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Processing of bilateral versus unilateral conditions:Evidence for the functional contribution of theventral attention network

Lena-Alexandra Beume a,b,c,*, Christoph P. Kaller a,b,c, Markus Hoeren a,b,c,Stefan Kl€oppel a,b,c,d, Dorothee Kuemmerer a,b, Volkmar Glauche a,b,Lena K€ostering a,b,c,f, Irina Mader a,e, Michel Rijntjes a,b,Cornelius Weiller a,b,c and Roza Umarova a,b,c

a Department of Neurology and Neuroscience, University Medical Centre Freiburg, Germanyb Freiburg Brain Imaging Centre, University Medical Centre Freiburg, Germanyc BrainLinks-BrainTools Cluster of Excellence, University Medical Centre Freiburg, Germanyd Department of Psychiatry and Psychotherapy, University Medical Centre Freiburg, Germanye Department of Neuroradiology, and University Medical Centre Freiburg, Germanyf Biological and Personality Psychology, Dept. of Psychology, University Medical Centre Freiburg, Germany

a r t i c l e i n f o

Article history:

Received 13 October 2014

Reviewed 27 January 2015

Revised 24 February 2015

Accepted 25 February 2015

Action editor Norihiro Sadato

Published online 6 March 2015

Keywords:

Bilateral visual processing

Multi-target perception

Visual extinction

Visual neglect

Normal aging

* Corresponding author. University MedicalFreiburg, Germany.

E-mail address: lena.beume@uniklinik-frhttp://dx.doi.org/10.1016/j.cortex.2015.02.0180010-9452/© 2015 Elsevier Ltd. All rights rese

a b s t r a c t

Processing of multiple or bilateral conditions presented simultaneously in both hemifields

reflects the natural mode of perception in our multi-target environment, but is not yet

completely understood. While region-of-interest based studies in healthy subjects reported

single cortical areas as the right inferior parietal lobe (IPL) or temporoparietal junction (TPJ)

to process bilateral conditions, studies in extinction patients with reduced ability in this

regard suggested the right superior temporal cortex to hold a key role. The present fMRI

study on healthy subjects aimed at resolving these discrepancies by contrasting bilateral

versus unilateral visual conditions in a paradigm similar to the bed-side test for patients

with visual extinction on a whole brain level. Additionally, reduced attentional capacity in

spatial processing was investigated in normal aging. Processing of bilateral conditions

compared to unilateral ones showed to require stronger activation of not one single cortical

region but the entire right-lateralized ventral attention network, bilateral parietal and vi-

sual association areas. These results might suggest a conceptual difference between uni-

lateral and bilateral spatial processing with the latter depending on additional anatomical

and functional brain resources. Reduced attentional capacity in elderly subjects was

associated with compensatory recruitment of contralateral functional homologues [left

IPL, TPJ, frontal eye field (FEF)]. These data reveal the functional anatomy of our ability to

Centre Freiburg, Department of Neurology and Neuroscience, Breisacherstrasse 64, 79106

eiburg.de (L.-A. Beume).

rved.

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 292

visually process and respond to the entity of the environment and improve our under-

standing of neglect and extinction. Moreover, the data demonstrate that a restriction of the

attentional capacity is based on processing limitations in the network of high-level cortical

areas and not due to restriction in the primary sensory ones.

© 2015 Elsevier Ltd. All rights reserved.

network (Umarova et al., 2011). Studies in primates support

1. Introduction

In everyday life we are constantly surrounded by a plethora of

visuospatial information. Our reaction to it is crucial, as it

enables us to perceive and communicate with our environ-

ment. Although visual input is predominantly received bilat-

erally in both hemifields, previous neuroimaging research on

visuospatial processing has mainly investigated focused

attention to unilateral targets. This research has led to the

now well-established conceptualization of a bilateral dorsal

and right-lateralized ventral system (for a review see Corbetta

& Shulman, 2002). Herein, the bilateral dorsal attention sys-

tem is composed of the intraparietal sulcus (IPS), superior

parietal lobe and the frontal eye field (FEF), whereas the right-

lateralized ventral attention system includes the tempor-

oparietal junction (TPJ) and ventral frontal cortex, composed

of the posterior inferior and middle frontal gyri (Corbetta &

Shulman, 2002). However, the role of these networks in pro-

cessing visual information presented simultaneously to both

hemifields is currently a matter of debate.

Several single cortical regions have been linked to bilateral

visual processing in fMRI-studies on healthy subjects. As the

applied fMRI tasks differ considerably in cueing (directional

versus non directional) and stimuli set up (competing versus

non competing) and most importantly are almost exclusively

based on region-of-interest analysis, the findings are

discrepant. They include areas located in the parietal lobe, such

as the right inferior parietal lobe (IPL) (Cicek, Gitelman, Hurley,

Nobre, & Mesulam, 2007) and right IPS (Geng et al., 2006; de

Haan, Bither, Brauer, & Karnath, 2014) or areas in the occipital

lobe, such as the right ventral occipital cortex (Avidan, Levy,

Hendler, Zohary, & Malach, 2003; Belmonte & Yurgelun-Todd,

2003) and the left and right occipitotemporal junction

(Macaluso et al., 2000). Lesion mapping data on patients with

impaired bilateral processing (phenomenon of extinction),

additionally found the right TPJ (Chechlacz et al., 2013; Karnath,

Himmelbach, & Kuker, 2003; Meister et al., 2006) and superior

temporal gyrus (STG) (Karnath, Ferber,& Himmelbach, 2001) to

be crucial. Until now, however, neuroimaging studies on

healthy subjects have failed to show the involvement of the

temporal cortex in bilateral perception (e.g., Corbetta &

Shulman, 2011; de Haan et al., 2014). Taken together, the pro-

cessing of bilateral visual information has been attributed to

one or another single cortical area, with inconclusive results so

far, and not yet been investigated on a network level.

Evidence suggesting that the ability to process bilateral

information is a network effect comes from fMRI activation

patterns in patients with limited capacity in bilateral visual

processing as in visual extinction, showing the neural corre-

lates of bilateral processing to lie in the whole attention

this notion by demonstrating that bilateral target perception

requires the whole visuospatial attention network and effec-

tive interaction between nodes (e.g., Bushman & Miller, 2007).

We therefore hypothesize that processing of bilateral condi-

tions cannot be attributed to one single cortical region, but

rather depends on the functional resources of the entire vi-

suospatial attention network. With the present study we thus

aimed to provide a basis for understanding the mechanism of

bilateral stimulus processing, incorporated in the current

functional anatomy of spatial attention provided by Corbetta

and Shulman (2002): we provide a comprehensive, whole-

brain analysis of the areas involved in bilateral attention.

Equally, it is to be expected that a limited attentional ca-

pacity would be compensated not by one single region but by

the compensatory effects in the whole network. To explore

the network effect in limited attentional capacity, we included

elderly subjects in our analysis. Older adults show a physio-

logical decline in sensory bottom-up processes with subse-

quent decline in behavioral performance associated with

changes of electrophysiological characteristics during visuo-

spatial attention tasks (Curran, Hills, Patterson, & Strauss,

2001; Folk & Hoyer, 1992; Lorenzo-Lopez et al., 2002; Salt-

house, Rogan, & Prill, 1984; Yamaguchi, Tsuchiya, & Kobaya-

shi, 1995). As a decline in memory performance is partly

compensated by recruitment of frontal resources (Madden

et al., 2007; Talsma, Kok, & Ridderinkhof, 2006) or the

contralateral hemisphere (Cabeza et al., 2002) we would in

analogy to these data, also expect age-related compensational

effects in the visuospatial attention network.

To address these issues, a visuospatial paradigm was

formulated using a stochastic block design with locally

increased probabilities, which were pseudo-randomly coun-

terbalanced so as to optimize the efficiency of the task design.

Cortical activation in response to unilaterally and bilaterally

presented stimuli was then investigated in two different age

groups on a whole brain level.

2. Methods

2.1. Subjects

This study assessed 50 (25 females) healthy right-handed

(Edinburgh Inventory; Oldfield, 1971; Laterality Index for

right-handedness > 70) community-dwelling subjects, divided

into two equally sized groups of younger [27 ± 3 years (mean

age ± SD); 13 females] and older subjects (67 ± 7 years; 12 fe-

males). None of the subjects had psychiatric or neurological

histories or was taking psychoactive medication. All subjects

had normal or corrected-to-normal vision. Written informed

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 2 93

consent was obtained from each subject prior to participation,

and the study protocol was approved by the local ethics

authorities.

2.2. Functional MRI visuospatial paradigm

The present paradigm was intended to mimic the bed-side

assessment of visual extinction (Azouvi et al., 2006). During

fMRI examination either unilateral or bilateral visual stimuli

(targets) appeared for 400 msec directly after the presentation

of a centrally located, non-directional cue (exclamation mark,

800msec). The targets were yellow circles (size 1.3�) presentedat a visual angle of 11� from the central fixation point. Targets

appeared in the right (25% of trials) or left visual hemifield

(25% of trials) or bilaterally (25% of trials). In the remaining

25% of trials no target appeared (none-event trials). The trials

were separated by the presentation of a central crosshair (size

1.4�, Fig. 1a). In total, 120 trials were presented in a stochastic

block design (Henson, 2007) with locally increased probabili-

ties of occurrence for the four individual trial types (i.e., left,

right, bilateral, none-event trials) (Fig. 1b). Over the course of

the trials, local increases to an 80% probability of occurrence

for a given trial type were switched every five trials. The

assignment of trial types to these local increases and the

duration of the inter-trial intervals (jitter period of 3000 or

5000 msec) were pseudo-randomly counterbalanced to opti-

mize the efficiency of the experimental design. The fMRI

session involved one run with a duration of 12 min.

Prior to the fMRI examination all subjects completed a

behavioral training session in which they practiced perform-

ing the task whilst maintaining central fixation. Subjects were

instructed to press a button with the right thumb once for the

unilateral and twice for bilateral targets as quickly as possible.

Fig. 1 e a. Visuospatial attention task during functional MRI ex

bilateral and none - were presented. b. A stochastic block design

with local increases to an 80% probability occurrence for a give

The paradigm was designed as an easy-to-understand

paradigm with the most intuitive response selection. We

thus chose single versus double button press as this most

closely reflects the one versus two targets in the different

conditions. The unilateral right-handed response mode was

deliberately chosen, as the present studywas intended to later

serve as control data in healthy subjects for comparison with

right-hemispheric stroke patients, who often suffer from

paresis of the left arm and who often exhibit severe atten-

tional deficits. Even though the double press would lead to

stronger activation of the left-sided motor areas in bilateral

conditions (J€ancke, Specht, Mirzazade,& Peters, 1999; Leh�ericy

et al., 2006), the option of pressing an adjacent button with a

different finger would have resulted in stronger activation in

prefrontal areas (Badre, Poldrack, Par�e-Blagoev, Insler, &

Wagner, 2005; Karch et al., 2009) due to a stronger demand

in terms of active response selection. Given that prefrontal

areas are also active during visuospatial processing (Duncan,

2010), activation in these areas would have been much more

difficult to interpret as it could have been attributed to either

change in response selection or change in visuospatial

attention.

Task performance was assessed by hit and false alarm

rates and reaction time (RT). Analysis of the behavioral data

was then based on a repeated-measure ANOVA with age

group as a between-subjects factor and trial type as a within-

subject factor (see analysis below).

2.3. Data acquisition

A 3.0 T TIM Trio whole-body MRI scanner (Siemens Erlangen,

Germany) with a 12-channel head coil was used for the

functional measurements, with a T2*-weighted echo-planar

amination. Four types of trials e unilateral left and right,

with locally increased probabilities of occurrence was used,

n trial type switched every five trials.

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 294

image (SS GE EPI) sequence with blood oxygen level-

dependent contrast (repetition time 1950.0 msec, time of

echo 30.0 msec, flip angle 74�). EPI volumes with 32 axial slices

were acquired covering the whole brain (slice thickness

3.0 mm, gap .6 mm, in-plane resolution 3.0 � 3.0 mm). The

fMRI data were online-corrected for motion and distortion

(Zaitsev et al., 2004). Anatomical scans were acquired with a

sagittal magnetization-prepared rapid-acquisition gradient

echo sequence (MPRAGE, repetition time 2200msec, inversion

time 1100 msec, echo time 2.15 msec, flip angle 12�, 176 slices,

voxel size 1 � 1 � 1 mm3).

Subjects lay supine on the scanner bed with neck and side

pillows positioned to prevent excessive head motion inside

the head coil. Visual stimulation was then projected onto a

screen mounted on the rear of the scanner bore and viewed

via a mirror system using the software Presentation (version

14; Neurobehavioural Systems Inc, Berkeley, CA; https://www.

neurobs.com).

2.4. Imaging data analysis

Image preprocessing and analyses were performed using

SPM8 (version r5638; http://www.fil.ion.ucl.ac.uk/spm/

software/spm8/). The ArtRepair toolbox (v4; http://cibsr.

stanford.edu/tools/human-brain-project/artrepair-software.

html) was used to despike the motion-corrected functional

images, which were then coregistered to subjects' anatomical

scans. These anatomical scans were segmented using the

VBM8 toolbox (r435; http://dbm.neuro.uni-jena.de/software/).

Deformation field parameters for non-linear normalization

into the Montreal Neurological Institute (MNI) space were

computed using the DARTEL (diffeomorphic anatomical

registration through exponentiated lie algebra; see Ashburner,

2007) approach implemented in VBM8.

First-level estimates of hemodynamic activation changes

were computed based on the General Linear Model. Individual

regressors for the four trial types (i.e., left, right, bilateral,

none-event trials) were built by convolving stick functions of

target presentation onsets with a canonical hemodynamic

response function. In addition, head-motion parameters and

their first derivatives as well as 1st to 4th order polynomial

regressors of slow drift were entered as nuisance regressors.

Before estimation, a standard 128 sec high-pass filter was

applied to the data and the model. Given that first-level ana-

lyses were conducted in individual space, the resulting beta

images were then transformed into stereotactic MNI space

using DARTEL deformation fields from the anatomical scans.

These images were resampled to a spatial resolution of

1.5 � 1.5 � 1.5 mm3 and smoothed with an isotropic Gaussian

kernel with a full width at half maximum of 9 mm.

In the second level analysis we addressed the first step of

the study, i.e., assessing the brain regions that are more active

during bilateral versus unilateral target perception. This was

done by calculating the mean beta-image for the two trials

with unilateral targets on a single-subject level and subtract-

ing it from the beta-image of the bilateral target trial

[bilateral � (left þ right)/2].

To further investigate bilateral attention independently

from visual perception the fMRI data were analyzed using a

2 � 2 � 2 repeated-measures ANOVA with age group as a

between-subjects factor, and the presence (L) or absence (N) of

targets in the left hemifield and the presence (R) or absence (N)

of the target in the right hemifield as within-subject factors.

The four trial types were thus represented by LN (target pre-

sentation in the left hemifield), NR (target presentation in the

right hemifield), LR (bilateral presentation of two targets) and

NN (no target in either hemifield, i.e., none-event trials).

Investigating the interaction between the two within-subject

factors presence of left target and presence of right

target allowed the differentiation of focussed attention to one

target presented on one side only (i.e., right or left unilateral

target presentation, further referred to as unilateral condi-

tions) and attention to both hemifields (i.e., bilateral presen-

tation of either two targets or no target, further referred to as

bilateral conditions). The significance of activations was

assessed at p < .05 (corrected for family-wise error) and a

cluster extent of k > 5 voxels (16.9 mm3). To explore the

functional meaning of the network reorganization in elderly

subjects, we conducted a region of interest (ROI) analysis. As

ROI we used spheres of 5 mm radius centered in the peaks of

activation clusters revealed in the main effect of group. We

calculated themean of the extracted percent signal change for

bilateral, unilateral (left and right) and none-event trials for

each ROI. Next, we modeled them in the 4 x 2 mixed ANOVA

with trial type as within and group as between subject factor.

For the post-hoc contrasting of trial types a Bonferroni

correction for multiple comparisons was applied. For inter-

pretation of the activations found in the main contrast of

group, a correlation analysis between the behavioral perfor-

mance and activation in the regions revealed in the main ef-

fect of group was conducted. For behavioral performance we

used relative RT-lateralization calculated as (RT left � RT

right)/(RT right þ RT left).

3. Results

3.1. Task performance

The subjects were divided into two groups according to their

age (Table 1). All 50 subjects successfully performed the fMRI

task, except one younger subject who showed extremely

prolonged RTs (z ¼ 3.91) and was therefore excluded from

subsequent analyses. As expected, accuracy was close to

ceiling in both age groups in all trials and was therefore not

subjected to further analyses (Table 1). Given that no RTs were

available for none-event trials (NN), we performed an 2 � 3

repeated-measures ANOVA with trial type (left, right, bilat-

eral) as a within-subject factor and age group (young

versus old) as a between-subjects factor. Results revealed that

older subjects were significantly slower overall (significant

main effect of age groups, F1,47 ¼ 4.761, p ¼ .034, h2p ¼ .092).

The main effect of trial type was also significant (F2,94 ¼ 8.463,

p < .001, h2p¼ .153) without an interaction between age groups

and trial type (F2,94 ¼ 1.578, p ¼ .212, h2p ¼ .032). Post-hoc

pairwise comparisons (Bonferroni-corrected) further showed

that subjects responded significantly slower to left compared

to right (p < .001) and bilateral trials (p ¼ .029), whereas RTs to

right and bilateral trials did not differ (p ¼ .614).

Table 1 e Behavioral results.

Age groups Measures Trial types

Left Right Bilateral Nones

Young subjects Accuracy 100 ± 0% 99.86 ± .68% 98.19 ± 2.60% 98.93 ± 2.41%

Latency 367 ± 62 msec 360 ± 64 msec 363 ± 63 ms e

Old subjects Accuracy 99.73 ± 1.33% 99.07 ± 3.40% 97.87 ± 3.95% 98.93 ± 2.49%

Latency 414 ± 66 msec 395 ± 60 msec 401 ± 74 msec e

N.B. Mean ± standard deviation.

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 2 95

3.2. Functional MRI analysis

The whole brain analysis contrasting activation for bilateral

versus unilateral targets revealed stronger involvement of the

right IPL, and the right ventral attention system including the

TPJ, posterior STG and middle temporal gyrus (MTG) (one-

sample t-test, p < .05, FWE corrected, Fig. 2, Supplementary

Table 1). Additionally, strong involvement of the left-sided

motor areas was observed (Fig. 2, Supplementary Table 1),

due to the double button presses in bilateral trials.

Analysis of the interaction between target presentation in

the left and/or right hemifield was modeled as a 2 � 2 � 2

repeated-measure ANOVA with group as a between-subjects

factor and target presentation in the left (absent

versus present) and right hemifield (absent versus present) as

within-subject factors. This interaction effect allowed the

differentiation of focussed attention to unilateral targets (i.e.,

right or left unilateral target presentation, further referred to

as unilateral conditions) and attention to both hemifields (i.e.,

bilateral presentation of either two targets or no target,

further referred to as bilateral conditions). The interaction

effect between presence/absence of left and right targets

revealed a strongly right-lateralized bilateral ventral attention

system (temporal regions with TPJ, STG, MTG, anterior tem-

poral pole and posterior IFG), bilateral IPL, and visual associ-

ation areas (LOC, fusiform gyrus) (p < .05, FWE corrected)

Fig. 2 e Contrast of bilateral versus unilateral visual

stimulation (one-sample t-test, p < .05, FWE corrected)

showing stronger activation of the right-lateralised ventral

attention network. Strong involvement of the left motor

network is a result of the double button press in response

to bilateral targets.

(Fig. 3a, Table 2). The interaction pattern was found to be

disordinal for all areas, with activation in the bilateral condi-

tions significantly stronger than in the unilateral ones (Fig. 3b).

As stronger activation accounts for the two bilateral condi-

tions (two targets presented in the left and right hemifield and

no target presented at all) compared to unilateral single tar-

gets, activation in the mentioned areas is to be seen inde-

pendently from the sensory target perception (Kastner, Pinsk,

De Weerd, Desimone, & Ungerleider, 1999).

For the two main effects of target presentation in the left

and the right visual hemifield, the expected activation pat-

terns in contralateral primary visual areas emerged as a pos-

itive control (p < .05, FWE corrected) (Supplementary Figure 1,

Supplementary Table 2).

The main effect of group showed stronger activation in

older subjects in the left IPL, left FEF, and left supplementary

motor area (SMA), as well as in the bilateral TPJ (p < .05, FWE

corrected, Fig. 4, Table 3). We did not find any interaction be-

tween group and trial type on the whole brain level. However,

to further explore the functional meaning of this additional

left hemisphere activation for each trial, we conducted a ROI-

analysis. The ROI-analysis showed a significantly higher

activation of the left attention network, including the left FEF,

IPL and left TPJ, in bilateral trials compared to unilateral ones.

As the older subjects were significantly slower in target

detection than the younger subjects and demonstrated a

rightward attentional bias by longer RT to left trials, we

further performed an exploratory correlation analysis be-

tween additional left hemisphere activation and behavioral

performance. For behavioral performance we used relative

RT-lateralization calculated as (RT left � RT right)/(RT

right þ RT left). A better performance with smaller left-right

RT-lateralization correlated with stronger activation in the

left IPL (Pearson correlation, r ¼ �.433, p ¼ .003) (Fig. 3c). Thus,

recruitment of the left analogues of the attentional network

could be considered as compensational and not as

maladaptive.

4. Discussion

The data elucidate the functional anatomy of the ability to

process visual information in both hemifields. Through an

investigation of 50 healthy adults with fMRI we showed on a

whole brain level that bilateral visuospatial processing re-

quires stronger activation of the right-lateralized ventral

attention network, bilateral IPL, and visual association areas.

These data confirm the hypothesis that attentional processing

Fig. 3 e The interaction effect between uni- and bilateral trials reveals stronger activation mostly in the right hemisphere including the IPL, TPJ, posterior STG, MTG, ATL,

ventral frontal cortex (including pars triangularis (BA 45) and pars opercularis (BA 44) of the IFG and anterior insula), and bilateral visual association areas (LOC and fusiform

gyrus) (p < .05, FWE corrected). Region of interest analyses yield disordinal interaction patterns for all areas, in that activation in the bilateral trials (RL and NN) are stronger

than in the trials with unilateral left and right target targets (RN and LN).

cortex

66

(2015)91e102

96

Table 2 e Contrast depicting the interaction between presence/absence of left and right targets (p ¼ .05, FWE, n ¼ 49,2 £ 2 £ 2 ANOVA). Peak voxel (smoothing 9 9 9).

Hemisphere Cluster size Brain area x y Z F-Score

Light 1442 Inferior frontal gyrus (IFG, area 45) 39 26 �5 59.6

1145 Inferior frontal gyrus (IFG, area 44) 42 8 22 49.2

430 Superior temporal gyrus (STG) 51 �21 �8 43.0

626 Middle temporal gyrus (MTG) 51 �39 10 47.0

68 Temporoparietal junction (TPJ) 63 �42 30 27.1

573 Inferior parietal lobe (IPL) 28 �67 36 37.9

2979 LOC 34 �84 4 56.2

Fusiform gyrus (FG) 47 �54 �14 49.3

Left 813 Inferior frontal gyrus (IFG, area 45) �30 23 �6 47.9

49 Superior temporal gyrus (STG) �52 �43 13 29.0

1659 Inferior parietal lobe (IPL) �23 �69 36 32.3

LOC �34 �87 6 42.4

2736 Fusiform gyrus (FG) �42 �61 �9 61.6

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 2 97

of bilaterally presented visual information depends on the

functional resources of the entire visuospatial network and

point to a conceptual difference between focused attention to

unilateral trials and attention to both hemifields. Moreover,

these results show that visuospatial attention tasks in states

of reduced attentional capacity such as normal aging will

induce recruitment of functional homologues in the left

hemisphere.

4.1. Bilateral attention to both hemifields functionallyrelies on the ventral attention network

The present study shows widespread involvement of the

entire right-lateralized visuospatial attention network as re-

sults are depicted in a whole brain analysis. We employed a

simple bottom-up paradigm with a non-spatial cue, which

should lead to stronger activation in the attention network

than those using spatial cues (de Haan et al., 2014). The pre-

sent fMRI task also imposed a higher attentional demand by

presenting fast sequences of trials with short interstimulus

intervals (for a review see Sarter, Givens, & Bruno, 2001).

Together with the stochastic block design of the fMRI para-

digm, this resulted in a higher effectiveness of the task

(Kastner et al., 1999), thus permitting analysis on a whole

brain level.

With activation in the right TPJ, in IPL and visual associa-

tion areas during bilateral trials, the present results partially

replicate previous ones (Belmonte & Yurgelun-Todd, 2003;

Cicek et al., 2007; Geng et al., 2006; de Haan et al., 2014).

Concerning the IPL, apart from activation of the dorsal cortical

areas associated with voluntary, goal-directed attentional

processes (i.e., endogenous “top-down selection”), it has more

recently been suggested to represent a region of “multiple-

demand” (Duncan, 2010), being active in many different kinds

of tasks and across many different domains, including

perception, response selection, language, memory, problem

solving, and task novelty (Duncan & Owen, 2000). In visuo-

spatial attention, studies have shown that IPL plays a key role

in the detection of salient new items embedded in a sequence

of events. The IPL has therefore to be attributed to functions of

both, the dorsal and ventral attention system (Husain &

Nachev, 2007; Umarova et al., 2011). Concerning the visual

association areas, a similar interaction effect has been

previously documented in fusiform gyrus and lateral occipital

areas (Schwartz et al., 2005); however, our study is the first to

demonstrate that this effect extends to none-event trials. On a

functional level, the stronger activation for bilateral compared

to unilateral conditions may be a result of an increased

interplay between hierarchically higher cortical areas and

early visual cortex, where separate zones of attentional

enhancement by multi-target processing have been found

(McMains & Somer, 2004; Driver, Eimer, Macaluso, & Velzen,

2003; Kastner et al., 1999).

Particularly noteworthy, however, is the broad activation

of the temporal cortex: The contrast of bilateral versus uni-

lateral targets (Fig. 2) depicts stronger activation in the right

TPJ, STG and MTG. The interaction contrast (Fig. 3) empha-

sizes the importance of the temporal cortex in processing

information in both hemispaces by additionally revealing

activation in the right ATL. This predominance of activation in

areas of the right ventral attention system cannot be

explained by the most commonly ascribed function of the

ventral network as a “circuit breaker” during ongoing atten-

tional processes (i.e., oddball detections) (Corbetta &

Shulman, 2002; for a review see also Kim, 2014). We used the

same probability of appearance for all four trial types and all

targets were equal in size, color, and location. Stronger acti-

vation was found for the bilateral conditions, that is presen-

tation of two target in both hemifields or no target in either

hemifield and has therefore to be considered independently

from primary visual perception. We thus propose that the

activation reflects the distribution of attention to the entire

spatial task setting. The ability to attend to and process in-

formation in both hemispaces thus differs fundamentally

from focused attention to one single target.

This assumption is in line with a hypothesis recently

developed by Karnath and Rorden (2012), who suggest that the

right MTG and STG together with the right TPJ and ventral

frontal cortex (VFC) create a “perisylvian network”, converting

vestibular, auditory, neck proprioceptive, and visual input into

higher-order egocentric spatial representations. Their notion

was formulated on the basis of lesion mapping data in

extinction and neglect patients which repeatedly highlighted

the crucial role of the STG andMTG for visuospatial processing

(Karnath et al., 2001; Saj, Verdon, Vocat, & Vuilleumier, 2012).

However, until now these regions have not been shown to be

Fig. 4 e Thenetworkreorganization ineldersubjectsduringspatialprocessing: themaineffectofgroupshowthatoldersubjectsactivatedstrongerFEF,SMA,TPJ, IPL in the left

hemisphere and right TPJ in all trails compared to younger subjects (A) (repeated-measures ANOVA, p < .05, FWE corr.), while this additional recruitment was significantly

stronger to bilateral trials (B). Correlation analysis betweenbetter spatial performancemeasured in smaller left-right RTe lateralization and activation in left IPL is shown (C).

cortex

66

(2015)91e102

98

Table 3 e Main effect of Group (p ¼ .05, FWE, n ¼ 49, 2 £ 2 £ 2 ANOVA). Peak voxel (smoothing 9 9 9).

Hemisphere Cluster size Brain area x y Z F-Score

Right 11 Temporoparietal junction (TPJ) 66 �40 12 24.8

Left 21 Inferior frontal gyrus (IFG, area 44) �38 2 24 24.7

178 Frontal eye field (FEF) �44 �3 53 35.7

45 Supplementary motor area (SMA) �8 �13 60 28.8

246 Temporoparietal junction (TPJ) �54 �43 16 35.4

162 Inferior parietal lobe (IPL) �28 �66 37 33.6

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 2 99

involved in the functional anatomy of spatial attention

(Corbetta & Shulman, 2011; de Haan et al., 2012). Here we

provide direct evidence for the crucial involvement of these

temporal regions in bilateral spatial perception.

Additional support for the hypothesis that the ventral

cortical areas are crucial for in the visual processing of the

entire space reaches back to 1968, when Trevarthen suggested

that there might be two parallel streams in the visual system,

a ventral “… one ambient, determining space at large around

the body, the other one focal, which examines detail in small

areas …” (p. 299, Trevarthen, 1968). The present data corrob-

orate this notion by extending it to the attention network: The

ventral attention network is crucial when information pre-

sented in both hemispaces e large around the body e is to be

processed and put into higher-order spatial representation.

Compared to focussed or detailed attention to one single

target, bilateral processing thus additionally needs informa-

tion about the spatial setting.We thus suggest that the ventral

attention system reflects this attribution of information to the

sensory visual input. It not only serves to direct attention to

novel or salient targets, but provides for the internal concept

about the global space and converges it with the visual input

for a higher-order spatial representation.

In the present study, the processing of bilateral conditions

compared to unilateral ones showed to require stronger acti-

vation of not one single cortical region but the entire right-

lateralized ventral attention network, bilateral parietal and

visual association areas. These results suggest a conceptual

difference between unilateral and bilateral spatial processing

with the latter depending on additional anatomical and

functional brain resources.

However, it is unclear, if the observed difference in atten-

tional modulation between unilateral and bilateral stimula-

tions is due to quality or quantity, e.g., if and how the

differences in attentional modulation changes when the

attended location is manipulated from bilateral to a wider or

narrower visual field. It seems possible that the difference in

activation to unilateral and bilateral conditions therefore re-

flects two extremes of what may be a continuous span of

attentional modulation. Further studies are required to

investigate if attention to multiple targets in juxtaposition to

each other or even in the same hemifield induces an all-or-

nothing brain response or rather a gradually-changing atten-

tional modulation.

4.2. Visual neglect and extinction

These findingsmay lend support to an alternative explanation

of visuo-spatial deficits in patients, incorporating the

observed dissociations between extinction and neglect after

right hemisphere lesion. While both conditions might coexist

in some cases and some neglect patients may “recover” into

extinction (Karnath et al., 2003; Manes, Paradiso, Springer,

Lamberty, & Robinson, 1999; Rees et al., 2000; Vuilleumier &

Rafal, 2000), lesion mapping and fMRI data have clearly

differentiated both symptoms (Chechlaz et al., 2013; Cocchini,

Cubelli, Della Sala, & Beschin, 1999; Ogden, 1985; Ticini et al.,

2010; Umarova et al., 2011; Vallar, Rusconi, Bignamini,

Germiniani, & Perani, 1994; Karnath et al., 2003).

In neglect patients, bed-side testing with visual stimula-

tion shows that the left side of their field of view simply seems

to have ceased to exist. Even though they can perceive a visual

target on a primary sensory level, they are unable to further

process and respond to it e the ability to attend to both sides

of space is lost. Our data suggest that the ability to represent

and process information in both hemifields is dependent on

functional integrity of the right temporal lobe (TPJ, STG, MTG,

ATL) as well as bilateral IPL and bilateral visual association

areas. In case of lesion to one hemisphere, it would thus be

assumed that the “core syndrome” of neglect to disregard one

side of space, may be related to lesion in the right temporal

lobe. And indeed, it was shown that patients with neglect tend

to have large temporal lesions (Karnath et al., 2001). Loss of

function in these cortical areas of the ventral network might

thus lead to an inability to put primary sensory information

about theworld around us into higher-order egocentric spatial

representations. As the right hemisphere provides for the left

space, notion of the left-sided “world” is thus lost.

Patients with extinction, however, are capable to focus

attention to any target in their field of view, be it the left or the

right hemifield. The representation of the entire space “large

around the body” can thus be assumed to be intact. The pa-

tients, however, fail to detect left sided stimuli in the case of

rivalry of information, that is, when presented simulta-

neously in both hemifields. As shown in the current experi-

ment, bilateral presentation of stimuli requires stronger

activation and thus more attentional capacity than unilateral

presentation. We hypothesize that extinction is due to a

quantitative alteration in visuo-spatial attentional capacity

after right-hemisphere lesion, however without the concep-

tually different categorical loss to information about the

spatial setting spanning both hemifields. On this background,

extinction can be explained by a consequence of biased

competitive interactions between the ipsilesional and con-

tralesional target in combination with a pathologically

limited attentional capacity (de Haan et al., 2012). Taken

together, neglect and extinction conceptually differ in their

quality of symptoms while extinction patients only quanti-

tatively fail due to a diminished extend of their attentional

capacity.

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 2100

4.3. Age-related reorganization of the attention network

The two age groups differed in RT, with slower RT in elderly

subjects. These findings are consistent with previous reports

and are considered to reflect a decline in sensory processes in

older adults (Curran et al., 2001; Folk & Hoyer, 1992; Madden,

Whiting, Provenzale, & Huettel, 2004; Lorenzo-Lopez et al.,

2002; Salthouse et al., 1984; Yamaguchi et al., 1995) or the

limitation of their attentional capacity (for a review see Raz &

Rodrique, 2006). A within-group analysis in older subjects

further revealed slower target detection for the left targets

compared to the right and bilateral ones, which is also in line

with previous studies (Cicek et al., 2007; for a review see Voyer,

Voyer, & Tramonte, 2012). In general, healthy subjects show

an attentional bias favoring the left hemispace and accord-

ingly demonstrate a “pseudoneglect” to the right (Bowers &

Heilman, 1980; McGeorge, Beschin, & Della Sala, 2006). This

leftward attentional bias is thought to reflect the strong right

hemisphere dominance for spatial attention (Mesulam, 1981;

Corbetta & Shulman, 2002). The RT to bilateral trials did not

differ from RT to right trials in younger or older subjects,

which is probably because subjects started their motor

response directly after visual processing of the right target of a

bilateral trial. Nonetheless, this does not influence our inter-

pretation of fMRI results, as the time difference between

awareness of bilateral stimulation and of its right target

cannot be captured by the fMRI experiment, being in the range

of milliseconds. This also influenced why the left-right RT-

lateralization and RT to bilateral trials could be used as mea-

sure for better spatial performance.

As for the fMRI results, the group contrast showed addi-

tional cortical activation for elderly subjects in attention

centers of the left hemisphere e left FEF, TPJ and IPSe and the

right TPJ (Fig. 4a, Table 3). No significant interaction between

group and trial typewas found, suggesting that additional left-

sided activation was required for both unilateral and bilateral

attention in older adults. However, bilateral trials required

stronger additional resources of the left hemisphere atten-

tional network compared to unilateral trials. Moreover, better

spatial performance correlated with left IPL activation. Alto-

gether, these factors argue for a compensational nature of

network reorganization in normal aging and not for a mal-

adaptive one. The compensational cortical reorganization

involving several nodes of the attention network in subjects

with reduced attentional capacity confirms that our restricted

attentional resources is due to process limitations in high-

level areas and not of primary sensory ones. The stronger

activation in the left IPL and FEF is in line with the notion of an

age-related increase of top-down attention during visual tasks

(Madden et al., 2007), necessary for a stable performance as

reflected by the high accuracy rates in elderly subjects in our

paradigm (Madden et al., 2007; Rajah & D'Esposito, 2005;

Talsma et al., 2006).

These findings are in line with the theory of hemispheric

asymmetry reduction as a general reflection of the more

distributed neural-processing in aging (HAROLD, Cabeza,

2002). This effect of hemispheric asymmetry reduction has

been discussed as either a compensatory activity in models of

brain reserve (Stern, 2009) or scaffolding (Park & Reuter-

Lorenz, 2009), or as the correlate of inefficient processing

such as in the dedifferentiation model (Logan, Sanders,

Snyder, Morric, & Buckner, 2002). Alternatively, an increase

of noise in the neural networks has also been put forward as

an explanation (Li& Silkstrom, 2002). The group differences of

brain activation observed in our older compared to younger

subjects are, however, unlikely to have originated solely from

physiological differences in blood flow, metabolic rate of ox-

ygen, and blood oxygenation (Persson et al., 2006), as the

higher activated regions were specifically found for the vi-

suospatial attention system, and not, for instance, for areas of

the motor system also involved in responding to the task. The

present study thus is the first to demonstrate the HAROLD

effect for spatial attention and to reveal its compensational

nature.

5. Conclusion

Our results show that the processing of visual information

presented to both hemifields conceptually differs from

attention to one single target. Bilateral processing requires

more attentional resources from the entire visuospatial

attention system with the temporal regions being strongly

right-lateralized. We suggest that these regions are necessary

to converge input from visual association areas into higher

order spatial representation and to integrate internalized

spatial information about the two hemifields.We propose that

right-hemisphere lesion here will thus lead to a loss of this

ability with the result of neglecte an inability to hold an intact

internal representation of the entire space around. Finally, the

stronger activation of the left hemisphere shown in elderly

subjects provides evidence that the theory of hemispheric

asymmetry reduction (HAROLD, Cabeza, 2002) may be applied

to spatial attention, that is, relating physiologic aging to

compensational recruitment of functional homologues in the

left hemisphere.

Notes

L.B. received travel funds from Bayer Vital GmbH and Novar-

tis. None of the other authors has any financial or personal

relationships with individuals or organizations that could

inappropriately influence this submission. This work was

supported by the Brain Links e Brain Tools Cluster of Excel-

lence funded by the German Research Foundation (DFG, grant

#EXC1086). LK is supported by scholarship funds from the

State Graduate Funding Program of Baden-Wurttemberg,

Germany. We thank T. Bormann for discussion and sugges-

tions for the manuscript and G. Lind, S. Hoefer, S. Karn and H.

Mast for assistance in data acquisition. We also thank J. Vagg

for proofreading.

Supplementary data

Supplementary data related to this article can be found at

http://dx.doi.org/10.1016/j.cortex.2015.02.018.

c o r t e x 6 6 ( 2 0 1 5 ) 9 1e1 0 2 101

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