Neuropsychologia 70 (2015) 196–205

Contents lists available at ScienceDirect

Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia

Repetitive transcranial magnetic stimulation over the left parietal cortex facilitates visual search for a letter among its mirror images Giuseppa Renata Mangano a,n, Massimiliano Oliveri a,b, Patrizia Turriziani a, Daniela Smirni a, Li Zhaoping c, Lisa Cipolotti a,d a

Dipartimento di Scienze Psicologiche Pedagogiche e della Formazione, Università di Palermo, Edificio 15, 90128 Palermo, Italy Fondazione Santa Lucia IRCCS, Rome, Italy c Department of Computer Science, University College, London, United Kingdom d Department of Neuropsychology, National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom b

art ic l e i nf o

a b s t r a c t

Article history: Received 9 October 2014 Received in revised form 25 February 2015 Accepted 1 March 2015 Available online 3 March 2015

Interference by task irrelevant information is seen in visual search paradigms using letters. Thus, it is harder to find the letter ‘N’ among its mirror reversals ‘И’ than vice versa. This observation, termed the reversed letter effect, involves both a linguistic association and an interference of task irrelevant information — the shape of ‘N’ or ‘И’ is irrelevant, the search requires merely distinguishing the tilts of oblique bars. We adapted the repetitive transcranial magnetic stimulation (rTMS) methods that we previously used, and conducted three rTMS experiments using healthy subjects. The first experiment investigated the effects of rTMS on the left and right posterior parietal cortex (PPC) on the search performance. The second experiment focused on the role of the left PPC. The third experiment explored whether another left posterior region, known to be involved in word reading (ventral occipito-temporal cortex, vOTC), plays a role. We found that rTMS on right PPC and left VOTC had no effect on the speed and accuracy of the visual search regardless of whether the target is ‘N’ or its mirror reversal. In contrast, rTMS on the left PPC speeded up the search on finding target ‘N’ among its mirror images. We suggest that left PPC is involved in letter recognition, and that rTMS on left PPC facilitated our visual search task by reducing task interference triggered by task irrelevant letter recognition. & 2015 Elsevier Ltd. All rights reserved.

Keywords: Reversed letter Visual search asymmetries Top-down attention rTMS Parietal cortex Ventral occipito-temporal cortex.

1. Introduction Task irrelevant information has been shown to interfere in a variety of cognitive and perceptual tasks. Typical examples are: Stroop effect (Stroop, 1935), global precedence in Navon letters task (Navon, 1977), Simon effect (Simon and Rudell, 1967; Umiltá and Nicoletti, 1990), and the Flanker effect (Eriksen and Eriksen, 1974). The Stroop effect is manifested in the reduced accuracy and speed in naming the ink color (e.g., green) of a word when the literal meaning of the word is another color (e.g., red). In the Navon letter task, observers trying to name many identical letters, for example, ‘A’, arranged in a global array shaped like, for example, ‘H’, are slower than if the array is shaped like ‘A’ instead. The Simon effect refers to the observation that, when observers try to, e.g., press a left or right button to report a green or a red object, respectively, their response is slower and less accurate when the green or red object is in the right or left part of the display, n

Corresponding author. Fax: þ39 091 23897750. E-mail address: [email protected] (G.R. Mangano).

http://dx.doi.org/10.1016/j.neuropsychologia.2015.03.002 0028-3932/& 2015 Elsevier Ltd. All rights reserved.

respectively, opposite to the lateral side of the associated response button (Umiltá and Nicoletti, 1990; Lu and Proctor, 1995). The flanker effect is the tendency to incorrectly report the direction of the central target arrow when the flanking arrows point in the opposite direction, for example in this stimulus { 4 { . These four examples indicate that the tasks elicited the processing of the task irrelevant information: the literal meaning of the text in the Stroop effect, the global array shape in the Navon task, the spatial location of the reported object in the Simon effect, and the property of the flanking arrows in the flanker effect. The processing of irrelevant information, when it is in conflict, caused interference to the task performance. A large body of neuroimaging and transcranial magnetic stimulation (TMS) studies has reported a role of the medial prefrontal cortex (mPFC) and especially the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), and posterior parietal cortex (PPC) in conflicting or interfering conditions (see Nee et al. (2007), for a meta-analysis). ACC activation is widely observed in tasks requiring participants to resolve response conflict (e.g., in Flanker or Stroop tasks, Botvinick et al., 1999, 2001, 2004; van Veen et al., 2001; Ridderinkhof et al., 2004; Chen et al., 2006;

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

Botvinick, 2007; Carter and van Veen, 2007). Meanwhile, TMS over the right PPC produced a reduction of the Simon effect (Schiff et al., 2011). In these studies, the results were interpreted as the disruption of the spatial representation following TMS. Interference by task irrelevant information is also seen in visual search paradigms developed by Zhaoping and Guyader (2007) and Zhaoping and Frith (2011). In these studies, the search task is to find a uniquely oriented bar in a visual display. However, this target bar is embedded in an object shape that is identical to the shape of many other objects in the display. For example, the target bar can be an oblique bar tilted 45° clockwise from vertical, and it intersects a horizontal or vertical bar to make an ‘X’ shape. Meanwhile, the display contains many other ‘X’ shapes, each made by intersecting an oppositely tilted oblique bar (45° counterclockwise from vertical) and a cardinal (horizontal or vertical) bar. Although the target bar is unique in the display by its low level feature, its orientation, the object shape (‘X’) that it is embedded in is not unique in the display. The shape information is task irrelevant, however, it interferes with the search task and prolongs the reaction time for the task decision (Zhaoping and Guyader 2007). In a repetitive-transcranial magnetic stimulation (rTMS) study (Oliveri et al., 2010), we documented that rTMS in the right but not left PPC reduced significantly the task reaction times (RTs) in this visual search task. Notably, a paradoxical facilitation, manifested again as a significant reduction in RTs in the same task, was reported in a group of patients with right parietal lesions (Mangano et al., 2014). These findings suggest that the right PPC is involved in processing the task irrelevant shape information, and that rTMS on the right PPC reduced such task irrelevant processing to make the search faster. Zhaoping and Frith (2011) extended the visual search paradigm to task-irrelevant shapes of letters. For example, in a search display containing a letter ‘N’ among many of its mirror reversals ‘И’, the unique target is the left tilted oblique bar in ‘N’. However, the same zig-zag shape shared by N and its mirror reversals confused the observers and prolonged their RTs, even though the task does not require any letter or shape recognition. This interference by the task-irrelevant shape is weaker when the target bar is the oblique bar in the mirror reversal, ‘И’, displayed among many normal ‘N’s. The difference in the interference is termed the reversed letter effect (Frith, 1974). This finding suggests a possible role of familiarity (Treisman and Souther, 1985; Wang et al., 1994; Malinowski and Hübner, 2001; Wolfe, 2001) and reading processes in the zigzag shape recognition that leads to the interference. There is some TMS evidence suggesting that right and left PPC may be differentially involved in processing sensory information according to whether the information has linguistic associations (Cattaneo et al., 2008, 2009). Using the TMS-adaptation paradigm,

197

Cattaneo et al. (2009) found a faster detection of the adapted letters after TMS of left but not the right PPC. In addition, they showed that this effect of the left PPC was independent of whether the letters were in capital or lower case, suggesting a causal role of the left PPC in abstract letter processing rather than a mere visual form processing. Related to the findings, a functional magnetic resonance imaging (fMRI) study by Callan et al. (2005) reported that activation of the left PPC is associated with processing visual shapes as letters when the visual forms carried phonological information. Meanwhile, a given auditory or visual stimulus, e.g., a letter presented in acoustic or visual form, elicited left PPC activation when the task was to discriminate phonological information but not when the task was to discriminate its non-linguistic attributes (Salo et al., 2013). Noting that the reversed letter effect involves both a processing of task irrelevant information and a linguistic association, we aim by the current rTMS study to investigate whether the right PPC and/or left posterior regions (left PPC, left ventral occipito-temporal cortex) play a role in the reversed letter effect. We adapted the rTMS methods that we previously used in Oliveri et al. (2010) onto the letter stimuli, and conducted three experiments using healthy subjects. The first experiment investigated the effects of rTMS on the left and right PPC on the task performance. Since the first experiment suggested that rTMS on the left PPC reduces RTs in our visual search task, the second experiment focused on the left PPC to verify this finding. The third experiment explored whether another left posterior region, known to be involved in word reading (ventral occipito-temporal cortex, vOTC, Duncan et al., 2010), played a role.

2. Material and methods 2.1. Participants A sample of 88 healthy right-handed subjects (17 males, 71 females; mean age: 2473 years) participated in three experiments. All participants were literate Italian native speakers and were naive to the purposes of the study. They had normal or corrected to normal vision. There was no previous history of neurological or psychiatric disorders. For each subject, we obtained written informed consent for participation in the studies. 2.2. Experiment 1: Left–right PPC rTMS The aim of the first experiment was to investigate the contributions of left and right PPC to visual search in stimuli involving linguistically meaningful symbols (“N” see target-in-N stimulus in Fig. 1) and linguistically meaningless symbols (“И” see target-in-

Fig. 1. Experimental stimuli. (a) In target-in-N stimulus, the target bar was in an object shape ‘N’ contained familiar verbal information. (b) In target-in-reversed N stimulus, the target bar was in an object shape ‘И’ which was the mirror reversal of ‘N’.

198

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

reversed-N stimulus in Fig. 1). Sixty healthy right-handed subjects (15 males, 45 females; mean age: 2473 years) were randomly assigned in two groups, according to the hemisphere stimulated: right PPC (N ¼30) and left hemisphere group (N ¼30). 2.2.1. Task We used two stimuli previous employed in the study of Zhaoping and Frith (2011) (Fig. 1). The task required search for a uniquely tilted, oblique bar. All the oblique bars were contained in an object shape ‘N’ or ‘И’. There were two stimuli types, one type had the target bar embedded an object shape ‘N’ that contained familiar verbal information, we call this the target-in-N stimulus; the other had the target bar embedded in an object shape ‘И’ which was the mirror reversal of ‘N’, and we call this the target-in-reversed-N stimulus. The target oblique bar was always tilted in the opposite direction to the other oblique bars. The pre-attentive feature, the unique oblique bar that makes the target salient, was present in both types of stimuli. The target was randomly in the left or right half of the display on a 17 in. monitor. Display was viewed at a distance of 55 cm on a white background. The fixation stimulus was a black cross at the display center. Each item in the search display was displaced at a position jittered randomly, horizontally and vertically, from its grid location in a regular grid of 6 rows  8 columns, spanning correspondingly 23  38° in visual angle. Each stimulus bar was 0.10  0.83° in visual angle. 2.2.2. Procedure There were two experimental sessions for each subject. One experimental session was without rTMS stimulation, we termed this session Baseline. The other session was with rTMS stimulation. The rTMS was administered immediately before the subjects performed visual search trials. We termed this session rTMS session. We counterbalanced the order of these two sessions between subjects. Between each session, there was a two hour delay. This delay allowed the rTMS effects to be washed out. Before each experimental session, all the participants performed 1 practice trial per stimulus type. The words “letter” or “N” were never mentioned. Subjects were instructed to search for the target item containing a uniquely tilted oblique bar that was tilted in the opposite direction from the uniformly oriented oblique bars in the distractors. A left or right button were pressed, as fast as possible, with the index or middle fingers of the right hand, respectively to indicate whether the target was in the left or right half of the display. To minimize the influences of strategic factors, subjects were asked not to search systematically as, for example, when reading. Each session (baseline and rTMS), contained 80 stimulus displays, with 40 trials for each stimulus type. The trials from the two stimulus types were randomly interleaved in each session. Participants were informed that the uniquely oriented target bar could be randomly tilted clockwise or counter-clockwise from vertical in each trial. They were instructed to ignore the vertical bars. Each trial started with a fixation stimulus lasting 600 milliseconds (ms), followed by blank screen lasting 200 ms, and then followed by the search display. The search stimulus stayed on the screen till the participant’s button press. Button presses and their RTs were recorded. 2.2.3. rTMS rTMS trains at 1 Hz frequency and 600 s duration were applied using a MagStim Rapid 2 magnetic stimulator and a figure-of-eight coil (diameter: 70 mm).

In each rTMS session, rTMS was applied over one scalp site corresponding to P3 or P4 positions of the 10–20 EEG system for the left or the right group, respectively. The target sites were marked on a tightly fitting Lycra cap worn by the subject. The figure-of-eight coil was applied tangentially on the target scalp site, with the handle pointing posteriorly, so as to induce a current with posterior-to-anterior direction in the underlying brain areas. The intensity of rTMS was at 90% of motor threshold (MT), defined as the minimal TMS intensity (as assessed with singlepulse TMS) able to elicit a visible muscle twitch of the contralateral hand in at least 50% of a sequence of 10 consecutive trials (Rossini et al., 1994). MT was determined on the same hemisphere of the stimulated left or right PPC. There were no interhemispheric differences in MT values between the left (57 77%) and the right hemisphere (56 75%) (p ¼0.30). 2.3. Experiment 2: Left PPC rTMS including target absent trial Since, as will be shown in detail later, experiment 1 implicated left PPC for the reversed letter effect, experiment 2 aimed to further substantiate the findings regarding the left PPC. In addition, it used catch trials, which had no target in the search display, to control for a possible lateral bias of the target location. In this experiment we included target absent trials and stimulated the left PPC only. Sixteen healthy right-handed subjects (1 males, 15 females; mean age: 227 1 years) were enrolled. We used the same stimuli and procedures as those administered in experiment 1 except for the rTMS site which was the left PPC. The differences with experiment 1 were the following: 50% were target absent trials, 50% were target present trials (25% with target-in-N stimulus, 25% with target-in-reversed-N stimulus); only the left PPC was tested; subjects pressed a left or right button, as fast as possible, with the index and middle fingers of the right hand, respectively to indicate whether the target was present or absent. 2.4. Experiment 3: Left vOTC rTMS The aim of the third experiment was to investigate whether some other areas in left hemisphere may play a role on our visual search task. In particular, we investigated the contribution of the left vOTC, an area known also as sensitive to reading visual words (Duncan et al., 2010). In a preliminary experiment to functionally localize the left vOTC, we tested 12 healthy right-handed subjects (1 male, 11 females; mean age: 2574 years). In each subject the rTMS of the left vOTC interfered with word recognition. The 12 subjects performed a visual lexical decision task while rTMS was delivered to the left vOTC following the procedure described in the study of Duncan et al. (2010). The visual lexical decision task included: low frequency Italian words and readable non-words. Frequency values were obtained from the database of Barca et al. (2002). The rTMS intensity was set to 100% of motor threshold; pulses were delivered at 10 Hz frequency and 500 ms duration using a MagStim Rapid 2 magnetic stimulator and a figure-of-eight coil (diameter: 70 mm). At the beginning of the localization procedure, rTMS was applied over the left vOTC, corresponding to the middle point between T3 positions of the 10–20 EEG system and the left cerebellum defined as Theoret et al. (2001) and Oliveri et al. (2009) (1 cm under and 3 cm left to the inion). The figure-of-eight coil was applied tangentially on the target scalp site, with the handle pointing posteriorly, so as to induce a current with posterior-to-anterior direction in the underlying brain areas. The onset time of rTMS pulses were synchronized with the presentation

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

of stimulus words or non-words. Each trial began with a fixation cross displayed for 500 ms, followed by a visual letter string for 200 ms and then a blank screen for 2300 ms. Subjects were instructed to press a left or a right button with the right index and middle fingers respectively to indicate whether the letter string was a real word in Italian or not. Subjects performed the task in baseline and during rTMS. We compared subjects’ RTs in baseline and in rTMS session. Difference in the averaged RTs between baseline and rTMS session was used as criteria to determine an effect in this visual lexical decision task. If rTMS interfered by prolonging RTs with word recognition we marked the target site on a tightly fitting Lycra cap worn by the subjects and they underwent the main experiment, otherwise the coil was moved slightly over the site along a 3 cm  3 cm grid and the procedure was repeated until the interference with word recognition was obtained. A two tailed t-test comparing the subjects’ averaged RTs in baseline and in rTMS, revealed that rTMS significantly increased RTs in word (p¼ 0.007) but not in non-word recognition (p ¼0.12). Once the left vOTC was localized, the same group of 12 subjects performed the visual search task. We used the same stimuli and procedures as those administered in experiment 1 except for the rTMS site which was the left vOTC. 2.5. Data analysis For each stimulus type, we calculated its accuracy, which is the proportion of correct button presses, and the averaged RTs of the correct button presses. We compared the accuracy and the averaged RTs in each stimulus type in baseline and in rTMS sessions, within subjects in each session. In experiment 1, separate ANOVAs were conducted on the accuracy and the averaged RTs, with stimulus type (targetin-N vs. target-in-reversed-N) and session (baseline vs. rTMS) as within-subject factors and hemisphere (right vs. left) as a between-subject factor. In addition, for each hemisphere group (left group and right group), two separate ANOVAs were conducted on the accuracy and the averaged RTs with stimulus type (target-in-N vs. target-in-reversed-N) and session (baseline vs. rTMS) as within-subject factors. In experiments 2 and 3, separate ANOVAs were conducted on the accuracy and the averaged RTs, with stimulus type (target-in-N vs. target-in-reversed-N) and session (baseline vs. rTMS) as within-subject factors. Although we can control for subject variability by comparing the rTMS and baseline data within subjects, due to learning, subjects typically perform the tasks faster and/or better in their second session, thereby bringing a large learning-related variability in data in each type of session (baseline or rTMS) since we counterbalanced the orders of the two session types. Therefore, we further compared rTMS and baseline data between subjects using only the data of the session which was carried out first (either baseline or rTMS) for each subject. In experiment 1, separate ANOVAs were conducted on the accuracy and the averaged RTs, with stimulus type (target-in-N vs. target-in-reversed-N) as within-subject factors and session (left PPC rTMS vs. baseline vs. right PPC rTMS) as a between-subject factor. In experiments 2 and 3, separate ANOVAs were conducted on the accuracy and the averaged RTs with stimulus type (target-in-N vs. target-in-reversed-N) as within subject factors and session (baseline vs. rTMS) as a between-subject factor. In addition to ANOVA, we also used targeted t-tests to address our pre-planned experimental question: whether there is any significant difference between the average RT in an rTMS session and the average RT in a baseline session, either within subjects (using matched-sample t-test) or between subjects (non-matchedsample t-test), for each stimulus type (target-in-N or target-in-

199

reversed-N). All t-tests are two-tailed except on the RT data in experiment 2 (where one-tailed t-test is used) to verify whether rTMS on the left PPC can indeed reduce RT, as suggested from the outcome of experiment 1. The p-values smaller than 0.05 from these t-tests are indicated in our figures. Value of po 0.05 was considered as significant.

3. Results 3.1. Experiment 1: Left–right PPC rTMS 3.1.1. Accuracy Overall subjects were very accurate. In the within subjects analysis, the mean accuracies for the target-in-N and target-in-reversed-N stimuli, respectively, were: 0.93 (sd ¼0.09) and 0.95 (sd ¼0.05) for the baseline session of the left PPC group, 0.93 (sd ¼ 0.08) and 0.94 (sd ¼0.06) for left PPC rTMS session, 0.94 (sd ¼0.05) and 0.94 (sd ¼ 0.05) for the baseline session of the right PPC group, and 0.96 (sd ¼0.04) and 0.96 (sd ¼0.04) for right PPC rTMS session. The corresponding values from the between subjects analysis were: 0.92 (sd ¼0.06) and 0.92 (sd ¼0.06) for the baseline (left group), 0.91 (sd ¼ 0.09) and 0.92 (sd ¼0.08) for left PPC rTMS; and 0.94 (sd ¼0.04) and 0.95 (sd ¼0.03) for right PPC rTMS. The ANOVAs showed no significant main effect for any factor stimulus type, session or hemisphere nor any significant interaction in both the within (stimulus type: F ¼2.38; d.f. ¼1,58; p ¼0.12; session: F¼0.43; d.f. ¼ 1,58; p ¼0.51; hemisphere: F¼0.79; d. f.¼ 1,58; p ¼0.37; stimulus type  hemisphere: F¼0.91; d.f. ¼1,58; p¼ 0.34; stimulus type  session: F ¼0.24; d.f. ¼1,58; p ¼0.62; session  hemisphere: F ¼2.38; d.f. ¼1,58; p ¼0.12; stimulus type session  hemisphere: F¼0.02; d.f. ¼ 1,58; p¼ 0.87) and the between subjects analysis (stimulus type: F¼ 1.58; d.f. ¼ 1,57; p¼ 0.21; session: F¼ 0.79; d.f. ¼2,57; p ¼0.45; stimulus type session: F¼ 0.04; d.f. ¼2,57; p¼ 0.95). Similarly, no significant main effect for the factor stimulus type or session nor significant interactions were found in the two separate ANOVAs conducted on each hemisphere group (“left group”: stimulus type: F¼2.42; d.f. ¼ 1,29; p ¼0.13; session: F¼0.34; d.f. ¼1,29; p¼ 0.55; stimulus type  session: F ¼0.12; d. f.¼ 1,29; p ¼0.72) (“right group”: stimulus type: F¼0.24; d.f. ¼1,29; p¼ 0.62; session: F¼2.76; d.f. ¼1,29; p ¼ 0.10; stimulus type session: F¼ 0.16; d.f. ¼ 1,29; p¼ 0.69). 3.1.2. Averaged RTs The ANOVAs on the averaged RTs showed a significant main effect of the stimulus type in both the within (F¼ 149.1; d.f. ¼1,58; po 0.0001; see Fig. 2a) and the between subject analysis (F¼126.58; d.f. ¼1,56; p o0.0001; see Fig. 2b). RTs were significantly longer for the target-in-N stimuli than the target-in-reversed-N stimuli. A significant interaction stimulus type  session  hemisphere was found in the within subject analysis (F¼4.60; d.f. ¼1,58; p¼ 0.03). In particular, the left PPC rTMS significantly reduced RTs only for the target-in-N stimuli (p ¼0.03, matched-sample twotailed t-test) but not for the target-in-reversed-N stimuli (p ¼0.21) (see Fig. 2a). In contrast, right PPC rTMS did not modify RTs in either stimulus type (target-in-N: p ¼0.71; target-in-reversed-N: p¼ 0.92) (see Fig. 2a). The other main effect of session and hemisphere as well as the interactions were all not significant (“within subject analysis”: session: F¼1.66; d.f. ¼1,58; p ¼0.20; hemisphere: F¼0.12; d. f.¼ 1,58; p ¼0.72; stimulus type  hemisphere: F¼0.06; d.f. ¼1,58; p¼ 0.79; stimulus type  session: F¼1.31; d.f. ¼ 1,58; p ¼0.25; session  hemisphere: F ¼2.30; d.f. ¼1,58; p ¼0.13) (“between

200

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

a

b

Fig. 2. Experiment 1. Baseline and post-rTMS performance in the visual search task. (a) Average RTs (ms) to report the lateral side of the target in Exp. 1 (within subjects for each hemisphere). (b) Average RTs (ms) to report the lateral side of the target in Exp. 1 (between subjects for different sessions).

subject analysis”: session: F¼1.32; d.f. ¼2,57; p ¼0.27; stimulus type  session: F¼1.12; d.f. ¼2,57; p ¼0.33). Two separate ANOVAs conducted on each hemisphere group showed a significant main effect of the stimulus type in both the left group (F¼84.02; d.f. ¼1,29; po 0.0001) and the right group (F¼ 67.64; d.f. ¼1,29; p o0.0001). The main effect of session (rTMS vs. baseline) approached significance in the left (F¼3.63; d. f. ¼1,29; p ¼0.06) but not in the right group (F¼ 0.02; d.f. ¼1,29; p ¼0.86). A significant interaction stimulus type  session was found only in the left group (F¼6.68; d.f. ¼ 1,29; p ¼0.015) but not in the right group (F¼0.42; d.f. ¼ 1,29; p¼ 0.52). In summary, Experiment 1 demonstrated that rTMS of the left but not the right PPC selectively decreased RTs in the target-in-N stimuli, although this effect did not reach significance in the between subject analysis. Although the effect of rTMS on the left PPC is only for the target-in-N and not the target-in-reversed-N stimuli, the ANOVA on the left PPC group revealed an almost significant main effect of rTMS (i.e., this effect is regardless of the type of the stimuli). 3.2. Experiment 2: Left PPC rTMS including target absent trial 3.2.1. Accuracy In the within subjects analysis, the mean accuracies for the target-in-N and target-in-reversed-N stimuli, respectively, were: 0.66 (sd ¼ 0.17) and 0.91 (sd ¼0.05) for the baseline session, and 0.67 (sd ¼ 0.17) and 0.88 (sd ¼ 0.10) for the left PPC rTMS session. In the between subjects analysis, the corresponding mean accuracies were: 0.68 (sd ¼0.16) and 0.89 (sd ¼ 0.05) for the baseline session, and 0.65 (sd ¼0.22) and 0.84 (sd ¼ 0.11) for the left PPC rTMS session. The ANOVAs showed only a significant main effect of the

stimulus type in both the within (F¼ 40.81; d.f. ¼1,15; p o0.0001) and the between subject analysis (F¼20.62; d.f. ¼ 1,14; p ¼0.0004). Subjects were significantly less accurate in target-in-N stimuli than in the target-in-reversed-N stimuli. The errors consisted in misses. However, the other main effect of session as well as the interaction stimulus type  session were not significant in both the within (session: F¼0.35; d.f. ¼1,15; p¼ 0.56; stimulus type session: F¼1.83; d.f. ¼1,15; p ¼0.19) and the between subjects analysis (session: F¼ 0.48; d.f. ¼1,14; p ¼ 0.49; stimulus type session: F¼ 0.02; d.f. ¼1,14; p¼ 0.88). 3.2.2. Averaged RTs For the target present trials, as in experiment 1, the ANOVAs showed a significant main effect of the stimulus type in both the within (F¼41.83; d.f. ¼ 1,15; p o0.0001; see Fig. 3a) and the between subject analysis (F¼22.83; d.f. ¼1,14; p ¼0.0002; see Fig. 3b). The averaged RTs were significantly longer for the targetin-N stimuli than for the target-in-reversed-N stimuli. The main effect of session, baseline vs. rTMS, almost reached significance in both the within (F¼ 3.4; d.f. ¼ 1,15; p ¼0.08) and between (F¼4.5; d.f. ¼ 1,14; p ¼ 0.051) subject analysis. In particular, in the within subject analysis, rTMS reduced RT (of the target present trials) significantly for the target-in-N stimuli (p¼ 0.019, matched-sample one-tailed t-test), although not significantly for the target-in-reversed-N stimuli (p ¼0.14), causing a significant interaction between session and stimulus type (F¼4.87; d.f. ¼1,15; p¼ 0.043). Meanwhile, for the between subject analysis, rTMS reduced RT significantly for both target-in-N and target-in-reversed N stimuli in the between subject analysis (p¼ 0.021 and p ¼0.049, respectively, one-tailed t-test), so there is no significant interaction

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

201

a

b

Fig. 3. Experiment 2. Baseline and post-rTMS performance in the visual search task. (a) Average RTs (ms) for target present trials in Exp. 2 (within subjects for different sessions). (b) Average RTs (ms) for target present trials in Exp. 2 (between subjects for different sessions).

between session and stimulus type (F¼ 1.3; d.f. ¼ 1,14; p ¼0.27), see Fig. 3a and b. Analogous ANOVA analysis was conducted on the RTs of the target absent trials. Interestingly, rTMS on left PPC also reduced RTs even in the target-absent trials. The main effect of session, rTMS vs. baseline, was significant in the between subject analysis (session: F¼5.53; d.f. ¼1,14; p ¼0.03) though not within subjects (F¼ 2.89; d.f. ¼1,15; p ¼0.11). The average RT in the rTMS session was significantly smaller than that in the baseline session for each stimulus type in the between subject analysis (p ¼0.017 for targetin-N and p ¼ 0.019 for target-in-reversed-N, one-tailed t-test), this was also the case for target-in-N and nearly so for target-in-reversed-N stimuli (p ¼0.048 and p ¼0.066, matched sample onetailed t-test) in the within subject analysis. Although a lack of a target in these target-absent trials should not cause a confusion between target and non-targets, a reduced task interference in the target-present trials in the same session may have caused a reduced cognitive demand for conflict management to improve task performance. As expected, there is no significant main effect of the stimulus type nor interaction between stimulus type and session in both the within (Fo0.9; d.f. ¼1,15; p 40.35) and between (Fo 0.034; d.f. ¼1,14; p 40.85) subject analysis. In summary, experiment 2 strengthened the findings reported in experiment 1 that rTMS over the left PPC significantly reduced RTs, particularly in the target-in-N stimuli and this was found in both the within and between subject analyses. Notably, rTMS on the left PPC was also found to reduce RT for the target-in-reversed-N stimuli by the between subject analysis.

3.3. Experiment 3: Left vOTC rTMS In this experiment we were able to investigate whether rTMS over a different left posterior hemisphere area could also modulate performance in the target-in-N stimuli. 3.3.1. Accuracy In the within subjects analysis, the mean accuracies for the target-in-N and target-in-reversed-N stimuli, respectively, were: 0.92 (sd ¼0.06) and 0.93 (sd ¼0.06) in the baseline session, and 0.89 (sd ¼0.10) and 0.90 (sd ¼0.07) in the left vOTC rTMS session. In the between subjects analysis, the corresponding mean accuracies were: 0.93 (sd ¼0.04) and 0.91 (sd ¼0.08) in the baseline session, and 0.85 (sd ¼ 0.09) and 0.87 (sd ¼0.07) in the left vOTC rTMS session. The ANOVAs showed no significant main effects for the factors stimulus type and session nor significant interaction between stimulus type and session in both the within (stimulus type: F¼0.41; d.f. ¼ 1,11; p ¼0.53; session: F¼3.18; d.f. ¼1,11; p ¼0.10; stimulus type  session: F¼0.00; d.f. ¼1,11; p ¼0.99) and the between subjects analysis (stimulus type: F¼0.00; d.f. ¼ 1,10; p ¼1; session: F¼1.73; d.f. ¼ 1,10; p ¼0.21; stimulus type  session: F¼1.13; d.f. ¼ 1,10; p ¼0.31). 3.3.2. Averaged RTs The ANOVAs showed only significant main effect for stimulus type in both the within (F¼15.87; d.f. ¼ 1,11; p ¼0.02) and the between subjects analysis (F¼12.14; d.f. ¼1,10; p ¼0.005) (see

202

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

a

b

Fig. 4. Experiment 3. Baseline and post-rTMS performance in the visual search task. (a) Average RTs (ms) for target present trials in Exp. 2 (within subjects for different sessions). (b) Average RTs (ms) for target present trials in Exp. 2 (between subjects for different sessions).

Fig. 4). The averaged RTs were significantly longer for the targetin-N stimuli than for the target-in-reversed-N stimuli. However, the other main effect of session as well as the interaction stimulus type  session were not significant in both the within (session: F¼0.30; d.f. ¼ 1,11; p ¼0.59; stimulus type  session: F¼ 0.04; d. f. ¼1,11; p ¼0.83) and the between subjects analysis (session: F¼0.01; d.f. ¼1,10; p ¼0.89; stimulus type  session: F¼0.87; d. f. ¼1,10; p ¼0.37) (see Fig. 4). In summary, experiment 3 indicated that rTMS over the left vOTC had no significant effect on either accuracy or RTs in each stimulus type.

4. Discussion In the current rTMS study we explored whether the right PPC and/or left posterior regions (left PPC, left vOTC) play a role in the reversed letter effect. We adapted the rTMS methods previously used in Oliveri et al. (2010) onto the letter stimuli, and conducted three experiments using healthy subjects. The first experiment investigated the effects of rTMS on the left and right PPC. It revealed that rTMS on right PPC had no effect in the task performance (speed and accuracy) regardless of whether the target, an uniquely tilted oblique bar, was embedded in ‘N’ or in its mirror reversal. In contrast, rTMS on the left PPC significantly speeded up the performance in the target-in-N stimuli not in the target-inreversed-N stimuli. The effect of the left PPC was only seen in the within subject analysis. Thus, we conduct a second experiment, using both target present and target absent trials, to probe the left PPC further. It confirmed the effects of left PPC stimulation seen in the first experiment in the within subject ANOVA analysis, and revealed through targeted t-tests in the between subject analysis

that left PPC stimulation shorted RTs in both the target-in-N and target-in-reversed-N stimuli. Our third experiment revealed that rTMS of the left VOTC had no effect on the task performance of either stimulus type. As Zhaoping and Frith (2011) suggested, a trial in the present visual search task is characterized by the following sequence of events. First, the location of the target bar is selected because it is highly (bottom-up) salient due to its unique bar orientation, attracting attention to it. It is well known that, due to visual crowding (Levi, 2008), object shape recognition in a cluttered scene is difficult when the object is not foveated. Hence, the zigzag shape of N or reverse-N that embeds the target bar is not recognized before the gaze arrives at it. Once target is located and selected (covertly or overtly by gaze), the subject could make a decision to press the button without recognizing the shape of the embedding object, because this shape is irrelevant to the task. However, if this task-irrelevant shape is recognized fast enough so that its zig-zag shape is extracted in a reflection-invariant (viewpoint-invariant) representation before the button press, confusion arises since this zig-zag shape is the same as those at the nontarget locations; this confusion causes task interference and thus prolongs RT. When the object embedding the target bar is N, it is in its familiar view point and so is more quickly recognized, and hence more likely to be recognized before the button press, than when the target bar is embedded in reversed N (a less familiar viewpoint). Hence, interference by task irrelevant shape information is more likely to happen for target-in-N than target-in-reversed-N trials (Zhaoping and Frith, 2011). Thus, target-in-reversed-N trials are easier; and the reversed letter effect is not in target selection (localization) by low-level bar orientation but is in task interference by (task-irrelevant) higher-level shape recognition. Indeed, target-in-N and target-in-reversed-N trials barely

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

differ in their RTs for the gaze to initially reach the target, but they differ mainly and substantially in the durations between the gaze reaching the target and the button press response (Zhaoping and Frith, 2011). We suggest that rTMS on left PPC reduces RT by interfering with the task-irrelevant shape recognition, thus reducing task interference. This is done without impairing target selection by gaze attraction to the target via the bottom-up saliency using low-level bar orientations processed by the primary visual cortex (Li, 2002). By this argument, left PPC rTMS could also reduce RT for the target-in-reversed-N trials. This RT reduction was indeed conspicuously present in our data from both experiments 1 and 2 (Figs. 2 and 3), reaching significance in exp 2 by the between subject analysis (see Fig. 3b). A weaker task interference in targetin-reversed-N trials may explain why the effect of the rTMS on left PPC did not reach significance in all our data analyses. In contrast to the findings of Oliveri et al. (2010), our current study indicated that the rTMS of the right PPC had no effect on the task performance, even though both stimulus types also had the interference by task irrelevant shape information (Zhaoping and Frith, 2011). It may be argued that our current search task is easier than the ones in Oliveri et al. (2010), as manifested by its shorter RTs. In particular, our search target is more salient. This enhanced saliency can reduce the degree of interference by irrelevant shape information, as suggested by observations in Zhaoping and Guyader (2007) and Zhaoping and Frith (2011). It may be that the effect of rTMS on the right PPC may only manifests itself when the interference is stronger to make RT longer. Meanwhile, in the face of a lack of a right PPC effect, the presence of a left PPC effect is remarkable, especially since Oliveri et al. (2010) showed that rTMS on the left PPC did not affect the degree of interference. This implies that the left PPC effect is likely to arise from the additional factor that is present in our current study but absent in the study by Oliveri et al. (2010), namely, the linguistic association of our search target. It is well known that the right hemisphere is mainly involved in processing non-linguistic stimuli while the left is implicated in processing linguistic stimuli (e.g. Bradshaw and Nettleton, 1981; Cattaneo et al., 2008, 2009; Callan et al., 2005; Salo et al., 2013; see Minagawa-Kawai et al. (2011) for review). Although visual processing of linguistic and non-linguistic forms share some brain areas, letter and words are also underpinned by brain areas different from non-linguistic stimuli (e.g. Joseph et al., 2006; Tagamets et al., 2000; Polk et al., 2002). For example, it has been reported that letter strings and faces preferentially activate left and right brain areas respectively (Puce et al., 1996; Tarkiainen et al., 2002). Patients with left posterior lesions showed selective impairment in processing written language (see Démonet et al. (2005) for review). In contrast patients with right posterior lesions show impairments in processing non-linguistic material such as faces and topographical stimuli (e.g. De Renzi et al., 1994). Our finding that left rather than right PPC stimulation improve performance in our search task involving letters is broadly consistent with this background literature. Several studies have suggested that there is an area specialized in word recognition and is needed in normal reading. This area, termed the visual word form area (VWFA), is thought to be located in the left VOTC (Cohen et al., 2000, 2002; Dehaene and Cohen, 2011). Our finding that rTMS on left VOTC had no effect on our search task suggests that the linguistic association of our search target is at a letter rather than word level. Moreover it suggests that letter (rather than word) processing does not involve left VOTC. Indeed, previous works suggest that left VOTC, which contains VWFA, is implicated on word rather than letter recognition (Cohen et al., 2000; Dehaene and Cohen, 2011). Furthermore, the recognition of single letters is dissociable from recognition of

203

strings of letters which form words (James et al., 2005). For example, patients with pure alexia, with damage to left VOTC, usually have an impairment in word but not in letter reading (Cohen et al., 2003; Beeson et al., 2005; Tsapkini et al., 2011; Seghier et al., 2012). The opposite type of impairment has also been described. Thus, Wilson and Patterson (1990) reported a patient with a posterior left hemisphere lesion who had an impairment in identifying single letters. Moreover, patients with attentional dyslexia, with damage to the left parietal cortex, have difficulties in identifying the constituent letters of words they can read (e.g. Shalev et al., 2008; Hall et al., 2001; Shallice and Warrington, 1977; Warrington et al., 1993). Our finding that rTMS stimulation of left PPC but not left VOTC reduces form-recognition-induced interference in our task implies a letter rather than word specific processing area in the left PPC. This is in line with studies implicating the left inferior parietal cortex in letter processing. Thus, neuroimaging studies have documented activation of the left inferior parietal cortex for letters but not for objects in passive viewing, silent naming and perceptual matching tasks (e.g. Joseph et al., 2003, 2006; Misra et al., 2004). Interestingly some of these studies reported that only the left inferior parietal cortex and the left insula showed a strong letter-selective response (Joseph et al., 2003, 2006). Recently Carreiras et al. (2014) reported an fMRI study documenting that the left parietal cortex is involved in letter identity and letter position coding whilst symbols and numbers are reported to recruit other brain areas. Interestingly it has also been reported that dyslexic adults who were less accurate than skilled readers to detect letter identity showed significantly less activation in a portion of the posterior parietal cortex (BA7) as well as in BA 40 (Reilhac et al., 2013). In addition to the clinical and neuroimaging literature discussed above, evidences for a causal role of the left PPC in letter processing have been documented in TMS studies using a different TMS approach to ours. In particular, two studies of Cattaneo et al. (2008, 2009) used priming and TMS-adaptation paradigm to investigate the performances on letter discrimination tasks. The authors reported that left PPC single-pulse TMS reversed the effects of priming by facilitating the detection of non-primed letters, whereas detection of primed letters was unaffected (Cattaneo et al., 2008). Facilitatory effect of left PPC single-pulse TMS was found regardless of whether the adapting letter and the target letter were perceptually identical to each other (Cattaneo et al., 2008) or presented in different cases (i.e. capital or lower case) (Cattaneo et al., 2009). Taken together these findings demonstrated abstract letter selectivity in the left PPC during discrimination tasks of letters presented in familiar view point. In our study, we used rTMS approach to reveal that rTMS over the left PPC facilitates performance on a visual search task involving a letter among its mirror images. In conclusion, this supports the view that this area plays a role in letter processing. Impairing the letter form recognition with rTMS reduces the top-down interference by task irrelevant linguistic information in our task, which requires only low-level visual feature (orientation of oblique bars) discrimination. Our finding should hopefully motivate future investigations into how left PPC is involved in a visual search task using linguistic stimuli.

Conflict of interest The authors report no competing financial or personal, interests in connection with the content of this manuscript.

204

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

Role of the funding source These funding institutions did not have any role in the collecting, analysis and interpretation of data.

Acknowledgements Giuseppa Renata Mangano’s work was supported by the University of Palermo Grant. Li Zhaoping’s work was supported by the Gatsby Charitable Foundation Grant.

References Barca, L., Burani, C., Arduino, L.S., 2002. Word naming times and psycholinguistic norms for Italian nouns. Behav. Res. Methods Instrum. Comput. 34, 424–434. Beeson, P.M., Magloire, J.G., Robey, R.R., 2005. Letter-by-letter reading: natural recovery and response to treatment. Behav. Neurol. 16, 191–202. Botvinick, M.M., 2007. Conflict monitoring and decision making: reconciling two perspectives on anterior cingulate function. Cogn. Affect. Behav. Neurosci. 7, 356–366. Botvinick, M.M., Braver, T.S., Barch, D.M., Carter, C.S., Cohen, J.D., 2001. Conflict monitoring and cognitive control. Psychol. Rev. 108, 624–652. Botvinick, M.M., Cohen, J.D., Carter, C.S., 2004. Conflict monitoring and anterior cingulate cortex: an update. Trends Cogn. Sci. 8, 539–546. Botvinick, M.M., Nystrom, L.E., Fissell, K., Carter, C.S., Cohen, J.D., 1999. Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature 402, 179–181. Bradshaw, J.L., Nettleton, N.C., 1981. The nature of hemispheric specialization in man. Behav. Brain Sci. 4, 51–63. Callan, A.K., Callan, A.E., Masakia, S., 2005. When meaningless symbols become letters: neural activity change in learning new phonograms. Neuroimage 28, 553–562. Carter, C.S., van Veen, V., 2007. Anterior cingulate cortex and conflict detection: an update of theory and data. Cogn. Affect. Behav. Neurosci. 7, 367–379. Carreiras, M., Quiñones, I., Hernández-Cabrera, J.A., Duñabeitia, J.A., 2014. Orthographic coding: brain activation for letters, symbols, and digits. Cereb. Cortex 30, pii: bhu163 [Epub ahead of print]. Cattaneo, Z., Rota, F., Vecchi, T., Silvanto, J., 2008. Using state-dependency of transcranial magnetic stimulation (TMS) to investigate letter selectivity in the left posterior parietal cortex: a comparison of TMS-priming and TMS-adaptation paradigms. Eur. J. Neurosci. 28, 1924–1929. http://dx.doi.org/10.1111/j.14609568.2008.06466.x. Cattaneo, Z., Rota, F., Walsh, V., Vecchi, T., Silvanto, J., 2009. TMS-adaptation reveals abstract letter selectivity in the left posterior parietal cortex. Cereb. Cortex 19, 2321–2325. Chen, Q., Wei, P., Zhou, X., 2006. Distinct neural correlates for resolving Stroop conflict at inhibited and noninhibited locations in inhibition of return. J. Cogn. Neurosci. 18, 1937–1946. Cohen, L., Dehaene, S., Naccache, L., Lehéricy, S., Dehaene-Lambertz, G., Hénaff, M. A., Michel, F., 2000. The visual word form area: spatial and temporal characterization of an initial stage of reading in normal subjects and posterior splitbrain patients. Brain 123, 291–307. Cohen, L., Lehericy, S., Chochon, F., Lemer, C., Rivaud, S., Dehaene, S., 2002. Language-specific tuning of visual cortex? Functional properties of the visual word form area. Brain 125, 1054–1069. Cohen, L., Martinaud, O., Lemer, C., Lehericy, S., Samson, Y., Obadia, M., et al., 2003. Visual word recognition in the left and right hemispheres: anatomical and functional correlates of peripheral alexias. Cereb. Cortex 13, 1313–1333. http: //dx.doi.org/10.1093/cercor/bhg079. Dehaene, S., Cohen, L., 2011. The unique role of the visual word form area in reading. Trends Cogn. Sci. 15, 254–262. http://dx.doi.org/10.1016/j. tics.2011.04.003. Démonet, J.F., Thierry, G., Cardebat, D., 2005. Renewal of the neurophysiology of language: functional neuroimaging. Physiol. Rev. 85, 49–95. De Renzi, E., Perani, D., Carlesimo, G.A., Silveri, M.C., Fazio, F., 1994. Prosopagnosia can be associated with damage confined to the right hemisphere—an MRI and PET study and a review of the literature. Neuropsychologia 32 (8), 893–902. Duncan, K.J., Pattamadilok, C., Devlin, J.T., 2010. Investigating occipito-temporal contributions to reading with TMS. J. Cogn. Neurosci. 22, 739–750. http://dx. doi.org/10.1162/jocn.2009.21207. Eriksen, B.A., Eriksen, C.W., 1974. Effects of noise letters upon the identification of a target letter in a nonsearch task. Percept. Psychophys. 6, 143–149. Frith, U., 1974. A curious effect of reversed letters explained by a theory of schema. Percept. Psychophys. 16, 113–116. Hall, D.A., Humphreys, G.W., Cooper, A.C., 2001. Neuropsychological evidence for case-specific reading: multi-letter units in visual word recognition. Q. J. Exp. Psychol. A 54, 439–467. James, K.H., James, T.W., Jobard, G., Wong, A.C., Gauthier, I., 2005. Letter processing in the visual system: different activation patterns for single letters and strings.

Cogn. Affect. Behav. Neurosci. 5, 452–466. Joseph, J.E., Cerullo, M.A., Farley, A.B., Steinmetz, N.A., Mier, C.R., 2006. fMRI correlates of cortical specialization and generalization for letter processing. Neuroimage 32, 806–820. Joseph, J.E., Gathers, A.D., Piper, G.A., 2003. Shared and dissociated cortical regions for object and letter processing. Cognit. Brain Res. 17, 56–67. Levi, D.M., 2008. Crowding—an essential bottleneck for object recognition: a minireview. Vis. Res. 48, 635–654. Li, Z., 2002. A saliency map in primary visual cortex. Trends Cogn. Sci. 6, 9–16. Lu, C.H., Proctor, R.W., 1995. The influence of irrelevant location information on performance: a review of the Simon and spatial Stroop effects. Psychon. Bull. Rev. 2, 174–207. http://dx.doi.org/10.3758/BF03210959. Malinowski, P., Hübner, R., 2001. The effect of familiarity on visual-search performance: evidence for learned basic features. Percept. Psychophys. 63, 458–463. Mangano, G.R., Oliveri, M., Turriziani, P., Smirni, D., Zhaoping, L., Cipolotti, L., 2014. Impairments in top down attentional processes in right parietal patients: paradoxical functional facilitation in visual search. Vis. Res. 97, 74–82. http://dx. doi.org/10.1016/j.visres.2014.02.002. Minagawa-Kawai, Y., Cristià, A., Dupoux, E., 2011. Cerebral lateralization and early speech acquisition: a developmental scenario. Dev. Cogn. Neurosci. 1, 217–232. http://dx.doi.org/10.1016/j.dcn.2011.03.005. Misra, M., Katzir, T., Wolf, M., Poldrack, P., 2004. Neural systems underlying Rapid Automatized Naming (RAN) in skilled readers: unraveling the puzzle of RANreading relationships. Sci. Stud. Read. Spec. Issue Neuroanat. Read. 8, 241–256. Navon, D., 1977. Forest before trees: the precedence of global features in visual processing. Cogn. Psychol. 9, 353–383 10.1016/0010-0285(77) 90012-90013. Nee, D.E., Wager, T.D., Jonides, J., 2007. Interference resolution: insights from a meta-analysis of neuroimaging tasks. Cogn. Affect. Behav. Neurosci. 7, 1–17. Oliveri, M., Bonnì, S., Turriziani, P., Koch, G., Lo Gerfo, E., Torriero, S., Vicario, C.M., Petrosini, L., Caltagirone, C., 2009. Motor and linguistic linking of space and time in the cerebellum. PLoS One 11 (4), e7933. Oliveri, M., Zhaoping, L., Mangano, G.R., Turriziani, P., Smirni, D., Cipolotti, L., 2010. Facilitation of bottom-up feature detection following rTMS-interference of the right parietal cortex. Neuropsychologia 48, 1003–1010. Polk, T.A., Stallcup, M., Aguirre, G.K., Alsop, D., D’Esposito, M., Detre, J.A., Farah, M.J., 2002. Neural specialization for letter recognition. J. Cogn. Neurosci. 14, 145–159. Puce, A., Allison, T., Asgari, M., Gore, J.C., McCarthy, G., 1996. Differential sensitivity of human visual cortex to faces, letterstrings, and textures: a functional magnetic resonance imaging study. J. Neurosci. 16, 5205–5215. Reilhac, C., Peyrin, C., Démonet, J.F., Valdois, S., 2013. Role of the superior parietal lobules in letter-identity processing within strings: fMRI evidence from skilled and dyslexic readers. Neuropsychologia 51, 601–612. Ridderinkhof, K.R., Ullsperger, M., Crone, E.A., Nieuwenhuis, S., 2004. The role of the medial frontal cortex in cognitive control. Science 306, 443–447. Rossini, P.M., Barker, A.T., Berardelli, A., Caramia, M.D., Caruso, G., Cracco, R.Q., Dimitrijevic, M.R., Hallett, M., Katayama, Y., Lücking, C.H., Maertens de Noordhout, A.L., Marsden, C.D., Murray, N.M.F., Rothwell, J.C., Swash, M., Tomberg, C., 1994. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr. Clin. Neurophysiol. 91, 79–92. Salo, E., Rinne, T., Salonen, O., Alho, K., 2013. Brain activity during auditory and visual phonological, spatial and simple discrimination tasks. Brain Res. 1496, 55–69 10.1016/j.brainres.2012.12.013. Shalev, L., Mevorach, C., Humphreys, G.W., 2008. Letter position coding in attentional dyslexia. Neuropsychologia 46, 2145–2151. Shallice, T., Warrington, E.K., 1977. The possible role of selective attention in acquired dyslexia. Neuropsychologia 15, 31–41. Schiff, S., Bardi, L., Basso, D., Mapelli, D., 2011. Timing spatial conflict within the parietal cortex: a TMS study. J. Cogn. Neurosci. 23, 3998–4007. http://dx.doi. org/10.1162/jocn_a_00080. Seghier, M.L., Neufeld, N.H., Zeidman, P., Leff, A.P., Mechelli, A., Nagendran, A., Riddoch, J.M., Humphreys, G.W., Price, C.J., 2012. Reading without the left ventral occipito-temporal cortex. Neuropsychologia 50, 3621–3635. Simon, J.R., Rudell, A.P., 1967. Auditory S–R compatibility: the effect of an irrelevant cue on information processing. J. Appl. Psychol. 51, 300–304. Stroop, J.R., 1935. Studies of interference in serial verbal reactions. J. Exp. Psychol. 18, 643–662. Tagamets, M.A., Novick, J.M., Chalmers, M.L., Friedman, R.B., 2000. A parametric approach to orthographic processing in the brain: an fMRI study. J. Cogn. Neurosci. 12, 281–297. Tarkiainen, A., Cornelissen, P.L., Salmelin, R., 2002. Dynamics of visual feature analysis and object level processing in face versus letter–string perception. Brain 125, 1125–1136. Theoret, H., Haque, J., Pascual-Leone, A., 2001. Increased variability of paced finger tapping accuracy following repetitive magnetic stimulation of the cerebellum in humans. Neurosci. Lett. 306, 29–32. Treisman, A., Souther, J., 1985. Search asymmetry: a diagnostic for preattentive processing of separable features. J. Exp. Psychol.: Gen. 114, 285–310. Tsapkini, K., Vindiola, M., Rapp, B., 2011. Patterns of brain reorganization subsequent to left fusiform damage: fMRI evidence from visual processing of words and pseudowords, faces and objects. Neuroimage 55 (3), 1357–1372. http://dx.doi.org/10.1016/j.neuroimage.2010.12.024. Umiltà, C., Nicoletti, R., 1990. Spatial stimulus–response compatibility In: Proctor, R. W., Reeve, T.G. (Eds.), Stimulus–Response Compatibility: An Integrated Perspective. North-Holland, Amsterdam, pp. 89–116.

G.R. Mangano et al. / Neuropsychologia 70 (2015) 196–205

van Veen, V., Cohen, J.D., Botvinick, M.M., Stenger, V.A., Carter, C.S., 2001. Anterior cingulate cortex conflict monitoring and levels of processing. Neuroimage 14, 1302–1308. Wang, Q., Cavanagh, P., Green, M., 1994. Familiarity and pop-out in visual search. Percept. Psychophys. 56, 495–500. Warrington, E.K., Cipolotti, L., McNeil, J., 1993. Attentional dyslexia: a single case study. Neuropsychologia 31, 871–885. Wilson, B., Patterson, K., 1990. Rehabilitation for cognitive impairment: Does cognitive psychology apply? Appl. Cogn. Psychol. 4 (4), 247–260.

205

Wolfe, J.M., 2001. Asymmetries in visual search: an introduction. Percept. Psychophys. 63 (3), 381–389. Zhaoping, L., Guyader, N., 2007. Interference with bottom-up feature detection by higher-level object recognition. Curr. Biol. 17, 26–31. Zhaoping, L., Frith, U., 2011. A clash of bottom-up and top-down processes in visual search: the reversed letter effect revisited. J. Exp. Psychol.: Hum. Percept. Perform. 37, 997–1006.