Left and right occipital cortices differ in their response to spatial cueing

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NeuroImage 18 (2003) 273–283

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Left and right occipital cortices differ in their response to spatial cueing Stefan Pollmanna,* and Micaela Morrillob b

a University of Leipzig, Cognitive Neurology, Leipzig, Germany Max-Planck-Institute of Cognitive Neuroscience, Leipzig, Germany

Received 13 May 2002; revised 11 September 2002; accepted 21 October 2002

Abstract We investigated cue and target-related laterality effects with event-related fMRI. Both left and right occipital areas responded maximally when both cue and target were presented in the contralateral visual hemifield (VF), and minimally when cue and target were presented in the ipsilateral VF. However, whereas signal increases in right ventromedial and lateral occipital cortex were intermediate in those trials in which the cue appeared in the VF contralateral to the target (invalid cue trials), signal strength in left occipital cortex was almost identical for valid and invalid cues, i.e., high for RVF cues, and low for LVF cues, independent of the VF of the target. These data support theories which postulate a greater ability of the right hemisphere for bilateral processing. However, these laterality effects were observed earlier in the visual pathway than previously thought, leading to the question whether the hemispheric differences observed in occipital cortex are generated in the activated areas or are the effect of reentrant processes from more anterior areas, potentially in parietal cortex. © 2003 Elsevier Science (USA). All rights reserved.

Introduction Selective attention enables us to extract relevant information from the multitude of stimuli that enter our senses. A particularly effective form of selective attention is the selection of locations in the visual field. Numerous behavioral studies have shown that attending to a particular location in space leads to faster detection of target stimuli at this location. Previous fMRI studies have shown that covertly attending to a location left or right of fixation leads to an increase of activation in contralateral visual occipital areas (Corbetta et al., 1993; Heinze et al., 1994; Mangun et al., 1997, 1998; Martinez et al., 1999; Hopfinger et al., 2000; Vandenberghe et al., 2000). More specifically, activation is increased in the representation area of the attended location in retinotopically organized visual areas in occipital cortex (Tootell et al., 1998; Brefczynski and De Yoe, 1999). The literature is less consistent with respect to lateralization in nonretinotopic brain areas. One influential model of * Corresponding author. Universita¨t Leipzig, Tagesklinik fu¨r Kognitive Neurologie, AG Experimentelle Neuropsychologie, Liebigstr. 22a, D-04103 Leipzig, Germany. Fax: ⫹⫹49-341-9724989. E-mail address: [email protected] (S. Pollmann).

the functional neuroanatomy of visuospatial processing posits that the hemispheres of the human brain differ in their capacity to process ipsilateral stimuli (Mesulam, 1981; Heilman et al., 1987, 1993). Based on the laterality of the neglect syndrome, which is mostly observed after right hemispheric lesions, it was proposed that the right hemisphere was better able to process ipsilateral stimuli than the left. While this model accords well with the neuropsychological data, it has not always been confirmed by functional imaging. In an early PET study (Corbetta et al., 1993), separate neighboring activations associated with shifting attention in the left (LVF) and right visual hemifield (RVF) were observed in right superior parietal cortex, whereas activations fell into the same location in the left superior parietal lobule (SPL). These activations were seen in comparison with a fixation baseline. In another study, cue laterality was explicitly addressed (Nobre et al., 1997). Activation in the vicinity of the left posterior intraparietal sulcus and left posterior superior temporal sulcus were only observed when participants were cued to the RVF, whereas the same structures in the right hemisphere were activated following right as well as left cueing. Again, these differences were only observed when the attend-left respectively attend-right con-

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ditions were compared to a resting baseline. No direct attend-left–attend-right comparison was calculated, so that there is no information about the significance of these laterality effects. Many of the early studies investigated blockwise sustained attention to one hemifield. Only in recent years eventrelated fMRI studies allowed investigation of shifts of covert attention which occured in random order from trial to trial. In one such study, Perry and Zeki (2000) reported direct comparisons between trials in which covert attention was directed to the left or right hemifield. They found significantly stronger activation associated with contralateral direction of attention in the left as well as the right superior parietal lobule. A similar contralateral activation pattern was observed in the left inferior frontal eye field (FEF; along the inferior precentral sulcus). In contrast, activation in the right supramarginal gyrus was equally strong for LVF and RVF attention conditions. It was further shown that brain areas may respond differently to cues, which may be used to covertly orient to the likely location of a subsequent target, and to the targets themselves (Corbetta et al., 2000; Hopfinger et al., 2000). Previous patient data showed that neglect patients had particular problems in reorienting from invalid cues in their intact hemifield, typically the RVF, to targets presented in the LVF (Posner et al., 1984; Friedrich et al., 1998). In studies with normal subjects, we found an analogous asymmetry, in that distractors in the RVF slowed responses to targets presented in the LVF more than LVF distractors slowed the detection of RVF targets (Pollmann, 1996, 2000). Such an asymmetric cueing effect in normal subjects is predicted by attentional gradient models, which postulate that both hemispheres respond more strongly to contralateral than ipsilateral stimuli, but that the gradient between contra- and ipsilateral activation is smaller in the right than the left hemisphere (Bisiach and Vallar, 1988; Pollmann and Zaidel, 1998). In the present study, we were interested in lateral asymmetries in brain activation elicited by lateralized cues and targets. We expected that RVF cues would lead to stronger activation changes in the left hemisphere than LVF cues in the right hemisphere, as hypothesized by hemispheric attentional gradient models. We expected this laterality effect to occur in brain areas supporting high-level vision, both in the contralateral and ipsilateral hemifields, because in such areas, different ratios of contra- and ipsilateral RF neurons could form the basis of differential hemispheric gradients (Rizzolatti et al., 1985; Bisiach and Vallar, 1988). An area containing a majority of contralateral and only few ipsilateral neurons (the expected left hemispheric pattern) would show a strong contra-ipsilateral activation gradient, while an area with a more balanced distribution of contra- and ipsilateral neurons (the expected right hemispheric pattern) would show a weak gradient. By the same reasoning, no hemispheric differences between contra- and ipsilateral activation gradients were expected in early reti-

Fig. 1. Trial schema: Presentation of a a peripheral cue was followed by the target, either a C or a O, at either the cued location or a location in the contralateral hemifield. Subjects had to discriminate the target and respond by a forced choice button press response.

notopic areas, with their equal distribution of mostly contralateral receptive fields in both hemispheres.

Methods Participants Thirteen right-handed neurologically normal participants (6 males/7 females, age range 22–29 years, with a mean of 25 years) took part in the experiment, each having given prior written informed consent according to the guidelines of the Max Planck Institute. The study was approved by the local ethics review board at the University of Leipzig. All participants were right handed, assessed by the Edinburgh Inventory (Oldfield, 1971). All had normal or corrected to normal vision. Stimuli Stimuli were projected by an LCD projector on a backprojection screen mounted in the bore of the magnet behind the participants’ head. The participants wore mirror glasses equipped with corrective lenses if necessary. The background of the screen was black and all stimuli were white. A white fixation asterisk (0.6° diameter) was shown at the center of the screen. It was located 1.3° under the imaginary line on which the stimuli appeared (Fig. 1). Two types of cue (small, big) were alternatively presented in one of two positions. The small cue consisted of 4 white edges delimiting a rectangular area of a side length of 1.5° visual angle; the big cue consisted of the same white edges, which delimited an area of 4.5° horizontal and 1.5° vertical side length. In this way, the cued area varied, but the cues had the same shape and luminance in both conditions. The target stimulus was either the letter “C” or “O” presented in Arial font of 0.5° height. The target could appear in one of seven positions, distributed at 6, 4.5, 3, 0° of eccentricity on

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the left and right of the midline. The cue was presented centered 4.5° to the left, respectively right of the midline. In the valid trials the target was shown at the geometrical center of the small cue, or in one of the three positions inside the big cue. In the invalid cue trials, targets were presented at the identical positions in the contralateral hemifield. In 5% of the invalid cue trials, the target appeared at the central position. These catch trials were run in order to check central fixation. Responses to uncued central trials were expected to be faster than responses to uncued peripheral trials. On each trial the sequence of events was as follows: the fixation mark was constantly presented. A cue was shown for a duration of 450 ms. After an additional interval of 150 ms (yielding a stimulus-onset-asynchrony (SOA) of 600 ms) the target appeared for 70 ms. Complete trial duration was 5000 ms. In 75% of the trials the cues were valid. In 48 trials only the fixation point was presented. These trials served as null events. We did not increase SOA to a duration of several seconds, in order to differentiate between the temporal onset of cue- and target-specific blood-oxygenation-level-dependent (BOLD) responses (cf. Corbetta et al., 2000; Hopfinger et al., 2000), because very long SOA are suboptimal from the point-of-view of the behavioral experiment. Endogenous cueing effects are observed as early as 400 ms after cue onset (Mu¨ ller and Rabbitt, 1989). At SOA longer than that, there is the danger that the endogenous allocation of attention is confounded by processes of sustaining attention at the cued location, eliminating interference with sustained attention, and development of response expectancies. Therefore, we chose to discriminate between lateralized cue- and target-related responses by contrasting trials in which cue and target appeared within left or right hemifield (valid cue trials) and trials in which cue and target appeared in contralateral hemifields (invalid cue trials). Participants were instructed to focus their attention to the cued area while fixating the central asterisk. They had to discriminate the target letter, indicating target identity by a forced choice button press response (middle finger for the O, index finger for the C) with their right hand. The experiment consisted of a total number of 304 trials (192 valid, 64 invalid, 48 null events). The order of trials was randomized for each subject. With the exception of validity, targets were equally distributed over the experimental factors. Blocks of 38 trials were separated by pauses lasting 20 s. Before the experiment, participants performed a practice session of 42 trials in the scanner during the acquisition of the anatomical images, just before the functional image acquisition.

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Table 1 Mean reaction times as a function of cue validity and hemifield of cue (upper rows) and size of cue (lower rows) Cue validity

Hemifield of cue Size of cued area

Left Right Big Small

Valid

Invalid

685 (97) 684 (87) 690 (99) 679 (85)

735 (84) 747 (101) 732 (82) 749 (103)

Note. Standard error of means in parentheses.

3000 ms, TE ⫽ 30 ms and a flip angle of 90°. We acquired a 64 ⫻ 64 matrix with a FOV of 19.2 cm, resulting in an in-plane voxel size of 3 mm. Aligned with the anterior and posterior commissures, 32 axial slices were acquired with a slice thickness of 3 mm and an interslice gap of 1 mm. For registration purposes, a set of T1-weighted EPI images was acquired with the same parameters as the functional EPI data. The data were analyzed with the software package LIPSIA (Lohmann et al., 2001). First, slice acquisition time differences were corrected by sinc interpolation. Then, data were corrected for movement artefacts (Friston et al., 1996). In the spatial domain, the data were filtered with a Gaussian filter with FWHM ⫽ 12 mm. Following this preprocessing, the functional datasets were coregistered with the subjects’ individual high-resolution anatomical datasets and normalized by linear scaling. Data were analyzed using the general linear model (Friston et al., 1995). Low frequency drifts were removed by high-pass filtering with a cutoff frequency of 1/60 Hz. Event-related analyses were computed using a model of the hemodynamic response and its temporal derivative (Josephs and Henson, 1999). The significance criterion was ␣ ⫽ 0.0001, uncorrected for multiple comparisons. Group activation was calculated using a random effects model (Holmes and Friston, 1998). We have previously shown that rapid eventrelated designs as the one used here allow measurement of the differential response between experimental conditions without amplitude loss due to BOLD overlap of successive trials (Pollmann et al., 2000; for a model approach cf. Friston et al., 1999). To visualize the event-related signal changes for selected regions-of-interest (ROI), we extracted the signal time course at the voxel with the highest Z value in the respective contrast. We analyzed signal amplitude changes in these time courses by calculating a repeated measures analysis of variance (ANOVA) on the range (minimum- maximum) of the signal in the first 8s after cue onset.

fMRI methods

Results

A session consisted of one scan. The scan started with the presentation of a fixation cross for 30 s, followed by 304 trials. FMRI data were acquired at 3 T (Medspec 30/100, Bruker, Ettlingen) using a gradient-recalled EPI sequence with a TR ⫽

Behavioral results A repeated-measures ANOVA with the factors validity (valid, invalid), size (small, big), and cue position (left,

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Fig. 2. Occipital activations in the contrast valid left cue trials–valid right cue trials. The color legend indicates z values. Positive z values indicate stronger activations for left cue trials, negative values stronger activations for right cue trials. Left hemisphere is on the left. The signal time courses represent the BOLD responses in the conditions valid left cue (vl), valid right cue (vr), invalid left cue (il), and invalid right (ir) cue. For each condition, the BOLD response elicited by the null events (null) was subtracted. The numbers correspond to the numbering in Table 2.

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Fig. 3. Anterior signal time courses in the contrast valid left cue trials–valid right cue trials. Abbreviations are as in Fig. 2. Please note that the scale for the anterior cingulate time courses differs from the scale of the other graphs. The numbers correspond to the numbering in Table 2.

right) was run on the reaction times of correct responses. Responses with a latency higher than 1000 ms or lower than 200 ms were excluded from the analysis. This resulted in the

loss of ⬃10% of responses. However, the pattern of significant effects remained the same as for an ANOVA over the uncorrected data.

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Table 2 Location of significant activations in the contrasts between valid left–valid right cues and invalid left–invalid right cues ROI Valid left–valid right cue trials 1. Lateral occipital gyrus 2. Lingual gyrus 3. Lingual gyrus 4. Lateral occipital gyrus 5. IPS/TOS 6. Inferior temporal sulcus 7. Superior frontal gyrus 8. Precentral sulcus (sup.) 9. Precentral gyrus 10. Anterior cingulate gyrus 11. Middle cingulate gyrus 12. Posterior cingulate gyrus 13. Precuneus 14. Angular gyrus Invalid left–invalid right cue trials 1. IPS/TOS 2. Lateral occipital gyrus 4. Lateral occipital gyrus 3. Lingual Gyrus

Location

Zmax

VF

Validity

VF ⫻ validity

L (⫺37 ⫺73 3) L (⫺14 ⫺81 ⫺4) R (10 ⫺80 ⫺1) R (35 ⫺73 3) R (28 ⫺69 22) R (37 ⫺60 6) R (13 7 58) L (⫺35 ⫺5 46) L (⫺38 ⫺8 44) R (4 24 37) R (11 ⫺2 46) R (16 ⫺16 40) R (13 ⫺33 46) L (⫺58 ⫺51 33)

⫺4.29 ⫺4.39 3.94 3.70 4.11 4.62 3.94 3.89 4.14 3.77 3.98 3.86 4.44 3.93

* * — — — — — — — — — * — —

— — — — — — — — — * — * — —

* — * * * * — — — — — * — —

⫺4.66 ⫺3.76 ⫺4.61 ⫺4.32

— * * *

— — — —

— — — —

L L L L

(⫺26 (⫺29 (⫺44 (⫺17

⫺82 ⫺85 ⫺68 ⫺78

31) 17) ⫺1) ⫺5)

Note. The table indicates the coordinates according to Talairach and Tournoux (1988). L, left hemisphere; R, right hemisphere, Zmax: maximal z score. IPS/TOS: junction of intraparietal and transverse occipital sulci. The last three rows indicate the significance of the main effects of visual hemifield of cue (VF), validity of cue, and their interaction in the ANOVA on signal amplitude changes. —, not significant; * P ⬍ 0.05.

We found a significant main effect of validity. Reaction time for target discrimination was faster on valid than invalid trials (F(1,12) ⫽ 12.12, P ⬍ 0.005; Table 1). The mean difference was 56.3 ms. The main effects of cue size (F(1,12) ⫽ 0.32, n.s.) and cue position (F(1,12) ⫽ 0.92, n.s.) and the interaction effects (all F(1,12) ⬍ 4.08, n.s.) were not significant. The invalid trials were further analyzed, in order to check the instruction to fixate at the center. A repeated-measures ANOVA was run on invalid trials, with size (small, big) and position of the target (left, center, right), as factors. The main effect of target position was significant (F(2,24) ⫽ 8,22, P ⬍ 0.002). The main effect of size (F(1,12) ⫽ 1.88, n.s.) and the interaction of size and position were not significant (F(2,24) ⫽ 1.41, n.s.). A post hoc t test showed that central targets were detected faster than lateral ones, with a mean difference of 50.2 ms between left and center (762.2 ms versus 712.01 ms, t(12) ⫽ ⫺3.67, P ⬍ 0.003) and a mean difference of 31.6 ms between right and center (743.6 ms versus 712.01 ms, t(12) ⫽ ⫺3.09, P ⬍ 0.009), indicating central fixation. A repeated-measures ANOVA with the factors validity (valid, invalid), size (small, big), and cue position (left, right) was run on the errors. We found a main effect of validity (F(1,12) ⫽ 11.89, P ⬍ 0.005). No other main effect or interaction was significant (all F(1,12) ⬍ 0.89, n.s.). The global error rate was 15%. The error rate was higher for invalidly cued than validly cued targets (22.6% versus 11.06%). We ran a separate ANOVA on invalid trials with size

(small, big) and position (left, center, right) of the target as factors. The main effect of position was significant (F(2,24) ⫽ 4.39, P ⬍ 0.024). The main effect of size (F(1,12) ⫽ 0.16, n.s.) and the interaction between size and position was not significant, but a tendency was observed (F(2,24) ⫽ 3.05, P ⫽ 0.066). With big cues, less errors were made in the central position than on either the left (t(12) ⫽ ⫺2.36, P ⬍ 0.036) or the right position (t(12) ⫽ ⫺5.15, P ⬍ 0.000). There were no such differences for small cues (all t(12) ⬍ 0.74, n.s.). Functional imaging Since the factor cue size did not yield significant main effects on reaction times or errors, we collapsed the data across large and small cues. Cue location: valid cues In order to find brain areas which are differentially activated when attention is directed to the left compared to when attention is directed to the right, we directly contrasted trials with valid left cues minus trials with valid right cues. In all cases, only trials with correct responses were entered in the analysis. We found symmetrical increases contralateral to the cued hemifield in the lingual gyri (Fig. 2-2,3) and in the inferior part of the lateral occipital gyri (Fig. 2-1,4) of both hemispheres. Since the cue represents a salient lateral visual stimulation, symmetric activations of visual areas are not

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surprising. However, these were the only areas symmetrically activated by left versus right cueing. Left versus right cues elicited an increased unilateral activation in the posterior portion of the right inferior temporal sulcus (Fig. 2-6), in the border zone of the occipital lobe. LVF-cue-related signal increases were further observed at the junction of the right intraparietal sulcus and the transverse occipital sulcus (IPS-TOS, Fig. 2-5) and in right anterior inferior precuneus. In right frontal cortex, LVF cues elicited increased activation in posterior superior frontal gyrus and in right anterior, middle (motor area), and posterior cingulate cortex (Table 2). Ipsilateral activation which was stronger after left, compared to right cues, was observed in left angular gyrus, as well as at the banks of the left central sulcus and in left superior precentral sulcus. Analysis of the BOLD time courses showed that the strength of the signal increases from baseline, as well as the differences between conditions, was strongest in the lingual gyri (Fig. 2-2,3), and declined progressively via the lateral occipital gyri (Fig. 2-1,4) to the right IPS-TOS junction (Fig. 2-5). In left lingual gyrus (Fig. 2-2), the strong signal increase was almost identical when the cue was presented in the RVF, independent of whether it was valid or not. When the cue was presented to the ipsilateral LVF, only a very weak increase was observed, again almost indistinguishable for valid and invalid cues. In contrast, valid LVF cues elicited a strong response in right lingual gyrus (Fig. 2-3). Invalid LVF cues elicited only a weak response, of comparable amplitude as invalid RVF cues, whereas valid RVF cues elicited almost no response. These same pattern of hemispheric differences was observed, although less pronounced, bilaterally at the lateral occipital gyri (Fig. 2-1,4), at the right inferior temporal sulcus (Fig. 2-6) and at the right IPS-TOS junction (Fig. 2-5). The statistical significance of this pattern was demonstrated by the significant interaction of VF ⫻ validity in these areas (Table 2). Analysis of BOLD amplitude changes yielded hardly a significant effect in the frontal and cingulate areas activated in this contrast (Table 2 and Fig. 3). One exception was the right anterior cingulate gyrus (Fig. 3-10), in which signal change was minimal for valid right cues compared to null events, leading to a significant validity effect, representing higher signal changes for invalid cues. Another exception was the right posterior cingulate gyrus, which yielded significant main effects for hemifield of cue and cue validity, and a significant interaction (Table 2). However, the time course of the BOLD responses in this area yielded only minimal amplitude changes (Fig. 3-12), and the results should thus be interpreted with caution. A common pattern of the frontal and cingulate activations was that the signal increase tended to be stronger for valid left and invalid right cue trials, suggesting an involvement of these areas in the processing of LVF targets (Fig. 3).

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Cue location: invalid cues There was not a single area in which invalid LVF cues elicited stronger activation than invalid RVF cues. Contrary, when invalid cues were presented in the RVF, these trials elicited stronger activation, compared to invalid cues presented in the LVF, in several posterior brain areas (Table 2). Increased activation for right over left invalid cue trials was observed in left lingual gyrus (Fig. 4-3), overlapping with the location which was activated by valid right cues (Fig. 2-2). It was further observed in left lateral occipital gyrus, in a ventral anterior (Fig. 4-4) and in a dorsal posterior (Fig. 4-2) location, as well as in left IPS-TOS (Fig. 4-1). Even when we lowered the threshold to P ⫽ 0.05 (uncorrected), to search for left–right invalid cue signal differences at the homologous right hemispheric areas, no significant difference was observed. One ipsilateral signal increase for right– left invalid cues was observed in the right inferior temporal gyrus (at the threshold of ␣ ⫽ 0.0001). The interpretation of these contrasts is complicated by the fact that cue and target are presented in different hemifields and thus when we compare invalid left cue to invalid right cue trials, areas mostly responsive to cues would behave in a different manner than areas mostly responsive to targets. To analyze these patterns, we extracted the BOLD time courses for the activated areas. The signal time courses showed a common pattern in all four areas. Strong signal increases were observed for contralateral cues, irrespective of their validity. Ipsilateral cues elicited less activation, and, as in the contrast between left–right valid cues, cue validity did not modulate signal strength in these left hemispheric areas. The difference between strong responses to contralateral versus weak responses to ipsilateral cues was most pronounced in left lingual gyrus (Fig. 4-3), weaker in lateral occipital cortex (Fig. 4-2,4), and weakest at the IPS-TOS junction (Fig. 4-1). This was reflected by significant main effects of VF in the former three areas and a nonsignificant VF main effect in the latter area. This activation pattern, which was almost independent of cue validity, contrasts sharply with the intermediate amount of activation which was elicited by invalid cues of both VF in the right hemisphere. The latter activation pattern seems to be a general property of the right hemisphere, indicated by the absence of activation in the left–right invalid cue contrast.

Discussion The clinical finding that visuospatial neglect is more frequently observed after right than left hemispheric lesions led to the formulation of theories of asymmetric responses of the left and right hemisphere to lateralized input. Specifically, it was postulated that the right hemisphere responds in a more balanced fashion to ipsi- and contralateral stimuli, while the left hemisphere responds to contralateral stimuli

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Fig. 4. Occipital activations in the contrast invalid left cue trials–invalid right cue trials. Abbreviations are as in Fig. 2. The numbers correspond to the numbering in Table 2.

much more vigorously than to ipsilateral stimuli (Mesulam, 1981; Heilman et al., 1987, 1991). Our data show that the hemispheres indeed differ in their response to contra- and ipsilateral stimuli. However, the most clear-cut evidence for ipsilateral processing in the RH was obtained relatively early in the visual pathway in the lingual gyri, instead of posterior parietal cortex, and specifically the temporo-parietal junction area, which was traditionally thought to be involved in attending to ipsilateral stimuli. Responses in left occipital cortex were almost completely determined by the hemifield of the cue, with contralateral cues eliciting stronger activation than ipsilateral cues. The hemifield of the subsequent target failed to con-

tribute to the activation within these areas, valid and invalid (in which the target appeared contralateral to the cue) cue trials elicited almost identical responses. This was markedly different in right occipital cortex, in which the pattern of activation suggested that signal increases were equally determined by the VF of the cue and the target. In right lingual gyrus, lateral occipital gyrus and at the junction of the right IPS/TOS, the invalid cue trials elicited signal increases lying in between the contralateral valid and the ipsilateral valid trials. Whether the cue appeared in the contralateral and the target in the ipsilateral VF or vice versa did not influence the size of the signal increase. Thus, activation in these areas was maximal when both cue and target appeared

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in the contralateral VF, intermediate when both appeared in different hemifields, and minimal when both appeared in the ipsilateral hemifield. These patterns, selective responsiveness to contralateral cues in left, and responsiveness to cues and targets in right occipital cortex, were most pronounced in the lingual gyri and became weaker in lateral occipital cortex and the IPS/TOS region. Consistent with our data, an intermediate increase in regional cerebral blood flow when participants consecutively allocated their attention to targets in the LVF and the RVF, compared to exclusively attending to the LVF or RVF, was previously reported in a PET study for a ROI in right occipital cortex with coordinates very close to our lingual gyrus activation (Vandenberghe et al., 1997). While the block design of this study did not allow an event-related analysis of signal changes, these findings are very similar to the present finding, and it is remarkable that Vandenberghe et al. found a graded response in right, but not left occipitotemporal, cortex, just as in the present data. In a study by Macaluso et al. (2000), blockwise attending to the RVF, compared to attending to the LVF, led to increased activation in left lateral occipital gyrus, while the reverse contrast yielded no significant activation. This fits with the contralateral cueing pattern which we found across left occipital cortex. Why are asymmetric occipital activations found in some studies, while most studies report a rather symmetrical activation pattern? In most studies which yielded symmetrical activation pattern, attention was directed to a specific hemifield or location by an instruction which indicated the attended field for a whole block of trials, or by symbolic cues, typically arrows presented at fixation, which indicated the to-be-attended location for the given trial. In contrast, we used peripheral cues, which elicited a stimulus-driven attentional capture of the cued location, which, in the case of invalid cues, had to be counteracted by an endogenous attention shift. Vandenberghe et al. (1997) observed an intermediate right occipital activation when their participants divided their attention between hemifields, compared to attending to the contralateral or ipsilateral hemifield. Our data suggest, somewhat counterintuitively, that right occipital cortex responds in the same ‘divided attention’ way to a lateralized precue and a subsequent contralateral target, as if participants were, by instruction, dividing their attention between hemifields. This implies that the observed activation is driven by recurrent, top-down, signals, which are generated after cue and target have been processed, rather than by sensory, bottom-up processes. Another aspect of the data underlines this. If the activation in right occipital areas was bottom-up driven, it would be hard to understand why invalid contralateral cues elicited less activation than contralateral valid cues, because the bottom-up effect of a contralateral cue cannot depend on its validity, which is only defined by the subsequent target location. Of course, the higher activation elicited by valid contralateral cues in right occipital cortex may be a summed response to the

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contralateral cue and the contralateral target. However, this is made unlikely by the fact that the response to contralateral valid cues is almost identical to the response to contralateral valid or invalid cues in left occipital cortex. Of course this comparison may be confounded by differences in the vascular response between these brain areas. However, the almost identical signal increase in response to contralateral valid trials in both areas makes this unlikely. Taken together, the data suggest that the observed responses in the lingual and lateral occipital gyri reflect a top-down controlled response to cue and target in the right hemisphere, in contrast to a response to the cue in the left hemisphere. The comparison of left valid–right valid cueing trials elicited several frontal and cingulate activations. The general pattern observed in right superior frontal gyrus and left precentral gyrus was a somewhat stronger response to valid left and invalid right trials, i.e., to those trials in which the target appeared on the left. In cingulate gyrus, the same pattern of strong responses to LVF targets was most clearly observed in anterior cingulate, with weaker responses in the cingulate motor area and weakest in posterior cingulate. It is noteworthy that this LVF bias was observed in the anterior brain areas of both hemispheres. Such an LVF bias was predicted by attentional gradients models under the assumption that the right hemispheric gradient is overall stronger than the left hemispheric gradient (Pollmann and Zaidel, 1998). Another aspect of this model is the steeper LH gradient, compared to a less steep RH gradient. This steepness difference explained that normal participants showed higher reaction time costs when they needed to reorient from distracting items in the RVF to targets in the LVF than vice versa (Pollmann, 1996, 2000). It may also explain why more activation was elicited by invalid RVF cues, compared to invalid LVF cues, in the current experiment. Analysis of reaction times showed a clear facilitation effect for target discrimination at the cued location at an SOA of 600 ms. This is a clear indication for the presence of endogenous allocation of attention. Since we used peripheral cues, which directly indicated the target location, it might be speculated that these cues elicited an automatic, stimulus-driven capture of attention. However, automatic capture of attention is a fast, short-lived process, which gives way to inhibition of return at latencies ⬎300 ms (Collie et al., 2000). Contrary, endogenous allocation of attention acts on a slower timescale, leading to facilitation at cue-target onset asymmetries of 400 ms and longer (Mu¨ ller and Rabbitt, 1989). A potent way to elicit endogenous allocation of attention is the use of informative cues, i.e., cues which indicate the target location with a probability substantially higher than chance, as in the present experiment. Stimulus-driven capture of attention, on the other hand, depends heavily on the physical salience of the cue. In our experiment, cues were of rather low salience, only indicated by lighting up the corners of the cued area. Thus,

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while we cannot rule out the presence of some automatic capture of attention, the experimental design favored endogenous allocation of attention, and the participants’ behavior indicated that this goal was achieved. An indirect support for this claim is that the network of activations was markedly different from the network which we recently found to be involved in automatic capture of attention and inhibition of return (Lepsien and Pollmann, 2002). Thus, we found clear evidence in favor of dominantly contralateral processing in the left hemisphere and bilateral processing in the right hemisphere. However, previous models had hypothesized that such hemispheric differences in the strength of attending to contra-versus ipsilateral stimuli might be caused by an imbalance of the receptive field distribution of very high level visual areas in parietal cortex. The reasoning was that these areas contain neurons with large receptive fields which are mostly contralateral, but in a minority of neurons are ipsilateral, leading to contralateral gradients of activation (Rizzolatti et al., 1985). In humans, the differences in the strength of behavioral responses elicited by the left versus right hemisphere towards contraversus ipsilateral stimuli were suggested to be due to a higher percentage of ipsilateral receptive fields in right parietal cortex (Bisiach and Vallar, 1988). Our data, however, show that the most clear-cut hemispheric gradients are observed rather early in visual processing, in the lingual and lateral occipital gyri. This finding does not support the idea that hemispheric differences in high-level visual processing in parietal areas are the cause of the different hemispheric gradients. In this case, we should have seen a stronger response to contra- than ipsilateral stimuli in left parietal cortex, which we did not find. An open question is whether the size and contra-/ipsilateral distribution of receptive fields in the activated occipital areas in the human brain are suitable to support the receptive field explanation of attentional gradients. However, the finding that the strongest separation between dominant contralateral LH processing versus bilateral RH processing was found in lingual and lateral occipital gyri does not allow the conclusion that these areas are the source of hemispheric attentional gradients. While this cannot be ruled out, it may as well be that these activation patterns are the effect of recently processes of higher level areas on visual discrimination processes in ventral occipital cortex. In support of the latter alternative is the typical neglect localization in the right parietal-temporal junction area (Vallar, 2001) or, as has been suggested recently, in right superior temporal gyrus (Karnath et al., 2002). We found a dominant response to contralateral target presentation in the right temporoparietal junction area, irrespective of the cued hemifield. This is in agreement with previous clinical and neuroimaging studies which postulated a role of the right TPJ area in target detection, especially when the target appears at an uncued location (Friedrich et al., 1998; Corbetta et al., 2000). However, the same target-related activation pattern was also observed in other anterior cor-

tical areas, so that the specificity of the right TPJ area for contralateral target detection remains unclear in the present study.

Conclusions Event-related analyses of the BOLD signal yielded a differential pattern of activation in left and right occipital cortices. Signal changes in left occipital cortex were almost completely determined by the contra- or ipsilateral cue location. Right occipital cortex, in contrast, responded in a graded fashion, with maximal signal increase when cue and target were presented in the contralateral hemifield, less signal increase when cue and target were presented in opposite hemifields, and least activation when both appeared in the ipsilateral hemifield. This graded response in right occipital cortex may reflect the ability of the right hemisphere to attend to ipsilateral as well as contralateral stimuli.

Acknowledgments We thank Prof. D.Y. von Cramon for his neuroanatomical advice and two anonymous reviewers for their helpful comments. This study was supported by a scholarship of the University La Sapienza of Rome to M.M.

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