spatial neglect and attention networks...ne34ch23-corbetta-shulman ari 13 may 2011 11:37 spatial...

NE34CH23-Corbetta-Shulman ARI 13 May 2011 11:37

Spatial Neglect andAttention NetworksMaurizio Corbetta1,2,3 and Gordon L. Shulman1

Departments of 1 Neurology, 2Radiology, and 3Anatomy and Neurobiology, WashingtonUniversity School of Medicine, St. Louis, Missouri 63110; email: [email protected],[email protected]

Annu. Rev. Neurosci. 2011. 34:569–99

The Annual Review of Neuroscience is online atneuro.annualreviews.org

This article’s doi:10.1146/annurev-neuro-061010-113731

Copyright c© 2011 by Annual Reviews.All rights reserved

0147-006X/11/0721-0569$20.00

Keywords

hemispheric dominance, stroke, neuroimaging, functionalconnectivity, arousal, white matter

Abstract

Unilateral spatial neglect is a common neurological syndrome follow-ing predominantly right hemisphere injuries and is characterized byboth spatial and non-spatial deficits. Core spatial deficits involve mech-anisms for saliency coding, spatial attention, and short-term memoryand occur in conjunction with nonspatial deficits that involve reorient-ing, target detection, and arousal/vigilance. We argue that neglect isbetter explained by the dysfunction of distributed cortical networks forthe control of attention than by structural damage of specific brain re-gions. Ventral lesions in right parietal, temporal, and frontal cortex thatcause neglect directly impair nonspatial functions partly mediated by aventral frontoparietal attention network. Structural damage in ventralcortex also induces physiological abnormalities of task-evoked activityand functional connectivity in a dorsal frontoparietal network that con-trols spatial attention. The anatomy and right hemisphere dominanceof neglect follow from the anatomy and laterality of the ventral regionsthat interact with the dorsal attention network.

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Contents

INTRODUCTION . . . . . . . . . . . . . . . . . . 570THE CORE SPATIAL DEFICIT:

EGOCENTRIC BIAS . . . . . . . . . . . . . 572Gradients of Spatial Attention and

Stimulus Saliency . . . . . . . . . . . . . . . 572An Egocentric Frame of Reference. . 573Does Spatial Neglect Involve Only

Attention/Salience? . . . . . . . . . . . . . 574Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 575

ANATOMY AND PHYSIOLOGY OFTHE EGOCENTRIC SPATIALBIAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576Structural Damage Does Not

Explain the EgocentricSpatial Bias . . . . . . . . . . . . . . . . . . . . . 576

A Dorsal Frontoparietal Network forSpatial Attention, StimulusSalience, and Eye Movements . . . 578

Physiological Correlates of theEgocentric Spatial Biasin Neglect . . . . . . . . . . . . . . . . . . . . . . 580

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 582RIGHT HEMISPHERE

DOMINANCE OF SPATIALNEGLECT . . . . . . . . . . . . . . . . . . . . . . . 583Right Hemisphere Lateralization of

Spatial Deficits . . . . . . . . . . . . . . . . . 583Right Hemisphere Lateralization

and Anatomy of CoreNonspatial Deficits . . . . . . . . . . . . . 584

Right Hemisphere Lateralizationand Physiology of CoreNonspatial Deficits . . . . . . . . . . . . . 585

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . 588VENTRAL AND DORSAL

ATTENTION NETWORKSAND SPATIAL NEGLECT. . . . . . . 588Interactions Between Ventral and

Dorsal Mechanisms . . . . . . . . . . . . . 588A Physiological Framework for

Understanding Spatial Neglect . . 589Problems and Omissions . . . . . . . . . . . 591

INTRODUCTION

L.J. is a 58-year-old schoolteacher, who suddenlydeveloped malaise and confusion while at school. Hewas brought to the hospital for evaluation. On firstappearance, his affect was flat and his vigilance re-duced; his responses were grammatically accuratebut delayed, and when asked “what was the mat-ter” he replied he was not sure why he had beenbrought in. On exam, his visual fields were normalbut his gaze tended to deviate to the right sponta-neously when looking ahead. When presented withtwo objects, one in each visual field, he always lookedfirst to the right object and denied the presence ofthe object on the left. However, when asked, he wasable to move his eyes to the left and reported seeingthe object. Overall, he was very slow in reportingstimuli even in his right visual field. When search-ing blindfolded for objects scattered on a table witheither the left or right hand, he explored mainlythe right side of the table, and his search progressedto the center only when objects on the right wereremoved. Touches on the right hand were easily re-ported and localized, whereas touches to the left handwere inconsistently detected and reported as belong-ing to the examiner. Motor function was normalin terms of strength, coordination, and dexterity onboth sides, but L.J. was reluctant to use his left handunless asked to do so. Head MRI showed a diffusionrestriction in the right inferior and middle frontalgyrus and anterior insula, consistent with an acuteischemic stroke.

This clinical history illustrates some key fea-tures of unilateral spatial neglect: a reductionof arousal and speed of processing; an inabil-ity to attend to and report stimuli on the sideopposite the lesion (contralesional) despite ap-parently normal visual perception; a spatial biasfor directing actions toward the hemi-space orhemi-body on the same side as the lesion (ip-silesional); and several disorders of awareness,including a degree of obliviousness toward be-ing ill and confabulation about body ownership.

Spatial neglect is caused by lesions, typi-cally strokes, in a number of different corti-cal and subcortical areas. Although acutely both

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Unilateral spatialneglect: a failure toattend and respond tocontralesional stimuli

Contralesional: theside of space oppositea brain lesion

Saliency: a measureof the sensorydistinctiveness andbehavioral relevance ofa stimulus

Egocentric spatialbias: a failure toattend tocontralesional stimuliwithin a referenceframe centered on theobserver

left and right hemisphere lesions can cause ne-glect, only right hemisphere lesions cause se-vere and persistent deficits (Stone et al. 1993),which is the primary basis for the widely heldview that the right hemisphere is dominant forattention.

Spatial neglect is unique among the behav-ioral disorders resulting from focal lesions be-cause its severity can be modulated by behav-ioral interventions over very short timescales(e.g., seconds). Deficits in attending to and re-porting objects in contralesional space can belessened by (a) encouraging a patient to attendto the previously ignored stimuli using verbalcues (Riddoch & Humphreys 1983); (b) pre-senting salient sensory stimuli, such as noises(Robertson et al. 1998); (c) asking the patient toperform hand movements controlled by the in-jured hemisphere (Robertson & North 1992);or (d ) training patients to increase their alert-ness (Robertson et al. 1995). These observa-tions suggest that the neural mechanisms un-derlying the spatial deficit can be dynamicallymodulated by signals from other parts of thebrain reflecting endogenous or exogenous at-tention, movement, and arousal. Moreover, ina matter of days or weeks, most patients withspatial neglect recover from the more obviousspatial impairments, which continue to nega-tively influence their ability to return to a pro-ductive life (Denes et al. 1982, Paolucci et al.2001).

Spatial neglect has attracted tremendous in-terest as a model for understanding the neu-rological basis of awareness, cerebral lateraliza-tion, spatial cognition, and recovery of function.Yet its neural bases remain poorly understood.Here, we provide a selective review of the vastliterature on neglect and present a frameworkfor understanding the disorder.

We propose that neglect is mediated by theabnormal interaction between brain networksthat control attention to the environmentin the healthy brain (see Heilman et al.1985 and Mesulam 1999 for other networkformulations). Although many authors haveemphasized dissociations and subtypes of

spatial neglect, we argue for a core set of spatialand nonspatial deficits that match the physio-logical properties of these networks. The corespatial deficit, a bias in spatial attention andsalience mapped in an egocentric coordinateframe, is caused by the dysfunction of a dorsalfrontoparietal network that controls attentionand eye movements and represents stimulussaliency. Core nonspatial deficits of arousal,reorienting, and detection reflect structuraldamage to more ventral regions that partlyoverlap with a right hemisphere dominantventral frontoparietal network recruited duringreorienting and detection of novel behaviorallyrelevant events.

Next, we emphasize that the ventral lesionsthat result in neglect alter the physiology ofstructurally undamaged dorsal frontoparietalregions, consistent with the fact that dorsal andventral attention regions interact in the healthybrain. Physiological dysfunction in dorsal fron-toparietal regions is empirically observed notonly during task performance but also at rest,and it correlates with the severity of the ego-centric spatial bias. Moreover, this dysfunctiondecreases the top-down modulation of visualcortex, reducing its responsiveness, which canalso contribute to neglect. The highly dynamicand plastic nature of the spatial deficits in ne-glect strongly argues that they are mediated byparts of the brain that still function, even if ab-normally. Measurements of the physiology ofbrain regions, not just of structural damage, areessential for understanding neglect (Deuel &Collins 1983), and we emphasize neuroimagingmethods that provide a window on physiologi-cal function.

Finally, perhaps the least understood clini-cal feature of spatial neglect is its right hemi-sphere lateralization. Brain imaging studieshave shown that dorsal frontoparietal regionscontrolling spatial attention and eye move-ments are largely symmetrically organized, witheach hemisphere predominantly representingthe contralateral side of space. In contrast, ven-tral regions that underlie the core nonspatialdeficits observed in neglect patients are strongly

www.annualreviews.org • Spatial Neglect and Attention 571

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fMRI: functionalmagnetic resonanceimaging

right hemisphere dominant. We argue thatlateralization of these latter functions, and theirinteraction with dorsal regions, rather thanasymmetries of spatial attention per se, primar-ily accounts for the hemispheric asymmetry ofneglect.

THE CORE SPATIAL DEFICIT:EGOCENTRIC BIAS

A large body of neuropsychological researchhas tried to characterize the nature of spa-tial deficits (i.e., involve predominantly oneside of space) in neglect. Factor analyticstudies have consistently isolated at leastone factor associated with impairments inattending/searching/responding to targetsin contralateral space, but have yielded in-consistent conclusions with regard to otherfactors (Azouvi et al. 2002, Halligan et al.1989, Kinsella et al. 1993, Verdon et al. 2010).Other studies have classified patients based ontheir performance on different behavioral tasksthought to isolate different subtypes, such asperceptual/attention versus motor/intentiondeficits (Coslett et al. 1990), but the consistency(Hamilton et al. 2008) and relevance to recoveryof these distinctions have been disappointing(Farne et al. 2004, Rengachary et al. 2011).Most patients suffer from perceptual/attentiondeficits that recover, albeit incompletely, inparallel with recovery from spatial neglect(Rengachary et al. 2011). We argue that atits core, spatial neglect represents a deficit ofspatial attention and stimulus saliency that ismapped in an egocentric reference frame.

Gradients of Spatial Attentionand Stimulus Saliency

Virtually all patients with spatial neglectmanifest a lateralized bias in visual informationprocessing that is evident both clinically andexperimentally as a gradient across space(Behrmann et al. 1997, Pouget & Driver 2000).Sensitivity and responsiveness to behaviorallyrelevant stimuli improve as one moves fromcontralesional to ipsilesional locations along a

continuous spatial gradient. This bias does notreflect abnormal early visual mechanisms,as indicated by normal measures of contrastsensitivity (Spinelli et al. 1990) and imagesegmentation based on low-level features inthe neglected visual field (Driver & Mattingley1998) and responses in occipital cortex based onvisually evoked potentials (Di Russo et al. 2008,Watson et al. 1977) and functional magneticresonance imaging (fMRI)(Rees et al. 2000).

In contrast, the saliency of objects in the ne-glected visual field is impaired. Saliency refersto the sensory distinctiveness and behavioralrelevance of an object relative to other objects.In a recent study, the saliency of objects inthe ipsilesional or contralesional visual fieldof neglect subjects was measured by indexingthe patients’ tendency to look at distinctivebut task-irrelevant stimuli or at task-relevantstimuli (Bays et al. 2010). Both kinds of stimuliproduced an increased probability of eye move-ments in their direction along a similar spatialgradient from contralesional to ipsilesionallocations, suggesting that exogenous (auto-matic) and goal-driven components of spatialattention were equally affected (Figure 1a).The abnormally high salience of ipsilesionalstimuli may prevent them from being filteredwhen they are task-irrelevant (Bays et al. 2010,Shomstein et al. 2010, Snow & Mattingley2006) or lead to repeated refixations duringsearch tasks (Husain et al. 2001).

Importantly, a spatially lateralized bias is ob-served even in the absence of a stimulus. Whenneglect subjects searched for a nonexistent ob-ject in complete darkness, search patterns asmeasured by eye or head position were stronglybiased toward the ipsilesional field (Hornak1992). Moreover, gaze deviations are observedtonically at rest, similar to those observed dur-ing task performance (Figure 1b) (FruhmannBerger et al. 2008).

Spatial biases in the dark during targetsearch could reflect a reduced salience of con-tralesional spatial locations during task perfor-mance, but the biases observed at rest also sug-gest an indwelling imbalance in the mechanismscontrolling gaze. These motor biases are likely


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cat dogcat

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Figure 1Behavioral and lesion analyses of the egocentric spatial bias in neglect patients. (a) Effects of stimulus salience on eye movements ofneglect patients. Patients were instructed to saccade to a target letter in an array. A sequence of arrays was presented, some containing atarget, some containing a distinctive probe stimulus of a higher luminance or different orientation than the distracter squares, and somecontaining both a target and a probe. The right graph shows that targets (red line) and irrelevant but distinctive luminance probes (blueline) produced more saccades in the ipsilesional than contralesional visual field with a similar linear gradient along the horizontalposition. This indicates a similar ipsilesional bias for automatic and goal-directed orienting (Bays et al. 2010). Lesions are localized inright temporoparietal junction. (b) Neglect patients show an ipsilesional gaze bias while searching for a target letter in a letter array(blue traces) and at rest ( green traces). Non-neglect patients (bottom) showed no bias (Fruhmann Berger et al. 2008). (c) Lesions classicallyassociated with neglect involve an ipsilesional bias within an egocentric reference frame, but not biases observed within stimulus-centered or object-centered frames. Each image shows the voxelwise lesion distribution associated with deficits within a particularreference frame (Medina et al. 2008). Panel a is adapted from figures 1, 2d, and 4b of Bays et al. 2010, with permission from the Societyfor Neuroscience. Panel b is adapted from figure 1 of Fruhmann Berger et al. 2008, with permission from the American PsychologicalAssociation. Lesion data in panel c are courtesy of Drs. Medina, Pavlak, and Hillis, Johns Hopkins and University of Pennsylvania, fromMedina et al. 2008.

associated with attentional biases because ofthe functional relationship between the corre-sponding neural systems (Corbetta et al. 1998,Rizzolatti et al. 1987).

An Egocentric Frame of ReferenceSpatial deficits can be separated based on thereference frame in which stimuli are coded.Neglect is often egocentric (viewer-centered),


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IPL: inferior parietallobule

STG: superiortemporal gyrus

IFG: inferior frontalgyrus

with left and right hemi-spaces based on theobserver’s midline (Figure 1c). Coding of thespatial midline can be further fractionated basedon eye, head, or body position. Although thesefactors have been shown to modulate the sever-ity of neglect in individual cases, no consis-tent dissociation has emerged between eye-,head-, or body-centered neglect (Behrmann &Geng 2002). These null results have tradition-ally been explained by the large volume andheterogeneity of lesions in humans. Compu-tational studies and physiological analyses inmonkeys, however, indicate an additional fac-tor, namely that activity in many areas reflectscombinations of different egocentric referenceframes (Chang & Snyder 2010, Pouget &Sejnowski 2001).

Neglect can also be allocentric, where themidline is defined from the central axis of astimulus, irrespective of its position in the en-vironment (stimulus-centered, Figure 1c) orof both its position and orientation (object-centered, Figure 1c). The great majority ofpatients with spatial neglect, however, suf-fer from egocentric deficits. Marsh & Hillisstudied 100 consecutive cases of right hemi-sphere acute stroke, and found that while17% and 34% showed visual and tactile ego-centric neglect, respectively, the correspond-ing figures for allocentric neglect were only4% and 2% (Marsh & Hillis 2008). Al-locentric and egocentric neglect rarely co-occur clinically and are dissociated anatomically(Medina et al. 2008, Verdon et al. 2010). Whileegocentric neglect is associated with regionsclassically damaged in spatial neglect, i.e., in-ferior parietal lobule (IPL), superior temporalgyrus (STG), and inferior frontal gyrus (IFG),stimulus- and object-centered neglect is associ-ated with damage of inferior temporal regions(Figure 1c).

Therefore, egocentric spatial deficits in ne-glect correspond much more closely to the clin-ical syndrome both behaviorally and anatomi-cally than do allocentric deficits, and representcore features of the syndrome.

Does Spatial Neglect Involve OnlyAttention/Salience?An important question is whether an atten-tion/saliency account of the spatial componentof neglect leaves out other impaired perceptual-cognitive functions, particularly visuospatialshort-term memory (VSTM) and spatialcognition. An influential account proposesthat neglect is a deficit in forming, storing, ormanipulating the left side of mental imagesor information in VSTM, termed represen-tational neglect (i.e., representation withinVSTM) (Bisiach & Luzzatti 1978, Della Salaet al. 2004). Most or all of the empirical findingsthat support an attentional/saliency interpre-tation of the spatial deficit in neglect patientscan also be explained within a representationalframework. This duality reflects the fact thatmechanisms for spatial attention, VSTM,and imagery are closely related, as shown bypsychological and physiological studies (Awh& Jonides 2001, Kosslyn et al. 2001), andentry into VSTM is often considered a normalconsequence of conscious perception. Notsurprisingly, representational neglect is nearlyalways observed in association with perceptualneglect (Bartolomeo et al. 1994). The few casesin which a dissociation has been reported (e.g.,Guariglia et al. 1993, Ortigue et al. 2001) usedpencil-and-paper tasks with lower sensitivitythan computerized tasks (Rengachary et al.2009) and did not control for differences ineye movements (Fruhmann Berger et al. 2008,Hornak 1992) and cognitive load or time-on-task, which affect the direction of spatial atten-tion (Dodds et al. 2008, Rizzolatti et al. 1987).Regardless, both the low frequency of dissocia-tions between perceptual and representationalneglect and the likelihood that each is mediatedby overlapping neural systems suggest that thisdistinction, while very important theoretically,may not be critical for first-order identificationof the psychological and neural mechanismsthat are damaged in the large majority of pa-tients with spatial neglect. Accordingly, in thisreview, we do not distinguish representational


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and spatial attention formulations of thecore egocentric deficit underlying spatialneglect.

Some neglect patients exhibit deficits inVSTM that may not show a contralesional-to-ipsilesional gradient and could be separate froma contralesional attention/salience/VSTMdeficit. VSTM deficits are observed for stim-uli presented along a central, vertical axis(Malhotra et al. 2005), while a more specializeddeficit has also been reported in trans-saccadicspatial memory (Mannan et al. 2005), possiblyreflecting saccadic remapping mechanisms(Vuilleumier et al. 2007). When coupled with abias to attend to ipsilesional locations, full-fieldVSTM and trans-saccadic deficits can exacer-bate contralesional neglect by leading to multi-ple refixations of already-searched, ipsilesionalobjects (Husain et al. 2001, Mannan et al. 2005).However, a recent study reported that bothVSTM deficits and visual search performancewere worse in the contralesional visual field.This result is consistent with the functionalsimilarity and neural overlap of mechanismsfor attention/perception and working memory(Kristjansson & Vuilleumier 2010).

In addition to spatial attention, spatial cog-nition is involved in many tasks used to assessspatial neglect. Line bisection, for example, re-quires fine judgments of spatial extent or posi-tion. Patients with neglect typically show right-ward biases in line bisection (Bisiach et al. 1983)or underestimate the size of objects placed onthe left side of space (Milner et al. 1998). Theseperceptual deficits are sometimes thought to re-flect a distortion of the horizontal dimension ofspace (Bisiach et al. 2002). However, extensiveinvestigations of eye movements during linebisection clearly indicate that neglect patientsfail to explore the left side of lines, most oftenjudging as midpoint the leftmost position thatwas fixated (Ishiai et al. 2006). Moreover, theirsubjective midline judgment is strongly biasedby the position of the rightward line endpoint(McIntosh et al. 2005). These findings suggesta more parsimonious explanation of line bisec-tion errors based on the relative saliency of the

right versus left side of lines (Figure 1a) andtonic oculomotor biases (Figure 1b). Anotheraspect of spatial cognition, processing of globalstimulus structure, is also impaired in at leastsome patients (Delis et al. 1986). A resultinglocal bias could increase the tendency to searchnear the current focus of attention, exacerbat-ing a bias to attend to ipsilesional locations(Robertson & Rafal 2000).

Overall, the egocentric spatial deficit inneglect reflects impairments in a set of relatedmechanisms for spatial attention, salience,and VSTM, and perhaps spatial cognition. Arecent study has shown that this deficit, whenassessed using even a very simple task, is highlyassociated with clinical judgments of neglect.In a paradigm involving simple reaction timeto a cued target, performance differences forleft- and right-field targets discriminated acuteand chronic neglect patients from healthycontrols with better accuracy than a variety ofstandard neuropsychological tests of neglect(Rengachary et al. 2009). Notably, this task didnot involve spatial imagery, spatial cognition(line bisection, clock-drawing, copying tasks),or shape identification in a cluttered field(cancellation tasks), and involved minimalVSTM demands.

Summary

Spatial neglect is characterized by a spa-tial gradient of impaired attention/saliency/representation within an egocentric referenceframe. The saliency deficit reflects both task andsensory factors and is linked with indwellingmotor imbalances that produce resting ipsile-sional deviations in eye, head, and body move-ments. Abnormal interhemispheric interactionslikely play a role in producing the spatial gra-dient. The gradient fluctuates depending onarousal and task instructions, suggesting thatthe underlying neural mechanisms are modu-lated by signals from other parts of the brainand are dysfunctional rather than obliteratedby structural damage.


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ANATOMY AND PHYSIOLOGY OFTHE EGOCENTRIC SPATIAL BIAS

We next discuss anatomical studies of neglect.The most commonly damaged brain regionsdo not contain physiological signals that canmediate the egocentric spatial bias. In contrast,physiological studies of spatial attention inhealthy adults have highlighted the importanceof a dorsal frontoparietal attention networkthat typically is not structurally damagedin neglect patients. The mismatch betweenanatomical lesions and physiology may beexplained by recent physiological studies of thedorsal network in neglect patients.

Structural Damage Does Not Explainthe Egocentric Spatial Bias

Spatial neglect was first associated with damageto parietal cortex (Critchley 1953), especiallyIPL (Mort et al. 2003, Vallar & Perani 1987).However, subsequent studies have also em-phasized STG (Karnath et al. 2001) and IFG(Husain & Kennard 1996), and convincingevidence exists that damage to other regions, in-cluding anterior insula and middle frontal gyrus(MFG), sometimes produces neglect. Interest-ingly, the distribution of cortical damage is sim-

ilar irrespective of the behavioral criteria (e.g.,neglect severity, clinical diagnosis, comparisonof neglect versus no-neglect individuals) usedto group the lesions (Figure 2a). Importantly,neglect patients, especially in severe cases,have white matter fiber damage, which can dis-connect frontal, temporal, and parietal cortex(Bartolomeo et al. 2007, Gaffan & Hornak1997, He et al. 2007, Thiebaut de Schottenet al. 2005). White matter damage mostcommonly involves a dorsal region lateralto the ventricle where arcuate and superiorlongitudinal fasciculi (II and III) run parallel inan anterior-to-posterior direction (Figure 2c)(Doricchi & Tomaiuolo 2003). Finally, neglectalso can be caused by damage to subcorticalnuclei (pulvinar, caudate, putamen) (Karnathet al. 2002a, Vallar & Perani 1987) that causecortical hypoactivation of regions importantfor the genesis of neglect (Karnath et al. 2005,Perani et al. 1987).

While the detailed profile of behavioraldeficits undoubtedly depends on the site of thelesion (Medina et al. 2008, Verdon et al. 2010),and some lesion sites are more likely than oth-ers to produce neglect, the striking fact re-mains that neglect of the left field can be causedby many different right hemisphere lesions.

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→Figure 2Relationship between anatomical distribution of lesions associated with neglect, attentional networks, and damage to fiber tracts.(a) Anatomical regions associated with neglect, as shown by lesion-symptom mapping (left panel ) (Karnath et al. 2011), overlap of lesionsin patients diagnosed with neglect (middle panel ) (A.R. Carter, G.L. Shulman, and M. Corbetta, unpublished data), and comparisons ofgroups of patients with severe neglect versus no neglect (right panel ) (Verdon et al. 2010). The three cortical distributions are quitesimilar and emphasize ventral regions in IPL (angular and supramarginal gyri), TPJ, STG, and VFC. (b) The dorsal (left panel ) andventral (right panel ) attention networks as determined by resting state functional connectivity in 25 healthy controls. The yellow-orange voxels indicate regions with strong and significant positive temporal correlation of spontaneous activity at rest. The blue voxelsin the left panel indicate regions negatively correlated with the dorsal network, corresponding to the default network. The anatomicaldistributions shown in Figure 2a match the distribution of the ventral but not dorsal attention networks. Seed regions for theconnectivity analysis were determined by meta-analyses of task activation paradigms (shown in Figures 3a and 6a). Dorsal seed regionswere determined from the activations evoked by a central cue to shift attention. Ventral seed regions were determined fromcomparisons of activations to targets presented at unattended and attended locations. (c) Slice representations from the anatomicaldistributions shown in the left (Karnath et al. 2011) and middle panels (A.R. Carter, G.L. Shulman, and M. Corbetta, unpublished data)of Figure 2a indicate that anatomical damage includes both gray and white matter. White matter tracts corresponding to the arcuatefasciculus (AF) and superior longitudinal fasciculus (SLF) II and III, as determined by diffusion tensor imaging (DTI) in 30 healthycontrols, are shown in the right panel (M. Glasser and K. Patel, unpublished data). The regions of maximal damage in neglect patients,shown in the left and middle panels, are outlined in green and blue. Lesion damage overlaps most strongly with the AF, but also withSLF II and III. These tracts connect regions within and across networks. Panels a and c, left panels, are adapted from figure 2 ofKarnath et al. 2011, with permission from Oxford University Press. Panel a, right panel, is adapted from figure 2 of Verdon et al. 2010,with permission from Oxford University Press.


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Attempts to identify a critical region based onstructural damage alone inevitably must explainaway a large number of reported lesions thatproduce neglect and yet do not involve the sup-posedly critical region.

Moreover, regions that are commonly dam-aged in spatial neglect do not contain the phys-iological signals expected based on deficits inspatial attention, eye movements, and coding ofsalience. These regions are not usually recruitedin neuroimaging experiments that isolate thoseprocesses, and none have yet been shown inhumans to contain maps of space. Right ven-tral frontal cortex (VFC), for example, has

been associated with target detection (Stevenset al. 2005), task control and error detection(Dosenbach et al. 2006), and response inhibi-tion (Aron et al. 2004).

To resolve this paradox, we propose that theheterogeneity of lesions in spatial neglect pa-tients masks a greater uniformity at the levelof physiology, with common physiological ab-normalities in remote neural systems special-ized for spatial processing (Corbetta et al. 2005,He et al. 2007). Next, we review evidence inhealthy subjects for a dorsal frontoparietal at-tention network that houses the physiologicalsignals impaired in spatial neglect.

SMG

Neglect severity (n = 54) Clinical diagnosis (n = 40)

Neglect severity (n = 54) Clinical diagnosis (n = 40)

Severe (n = 16) versus no neglect (n = 25)

AG

STGIFG

Ins

a

b

c White matter tracts

SLF II SLF III AFSeverityOverlap

SMG

STG

IFG

Ins

AG

IPS/SPL FEF

IFJ

MT

V3A

Dorsal attention network Ventral attention network

IFJ

t-value0 6

Chi-square7 20

% overlap10 40

t-value0 6

% overlap10 40

–3–5 53z -score functional connectivity


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SPL: superior parietallobule

FEF: frontal eye field

IPS: intraparietalsulcus

A Dorsal Frontoparietal Network forSpatial Attention, Stimulus Salience,and Eye MovementsRegions in dorsal frontal and parietal cortex,including bilateral medial intraparietal sulcus(mIPS), SPL, precuneus, supplementary eyefield (SEF), and frontal eye field (FEF), respondto symbolic cues to shift attention voluntarily toa location (e.g., Corbetta et al. 2000, Hopfingeret al. 2000, Kastner et al. 1999) (Figure 3a). Insome studies, additional responses are reportedin lateral prefrontal cortex, including the infe-rior frontal sulcus/junction (IFS/IFJ) (Sylvesteret al. 2007) and MFG (Hopfinger et al. 2000).The standard regions are also recruited whenattention is shifted to salient objects basedon task relevance and sensory distinctiveness(Shulman et al. 2009) (Figure 3b), consistentwith the idea that these regions are involved incoding the saliency of objects under both goal-driven and stimulus-driven conditions. Dorsalfrontoparietal regions (mIPS, precuneus/SPL,

FEF, SEF, DLPFC) are also recruited duringvisually and memory-guided saccades, with al-most complete overlap of attention- and eyemovement–related activations (Corbetta et al.1998), and in some regions sensory signalsare remapped during eye movements (Merriamet al. 2003). Both body-centered and stimulus-centered coding has been reported in IPS/SPL(Galati et al. 2010).

We previously proposed that these fron-toparietal regions constituted a dorsal corticalnetwork for the control of spatial and featuralattention and stimulus-response mapping(Corbetta & Shulman 2002). Subsequentwork demonstrated that at rest, many ofthese regions show highly correlated activity(Figure 2b), consistent with the notionthat they represent a separate functional-anatomical network analogous to sensory andmotor systems (Fox et al. 2006, He et al. 2007).Importantly, these dorsal frontoparietal regionsare not generally damaged in neglect patients,

−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−→Figure 3Physiology of spatial attention in healthy adults. (a) Dorsal frontoparietal regions are activated following a central cue to shift attention.The statistical map shows the z-map from a meta-analysis of four experiments (n = 58) in which BOLD activity was measuredfollowing a central cue to shift attention to a peripheral location (Astafiev et al. 2003, Corbetta et al. 2000, Kincade et al. 2005). Thetime course of the response to the cue shows bilateral activity from right (R) IPS with a contralateral preponderance indicating spatialselectivity. (b) Occipital and dorsal frontoparietal regions show spatially selective attentional modulations following a stimulus-drivenshift of attention [from a meta-analysis of two experiments (n = 47) (Shulman et al. 2009; A. Tosoni, G.L. Shulman, D.L.W. Pope,M.P. McAvoy, and M. Corbetta, unpublished data)]. Subjects were cued to attend left or right to detect targets in a rapid-serial-visual-presentation (RSVP) stream presented among distracter streams. The z-map indicates voxels showing contralateral activity >

ipsilateral BOLD activity following a shift of attention to the peripheral cue (red square). Note the strong spatially selective response inright IPS and visual cortex for shifting and attending to contralateral rather than ipsilateral stimulus streams. Also, maps for purelygoal-driven (Panel a) versus stimulus-driven (Panel b) shifts of attention are very consistent with a role of these regions in codingstimulus saliency under both conditions. (c) Contralateral topographic maps in dorsal parietal cortex. The left image shows fivecontralateral polar angle maps along R IPS. The right image shows the activations in these maps during a VSTM task in which subjectsremembered the orientation and location of target lines presented among distracters. The bottom graph shows a comparison of themagnitude of contralateral and ipsilateral activations in left and right IPS maps as a function of VSTM load. Although left and right IPScontains contralateral polarangle maps (left IPS not shown), right IPS was equally activated by VSTM load in the contralateral andipsilateral hemifields and left IPS was only modulated by load in the contralateral hemifield (Sheremata et al. 2010). This pattern ofactivity matches that postulated by the standard model for neglect (Mesulam 1981). (d ) Interhemispheric coding of spatial attention.BOLD activity was measured following an auditory cue to attend to a peripheral location. The top right graph shows the magnitude ofactivity in left (L) and R FEF on a trial-to-trial basis following leftward (blue dots) and rightward (red dots) cues. Activity in L and R FEFis highly correlated across trials, but a contralateral signal is superimposed on the positively correlated noise (i.e., blue dots plot above reddots). This correlated noise is partly explained by the presence of strong correlations at rest (bottom graph) between homologous regions(e.g., left-right FEF) or parts of maps (e.g., left-right fovea in V1). The locus of attention is only weakly predicted (AUC value = ∼.60,chance = 0.50) by reading out activity only from the portion of the map in visual cortex or area (e.g., FEF) coding for the attendedlocation. The prediction increases significantly (AUC = ∼.80) when subtracting activity from the attended-minus-unattendedhomologous portion of map or area in the two hemispheres (Sylvester et al. 2007). Figure 3c is adapted from figures 3a, 3b, and 5b ofSheremata et al. 2010, with permission from the Society for Neuroscience.


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as shown in the comparison of Figure 2a and2b. Recent physiological studies of these dorsalfrontoparietal regions, discussed next, have sug-gested two mechanisms for coding the locus ofbehaviorally relevant stimuli that may provideinsights into the pathogenesis of spatial neglect.

Topographic maps of contralateral space.Computational theories show that the co-occurrence of topographic maps, eye/attention,and saliency signals is useful for stimulus selec-tion (Koch & Ullman 1985). Correspondingly,many dorsal frontoparietal regions modulated

by spatial attention, eye movements, andsalience also contain polar angle maps of thecontralateral hemifield (Figure 3c, left image)(Hagler & Sereno 2006, Sereno et al. 2001,Swisher et al. 2007): medial IPS, precuneus,medial parieto-occipital cortex, SPL, FEF, andIFS/IFJ. Polar angle maps of the ipsilateralhemifield, however, have not been reported,indicating no evidence for separate topographicrepresentations of both visual fields within ahemisphere, a longstanding explanation for theright hemisphere dominance of neglect (seebelow).

VisCx

FEF

VCx

FEF

IPS1

IPS0

IPS3

IPS2

IPS4

160 ms

Spatial cue

120 ms

Target

120 ms

Distracters

L FEF response

R F

EF

re

spo

nse

L cuetrials

L

R cuetrials

R

L FEF

R FEF

Target

a

FEF

IPS

MT

VisCx

IPS IPS

b

c d

% s

ign

al

cha

ng

e

% s

ign

al

cha

ng

e

RemembercontralateralRememberipsilateral

61 3Set size

LH

61 3

RH

BO

LD

(% s

ign

al

cha

ng

e) 0.4

0

0.2

IPS

VCx

IPS

Time (s)3000 150

No

rma

lize

dsp

on

tan

eo

us

act

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y (

%)

TTTimTimTimTimTimTimTimT mmmTimeeeTimeTimimTimTiTTiTiTTTTT eTime

Shift and attend LVFShift and attend RVF

IPS1IPS0

IPS3

IPS2

IPS4

5

–5

0

UpperVFVF

Statisticalsignificancce

werLowFVF

Ss

werLow

10–2

–10–2

–10–3

10–3

Statisticalsignificance

(p value)


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BOLD: bloodoxygenation leveldependent

Dorsal attentionnetwork: regionscentered around IPS,SPL, and FEFinvolved in selectivelyattending to stimuliand linking them toresponses

Conversely, topographic maps have notbeen reported in ventral regions typically dam-aged in neglect patients, consistent with thelack of evidence for their involvement in spatialattention. However, this null result should betreated cautiously. Maps in these regions mayonly be imaged with appropriate tasks or may bemasked by a larger-scale organization involvingother variables, such as eye position (Siegel et al.2003). Moreover, the absence of a topographicmap does not imply null spatial coding, as in rathippocampus and entorhinal cortex (O’Keefe2006). Spatial coding in ventral regions may oc-cur at a scale and organization that are amenableto multivariate analyses of activation pat-terns, but not to standard retinotopic mappingprocedures.

Interhemispheric control of the locus ofattention. Interhemispheric competition mayplay a key role in the efficient control of spatialattention by the dorsal network (Kinsbourne1987). Sylvester and colleagues (Sylvester et al.2007) found that attention-related blood oxy-genation level–dependent (BOLD) activity indorsal frontoparietal and occipital regions con-tralateral to an attended location was only mod-estly predictive of whether a left- or right-fieldlocation had been cued on that trial. However,predictability was greatly increased by subtract-ing the activity of homologous left and righthemisphere regions, largely because activationsin the two hemispheres showed strong posi-tive trial-to-trial correlations (Figure 3d, rightgraph). Differencing the signals between thetwo hemispheres eliminated this common noise(Figure 3d, left). High interhemispheric corre-lation of activity also occurs at rest (Figure 3d,bottom), indicating tonic interhemisphericinteractions.

Computational studies show that whensignals in two brain regions are negativelycorrelated, as is the case with spatially selec-tive signals in the two hemispheres, positivecorrelations in the noise increase the amountof information that is encoded by the corre-sponding neurons (Averbeck et al. 2006). The

locus of attention may be efficiently codedby the two hemispheres through a differencesignal implemented by interactions via eitherthe corpus callosum (Innocenti 2009) orsubcortical routes. Enhanced prediction of thelocus of attention based on an interhemisphericdifference signal also has been observed withelectroencephalography (Thut et al. 2006) andsingle-unit recordings in monkey posteriorparietal cortex (Bisley & Goldberg 2003).

A prediction of this model is that abnor-malities in the computation of the locus ofattention should correlate with abnormalinterhemispheric interactions or response im-balances between the left and right hemispheredorsal attention network. The next sectiondiscusses the physiological activity of theseregions in neglect patients.

Physiological Correlates of theEgocentric Spatial Bias in Neglect

Patients with spatial neglect following lesionsto right ventral cortex and underlying whitematter have shown two types of physiologicalabnormalities in the structurally intact, dorsalattention network. First, at three weeks post-stroke, a widespread cortical hypoactivationduring a spatial attention task was observed inboth right and left hemispheres (Figure 4a),a finding consistent with other studies in theliterature (Pizzamiglio 1998, Thimm et al.2008). The cortical hypoactivation was asso-ciated with a large interhemispheric imbalanceof activity in dorsal parietal cortex (Figure 4b).The interhemispheric imbalance normalizedat the chronic stage (9 months poststroke) inparallel with an overall improvement of cor-tical activity and spatial neglect (Figure 4a,b)(Corbetta et al. 2005). Interestingly, activityin ipsilesional occipital visual cortex was alsoimbalanced, showing reductions in magnitudeand spatial selectivity (Corbetta et al. 2005)that were particularly marked under high at-tentional loads (Vuilleumier et al. 2008). Theseimpairments in sensory-evoked activity, possi-bly reflecting abnormal top-down control from


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Healthy controls Spatial neglect acute

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% s

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% signal changeL SPL/IPS

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600

–200

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ntr

a-I

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RT

600

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d

Left IPS/SPL Right IPS/SPL

2 weeks poststroke

9 months poststroke

Left IPS/SPL Right IPS/SPL

Time (s)

0.4

0.3

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300Time (s)

0 150

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c

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15

–5

–10

–15

0

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–5

–10

–15

0

DAN-homologousnormalized functional

connectivity

0 1.0

Figure 4Physiology of egocentric spatial bias in neglect patients. (a) Statistical map of BOLD activations during a Posner spatial attention task(same as in Figure 3a), in which subjects are cued to a peripheral location and detect a subsequent target. Right hemisphere acuteneglect patients show hypoactivation of both hemispheres (right>left) that partly recovers at the chronic stage. The dark shading in theanatomical image indicates the distribution of structural damage (Corbetta et al. 2005). (b) As a result of right hemispherehypoactivation, acute patients show a large imbalance of BOLD activity in IPS/SPL, with relatively greater left than right hemisphereactivity, even though activity in both hemispheres is lower than normal. This imbalance normalizes at the chronic stage. The leftcolumns show statistical maps of activity in parietal cortex, the right column shows the averaged time course of activity time-locked tothe presentation of the cue over a trial of the Posner task in left (blue line) and right (red line) parietal cortex (Corbetta et al. 2005).(c) Acute neglect patients (top graph) show low correlations in BOLD spontaneous activity between homologous regions of left (bluelines) and right (red lines) parietal cortex, but the correlation recovers at the chronic stage (bottom graph) (He et al. 2007). (d ) Abnormalphysiological signals in the dorsal attention network of acute neglect patients are functionally significant. (Left graph) Left parietalactivity was stronger in subjects with more severe neglect, as indexed by longer response times (RTs) to contralesional versusipsilesional visual targets. (Right graph) Reduced interhemispheric correlation within frontoparietal regions of the dorsal attentionnetwork correlates with the severity of neglect of the left visual field, as indexed by longer RTs to contralesional versus ipsilesionalvisual targets (Carter et al. 2010).


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Functionalconnectivity: thecorrelation over timeof the spontaneousactivity betweendifferent brain regions

frontoparietal cortex (Bressler et al. 2008), mayfurther lessen the saliency of contralesionalstimuli.

Second, neglect patients have shown anoma-lies in the pattern of spontaneous activity fluc-tuations within the dorsal attention network(Figure 4c). Coherence between left and rightparietal regions was disrupted three weeks post-stroke and improved over time in parallel withthe improvement of neglect (Figure 4c) (Heet al. 2007).

Dorsal frontoparietal abnormalities in bothtask-evoked activity and resting coherence arefunctionally significant. Left parietal activity isstronger in subjects with more severe neglect,as indexed by the difference in response timesto contralesional versus ipsilesional visualtargets (Figure 4d) (Corbetta et al. 2005).Stronger left than right hemisphere activationof parietal and occipital regions may reflecta biased representation of stimulus salienceand the locus of spatial attention (Bisley &Goldberg 2003, Sylvester et al. 2007). Thisinterpretation is consistent with trans-cranialmagnetic stimulation studies, in which inacti-vation of left posterior parietal cortex reducedleft-field neglect (Brighina et al. 2003, Kochet al. 2008). At rest, significant correlations arefound throughout the dorsal attention networkbetween reductions in interhemispheric co-herence and the magnitude of the spatial bias(Figure 4d) (Carter et al. 2010, He et al. 2007).The anomalies in spontaneous activity mayunderlie the lateral rotation of the eyes, head,and body in neglect patients at rest (FruhmannBerger et al. 2008), which likely reflect biasedcoding of the locus of attention and salience,and contribute to the observed abnormalitiesin task-evoked responses.

Therefore, in structurally intact regions ofthe dorsal attention network, ventral lesions in-duce changes in BOLD resting functional con-nectivity and task-evoked activity that reflectabnormal interhemispheric interactions andresponse balances (Kinsbourne 1987), whichplausibly explain the egocentric spatial biasin neglect. Recent studies of resting bloodperfusion, which assess physiological function,

have associated spatial deficits in neglect pa-tients with hypoperfusion of right IPL (Hilliset al. 2005), STG (Zopf et al. 2009), andIFG/anterior insula (Medina et al. 2008), butnot of dorsal frontoparietal regions. However,these studies did not assess the functional rela-tionship or coherence between regions, corre-sponding to the resting BOLD measure of thedorsal network that shows abnormalities, anddid not measure task-evoked signal changes,corresponding to the other BOLD measureof dorsal network function that shows abnor-malities. Moreover, the task-evoked changesmeasured in BOLD studies are quite small,well under 1% (Corbetta et al. 2005), and maynot be detected with less-sensitive perfusionmethods.

Summary

The extant literature strongly supports thepresence of physiological signals (spatial atten-tion, eye movement, saliency, maps of con-tralateral space, interhemispheric interactions,egocentric frame of reference) in the dorsalfrontoparietal network that are likely highly rel-evant to the pathogenesis of spatial neglect. Re-cent neuroimaging results potentially resolvethe paradox that ventral regions traditionallyassociated with neglect do not contain physio-logical signals that could account for an ego-centric spatial bias, whereas dorsal frontopari-etal regions that contain these signals are nottypically damaged in strokes that cause ne-glect. However, only a few BOLD imagingstudies have been conducted, involving rela-tively small patient samples. Further studies willbe necessary to determine if similar changesin dorsal network physiology are observedacross the different lesions that cause spatialneglect.

The above neuroimaging results, moreover,do not explain why lesions that cause neglect oc-cur ventrally and in the right hemisphere. Aftermore than 50 years of research, the right hemi-sphere dominance of spatial neglect remains themost puzzling aspect of this syndrome. Theseissues are considered next.


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RIGHT HEMISPHEREDOMINANCE OF SPATIALNEGLECT

Right Hemisphere Lateralizationof Spatial Deficits

The right hemisphere dominance of neglectmight reflect a corresponding asymmetry forspatial attention, the primary mechanism un-derlying the egocentric spatial deficit, and forrelated functions of VSTM and spatial cogni-tion. Perhaps the most widely accepted, stan-dard theory of neglect postulates that the righthemisphere controls shifts of attention to bothsides of space. while the left hemisphere onlycontrols attention to the right side (Mesulam1981). Damage to the right hemisphere im-pairs attention to the left hemifield, whereasdamage to the left hemisphere can be compen-sated. A second, opponent-process theory pro-poses that each hemisphere promotes orientingin a contralateral direction, but the strength ofthis bias is stronger in the left than right hemi-sphere (Kinsbourne 1987). Left hemisphere le-sions cause only mild right spatial neglect be-cause the unopposed orienting bias generatedby the right hemisphere is relatively weak.

Empirical support for each theory fromneuroimaging studies is surprisingly modest.Mapping studies have reported contralateralretinotopic maps in both hemispheres butno evidence of ipsilateral maps in the righthemisphere. Most neuroimaging studiesof cueing paradigms have reported largelybilateral dorsal frontoparietal activations fordirecting spatial attention to locations in eithervisual field (e.g., Hopfinger et al. 2000, Kastneret al. 1999, Shulman et al. 2010, Sylvester et al.2007). Several studies, however, have reportedlarger activations for contralateral than ipsi-lateral stimuli (contralateral bias) in some leftthan right dorsal regions (e.g., Szczepanskiet al. 2010, Vandenberghe et al. 2005). Theseasymmetries in contralateral bias are consistentwith either the standard or opponent processtheory, depending on whether the bias inthe right hemisphere was completely absent

(standard theory) or was simply present to alesser degree (opponent process). Given thelarge number of discrepant findings, however, itwill be important to identify the factors control-ling when the specific hemispheric asymmetrypostulated by either theory is observed.

A recent study suggested that one fac-tor might involve high loading of VSTM(Sheremata et al. 2010). Under conditionsthat involved high VSTM load and spatialfiltering of distracters, left and right hemi-sphere activations in regions of IPS, whichcontained strictly contralateral polar anglemaps, nevertheless showed the postulatedvisual field profile (Figure 3c). Despite thisintriguing result, however, the presence of thestandard visual field organization under highVSTM load does not satisfactorily explain thelaterality of neglect. Contralesional neglect iscorrelated with conditions that do not involvehigh VSTM loads, such as simple detectionof a single visual target (Rengachary et al.2009). Similarly, gaze biases that correlate withcontralesional neglect are present even at rest.

Finally, the laterality of contralesional ne-glect could partly reflect a similar lateralityfor aspects of spatial cognition. Variants ofline bisection tasks qualitatively produce right-dominant activity in IPS/SPL after they are ref-erenced to control tasks that largely subtract outactivations from shifting and maintaining atten-tion (Fink et al. 2001). Similarly, Sack and col-leagues observed right hemisphere dominanceduring variants of a clock task, in which sub-jects judge the angle formed by hour and minutehands (Sack 2009). To explain the laterality ofcontralesional neglect, however, mechanisms ofspatial cognition must also show the visual fieldorganization postulated by the standard atten-tion theory, for which there is only limited ev-idence (Kukolja et al. 2006).

Most importantly, right lateralization ofspatial attention, VSTM, and spatial cognitionhas primarily been observed in dorsal parietalregions, leaving unanswered the critical ques-tion of why ventral (e.g., IFG or IPL) ratherthan dorsal (e.g., IPS/SPL) right hemispherelesions cause neglect.


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TPJ: temporoparietaljunction

Right Hemisphere Lateralization andAnatomy of Core Nonspatial Deficits

An alternative explanation that addresses thisquestion, and is fully compatible with eitherthe presence or absence of hemispheric asym-metries in dorsal visuospatial mechanisms, linksthe laterality of neglect to several nonspatial be-havioral deficits that are commonly observed inneglect patients (Heilman et al. 1987, Husain& Rorden 2003, Robertson 2001). Nonspa-tial refers to deficits that are nominally presentacross the visual field (e.g., the putative full-field VSTM and global processing deficits dis-cussed above). In practice, a nonspatial deficitis rarely if ever shown to be of equal severity inthe two hemifields, and measurements acrossthe visual field are often not made, mainly be-cause of the difficulty of separating nonspatialdeficits from the egocentric spatial bias (but see(Duncan et al. 1999). More commonly, con-clusions are based on finding a deficit relativeto control subjects for stimuli located centrallyor in the ipsilesional field, although this proce-dure does not control for spatial gradients thatextend across the visual field (e.g., Figure 1a).

Below, we briefly review three core non-spatial deficits consistently observed in neglectpatients. These deficits are of particular interestbecause, unlike the egocentric spatial mecha-nisms discussed above, their physiology mapsclosely onto the anatomy of neglect, with clearinvolvement of ventral right hemisphere re-gions. We discuss evidence for the interactionof these ventral regions, damaged in neglect,with the dorsal attention network, a criticallink for understanding the pathophysiologyand right hemisphere dominance of the neglectsyndrome.

Reorienting of attention. Michael Posnerand colleagues reported that neglect patientsare impaired in reorienting to unexpectedevents (Posner et al. 1984). Patients showedespecially large deficits in detecting contrale-sional targets when they were expecting an ip-silesional target, suggesting a deficit in dis-engaging attention from the ipsilesional field.

A comparison of temporoparietal junction(TPJ)/STG versus SPL patients originally lo-calized disengagement/reorienting deficits toright TPJ/STG (Friedrich et al. 1998). A re-cent study confirmed that a reorienting deficitwas stronger for contralesional than ipsilesionaltargets following TPJ lesions, but the magni-tude of the ipsilesional deficit was substantiallyincreased following VFC lesions (Rengacharyet al. 2011) (Figure 5a), indicating a bilateraldeficit in reorienting.

Detection of behaviorally relevant stimuli.Right hemisphere and neglect patients showdeficits in target detection in even the simplestparadigms. Simple auditory reaction time (RT),for example, is much slower following rightthan left hemisphere damage (Howes & Boller1975). Related differences have been reportedfor auditory stimuli presented at ipsilesional lo-cations in right hemisphere patients with ne-glect versus those without neglect (Samuels-son et al. 1998), indicating that the RT slowingmay reflect damage to right hemisphere brainregions specifically associated with neglect(Figure 5b). Impairments are sometimesreported even for accurate detection ofsuprathreshold stimuli presented centrally(Malhotra et al. 2009) or ipsilesionally [al-though only acutely (Rengachary et al. 2011)],indicating that RT slowing likely does not re-flect motor difficulties with the ipsilesional orgood hand. RT slowing could reflect deficits inarousal and processing capacity (Duncan et al.1999, Husain et al. 1997), although the lattereffects occur following both left and right hemi-sphere damage (Peers et al. 2005).

Arousal and vigilance. Reduced arousal andvigilance is an important component of the ne-glect syndrome following right hemisphere in-jury. Clinically, patients with neglect and righthemisphere injuries suffer from lower arousalthan patients with similar lesions in the lefthemisphere. Arousal refers to the combinationof autonomic, electrophysiological, and behav-ioral activity that is associated with an alert


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A

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Figure 5Behavioral analyses of nonspatial deficits in neglect patients. (a) Reorienting deficits in neglect patients with VFC and TPJ lesions(Rengachary et al. 2011). Patients detected a visual target (asterisk) that occurred in a validly cued location (dotted circle) or at an invalidlycued location (shown in the figure). Both TPJ and VFC patients showed large contralesional deficits in reorienting, as indexed bylonger response times (RTs) to unattended (invalid) than attended (valid) targets. The VFC group additionally showed reorientingdeficits in the ipsilesional field and larger overall detection deficits. Similar results were observed for accuracy (not shown), but the TPJgroup showed evidence of a small reorienting deficit in the ipsilesional field. (b) Detection deficits in neglect patients. Neglect patientsshow abnormally slow simple RTs to an ipsilesional auditory stimulus (Samuelsson et al. 1998). Controls were healthy age- andgender-matched subjects. The mild and severe groups consisted of non-neglect patients with minor and major right hemisphere strokes.(c) Arousal deficits in neglect patients. Parietal neglect patients show a vigilance decrement (red curve) in a task that involved detectionof letter targets in two locations (arrows) within a central column. No deficit is observed in right hemisphere stroke controls withoutneglect (blue curve). The anatomical images show the association of damaged voxels in right TPJ with the vigilance decrement, withdarker areas indicating a weaker association (Malhotra et al. 2009). Panel b is adapted from Samuelsson et al. 1998, with permission fromTaylor & Francis. Panel c is adapted from figures 5a, 6c, and 7 of Malhotra et al. 2009, with permission from Oxford University Press.

state, whereas vigilance refers to the ability tosustain this state over time.

Kenneth Heilman and colleagues have ar-gued that neglect patients have decreasedarousal due to hypoactivation of the righthemisphere (Figure 4a) (Corbetta et al. 2005,Heilman et al. 1987). For instance, patients withright as opposed to left hemisphere damage donot show the typical slowing of heart rate fol-lowing a cue that signals a subsequent target(Yokoyama et al. 1987) and show reduced gal-vanic skin responses to electrical stimulation(Heilman et al. 1978). Lesions studies have as-sociated right frontal damage with decreasedarousal (Wilkins et al. 1987) and a decrementover time in sustaining attention and detect-ing targets (vigilance decrement) (Rueckert &Grafman 1996).

Importantly, there is evidence for inter-action between arousal/vigilance and spatialdeficits. A nonspeeded, auditory counting test

of arousal discriminated neglect from non-neglect patients in a right hemisphere groupwith heterogeneous lesions, indicating a stronglinkage between arousal and spatial deficits inneglect (Robertson et al. 1997). A recent studyreported a specific association between damageto right TPJ cortex and vigilance decrements,but only when attention had to be sustained toa spatial location, not for targets presented atrandom locations (Figure 5c) (Malhotra et al.2009). The interaction between mechanismsunderlying nonspatial and spatial deficits islikely critical for the pathogenesis and righthemisphere lateralization of spatial neglect(see below).

Right Hemisphere Lateralization andPhysiology of Core Nonspatial Deficits

The above results indicate that neglect pa-tients show nonspatial deficits in reorienting,


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target detection, and arousal that are likely righthemisphere dominant. We next show that, cor-respondingly, physiological signals mediatingthese functions in the healthy brain are rightlateralized and occur in ventral regions typically

RIGHT HEMISPHERE DOMINANCEIN VERTEBRATES

While right lateralization in humans is often considered abyproduct of left hemisphere dominance for language, compar-ative studies suggest the basic specialization of each hemispheremay have been present early in vertebrate evolution. MacNeilageand colleagues (2009), summarizing this work, write “. . . theright hemisphere, the primary seat of emotional arousal, wasat first specialized for detecting and responding to unexpectedstimuli in the environment.”

The latter sentence describes the human ventral attention net-work (Corbetta et al. 2008, Corbetta & Shulman 2002). Whenvisual input is confined to the left eye/right hemisphere of chicks,their behavior is greatly affected by salient or novel stimuli(Rogers & Anson 1979). Feeding behavior, for example, is dis-rupted by the presence of brightly colored pebbles scatteredamong grains (Rogers et al. 2007). Similarly, during feeding, asimulated hawk is detected faster when it appears in the left thanright monocular field (Rogers 2000).

Behavioral asymmetries in chicks arise partly from asymmet-ric light exposure prior to hatching. Following exposure, con-nections from the ipsilateral visual field innervate more the rightthan left hyperstriatum (Rogers & Sink 1988), reminiscent ofthe standard neglect theory. This physiology, however, varieswidely across avian species. In pigeons, the asymmetry is reversedand is mediated by tectofugal rather than thalamofugal pathways(Valencia-Alfonso et al. 2009).

In mammals, right hemisphere dominance for several non-spatial functions may partly reflect asymmetric brainstem pro-jections. The locus coeruleus/noradrenergic system in rats showsan asymmetric organization (Robinson 1985) that Posner &Petersen (1990) have linked to right lateralization of arousal. Re-cent evidence also points toward locus coeruleus/noradrenergicinvolvement in reorienting and target detection, two other later-alized, nonspatial functions associated with neglect (Aston-Jones& Cohen 2005, Bouret & Sara 2005, Corbetta et al. 2008).

The similar right hemisphere specializations in animals andhumans may reflect convergent evolution rather than homology,but raise the possibility that the lateralization underlying humanneglect is of longstanding origin.

damaged in neglect (IPL, STG, and IFG). In-terestingly, the lateralization of these processesis supported by similar findings in other species(see Right Hemisphere Dominance in Verte-brates sidebar).

Reorienting of attention. Neuroimagingstudies of healthy adults have shown thatreorienting to stimuli in either visual field thatare presented outside the focus of attention(stimulus-driven reorienting) recruits a rightlateralized ventral attention network in TPJ(including separate foci in SMG and STG)(Shulman et al. 2010) and VFC (Insula, IFG,MFG), in conjunction with the dorsal network(Figure 6a) (Corbetta & Shulman 2002).While TPJ is uniformly activated by stimulus-driven reorienting, VFC is mainly activatedwhen reorienting is unexpected and requirescognitive control (Shulman et al. 2009) or iscoupled to a response. Because one or both con-ditions usually apply in real-world situations,the two regions are typically coactivated and asimilar network is observed in the resting state(Figure 2b) (Fox et al. 2006, He et al. 2007).

Importantly, the cortical anatomy of theventral attention network includes the pri-mary regions damaged in neglect (Figure 2b,Figure 6a) and matches the localization of thereorienting/disengagement deficit (Figure 5a),indicating a clear convergence between stud-ies in neglect patients and healthy adults (Foxet al. 2006, Friedrich et al. 1998, He et al. 2007,Rengachary et al. 2011, Shomstein et al. 2010,Shulman et al. 2010).

Detection of behaviorally relevant andnovel stimuli. The ventral (and dorsal) atten-tion network is activated by detection of behav-iorally relevant stimuli that are unattended orunexpected with respect to a wide range of at-tributes, not just their location, as demonstratedby oddball tasks in which subjects report infre-quent targets that differ in some feature (e.g.,color, tone frequency) from a standard stimu-lus (Corbetta & Shulman 2002). Oddball de-tection, however, activates not only the ventralattention network but also additional regions


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SMG

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Invalidlycued target

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StrokeTarget

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Figure 6Physiology of nonspatial attention in healthy adults. (a) Physiology of reorienting attention in healthy adults. BOLD activity wascompared for visual targets that occurred in invalidly cued (left panel ) versus validly cued (right panel ) locations. The statistical mapshows the z-map from a meta-analysis (n = 58) of four experiments (Astafiev et al. 2003, Corbetta et al. 2000, Kincade et al. 2005).Strong activations are observed in right TPJ, extending from posterior temporal cortex (STG) to ventral IPL (SMG), and in rightIFG/insula. These ventral regions are coactivated with dorsal attention regions in IPS and FEF. (b) Physiology of detection in healthyadults. A spatial cue directed subjects to attend to a rapid-serial-visual-presentation (RSVP) stream in the left or right visual fields thatmight contain a target. The z-map shows all voxels with greater right than left hemisphere BOLD activity to detected targets. The mapincludes ventral voxels that showed significant activations from reorienting in panel a, but also additional regions in prefrontal cortex.The dorsal attention network, however, does not show an asymmetry. (c) Physiology of arousal in healthy adults. A meta-analysis of focifrom five experiments reporting activations that index arousal/vigilance, visual (red spheres) or auditory ( green spheres) (Coull et al. 1998,Foucher et al. 2004, Paus et al. 1997, Sturm et al. 1999, Sturm et al. 2004). The right hemisphere foci are superimposed on the averageof z-maps for reorienting and detection-related hemispheric asymmetries from panels a and b. The dark shading shows the distributionof neglect lesions from a recent neglect study (Rengachary et al. 2009). Many more foci are observed in the right than left hemisphere.Foci are clustered around the TPJ and insula/frontal operculum regions that are activated by reorienting and target detection, but manyprefrontal foci are anterior to both distributions. Few foci occur in dorsal frontoparietal regions, indicating that arousal-relatedactivations overlap more the ventral than dorsal attention network.

Ventral attentionnetwork: regionscentered around TPJand ventral frontalcortex, involved inreorienting to salientstimuli outside thefocus of attention

in frontal, parietal, and temporal cortex thatshow right hemisphere dominance in direct in-terhemispheric voxelwise comparisons (Stevenset al. 2005). Similar, although not identical,right hemisphere regions are activated by novelstimuli that are task irrelevant (Stevens et al.2005).

Right hemisphere dominance during tar-get detection is observed in regions that arefrequently associated with neglect (IPL, STG,IFG) and for visual targets in both left and righthemifield (Shulman et al. 2010), consistent withthe nonspatial deficit in neglect (Figure 6b).Unlike the simple detection tasks studied in ne-glect patients, however, the above paradigmspresented both targets and nontargets, and thefrequency of targets was relatively low.

Arousal and vigilance. Neuroimaging studiesof arousal and vigilance using simpler auditoryand visual detection paradigms, more similar tothose adopted in neglect subjects, have quali-tatively reported right hemisphere dominance(direct interhemispheric comparisons were notconducted), usually in lateral prefrontal, in-sula/frontal operculum, and TPJ regions (Coullet al. 1998; Foucher et al. 2004; Pardo et al.1991; Paus et al. 1997; Sturm et al. 1999,2004). Figure 6c shows that arousal-relatedactivations are recorded more frequently inventral cortex of the right than left hemi-sphere, and are not frequently reported in dor-sal frontoparietal cortex, indicating a muchstronger overlap with ventral than dorsal at-tention networks. Importantly, arousal-related


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activations in the TPJ and insula/frontal oper-culum overlap with regions that are damaged inspatial neglect, and recruited during reorient-ing and target detection, although prefrontalactivations are localized more anteriorly.

Summary

The widespread view that attention in healthyadults is right hemisphere dominant is moreconsistent with the evidence for right lateraliza-tion in ventral frontoparietal cortex of reorient-ing, detection, and arousal than the more mod-est evidence for right lateralization in dorsalfrontoparietal cortex of the mechanisms con-trolling spatial attention. The main conclusionis that the right hemisphere ventral regions(IPL, STG, IFG/insula) associated with ne-glect underlie the above nonspatial functionsimpaired in patients.

VENTRAL AND DORSALATTENTION NETWORKSAND SPATIAL NEGLECT

What remains to be considered is how dam-age to these ventral regions produces the doc-umented abnormalities in the dorsal attentionnetwork that likely underlie the egocentric spa-tial bias. We next consider behavioral evidencefor interactions between nonspatial and spatialfunctions that map to ventral and dorsal re-gions, and physiological studies that have at-tempted to identify the specific pathways thatmight mediate these interactions. Finally, wepresent a novel physiological model of spatialneglect based on the structural-physiologicalinteraction of ventral and dorsal attentionnetworks.

Interactions Between Ventraland Dorsal Mechanisms

Recent behavioral evidence in healthy adults in-dicates that arousal, a right lateralized, nonspa-tial function impaired in neglect patients, inter-acts with spatial attention, the primary spatialfunction impaired in neglect patients. Healthy

adults show a slight tendency to attend to theleft side of an object (Nicholls et al. 1999), butthis bias is reduced or shifted to the right un-der conditions of low arousal (Bellgrove et al.2004, Manly et al. 2005, Matthias et al. 2009).The specific form of the interaction betweenarousal and spatial attention predicts that in-creases in arousal should bias attention to theleft visual field, ameliorating left-field neglect.

Robertson and colleagues observed this re-sult in two important studies. Increases in ei-ther phasic (Robertson et al. 1998) or sustainedarousal (Robertson et al. 1995) decreased ne-glect of the contralesional field, consistent witha direct effect of the activation of ventral righthemisphere mechanisms on the dorsal atten-tion network. Biases in spatial attention havealso been observed immediately following tar-get detection, another right lateralized, non-spatial function damaged in neglect patients(Perez et al. 2009). Perez and colleagues suggestthat conditions that reduce processing capacity,such as the attentional blink and low arousal,bias spatial attention to the right.

There is currently only limited evidence ofthe anatomy and physiology underlying the in-teractions between nonspatial and spatial mech-anisms observed in behavioral studies of healthyadults, and the effects of ventral lesions ondorsal physiology observed in neglect patients.Both may involve similar pathways. Studies inhealthy adults have suggested possible linkagesbetween ventral and dorsal regions that runthrough lateral frontal cortex. A region nearIFJ, for example, that shows resting-state con-nectivity with both dorsal and ventral networks(Figure 2b) (He et al. 2007) and shares task-evoked properties with each network (Asplundet al. 2010) may act as a pivot point. Ven-tral frontal lesions that include IFJ producegreater deficits in spatial attention than tem-poroparietal lesions (Figure 5a) (Rengacharyet al. 2011).

Putative ventral-dorsal linkages have alsobeen evaluated by measuring the relationshipbetween ventral to pivot-region functionalconnectivity and connectivity within the dorsalnetwork. Impaired functional connectivity


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between STG/TPJ and MFG, for example,is correlated with impaired interhemisphericconnectivity between left and right posteriorIPS/SPL, which in turn relates to the magni-tude of the spatial deficit (He et al. 2007). Thesame study also assessed structural damage toa white matter tract that putatively connectedventral/pivot regions to the dorsal network,and observed the resulting effects on dorsalnetwork connectivity and spatial behavioralbiases. Neglect patients who suffered dam-age to the superior longitudinal fasciculusshowed reduced interhemispheric functionalconnectivity in posterior parietal cortex andmore severe spatial neglect. This may explainwhy patients with more severe neglect havemore involvement of the white matter tractsconnecting parietal, temporal, and frontalregions (Gaffan & Hornak 1997, Karnathet al. 2011, Verdon et al. 2010) (Figure 2c).Consistent with this latter result, stimulatinga white matter tract that connects right frontaland parietal cortex produced rightward devi-ations in bisection performance (Thiebaut deSchotten et al. 2005). Finally, the neural mech-anisms behind ventral-dorsal interactions areunknown but may depend on synchronizationof neural activity in ventral and dorsal regionsthat is time-locked to behaviorally relevantevents (Daitch et al. 2010).

These results are provisional and ex-ploratory but suggest that in neglect patients,both the severity of spatial biases and the inter-hemispheric functional connectivity of dorsalregions are related to the functional connectiv-ity or integrity of ventral/pivot regions and tothe integrity of white matter tracts that likelyconnect ventral and dorsal regions.

A Physiological Framework forUnderstanding Spatial Neglect

Our review suggests the following accountof spatial neglect, as observed in L.J.’s casereport. L.J.’s reduced vigilance and slownessin responding to targets, even in his rightvisual field, reflected impairments in arousal,reorienting, and the detection of novel and

behaviorally important stimuli. These nonspa-tial processes are directly damaged by strokeand other focal brain injuries in neglect pa-tients (in L.J. a ventral frontal stroke involvingthe anterior insula), and correspondingly, allinvolve in healthy adults right hemisphereventral regions that are commonly associatedwith neglect, including superior temporalcortex, TPJ, IPL, and VFC/insula. Thesenonspatial mechanisms directly interact withspatial attention mechanisms, providing a linkbetween damage to ventral regions and theabnormal physiology of dorsal regions. Dam-age to right hemisphere ventral regions, whichimpairs arousal, reorienting, and detection,hypoactivates the right hemisphere, reducinginteractions between the ventral and dorsalattention networks and between regions of theipsilesional (right) dorsal network. The resultis unbalanced interhemispheric physiologicalactivity in the dorsal network, both at rest andduring a task, in a direction that favors the lefthemisphere. As the locus of attention is codedby mechanisms that take into account activityfrom both sides of the brain, this imbalancedrives spatial attention and eye movements tothe right visual field (Figure 7a and 7b). Thisspatial bias explains L.J.’s tendency to look atand explore first the right visual field, and hisinability to detect stimuli in the left visual field.

The right hemisphere dominance of neglectfollows from the specific biases produced byright lateralized nonspatial mechanisms onthe direction of spatial attention, reflectingthe interhemispheric balance of activity inthe dorsal network. Right hemisphere lesionsmay also impair mechanisms that do notdirectly affect the interhemispheric balance ofactivity within the dorsal attention network,but increase the behavioral effects produced bythe extant stroke-induced imbalance. Full-fielddeficits in VSTM, trans-saccadic memory,and global perception may act in this fashion(Husain et al. 2001, Robertson & Rafal 2000).Finally, while physiological evidence that theright but not left hemisphere directs spatialattention to both visual fields has not been re-ported in the majority of studies, the predicted


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FEF

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a b

ArousalArousal

Figure 7Pathophysiology of spatial neglect. (a) In the healthy brain, activity during visual search is symmetric, and interhemispheric interactionsbetween left and right dorsal attention and visual occipital areas are balanced. Each side of the dorsal attention network directs shifts ofattention and eye movements contralaterally, and the locus of spatial attention is coded by a differencing mechanism that takes intoaccount activity from both hemispheres, as described in Figure 3d and by Sylvester et al. (2007). Balanced interhemispheric activityresults in a normal eye movement search pattern, shifts of attention, and coding of stimulus saliency. The ventral network is lateralizedto the right hemisphere due to a slight asymmetric (right > left) arousal input from the brainstem locus coeruleus/norepinephrine(LC/NE) system, and interacts with the dorsal network (right > left). Accordingly, decreases in arousal shifts spatial attentionrightward because of greater left than right activity in the dorsal attention network, while under normal conditions spatial attentionshows a slight leftward bias due to slightly greater right than left dorsal activity. (b) In a patient with a ventral stroke, direct damage ofventral regions causes a reduction of arousal, target detection, and reorienting that leads to a bilateral visual field impairment.Abnormal ventral-to-dorsal interactions cause an interhemispheric imbalance in the dorsal attention network and visual cortex, leadingto tonic and task-dependent rightward spatial biases in attention, eye movements, and stimulus salience.


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responses are sometimes observed (Sheremataet al. 2010), suggesting that hemisphericasymmetries in dorsal attentional mechanismsmay contribute to the laterality of neglecteven if they do not account for its ventralanatomy.

An important future goal is to identifythe basis of right hemisphere lateralization ofnonspatial mechanisms underlying reorient-ing, detection, and arousal. Several authors(Corbetta et al. 2008, Posner & Petersen1990) have argued that this lateralizationreflects asymmetries in cortical modulationfrom the locus coeruleus/norepinephrine(LC/NE) system (Robinson 1985). Lesions toright ventral cortex may damage mechanismsnormally receiving strong LC/NE inputs, suchas IPL (Morrison & Foote 1986), and causewidespread cortical hypoactivation.

Problems and Omissions

While we propose that the dorsal frontoparietalnetwork underlies control of overt and covertspatial orienting, unilateral lesions of IPS andSPL in humans are traditionally associated withoptic ataxia, i.e., difficulties in pointing ratherthan a general egocentric spatial bias. However,carefully placed lesions in monkey dorsal ar-eas (e.g., Lateral Intraparietal area) cause con-tralesional deficits in visual search and memory-guided saccades (Wardak et al. 2004). Similarly,recent lesion studies in humans involving care-ful psychophysical testing found that lesions

centered in SPL or in the white matter con-necting IPS/SPL to FEF (superior longitudinalfasciculus) cause deficits in goal-driven shifts ofattention (Shomstein et al. 2010) and abnor-mal capture by irrelevant distracters (Ptak &Schnider 2010, Shomstein et al. 2010), consis-tent with the proposed role of the dorsal atten-tion network in directing spatial attention andcoding of stimulus saliency.

The more important point, however, is thatdamage to dorsal regions alone is insufficientto produce the full neglect syndrome. We ar-gue that the full syndrome depends on a com-bination of bilateral hypoactivation but greateron the right, associated with damage to mech-anisms for reorienting, detection, and arousalin ventral frontoparietal regions and a resultingimbalance in the dorsal network, generating anegocentric spatial bias. The latter emphasis onthe dysfunction of dorsal frontoparietal cortexis necessarily provisional because it partly re-flects the lack of evidence that in the healthyhuman brain ventral regions control spatial at-tention and eye movements or contain topo-graphic maps.

An important topic that we have omitted ow-ing to space limitation concerns the role of sub-cortical nuclei in spatial neglect. Similarly, thecurrent review does not consider how visuospa-tial deficits interact with body representations,which may underlie some of the striking symp-toms shown by neglect patients, such as theirdenial of symptoms and confabulations aboutbody ownership (e.g., L.J.).

SUMMARY POINTS

1. The primary spatial impairment in neglect patients is a failure to attend to the contrale-sional side of space within a reference frame centered on the observer.

2. This spatial deficit is observed both at rest and during task performance.

3. The spatial deficit reflects tonic and task-evoked interhemispheric imbalances of activitywithin the dorsal attention network.

4. The dorsal attention network may be physiologically impaired across the wide variety ofright hemisphere ventral frontal and temporoparietal lesions that can produce neglect.


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5. The right hemisphere dominance of neglect primarily reflects the laterality of nonspatialmechanisms for reorienting, detection, and arousal in right ventral frontoparietal cortex,rather than the laterality of mechanisms for spatial attention within dorsal frontoparietalcortex.

6. The activation of nonspatial mechanisms directly biases spatial attention, correspondingto the interaction of ventral and dorsal frontoparietal regions.

7. Damage to right ventral frontoparietal cortex in neglect patients impairs nonspatial func-tions, hypoactivates the right hemisphere, and unbalances the activity of the dorsal at-tention network.

8. Ventral-dorsal interactions link the ventral lesions that cause neglect to the egocentricspatial bias that is the hallmark of the neglect syndrome.

FUTURE ISSUES

1. What are the anatomy and physiology of the interaction between dorsal and ventralnetworks? Are there critical frontal regions and fiber tracts that link the two networks?How is activity in the two networks synchronized?

2. Is the right hemisphere dominance of mechanisms for arousal, reorienting, and detectionrelated to asymmetries in the locus coeruleus/noradrenaline system?

3. Are interhemispheric imbalances in the attention-related activity of dorsal frontoparietalregions present across the wide variety of right hemisphere lesions that can cause neglect?

4. Do the ventral frontoparietal regions associated with neglect contain spatial maps thatare involved in controlling attention, either independently or in conjunction with thedorsal network?

5. Under what conditions does the dorsal attention network consistently show hemisphericasymmetries in visual field organization?

6. What nonspatial manipulations bias spatial attention to the right hemifield in healthyadults? Are saliency and eye movement deficits related to arousal deficits?

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

We acknowledge the help of many colleagues who generously made their data available for thisreview: Drs. Bays and Driver, University College London, for Figure 1a; Drs. Karnath andFruhmann-Berger, University of Tubingen, for Figure 1b; Drs. Medina, Pavlak, and Hillis,Johns Hopkins and University of Pennsylvania, for Figure 1c; Drs. Karnath, University of Tub-ingen, Verdon and Vuilleumier, University of Geneva, for Figure 2a; Dr. Karnath, Universityof Tubingen, and M. Glasser and K. Patel, Washington University in St. Louis, for Figure 2c;Drs. Sheremata and Somers, Boston University, for Figure 3c; Dr. Samuelsson, University of


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Goteborg, for Figure 5b; Drs. Malhotra and Husain, University College London, for Figure 5c.Drs. Jon Driver, David Somers, and Patrick Vuilleumier, as well as Dr. Michael Posner of Uni-versity of Oregon, and Dr. John Duncan of the MRC, Cambridge, also made useful suggestionsconcerning the manuscript. Finally, we thank Dr. Serguei Astafiev for help in preparing the figures.

This work was supported by the National Institute of Child Health and Human Development(NICHD) RO1 HD061117-05A2 and the National Institute of Mental Health (NIMH) RO1 MH71920-06.

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