TMS of the FEF Interferes with Spatial Conflict

Lara Bardi1, Ryota Kanai2, Daniela Mapelli1, and Vincent Walsh2

抽象的

■ In the Simon task, a conflict arises because irrelevant spatial
information competes for response selection either facilitating
or interfering with performance. Responses are faster when
stimulus and response position correspond than when they
不要. The FEFs, which have long been characterized for their
role in oculomotor control, are also involved in the control of
visuospatial attention when eye movements are not required.
This study was aimed at investigating whether the FEFs con-
tribute to spatial conflict. Double-pulse TMS was applied to
the FEF of either left or right hemisphere during the execution
of a Simon task at different time windows after the onset of
the visual stimulus. A suppression of the Simon effect was ob-
served after stimulation of the FEF for stimuli appearing in the

contralateral hemifield when TMS was applied to the left hemi-
sphere after stimulus onset (0–40 and 40–80 msec). A reduction
of the correspondence effect was observed after right FEF TMS
for stimuli presented in the left visual hemifield when stim-
ulation was delivered in the 80–120 msec range after stimulus
onset. These outcomes indicate that the FEF play a critical
role in encoding spatial attribute of a stimulus for response
priming, which is the prerequisite for response conflict in the
Simon task. 而且, our finding that the left FEF have a
dominant role during spatial conflict extends the idea of the
left-hemisphere lateralization of the motor network in action
selection by suggesting that the FEF may constitute part of this
网络. ■

介绍

The visual environment continuously presents us with
multiple opportunities for action, and a conflict often
arises between sensorimotor processes and different pos-
sible responses. In many situations, irrelevant information
may interfere with response selection, and this effect of
interference is particularly robust when the irrelevant in-
formation is strongly associated with a dimension of the
response.

In the Simon task, a conflict arises because irrelevant
spatial information competes with relevant nonspatial in-
formation for response selection. 这里, participants are
required to respond to a nonspatial attribute of lateralized
targets (例如, color or shape) while ignoring their spatial
位置. 例如, participants may be asked to press
the left key when a red circle appears and the right key
when a green circle appears. Although stimulus location
is irrelevant to the task, RTs are faster when stimulus and
response positions correspond than when they do not
(鲁 & Proctor, 1995; Umiltà & Nicoletti, 1990; 西蒙 &
Rudell, 1967).

To explain mechanisms underlying conflict, dual-route
型号 (德容, 梁, & Lauber, 1994; Kornblum,
Hasbroucq, & Osman, 1990) postulate two parallel routes
of information processing: spatial information automati-
cally activates its spatially corresponding response via a
fast direct route, whereas the task-relevant stimulus code

1University of Padua, 2伦敦大学学院

activates the required response via a slow controlled in-
direct route ( Wascher, Schatz, Kuder, & Verleger, 2001;
Kornblum et al., 1990). The direct route may be estab-
lished by long-term associations between perceptual
and motor processes, which may depend on the synaptic
consolidation of stimulus–response (S-R) 协会
widely overlearned during lifetime (Tagliabue, Zorzi,
Umiltà, & Bassignani, 2000; 科恩, Dunbar, & 麦克莱兰,
1990). When the direct route (carrying the response linked
to the spatial position of the stimulus) and the indirect
一 (holding the task demands) generate the same re-
sponse codes (IE。, in the corresponding condition [C]),
RTs are speeded up, whereas when the two routes gener-
ate different response codes (IE。, in the noncorresponding
状况 [NC]), a conflict must be resolved, 导致
slower responses.

The “attention shift” hypothesis maintains that the irrele-
vant spatial code of the stimulus is generated by the direc-
tion of the attention shift implemented before response
选择. When the peripheral stimulus is presented, atten-
tion covertly shifts toward its position (Rubichi, Nicoletti,
Iani, & Umiltà, 1997; Nicoletti & Umiltà, 1994). 根据
to the premotor theory of attention, shifting attention is
accomplished by the generation of the motor program for
the corresponding saccade regardless of whether the sac-
cade is subsequently executed or not (Umiltà, Riggio,
Dascola, & Rizzolatti, 1991; Rizzolatti, Riggio, Dascola,
& Umiltà, 1987). The alternative hypothesis, known as
the “referential coding” hypothesis (Hommel, 1993; 看
also Hommel, 2011), states that the irrelevant spatial code

认知神经科学杂志 24:6, PP. 1305–1313

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is generated as a result of the comparison between the
location of the target stimulus and the location of an in-
tentionally defined reference stimulus (例如, the fixation
观点). Both the attention shifting and the referential cod-
ing accounts of the Simon effect have linked the process-
ing of the spatial code to attention, to some extent at least
(for a recent discussion of these hypotheses, see also
Van der Lubbe & Abrahamse, 2011).

A neural correlate for encoding spatial coordinates of
stimulus and response during conflict may be attributed
to cerebral areas devoted to the control of visuospatial at-
tention and visuomotor integration. The posterior parietal
cortex (个人电脑), as part of the dorsal visual stream, is thought
to be involved in both visuospatial attention and trans-
formation of sensory information into codes for action
(Kravitz, Saleem, 贝克, & Mishkin, 2011; Goodale &
Milner, 1992; Rizzolatti et al., 1987). Recent studies sug-
gested that PPC plays a critical role in processing irrelevant
spatial information for response priming during conflict.
TMS of PPC, applied after stimulus onset, causes a suppres-
sion of the Simon effect as if no stimulus spatial code inter-
fered with performance (Schiff, Bardi, Basso, & Mapelli,
2011; Rusconi, Turatto, & Umiltà, 2007; Stürmer, Redlich,
Irlbacher, & Brandt, 2007). On the basis of these results,
PPC has been identified as the main neural substrate of
visuomotor transmission within the direct route.

A growing body of anatomical and physiological evi-
dence suggests, 然而, that space representation and
visuomotor transformation involve other brain areas than
PPC within a distributed fronto-parietal cortical circuit. A
prominent role within this network has recently been
assigned to the FEF (科尔贝塔 & 舒尔曼, 2002), 哪个
have been shown to contribute to transformation of visual
signals into saccade commands. This area has long been
characterized for its role in the control of eye movements
(例如, Olk, 张, Kingstone, & Ro, 2006; 摩尔 & Farah,
2001; Gaymard, Ploner, Rivaud, Vermersch, & Pierrot-
Deseilligny, 1998) and has also been shown to play a role
in the allocation of attention in space, regardless of whether
movements are executed or not (例如, Gosbras & Paus,
2002; Collin, Cowey, Latto, & Marzi, 1982; Collin & Cowey,
1980).

In recent studies, TMS was applied to interfere tempo-
rarily with the activity of the FEF while participants were
engaged in a cuing task where a central cue predicted the
location of the upcoming target and the gaze was main-
tained at fixation. The results revealed that FEF TMS affects
the covert shift of attention with the control of either bilat-
eral or contralateral visual hemifield (例如, 史密斯, Jackson,
& Rorden, 2005; Grosbras & Paus, 2002). 例如,
Smith et al. (2005) showed that briefly disrupting the left
FEF eliminated the slow RTs associated with the invalid
strategic cues when the target appeared in the right visual
场地.

而且, there is evidence that TMS over the FEF of
the right hemisphere disrupts performance during con-
junction visual search tasks that require the covert alloca-

tion of attention to the target. In their study, Muggleton,
Juan, Cowey, and Walsh (2003) found that performance
was worse when the right FEF was stimulated at the same
time as the target display was presented. 有趣的是,
although many functions of the FEF and PPC seem to
重叠, the contribution of these areas to visual search
has been dissociated in the time course of their involve-
蒙特 (OʼShea, Muggleton, Cowey, & Walsh, 2006). Kalla,
Muggleton, Juan, Cowey, and Walsh (2008) reported that
TMS over the right FEF disrupted performance (caused a
reduction in d-prime scores) in an earlier period than the
right PPC in the same conjunction search task. The FEF
TMS effect occurred in a 0–40 msec range after stimulus
onset and the same effect was obtained by TMS over PPC
在 120 和 160 毫秒, a timing similar to that obtained
in previous studies ( Walsh, Ashbridge, & Cowey, 1998;
Ashbridge, Walsh, & Cowey, 1997).

The activity of the FEF in tasks in which eye movements
are not required has been interpreted in terms of the pre-
motor theory of attention (Rizzolatti et al., 1987). 然而,
this interpretation has also been challenged by more recent
findings supporting the idea that stimulus encoding and
response preparation can be decoupled in the FEF ( Juan
等人。, 2008; Juan, Shorter-Jacobi, & 沙尔, 2004; Sato &
沙尔, 2003; 汤普森, Bichot, & 沙尔, 1997). 在里面
macaque brain, two overlapping neuronal populations
have been identified, one population of visual neurons that
code visual attention and a second population of motor
neurons that code saccadic movements. Sato and Schall
(2003) recorded the activity of single neurons in the FEF
of macaque monkeys during the execution of a search task
with prosaccade or antisaccade responses. Two types of
neurons were distinguished responding differently to the
position of the target and to the endpoint of saccade.
此外, visual analysis and saccade preparation have
been dissociated in time in human FEF as indicated by
two distinct time points of TMS delivery that resulted in ele-
vated saccade latencies in a visually instructed prosaccade/
antisaccade task ( Juan et al., 2008).

On the basis of the reported functions of the FEF in
both orienting attention and transforming visual signals
into motor commands, a question arises concerning a pos-
sible role of the FEF in encoding irrelevant spatial infor-
mation for response priming in situations of conflict. 这
role of the FEF in spatial S-R conflict has never been inves-
tigated, 然而. Only one study (Rusconi, Bueti, Walsh, &
Butterworth, 2011) tested the effect of FEF TMS in the S-R
compatibility effect induced in numerical tasks (这
Spatial–Numerical Association of Response Codes [SNARC]
影响). Results revealed that the right FEF TMS after stimu-
lus onset interferes with contralateral orienting attention
in the representational space of numbers (IE。, the men-
tal number line) abolishing the compatibility effect for
small numbers (referring to the left portion of the mental
number line).

This study aimed at investigating the role of the FEF
in spatial conflict. To address this issue, we temporarily

1306

认知神经科学杂志

体积 24, 数字 6

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interfered with activity of the left and right FEF by applying
double-pulse TMS while participants were performing a
standard Simon task with lateralized stimuli. We predicted
that if the FEF play a role in automatic encoding of the
irrelevant stimulus spatial code, temporary interference
with the neural activity in this area should reduce the im-
pact of direct route processing on performance, thus reduc-
ing the correspondence effect. FEF TMS during the Simon
task was thus expected to interfere with the processing of
the irrelevant spatial attribute of the target, at least for stim-
uli appearing in the contralateral visual hemifield. 而且,
to evaluate the timing of the involvement of the FEF, 我们
applied magnetic stimulation at various time intervals after
stimulus onset. On the basis of previous data on visual
search tasks (例如, OʼShea et al., 2006), we predicted that
TMS would interfere in the Simon task in an early timing
after the onset of the visual stimulus.

方法

参加者

Fourteen healthy undergraduate students of University
College London (all right-handed; mean age = 23 年,
标准差= 2 年) with normal or corrected-to-normal visual
acuity took part in this experiment. All participants were
checked for TMS exclusion criteria ( Wassermann, 1998)
and gave their written informed consent before participa-
的. The local ethics committee approved the procedure.
The participants were reimbursed with cash for partici-
pating in the experiment. All participants were naive as to
the purpose of the study.

Apparatus and Stimuli

The participants were seated in a dimly lit and soundproof
room with their head held by a fixed head-and-chin rest at a
distance of 60 cm from a 17-in. monitor. 本实验
was programmed with Matlab Psychtoolbox (Brainard,
1997). The target stimulus was either a red or green square
subtending 1.5° × 1.5° (width × height) of visual angle
presented for 200 msec on a black background.

Procedure and Experimental Design

Each participant was tested in one experimental session
(1 天) lasting approximately 1.5 小时. Participants completed
a block of 20 practice trials followed by the experimental
blocks. A trial started with the presentation of a central fixa-
tion point (a circle subtending 0.5° of visual angle) lasting
400 毫秒. Then a stimulus was presented for 200 msec at a
visual angle of 4.5° either to the left or to the right of the
central fixation point. The intertrial interval was 3000 毫秒.
After an incorrect response, a tone (600 赫兹) was delivered
to provide feedback on the wrong answer. 参加者
were instructed to maintain their gaze on the fixation point
during the whole experimental session and were asked to
keep their eyes on the central point. Participants were in-
structed to respond, as quickly and as accurately as possi-
布莱, by pressing the left key (“F”) on the keyboard with the
index finger of the left hand when the target square was red
and the right key (“J”) with the index finger of the right
hand when the target square was green (数字 1). 这
maximum RT was 1200 毫秒.

The design involved within-participant manipulation of
sites of stimulation, S-R correspondence, and time intervals

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数字 1. A schematic representation of the trial sequence in the Simon task. (A) Paired-pulse TMS was randomly delivered in each trial at
different time intervals after the onset of the visual stimulus. (乙) The left FEF stimulation site is shown in coronal, sagittal, and transverse
sections of a participant MRI. The targeted location was identified for each participant by applying a normalization procedure. The left
FEF site corresponded to the Montreal Neurological Institute standard coordinates −32, −2, 57 and the right FEF to +32, −2, 57.

Bardi et al.

1307

between the onset of the target and the application of the
double-pulse TMS (SOA). Participants performed a baseline
condition without TMS of 64 trials followed by 12 experi-
mental blocks, four for each stimulation site (right FEF, 左边
FEF, and control site). Each block was composed of 64 试验
in which stimulus position (left or right), response position
(left or right), and TMS timing (0–40, 40–80, 80–120, 120–
180 毫秒) were fully crossed to produce the same num-
ber of trials for each possible combination presented in a
random order. A total of 256 trials were given for each
stimulation site. The order of the site of stimulation was
counterbalanced across participants.

Localization of Brain Targets for TMS Stimulation

Right and left FEF were localized by using the Brainsight
frameless stereotaxy system (Rogue Research, 蒙特利尔,
加拿大). The stimulation sites were identified on each
subjectʼs T1-weighted MRI scan and were then coregis-
tered with scalp coordinates over which TMS was delivered
(数字 1). The location of each subjectʼs right and left
FEF was determined according to anatomical landmarks.
Stimulation was applied over the posterior middle frontal
gyrus, just rostral of the junction of the precentral sulcus
and the superior frontal sulcus (Blanke et al., 2000). 我们
also checked the site of stimulation by referencing it to
each individual motor hand area (Ro, Cheifet, Ingle, Shoup,
& Rafal, 1999). With this method, 一般, TMS was ap-
plied 5 cm lateral of the sagittal midline and 3–4 cm rostral
of each subjectʼs motor hand area. This site corresponds
well with scalp coordinates used in other TMS studies of
the FEF (Kalla et al., 2008; Muggleton et al., 2003; Müri,
赫斯, & Meienberg, 1991). After normalization of the MRI
images to the Montreal Neurological Institute series aver-
年龄 (埃文斯, 柯林斯, & Holmes, 1996), mean coordinates
for the sites stimulated were ±32, −2, 57. These coordi-
nates correspond well with mean Talairach coordinates
for the FEF derived from a review of PET imaging studies
(Paus, 1996). As a control site, the point on the scalp cor-
responding to CPz in the 10–20 international system for
electrode placement was chosen. TMS over a control
site was chosen for the nonspecific effects of TMS, 这样的
as somatosensory and acoustic artifacts.

TMS Parameters

A Magstim Super Rapid2 machine (Magstim Company,
Dyfed, 英国) was used to deliver two magnetic
pulses at a frequency of 25 Hz during the task over the
right FEF, the left FEF, and CPz. A fixed level of 60% 的
the maximum machine output was employed. This level
was selected as it has previously proved effective in TMS
studies of FEF (例如, Kalla et al., 2008). A series of figure-
of-eight TMS coils (70 毫米) was used to apply stimula-
tion over the cortical sites of interest. Coils were cooled
before use to prevent overheating during a trial block

and were replaced after two blocks. For all the stimulation
站点, the experimenter clamped the coil with the handle
running in an anterior–posterior direction.

Control Experiment

Twelve healthy undergraduate students of University Col-
lege London (all right-handed; mean age = 23 年, 标准差=
1 年) took part in this experiment. Apparatus, 刺激,
and procedure were the same as in the main study. 每个
participant was tested in one experimental session (1 天)
lasting approximately 1 小时. Participants completed a prac-
tice block followed by the experimental blocks. The de-
sign involved the same within-participant manipulation
of factors as in the main experiment except for the num-
ber of TMS sites. Two sites were stimulated: the inter-
hemispheric control site used in the main experiment (这
point on the scalp corresponding to CPz in the 10–20 EEG
系统) and a left-lateralized sensorimotor (SM) 控制
site. For the SM site, the TMS coil was positioned at 2 厘米
posterior at the same laterality from each individual motor
hot spot. A similar procedure was adopted in previous
学习 (例如, Schluter, 拉什沃斯, Passingham, & 米尔斯,
1998). The TMS of this site did not induce a motor twitch
in the contralateral hand.

结果

Statistical analyses were performed on the magnitude of
the Simon effect (mean RTs for noncorresponding trials
minus mean RTs for corresponding trials) calculated as a
function of stimulus position (IE。, for left- and right-side
stimuli separately). The Simon effect for left-side stimuli
was obtained by subtracting left-side responses to left-side
刺激 (C) from right-side responses to left-side stimuli
(NC). The Simon effect for right-side stimuli was calculated
by subtracting right-side responses to right-side stimuli
(C) from left-side responses to right-side stimuli (NC). A
repeated-measures ANOVA was performed on the magni-
tude of the Simon effect with TMS Site (left FEF, right FEF,
CPz), TMS Timing Condition (0–40, 40–80, 80–120, 和
120–160 msec) and Stimulus Position (左边, 正确的) as within-
participants factors. Pairwise comparisons were then per-
formed to evaluate significant interactions.

Results showed a significant interaction of Site × Stimu-
lus position [F(2, 26) = 4.74, p < .05, ηp 2 = .27]. Left FEF TMS reduced the Simon effect for right-side stimuli com- pared with the control site ( p < .05; Figure 2). The Simon effect for right-side stimuli was 4 msec following TMS over the left FEF (C, 411 msec; NC, 415 msec), whereas it was 27 msec following TMS over the control site (C, 394 msec; NC, 421 msec). Furthermore, the effect of double-pulse TMS over the left FEF was better understood by the Site × TMS Timing × Stimulus Position interaction [F(6, 78) = 2.538, p < .05, η p 2 = .16]. This outcome revealed that the TMS inter- ference had different effects across time windows. TMS 1308 Journal of Cognitive Neuroscience Volume 24, Number 6 D o w n l o a d e d f r o m l l / / / / j f / t t i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 4 / 6 2 4 1 / 3 6 0 / 5 1 1 3 9 0 4 5 3 / 8 1 2 7 6 7 o 8 c 0 n 2 _ 5 a / _ j 0 o 0 c 2 n 2 3 _ a p _ d 0 0 b 2 y 2 g 3 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j t / f . u s e r o n 1 7 M a y 2 0 2 1 reduced the Simon effect for right-side stimuli, compared with the control site, when applied over the left FEF in the 0–40 and 40–80 msec range after stimulus onset. In the first time window, the Simon effect was reduced by TMS over the left FEF (8 msec; C, 402 msec; NC, 410 msec) com- pared with the control site (37 msec, p < .05; C, 379 msec; NC, 416 msec). When TMS was applied at 40–80 msec, the Simon effect was inverted (−10 msec; C, 416; NC, 406) as compared with the control site (32 msec; C, 383; NC, 415). In the 80–120 msec time window, there was a significant difference in the magnitude of the Simon effect for left-side stimuli between the left and right FEF TMS ( p < .05). This effect was primarily driven by a reduction of the Simon effect after right FEF TMS. The Simon effect for left-side stimuli amounted to 5 msec after right FEF TMS (C, 414 msec; NC, 419 msec) and to 44 msec after the left FEF TMS (C, 402 msec; NC, 446 msec). No differ- ence was detected between the Simon effect for left-side stimuli and the Simon effect for the control site (41 msec; C, 400 msec; NC, 441 msec; Figure 3). Figure 2. The magnitude of the Simon effect (noncorresponding minus corresponding trials) is shown separately for stimuli presented in the left and right hemifield. Left FEF TMS resulted in a suppression of the Simon effect for right-side stimuli. D o w n l o a d e d f r o m l l / / / / j t t f / i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 4 / 6 2 4 1 / 3 6 0 / 5 1 1 3 9 0 4 5 3 / 8 1 2 7 6 7 o 8 c 0 n 2 _ 5 a / _ j 0 o 0 c 2 n 2 3 _ a p _ d 0 0 b 2 y 2 g 3 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j t . / f u s e r o n 1 7 M a y 2 0 2 1 Figure 3. The magnitude of the Simon effect (noncorresponding–corresponding trials) is depicted separately for stimuli presented in the left and right visual hemifields. Double-pulse TMS caused a suppression of the Simon effect for right-side stimuli when applied in the 0–40 time windows after stimulus onset as compared with the control site. A reduction of the Simon effect has been observed for left-side stimuli when TMS was applied in the 80–120 msec timing over the right FEF. Bardi et al. 1309 Control Study DISCUSSION Results revealed that temporary interfering with activity of the FEF modulates the magnitude of spatial conflict (i.e., the Simon effect). The left FEF TMS caused a sup- pression of the Simon effect for stimuli appearing in the contralateral visual hemifield. This effect emerged when TMS was applied early after stimulus onset (0–40, 40– 80 msec). Because the position of the TMS coil could provide an additional spatial cue, one might argue that this might have interfered with S-R correspondence. To address this issue, we conducted a control experiment in which an additional left-lateralized site was stimulated to test possible nonspecific effects from left-lateralized position of the TMS coil. As in the main experiment, a repeated-measures ANOVA was performed on the magnitude of the Simon effect with TMS Site (left SM, CPz), TMS Timing Condition (0–40, 40– 80, 80–120, and 120–160 msec) and Stimulus Position (left, right) as within-participants factors. Results revealed no sources of variance. For CPz TMS, the Simon effect amounted to 26 msec for left and right FEF TMS (C, 401 msec; NC, 427 msec) and to 50 msec for right side stimuli (C, 388 msec; NC, 438 msec). For SM TMS, the Simon effect amounted to 35 for the left-side stimuli (C, 392 msec; NC, 427 msec) and to 42 for right-side stimuli (C, 389 msec; NC, 431 msec). This outcome revealed that the TMS of the left SM did not affect the magnitude of the Simon effect. This result allows us to rule out a possible confound of spatial cue introduced by the position of the coil over one hemisphere. Eye Monitoring In this study, participants were instructed to maintain fixation at the center of the screen throughout each trial. To verify that TMS delivery over the FEF did not induce involuntary gaze shifts during the task, eye posi- tion was monitored in five additional participants in the same experimental conditions as in the main experi- ment. Participantsʼ gaze behavior was recorded using a Tobii T120 eye-tracking screen run via the Tobii Studio package. The eyes were monitored from the onset of the fixation cross until the end of the stimulus presen- tation. A gaze movement was determined as a shift of at least 1.5° of visual angle from the central point. Each participant underwent two blocks of task (120 trials per block), in which paired-pulse TMS was applied over the left FEF and CPz (0–40, 40–80, 80–120 msec SOA), respectively. The rate for eye movements in valid trials (after excluding eye blinks) was 0.6% for left FEF stim- ulation and 0.7% for CPz stimulation. This outcome is in line with data from previous studies that failed to trigger eye movements by TMS of the frontal cor- tex even when high stimulation intensities were used (Müri et al., 1991; Wessel, Kcempf, Klostermann, & Moser, 1991). Previous studies suggested that the FEF play an impor- tant role in encoding stimulus position which may be independent of the execution of eye movements. No studies had investigated the contribution of the FEF in a spatial conflict task, however. In the Simon task, a conflict arises because irrelevant spatial information com- petes for response selection. In the corresponding condi- tion, responses are speeded up because stimulus spatial code automatically activates a response code that overlaps with the correct response code. In the noncorresponding condition, spatial information competes with manual re- sponse preparation generated on the basis of task instruc- tions. The results of this study support the hypothesis that the FEF contribute to the encoding of irrelevant spa- tial information, which is the precondition of response conflict in the Simon task. In line with our predictions, paired-pulse TMS applied over the FEF caused a suppres- sion of the Simon effect for visual stimuli presented in the hemifield contralateral to the site of stimulation. This effect was evident when TMS was applied to the left FEF in the first three time windows (0–40, 40–80, 80–120 msec), but this value was significant only in the earlier timings (0–40, 40–80 msec) when compared with the vertex stimulation. In contrast, a reduction of the Simon effect was observed for right FEF TMS in the late 80–120 msec time window. Previous studied reported similar involvement of PPC in the Simon task (Schiff et al., 2011; Rusconi et al., 2007). Schiff et al. (2011) applied single-pulse TMS over the left and right PPC and found a suppression of the Simon effect when the stimulation was delivered in a 130–160 msec range after stimulus onset. The present outcome suggests that both FEF and PPC may be seen as components of visuomotor processing through the direct route during spatial conflict (De Jong et al., 1994). Interestingly, the con- tribution of these areas to spatial conflict may be disso- ciated in the time course of their involvement revealing an early role of the FEF and a late role of PPC. A similar dissociation was previously found in visual search tasks (OʼShea et al., 2006; OʼShea, Muggleton, Cowey, & Walsh, 2004). Our results can well accommodate both with a premotor theory of attention and with the view that visual analysis and saccade preparation are dissociated in human FEF ( Juan et al., 2008). In the Simon task, the target may auto- matically activate a saccade preparation that competes with endogenously generated manual responses. When the TMS is applied over the FEF, the saccade preparation is disrupted, so that the spatially corresponding response receives neither facilitation nor interference from the com- peting action. Our data support the idea that TMS specifi- cally interfered with the stimulus spatial code, which probably represents saccade parameters and interacts with the selection of the manual response. Nevertheless, be- cause the effect of FEF TMS in our task is evident along 1310 Journal of Cognitive Neuroscience Volume 24, Number 6 D o w n l o a d e d f r o m l l / / / / j t t f / i t . : / / h t t p : / D / o m w i n t o p a r d c e . d s f i r o l m v e h r c p h a d i i r r e . c c t . o m m / j e d o u c n o / c a n r a t r i t i c c l e e - p - d p d 2 f 4 / 6 2 4 1 / 3 6 0 / 5 1 1 3 9 0 4 5 3 / 8 1 2 7 6 7 o 8 c 0 n 2 _ 5 a / _ j 0 o 0 c 2 n 2 3 _ a p _ d 0 0 b 2 y 2 g 3 u . e p s t d o f n b 0 y 8 S M e I p T e m L i b b e r r a 2 r 0 2 i 3 e s / j t f / . u s e r o n 1 7 M a y 2 0 2 1 different timings after stimulus onset, we cannot exclude that TMS had interfered with both visual and motor neu- rons in the FEF being both related to the automatic activa- tion of the corresponding response in the Simon task. In fact, a reduction of the Simon effect in specific conditions may be obtained by preventing the shift of spatial attention toward the position of the peripheral target (Nicoletti & Umiltà, 1994) or inducing changes in the locus of attention in paradigms with peripheral and central spatial precues (see Van der Lubbe & Abrahamse, 2011). The predominant role of the left hemisphere in the Simon task, compared with the right-hemisphere domi- nance found in SNARC task (Rusconi et al., 2011) provides new insight into differences in neural circuits that may underlie the Simon and SNARC effects (Rusconi, Umiltà, & Galfano, 2006; Mapelli, Rusconi, & Umiltà, 2003). These effects of compatibility share some important characteris- tics: The fact that RTs are affected by task-irrelevant infor- mation (stimulus position or magnitude) and the fact that the information influencing response selection is spatial in nature (perceptual or representational). However, some important differences must be considered as the processing of a stimulus appearing in the peripheral field and the processing of central symbolic cues bearing a spa- tial meaning (the number) could follow different paths before converging and gaining access to the primary mo- tor cortex for response execution (Rusconi et al., 2007). In the Simon task, the spatial irrelevant information pro- vided by stimulus position can be directly extracted and has direct access to motor selection, whereas position on the mental number line is not as directly accessible to the viewers as the physical position of a stimulus. Dif- ferences between the Simon effect and the SNARC effect also manifest themselves in their behavioral patterns. For instance, several studies reported that the size of the Simon effect, with standard horizontal S-R mapping, de- creases with longer RTs (Vallesi, Mapelli, Schiff, Amodio, & Umiltà, 2005; Rubichi et al., 1997; Hommel, 1993), whereas the size of SNARC effect is stable across differ- ent RT ranges (e.g., Mapelli, Rusconi, & Umiltà, 2003). According to Wascher and colleagues (2001), the time course of the Simon and the SNARC effects (decreasing vs. stable/increasing) reflects the presence or absence of the automatic activation of the response. According to these authors, only with spatial–anatomical S-R mapping and visual stimuli, spatial parameters are processed within privileged visuomotor pathways, automatically activating the correspondent response. Spatial–anatomical S-R map- ping refers to the overlap between stimulus and natural hand position. Our results, along with data from Rusconi et al. (2007), support the view that cognitive mechanisms subtending the Simon and the SNARC effects may be instantiated in different neural circuits even if they may still converge to a common area where the conflict is resolved. The access to a representational space and the activation of the response code in the SNARC effect seems to follow a different temporal dynamics, which may be reflected in the activation of different neural circuits. Beside the need of further investigation, we speculate that the automatic activation of the corresponding re- sponse and the resulting time course of the Simon effect with horizontal S-R mapping may be due in part to an early activation of the left FEF, which may exert their in- fluence by a direct connection with the left-lateralized system for action selection in right-handed participants (Rushworth, Johansen-Berg, Gobel, & Devlin, 2003; Schluter, Krams, Rushworth, & Passingham, 2001). The early involvement of the FEF of the left hemisphere compared with the right hemisphere during spatial conflict may be attributed to the dominance of the left hemisphere in motor attention and action selection processes in right- handed participants (Rushworth et al., 2003; Schluter et al., 2001). In the Simon task, spatial information affects perfor- mance at the response selection stage, and visuomotor processing through the direct (automatic) pathway has been proposed to be more efficient for the dominant hand in right-handed participants (Spironelli, Tagliabue, & Umiltà, 2009; Rubichi & Nicoletti, 2006). In summary, this study provides the first evidence of the involvement of the FEF in a conflict task. Our findings also provide insight into the hemispheric asymmetries of the FEF, which have been explored very little compared with the parietal lobes. 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