Cerebral Cortex Advance Access published August 21, 2006

Transcription

1 Advance Access published August 21, 2006 doi: /cercor/bhl060 Human Ventral Parietal Cortex Plays a Functional Role on Visuospatial Attention and Primary Consciousness. A Repetitive Transcranial Magnetic Stimulation Study In this paper, we used repetitive transcranial magnetic stimulation (rtms) in 18 normal subjects to investigate whether the ventral posterior parietal cortex (PPC) plays a causal role on visuospatial attention and primary consciousness and whether these 2 functions are linearly correlated with each other. Two distinct experimental conditions involved a similar visual stimuli recognition paradigm. In Consciousness experiment, number of consciously perceived visual stimuli was lower by about 10% after rtms (300 ms, 20 Hz, motor threshold intensity) on left or right PPC than after sham (pseudo) rtms. In Attentional Posner s experiment, these stimuli were always consciously perceived. Compared with sham condition, parietal rtms slowed of about 25 ms reaction time to go stimuli, thus disclosing effects on endogenous covert spatial attention. No linear correlation was observed between the rtmsinduced impairment on attention and conscious perception. Results suggest that PPC plays a slight but significant causal role in both visuospatial attention and primary consciousness. Furthermore, these high-level cognitive functions, as modulated by parietal rtms, do not seem to share either linear or simple relationships. Keywords: primary consciousness, repetitive transcranial magnetic stimulation (rtms), ventral posterior parietal cortex, visuospatial attention Introduction Primary consciousness is an early process by which a conscious perceptive image of a sensory stimulus emerges by cortical activity, as opposed to parallel not conscious, automatic processing of the same stimulus. As a simple operational definition, here visual primary consciousness was considered as the process underlying immediate subject s self-report about an adequate visual stimulation given to himself or herself. In line with Pinker s (1997) theoretical view, that report implies subjective phenomenal experience ( sentience ) and the ability to report on the content of short-term phenomenal/mental experience ( access to information ). Primary consciousness is strictly connected to selective attention. High-focused visual attention toward an external object is related to a vivid and prolonged conscious perceptive image of the object, whereas a low attentive level is related to a dummy perceptive image. Ventral posterior parietal cortex (PPC) seems to be deeply involved in both visuospatial selective attention and primary consciousness. Patients with lesions including ventral PPC (especially of the right hemisphere) are not able to consciously perceive unilateral stimuli at visual hemifield or hemibody contralateral to the lesion (i.e., neglect, Vallar and others 1988; Driver and Vuilleumier 2001; Corbetta and others 2005). In Claudio Babiloni 1--3, Fabrizio Vecchio 1,3, Simone Rossi 4, Alberto De Capua 5, Sabina Bartalini 4, Monica Ulivelli 4 and Paolo Maria Rossini 2,3,6 1 Dipartimento Fisiologia Umana e Farmacologia, Universita` degli Studi di Roma La Sapienza, Rome, Italy, 2 IRCCS Centro S. Giovanni di Dio-F.B.F., Brescia, Italy, 3 A.Fa.R. Dipartimento Neuroscienze, Osp. FBF, Isola Tiberina, Rome, Italy, 4 Dipartimento di Neuroscienze, Sezione Neurologia, Universita` Siena, Italy, 5 Dipartimento di Neuroscienze, Sezione Psichiatria, Universita` Siena, Italy and 6 Clinica Neurologica, Campus Biomedico, Universita` di Roma, Italy some cases, they just miss contralesional stimuli at left visual hemifield or hemibody during bilateral stimulations (i.e., hemiinattention or extinction). This lack of primary consciousness is supposed to rely on a pathological bias in spatial attention toward the hemifield or hemibody contralateral to the intact left hemisphere (Posner and others 1984; Vallar and others 1988; Desimone and Duncan 1995; Corbetta and others 2005). The causal role of PPC in visuospatial selective attention and primary consciousness has been also proven by single-pulse or repetitive transcranial magnetic stimulation (rtms), which can transiently interfere with the functions of the stimulated cortical area (Oliveri and others 1999, 2000; Walsh and Cowey 2000; Sack and Linden 2003; Rossi and Rossini 2004; Hung and others 2005; Campana and others 2006; Fuggetta and others 2006). Converging evidences indicate that TMS on the PPC modulated conscious perceptive deficits of patients suffering from neglect of visual or somatic stimuli at contralesional side, and that these deficits can even be transiently induced in normal subjects (Pascsual-Leone and others 1994; Oliveri and others 1999, 2000, 2002; Walsh and Rushworth 1999; Fierro and others 2000, 2001; Hilgetag and others 2001; Bjoertomt and others 2002; Brighina and others 2002; Muri and others 2002). The mentioned data suggest a simple linear relationship between attention and primary consciousness and a causal role for both functions of PPC. However, such a simple relationship is challenged by several lines of evidence. Residual selective attention can be observed in particular epileptic patients that, during complex partial seizures, can still perform aimed actions (e.g., bringing and drinking a glass of water; getting out of the room) without any apparent perceptive conscious experience; the same is true in sleepwalkers and in subjects under hypnotic commands (Damasio 1998). In these cases, sentience and/or access to information of the visual consciousness seems to be affected in some way. The relationship among selective attention, primary consciousness, and PPC might be much less simple than those emerging from field literature. In the present study, we wondered whether human ventral PPC plays a causal role on visuospatial attention and primary consciousness and whether these 2 functions are correlated with each other. For this purpose, rtms was applied over right or left ventral PPC of normal subjects during 2 experiments. The first experiment tested the functional relationship between PPC activity and primary visual consciousness (Babiloni and others 2005, 2006), whereas the second experiment those between PPC and visuospatial attention (Posner and others 1984; Thuth and others 2005). In particular, 3 working hypotheses were tested. The first hypothesis was that rtms of ventral PPC could reduce the number of consciously seen cue stimuli. The Ó The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org

2 Babiloni second hypothesis was that rtms of ventral PPC could impair visuospatial attention and could slow the reaction time to predicted go stimuli (valid trials = spatial congruence between cue and go stimuli). The third hypothesis was that the predicted effects of rtms on visuospatial primary consciousness and attention were linearly correlated each other. Materials and Methods Subjects Experiments were performed on 18 healthy adult volunteers (with ages spanning from 20 to 40 years). Edinburgh Inventory for right handedness was 77.5% (±9 standard error [SE]). They had no previous psychiatric or neurological history. Their sight was normal or corrected-tonormal. All experiments were undertaken with the understanding and written consent of each participant according to Code of Ethics of the World Medical Association and the standards established by the Author s Institutional Review Board. The present study was approved by local ethical committee. Experimental Tasks The subjects were seated in a comfortable reclining armchair. They kept their forearms resting on the armchairs, with the right index finger resting between 2 buttons of a mouse connected to a computer. The computer monitor was placed in front of them at a distance of about 100 cm. As aforementioned, 2 distinct experiments were performed (Fig. 1). The first experimental paradigm served to emphasize the strict functional relationships between ventral PPC and primary visual consciousness. In the Consciousness experiment, a preliminary procedure ascertained the individual perceptive threshold time (ms) of the cue stimulus. The cue stimulus was a white circle (diameter of about 0.5 of visual angle) appearing at 6 right or left side of the background central white cross (diameter of 0.5 ). The cue stimulus was preceded and followed by a masking visual stimulus formed by 2 Xs (large about 0.8 ), located at 6 right and left sides of the central white cross. The subjects had to say seen any time they perceived the position of the cue stimulus. In detail, the procedure was as follows. The duration of the cue stimulus varied randomly trial-by-trial within the following values: 20, 40, 60, 80, 100, 120, 140, 160 ms for 80 trials (10 for each duration value). The procedure was repeated 7 times. The threshold time was defined as the duration of the cue stimulus determining about 50% of correct stimulus detections within a series of 10 trials, in the majority of the 7 repetitions of the procedure. Just before starting with the experimental session, this threshold time was systematically varied up and down (10 ms) for some preliminary trials, to verify the stability of that time based on subject s self-report. There was always a confirmation of the threshold time of cue presentation as indicated by the above preliminary procedure. Subject-by-subject, the mean threshold time of the cue stimulus was 72 ms (±7.9 SE). Of note, a previous study allowed to ascertain that individual values of perceptive threshold remained substantially stable for the entire recording session (Babiloni and others 2006). The sequence of the visual stimuli was as follows (Fig. 1): 1) the masking stimulus Xs lasting 5.5 s; 2) the cue stimulus small circle appearing on the right or left (50%) monitor side for the threshold time; 3) the masking stimulus Xs lasting about 2 s; 4) a go (target) stimulus lasting about 0.5 s. The go stimulus was a small green circle with a diameter of about 0.5, which appeared on 6 right or left (50% of probability) side of the central white cross. The subjects had to press the left mouse button if the go stimulus appeared on the left monitor side, whereas they had to press the right mouse button if the go stimulus appeared on the right monitor side. The computer receiving the mouse inputs registered the corresponding reaction time and the side of the button pressed. Immediately after the hand motor response, the subjects had to say seen if they had detected the cue stimulus ( seen trial ) or not seen if they had missed the cue stimulus ( not seen trial ). Noteworthy, subjects denied the use of mental verbal codes for the cue or go stimuli after the experiment. Verbal self-report was registered by the manual note of an experimenter. The experimenter Figure 1. Left column: Sequence of events during a trial of the Consciousness experiment: 1) masking stimulus lasting 5.5 s; 2) cue stimulus appearing on the right or left monitor side for the threshold time giving about 50% of stimulus recognition; 3) masking stimulus lasting about 2 s (i.e., 2 s minus the threshold time); 4) go stimulus lasting about 0.5 s. The go stimulus was a green circle with a diameter of about 0.5, which appeared on the right or the left monitor side. Subjects had to click the left mouse button if the go stimulus appeared on the left monitor side, whereas they had to click the right mouse button if the go stimulus appeared on the right monitor side (selfreport). The computer receiving mouse inputs registered the corresponding reaction time and the side of the mouse button clicked. After hand motor response, subjects had to say seen if they had detected the cue stimulus ( seen trial) or not seen if they had missed the cue stimulus ( not seen trial). When required by the experimental demands, an rtms train (300 ms, 20 Hz) was delivered simultaneously to cue presentation. Right column: Sequence of events during a trial of the Attentional experiment. They are as the Consciousness experiment except that the cue stimulus lasted 500 ms, and no self-report was required. even controlled what the subjects watched on the computer monitor during the task. Of note, the same presentation time and physical features (shape, position, luminance etc.) characterized the cue stimuli consciously perceived ( seen trials ) and those not consciously perceived ( not seen trials ). Therefore, these features cannot explain the reason why some cue stimuli were seen and others were consciously not seen. The Attentional experiment tested whether the applied rtms train impaired specific processes of visuospatial attention. The Attentional experiment differed from the Consciousness experiment for the duration of the cue stimulus and the spatial relationships between cue and go stimuli. In the Attentional experiment, the cue stimulus lasted 500 ms for all subjects to produce 100% of conscious detection. Furthermore, the go stimulus was given to the same side of the cue stimulus in the 80% of the cases (valid trials; Posner and others 1980), to induce a covert spatial attention toward the portion of the monitor in which cue stimulus appeared. Finally, no self-report was required in the Attentional experiment. Procedures of rtms and Identification of Target Scalp Regions The rtms was delivered through a focal, figure-of-eight coil (outer diameter of each wing 7 cm), connected with a standard Mag-Stim Super Rapid stimulator (maximum output 2.2 Tesla). Individual resting excitability thresholds for left and right motor cortices stimulation were first determined by using the same coil and stimulator and following standardized procedures (Rossini and others 1994; Rossi and others 2001). Left and or right ventral PPC (epicenter in Broadman area [BA] 39) was stimulated by placing the anterior end of the junction of the 2 coil wings at the predetermined scalp site, respectively. A mechanical arm maintained the handle of the coil angled backward of about 45 away from the midline. This position was marked on a transparent bathing cap Page 2 of 7 Parietal Cortex, Attention, and Consciousness d and others

3 firmly adherent to the scalp. The procedure allowed the correct repositioning of the coil prior to the appearance of each warning signal. The left and right PPC locations were automatically identified on the subject s scalp using SofTaxic Navigator system, on the basis of digitized skull landmarks (nasion, inion, and 2 preauricular points) and about 40 scalp points (Fastrak Polhemus digitizer, Polhemus, Colchester, VT). Talairach coordinates of the putative cortical sites were automatically estimated by the SofTaxic Navigator Stereotaxic Navigator System (E.M.S. Italy, on the basis of an MRI-constructed stereotaxic template (estimated accuracy of ±0.5 cm, Talairach space; Fig. 2). Of note, error of TMS coil positioning (SofTax system) may be less than 1 cm across subjects, a negligible displacement with respect to the large cortical area of interest, namely, ventral PPC. Furthermore, the intensity of stimulation (100% of individual motor threshold) reasonably minimized the possibility of an insufficient interferential effect due to a mismatch between the scalp site and the underlying anatomy. Very similar scalp position and stimulation intensity have been previously used in TMS studies to interfere with cognitive functions of PPC such as sensory perception, mental rotation, grasping or visuospatial and verbal working memory, and episodic memory (Mottaghy and others 1999; Oliveri and others 1999, 2000; Rossi and others 2006). Trains of rtms (100% of individual motor threshold; length of each rtms train: 300 ms; rtms frequency: 20 Hz) were delivered from the onset of the cue stimulus presentation in both Consciousness and Attentional experiments. The length of the rtms train corresponded to the activation timing of PPC previously found in an electroencephalography (EEG) study carried out with the same paradigm (Babiloni and others 2006). In both Consciousness and Attentional experiments, each subjects performed 4 different times the same experimental task. In a block, the subjects were not stimulated by the rtms (baseline condition). In other 2 blocks, the sites of stimulation were either at left or at right ventral PPC. Finally, there was a block in which the rtms coil was centered at scalp vertex, but it was held perpendicularly to the scalp surface (sham condition). In the sham condition, scalp contact and discharging noise were practically equal to the active stimulation, but the induced magnetic field did not activate cortical neurons. Each of the 4 blocks (No stimulation, active rtms overlying the left or right ventral PPC, and sham rtms) included about 40 trials. To avoid a possible effect Figure 2. MRI-constructed stereotaxic template showing the coronal (a), sagittal (b), and axial (c) projections on the cortical surfaces of stimulation sites in the left hemisphere, corresponding to the intraparietal suclus (Talaraich coordinates of left ventral PPC: 43, 68, 39). Talaraich coordinates of the homologous right stimulation site (not shown) were 40, 66, 40. Such positions corresponded to an epicenter at BA 39. of adaptation to the coil scalp contact, the sequence of these 4 blocks was randomly delivered at group level. Statistical Analysis To test the causal role of ventral PPC on primary visual consciousness (first working hypothesis; see Introduction), an analysis of variance (ANOVA) test included factor Site of Stimulation (real left PPC, real right PPC, sham) and number of seen trials as a dependent variable. Duncan test was used for post hoc comparisons between sham andreal rtms conditions (P < 0.05). To test the causal role of ventral PPC on visual attention (second working hypothesis), an ANOVA test included factor Site of Stimulation (real left PPC, real right PPC, sham) and reaction time in milliseconds as a dependent variable. Duncan test was used for post hoc comparisons between sham and real rtms conditions (P < 0.05). To test the hypothesis of linear relationships among ventral PPC, attention and primary consciousness, we evaluated the linear correlation of the number of seen trials in the Consciousness experiment with the reaction time in the Attentional experiment (Pearson test; Bonferroni corrected, P < 0.05). Furthermore, we also evaluated the linear correlation of the variation of the number of seen trials in the Consciousness experiment with the variation of reaction time in the Attentional experiment with respect to the No Stimulation block (Pearson test; Bonferroni corrected, P < 0.05). Results Consciousness Experiment In all conditions of the Consciousness experiment, the percentage of correct responses (right mouse button press for right go stimulus; left mouse button press for left go stimulus) was higher than 95%. Trials associated with the conscious perception of cue stimuli were defined as seen trials. Across subjects mean percentage of the seen trials was 52.9% (±0.8 SE) in the baseline condition (no rtms), 52.2% (±0.6 SE) in the sham condition (pseudo rtms), 44.4% (±1.9 SE) after rtms at left PPC, and 45.9% (±1.7 SE) after rtms at right PPC. The hypothesis that rtms of PPC could reduce the number of consciously seen cue stimuli was evaluated by ANOVA including factor Site of rtms (real right PPC, real left PPC, sham). There was a statistically significant main effect (F 2,34 = 3.77; P < 0.03; left side of Fig. 3). Compared with the sham condition, the number of seen trials was significantly reduced after rtms at both left (P < 0.02) and right PPC (P < 0.04), reflecting the reduction of primary visual consciousness. Attentional Experiment In the Attentional experiment, the cue stimuli persisted enough to be always consciously perceived, and valid trials were those with spatial congruence between cue and go stimuli. In all conditions, the percentage of correct responses (right mouse button press for right go stimulus; left mouse button press for left go stimulus) for the valid trials was higher than 95%. Mean reaction time of the valid trials across subjects was 456 ms (±12 SE) in the baseline condition (no rtms). The presence of rtms, either real or sham, generally shortened reaction times: 418 ms (±10 SE) in the sham condition (pseudo rtms), 446 ms (±12 SE) after rtms at left PPC, and 438 ms (±11 SE) after rtms at right PPC. The hypothesis that rtms of PPC could slow the reaction time (vs. sham) to valid trials was evaluated by ANOVA including factor Site of rtms stimulation (real left PPC, real right PPC, sham). There was a statistically significant main effect (F 2,34 = 5.25; P < 0.01; right side of Fig. 3). Compared with the sham condition, the reaction time of valid trials increased after rtms Page3of7

4 Babiloni Figure 3. On the left: Results of the Consciousness paradigm showed that rtms at either left or right ventral PPC reduced the percentage of seen stimuli. On the right: Results of the Attentional Posner s paradigm showed that the same stimulations slowed reaction time to stimuli affected by cover spatial attention. at both left (P < 0.02) and right (P < 0.03) PPC, reflecting the reduction of visuospatial attention. Correlation between Results of the Consciousness and Attentional Experiments Pearson s test (P > 0.05) evaluated the hypothesis that the predicted effects of rtms on visuospatial attention and primary consciousness were correlated. The correlation was calculated between the number of seen trials after rtms at left or right PPC in the Consciousness experiment and the reaction time to valid trials after the same rtms in the Attentional experiment. First row of Figure 4 shows no statistically significant correlation (rtms at left PPC: r = 0.36, P = 0.13; rtms at right PPC: r = 0.18, P = 0.46). As a control, the correlation was also calculated between the difference (sham-rtms at left or right PPC) of seen trials in the Consciousness experiment and the difference (sham-rtms at left or right PPC) of reaction times to valid trials in the Attentional experiment. Second row of Figure 4 shows no statistically significant correlation (sham-rtms at left PPC: r = 0.31; P < 0.21; sham-rtms at right PPC: r = 0.14; P < 0.59). Control Analyses Trials of the Consciousness experiment were classified as follows: 1) congruent trials, in which the go stimulus appeared on the cued location; 2) incongruent trials, in which the go stimulus appeared on the uncued location. The congruent and the incongruent trials were equally numbered (50%). For the Attentional experiment, we considered only the valid trials. The reaction time for each trial class was defined as the period between the onset of the go stimulus and the mouse button click. The correctness of subjective reports about recognition performance of the Consciousness experiment was evaluated by an ANOVA analysis of reaction time to go stimuli in the baseline (no rtms) and sham conditions (pseudo rtms), which included factors Condition ( seen trials, not seen trials), Side of the cue stimulus (right, left), and Congruence (spatial congruence between cue stimulus and subsequent go stimulus; spatial incongruence between cue stimulus and subsequent go stimulus). The results showed statistically significant main factors Condition (F 1,18 = 5.84; P < 0.025) and Congruence (F 1,18 = 5.16; P < 0.035). According to the control hypothesis, mean reaction time was shorter in the seen trials than in the not seen ones regardless the spatial congruency between cue and go stimuli, thus demonstrating the global positive effect of conscious visual perception. Furthermore, the mean reaction time was shorter in the spatially congruent than incongruent trials regardless the consciousness of the stimuli, indicating that the requirement of a self-report induced a covert attention on cued location even when the cue stimuli were not consciously perceived ( not seen trials). The latter result was possibly due to covert attention on cued location regardless the conscious perception, which may be induced by the requirement of self-report (Ivanoff and Klein 2003; Babiloni and others 2006). The covert attention probably suppressed inhibition of return mechanism by which reaction time to go stimuli is typically lengthened by noninformative cue stimuli at the same location or hemifield (Posner and Cohen 1984). Well conduction of the Attentional experiment was evaluated by an ANOVA analysis of reaction time to go stimuli in the baseline (no rtms) and sham conditions, which included factor Condition (valid trials, invalid trials) and Side of the cue stimulus (right, left). The results showed a statistically significant main factor Condition (F 1,18 = 17.08; P < ). According to the control hypothesis, mean reaction time was shorter in the valid than in the invalid trials regardless of the spatial congruency between cue and go stimuli, thus demonstrating the global positive effect of covert attention on cued location. Discussion The rtms overlying left or right ventral PPC reduced the consciously perceived (cue) stimuli, thus confirming a certain causal role of PPC for primary visual consciousness. The small but significant magnitude of rtms effects on ventral PPC (about 10%) is likely due to the use of focal coil and near-threshold intensity of rtms. These 2 factors limited the induced neural interference in relation to the distributed cerebral networkspanning occipital, parietal, and temporal cortical areas of both hemispheres subserving primary visuospatial consciousness (Crick and Koch 1995; Ress and Heeger 2003; de Lafuente and Romo 2005; Fang and He 2005; Sergent and others 2005). Page 4 of 7 Parietal Cortex, Attention, and Consciousness d and others

5 Figure 4. On the top: Scatterplots of the linear correlation of the number of seen trials in the Consciousness experiment with the reaction time in the Attentional experiment (Pearson test; Bonferroni corrected, P < 0.05). On the bottom: Scatterplots of the linear correlation of the variation of the number of seen trials in the Consciousness experiment with the variation of reaction time in the Attentional experiment, after subtraction of the reaction time in No Stimulation block. No statistical significance emerged. Higher stimulation might have probably been more effective behaviorally, but carrying the risk of strong arousal (i.e., higher discharging noise and trigeminal afferents activation) disturbing the demanding cognitive performance, as already described for episodic memory (Rossi and others 2006). The involvement of bilateral ventral PPCs in primary visual consciousness probably occurs with peculiar aspects. Previous studies have emphasized the role of left hemisphere for consciousness, whereas others have favored right hemisphere (Shevrin 1992; Gazzaniga 1993; Henke and others 1993). Left hemisphere may subserve sequential organization of percept, linguistic elaboration of behavioral control, and theorization on experience flux (Gazzaniga 2000). Whereas, right hemisphere may subserve global visuospatial search and somatic perceptive processes, as revealed by neurological deficits such as neglect, visual extinction, prosopagnosia following righthemisphere damage (Berti and Rizzolatti 1992; Wallace 1994; Baudena and others 1995; Farah and Feinberg 1997; De Renzi 2000). In the Attentional experiment, cue stimuli were always consciously perceived in all conditions, thus indicating a full primary consciousness. Instead, attentional processes were modulated, as reflected by reaction time to go stimuli under covert visuospatial attention. Compared with the baseline condition (no rtms), the reaction time was faster after both sham and real rtms. These results are in line with previous findings showing that TMS coil sound per se shortens reaction time possibly due to enhanced arousal, intersensory, and/or motor output facilitation (Nickerson 1973; Rossi and others 2001, 2006). With respect to the sham, the real rtms of right or left ventral PPC slowed reaction time to go stimuli. It is reasonable that the slowing of the reaction time is mainly due to visuospatial sensory processing, although a slight influence on motor output cannot be excluded. These results corroborate the well-known notion that ventral PPC is a putative substrate of neglect and other visuospatial deficits (e.g., Vallar 2001; Corbetta and Shulman 2002; Karnath and others 2003; Corbetta and others 2005). In parallel, dorsal PPC regions along the intraparietal sulcus are supposed to contribute to spatial attention (Corbetta and Shulman 2002; Corbetta and others 2005; Thuth and others 2005), as shown by previous functional neuroimaging studies in healthy subjects (Nobre and others 1997; Kastner and others 1999; Corbetta and others 2000; Hopfinger and others 2000). Dorsal PPC would be deeply implied with motor component of the attentional processes. According to Posner s theoretical framework, visuospatial attention depends on 3 elementary mental operations that can be performed covertly: 1) disengagement from a current focus of attention (spatial disengagement); 2) directing attention to a new spatial location (spatial orienting); and 3) engagement of target. These attentional operations can be performed under endogenous control (e.g., voluntary orienting) or under the Page5of7

6 Babiloni influence of peripheral cues (e.g., reflexive orienting). It is likely that the present rtms of ventral PPC mainly effected spatial disengagement, in agreement with previous clinical studies showing that ventral PPC lesions are related to prominent spatial disengagement deficits (Posner and others 1984; Posner 1987; Friedrich and others 1998; Losier and Klein 2001). In addition, functional imaging studies have revealed an activation of ventral PPC accompanying disengagement of spatial attention in healthy subjects (Corbetta and others 2000). Conversely, patients with dorsal PPC damage would use endogenous information to facilitate and direct visuospatial attention (Posner and others 1984; Friedrich and others 1998; Smania and others 1998; Bartolomeo and Chokron 2002). In the current study, no linear or simple correlation emerged between the effects of rtms in the Consciousness and Attentional experiments; this is the first direct correlative evidence of parietal neural correlates of visual attention and consciousness, and requires to be carefully discussed in the following. As a premise, it should be remarked that the effect of rtms does not remain limited to the targeted brain region but spread transynaptically. Therefore, it can be speculated that ventral PPC is implied in some way with the cerebral networks subserving visuospatial attention and primary consciousness. Interaction of these networks might be nonlinear and too complex to cause simple relationships between visuospatial attention and primary consciousness, at least due to the focal and week TMS-induced perturbation of ventral PPC. In this sense, the present findings challenge the idea that visuospatial attention and primary consciousness are subserved by strictly interdependent networks. That questionable idea stems from a fatal association of several lines of evidence: 1) In neglect patients with (especially right) PPC lesion, both primary consciousness and selective attention are impaired and can be modulated by parietal rtms (Pascsual-Leone and others 1994; Walsh and Rushworth 1999; Fierro and others 2000, 2001; Oliveri and others 2000, 2002; Hilgetag and others 2001; Bjoertomt and others 2002; Brighina and others 2002; Muri and others 2002); 2) in healthy subjects, rtms of PPC transiently impairs both primary consciousness and selective attention to stimuli projected to the contralateral visual hemifield (Walsh and Rushworth 1999; Hilgetag and others 2001; Muri and others 2002); and 3) in healthy subjects, rtms of PPC paradoxically enhances both primary consciousness and selective attention to stimuli projected to the ipsilateral visual hemifield (Walsh and Rushworth 1999; Hilgetag and others 2001). The present results would enlighten previous EEG evidence in which functions of primary consciousness and attention were probed using the so-called oddball paradigm. In the oddball paradigm, subjects had to respond (i.e., moving or counting) after rare but not after frequent stimuli of a sequence. Therefore, both selective attention and conscious perception were involved. It has been shown that, compared with the unconscious ( subliminal ) perception of the rare stimuli, the conscious one evoked parietal P300 with higher amplitude (Shefrin and others 1988; Brazdil and others 1998, 2001, 2002). Keeping in mind the mentioned EEG evidence, the results of the current study suggest future oddball investigations performing separate modulations of attentional processes (i.e., varying the level of stimulus novelty) and primary consciousness (i.e., varying the rate of conscious stimulus perception), to disentangle the effects of selective attention and primary consciousness on cortical generators of P300. Conclusions To our knowledge, this is the first direct experimental evidence of functional effects of bilateral ventral PPC on both visuospatial attention and primary consciousness. At group level, the rtms overlying left or right ventral PPC reduced the number conscious perceptions and modified reaction time to stimuli affected by spatial cover attention. However, at individual level, there was no linear correlation between the above effects. The present results suggest that ventral PPC plays a slight but significant causal role on both visuospatial attention and primary consciousness, in line with the mentioned literature on spatial neglect. As a novelty, these cognitive functions, as modulated by parietal rtms, do not seem to share either linear or simple relationships. The present results also represent a neurophysiologic explanation for the well-known anecdotes reporting dissociations between selective attention and primary consciousness in epileptic subjects during seizures, in sleepwalkers, and in subjects under hypnotic commands (Damasio 1998). Notes The research was granted by Association Fatebenefratelli for Research (AFaR). We thank Prof. Fabrizio Eusebi for his continuous support. Conflict of Interest: None declared. Address correspondence to Dr Claudio Babiloni, Dipartimento di Fisiologia Umana e Farmacologia, Universita` degli Studi di Roma La Sapienza, P.le Aldo Moro 5, Rome, Italy. References Babiloni C, Vecchio F, Bultrini A, Romani GL, Rossini PM. Dec 28, Pre- and poststimulus alpha rhythms are related to conscious visual perception: a high-resolution EEG study. Cereb Cortex. doi: / cercor/bhj104 Babiloni C, Vecchio F, Miriello M, Romani GL, Rossini PM Visuospatial consciousness and parieto-occipital areas: a high-resolution EEG study. Cereb Cortex 16(1): Bartolomeo P, Chokron S Orienting of attention in left unilateral neglect. Neurosci Biobehav Rev 26: Baudena P, Halgren E, Heit G, Clarke JM Intracerebral potentials to rare target and distractor auditory and visual stimuli. III. Frontal cortex. Electroencephalogr Clin Neurophysiol 94: Berti A, Rizzolatti G Visual processing without awareness: evidence from unilateral neglect. J Cogn Neurosci 4: Bjoertomt O, Cowey A, Walsh V Spatial neglect in near and far space investigated by repetitive transcranial magnetic stimulation. Brain 125: Brazdil M, Kuba R, Daniel P, Sochurkova D, Dobsik M, Rektor I Covert vision sign. Eur J Neurol 9(3): Brazdil M, Rektor I, Daniel P, Dufek M, Jurak P Intracerebral eventrelated potentials to subthreshold target stimuli. Clin Neurophysiol 112(4): Brazdil M, Rektor I, Dufek M, Jurak P, Daniel P Effect of subthreshold target stimuli on event-related potentials. Electroencephalogr Clin Neurophysiol 107: Brighina F, Bisiach E, Piazza A, Oliveri M, La Bua V, Daniele O, Fierro B Perceptual and response bias in visuospatial neglect due to frontal and parietal repetitive transcranial magnetic stimulation in normal subjects. Neuroreport 13: Campana G, Cowey A, Walsh V Visual area V5/MT remembers what but not where. Cereb Cortex [Epub ahead of print]. Corbetta M, Kincade JM, Ollinger JM, McAvoy MP, Shulman GL Voluntary orienting is dissociated from target detection in human posterior parietal cortex. Nat Neurosci 3(3): Corbetta M, Shulman GL Control of goal/directed and stimulus driven attention in the brain. Nat Rev Neurosci 3: Corbetta M, Tansy AP, Stanley CM, Astafiev SV, Snyder AZ, Shulman GL A functional MRI study of preparatory signals for spatial location and objects. Neuropsychologia 43(14): Page 6 of 7 Parietal Cortex, Attention, and Consciousness d and others

7 Crick F, Koch C Are we aware of neural activity in primary visual cortex? Nature 375(6527): Damasio AR Investigating the biology of consciousness. Philos Trans R Soc Lond B Biol Sci 353(1377): de Lafuente V, Romo R Neuronal correlates of subjective sensory experience. Nat Neurosci 8(12): De Renzi E Disorders of visual recognition. Semin Neurol 20(4): [review]. Desimone R, Duncan J Neural mechanisms of selective visual attention. Annu Rev Neurosci 18: [review]. Driver J, Vuilleumier P Perceptual awareness and its loss in unilateral neglect and extinction. Cognition 79(1--2): [review]. Fang F, He S Cortical responses to invisible objects in the human dorsal and ventral pathways. Nat Neurosci 8(10): Farah MJ, Feinberg TE Consciousness of perception after brain damage. Semin Neurol 17(2): Fierro B, Brighina F, Oliveri M, Piazza A, La Bua V, Buffa D, Bisiach E Controlateral neglect induced by right posterior parietal rtms in healthy subjects. Neuroreport 11: Fierro B, Brighina F, Piazza A, Oliveri M, Bisiach E Timing of right parietal and frontal cortex activity in visuo-spatial perception: a TMS study in normal individuals. Neuroreport 12: Friedrich FJ, Egly R, Rafal RD, Beck D Spatial attention deficits in humans: a comparison of superior parietal and temporal/parietal junction lesion. Neuropsychology 12: Fuggetta G, Pavone EF, Walsh V, Kiss M, Eimer M Cortico-cortical interactions in spatial attention: a combined ERP/TMS study. J Neurophysiol [Epub ahead of print]. Gazzaniga MS Brain mechanisms and conscious experience. Experimental and theoretical studies of consciousness (CIBA Foundation Symposium 174). Chichester, UK: Wiley. p Gazzaniga MS Cerebral specialization and interhemispheric communication: does the corpus callosum enable the human condition? Brain 2000 Jul;123: Henke K, Landis T, Markowitsch HJ Subliminal perception of pictures in the right hemisphere. Conscious Cogn 2: Hilgetag C, Theoret H, Pascual-Leone A Enhanced visual spatial attention ipsilateral to rtms-induced virtual lesion of human parietal cortex. Nat Neurosci 4: Hopfinger JB, Buchel C, Holmes AP, Friston KJ A study of analysis parameters that influence the sensitivity of event-related fmri analyses. Neuroimage 11(4): Hung J, Driver J, Walsh V Visual selection and posterior parietal cortex: effects of repetitive transcranial magnetic stimulation on partial report analyzed by Bundesen s theory of visual attention. J Neurosci 25(42): Ivanoff J, Klein RM Orienting of attention without awareness is affected by measurement-induced attentional control settings. J Vis 3(1): Karnath HO, Himmelbach M, Perenin MT Neglect-like behaviour in healthy subjects: dissociation of space exploration and goal directed pointing after vestibular stimulation. Exp Brain Res 153(2): Kastner S, Pinsk MA, De Weerd P, Desimone R, Ungereider LG Increased activity in human visual cortex during directed attention in the absence of visual stimulation. Neuron 22: Losier BJ, Klein RM A review of the evidence for a disengage deficit following parietal lobe damage. Neurosci Biobehav Rev 25(1): Mottaghy FM, Hungs M, Brugmann M, Sparing R, Boroojerdy B, Foltys H, Huber W, Topper R Facilitation of picture naming after repetitive transcranial magnetic stimulation. Neurology 56: Muri RM, Buhler R, Heinemann D, Mosimann UP, Felbinger J, Shalaepfer TE, Hess CW Hemispheric asymmetry in visuospatial attention assessed with transcranial magnetic stimulation. Exp Brain Res 143: Nickerson RS Intersensory facilitation of reaction time: energy summation or preparation enhancement? Psychol Rev 80: Nobre AC, Sebestyen GN, Gitelman DR, Mesulam MM, Frackowiak RS, Frith CD Functional localization of the system for visuospatial attention using positron emission tomography. Brain 120: Oliveri M, Rossini PM, Cicinelli P, Traversa R, Pasqualetti P, Filippi NM, Caltagirone C Neurophysiological evaluation of tactile space perception deficits through transcranial magnetic stimulation. Brain Res Protoc 5(1): Oliveri M, Rossini PM, Filippi MM, Traversa R, Cicinelli P, Caltagirone C Specific forms of neural activity associated with tactile space awareness. Neuroreport 13(8): Oliveri M, Rossini PM, Traversa R, Cicinelli P, Filippi MM, Pasqualetti P, Tomaiuolo F, Caltagirone C Left frontal transcranial magnetic stimulation reduces contralesional extinction in patients with unilateral right brain damage. Brain 122(9): Pascsual-Leone A, Grafman J, Hallett M Explicit and implicit learning and maps of cortical motor output. Science 265: Pinker S How the mind works. London: Penguin Press Science S. Posner MI Cognitive neuropsychology and the problem of selective attention. Electroencephalogr Clin Neurophysiol Suppl 39: Posner MI, Cohen Y Components of visual orienting. In: Bumpy H, Bouwhuis TU, editors. Attention and performance, Volume X. Hillsdale: Erlbaum. p Posner MI, Snyder CR, Davidson BJ Attention and the detection of signals. J Exp Psychol 109(2): Posner MI, Walker JA, Friedrich FJ, Rafal RD Effects of parietal injury on covert orienting of attention. J Neurosci 4(7): Ress D, Heeger DJ Neuronal correlates of perception in early visual cortex. Nat Neurosci 6(4): Rossi S, Cappa SF, Babilioni C, Pasqualetti P, Miniussi C, Carducci F, Babiloni F, Rossini PM Prefrontal cortex in long term memory: an interference approach using magnetic stimulation. Nat Neurosci 4(9): Rossi S, Pasqualetti P, Zito G, Vecchio F, Cappa SF, Miniussi C, Babiloni C, Rossini PM Prefrontal and parietal cortex in episodic memory. An interference study by rtms. Eur J Neurosci 23(3): Rossi S, Rossini PM TMS in cognitive plasticity and the potential for rehabilitation. Trends Cogn Sci 8(6): Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Gracco RQ, Dimitrijevic MR, Hallett M, Katayama Y, Lucking CH, and others Non invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Electroencephalogr Clin Neurophysiol 91: Sack AT, Linden DE Combining transcranial magnetic stimulation and functional imaging in cognitive brain research: possibilities and limitation. Brain Res Rev 43(1): Sergent C, Baillet S, Dehaene S Timing of the brain events underlying access to consciousness during the attentional blink. Nat Neurosci 8(10): Shefrin SL, Goodin DS, Aminoff MJ Visual evoked response in the investigation of blindsight. Neurology 38: Shevrin H Subliminal perception, memory, and consciousness: cognitive and dynamic perspectives. In: Bornstein RF, Pittman TS, editors. Perception without awareness: cognitive, clinical, and social perspectives. New York: Guilford. p Smania N, Martini MC, Gambina G, Tomelleri G, Palamara A, Natale E, Marzi CA The spatial distribution of visual attention in hemineglect and extinction patients. Brain 121: Thuth G, Ives JR, Kampmann F, Pastor MA, Pascual-Leone A A new device and protocol for combining TMS and online recordings of EEG and evoked potentials. J Neurosci Methods 141(2): Vallar G Extrapersonal visual unilateral spatial neglect and its neuroanatomy. Neuroimage 14: Vallar G, Bisiach E, Cerizza M, Rusconi ML The role of the left hemisphere in decision-making. Cortex 24(4):605. Wallace MA Unconscious perception in neglect and extinction. In: Farah MJ, Ratcliff G, editors. The neuropsychology of high-level vision: collected tutorial essays. Hillsdale, NJ: Lawrence Erlbaum Associates. p Walsh V, Cowey A Transcranial magnetic stimulation and cognitive neuroscience. Nat Rev Neurosci 1: Walsh V, Rushworth M A primer of magnetic stimulation as a tool for neuropsychology. Neuropsychologia 37: Page7of7