Neural circuits of spatial attention: Evidence from

Thèse de doctorat de l’Université Pierre et Marie Curie (UPMC) Spécialité Neurosciences

       

Neural circuits of spatial attention: Evidence from healthy participants and brain-damaged patients

ALEXIA BOURGEOIS

DIRECTEURS

Dr PAOLO BARTOLOMEO & Dr ANA B. CHICA

Membres du Jury Rapporteurs : Pr Juan Lupiáñez, Pr Giovanni Berlucchi Examinateurs : Dr Lionel Naccache

Date de soutenance: 17 mai 2013 INSERM UMR-S 975 Centre de Recherche de l’Institut du Cerveau et de la Moëlle Epinière

Remerciements

Un ringraziamento speciale va a Paolo Bartolomeo per avermi accettata nel suo gruppo. 'È stato un vero piacere lavorare in questi quatro anni in un 'atmosfera rilassata ed in un clima di fiducia reciproca. Un secondo PhD non è apparentemente possibile ma spero sinceramente che potremmo continuare a lavorare insieme e che saro invitata all'attentional pizza ogni anno. Ana, no puedes imaginarte cuánto me alegro de haberte conocido. Ningún día durante estos tres años me he arrepentido de comenzar esta tesis. Ha cautivado mi mente, cambiado la forma en la que concibo el futuro, y todo ello es mayormente gracias a ti. Desde un punto de vista profesional, no concibo cómo consigues que el trabajo resulte tan fácil, tan placentero, y al mismo tiempo tan eficiente. Lo considero simplemente perfecto. My gratitude towards Bruno Dubois for accepting me in this lab. Thanks a lot to Juan Lupiáñez, Giovanni Berlucchi, and Lionel Naccache for accepting to be part of my jury. L'amitié double les joies et réduit de moitié les peines (F. Bacon), pas besoin d’en dire plus.

Résumé Ce travail s’est centré sur l’étude d’une composante de l’orientation exogène de l’attention : l’inhibition de retour (IOR). L’IOR correspond à l’inhibition du retour de l’attention vers un endroit venant d’être exploré, permettant ainsi une exploration efficace de notre environnement. Nous avons mis en évidence que les patients avec lésion cérébrale droite et syndrome de négligence présentaient un déficit de l’IOR lorsque la réponse était manuelle pour les cibles présentées à droite, tandis que l’IOR saccadique était préservée. Sur le plan des corrélats cérébraux, l’ensemble des patients négligents présentait une lésion pariétale droite ou une atteinte des voies de connection fronto-pariétale sous-corticale. Nous avons ensuite reproduit ces résultats à l’aide de la stimulation magnétique transcrânienne répétitive chez un groupe de sujets sains. La stimulation du sillon intra-pariétal ou de la jonction temporopariétale au sein de l’hémisphère droit, tout comme la présence d’une lésion cérébrale pariétale, induisait une abolition de l’IOR manuelle pour les cibles présentées à droit. Concernant les cibles présentées à gauche, la stimulation du sillon intra-pariétal seulement induisait une abolition de l’IOR manuelle et saccadique. La stimulation de ces mêmes régions, au sein de l’hémisphère gauche n’abolissait pas l’IOR, tant manuelle que saccadique. Nous avons enfin étudiés le lien entre les performances comportementales et l’exploration saccadique de patients négligents, avec et sans hémianopsie, dans une tâche de recherche visuelle, au sein de laquelle nous avons manipulé l’orientation attentionnelle. Les bases neurales de ces processus ont été explorées grâce à une étude anatomique voxel-based lesion symptom mapping. Mots-clés : attention visuo-spatiale, négligence spatiale, inhibition de retour, stimulation magnétique transcrânienne (SMT), recherche visuelle

Abstract This thesis investigates the mechanisms and neural bases of exogenous attentional orienting processes leading to inhibition of return (IOR), with manual and saccadic responses. IOR reflects a bias to preferentially attend to novel spatial locations, a phenomenon that is paramount to explore our environment more efficiently. We demonstrated that patients with right brain-damaged and signs of left visual neglect had impaired manual IOR for right-sided targets, while saccadic IOR was preserved. All neglect patients presented a grey matter parietal lesion and/or a white matter fronto-parietal disconnection in the right hemisphere. We then explored the neural basis of IOR in healthy participants, benefiting from the power of Transcranial Magnetic Stimulation (TMS) to establish causality. We applied inhibitory patterns of focal rTMS to the right intra-parietal sulcus (IPS), or the right temporo-parietal junction (TPJ) to induce transient lasting interference of local and connectivity-mediated brain activity. We found an impaired manual IOR for right-sided targets after either IPS or TPJ stimulations, mimicking the results observed in neglect patients after right parietal damage or right fronto-parietal disconnection. For contralateral, left-sided targets, rTMS over the right IPS, but not over the right TPJ, impaired both manual and saccadic IOR. Contrary to the stimulation of the right hemisphere, rTMS over the left IPS or TPJ did not produce significant modulations of either manual or saccadic IOR. Finally, in order to better understand the mechanisms giving rise to the lack of awareness of left-sided stimuli observed in neglect patients, we investigated in these patients, manual and saccadic responses to lateralized targets during a cued visual search task. Voxel-based lesion symptom mapping

analysis provided preliminary evidence on the lesional correlates of the observed patterns of performance. Keywords: visuo-spatial attention, spatial neglect, inhibition of return, Transcranial Magnetic Stimulation (TMS), visual search

Abbreviations

IOR, inhibition of return RT, response time SOA, stimulus-onset asynchrony RBD, right brain-damaged IPS, intra-parietal sulcus TPJ, temporo-parietal junction IPL, inferior parietal lobe VFC, ventral frontal cortex DLPFC, dorso-lateral pre-frontal cortex TMS, transcranial magnetic stimulation rTMS, repetitive transcranial magnetic stimulation VAN, ventral attentional network DAN, dorsal attentional network DTI, diffusion tensor imaging SLF, superior longitudinal fasciculus IFOF, inferior fronto-occipital fasciculus ILF, inferior longitudinal fasciculus PO, pop-out VS, visual search

Main index

I Introduction

pp 1

Chapter 1: Visuo-spatial attention

pp 2

1.

Taxonomy of attentional processes

pp 3

2.

Attentional orienting: the exogenous/endogenous dichotomy

pp 4

3.

Neuro-anatomical basis of attentional orienting

pp 8

3.1 Dorsal and ventral fronto-parietal networks in attentional orienting pp 8 4.

3.2 Neural correlates of endogenous and exogenous spatial orienting

pp 11

Attention, eye movements and visual search

pp 13

Chapter 2: Spatial neglect

pp 16

1.

Introduction

pp 17

2.

Impaired orienting of attention in neglect

pp 18

2.1 Non-spatial selective attention: the attentional blink

pp 24

Non-spatial deficits in neglect

pp 22

3.1 Non-spatial selective attention: the attentional blink

pp 23

3.2 Sustained attention

pp 24

3.3 Trans-saccadic spatial working memory

pp 24

Assessment of neglect

pp 25

4.1

Preliminary assessment of associated deficits in neglect

pp 26

4.1.1 Extinction

pp 26

4.1.2 Directional hypokinesia

pp 27

3.

4.

4.2 Paper and pencil tests of extrapersonal neglect

pp 27

4.2.1 Bells cancellation test (Gauthier, Dehaut, & Joanette, 1989) pp 27 4.2.2 Figure copying (Gainotti, et al., 1991; Ogden, 1985)

pp 28

4.2.3 Line bisection

pp 28

4.2.4 Reading

pp 29

4.2.5 Overlapping figures

pp 29

4.3 Behavioral assessment of neglect and anosognosia in daily life 4.3.1 The Catherine Bergego Scale (Bergego, et al., 1995) 5.

6.

pp 30 pp 30

4.4 Sensitivity of neglect tests

pp 30

Clinical dissociations

pp 31

5.1 Spatial reference frames

pp 31

5.2 Personal, peripersonal, and extrapersonal neglect

pp 32

5.3 Imaginal neglect

pp 32

Neuroanatomy of neglect

pp 35

6.1 Anatomical lesional studies

pp 35

6.1.1 Cortical grey matter lesions

pp 35

6.1.2 Subcortical white matter lesions: understanding spatial neglect with connectivity in mind

pp 39

6.2 Functional studies

pp 43

6.3 TMS studies

pp 45

II Experimental part

pp 48

Aims of the thesis

pp 49

Chapter 3: Cortical control of inhibition of return: Evidence from patients with inferior parietal damage and visual neglect

pp 52

Chapter 4: Cortical control of inhibition of return: Causal evidence for task-dependent modulations by dorsal and ventral parietal region

pp 64

Chapter 5: Cortical control of inhibition of return: Exploring the causal contribution of the left parietal cortex

pp 75

Chapter 6: Looking without seeing: Decoupling of saccadic production and conscious awareness in spatial neglect

pp 110

III Discussion

pp 152

REFERENCES

pp 164

ANNEXES

pp 183

I Introduction

 

1  

Chapter 1: Visuo-spatial Attention

 

2  

1. Taxonomy of attentional processes Human attentional processes have been conceptualized as a system of specialized networks segregated in different anatomical areas. Posner and Petersen (1990) identified three independent but interacting systems: alerting, orienting, and the executive control networks. These three networks seem to be roughly independent and involve different anatomical areas (Fan, McCandliss, Fossella, Flombaum, & Posner, 2005; Fan, McCandliss, Sommer, Raz, & Posner, 2002), as well as distinct set of oscillations related to their activity (Fan, et al., 2007). The alerting system corresponds to the achievement and maintenance of a general alert state, preparing the system for fast reactions by means of a change in the internal state. It involves the right frontal cortex, the inferior parietal lobe (IPL), and subcortical structures (Fan, et al., 2005;

Sturm

&

Willmes,

2001).

This

network

is

modulated

by

the

locus

coeruleus/norepinephrine system (Coull, Buchel, Friston, & Frith, 1999). More precisely, two types of alerting have been described, based on the tasks used to measure them: tonic alerting or vigilance refers to a sustained activation over a period of time, whereas phasic alerting refers to a non-specific activation subsequent to external stimuli. In addition to structures involved in vigilance processes, phasic alertness is associated with activity in the left frontal cortex and the thalamus (Sturm & Willmes, 2001). The alerting network is associated with a specific decrease in theta-, alpha-, and beta-band activity 200-450 ms after the presentation of a cue (Fan, et al., 2007). The executive control system requires both monitoring and conflict solving. This network is believed to be active in situations involving planning, decision making, detection of errors, as well as overcoming of habitual actions (Norman & Shallice, 1986). Tasks involving both monitoring and conflict solving such as the flankers task, developed by Eriksen and Eriksen (1974) activate the dorsal anterior cingulated cortex (ACC) and the dorsal lateral pre-frontal cortex (DLPFC) (Bush, Luu, & Posner, 2000). Slightly different activations are found as a function of the task at hand (see e.g. Fan, et al., 2005).

 

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2. Attentional orienting: the exogenous/endogenous dichotomy The orienting network selectively allocates attention to a relevant area or stimulus, improving its perceptual processing. In fact, our visual system is constantly overloaded with cluttered information of our environment, requiring organisms to select stimuli appropriate to their goals, while ignoring other less important stimuli. In this context, in order to maintain a coherent behavior, attention have to (a) allow for processing of novel and unexpected events in order to respond to them appropriately while (b) the behavior can be maintained in function of goal-directed strategy in spite of distractor events (Allport, 1989). These two ecological constraints correspond to a continuous dynamical equilibrium between exogenous or involuntary, bottom-up orienting, and endogenous or voluntary, top-down orienting of attention. These two types of attention have been extensively studied with the cue-target paradigm, made popular by Michael I. Posner and his colleagues in the middle of the 80s (Posner, 1980; Posner & Cohen, 1984). Participants are classically presented in this paradigm with two horizontally arranged boxes and a fixation point, displayed at the centre of the screen. A target presented in one of the peripheral boxes has to be manually detected or discriminated as fast and as accurately as possible. Targets are preceded by attentional cues that can be either valid or invalid. Valid cues are presented at the same location of the target, whereas invalid cues are presented at a different location to that of the target. Cues can be central (e.g. an arrow presented at fixation, pointing left or right) or peripheral (e.g. a brief brightening of one of the peripheral boxes), and can or cannot be informative about the spatial location of the target. Central informative cues induce an endogenous or voluntary shift of attention, motivated by strategic considerations. Participants can use the predictive value of the cue to orient attention at the expected location until the appearance of the target. Response times (RTs) are usually faster for valid as compared to invalid locations. Alternatively, peripheral non-informative cues elicite an exogenous or automatic shift of attention (Posner &

 

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0

Cohen, 1984). The effect of these cues consists of a short-lasting facilitory effect, that is, RTs are faster for valid than invalid locations when the time interval between the cue and the target (Stimulus Onset Asynchrony, SOA) is shorter than 300-700 ms (depending on the task at hand, Lupiáñez, Milán, Tornay, Madrid, & Tudela, 1997). If the SOA is longer than 300700 ms, the effect reverses, and RTs are faster for invalid than valid trials (Posner, Rafal, Choate, & Vaughan, 1985). This effect is known as Inhibition of Return (IOR) (Klein, 2000; Lupiáñez, Klein, & Bartolomeo, 2006; Posner, et al., 1985) (see Chap.1-Figure 1 for an illustration of the paradigm and mean RTs results classically observed). A.B. Chica et al. / Behavioural Brain Research 237 (2013) 107–123

g. 1. (A) Illustration of a typical Posner paradigm in which targets can be preceded by either peripheral or central cues. (B) Typical mean RT results observed when peripheral n-predictive cues precede targets at different SOAs. RTs are faster for valid vs. invalid trials at short SOAs, but the effect reverses at SOAs longer than 300 ms, demonstrating IOR effect. (C) Typical mean RT results observed when central predictive cues precede targets at different SOAs. RTs are faster for valid vs. invalid trials, and the effect is stained even at the longest SOA.

Chap.1-Figure 1: A) Illustration of a typical Posner paradigm in which targets can be preceded by either peripheral or central cues. B) Typical mean RT results observed when peripheral non-predictive

valid, location. They speculated that endogenous attention did will capture attention. In other words, this hypothesis predicts that precede targets atattention, differentbut SOAs. RTs are faster validfor vs.something invalid trials short but the capture ot directly modify cues when for the effect of exogenous the modulooking red,atonly redSOAs, objects would tion occurred by strengthening the effect of exogenous attention. our attention. However, as it will be discussed in the next section, effect reverses atorienting SOAs longer than 300 ansupporting IOR effect. C)idea Typical mean RTis results hey concluded that the evidence the exogenous mechanism wasms, an demonstrating this is mixed, and currently under utonomous module that can be modified but not suppressed by debate [44–46]. observed when central predictive cues precede targets at different SOAs. RTs are faster for invalid vs. ndogenous attention”. A different line of research has shown that task set can modulate Yantis and Jonides [20] explored whether the exogenous attencuing effects, both facilitation and IOR. Lupiánez invalid trials, and the effect is sustained evenexogenous at the longest SOA (Chica, Botta, Lupianez, ˜& and colonal capture produced by abrupt onsets was automatic or could leagues [47–50] have consistently demonstrated that facilitation e modulated by endogenous is larger in magnitude in discrimination tasks as compared with Bartolomeo,attention. 2012). They demonstrated that nly when a central arrow cue was completely reliable (indicatdetection tasks, while IOR is larger, and appears sooner, in detecg the target location with 100% validity), abrupt onsets did not tion tasks than in discrimination tasks. It has been proposed that the apture attention when they were presented at a distracting locamore difficult the task at hand, the greater the orienting of attention on. However, when central cues were not 100% predictive, abrupt produced by the cue [30] and/or the longer attention would remain nset distractors did produce an effect on performance, as shown oriented to the cued location [50]. Klein [30] proposed that because y slowed RTs to the target when the response associated to distracdiscrimination tasks are more difficult than detection tasks, attenrs was incompatible with the target’s response (see also [40], for tion is captured to a greater degree by the cue, giving rise to larger milar results using a different paradigm). As suggested by Müller facilitatory effects, and a later disengagement of attention, which nd Rabbitt [29], this result might indicate that exogenous attention delays the appearance of IOR. This hypothesis has recently been 5   to locate an be modulated,  but rarely completely suppressed by endogechallenged by using a paradigm in which participants had ous attention. In other words, an interim conclusion at this point or discriminate both target and cue features. Contrary to Klein’s ight be that exogenous attention can be automatic by default, but proposal, it was demonstrated that a deeper processing of either can be endogenous modulated, or even suppressed under certain the cue or the target actually anticipated, rather than delayed, the

The IOR effect was first reported in Posner and Cohen’s seminal paper (Posner, et al., 1985). Using spatially non-informative peripheral cues in a cue-target paradigm, these authors noted that at long cue-target intervals, RTs were slower for targets presented at valid location than for targets presented at invalid location. This effect was however absent with spatially informative cues, suggesting that IOR is independent of endogenous orienting. An IOR effect has been also reported with target-target paradigms, in which participants had to respond to successive targets presented at the same location (Bartolomeo, Chokron, & Sieroff, 1999; Bourgeois, Chica, Migliaccio, Thiebaut de Schotten, & Bartolomeo, 2012; Maylor & Hockey, 1985), as well as in discrimination tasks (Lupiáñez, et al., 1997). However, while IOR is observed at ~300 ms SOAs in detection tasks, it appears around 700 ms in discrimination tasks (Lupiáñez, et al., 1997). IOR is generated under both covert and overt orienting of attention, i.e. when the eyes move to the cue or remain at fixation, respectively (Posner, et al., 1985). IOR was proposed to be caused by the inhibition of the return of attention to a previously attended location (Posner, et al., 1985), and has been considered to be a foraging facilitator while searching in visual environments (Klein, 1988; Klein & MacInnes, 1999). Klein et al. (1999) demonstrated using a free visual search task that when searching a target stimulus, participants were slower to detect an unexpected dot, presented at a recently inspected location as compared to situations in which the dot was presented at a previously non-inspected location. Alternatively to the attentional hypothesis of IOR, the oculomotor hypothesis proposes that IOR is caused by the inhibition of a previously prepared movement (to the cue) or the activation of an oculomotor program (Chica, Klein, Rafal, & Hopfinger, 2010; Rafal, Calabresi, Brennan, & Sciolto, 1989). Several behavioral studies suggest that IOR can produce effects on either attentional/perceptual processes or response processes, depending on task demands (Chica, Taylor, Lupiáñez, & Klein, 2010). In covert orienting, i.e. when the eyes are restrained throughout a trial, IOR may reflect impaired perceptual

 

6  

processing of targets in the cued peripheral location, perhaps due to the impaired reallocation of attention to that location. In contrast, when the oculomotor system cannot be inhibited because a saccadic response is required, as it is the case for saccadic responses and overt attention, IOR may rather reflect a motoric effect wherein responses in the direction of the cued location are slowed. Another fundamental mechanism contributing to IOR may be the relative lack of novelty of a target appearing at the same location of a previously presented event, separated by a long SOA (Milliken, Tipper, Houghton, & Lupiáñez, 2000). “Habituation” of the orienting response some time after the first stimulus has been presented can contribute to IOR (Dukewich, 2009; Milliken, et al., 2000). Such phenomena would bias attention towards locations that have neither been previously attended nor explored. Activity in the retinotectal visual pathway is traditionally considered as being important for IOR (Dorris, Klein, Everling, & Muñoz, 2002; Sapir, Soroker, Berger, & Henik, 1999); indeed, focal lesions (Sapir, et al., 1999) or degeneration (Rafal, Posner, Friedman, Inhoff, & Bernstein, 1988) of the superior colliculus (SC), a structure of the midbrain tectum involved in sensory-guided eye and upper trunk movements, can lead to impaired IOR when attention is covertly oriented. Neuroimaging data obtained in intact humans (Anderson & Rees, 2011) and neurophysiological evidence from monkeys (Dorris, et al., 2002) also suggests a critical involvement of this structure in the building of IOR. Nonetheless, the latter of these studies also hypothesized that such contribution would be developed in concert with up-stream cortical structures such as the posterior parietal cortex. Indeed, fronto-parietal networks involved in spatial attention (Corbetta & Shulman, 2002) are plausible candidates for the cortical control of IOR. For example, experiments with Transcranial Magnetic Stimulation (TMS) found disturbed manual IOR upon stimulation of frontal eye fields (Ro, Farne, & Chang, 2003), intraparietal sulcus (Chica, Bartolomeo, & Valero-Cabre, 2011), and temporo-parietal junction (Chica, et al., 2011). These results are important in suggesting that

 

7  

cortical networks, including the parietal lobe that is typically dysfunctional in brain-damaged patients with signs of neglect (He, et al., 2007; Mort, et al., 2003; Thiebaut de Schotten, et al., 2005), are implicated in the occurrence of IOR. 3. Neuro-anatomical basis of attentional orienting 3.1 Dorsal and ventral fronto-parietal networks in attentional orienting Influential functional Magnetic Resonance Imaging (fMRI)-based models (Corbetta & Shulman, 2002, 2011) have proposed a dorsal (DAN) and a ventral attentional network (VAN) underlying shifts of visuo-spatial attention. According to this model, the dorsal network involves dorsal frontal and parietal regions including bilateral medial intraparietal sulcus (IPS), precuneus, supplementary eye field (SEF), and frontal eye field (FEF) (see Chap.1-Figure 2). These regions show an increase of the hemodynamic blood oxygen level dependent (BOLD) responses during voluntary orienting and maintenance of attention to a target location (goal-driven attention) (see e.g. Corbetta, Kincade, Ollinger, McAvoy, & Shulman, 2000; Hopfinger, Buonocore, & Mangun, 2000). The ventral network is composed of the temporo-parietal junction (TPJ) and the inferior and middle ventral frontal cortex (VFC) and seems to be strongly lateralized to the right hemisphere. This network seems implicated in the detection of behaviorally relevant stimuli, particularly when they are salient or unexpected (stimulus-driven attention) (see e.g. Corbetta, et al., 2000; Kincade, Abrams, Astafiev, Shulman, & Corbetta, 2005). Corbetta and Shulman (2002) proposed that the reorienting of attention towards a new source of information is implemented in the ventral network, which interrupts the ongoing selection of information occurring in the dorsal network, acting as a “circuit-breaker”. The dorsal network may then shift attention toward the novel object of interest. Dorsal and ventral fronto-parietal networks and their interactions are presented in Chap.1-Figure 2.

 

8  

REVIEWS

REVIEWS a

a

IPs/SPL

TPJ (IPL/STG)

circuit-br action be action between the TPJ and IPs. We the IPs pr the IPs provides the TPJ with infor behaviou behavioural relevance of stimuli, eith rectly through top-down modulation rectly throo The frontal component of the Theventral front involved specifically in the evaluation involved s It is possible that part of theItsignal is po work depends on noradrenergic mo work dep

Cortical areas damagedcircuit-breaking in spatial neglectfunction depends on Cortical FEF areas damaged in spatial neglect

IPs/SPL FEF

VFC

LOCUS COERULEUS. Cortically projecting LOCUS COER minals are most concentrated in the minals ar 99 parietal cortex . In humans, there is a parietal co b tion of noradrenaline in the right tha Top-down control b tiontoofthe no Top-down control 100 mus , which might be related 100 , wh L FEF R FEF of the TPJ–VFC network. mus A similar Novelty L FEF R FEF of the TP system is activated Novelty in humans durin is that are thought to dependsystem on norad L VFC R VFC that are th The Rlocus L VFC VFC coeruleus noradrenergic Circuit The locu extensively implicated not only in aro breaker Stimulus– Circuit but also in selective part response extensivel breakerattention, Stimulus– selection unexpected stimuli102. Thebut delivery alsooi response selection the rat prefrontal cortex is enhance unexpect L IPs R IPs L TPJ R TPJ changes in response/rewardthe contingen rat pr L IPs R IPs L TPJ R TPJ noradrenaline to the prefrontal cortein changes gencies might serve to detect a misma Behavioural noradren and reward, and disengage ongoing a valence gencies m Behavioural new behavioural responses103. This c Visual areas and rewar valence akin to our proposal that the TPJ–VF Stimulus-driven control new beha Visual areas a circuit breaker of ongoing cognit Figure 7 | Neuroanatomical model of attentional control. a | Dorsal and ventral frontoparietal Stimulus-driven control to ou unexpected or novel stimuliakin are detect networks and their anatomical relationship with regions of damage in patients with unilateral a circuit Our model has important implica neglect. Areas in blue indicate the dorsal frontoparietal network. FEF, frontal eye field; IPs/SPL, Figure 7 | Neuroanatomical model of attentional control. a& | Dorsal and ventral frontoparietal Chap.1-Figure 2: Neuro-anatomical model of attentional control (from Corbetta Shulman, 2002). a) unexpecte roanatomy and neurophysiology of intraparietal sulcus/superior parietal lobule. in orange indicate the stimulus-driven ventral in patients networks and theirAreas anatomical relationship with regions of damage with unilateral Our m frontoparietal network. frontoparietal TPJ, temporoparietal junction (IPL/STG, inferior parietal lobule/superior Areas in blue indicate the dorsal network. FEF, frontal eye field; IPs/SPL, intraparietal common and disabling re neglect. Areas in blue indicate the dorsal frontoparietal network. FEF, frontalneglect, eye field;a IPs/SPL, temporal gyrus); VFC, ventral frontal cortex (IFg/MFg, inferior gyrus/middle frontalindicate gyrus). the stimulus-driven roanatom intraparietal sulcus/superior parietalfrontal lobule. Areas in orange ventral brain damage. Patients with negle The areas lobule. damaged inAreas neglect (right) better match thetemporoparietal ventralthe network. bjunction | Anatomical modelventral of sulcus/superior parietal in orange indicate stimulus-driven frontoparietal frontoparietal network. TPJ, (IPL/STG, inferior parietal lobule/superior stimuli towards the side neglect, of spacea top-down and stimulus-driven control. The IPs–FEF network involved in the top-down temporal gyrus); VFC, ventral frontaliscortex (IFg/MFg, inferior control frontal gyrus/middle frontal gyrus). afterbrain lesion. For instance, a lesion t dam of visual processing (blue arrows). The TPJ–VFC network is involved in stimulus-driven control network. TPJ, temporo-parietal junction inferior parietal lobule/superior gyrus); The areas (IPL/STG, damaged in neglect (right) better match the ventral network.temporal b | Anatomical model of the brain, they ignore people on th stimuli t (orange arrows). The IPs and FEF are also modulated by stimulus-driven control. Connections top-down and stimulus-driven control. The IPs–FEF network is involved in the top-down on the control left side of thelesion. plate, an between the TPJ(IFg/MFg, and IPs interruptinferior ongoing top-down when unattended stimuli aregyrus). b)food VFC, ventral frontal cortex frontalcontrol gyrus/middle frontal Anatomical Fo of visual processing (blue arrows). The TPJ–VFC network is involved in stimulus-driven control detected. Behavioural relevance is mediated by direct or indirect (not shown) connections left side of the body or tothe shave the brain (orange arrows). IPs andin FEF are also modulated stimulus-driven control. Connections between the IPs and TPJ. The VFC mightThe be involved novelty detection. L,(IPs-FEF) left; by R, right. model of top-down and stimulus-driven orienting. The dorsal network is mainly involved in neglect face. In addition, patien food on t between the TPJ and IPs interrupt ongoing top-down control when unattended stimuli are attracted towards stimuli on their rigo detected. Behavioural relevance is mediated by direct or indirect (not shown) connections left side the top-down control of visual processing (blue arrows). The ventral network (TPJ-VFC) is were involved tion ‘stickier’ on the right side o between the IPs and TPJ. The VFC might be involved in novelty detection. L, left; R, right. face. In Two orienting neglect have problems in directing actions ( in stimulus-driven orienting (orange arrows). The IPs networks and FEF and are spatial also modulated by stimulus-driven attracted We propose that orienting is controlled in humans by ments) towards the contralateral sid tion werew twoIPs interacting networks. The model presented in FIG. 7 when neglect patients have low vigilance, control. Connections between the TPJ and interrupt ongoing top-down control unattented Two orienting prob 97,98 networks and spatial neglect 98,104,105 is a modification of earlier models . A largely bilat. deficits in spatial processinghave We propose that orienting is controlled in humans by ments) to stimuli are detected. L, left; R, right. eral IPs–FEF system is involved in the generation of It has been proposed that neglect twois,interacting networks. The model presented FIG. 7IPs–FEF neglect p attentional sets — that goal-directed stimulus– function of theindorsal networ 97,9898 is a modification modelstion .A largely bilat. However, we proposedeficits that theina response selection — and the applicationofofearlier those sets eral IPs–FEF system is involved inbetter the generation It has matches theof ventral TPJ–VF during stimulus processing. This system corresponds lesions that cause neglect are locatedo to the parietal and frontal cores of sets the attention netattentional — that is, goal-directed stimulus– function 98 98 the the relevance brainofthan thesets core regions , and selection extends theand FEF theapplication of Mesulam’s . Ho response — the those tionof Reorienting to an object can bework driven by themodel saliency and/ortothe behavioral and most frequently involve the rig ‘orienting’ function of Posner’s posterior attentionThis system better ma during stimulus processing. corresponds is that this system without a visual field deficit,lesions the right system97. Our currenttohypothesis th the parietal and frontal cores of the attention netof this object. Relevance seems however to besensory the critical factor torelevant activate gyrus the isventral links relevant representations common of thesite brain to the the most FEF the work of Mesulam’s to model98, and extends frontal cortex, lesions thatand cause ne motor representations.‘orienting’ function of Posner’s posterior most attention localized in right ventral prefrontal a A second system, is strongly lateralized to the salient) network, which is well activated by important but which not very (or stimuli 97 distinctive without a system . Our current hypothesis is that this system tex, rather than in the more dorsal right hemisphere, detects behaviourally relevant stimuli links relevant sensory representations to relevant gyrus is t LOCUS COERULEUS Therefore, the anatomical localizatio and works as an alerting mechanism or circuit breaker A nucleus of the2007). brainstem. The frontal co motor representations. (Indovina & Macaluso, Furthermore, using an event-related functional fMRI design, matches the ventral TPJ–VFC attent for the first system when these stimuli are detected main supplier of noradrenaline A second system, which is strongly lateralized to the the dorsal IPs–FEF attentionlocalized network. outside the focus of processing. We propose that this to the brain.

 

TPJ (IFg/MFg) (IPL/STG)

LOCUS COERULEUS

A nucleus of the brainstem. The

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| MARCH 2002 |main VOLUME 3 of noradrenaline supplier to the brain.

VFC (IFg/MFg)

right hemisphere, detects behaviourally relevant stimuli and works as an alerting mechanism or circuit breaker 9   for the first system when these stimuli are detected outside the focus of processing. We propose that this

tex, rathe Therefore www.nature matches t the dorsal

Kincade et al. (2005) showed that the right TPJ was strongly modulated by stimulus-driven attentional shifts (referring to target-related processing) to relevant stimuli but not by salient but task-irrelevant color singletons. Some studies have also demonstrated an activation of the ventral network by irrelevant objects sharing some features with the target (Serences, et al., 2005), consistent with the hypothesis that the ventral network responds mainly to stimuli thought to be behaviorally relevant. Studies in monkeys (Colby & Goldberg, 1999; Gottlieb, Kusunoki, & Goldberg, 1998), and humans (see Silver & Kastner, 2009 for a review) have demonstrated that dorsal regions contain an explicit two-dimensional map that encodes the saliency of objects. Topographic maps have however not been reported in ventral regions, suggesting a possible need of joint activation of dorsal and ventral regions during reorienting. The lateral prefrontal component of the ventral network, the inferior frontal junction, may be the site of convergence for stimulus-driven and goal-directed attention (Asplund, Todd, Snyder, & Marois, 2010). Similarly, on the basis of spontaneous BOLD fluctuations at rest, Fox et al. (2006) demonstrated that BOLD fluctuations of the right posterior middle frontal gyrus (MFG) correlated with both the VAN and DAN networks, suggesting that this region may interconnect these two networks. Recently, an advanced tractography study have shown that the third branch of the superior longitudinal fasciculus (SLF), a parieto-frontal white matter pathway, connects brain regions within the VAN, whereas regions of the DAN are connected by the first branch of the SLF. The SLF II overlaps with the parietal component of the ventral network and the prefrontal component of the dorsal network, and may represent an interconnection between the DAN and the VAN (Thiebaut de Schotten, et al., 2011). Moreover, this study reported a significant correlation between the degree of anatomical lateralization of the SLF and the asymmetry of performance on visuo-spatial tasks. In good agreement with fMRI studies, these authors showed that the SLF I (connecting the DAN)

 

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seems to be relatively symmetrically organized, while the SLF III (connecting the VAN) is anatomically larger in the right hemisphere than in the left hemisphere. Evidence coming from right brain-damaged patients and spatial neglect also suggests an interaction of dorsal and ventral networks during reorienting of attention. Spatial neglect is a syndrome characterized by a rightward attentional bias (see Chapter 2 of this thesis). In this context and among others symptoms, neglect patients are particularly impaired in reorienting attention to left-sided stimuli after attention has been ipsilesionally oriented (Losier & Klein, 2001; Posner, Cohen, & Rafal, 1982). This syndrome typically follows right fronto-parietal ventral lesions, while regions of the DAN are generally structurally preserved (Corbetta, Kincade, Lewis, Snyder, & Sapir, 2005; Mort, et al., 2003; Vallar & Perani, 1986). It has been proposed that damage to the right ventral network could induce a hyperactivity of the left dorsal fronto-parietal network, leading to a functional imbalance between left and right DANs. This functional imbalance may underline the rightward attentional bias, observed in neglect patients (He, et al., 2007). 3.2 Neural correlates of endogenous and exogenous spatial orienting According to Corbetta et al’ s proposal (2008), “the psychological distinction between exogenous and endogenous attention (Jonides, 1981) may not map onto different neural systems. Rather, a more fundamental distinction appears to be between systems involved in orienting, both exogenous and goal-driven, i.e., the dorsal attention system, and those involved in stimulus-driven reorienting, i.e., the ventral and dorsal attention systems.” It is however difficult to conceive that systems that are clearly differentiated at the behavioral level map onto the same neural system. One potential source of confound is that some studies equate stimulus-driven orienting and exogenous attention. However, these two processes refer to conceptually different mechanisms. Exogenous orienting refers to the involuntary capture of attention to salient stimuli, regardless of their relevance. Stimulus-driven orienting in  

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contrast is related to the processes of behavioral task-relevant stimuli and refers to target, but not cue-related processes. In this context, Kincade et al. (2005), studied the brain activations occurring during either the cue or the target period in response to endogenous, exogenous, or neutral cues. The analysis conducted during the cue period indicated that endogenous cues produced activations in the dorsal network (bilateral FEF and IPS). Moreover, exogenous cues did not seem to recruit the TPJ portion of the ventral system but seems only involved in stimulus-driven shifts of attention if the stimuli share features that were behaviorally relevant (contingent orienting). Note however that no behavioral effect in the fMRI design was associated with exogenous cues in this study. Similarly, uninformative but salient distracters that attract attention activate the dorsal but not the ventral system (De Fockert, Rees, Frith, & Lavie, 2004). Nonetheless, these studies confirmed the importance of the dorsal frontoparietal network in endogenous orienting and suggested that exogenous orienting recruits the same dorsal frontoparietal network implicated in goal-driven attention. The second potential limitation of fMRI-based model of attentional orienting is that the low temporal resolution of fMRI prevents the capture of fast and brief events, such as BOLD activity evoked by exogenously driven attentional orienting. In this context, a recent event-related TMS study (Chica, et al., 2011) provided causal evidence for the implication of the right IPS in both endogenous and exogenous attentional orienting, while the right TPJ was only causally implicated in exogenous orienting (in particular IOR). 4. Attention, eye movements, and visual search The visual environment is an enormously rich source of information. In this context, saccadic eye movements and visuo-spatial attention work together in a coordinated fashion in order to sample the visual world and to subserve final search decisions. Visuo-spatial attention can act independently of eye movements. As detailed in the Chapter 2 of this thesis,

 

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it is possible to covertly attend to a location or to an object in the periphery, without moving the eyes. Moreover, when covertly searching for a specific object in a crowded visual scene, search duration varies as a function of the similarity between the objects and its surroundings. In this context, two types of visual search are classically distinguished (Treisman & Gelade, 1980). When targets capture attention because they differ from the background in a simple dimension (orientation, color, luminance, direction of motion), the search is though to be efficient or pop-out, with no individuation of separate elements (Treisman, 1996). That is, the search is based on fast operations executed in parallel over the visual field. The predominant views suggest that the capture of attention by pop-out targets is mainly a bottom-up process (Desimone & Duncan, 1995; Treisman & Gelade, 1980). On the contrary, inefficient, or serial visual search requires attention to be shifted serially across the entire visual display until the target is identified. In this context, a linear relationship between the search time and the number of items is typically observed. Based on the spotlight metaphor of attention, the visual search is supposed to be performed with this metaphoric “spotlight”, which successively shifts attention to different locations in the visual field (Treisman, 1991). Parallel models (see e.g. Palmer, Verghese, & Pavel, 2000) questioned the parallel-serial dichotomy, and proposed to go beyond the dissociation between automatic versus attentive or parallel versus serial processing. According to these models, increasing effort or global attention, rather than spatial attention, produces longer RTs in visual search tasks as compared to pop-out tasks. In this context, an almost complete overlap of regions underlying these two types of visual search, favoring the concept of a single parallel processing mode have been observed (Leonards, Sunaert, Van Hecke, & Orban, 2000). Ossandon et al. (2012) studied the spatio-temporal dynamics of pop-out and visual search with intracranial electroencephalographic recording (iEEG). These authors reported sustained gamma-band activity (50-150 Hz) in dorsal frontoparietal regions (superior parietal lobule and FEF), as well as in more executive frontal

 

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regions (the dorso-lateral pre-frontal cortex and the dorsal anterior cingulated cortex) for both types of search. Active visual search, i.e. the search for task-relevant information in a visual scene, may thus involve dorsal fronto-parietal networks and executive attention resources, regardless of target saliency. Buschman and Miller (2007) recorded neural activity of monkeys prefrontal and posterior parietal cortices, during the execution of either a pop-out or a visual search task. These authors demonstrated that both the frontal and parietal cortex were involved in both tasks but fast, bottom-up target selection arose from the parietal cortex (the lateral intraparietal area, LIP), whereas longer-latency top-down selection arose from frontal areas (the lateral prefrontal cortex and the FEF). Functional fMRI studies have also demonstrated that the dorsal fronto-parietal attentional network (including the IPS and FEF) showed search-related activations (see e.g. Shulman, et al., 2003). The ventral network (mainly the right TPJ) was deactivated during search for a target embedded within a series of non-targets (Shulman, et al., 2003). Deactivation of the ventral network may thus prevent an inappropriate response to irrelevant stimuli. Moreover, the right TPJ average deactivation in Shulman et al.’s study (2003) was significantly stronger on trials in which the subsequent target was detected compared to missed targets. Similarly, the right TPJ is activated when distractor stimuli where presented at non-target locations, if they contained features matching the target (Serences, et al., 2005). All together, these results suggested that the right TPJ act as a filter during search, the source of the filtering signal possibly coming from the dorsal network (IPS, FEF), or the prefrontal cortex (see e.g. Desimone & Duncan, 1995; Miller & Cohen, 2001). Importantly, regarding overt attentional orienting, it has been proposed that if attention may operate without saccades, saccades cannot be planned without attention. The relationship between covert shifts of attention and overt saccades appears thus closely related. In this context, the well-known premotor theory (Rizzolatti, Riggio, Dascola, & Umilta, 1987)

 

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equated the control of attention and the overt orienting of saccades. According to this theory, attentional shifts always involve oculumotor preparation, with or without a subsequent saccade. This theory has received support from studies demonstrating overlapping neural substrates for overt and covert shifts of attention, both from recordings in non-human primates (see e.g. Moore, Armstrong, & Fallah, 2003; Moore & Fallah, 2004), and imaging studies in humans (see e.g. Corbetta, et al., 1998; Fairhall, Indovina, Driver, & Macaluso, 2009; Nobre, et al., 1997; Perry & Zeki, 2000). Overall, these studies demonstrated an involvement of a fronto-parietal network during both overt and covert orienting. However, these studies did not compare in a strict manner the involvement of either endogenous or exogenous shift of attention with overt saccadic orienting. Furthermore, the involvement of common cortical regions during overt and covert orienting need not entail a strictly common mechanism. The exact relationship between oculomotor control and shifting of attention remains thus under debate.

 

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Chapter 2: Spatial Neglect

 

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1. Introduction Visual spatial neglect is a multi-component syndrome classically defined by a failure to attend, respond, or orient attention to stimuli occurring in the contralesional hemispace, even in the absence of primary sensory or motor deficits (Heilman & Valenstein, 1979). Neglect patients present a tendency to attend to right-sided stimuli as soon as the visual scene deploys, as if their attention were magnetically attracted by these details (Gainotti, D'Erme, & Bartolomeo, 1991). This syndrome is a substantial source of handicap and disability for patients in daily life. Moreover, as patients are usually unaware of their deficits (anosognosia), the neglect syndrome induces a poor functional outcome. Neglect is typically associated with inferior parietal injury of the right hemisphere, following vascular strokes, occurring mainly in the territory of the right middle cerebral artery (MCA) (Mort, et al., 2003; Vallar & Perani, 1986). However, neglect may also be observed as a consequence of brain tumors (Shallice, Mussoni, D'Agostino, & Skrap, 2010) and of neurodegenerative conditions, such as Alzheimer disease (Bartolomeo, et al., 1998) or posterior cortical atrophy (Andrade, et al., 2010; Migliaccio, et al., 2011). The neglect syndrome is characterized by a hemispheric asymmetry with more severe and persistent neglect signs after right-sided lesions (see Bowen, McKenna, & Tallis, 1999; for a review). In a review of thirty published reports, Bowen et al. (1999) showed that the frequency of contralesional left neglect after right-brain damage (RBD) ranged from 12% to 100%. Azouvi et al. (2002) tested 206 subacute (11.1 weeks) RBD stroke patients with a comprehensive battery of behavioral tests of neglect. About 85% of patients demonstrated neglect on at least one measure. Even if neglect occurs more frequently after RBD, patients with left brain-damage (LBD) and right neglect have been reported. For instance, Beis et al. (2004) observed that out of 78 left hemisphere stroke patients, 43.5% presented some degree of neglect on at least one measure in subacute stage

 

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(mean 10.8 weeks). Moreover, when observed, right neglect is usually less severe and longlasting than left neglect following right hemispheric damage. 2. Impaired orienting of attention in neglect 2.1 Evidence from cueing paradigms The neglect syndrome is characterized by severe attentional orienting impairments concerning first and foremost exogenous orienting. Endogenous orienting however seems to be relatively spared, even if slowed (Bartolomeo & Chokron, 2002 for a review; Bartolomeo, Sieroff, Decaix, & Chokron, 2001). Bartolomeo et al. (2001) used a cue-target paradigm, and manipulated the spatial informative value of peripheral cues. When cues were spatially noninformative about the future location of the target, eliciting a pure exogenous shift of attention, neglect patients demonstrated a disproportionate cost for left-targets preceded by right invalid cues, particularly at short SOAs. Posner et al. (1984) called this phenomenon ‘extinction-like RT pattern’ and suggested that it resulted from an impaired disengagement of attention from the ipsilesional side (see Chap.1-Figure 3). Moreover, only RBD patients, compared to LBD patients, demonstrated a significant extinction-like RT pattern, and the cost for invalid contralesional targets correlated with the severity of neglect, suggesting a possible causal relationship between the two phenomena (Morrow & Ratcliff, 1988). Neglect patients present, together with the disengagement deficit described above, a deficit of IOR for rightsided targets. When manually responding to peripheral visual targets, which were occasionally repeated on the same side of space, patients with left neglect presented abnormal facilitation, instead of inhibition, for repeated right-sided items, i.e., for items appearing in their supposedly normal hemispace. Other patients with right hemisphere damage but without neglect had, instead, normal IOR for both sides of space (Bartolomeo, et al., 1999) (see Chap.1-Figure 3). These results were later confirmed in neglect patients with cue-target

 

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paradigms (Bartolomeo, et al., 2001). Patients with parietal damage also demonstrated decreased IOR (but not facilitation) on the ipsilesional side, even in the absence of neglect signs (Vivas, Humphreys, & Fuentes, 2003, 2006). IOR has been considered to be a foraging facilitator while searching in visual environments (Klein, 1988; Klein & MacInnes, 1999). A deficit of IOR in neglect patients may therefore participate to visual search impairments to reorient attention to new locations. This deficit may also contribute to the pathological revisiting behavior of items presented in the right hemispace observed in these patients (Mannan, et al., 2005). Alternatively, when counter-predictive endogenous cues (20% of valid cues and 80% invalid cues) were used, neglect patients were able to overcome their spatial bias and to endogenously orient attention toward the box opposite to the cued one (see Chap.1-Figure 3). Other converging evidence for preserved endogenous orienting in neglect comes from a study employing simple RTs to lateralized visual stimuli (Smania, et al., 1998). In this study, neglect patients displayed faster RTs for both hemifields when the side of stimulus presentation was predictable as compared to the case when stimuli were presented randomly. In conclusion, these studies have demonstrated that neglect is associated to severe deficits in exogenous attentional orienting, while endogenous orienting seems to be relatively spared.

 

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