Abstract

The topic of spatial attention is of great relevance for researchers in various fields, including neuropsychology, cognitive neuroscience, and cognitive psychology, as well as for clinical practice. Deficits of spatial attentional arising from parietal brain damage remain largely confined to the left visual field. The mechanisms underlying this hemispheric asymmetry are still elusive. We mimicked the neuropsychological syndrome of contralesional extinction by temporarily inducing a spatial attentional bias in healthy volunteers with TMS. We investigated whether directing covert spatial attention could enhance or, more importantly, counteract the resulting behavioral deficits. Although both the left and right parietal TMS induced contralateral extinction, only left hemifield extinction following right parietal TMS was severely aggravated by a competing stimulus in the ipsilesional (right) hemifield. We put forward the hypothesis that an asymmetry with respect to the ability of detaching attention from a distractor is contributing to the right hemispheric lateralization with regard to extinction. On a broader level, we suggest that “virtual patients” might be used for evaluating neuropsychological treatment in an early stage of development, reducing the burden on actual patients.

INTRODUCTION

Damage to parietal cortex often results in spatial attention deficits, the most prominent of which is known as hemispatial neglect. Patients suffering from hemispatial neglect fail to perceive and react to stimuli appearing in the contralesional hemifield and have been shown to display increased perception and anticipation toward stimuli appearing in the ipsilesional hemifield (see, e.g., Kerkhoff, 2001; Vallar & Perani, 1986). In healthy adults, commonly, a slight attentional bias toward the left hemifield is observed, a phenomenon referred to as pseudoneglect (Orr & Nicholls, 2005). This phenomenon, resulting, for example, in overestimation of the left part of a line in a line bisection task indicates a dominance of the right hemisphere over the left hemisphere in healthy right-handed adults. The neuropsychological syndrome of hemispatial neglect, on the other hand, is strongly lateralized in the opposite direction: It is most frequently observed after right hemispherical damage and thus usually induces hemispatial neglect of the left and an attentional bias toward the right hemifield (Vallar & Perani, 1986). A condition often bracketed together with hemispatial neglect is extinction. Patients suffering from extinction also fail to report a stimulus in the contralesional hemifield, but only if this stimulus is presented simultaneously with a competing stimulus in the ipsilesional hemifield. This failure to detect bilateral stimuli increases with stimulus eccentricity (Smania et al., 1998). Extinction in response to bilateral visual stimuli has also been demonstrated in healthy adults, as a result of saliency manipulation of the stimulus in the contralateral hemifield (Gorea & Sagi, 2000; Meador, Ray, Day, Ghelani, & Loring, 1998).

It is still highly debated whether neglect and extinction are part of the same neuropsychological condition. Nonetheless, the terms are often used interchangeably (Corbetta & Shulman, 2002; Hilgetag, Theoret, & Pascual-Leone, 2001; Manes, Paradiso, Springer, Lamberty, & Robinson, 1999), and extinction is sometimes referred to as a milder form of neglect (Hilgetag et al., 2001). Often, spatial neglect is very broadly defined, like “disorders of spatial cognition which concern a specific sector of space with reference to a given coordinate system” (Vallar, Rusconi, & Bernardini, 1996). However, there is increasing evidence that neglect and extinction may represent two different neuropsychological conditions, and respective double dissociations between neglect and extinction are common (Becker & Karnath, 2007). Pavlovskaya, Soroker, and Bonneh (2007) found extinction in neglect patients even after they controlled for the difference in attentional saliency between the affected and healthy hemifield. It has also been proposed that, whereas neglect is largely confined to right hemispherical damage, extinction is much less subject to hemispherical asymmetry (Bonato, Priftis, Marenzi, Umiltà, & Zorzi, 2010; Becker & Karnath, 2007).

At present, two competing theories try to account for the highly asymmetrical manifestation of hemineglect. Because it can be assumed that lesions are as likely to occur in the left hemisphere as they are in the right, the answer must lie in the asymmetry of the expression of these lesions rather than in the location of their occurrence. The finding that neglect is most common following right-sided lesions has led many to assume a hemispheric asymmetry in spatial attention (Corbetta, Miezin, Shulman, & Petersen, 1993). It is proposed that the left hemisphere controls attention only in the right hemifield, whereas the right hemisphere is able to control both sides (Corbetta et al., 1993; Heilman, Bowers, Valenstein, & Watson, 1993; Mesulam, 1981). This implies that the right hemisphere is able to compensate for a lesion in the left hemisphere, but not vice versa (Sack et al., 2002, 2007; Sack, Camprodon, Pascual-Leone, & Goebel, 2005). These empirical accounts and clinical phenomena are formalized in the theory of hemispheric asymmetry in attention, with the right hemisphere being dominant (Corbetta et al., 1993). An alternative model of neglect, the opponent processor model, has been proposed by Kinsbourne (1993), claiming that the attention of each hemisphere is biased in the direction of the contralateral hemifield, with the rightward bias of the left hemisphere being stronger. Normally, both hemispheres mutually inhibit each other's orienting biases, leading to equal allocation of spatial attention across space. This balanced gradient remains until one of the two hemispheres is damaged. If this occurs, the inhibition of the intact hemisphere by the injured hemisphere is reduced, and it becomes overactivated, thereby further suppressing function in the injured hemisphere. This results in a spatial deficit contralateral to the lesion. Because the contralateral orientation bias of the left hemisphere is stronger, its reduced suppression after right parietal damage results in more pronounced behavioral deficits, as documented by the higher frequency of hemispatial neglect of the left and an attentional bias toward the right hemifield.

Hence, while claiming different underlying physiological mechanisms, both theories account in their own way for the fact that the prevalence of neglect is much higher following right hemisphere lesions. This makes it difficult to distinguish between the different models at a behavioral level. Because spatial attention deficits such as hemispatial neglect and extinction normally only become manifest after brain damage, their underlying mechanisms have almost exclusively been studied in lesion patients. The reasons for studying patients are twofold. On the one hand, by understanding which changes occur in brain and behavior and by assessing how patients respond to medication or other rehabilitative treatments, it is hoped that the functional damage can be reduced or, optimally, even reversed. On the other hand, for this venture to be successful, knowledge of the mechanisms underlying certain functionality in the healthy brain is crucial. By evaluating which cognitive changes occur in lesion patients compared with healthy adults, a vast amount of information can be obtained about functions previously represented in the now damaged part of the brain, like directing spatial attention.

However, investigating the cognitive consequences of brain lesions is hampered by several limitations. No two lesions are the same with regard to their location, size, and functional impact, and lesions are rarely small enough to be confined to a single functional area or module in the brain. In addition, as a result of cortical reorganization, the cognitive consequences of a lesion are not stable over time. Also, importantly, patients suffering from lesion-induced loss of brain function are in most cases only monitored from the moment they report their deficits and seek treatment. This makes it impossible to objectively compare cognitive brain functioning after the lesion to cognitive functioning in the same person before lesion occurrence, when the brain was presumably still healthy. Finally, in the same line of thought, differences in age, education, personality, and other possibly confounding background factors cannot be controlled for, for the simple reason that patients can, by definition, not be randomly assigned to a patient or nonpatient group. Despite these limitations, studying patients suffering from altered cognitive functioning as a result of brain damage has so far been an extremely important source of information about the functional architecture of the healthy brain.

Complementary to patient studies, another way to investigate the relationship between brain and behavior under controlled experimental conditions and to study brain functions of neurologically healthy, randomly selected adults who can serve as their own controls when comparing behavioral performance with and without local neural activity disruptions is TMS. Unlike functional imaging that provides observational measures of the functional architecture of the healthy or diseased brain, TMS allows for noninvasive direct local interference of cortical processing in a certain brain area, thus temporarily creating a “virtual lesion” in conscious healthy volunteers. Observation of resulting behavioral changes provides causal information about the functional relevance of a certain brain area. With this virtual lesion approach of TMS, neuropsychological conditions can temporarily be mimicked in healthy volunteers under controlled experimental conditions (Sack, 2010). This allows for random selection of “patients” or balanced selection with regard to a certain trade, if relevant. It also allows for within-person balanced comparison between behavior observed with and without the virtual lesion, ruling out the many confounding factors that limit most patient studies.

This TMS virtual lesion approach has successfully been applied to the domain of visuospatial attention. Pascual-Leone and colleagues (1994) already observed that left or right parietal repetitive TMS applied to healthy adults led to a large number of misses of the contralateral part of a bilateral stimulus, whereas performance on unilateral trials remained unaffected by TMS. Fierro and colleagues (2000) aimed to mimic hemispatial neglect in healthy volunteers. After right, but not left, parietal TMS, an overestimation of the length of the right section of a bisected line was observed, indicating a rightward shift in attentional bias. By now, several studies have demonstrated that parietal TMS is capable of causing contralateral hemineglect-like symptoms in healthy volunteers (Koch et al., 2008; Dambeck et al., 2006; Fierro, Brighina, & Bisiach, 2006; Meister et al., 2006; Muggleton et al., 2006; Koch, Oliveri, Torriero, & Caltagirone, 2005; Bjoertomt, Cowey, & Walsh, 2002; Fierro, Brighina, Piazza, Oliveri, & Bisiach, 2001; Hilgetag et al., 2001; Fierro et al., 2000; Pascual-Leone et al., 1994). Taken together, these studies showed that TMS can be employed to mimic lesions under controlled experimental conditions in healthy adults (Sack, 2010).

In the same line, Hilgetag and colleagues (2001) applied 10 min of 1-Hz repetitive TMS to the right or left intraparietal sulcus (IPS; P3 and P4 of the 10–20 EEG positioning system, respectively) during the execution of a visuospatial detection task. In addition to virtual neglect, they also observed virtual extinction. Healthy volunteers showed decreased detection of the contralesional part of a bilateral stimulus, an effect that was most strongly observed in the left hemifield, as a result of right parietal TMS. Interestingly, Hilgetag et al. (2001) also reported an increase in detection of unilateral stimuli appearing in the periphery of the ipsilesional hemifield. In line with evidence from real lesions, this occurred most strongly in the right hemifield, after right parietal TMS. According to Kinsbourne's opponent processor model (1993), hemispatial neglect is a result of a disturbance in interhemispheric balance, which causes the attentional gradient to shift. The authors thus interpreted their ipsilesional enhancement finding as a consequence of a reduced suppression of the left hemisphere by the TMS-disrupted right hemisphere. However, theoretically and consequently in line with this logic, a simultaneous lesion in both parietal cortices should restore this balance and result in unaffected visuospatial attention. This scenario was experimentally created by Dambeck and colleagues (2006) using the virtual lesion approach of TMS. First, the virtual neglect and extinction reported by Hilgetag et al. (2001) were replicated by applying a single-pulse TMS over the right parietal hemisphere, 150 msec after stimulus onset. Subsequently, TMS was applied simultaneously over the previously unstimulated left hemisphere. In line with Kinsbourne's predictions, spatial neglect was restored and behavior returned to normal.

These studies demonstrate that TMS can be used to mimic a neuropsychological condition, like hemispatial neglect, in healthy volunteers. They also demonstrate that TMS can subsequently be used to reveal the neural mechanisms underlying the function that is disturbed by either the real or virtual lesion. However, another important pillar of patient research is the constant strive to improve treatment, such as to reduce or reverse the behavioral deficit caused by a lesion. The question arising is whether TMS-induced virtual lesions can be used to explore and improve ways of treatment, using healthy volunteers under controlled experimental conditions, instead of patients. The current study takes a first step in this direction.

In the current study, we aimed to investigate in healthy volunteers whether TMS-induced extinction could be influenced by external manipulation of spatial attention during stimulus perception. In daily life, we are rarely presented with an isolated stimulus in only one hemifield, rather we observe scenes in which several possibly interesting and important stimuli are simultaneously present at different locations in both visual fields, attracting and competing for our attention. Consequently, the ability to deal with competing stimuli by directing or dividing attention and ignoring distractors, if necessary, seems crucial for everyday functioning. In this light, extinction can be considered a realistic and clinically relevant experimental model for behavioral disorders of spatial attention. Because extinction occurs only when two bilateral stimuli are competing for attentional resources, directing spatial attention toward the ipsilesional hemifield before induction of the virtual lesion could be hypothesized to increase the strength of induced extinction. More importantly, the other way round, if spatial attention would be directed toward the hemifield in which extinction is experienced, this could counteract the TMS-induced symptoms of extinction.

We used exogenous, peripheral attentional cues, a manipulation which has previously been shown to covertly direct spatial attention toward the left or right hemifield (Carrasco, Ling, & Read, 2004; Fu, Fan, Chen, & Zhuo, 2001). Subsequently, we induced a virtual lesion by disrupting neuronal processing in the left or right intraparietal cortex using TMS. We recorded the accuracy with which healthy volunteers reported small bilateral stimuli presented in the visual periphery. Moreover, we employed the net direction in which the percept of inaccurately reported bilateral stimuli shifted as a measure of a change in the attentional gradient. We observed an interaction, and a hemispheric difference thereof, between the location of the attentional cue in the left or right hemifield, and the effect of TMS over the left or right IPS on visual extinction. Our results indicate that an attentional cue presented in the contralesional hemifield can significantly reduce and thus counteract the extinction syndrome following TMS-induced parietal brain lesions. This “therapeutic” effect of directing spatial attention to the affected hemifield was of similar benefit for left and right extinction symptoms following right and left TMS-induced parietal lesions. However, an attentional cue presented in the ipsilesional hemifield significantly worsened the behavioral deficits of the virtual lesion, but only in case of a TMS-induced right parietal disruption. Thus, it seems that the right parietal disruption and the subsequent left hemifield extinction are more vulnerable to an additionally presented distractor stimulus in the ipsilesional, that is, right, visual hemifield during bilateral stimulus processing. This might not only contribute a new explanation to the reported higher prevalence of clinical symptoms following right hemispheric lesions, but it may also serve as a basis for an interesting therapeutical perspective for treatment of real lesion patients suffering from extinction. Furthermore, our study implies that healthy volunteers might not only be employable for mimicking the effects of actual brain damage but also for evaluating the effectiveness of treatments in an early stage of development under controlled experimental conditions, thereby not immediately placing a burden on the limited amount of real lesion patients.

METHODS

Participants

A total of 30 right-handed healthy volunteers with normal or corrected-to-normal vision (mean age = 24.2 years, SD = 7.4 years, 9 men) participated in this study. All participants were unaware of the goal of the study and were naive about whether they received real or sham TMS until after having completed their participation. Before the start of each experimental session, each participant provided written informed consent and was screened for TMS experimentation safety by an independent medical supervisor. Ethical approval was given by the local medical ethical committee.

Experimental Design

Participants were randomly assigned to a left hemisphere stimulation (L-IPS), right hemisphere stimulation (R-IPS), or sham stimulation group to avoid carry-over and order effects. The experiment consisted of a single session, divided into a stimulus-tailoring procedure and an actual experimental part.

The tailoring procedure was similar to that employed by Hilgetag and colleagues (2001). During this procedure, participants were positioned in a head-and-chin rest and asked to fixate on the center of the screen. During each trial of the visuospatial detection task, small squares appeared shortly in the visual periphery, on the left or right side of the screen, or bilaterally. Participants were asked to indicate via right hand button presses whether they observed a stimulus on the left (index finger), right (ring finger), or bilaterally (middle finger). If they did not observe any stimulus they were asked to refrain from responding. Five different stimulus sizes were presented nine times on the left, right or bilaterally, in random order. Afterward the detection rates of each stimulus size in each condition were plotted, and the obtained response pattern of the participant was inspected to evaluate which stimulus sizes were situated around the individual detection threshold and would thus be most suited to avoid floor and ceiling effects. The two stimulus sizes, which were centerd around 50% detection, were selected for use in the actual experiment.

The actual experiment consisted of a similar visuospatial detection task (Figure 1), adapted from the design employed by Hilgetag and colleagues (2001). Again, participants were asked to fixate in the center of the screen and to indicate with their dominant right hand whether and where they observed a stimulus: left (index finger), right (ring finger), or bilaterally (middle finger) or no stimulus (no button press). In addition, in two of three trials, the stimulus was now preceded by an exogenous attention cue consisting of a small circle, presented slightly more central and higher compared with the square target stimulus, either left or right of fixation. At 1000 msec after the fixation cross appeared, the attention cue was presented for 50 msec. Following a gap of 50 msec, the target stimulus appeared at the left, right or bilaterally for 40 msec. Cue and gap duration were adapted from Fu and colleagues (2001) and in line with Carrasco and colleagues (2004) among others, whereas stimulus duration was similar as in the design employed by Hilgetag and colleagues (2001). Trial onset asynchrony was jittered between 6 and 8 sec.

Figure 1. 

Experimental paradigm. After 1000 msec of fixation cross, in two of three trials, an exogenous attentional cue appeared for 50 msec, at 16° eccentricity left or right or fixation. After a gap of 50 msec, the target stimulus appeared for 40 msec at 24°, either unilaterally left, unilaterally right, or bilaterally. The size of the target stimuli was individually tailored according to stimulus detection threshold. In 50% of the trials, three TMS pulses were delivered over left or right parietal cortex at 100, 150, and 200 msec. Participants were asked to indicate by button presses if and where they observed a target stimulus: left, right, bilaterally, or no stimulus observed (no response).

Figure 1. 

Experimental paradigm. After 1000 msec of fixation cross, in two of three trials, an exogenous attentional cue appeared for 50 msec, at 16° eccentricity left or right or fixation. After a gap of 50 msec, the target stimulus appeared for 40 msec at 24°, either unilaterally left, unilaterally right, or bilaterally. The size of the target stimuli was individually tailored according to stimulus detection threshold. In 50% of the trials, three TMS pulses were delivered over left or right parietal cortex at 100, 150, and 200 msec. Participants were asked to indicate by button presses if and where they observed a target stimulus: left, right, bilaterally, or no stimulus observed (no response).

In 50% of the trials, 20-Hz triple-pulse TMS was applied to the left (P3, L-IPS group) or right (P4, R-IPS group) posterior parietal cortex. Stimulation sites were determined according to the international 10–20 EEG positioning system and have previously been shown to overlie the IPS (Hilgetag et al., 2001). Existing MRI data available from a subgroup of the participants allowed us to validate with TMS neuronavigation that our P3 and P4 stimulation sites were indeed overlying the respective intraparietal sulci (Figure 2).

Figure 2. 

TMS stimulation sites. Reconstruction of the cortical surface of a single participant based on anatomical MRI data. Important sulci are indicated: CS = central sulcus; PCS = postcentral sulcus. The red beam represents the projection of the peak of the magnetic field. Participants assigned to the L-IPS group received TMS over 10–20 electrode position P3 (top), participants assigned to the R-IPS group were stimulated over position P4 (bottom). P3 and P4 are generally assumed to overlie the left and right IPS, respectively. Existing MRI data available from a subgroup of the participants allowed us to validate with neuronavigation that our P3 and P4 stimulation sites were indeed overlying the respective intraparietal sulci (shown in pink).

Figure 2. 

TMS stimulation sites. Reconstruction of the cortical surface of a single participant based on anatomical MRI data. Important sulci are indicated: CS = central sulcus; PCS = postcentral sulcus. The red beam represents the projection of the peak of the magnetic field. Participants assigned to the L-IPS group received TMS over 10–20 electrode position P3 (top), participants assigned to the R-IPS group were stimulated over position P4 (bottom). P3 and P4 are generally assumed to overlie the left and right IPS, respectively. Existing MRI data available from a subgroup of the participants allowed us to validate with neuronavigation that our P3 and P4 stimulation sites were indeed overlying the respective intraparietal sulci (shown in pink).

TMS trials were randomly intermixed with baseline trials. During a TMS trial, three TMS pulses were administered with an intensity of 150% of the individual resting motor threshold, which was determined at the start of the session by visually inspecting which TMS intensity represented the threshold for inducing movement in the index finger or thumb. Resting motor threshold values measured on average 33.7 ± 6.3% maximal machine output (MO), resulting in stimulation intensities of on average 50.5 ± 9.4% MO. None of the participants reported any adverse effects. TMS pulses were delivered at 100, 150, and 200 msec after the onset of the target stimulus, a time window previously demonstrated to be maximally effective in disturbing posterior parietal cortex (Dambeck et al., 2006; Fierro et al., 2001). The TMS coil was mounted in an adjustable arm, perpendicular to the skull with the handle pointing 90° in the lateral direction. During each experimental session, a total of 378 TMS pulses were delivered. Participants wore protective earplugs throughout the experimental session.

Participants in the sham stimulation group carried out the same experiment, without attentional cueing, to control for nonspecific effects of TMS stimulation, such as a shift in spatial attention caused by the lateralized sound of TMS. Sham pulses were delivered through a magnetically shielded figure-eight coil at the fixed intensity of 50% MO, the sound level of which (67 dB) is equal to 85% MO stimulation delivered through the non-shielded experimental TMS coil. Sham stimulation was applied over P4 (hence over the same location as the R-IPS group).

Hence, the experimental conditions added up to 3 (stimulus location: left, right, or bilateral) × 3 (cue location: left, right, or none) × 2 (TMS or no TMS) = 18 possible combinations, which were each presented 14 times during each experimental session. The trials were divided over seven blocks with 36 trials each. Each block additionally contained one randomly intermixed catch trial in which no visual stimulus was presented. Trial onset asynchrony was jittered between 6 and 8 sec to avoid a slow repetitive TMS pattern and carry over between TMS and baseline trials. The experimental session lasted around 30 min.

Stimulus Material

Participants were seated 40 cm from a 19-in. TFT screen (Samsung SyncMaster931 BF, Ridgefield, NJ) in a head-and-chin rest. Stimuli consisted of one (left or right) or two (bilateral) 60% gray squares sized between 2 × 2 and 4 × 5 pixels, with a pixel size of 0.07 mm2. Stimulus sizes were chosen for each individual participant according to data obtained from the tailoring procedure at the start of the session. Stimuli were presented for 40 msec on a white background, at 24° (17.8 cm, 600 pixels) visual angle eccentricity left and/or right of fixation. The attentional cue consisted of a 20- point capital letter “O” and was presented for 50 msec. To avoid confusion between cue and target stimuli, the cue was presented at 16° (11.8 cm, 400 pixels) left or right of fixation, 50 pixels above the horizontal midline. Between cue offset and target onset there was a temporal gap of 50 msec during which the fixation cross remained visible.

Apparatus and Data Acquisition

Biphasic magnetic stimulation was generated using a Medtronic MagPro 2 Tesla X100 stimulator (Medtronic Functional Diagnostics A/S, Skovlunde, Denmark). Magnetic pulses were delivered with a figure-eight coil (Magnetic Coil Transducer MC-B70, Medtronic, wing diameter = 70 mm), mounted in an adjustable arm. Sham stimulation was delivered via an otherwise identical MC-B70 coil, which has been insulated to prevent the magnetic field from passing through the scalp and entering the brain. BrainVoyager TMS Neuronavigator (Brain Innovation BV, Maastricht, the Netherlands) was used to position the TMS coil and maintain its position throughout the experiment. Although the stimulation sites were determined based on 10–20 system coordinates, the neuronavigation system aided in precise placement and maintenance of coil position and allowed for coil position adjustment during breaks, when necessary.

Throughout this study Presentation software (Neurobehavioral Systems, Inc., Albany, CA) was used for both stimulus presentation and recording of the behavioral responses.

Data Analysis

Analyses focused specifically on those conditions indicative for visual extinction: trials in which a bilateral stimulus was presented, but in which participants reported to have sighted only one unilateral left or right stimulus. As a dependent variable, individual difference scores were computed for each participant in each condition, by subtracting the percentage of “left” responses from the number of “right” responses. Thus a negative difference score reflects a bias to the left, whereas a positive difference score reflects a rightward bias. Results were collapsed across different stimulus sizes.

To first establish whether there was an attentional response bias (pseudoneglect) in the absence of TMS, the aforementioned individual difference scores were entered into a one-sample t test (test value, 0). To rule out that the three participant groups differed in this aspect, their individual difference scores were compared using a one-way ANOVA. Subsequently, we verified whether any observed attentional bias was differentially influenced by TMS over left or right intraparietal cortex by carrying out a repeated measures ANOVA procedure with a within-subject factor TMS (TMS vs. baseline) and a between-subject factor Stimulated Hemisphere (L-IPS vs. R-IPS). To control for lateralized TMS shifting the focus of attention as a result of multisensory attentional cueing, a repeated-measures ANOVA procedure was employed to compare the effects of sham TMS over right intraparietal cortex with baseline performance in the sham TMS group. Finally, to assess the influence of exogenous attentional cues on any observed TMS-induced attentional biases, a repeated-measures ANOVA procedure with the within-subject factors Cue (no cue, cue left, or cue right) and TMS (TMS vs. baseline) was carried out, with Stimulated Hemisphere (L-IPS vs. R-IPS) as a between-subject factor. Follow-up paired sample t tests were conducted separately for the L-IPS and R-IPS group over TMS-minus-baseline values, with cue as the independent factor (cue right vs. no cue or cue left vs. no cue). Reported p values are one-tailed.

RESULTS

Mean accuracy scores across all conditions, including unilateral stimulus presentations, are depicted in Figure 3. Only bilateral stimuli were used for further analysis, because extinction is closely associated with competition between bilateral visual stimulation.

Figure 3. 

Overview of accuracy scores for unilateral and bilateral visual stimuli. Depicted are the mean percentages of correctly reported unilateral and bilateral stimuli across conditions. Means are pooled across the two employed stimulus sizes, which were individually tailored to match each participant's detection threshold. Error bars represent standard errors of mean.

Figure 3. 

Overview of accuracy scores for unilateral and bilateral visual stimuli. Depicted are the mean percentages of correctly reported unilateral and bilateral stimuli across conditions. Means are pooled across the two employed stimulus sizes, which were individually tailored to match each participant's detection threshold. Error bars represent standard errors of mean.

A one-sample t test over individual difference scores resulting from subtracting the percentage of “left” responses from the number of “right” responses revealed a significant leftward attentional bias in the baseline condition (t(29) = −2.807, p = .009, two-tailed). Hence, without TMS and without any attentional cues, an attentional bias toward the left hemifield is observed across all three groups in the baseline condition (Figure 4). This leftward attentional bias, also known as ‘pseudoneglect,’ is frequently observed in healthy adults (Orr & Nicholls, 2005), yet systematic empirical data on this phenomenon is scarce. The leftward bias was observed similarly across the three groups, with no significant difference between them (F(2, 27) = 0.70, p = .51), ruling out existing differences between the three groups as an alternative explanation for any group effect described.

Figure 4. 

Pseudoneglect: leftward attentional bias in healthy adults. In healthy adults, an attentional bias toward the left hemifield has previously been described as “pseudoneglect.” Individual difference scores were computed for each participant by subtracting the percentage of “left” responses from the number of “right” responses. A leftward extending bar (negative difference score) reflects a bias to the left, whereas a rightward extending bar (positive difference score) reflects a rightward bias. The direction and amount of attentional bias of each of the 30 neurologically healthy participants (y axis) is displayed from top to bottom in random order, the average and its standard error of mean are depicted at the bottom. On average, there is a significant leftward attentional bias in our random sample (p = .007, two-tailed).

Figure 4. 

Pseudoneglect: leftward attentional bias in healthy adults. In healthy adults, an attentional bias toward the left hemifield has previously been described as “pseudoneglect.” Individual difference scores were computed for each participant by subtracting the percentage of “left” responses from the number of “right” responses. A leftward extending bar (negative difference score) reflects a bias to the left, whereas a rightward extending bar (positive difference score) reflects a rightward bias. The direction and amount of attentional bias of each of the 30 neurologically healthy participants (y axis) is displayed from top to bottom in random order, the average and its standard error of mean are depicted at the bottom. On average, there is a significant leftward attentional bias in our random sample (p = .007, two-tailed).

A subsequent repeated-measures ANOVA revealed a significant interaction effect between TMS and Stimulated Hemisphere (F(1, 18) = 4.88, p = .040). Hence, TMS over L-IPS or R-IPS differentially influences the leftward bias observed in the baseline condition. L-IPS TMS, without attentional cues, induces visual extinction of stimuli in the right hemifield (Figure 5) and thus induces an even more leftward bias than in the baseline condition (increased pseudoneglect), whereas R-IPS TMS reverses the pseudoneglect by inducing visual extinction of stimuli in the left hemifield and strongly shifting attention more rightward compared with baseline (Figure 5). Sham TMS over the same right intraparietal stimulation site did not result in any shift of attention (F(1, 9) = 0.011, p = .92), ruling out nonspecific effects of TMS as an alternative explanation. These findings replicate earlier findings describing extinction induced by repetitive TMS over the same stimulation sites (Dambeck et al., 2006; Hilgetag et al., 2001).

Figure 5. 

TMS-induced attention shifts. Effects of TMS over L-IPS (orange) or R-IPS (red), relative to baseline (no TMS). Bars represent mean individual difference scores computed by subtracting the percentage of “left” responses from the number of “right” responses; error bars represent standard errors of mean. The end of each bar represents the “center of attention” in each respective condition as a result of TMS. Zero point represents baseline (no TMS). Top: left versus right parietal TMS without attentional cue, middle: left versus right parietal TMS with attentional cue in the left hemifield, bottom: left versus right parietal TMS with attentional cue in the right hemifield.

Figure 5. 

TMS-induced attention shifts. Effects of TMS over L-IPS (orange) or R-IPS (red), relative to baseline (no TMS). Bars represent mean individual difference scores computed by subtracting the percentage of “left” responses from the number of “right” responses; error bars represent standard errors of mean. The end of each bar represents the “center of attention” in each respective condition as a result of TMS. Zero point represents baseline (no TMS). Top: left versus right parietal TMS without attentional cue, middle: left versus right parietal TMS with attentional cue in the left hemifield, bottom: left versus right parietal TMS with attentional cue in the right hemifield.

Finally, a repeated-measures ANOVA including the effect of attentional cueing on the previously described TMS effects revealed a significant interaction between Stimulated Hemisphere and TMS (F(1, 18) = 4.52, p = .048), as well as between Cue and TMS (F(2, 17) = 4.75, p = .023). There was no significant three-way interaction between the factors Stimulated Hemisphere, Cue, and TMS (F(2, 17) = 0.461, p = .639). A visualization of the observed results is depicted in Figure 5. The post hoc simple contrast analyses revealed that only left hemifield extinction following right parietal TMS (R-IPS) reveals a significant difference between “no cue” versus “cue right” (t(9) = 1.843, p = .049), indicating that after a right parietal virtual lesion, an ipsilesional (right) cue severely aggravates the left hemifield extinction, even extending the center of attention far into the right hemifield. In contrast, right hemifield extinction following left parietal TMS (L-IPS) was not significantly aggravated by an ipsilesional (left) cue (t(9) = 0.966, p = .18).

DISCUSSION

TMS has already successfully been used to mimic the behavioral deficits following brain lesions, as well as for unraveling the mechanisms underlying some of these deficits. In the current study, we aimed to explore whether TMS could also be employable to probe the effectiveness of treatments in an early stage of development in healthy adults and under controlled experimental conditions, thereby sparing the limited amount of real acute lesion patients. More specifically, we investigated whether externally manipulating covert spatial attention influences TMS-induced virtual extinction in healthy volunteers.

In response to bilateral stimuli presented under neutral baseline conditions, we observed a clear leftward attentional bias across all three of our groups of healthy participants (Figure 4). This uneven distribution of covert spatial attention has been described before and is commonly known as pseudoneglect or, in this case, pseudo extinction. The shift of the center of attention well into the left visual hemifield could be explained, according to Corbetta and Shulman (2002), as a result of a right hemispheric dominance with regard to spatial attention, which pulls spatial attention toward the left in neutral baseline conditions. However, in line with Kinsbourne's (1993) theory, it could also be explained as the result of a shifted attentional gradient resulting from interhemispheric inhibition, whereby the right hemisphere exerts stronger inhibition onto the left hemisphere, than vice versa.

It is by now well established that application of TMS over parietal cortex has the ability to temporarily induce visuospatial deficits like neglect and extinction. In many previous studies, visuospatial deficits were, in line with neuropsychological patient data, established more strongly after right parietal TMS, whereas no such effects are observed following left parietal TMS. In some of these studies, left parietal TMS exerted no behavioral effect on stimuli presented in the right visual field (see, e.g., Dambeck et al., 2006; Chambers, Payne, Stokes, & Mattingley, 2004; Fierro et al., 2000, 2001; Hilgetag et al., 2001). In the current study, we found extinction of the contralesional part of a bilateral stimulus after right as well as after left parietal TMS. It is still highly debated whether extinction is merely a symptom of hemineglect or whether it constitutes a different visuospatial defect altogether (Pavlovskaya et al., 2007; Smania et al., 1998). One aspect in which neglect and extinction seem to differ is the degree of lateralization of the symptoms; whereas neglect is well known to affect almost exclusively the left visual hemifield, extinction seems to be less confined to one hemifield. Our observation that both right and left parietal TMS induce extinction of the contralesional part of a bilateral stimulus further contributes to this ongoing discussion about the proposed lateralization of extinction by showing that this “virtual extinction” seems to occur equally strong after left and right parietal TMS.

Knowing that TMS is able to induce temporary behavioral deficits, so-called virtual lesions, we wanted to investigate whether TMS could possibly also enlarge our insights into the workings and applicability of rehabilitative treatment approaches. In a subsequent stage of data analysis, we therefore looked at interactions between the aforementioned effects of right versus left parietal TMS and the external manipulation of covert spatial attention using a brief visual cue, presented in either the left or right visual hemifield. Although a visual cue presented in the left hemifield shortly before target stimulus onset did not further increase the leftward bias caused by left parietal TMS, a visual cue presented in the right hemifield showed a significant interaction with the rightward bias caused by right parietal TMS. More specifically, a rightward visual cue substantially increased the extinction of left stimuli induced by right parietal TMS to a degree in which, on average, 25% more bilateral stimuli were misperceived as unilateral right stimuli, compared with neutral baseline, and about 22% more compared with right parietal TMS alone. This implies that directing covert attention toward the right hemifield can aggravate left hemifield extinction induced by right parietal TMS. The fact that we did not find a similar aggravation of right hemifield extinction induced by left parietal TMS after directing covert attention toward the left hemifield coincides with the extensive body of neuropsychological literature showing a strong right hemispherical lateralization of hemispatial neglect and extinction. Although both left and right parietal TMS result in contralateral extinction, implying equal vulnerability in both hemispheres, only left hemifield extinction following right parietal TMS is severely aggravated by a competing stimulus in the ipsilesional (right) hemifield. Apparently, a competing stimulus in the right hemifield captures attention in such a fashion that it severely deteriorates the ability to subsequently redistribute attention also toward the contralesional left hemifield when a bilateral stimulus is presented. This could signal an inability to detach attention from the ipsilesional hemifield once it has been drawn there by a visual stimulus, be it a visual cue or an object that catches attention in a natural scene. These observations speak to a model proposing an incapacity with regard to the redistribution of attention in the presence of an attention-binding distractor as a possible catalyst underlying the deficits characteristic of extinction and maybe also one of the neural mechanism accounting to the hemispheric asymmetry of attention deficits following unilateral brain lesions. Furthermore, it seems that only after disruption of the right parietal, as opposed to the left parietal, cortical functioning a distractor presented in the ipsilesional hemifield poses an insurmountable problem for detecting the contralesional counterpart of a subsequent bilateral stimulus. We put forward the possibility that the asymmetry with respect to this ability of detaching attention from a distractor, an ability crucial in almost every daily life setting, is contributing to the well-described right hemispheric lateralization with regard to extinction. The mixed empirical reports with regard to the lateralization of extinction could be related to a less or more severe disruption of the attention redistributing ability. In line with the fact that double dissociations between hemispatial neglect and extinction are observed frequently, our results further support the notion that these symptoms are not part of the same condition.

Hence, the observation that specifically left hemifield extinction induced by right parietal TMS can be aggravated by cueing covert spatial attention toward the right hemifield reveals new and important information about the cortical processes underlying bilateral extinction. However, from a therapeutic perspective, it is even more interesting to explore whether directing covert spatial attention toward the contralesional hemifield could also counteract TMS-induced extinction rather than aggravating it. Indeed, a visual cue presented in the left hemifield effectively drew the center of attention away from the right hemifield, thus counteracting the extinction of left hemifield stimuli caused by right parietal TMS. Similarly, a visual cue presented in the right hemifield counteracted the right hemifield extinction brought about by left parietal TMS. Thus, it seems that visual cues in both contralesional hemifields can counteract the behavioral impairments brought about by a TMS-induced virtual lesion to the respective contralateral parietal cortices. Consequently, both potentially have therapeutic value. However, because in practice behavioral impairments are often restricted to the left hemifield, presenting cues in the left visual field potentially provides the most therapeutic gain. Future studies should aim at validating and further exploring the possible therapeutic benefits of attentional cueing in treating extinction patients, also extending to the effects of central visual cues or cross-modal cues, which might be even more efficient than unisensory visual cues (Spence, 2010).

In conclusion, our findings imply that externally manipulating covert spatial attention can enhance or counteract symptoms of extinction induced temporarily by parietal TMS. The enhanced symptoms of left hemifield extinction after right parietal TMS after a right attention cue, specifically, might reflect a disruption of the ability to detach attention from a distracting cue and redistribute it over both hemifields to correctly perceive a bilateral visual stimulus. This ability is very likely right lateralized, thus contributing to the right hemispheric lateralization of extinction. In addition, a visual cue presented in the contralesional hemifield shortly before a bilateral visual stimulus appears can reduce TMS-induced extinction of the contralesional counterpart of the bilateral stimulus. Whether this is also effective in patients suffering from chronic behavioral impairments caused by actual brain lesions remains to be studied, but if so the manipulation of spatial attention could possibly prove useful for therapeutic interventions in the future. On a broader level, our results show that TMS might not only be used to evaluate which behavioral impairments occur after disruption of a certain brain area, the so-called virtual lesion approach, and which cortical processes are underlying the disturbed functions, but that TMS might also be employable as a tool for probing and evaluating rehabilitative treatment options in an early stage. Such an approach increases explorative possibilities, limits the burden placed on the small amount of available acute lesion patients, and drastically reduces the impact of the many confounding factors inevitably associated with studying patients.

Acknowledgments

We thank our medical supervisor Cees van Leeuwen and our independent physician Martin van Boxtel. We also thank Caroline Benjamins, Sasa Redzepovic, Janna Didden, Roy Haex, Jochem Jansen, Gesa Kappen, Sebastian Laufer, Sanne ten Oever, Rianne Opstelten, and Mareike Voget for their contributions to this study. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement (263472; awarded to A. T. S.).

Reprint requests should be sent to Dr. Nina Bien, Department of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands, or via e-mail: nina.bien@maastrichtuniversity.nl.

REFERENCES

Becker
,
E.
, &
Karnath
,
H. O.
(
2007
).
Incidence of visual extinction after left versus right hemisphere stroke.
Stroke
,
38
,
3172
3174
.
Bjoertomt
,
O.
,
Cowey
,
A.
, &
Walsh
,
V.
(
2002
).
Spatial neglect in near and far space investigated by repetitive transcranial magnetic stimulation.
Brain
,
125
,
2012
2022
.
Bonato
,
M.
,
Priftis
,
K.
,
Marenzi
,
R.
,
Umiltà
,
C.
, &
Zorzi
,
M.
(
2010
).
Increased attentional demands impair contralesional space awareness following stroke.
Neuropsychologia
,
48
,
3934
3940
.
Carrasco
,
M.
,
Ling
,
S.
, &
Read
,
S.
(
2004
).
Attention alters appearance.
Nature Neuroscience
,
7
,
308
313
.
Chambers
,
C. D.
,
Payne
,
J. M.
,
Stokes
,
M. G.
, &
Mattingley
,
J. B.
(
2004
).
Fast and slow parietal pathways mediate spatial attention.
Nature Neuroscience
,
7
,
217
218
.
Corbetta
,
M.
,
Miezin
,
F. M.
,
Shulman
,
G. L.
, &
Petersen
,
S. E.
(
1993
).
A PET study of visuospatial attention.
Journal of Neuroscience
,
13
,
1202
1226
.
Corbetta
,
M.
, &
Shulman
,
G. L.
(
2002
).
Control of goal-directed and stimulus-driven attention in the brain.
Nature Reviews Neuroscience
,
3
,
201
215
.
Dambeck
,
N.
,
Sparing
,
R.
,
Meister
,
I. G.
,
Wienemann
,
M.
,
Weidemann
,
J.
,
Topper
,
R.
,
et al
(
2006
).
Interhemispheric imbalance during visuospatial attention investigated by unilateral and bilateral TMS over human parietal cortices.
Brain Research
,
1072
,
194
199
.
Fierro
,
B.
,
Brighina
,
F.
, &
Bisiach
,
E.
(
2006
).
Improving neglect by TMS.
Behavioural Neurology
,
17
,
169
176
.
Fierro
,
B.
,
Brighina
,
F.
,
Oliveri
,
M.
,
Piazza
,
A.
,
La Bua
,
V.
,
Buffa
,
D.
,
et al
(
2000
).
Contralateral neglect induced by right posterior parietal rTMS in healthy subjects.
NeuroReport
,
11
,
1519
1521
.
Fierro
,
B.
,
Brighina
,
F.
,
Piazza
,
A.
,
Oliveri
,
M.
, &
Bisiach
,
E.
(
2001
).
Timing of right parietal and frontal cortex activity in visuo-spatial perception: A TMS study in normal individuals.
NeuroReport
,
12
,
2605
2607
.
Fu
,
S.
,
Fan
,
S.
,
Chen
,
L.
, &
Zhuo
,
Y.
(
2001
).
The attentional effects of peripheral cueing as revealed by two event-related potential studies.
Clinical Neurophysiology
,
112
,
172
185
.
Gorea
,
A.
, &
Sagi
,
D.
(
2000
).
Failure to handle more than one internal representation in visual detection tasks.
Proceedings of the National Academy of Sciences, U.S.A.
,
97
,
12380
12384
.
Heilman
,
K. M.
,
Bowers
,
D.
,
Valenstein
,
E.
, &
Watson
,
R. T.
(
1993
).
Disorders of visual attention.
Baillieres Clinical Neurology
,
2
,
389
413
.
Hilgetag
,
C. C.
,
Theoret
,
H.
, &
Pascual-Leone
,
A.
(
2001
).
Enhanced visual spatial attention ipsilateral to rTMS-induced “virtual lesions” of human parietal cortex.
Nature Neuroscience
,
4
,
953
957
.
Kerkhoff
,
G.
(
2001
).
Spatial hemineglect in humans.
Progress in Neurobiology
,
63
,
1
27
.
Kinsbourne
,
M.
(
1993
).
Integrated cortical field model of consciousness.
Ciba Foundation Symposium
,
174
,
43
50
; discussion 51-60.
Koch
,
G.
,
Oliveri
,
M.
,
Cheeran
,
B.
,
Ruge
,
D.
,
Lo Gerfo
,
E.
,
Salerno
,
S.
,
et al
(
2008
).
Hyperexcitability of parietal-motor functional connections in the intact left-hemisphere of patients with neglect.
Brain
,
131
,
3147
3155
.
Koch
,
G.
,
Oliveri
,
M.
,
Torriero
,
S.
, &
Caltagirone
,
C.
(
2005
).
Modulation of excitatory and inhibitory circuits for visual awareness in the human right parietal cortex.
Experimental Brain Research
,
160
,
510
516
.
Manes
,
F.
,
Paradiso
,
S.
,
Springer
,
J. A.
,
Lamberty
,
G.
, &
Robinson
,
R. G.
(
1999
).
Neglect after right insular cortex infarction.
Stroke
,
30
,
946
948
.
Meador
,
K. J.
,
Ray
,
P. G.
,
Day
,
L.
,
Ghelani
,
H.
, &
Loring
,
D. W.
(
1998
).
Physiology of somatosensory perception: Cerebral lateralization and extinction.
Neurology
,
51
,
721
727
.
Meister
,
I. G.
,
Wienemann
,
M.
,
Buelte
,
D.
,
Grunewald
,
C.
,
Sparing
,
R.
,
Dambeck
,
N.
,
et al
(
2006
).
Hemiextinction induced by transcranial magnetic stimulation over the right temporo-parietal junction.
Neuroscience
,
142
,
119
123
.
Mesulam
,
M. M.
(
1981
).
A cortical network for directed attention and unilateral neglect.
Annals of Neurology
,
10
,
309
325
.
Muggleton
,
N. G.
,
Postma
,
P.
,
Moutsopoulou
,
K.
,
Nimmo-Smith
,
I.
,
Marcel
,
A.
, &
Walsh
,
V.
(
2006
).
TMS over right posterior parietal cortex induces neglect in a scene-based frame of reference.
Neuropsychologia
,
44
,
1222
1229
.
Orr
,
C. A.
, &
Nicholls
,
M. E.
(
2005
).
The nature and contribution of space- and object-based attentional biases to free-viewing perceptual asymmetries.
Experimental Brain Research
,
162
,
384
393
.
Pascual-Leone
,
A.
,
Gomez-Tortosa
,
E.
,
Grafman
,
J.
,
Alway
,
D.
,
Nichelli
,
P.
, &
Hallett
,
M.
(
1994
).
Induction of visual extinction by rapid-rate transcranial magnetic stimulation of parietal lobe.
Neurology
,
44
,
494
498
.
Pavlovskaya
,
M.
,
Soroker
,
N.
, &
Bonneh
,
Y.
(
2007
).
Extinction is not a natural consequence of unilateral spatial neglect: Evidence from contrast detection experiments.
Neuroscience Letters
,
420
,
240
244
.
Sack
,
A. T.
(
2010
).
Using non-invasive brain interference as a tool for mimicking spatial neglect in healthy volunteers.
Restorative Neurology and Neuroscience
,
28
,
485
497
.
Sack
,
A. T.
,
Camprodon
,
J. A.
,
Pascual-Leone
,
A.
, &
Goebel
,
R.
(
2005
).
The dynamics of interhemispheric compensatory processes in mental imagery.
Science
,
308
,
702
704
.
Sack
,
A. T.
,
Kohler
,
A.
,
Bestmann
,
S.
,
Linden
,
D. E.
,
Dechent
,
P.
,
Goebel
,
R.
,
et al
(
2007
).
Imaging the brain activity changes underlying impaired visuospatial judgments: Simultaneous fMRI, TMS, and behavioral studies.
Cerebral Cortex
,
17
,
2841
2852
.
Sack
,
A. T.
,
Sperling
,
J. M.
,
Prvulovic
,
D.
,
Formisano
,
E.
,
Goebel
,
R.
,
Di Salle
,
F.
,
et al
(
2002
).
Tracking the mind's image in the brain: II. Transcranial magnetic stimulation reveals parietal asymmetry in visuospatial imagery.
Neuron
,
35
,
195
204
.
Smania
,
N.
,
Martini
,
M. C.
,
Gambina
,
G.
,
Tomelleri
,
G.
,
Palamara
,
A.
,
Natale
,
E.
,
et al
(
1998
).
The spatial distribution of visual attention in hemineglect and extinction patients.
Brain
,
121
,
1759
1770
.
Spence
,
C.
(
2010
).
Crossmodal spatial attention.
Annals of the New York Academy of Sciences
,
1191
,
182
200
.
Vallar
,
G.
, &
Perani
,
D.
(
1986
).
The anatomy of unilateral neglect after right-hemisphere stroke lesions. A clinical/CT-scan correlation study in man.
Neuropsychologia
,
24
,
609
622
.
Vallar
,
G.
,
Rusconi
,
M. L.
, &
Bernardini
,
B.
(
1996
).
Modulation of neglect hemianesthesia by transcutaneous electrical stimulation.
Journal of the International Neuropsychological Society
,
2
,
452
459
.