquez and Danckert, 2008), in accordance with the classic premotor theory of attention (Rizzolatti et al., 1987). Further, such asymmetry in visual memory was not found for the color of targets presented prior to exogenous peripheral distractors. However, as we discuss below, other factors might also contribute to losses in short-term memory for locations across 381
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attentional shifts in neglect patients, including overall task difficulty and asymmetric distractor effects during the encoding phase itself. Although we feel the latter mechanisms are unlikely to play a major role, future research needs to confirm and extend our findings with other paradigms and a larger number of patients.
4.1. Spatial remapping and neglect
The current results add novel empirical support to the notion that remapping deficits might be critically associated with spatial neglect, as put forward by Pisella and Mattingley (2004).
Moreover, we confirm their hypothesis that similar remapping mechanisms might be involved in covert and overt shifts of attention. While these data broadly support a spatial remapping deficit during displacement of attentional focus in left neglect patients, they diverge from the predictions of Pisella and Mattingley (2004) in terms of the direction of shifts that produce the most detrimental losses in spatial memory. Whereas these authors hypothesized that leftward shifts would erase locations held in spatial memory due to an impairment of remapping processes mediated by right parietal areas, we found that only rightward shifts disrupted neglect patients’ ability to remember the target location, across the whole hemifield. This did not impair memory for the target color, however, and leftward shifts produced no significant difficulty. It is possible that some neglect patients did not fully shift attention to the flash in the left visual field due to their inherent ipsilesional attentional bias, yet it has been shown that even when patients saccade to left targets (Vuilleumier et al., 2007) no remapping deficit is evident, while right visual field flashes and saccades produce a clear deficit in spatial memory performance.
This asymmetry replicates previous results obtained in a similar paradigm with overt gaze shifts (Vuilleumier et al., 2007), and supports the notion that visual locations might be 405
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represented in cortical (e.g. parietal) areas using gaze centered coordinates based on the combination of retinal position and gaze direction information (Colby et al., 1995; Pouget and Driver, 2000). Hence, right hemisphere networks code for spatial locations on the left side of current focus of gaze and/or attention, such that a target initially seen in the right visual field (represented in the left hemisphere) would fall to the left of gaze and/or attention when the subject orients to farther right locations in space (e.g. when exogenously captured by a salient flash in right visual periphery), and consequently would be transferred transiently to the right hemisphere. Critically, a destruction of cortical areas (parietal/frontal lobe) holding these left- sided representations (Vuilleumier et al., 2007; Verdon et al., 2001) or a disconnection with subcortical relays and white-matter tracts implicated in this transfer (Vaessen et al., 2016;
Vuilleumier, 2013) would result in a loss of the target information when it is remapped to the damaged neuronal population. Such loss of the remapped location on the contralesional side might account for many clinical symptoms of left spatial neglect, notably when attention is (endogenously or exogenously) attracted by other competing stimuli on the right side. This could eventually lead to difficulties not only in remembering the explicit location of a previously seen target but perhaps also re-orienting attention toward its location.
4.2. Attention and oculomotor control
Most of the previous studies of spatial remapping in humans (e.g. Vuilleumier et al., 2007) and monkeys (e.g. Duhamel et al., 1992) have focused on conditions with overt eye movements, such as the DSST described by Pisella et al. (2004) or the location memory task used by Vuilleumier et al. (2007). However, seminal work by Rafal and colleagues (Ro et al., 2000) showed that inhibition of return (IOR) can influence spatial, as well as temporal, parameters of saccadic eye movements, suggesting that the exogenous orienting of attention, 429
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in addition to influencing target detection, also influence spatial memory processes implicated in oculomotor programming (Ro et al., 2000). The present work extends these studies by showing that transient attention shifts might be sufficient to induce remapping of a visual target location held in spatial working memory, even without overt or systematic eye displacement. Accordingly, we made sure to include only participants who could maintain reliable fixation throughout the task and excluded trials where over gaze shifts were observed in eye-tracking data. This similarity in remapping deficits across different paradigms globally accords with the tight anatomical and functional links of spatial attention with saccade systems in the brain, as initially put forward in the premotor theory of attention by Rizzolatti et al. (1987). These authors found that latencies to a visual target after an invalid spatial cue (relative to a neutral or valid cue) increased proportionally as the physical distance between the actual target and cued location increased. This shifting cost was even bigger when locations were in opposite visual hemifields, crossing the vertical meridian, implying an interhemispheric information transfer during the reorienting process. They therefore concluded that moving attention across space shared common features with moving the eyes, supporting a premotor theory of attention according to which “attention is oriented to a given point when the oculomotor program for moving the eyes to that point is ready to be executed”.
More recent neuroimaging (Corbetta et al., 1998) and neurophysiological studies (Moore & Fallah, 2001) also suggest an intimate neural overlap of attentional networks with cortical areas coding for saccadic eye movements. More broadly, these data therefore support the notion that attention and vision are closed linked to oculomotor and action systems that control selective access of sensory information to awareness, hence that “seeing” is intimately related to “looking” (Rafal, 2010)
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4.3. Endogenous and Exogenous Attention
In the current task, attention was captured exogenously by presenting a salient peripheral flash, whereas in Vuilleumier et al. study (2007) it was endogenously shifted to a small peripheral letter that the subjects had to foveate and name. Therefore, these studies differ in terms of both attentional mechanisms and oculomotor outputs, a distinction that highlights the pervasive role of a remapping deficit in spatial disturbances associated with spatial neglect.
Endogenous attention is displaced according to top-down cognitive intentional processes dictated by task-relevant goals, while exogenous attention is displaced according to bottom-up automatic processes dependent on the detection of salient or unexpected stimuli (Rafal &
Posner, 1987). Moreover, many dissociations indicate that these two types of attention rely on distinct neural substrates (Rafal, 2006). Importantly, exogenous attention is more often impaired in spatial neglect, with abnormal ipsilesional biases in orienting that lead to exaggerated capture by right sided stimuli (Chokron et al., 2008).
While some studies (Rosen et al. 1999) in healthy subjects found substantial overlap in dorsolateral fronto-parietal areas activated during endogenous and exogenous shifts of attention, more recent work (Corbetta and Shulman, 2002) has distinguished a bilateral dorsal network implicated in endogenous orienting and a more ventral right-dominant network preferentially engaged during exogenous shifts and re-orienting. The dorsal attention network (DAN) is composed of the intraparietal sulcus (IPS) and the intersection of the superior frontal sulcus and precentral sulcus (around the FEF), while the ventral network (VAN) is composed of the temporoparietal junction (TPJ) and inferior frontal gyrus (IFG), with tight interconnections between them (He et al., 2007; Chica et al., 2011). It is thought that structural damage to the VAN (e.g. TPJ) can induce dysfunction in spared regions of both 477
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networks, and thus impair spatial attention functions mediated by the dorsal network. Thus, even when structurally intact, cortical regions in right IPS and FEF might fail to activate, leading to failures in orienting attention toward the left space in neglect patients.
Importantly, IPS has been found to hold neuronal populations with gaze-centered representations of contralateral visual space (Duhamel et al., 1992; Jerde et al., 2012), which may integrate both retinotopic inputs and eye-position information, such that a dysfunction or destruction of these populations might suppress the ability to represent targets when their location is on the contralesional side of the current gaze direction or focus of attention. In both humans and monkeys, similar regions in IPS and FEF appear responsible for oculomotor control. Endogenous attention and overt eye movements would thus be expected to engage partly similar circuits and produce similar effects on spatial remapping. Accordingly, if overt gaze-shifts (as tested by Vuilleumier et al., 2007) induce spatial remapping by transferring visual information about a contralateral target location from IPS in one hemisphere (e.g. left IPS for right visual field) to IPS in the other hemisphere (e.g. right IPS for same location in space when gaze is now directed rightward), the same remapping process should also be required when attention is shifted (e.g. from center to right), perhaps due to preparatory eye movements underlying attentional selection (Steinmetz and Moore, 2012). In any case, further research is needed to better identify the neural substrates of spatial remapping and their link to specific attentional and oculomotor circuits.
In conclusion, we provide novel evidence that in right-hemisphere stroke patients with left neglect (but not in those without), the representation of contralesional spatial locations is impaired when attention is transiently captured by a task-irrelevant, salient stimulus presented in the right visual periphery. This suggests that these patients may suffer from a selective impairment in remapping locations to the contralesional side of their current focus of 501
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attention, and that spatial remapping processes may operate even during covert and transient shifts of attention, not just during overt shifts with saccades.
However, our study is not without limitations. First of all, our sample size was relatively small, both for the main experiment and the auxiliary control experiment (color number control), a constraint due to the need to exclude patients who made too many overt saccades to peripheral stimuli during the task. In addition, encoding location might be more difficult and require finer grained resolution capacities than encoding color categories, an effect that was mitigated in our control experiment to some degree, but perhaps not sufficiently so. Further research is therefore needed not only to replicate our findings in a larger sample, but also to clarify the exact mechanisms underlying these effects, uncover the brain circuits engaged during remapping, and assess their precise overlap with exogenous and endogenous attentional mechanisms. Additional experiments should also attempt to provide more direct, quantitative measures of attentional capture by left vs right side distractors, in order to better assess the asymmetrical impact of spatial orienting on memory for contralesional locations. In our study, we assume that visual cherckerboard distractors were salient enough to produce equivalent exogenous orienting effects but we did not directly compared capture across the two hemifields. We cannot fully exclude that left peripheral checkerboards induced less robust exogenous orienting compared to right checkerboards, hence resulting in weaker distraction and paradoxically better memory maintenance.
However, we feel this is unlikely given the lack of a similar asymmetry for color memory. It is also important to link remapping processes with particular behavioral manifestations of neglect in a diverse group of patients. Among others, recent findings suggest that impairments in spatial remapping in neglect may contribute to deficits in the ability to learn and anticipate sequences of stimuli (Saj, et al., 2018). In turn, identifying deficient remapping as a specific component of the neglect syndrome may in turn lead to novel methods of assessment and, 525
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more importantly, novel training approaches to foster rehabilitation and functional recovery.
For example, prism adaptation may reduce the local attention bias observed in neglect patients (Bultitude, et al., 2009; Bultitude et al., 2013). The deficit for maintaining left visual field spatial information across eye movements appears specific to a failure of remapping mechanisms (Pierce & Saj, 2018, for review).
Acknowledgments
This study was supported by grants from the Swiss National Science Foundation (SNSF, Grant no. 162744 and no.166704).
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Legends
Figure 1:
Lesion overlap for (a) non-neglect patients and (b) neglect patients. The color range indicates the number of patients presenting a lesion in each pixel (violet = 1 patient, red = 6 patients). L
= left, R = right.
Figure 2:
Experimental task. Example of (a) a trial without flash during the interval, with the second dot appearing in a different position than the first; (b) a trial with a flash in the left periphery during the interval, with the second dot appearing in the same position as the first. In the latter case, the spatial position of the to-be-remembered dot might be transiently remapped to the left of attentional focus when attention is exogenously oriented to the flash.
Figure 3:
Proportion of correct responses in the color and position discrimination tasks for the three groups of subjects as a function of the side of the flash appearance.
Table - Demographic and clinical data of patients.
Scene copy: the scene includes 4 distinct elements from the left to the right of the sheet;
performance is coded from 0 (no omissions) to 4 (severe omissions on the contralateral side).
Bells test: number of omitted bells in the left (/15), central (/5), and right (/15) parts of the test sheet. Line bisection: mean error in percentage of maximal possible error. MMSE: number of total points (among items 1-23).
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