Parcellation of parietal cortex: Convergence between lesion-symptom mapping and mapping of the intact functioning brain

Behavioural Brain Research 199 (2009) 171–182

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Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr

Review

Parcellation of parietal cortex: Convergence between lesion-symptom mapping and mapping of the intact functioning brain Rik Vandenberghe a,b,∗ , Céline R. Gillebert a a b

Cognitive Neurology Laboratory, Experimental Neurology Section, K.U. Leuven, Belgium Neurology Department, University Hospitals Leuven, Belgium

a r t i c l e

i n f o

Article history: Received 31 October 2008 Accepted 2 December 2008 Available online 9 December 2008 Keywords: Attention Shifting Intraparietal sulcus fMRI Neglect

a b s t r a c t Spatial-attentional deficits are highly prevalent following stroke. They can be clinically detected by means of conventional bedside tests such as target cancellation, line bisection and the visual extinction test. Until recently, lesion mapping studies and functional imaging of the intact brain did not agree very well on exactly which parietal areas play a key role in selective attention: the inferior parietal lobule or the intraparietal sulcus. Recently, the use of a contrastive approach in patients akin to that commonly used in functional imaging studies in healthy volunteers together with voxel-based lesion-symptom mapping have allowed to bring the patient lesion mapping much closer to the functional imaging results obtained in healthy controls. In this review we focus on converging evidence obtained from patient lesion studies and from fMRI studies in the intact brain in humans. This has yielded novel insights into the functional segregation between the middle third of the intraparietal sulcus, the superior parietal lobule and the temporoparietal junction in the intact brain and also enhanced our understanding of the pathogenetic mechanisms underlying deficits arising in patients. © 2008 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Compilation of a saliency map and right IPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Convergence from patients and fMRI in the intact brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The middle third of IPS as a putative homologue of area LIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Reference frames . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Saliency map . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.3. Decision making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transitions between saliency maps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Spatial shifting and superior parietal lobule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Breaches of expectancy and temporoparietal junction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Lesions of the right inferior parietal lobule, in particular the angular gyrus, are commonly associated with left-sided neglect

∗ Corresponding author at: Neurology Department, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 16 344280; fax: +32 16 344285. E-mail address: [email protected] (R. Vandenberghe). 0166-4328/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2008.12.005

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[47,72,102]. Many functional imaging studies of spatial attention have implicated a more superior structure, the intraparietal sulcus, in spatial attention [24,75,105]. A priori, several reasons can be provided why structural lesion studies and functional imaging of the intact brain could yield discrepant results: pathological alterations in functional activity levels may extend beyond the structural lesion, partly because structural lesions often extend into white matter tracts. A lack of concordance may also arise from functional reorganisation following brain lesions. The discrepancy however

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may also be explained by methodological differences between how attentional problems in patients have been traditionally addressed in the past and how attention has been analysed in functional imaging of the intact brain. These differences relate to both the type of behavioral tasks performed and the image analysis procedures. Traditionally, in lesion mapping studies of spatial attention subjects have been dichotomized according to whether or not they had neglect or extinction, usually defined on the basis of conventional bedside tests. These tests were originally developed with the purpose of detecting spatial-attentional deficits in a sensitive manner and call upon the integration of many different perceptual, cognitive and motor processes. In contrast, the purpose of functional imaging is in many instances a maximal specificity in cognitive terms, often brought about by a contrastive approach where two closely matched conditions are compared. A first strategy to bring patient studies and functional imaging in the intact brain together is to apply a similar contrastive approach in both populations [26,70]. Secondly, traditional approaches for relating lesions with symptoms have been a lesion overlap analysis [56,100] or a lesion subtraction analysis [55,72]. Both methods require a prior dichotomization of subjects into a group who has a particular deficit and a group who does not have such a deficit. A novel lesion mapping method, voxel-based lesion-symptom mapping (VLSM) [7,26,70,86], offers distinct advantages compared to these methods as far as comparison with functional activity maps is concerned: the input to a VLSM analysis can be a continuous parameter, e.g. obtained by contrasting performance under two different conditions. There is no need for dichotomizing the patient groups on the basis of cut-offs or symptom clusters. Behavioral deficits in patients are often distributed along a continuum and the quantitative approach taken by VLSM respects this gradual nature and is very suited for a contrastive approach between experimental conditions. Moreover, VLSM determines for each voxel whether the group who has a lesion of that voxel differs in the parameter of interest from the group who does not have a lesion of that voxel. This voxel-based approach allows for a direct comparison between the coordinates of brain lesions associated with a deficit and coordinates obtained using fMRI in healthy volunteers. Needless to say that all lesion mapping methods mentioned are critically dependent on the lesion distribution volume. In its turn this is mainly determined by the underlying etiology. In this review we will focus on converging evidence recently obtained by harmonizing both the behavioral part and the image analysis approach in patients and healthy volunteers within the same experiments. Neglect is a highly prevalent syndrome that is defined on the basis of a set of conventional spatial-attentional tests that have been widely implemented in clinical neurology and neuropsychology, such as target cancellation (Fig. 1), line bisection, drawing-oncommand, copy and reading [46,67,101]. In one of the most widely used tasks, target cancellation [67], neglect patients first fixate

Fig. 1. Two examples of conventional clinical tests carried out by a neglect patient. (A) Letter cancellation task (target letter ‘A’). (B) Clock test. In addition to the spatial bias this patient also showed a dominance of a prepotent response, increasing the numbers starting from 12 rather than switching to 1. This illustrates that neglect is often associated with non-spatial attentional deficits even in the ‘intact’ field [50].

to the right of the midline contrary to the controls who usually first fixate to the left [10]. In neglect fixation duration and the number of fixations decrease along a right-left horizontal gradient [10]. The number of large-amplitude saccades that land on a target is significantly reduced in the contralesional compared to the ipsilesional direction [97]. This is true when the target is defined by pop-out as well as by feature conjunction [8,97]. When gaze is directed 15◦ ipsilesionally, the contralesional saccades are no longer abnormal compared to controls [9], proving that the problem does not lie in the execution of saccades as such [9]. A wide variety of other clinical manifestations of the neglect syndrome have been described for which we refer to reviews elsewhere [46,64,67]. A key feature that distinguishes neglect from sensory syndromes, is its sensitivity to contextual variables, such as motivation, experience [87], nonvisual input [54], or other stimuli that are present in the display in addition to the target. In patients the addition of a distracter has a profound effect on detection [11] and discrimination tasks [37,38] compared to single target presentation. In the conventional clinical task for visual extinction a stimulus is presented either unilaterally to the left or the right or bilaterally at symmetrical locations [11]. Subjects with extinction are able to detect the ipsi- or contralesional stimulus when it is presented alone but fail to detect the contralesional stimulus when it is presented simultaneously with an ipsilesional stimulus at a symmetrical position [11]. The relative position of the distracter is of critical importance [4]. For an identical position with respect to the viewer, reaction times are longer when the target is to the left of the distracters than in the opposite situation [4]. The effect does not depend on between-hemifield symmetry or bilaterality of stimulation [31]. Context also refers to effects of expectancy, e.g. based on prior spatial probability, which is known to affect performance in extinction patients [39,84]. The context-dependency of the attentional deficit in patients provides an opportunity for adopting a contrastive approach since a same subject may perform a task substantially differently depending on the value of one of the contextual variables. Overt clinical neglect is much more common after righthemispheric than after left-hemispheric lesions [46,67]. This may be partly due to a sampling bias as aphasia symptoms may hamper detailed testing of spatial attention in left-hemispheric patients. Consecutive series however of left- and right-hemispheric lesion patients confirm a higher prevalence, severity and persistence of neglect in right- versus left-hemispheric patients [8,29]. A theory that has prevailed in clinical neurology for a long period of time, called the right-hemispheric dominance of spatial attention theory, states that the right hemisphere represents ipsi- and contralateral hemispace while the left hemisphere represents contralateral hemispace only [115]. Damage to the right hemisphere wipes out the representation of contralesional hemispace while the impact of left-hemispheric damage on the representation of the contralesional hemispace can be compensated for by the right hemisphere [115]. This theory yields clear predictions about how left and right parietal fMRI responses may differ depending on the direction of attention (see below). As an early example of the combination of lesion overlap analysis with fMRI in the intact brain, Binkofsky et al. conducted a mathematical analysis of component processes underlying grasping deficits in patients [12]. Patients with lesions of the anterior intraparietal sulcus showed an abnormally wide aperture of the fingers [52] prior to contact with the object [12] compared to patients in whom this region was preserved. In an fMRI study of the same paradigm, grasping was associated with an area of activation that coincided with the region of overlap defined on the basis of the patient studies [12]. This area is probably homologous to what has been called the anterior intra-parietal area AIP in

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monkeys. Inactivation of area AIP in monkeys leads to similar deficits as those observed in patients [35]. The degree of parcellation of cerebral cortex that has been reached in humans remains far below the level reached in monkeys, mainly because the criteria for defining areas in monkeys, such as cytoarchitectonic delineation and detailed analysis of connectivity, cannot be ascertained in humans to the same degree [77]. Monkey single neuron electrode recording studies provide invaluable information about the organisation of parietal cortex which is indispensable if we wish to understand the deficits seen in patients. The most rigorous way to study homologies between the nonhuman primate and the human brain is to apply a same method in the two species, i.e. fMRI in monkeys and in humans using identical experimental paradigms [76]. The fMRI activity foci can subsequently be characterized in the same animals by single neuron or histological studies [74]. As a second possible strategy, lesions can be applied to specific monkey areas and their consequences can be compared with the effects of lesions in humans [112,113]. Finally, a less stringent but more widely available approach is to examine how variables that have been typically studied in single neuron electrode studies affect the fMRI response in the human brain [15,90,91]. In this review we will focus on converging evidence of the critical contribution of the middle third of the right IPS to selective attention. We will review evidence that this region, in concert with other areas, is critically involved in selection between competing stimuli and in the compilation of a saliency map. Within the framework of the neural theory of visual attention (NTVA) [16,18,17], selection between competing stimuli is conceptualized as the calibration of relative attentional weights. In NTVA, each perceptual unit receives an attentional weight. The speed with which a unit reaches visual short-term memory (VSTM) is determined by the attentional weight the unit receives compared to other simultaneously presented units. Whether a unit is coded in VSTM is determined by this speed according to a ‘winner takes all’ principle [16,18]. Another computational model of attention, proposed by Koch and Ullman [51,59], incorporates the spatial distribution of the attentional weights more explicitly than NTVA and is therefore of particular interest for the study of spatial-attentional deficits. During an initial processing stage parallel topographical representations of single stimulus features are processed [59]. The different feature maps code for the conspicuity within a particular feature

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dimension. In order to assess the overall conspicuity of a location, another topographical map is computed, termed the saliency map. The saliency map combines the information of the individual maps into one global measure of conspicuity while retaining the visual topography. A final processing step is the construction of a nontopographical representation of properties of the selected object (winner takes all) [59]. 2. Compilation of a saliency map and right IPS 2.1. Convergence from patients and fMRI in the intact brain In a series of experiments using orientation discrimination and fMRI in healthy volunteers combined with VLSM in patients, we defined areas involved in attentional selection by determining the effect of adding a distracter along several configuration axes (horizontal, vertical, diagonal) [37,70,106] (Fig. 2A). Psychophysically, when the target and the distracter are configured along the horizontal axis, responses are slightly slower than when a single target stimulus is presented on its own or when the two stimuli are configured along a vertical or a diagonal axis [70]. During fMRI, even if performances are carefully matched between conditions by adapting orientation differences, the fMRI response in the middle third of the left and right IPS is increased when target and distracter are positioned along a horizontal configuration axis compared to single stimulation or stimulation with a target and distracter along a vertical or diagonal axis [70]. In accordance with behavioral data, when the two stimuli are presented asymmetrically on the horizontal meridian or when the two stimuli are presented within a same quadrant, IPS activity is consistently higher if they are positioned on a horizontal axis compared to a vertical axis. In a control experiment we varied the reference orientation of target and distracter which did not affect our results. The effect of configuration axis is robust and is present in both younger and older adults [70]. A central purpose of this study was to apply the same paradigm in patients and examine how the lesion map related to the fMRI activity map [70]. Patients were included only if they had a unifocal cortical lesion of recent origin confirmed on clinical diffusionweighted imaging or fluid-attenuated inversion recovery (FLAIR) sequences. Subjects also had to be sufficiently cooperative to be

Fig. 2. Converging evidence from VLSM and fMRI in the intact brain [70]. (A) Stimuli. Note that the different conditions (horizontal, vertical or diagonal configuration axis) are sensorially matched when the different instances are summed for each axis. (B) Overlay between patient lesion map (green) and activity map (red). The overlap is shown in yellow and localises to the middle third of the right IPS.

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able to undergo detailed computerized testing. The lesion distribution volume was biased towards the right hemisphere, principally the middle cerebral artery territory: left-hemispheric lesions in the middle cerebral artery territory are often accompanied by language comprehension deficits precluding detailed computerized testing and ischemia affects the middle cerebral artery much more frequently than the anterior or posterior cerebral artery territories. We calculated an index that reflects how the contralesional orienting deficit is influenced by stimulus configuration: we contrasted accuracy during contra- versus ipsilesional orienting under bilateral symmetrical stimulation conditions with accuracy during contraversus ipsilesional orienting under vertical-axis or bilateral diagonal stimulation conditions. The index corresponds to the interaction between direction of orienting and the relative position of the target wit respect to the distracter. It reflects how the contralesional orienting deficit is augmented by adding an ipsilesional distracter at a symmetrical position. We used this index as input for a VLSM analysis. This analysis showed that the critical lesion site was the right inferior parietal lobule [70] corresponding to the region that has been commonly implicated in neglect [72,102]. The lesion extended superiorly into the lower bank of the IPS and anteriorly into the posterior end of the superior temporal sulcus. As a final step, we directly overlaid the fMRI activity map (Fig. 2B, red) with the patient lesion map (Fig. 2B, green). Overlapping brain areas fulfill a double criterion:

1. activation in healthy volunteers when two competing stimuli are configured along the horizontal axis compared to a vertical or diagonal axis of configuration; 2. if the area is lesioned, the contralesional orienting deficit is exacerbated by adding a distracter on the same horizontal axis compared to a vertical or a diagonal configuration axis.

The area of overlap was located in the lateral wall of the middle third of IPS (Fig. 2B, yellow). As predicted on the basis of the fMRI findings in the intact brain, patients in whom this area was lesioned performed worse during contralesional orienting if a second, irrelevant stimulus was present on the same horizontal axis, regardless of symmetry or bilaterality [70]. A recent VLSM analysis in neglect patients [26] studied conflict between motor choices rather than selection between stimuli but yielded nevertheless very similar results (Fig. 3, magenta square) as the study presented above [70] (Fig. 3, magenta circle). The study [26] made use of two paradigms: the flanker paradigm and a subliminal priming paradigm [26]. In the flanker paradigm, subjects are presented with a central arrow directed to the left or the right, flanked by distracter arrows, which point either in the same (congruent condition) or opposite directions (incongruent condition), as well as a neutral condition. Paradoxically, if the arrow pointed ipsilesionally, neglect patients with inferior parietal lesions extending into the IPS were faster in the incongruent than in the congruent condition [26]. In a related paradigm, when a prior masked prime pointed ipsilesionally compared to contralesionally, the priming effect was enhanced in right parietal patients compared to intact controls. The critical lesion site for this priming effect was the lower bank of the right IPS, possibly somewhat anterior to the middle IPS area we found in our overlap analysis (34, −52, 40) [26] (Fig. 3, magenta square). The priming effect can be accounted for by a directional bias in the motor plan. The facilitation during the incongruent flanker task with the arrow pointing ipsilesionally is more difficult to explain. It is an intriguing effect that requires further confirmation with response conflict paradigms that are driven by other types of cues than vertical triple rows of arrows. It may be an effect of conflicting motor choices, however perceptually the incongruent arrows also differ from the congruent arrows. Importantly, this study [26] complements our study [70] by providing VLSM evi-

Fig. 3. Projection of IPS peaks obtained in the studies mentioned in the paper and related studies [98]. (A) Coronal section at a y-level= −60 mm. On this section all foci are projected with a y-coordinate that falls within a range between −48 and −72 mm. (B) Sagittal section at an x-level= 36 mm. On this section all foci are projected with an x-coordinate that falls within a range between 27 and 44 mm. (C) Projection of the same foci as in A and B on a rendered surface plus two posterior IPS foci that show a strong visual response as well as clear sensitivity for the direction of attention [61,106]. Circles and triangles: peak coordinates of fMRI activity foci obtained in healthy volunteers and localised to the middle third of IPS. Diamonds: peak coordinates of fMRI activity foci obtained in healthy volunteers by contrasting left-sided and right-sided attention and localised to the crossing between IPS and the parietooccipital sulcus. Stars: TMS sites. Square: centre of mass of VLSM result [26].

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dence for a role of IPS in selection between motor choices [26] along with its role in attentional selection between stimuli [70](Fig. 3). When stimulus conditions are strictly matched and direction of attention is manipulated, the BOLD signal differences between leftsided and right-sided attention conditions in left and right IPS do not follow predictions one would make on the basis of the theory of the right-hemispheric dominance for spatial attention [115]: in most functional imaging studies the middle third of left and right IPS show very similar profiles and the direction of attention exerts relatively little effect on this region under sensorially matched conditions [70,103,104,107]. This clearly differs from a more posterior IPS region at the crossing between the parietooccipital sulcus and the IPS where clear effects of direction of attention can be found [106] (Fig. 3C, blue diamond). Recent studies have revealed the presence of a number of retinotopically organised areas in IPS beyond this posterior region [60,88,96,99]. Some of these studies examined purely visual retinotopy but in the context of this review our main interest lies in retinotopically organised cognitive functions residing in IPS [88,91]. These studies showed very similar patterns of retinotopy in left and right IPS and until now have not yielded clear fMRI evidence in favor of a difference in direction-sensitivity between left and right IPS. Other factors than sensory or cognitive retinotopy can have a differential effect on left and right IPS. Left IPS may be relatively more activated when the need for endogenous control increases, for instance when distracters are more salient than targets [69], when multiple features must be discriminated concurrently [104] or during endogenous spatial cueing [57]. A repetitive transcranial magnetic stimulation (rTMS) study suggested a double dissociation, with a critical role of left IPS in processing low-salient targets and of right IPS in processing high-salient targets [68] (Fig. 3, yellow star). fMRI data until now have mainly shown a single dissociation, with left IPS involvement added on top of the right IPS involvement under specific experimental conditions [57,69,104]. Attention is a distributed process and an emergent feature of the working brain [30,65]. Many different brain areas are affected by attentional variables. Compilation of a saliency map does by no means need to be an exclusive function of the middle third of IPS. An area that is often coactivated with IPS, the FEF, may also contribute to coding saliency, as well as subcortical regions such as the pulvinar [93]. Early visual areas, such as V4 and TEO, are also essential. In a lesion study monkeys were presented with a target grating surrounded by filled distracter circles, all falling within the receptive field of a typical V4 neuron. A lesion of V4 or TEO increased the orientation threshold when distracters were present, in particular when they were highly salient, as defined by their luminance with respect to background [114]. Different selection processes are probably in play and not all of them rely on IPS to the same degree. For instance, when a target is defined by sudden onset, it captures attention much more readily than when the target is defined by sudden offset [49,53,117]. Inversely, when a set of preview letters is shown for 1000 ms and a set of target and distracters are added subsequently, processing of the previewed stimuli is inhibited (‘deprioritized’), a process called visual marking [49]. Reaction times to detect the target in the second stimulus set are as fast as when only the second set of stimuli were shown [49]. In patients with left- or right-sided parietal lesions, visual marking is impaired in the contralesional field while attentional capture is preserved [49]. The opposite dissociation, a deficit in capture with preserved marking, has not yet been described to our knowledge. In any case, these studies indicate that some aspects of stimulus selection may be relatively spared in neglect, such as processes mediating attentional capture by sudden onset, while others, such as visual marking, are affected in a lateralized manner. In the intact brain, visual marking relies on the middle third of IPS [79] (Fig. 3, green circle) providing a further indirect confirmation of the role

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of the middle third of IPS in the spatial-attentional deficits seen in neglect. 2.2. The middle third of IPS as a putative homologue of area LIP In a monkey fMRI study [61] the contrast between visually guided saccades and fixation yielded two parietal activity clusters: one near the junction of the intraparietal and the parietooccipital sulcus and one in the middle third of IPS. The latter area was further divided into ‘LIPd’ (dorsal lateral intraparietal) at the surface of the sulcus, LIPv (ventral lateral intraparietal) and ‘LIPv/VIP’ in the fundus of IPS [61]. Together these subdivisions constitute the LIP complex [61,76]. These regions were sensitive to the direction of saccades. Using the identical paradigm in humans [61], two IPS regions responded to saccades in a direction-sensitive manner: one at the border between IPS and the transverse occipital sulcus, also referred to as V7 or ventral intraparietal sulcus (VIPS) [76](Fig. 3, red diamond), and one in the middle third of IPS (Fig. 3, yellow circle). The coordinates of the two peaks fit closely with those found in our study [70] in the posterior (Fig. 3, blue diamond) and in the middle IPS (Fig. 3, magenta circle), respectively. In these experiments [61] the LIP area is co-activated with a region in the arcuate sulcus in monkeys and, in humans, with a region at the crossing between the superior frontal sulcus and the precentral sulcus in humans [61]. This region corresponds to the frontal eye fields (FEF) [61]. LIP was first defined on the basis of its dense connections with ipsilateral FEF [1,2,6]. According to a second and more indirect line of evidence for homology between the middle third of human IPS and LIP, lesions of LIP [112,113] provoke deficits that resemble the selective attention deficit observed in patients who have a lesion of the middle third of IPS [70]: Reversible inactivations of monkey area LIP lead to a deficit in targeted saccades when the target is presented together with a distracter but not when it is presented on its own [112,113]. This strongly suggests a role of LIP in selection between stimuli, similarly to our findings in the middle third of IPS which is implicated in selection between competing stimuli [70,106]. According to a third line of evidence, fMRI responses in the middle third of IPS are influenced by a number of experimental variables that affect LIP neuronal activity in monkeys. Delay activity during memory saccades is one of the defining features of monkey LIP. In a human fMRI study [91], a brief peripheral target was presented while participants fixated a central point. A ring of targetsized blinking distractors at the same eccentricity as the target then appeared during a 3-s delay period while participants maintained fixation. At fixation dimming and distractor offset, participants made a saccade from the fixation point to the remembered target location on a black screen. Then they immediately made a saccade back to the fixation point. The angle of the remembered target location was stepped in a counterclockwise direction through 360◦ . An area in the middle third of IPS was activated in a retinotopic fashion (Fig. 3, blue triangle), identical or nearby to the middle third of IPS obtained in our studies (Fig. 3, magenta circle). In the mnemonic saccade paradigm there are some minor sensory or motor differences, such as the presence of the target and the visual effects of carrying out a saccade. Several additional versions of the task were then used to control for these potential confounds [91]. In a subsequent study [88], an attentional retinotopical organisation of the middle third of IPS was shown in the absence of saccades [88] and with only minimal sensory differences. Another experimental paradigm apart from mnemonic saccades that causes analogous effects in monkey LIP [3] and in the middle third of IPS in cognitively intact volunteers [44] as well as in patients [45] is the double-step saccade paradigm. Two targets are successively presented and the subject is instructed to make a saccade to the first and subsequently from the first to the sec-

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ond target. If the second target is presented before the first target has been fixated, the computation of the saccadic trajectory from the first to the second target cannot be based purely on retinal coordinates. A transformation is needed under such conditions of ‘retino-spatial dissonance’. LIP neurons code the target for the second saccade not purely on the basis of retinal information: the neuronal responses show a modulation by the changes in gaze direction during performance of the first saccade [3]. In cognitively intact human volunteers, three-step saccades activate the middle third of IPS [44] (Fig. 3, red circle). This transformation is impaired in neglect patients, even when the second target is located ipsilesionally [45]. In a variant of the delayed spatial memory paradigm [111], neglect patients were asked to execute a back-and-forth ipsior contralesional saccade during the delay phase. Paradoxically, when subjects performed a saccade into the intact (ipsilesional) hemispace, their spatial memory was impaired but not when the saccade was performed into the contralesional hemispace. This can be explained by the fact that the re-mapping of the spatial representation during an ipsilesional saccade is in the contralesional direction [111]. Taken together these neurophysiological, functional imaging and neuropsychological findings on two- or three-step saccades indicate a similarity between the role of LIP and the middle third of human IPS in re-mapping spatial representations. Assuming that the area of overlap between the fMRI activity map in humans and the lesion map in patients is homologous to LIP, we can extrapolate many of the functions attributed to monkey LIP to the area that is critically important for stimulus selection in humans (Fig. 3). In particular the way in which nonretinal factors affect responses is of direct relevance to the deficits observed in patients. 2.2.1. Reference frames Receptive fields of neurons in areas LIP and the parietal reach region (PRR) are in retinal coordinates, independent of the sensory modality used to cue target location (audition versus vision) and the action that will ultimately be performed (reaches versus saccades) [3]. These retinal fields are modulated by eye, head and limb positions. LIP and PRR neurons code locations in a distributed manner, which can be read out in a variety of reference frames [3]. Computationally, this flexibility of reference frames has been modelled as a combination of different basis functions which allows for non-linear transformations between reference frames [83]. The same computational approach has been applied to deficits in spatial neglect, such as detection of a target among distracters [4] and object-centered neglect [34]. Together with the assumption of a spatial-attentional gradient, a combination of basis functions can reproduce the behavioral deficit seen in patients in a reliable manner [83]. 2.2.2. Saliency map Single neuron data provide strong evidence that LIP plays a key role in the compilation of a saliency map [19,21,43,59]. One study combined a sudden onset attentional capture and a delayed saccade paradigm and measured LIP responses across neuronal populations with different receptive fields: when during the delay phase monkeys attend to the target position, LIP neurons with receptive fields that coincide with the target location show delay activity. If during this delay phase a distracter appears at a different location, a second pool of LIP neurons with receptive fields that coincide with the distracter location show a transient visual response [13]. If activity in these two neuronal pools is compared, a period of time can be delineated during which the delay activity of neurons representing the target location and the decaying visually evoked activity of neurons representing the distracter location are similar in magnitude [13]. This electrophysiologically defined time period coincides with a period defined behaviorally by lack of any attentional bias to

either the target or the distracter location [13]. These findings indicate that populations of LIP neurons code relative conspicuity, or saliency, of locations. Differences in saliency between locations can be read out from differences in firing rate averaged over populations of LIP neurons with different receptive fields [13,36]. 2.2.3. Decision making The integrative role [41] of LIP has been studied in monkeys by means of the dot motion task [41,42,85,92]. Two or more choice targets are presented peripherally, e.g. one to the left and one to the right (target onset). The monkey fixates until a moving dot pattern appears (motion onset) outside the receptive field of the LIP neurons recorded. A variable fraction of dots move in one particular direction. The monkey must direct a saccade in the direction that corresponds to the direction of motion. LIP neurons show a gradual buildup of activity during this task until a threshold (a bound criterion) is reached and a saccade is made. The slope of the gradual build-up is steeper for trials in which the monkey decides more quickly and for trials with a higher stimulus strength [20]. The direction of the saccade that the animal will make can be predicted from the LIP responses during the build-up phase. The gradual build-up of pre-saccadic activity is also influenced by the number of choices the animal has [20], by the prior probability that a stimulus within the neuron’s receptive field will be a target for a saccade and by the magnitude of reward the animal will receive depending on which stimulus is the target. The correlation between reward magnitude and firing rate is not present for single stimuli but depends on the relative magnitude of rewards associated with the left- versus rightsided targets. The integrative role of LIP has many analogies with the deficits found in neglect patients in whom perceptual, intentional and motivational elements all interact. Contextual effects, such as prior probability, are a key variable in neurophysiological studies of decision making in LIP [42,78] and also in neglect [40]. The effect of the presence of a distracter also fits with the effect of adding distracters upon fMRI responses in the middle third of IPS [70]. The recent findings in single neuron studies may provide clues on how to explore the effect of e.g. reward and motivation on performance of parietal lesion patients. 2.3. Summary To conclude, converging evidence indicates that the lateral bank of the middle third of IPS is activated when subjects must select between competing stimuli. Lesions of this area lead to strong interference from ipsilesional distracters. The selection deficit has a strong spatial determinant: it is present when stimuli are configured on a horizontal configuration axis compared to a vertical or diagonal configuration axis. The effect of horizontal configuration axis is entirely congruent between the fMRI data and the patient lesion data. The area of overlap between patient lesion maps and fMRI activity maps (Fig. 2) coincides with the human homologue of monkey area LIP (Fig. 3). This area is principally activated when subjects have to deal with multiple stimuli rather than single stimulation and plays a key role in selection between competing stimuli. Computationally, the role of this IPS area lies in the calibration of relative attentional weights [18], or, in other words, the compilation of a saliency map [43,59]. One of the aspects of saliency that may rely relatively more on IPS than on other regions, is saliency based on internal weighting of stimulus relevance rather than saliency that is predominantly driven by sensory events such as sudden onset [49]. 3. Transitions between saliency maps Transitions from one saliency map to another may involve at least two dissociable processes: the re-calibration of attentional weights and spatial shifting [71]. Following a re-calibration

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of weights, the perceptual unit that originally had the highest attentional weights may remain highest in weight. In such a case no spatial shift occurs although the attentional weights have been re-calibrated. Inversely, when a relevant stimulus retains its attentional weight and shifts its position, the requirement for recalibration of attentional weights may be limited despite the fact that a spatial-attentional shift has occurred. 3.1. Spatial shifting and superior parietal lobule A relatively recent experimental strategy to examine transitions between saliency maps makes use of a sustained attention baseline against which responses to transient events are studied

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[71,94,95,108,118]. This strategy has the unusual feature of maintaining continuous stimulation levels throughout the fMRI run. Subjects have to continuously perform a task, usually a target detection task. Against this sustained attention baseline, responses to the transient events are measured. This allows one to subtract out attentional factors that are not specifically related to attentional transitions per se. If the targets are distributed randomly over the baseline period and have no temporal relationship with the transient events of interest [71,108], effects arising from processes related to response choices can also be removed by this procedure. In a number of experiments the medial and lateral wall of the superior parietal lobule was significantly activated when subjects had to make a spatial shift [71,94,95,108,118](Figs. 4 and 5). In an

Fig. 4. Dissociation between SPL and IPS [71]. (A) Stimuli. Stimuli are maintained on the screen throughout a run. The event-related fMRI response is time-locked to the transitions between stimuli. A1: change in a relevance-defining feature leading to a spatial shift. A2: change in a relevance-defining feature that does not lead to a spatial shift. A3: spatial displacement of the relevant stimulus. A4: spatial displacement of the irrelevant stimulus. For further details see [71]. (B) Green: IPS activity focus corresponding to the contrast between changes in relevance-defining features minus spatial displacement of stimuli. Red: SPL activity focus corresponding to the contrast between a change in a relevance-defining feature that leads to a spatial shift minus a change in a relevance-defining feature that does not lead to a spatial shift. The plots represent the event-related responses to each of the four different types of transition, averaged over all participants and all voxels included in the activity foci represented on the coronal sections [71].

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Fig. 5. Projection of SPL peak coordinates from studies mentioned in the paper. (A) Coronal section at a y-level of −64 mm. On this section all foci are projected with a y-coordinate that falls within a range between −51 and −72 mm. (B) Transverse section at a z-level of 47 mm. On this section all foci are projected with a z-coordinate between 36 and 57 mm.

initial study, subjects performed a dimming detection task with a single stimulus on the horizontal meridian at varying eccentricities [108]. At irregular intervals the relevant stimulus changed its position, leading to strong SPL activation (Fig. 5A). The amplitude of the SPL activation correlated with the amplitude of the shift [108]. In a subsequent experiment, a target and a distracter were presented on the horizontal meridian at varying eccentricities [71]. A spatial shift could be elicited by a change in a relevance-defining feature of the stimuli or by a displacement of the relevant or the irrelevant stimulus (Fig. 4A). When relevance-defining features changed, this could result in a shift of position of the relevant stimulus if relevance switched between stimuli. If the change in relevance-defining features did not cause a switch in relevance between stimuli, no spatial shift occurred [71]. SPL was strongly activated when a change in relevance-defining features elicited a spatial shift compared to a feature change that did not elicit a spatial shift (Fig. 4B, red versus blue). These two event types were strictly matched sensorially [71]. Within the same experiment, we found a functional dissociation between SPL and IPS (Fig. 4B). IPS activity did not depend on the occurrence of a spatial shift but on the need to re-compile a saliency map. When relevance-defining features changed, IPS was activated compared to baseline regardless of whether the feature change elicited a spatial shift (Fig. 4B, red and blue versus black and magenta) [71]. Its activity levels were higher when the recalibration was based on internal rules of relevance rather than sensory events such as the actual displacement of the relevant stimulus [71]. In a series of related experiments [62,89,94,118](Fig. 5), subjects viewed a rapid visual stream of letters and numbers to each side of the visual field. When a pre-specified target appeared, subjects had to shift attention to the stimulus in the opposite hemifield. In line with the abovementioned study, shifting events were associated with SPL activation compared to the sustained attention baseline

[118](Fig. 5). Subsequent experiments confirmed that this SPL activation was not due to the detection of the go-signal leading to a shift but to the actual shift made. Other experiments aimed to determine whether a shift between features yielded similar effects as a shift between locations. In one dichotic listening experiments a male voice was played simultaneously with a female voice [95]. Subjects had to endogenously shift from one voice to the other. SPL was highly activated at the time of a shift (Fig. 5). Likewise, when a face and a house picture overlapped and subjects had to shift from the face to the house or vice versa, SPL was more active [89]. Comparisons within [95] and across studies suggest that the same or nearby areas are involved in both spatial and feature shifts (Fig. 5). The strength of activity between the spatial and the feature shifts however may differ, with stronger activity during a spatial than during a feature shift [71]. Furthermore, when visual stimuli overlap, the brain may utilize spatial strategies to solve the rather unusual problem of shifting between the overlapping visual stimuli. For instance, since a house and a face never appear in superposition in real life, the brain may solve the problem by analysing the overlapping figures as different spatial layers. Another paradigm that has been used to study feature shifts makes use of coherent motion of coloured dots [62]. Subjects attend to either the motion or the color of the dots. In response to a particular motion direction or a particular color, subjects had to shift between dimensions (from color to motion or vice versa). When subjects shift from one dimension to the other, SPL is activated. This may indicate that a shift between feature dimensions activates SPL as does a spatial shift [62] (Fig. 5). SPL activation during spatial shifts is an important novel finding. Patient lesion studies in the past had not provided clear clues that this area is critical for spatial shifting. Ischemic lesions only rarely affect superior parietal cortex. To relate the SPL activation to deficits in patients with SPL lesions, we would need a direct comparison using closely similar paradigms in such patients and cognitively

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Fig. 6. Projection of TPJ peak coordinates from studies mentioned in the paper and related experiments [5,14,63,110]. (A) Sagittal section at an x-level of 53 mm. On this section all foci are projected with an x-coordinate between 47 and 59 mm. (B) Transverse section at a z-level of 21 mm. On this section all foci are projected with a z-coordinate between 11 and 30 mm.

intact volunteers, similarly to what we did in the study of stimulus selection and IPS [70]. It also remains to be determined which is the monkey homologue of this SPL area. 3.2. Breaches of expectancy and temporoparietal junction A deficit in shifting attention contralesionally was among the earliest cognitive deficits specified in neglect patients [81,82]. In the classical Posner paradigm subjects receive a prior spatial cue, either peripherally or centrally, followed by a delay and a test stimulus, e.g. a low-luminance stimulus [80]. A key contrast is between validly and invalidly cued trials. Subjects with neglect are mainly impaired when the cue is invalid and they have to shift attention contralesionally [81]. In the intact brain invalid versus valid cueing activates the right temporoparietal junction [22] (Fig. 6). A contrast between validly and invalidly cued trials reflects a breach of expectancy: subjects have to adapt their saliency map in response to the unexpected position of the test stimulus and displace the focus of attention. Note that an endogenous spatial shift is also present during validly cued trials in response to the spatial cue and in preparation of the upcoming test stimulus. Many studies have aimed to disentangle the responses between the different trial phases: cue, delay, and test phase, in analogy with a strategy that has been extremely successful in single neuron studies. Given the low time resolution of fMRI this approach has its intrinsic shortcomings: in order to be able to separate out the different phases, it is necessary to vary the delay duration between e.g. 2–12 s. Psychophysical studies provide evidence that even a difference of a few tens of ms may introduce a fundamental change in how a delayed matching to sample task is solved [73], let alone that drastic changes such as those used in some fMRI studies will have inadvertent effects on how the delay period is bridged. The right temporoparietal junction responds mainly to

the appearance of the invalidly cued target stimulus [22] (Fig. 6). In contrast, the IPS response is linked to the cue and the delay phase [22,48]. The differential chronometry between IPS and TPJ led to the hypothesis that IPS is mainly involved in the endogenous control of attention [25,116] while TPJ activation is mainly related to the breach of expectancy [25]. One can also abort the trial after the cue phase and measure the response to the cue while the subject is expecting the test stimuli to come up [58]. This yields mainly IPS activation (Fig. 3). The TPJ area that is activated in the intact brain falls well within the extensive lesion overlap that is found when neglect patients are compared with non-neglect patients (Fig. 6). In the acute stage following an IPL ischemic lesion, right IPS activity is decreased even in those subjects in whom it falls outside the lesion [23]. Left-sided IPS activity is enhanced in the acute stage. This creates an imbalance between left and right IPS. As patients recover, an equilibrium is restored between left and right IPS [23]. Other studies have confirmed that right TPJ is activated during a breach of expectancy. Whether the breach of expectancy relates to the spatial mismatch or to nonspatial factors, has been studied by several groups. Downar et al. (2000) found bilateral TPJ activation in a rapid serial stimulus presentation paradigm whenever stimulus type changed abruptly within a dimension, regardless of modality (visual, auditory or somatosensory) [32] (Fig. 6). The TPJ response was further enhanced when the change was behaviorally relevant [33]. This has led to the description of TPJ as a ‘circuit-breaker’. The TPJ findings have led to a model where TPJ is part of a ventral frontoparietal network involved in novelty detection, together with inferior frontal regions [23]. The role of inferior frontal cortex in this network builds upon electrophysiological data regarding P300 [27,28]. Importantly, the P300 findings do not necessarily implicate inferior frontal cortex in stimulus-driven ori-

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enting. Novel events may be more significant and the re-allocation of attentional resources to such events may be based on the behavioral significance rather than on exogenous stimulus-driven variables. 4. Conclusion Converging evidence from different sources is necessary to construct a model of how the brain system for attentional selection and spatial shifting is organised. We attempted to bring together evidence from patient lesion studies and from fMRI in healthy volunteers. Evidence converged onto a critical role of the middle third of right IPS in selective attention. On its own the VLSM map obtained by our contrastive approach closely resembled that obtained in previous lesion mapping studies. The key factor in resolving the discrepancy between the two sources of evidence was the ability to directly overlay VLSM with fMRI activity maps. We propose that the middle third of IPS, the putative human homologue of area LIP, has a critical role in selection between competing stimuli and in the compilation of a saliency map. The calibration of relative attentional weights relies on IPS in particular when it is based on internal value rather than sensory events such as sudden-onset. Anatomically and functionally this IPS area is tightly connected with the FEF, as one would expect for an LIP homologue. A second parietal area, TPJ, is mainly activated at the time when expectancy is breached, and probably also contributes to part of the deficits that are seen in neglect. A nearby area, SPL is active at the time of transition between saliency maps but only if the spatial distribution of relative attentional weights changes from one saliency map to another. Future studies that combine patient lesion data and fMRI in cognitively intact volunteers are needed to find out how deficits following SPL lesions relate to the SPL findings obtained using fMRI in the intact brain. Acknowledgements We thank Peter Janssen and Patrick Dupont for helpful comments on an earlier version of this paper as well as for help with preparation of the figures. Supported by FWO grants G.0076.02 and G0668.07 (EuroCores) (R.V.), KU Leuven Research grants OT/04/41 and EF/05/014 (R.V.), and Inter-University Attraction Pole P6/29. R.V. is a Clinical Investigator of the Fund for Scientific Research (FWO), Flanders (Belgium), and C.R.G. a research fellow of the FWO. References [1] Andersen R, Asanuma C, Cowan W. Callosal and prefrontal associational projecting cell populations in area 7a of the macaque monkey: a study using retrogradely transported fluorescent dye. J Comp Neurol 1985;232: 443–55. [2] Andersen R, Asanuma C, Essick G, Siegel R. Corticocortical connections of anatomically and physiologically defined subdivisions within the inferior parietal lobule. J Comp Neurol 1990;296:65–113. [3] Andersen R, Buneo C. Intentional maps in posterior parietal cortex. Annu Rev Neurosci 2002;25:189–220. [4] Arguin M, Bub D. Evidence for an independent stimulus-centered reference frame from a case of visual neglect. Cortex 1993;29:349–57. [5] Arrington C, Carr T, Mayer A, Rao S. Neural mechanisms of visual attention: object-based selection of a region in space. J Cogn Neurosci 2000;12: 106–17. [6] Barbas H, Mesulam M. Organization of afferent input to subdivisions of area 8 in the rhesus monkey. J Comp Neurol 1981;200:407–31. [7] Bates E, Wilson SM, Saygin AP, Dick F, Sereno MI, Knight RT. Voxel-based lesionsymptom mapping. Nat Neurosci 2003;6:448–50. [8] Behrmann M, Ebert P, Black S. Spatial neglect and visual search: a large scale analysis. Cortex 2004;40:247–63. [9] Behrmann M, Ghiselli-Crippa T, Sweeney J, Dimatteo I, Kass R. Mechanisms underlying spatial representation revealed through studies of hemispatial neglect. J Cogn Neurosci 2002;14:272–90.

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