INSERM U1028; CNRS UMR5292; Lyon Neuroscience Research Center, ImpAct Team, Lyon, F-69000, FranceUniversity Claude Bernard Lyon I, Lyon, F-69000, FranceDepartment of Neuroscience, Karolinska Institutet, S-17177, Sweden
r t i c l e i n f o
rticle history:eceived 17 October 2011eceived in revised form 12 March 2012ccepted 16 March 2012vailable online 28 March 2012
Neglect is a neurological syndrome characterised by a lack of conscious perception of events localised inthe contralesional side of space. Here, we consider the possible multisensory nature of this disorder, criti-cally reviewing the literature devoted to multisensory manifestations and processing in neglect. Althoughits most striking manifestations have been observed in the visual domain, a number of studies demon-strate that neglect can affect virtually any sensory modality, in particular touch and audition. Furthermore,a few recent studies have reported a correlation in severity between visual and non-visual neglect-relateddeficits evaluated in the same patients, providing some preliminary support for a multisensory con-ception of neglect. Sensory stimulation and sensorimotor adaptation techniques, aimed at alleviatingneglect, have also been shown to affect several sensory modalities, including some that were not directlyaffected by the intervention. Finally, in some cases neglect can bias multisensory interactions known tooccur in healthy individuals, leading to abnormal behaviour or uncovering multisensory compensationmechanisms. This evidence, together with neurophysiological and neuroimaging data revealing the mul-tisensory role played by the areas that are most commonly damaged in neglect patients, seems to speak
in favour of neglect as a multisensory disorder. However, since most previous studies were not conductedwith the specific purpose of systematically investigating the multisensory nature of neglect, we concludethat more research is needed to appropriately assess this question, and suggest some methodologicalguidelines that we hope will help clarify this issue. At present, the conception of neglect as a multisen-sory disorder remains a promising working hypothesis that may help define the pathophysiology of this syndrome.
presentation includes a lack of awareness of stimuli presented inthe patients’ contralesional hemispace (i.e. the left hemispace forpatients with right hemisphere lesions) and an absence of explo-rative behaviours and actions directed towards that side of space.Patients with neglect usually present a strong bias in favour of theirright, ipsilesional side, which may translate into striking impair-ments in everyday life behaviours, such as an abnormal rightward
shift in head and eye position, drawing or describing only theright part of a remembered or visually presented scene, or eatingonly from the right side of the plate (Driver & Vuilleumier, 2001).Neglect is widely recognised as a heterogeneous syndrome, whose
ifferent symptoms may be present or not, to various degrees, inifferent patients (Buxbaum et al., 2004; Halligan, Fink, Marshall,
Vallar, 2003; although see Karnath & Rorden, 2012). It may fornstance manifest itself only in personal space (Bisiach, Perani,allar, & Berti, 1986), or in the space within (Berti & Frassinetti,000; Halligan & Marshall, 1991) or beyond (Vuilleumier, Valenza,ayer, Reverdin, & Landis, 1998) reaching distance, or be restricted
o mentally represented or actually perceived scenes (Guariglia,adovani, Pantano, & Pizzamiglio, 1993; Palermo, Piccardi, Nori,iusberti, & Guariglia, 2009; Rode et al., 2010). Several core deficitsre, however, widely considered part of this protean disorder,ncluding a rightward deviation of the head and gaze, omissionsf left-sided items in spatial exploration and cancellation taskse.g. Gauthier, Dehaut, & Joanette, 1989), and a rightward biasn line bisection tasks (Schenkenberg, Bradford, & Ajax, 1980).xtinction is also commonly considered to be a component, if not
lthough see Karnath, Himmelbach, & Küker, 2003). In the casef extinction, the ipsilesional bias is evident only in conditions ofouble simultaneous stimulation (DSS), where two sensory eventsompete for processing resources (Driver, Mattingley, Rorden,
Davis, 1997; Duncan, 1996). In this situation, patients fail toeport the most contralesional stimulus, while they detect (almostormally) the same stimulus when delivered in isolation (Bender,952). In addition, non-spatially lateralised mechanisms, such as
mpaired sustained attention (Hjaltason, Tegnér, Tham, Levander, Ericson, 1996; Robertson et al., 1997) or spatial working memory
Malhotra, Mannan, Driver, & Husain, 2004), may also interact withpatial deficits and exacerbate their severity in neglect patientsBuxbaum et al., 2004; Husain & Rorden, 2003).
The most striking manifestations of neglect affect the visualomain, most probably because this sensory modality prevails souch in most human activities. However, it is now well known that
eglect can affect most – if not all – of the other senses, as well ashe motor domain (Brozzoli, Demattè, Pavani, Frassinetti, & Farnè,006). This observation leads naturally to the question of whethereglect should be conceived of as a multisensory disorder, causedrimarily by the disruption of multisensory mechanisms involved
n spatial representation and orienting of attention. Such a concep-ion could have profound theoretical and practical implications.n its extreme version, it would imply that neglect is necessarilylways present – with equivalent severity – across several, if not all,he sensory modalities. A milder version of this conception woulduggest that patients systematically show highly correlated deficitshen similar tasks are presented across different sensory modali-
ies. Both the extreme and mild versions of this idea have profoundmplications on both the theoretical level, by contributing to a bet-er definition of the pathophysiology of neglect, and the clinicalevel, ultimately advocating for the need of new multisensory testatteries. Answering the question of whether or not neglect is aultisensory disorder on the basis of previously published empiri-
al work is, however, extremely difficult (if not clearly impossible),s the aim of most previous studies was not to systematicallynvestigate this issue. The validity of a multisensory conception ofeglect, even in its milder version, which is easier to reconcile withossible counter-examples from the available literature and withhe clinicians’ experience, is therefore difficult to assess.
In this paper, we will nonetheless seek to critically review thexisting literature that might help address this question, point-ng out the (mostly methodological) reasons for which we think
definitive answer is premature, and those for which we believehe multisensory framework is worthy of consideration in theeglect domain. In the first sections, we will thus briefly outlinehe evidence supporting the existence of neglect in the different
ia 50 (2012) 1029– 1044
sensory modalities, and then review recent work investigating thepossible common impairment of several senses within the sameneglect patients. A third section will be dedicated to biased inter-actions between senses and multisensory compensation in neglectpatients. Finally, we will provide a brief overview of the neurophys-iological and brain-imaging literature showing the involvementof the inferior parietal cortex and the temporo-parietal junction,which are most commonly damaged in neglect patients, in mul-tisensory interactions and integration in the healthy brain. Weconclude by providing suggestions for future research aimed ataddressing this question more systematically.
2. Manifestations of neglect in different sensory modalities
Although often thought of as a primarily visual disorder, neglectmay affect other senses as well as motor behaviour. Here we presenta short overview of the deficits attributed to the neglect syndromein each sensory modality. For a more extensive review on this point,the reader may refer to a recent review by Brozzoli et al. (2006).
Visual manifestations of neglect are the most striking, and areevident in many daily-life activities: patients may act as if theleft half of their environment no longer existed, ignoring peopleand objects and running into obstacles located in their contrale-sional visual hemifield. Accordingly, cardinal tests used to diagnoseneglect all rely on visual tasks, whether it be visual search and can-cellation tasks, line bisection, or drawing. All of these tests reveala spatial bias in favour of the right, ipsilesional side in neglectpatients, even in the absence of primary sensory deficits such asvisual field defects. This last crucial point defines neglect as ahigher-order deficit of spatial cognition (DeRenzi, Faglioni, & Scotti,1970), which has been attributed to impaired spatial attentionand/or representation or to disturbed computation of spatial mapsin egocentric coordinates (Vallar, Rusconi, Bignamini, Geminiani, &Perani, 1994). Several visuospatial deficits have been documentedin neglect patients. As might be expected from the general pre-sentation of visual neglect, patients show deficits in the automaticorientation of their attention towards novel, left-sided stimuli, i.e.reduced exogenous attentional capacities (Bartolomeo & Chokron,2002; Làdavas, Carletti, & Gori, 1994), while voluntary, endoge-nous attentional orientation is preserved (Riddoch & Humphreys,1983). The resulting bias in favour of the ipsilesional hemifield isalso increased by an automatic capture of attention by ipsilesionalevents (Gainotti, D’Erme, & Bartolomeo, 1991; Mark, Kooistra, &Heilman, 1988) and by difficulties in disengaging attention fromits current focus in ipsilesional space (Posner, Walker, Friedrich, &Rafal, 1984). For example, if an ipsilesional distractor is presentedslightly before a contralesional target, patients show abnormallylong response times (Posner et al., 1984). Further, patients’ searchtimes for contralesional targets increase with the number of ipsile-sional distractors in a visual search task (Behrmann, Ebert, & Black,2004).
An important issue when characterising neglect-related phe-nomena is to disentangle them from purely primary sensorydeficits. Indeed, a failure to detect contralesional stimuli or anipsilesional orientation bias may be due to primary sensory loss,such as hemianopia or hemianaesthesia in the visual and tactilemodality, respectively, rather than to an attentional or spatial rep-resentational deficit. Several pieces of evidence support the ideathat low-level sensory processing of stimuli can nonetheless bepreserved in neglect patients. First, electrophysiological studiessuggest that neglect patients, contrary to patients with primary
sensory loss, still show sensory evoked potentials, although notcompletely normal (Angelelli, de Luca, & Spinelli, 1996), in responseto stimuli that were not consciously perceived (Vallar, Sandroni,Rusconi, & Barbieri, 1991; for discussion on this point, see Gainotti,
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e Luca, Figliozzi, & Doricchi, 2009). Similarly, extinguished con-ralesional visual stimuli have been shown to induce residualncreased activity in primary visual cortex (Driver, Vuilleumier,imer, & Rees, 2001; Rees et al., 2000). However, other studiesave shown that electrophysiological responses to extinguishednd detected stimuli differ, suggesting that the sensory pro-essing of extinguished contralesional stimuli is not completelyormal (see also Marzi, Girelli, Miniussi, Smania, & Maravita, 2000;arzi, Girelli, Natale, & Miniussi, 2001). Furthermore, consistentith the conception of neglect as a disorder of high level pro-
essing of sensory information, many aspects of pre-attentive,mplicit processing of perceptual information about neglectednd extinguished events may remain preserved and influenceatients’ performance on subsequent tasks (e.g. Berti et al., 1992;uilleumier, Schwartz, Clarke, Husain, & Driver, 2010; Vuilleumier,alenza, & Landis, 2001; for review, see Driver & Vuilleumier, 2001;iddoch, Rappaport, & Humphreys, 2009).
While neglect symptoms cannot be fully accounted for by pri-ary sensory loss, the concomitant presence of such deficits may
nfluence their severity. For example, Gainotti et al. (2009) showedhat hemianopia aggravates the rightward bias of automatic ori-ntation of attention commonly observed in neglect patients.he presence of ipsilesional distracters increased the tendency ofeglect patients without hemianopia to generate saccades towardshe right side of space especially for short stimulus duration.
hen stimuli were presented for a longer time, allowing volun-ary deployment of attention towards contralesional space, theseatients’ bias was reduced. By contrast, neglect patients with hemi-nopia showed a stronger bias that did not improve for longertimulus duration. The authors concluded that the rightward biasf automatic orienting of attention is specific to neglect, but thatt is worsened and prolonged over exploration time by primaryisual defects. Similarly, distortion in horizontal distance per-eption (Ferber & Karnath, 2001) and reproduction (Doricchi &ngelelli, 1999; Doricchi, Galati, DeLuca, Nico, & D’Olimpio, 2002),
hought to be a distinctive symptom of neglect, is in fact moreronounced in patients suffering from neglect and hemianopiahan in those showing neglect alone. These findings are in accor-ance with the notion that the clinical expression of neglect is
nfluenced by low-level sensory deficits, which would not inducettentional disorders in isolation. Importantly, the effect of thenteraction between neglect and hemianopia, which was obviousor horizontal space representation, was absent in patients’ per-ormance on cancellation tasks, suggesting that different neglectymptoms can be differentially affected by the co-occurrence ofrimary sensory deficits. In general, the fact that the expressionf neglect symptoms may be modulated by the co-occurrencef low-level sensory disorders should be borne in mind whenomparing the severity of neglect manifestations across sensoryodalities within the same patients; the fact that visual symptoms
f neglect may be more pronounced than non-visual ones, as isften the case, may well be explained (at least in some instances)y the presence of primary deficits in vision but not in the otherenses.
Given the classical definition of neglect, it is not surpris-ng that non-visual manifestations of neglect are less frequentlyocumented in the literature than visual ones. However, spatial ori-ntation deficits similar to those attributed to visual neglect haveeen described in other senses, especially in the tactile and audi-ory domains. There have also been occasional reports of extinctionn the olfactory (Bellas, Novelly, Eskenazi, & Wasserstein, 1988a,988b; Mesulam, 1981) and gustatory (Bender & Feldman, 1952)
odalities (for review, see Brozzoli et al., 2006). However, it is
nclear whether these findings truly reflected extinction, or if theyere the mere consequence of somatosensory deficits (Berlucchi,oro, Guerrini, & Aglioti, 2004; Kobal, Van Toller, & Hummel, 1989).
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We will therefore focus here on the study of tactile and auditorymanifestations of neglect.
In the tactile domain, outright omissions of contralesional stim-uli, akin to those observed in the visual domain, have rarelybeen documented. One likely reason for this is that it is easy toerroneously attribute such behaviour to primary somatosensorydeficits. In line with this idea, one study showed that some rightbrain damaged (RBD) patients with apparent hemianaesthesia (fail-ure to detect simple contralesional touches) had normal evokedpotentials in response to undetected stimuli, whereas no evokedresponses were observed in left brain damaged patients present-ing right-sided hemianaesthesia and no signs of neglect (Vallar,Sandroni, et al., 1991). Further, these symptoms can be temporarilyalleviated in some RBD patients by sensory stimulation techniquesknown to transiently relieve symptoms of visual neglect, such asvestibular stimulation (Vallar, Bottini, Rusconi, & Sterzi, 1993; seealso Rode et al., 1992). Finally, in a study investigating the effectsof postural manipulations on tactile extinction, Moro, Zampini, andAglioti (2004) reported the cases of two neglect patients who failedto detect even single tactile stimulations applied on their left handwhen it was located in the left hemispace. Placing their left hand inthe right hemispace, however, yielded a flawless detection of singletouches in these two patients, demonstrating that their apparentcontralesional hemianaesthesia was in fact due to spatial deficits.According to these observations, the prevalence of tactile neglectmay thus in fact be underestimated, mainly because its manifesta-tions are not as readily observable in everyday behaviour as thoseof visual neglect.
In addition to the rare demonstrations of the simplest man-ifestation of tactile neglect, several studies have reported thatvisual neglect patients show impaired performance on haptic tasksadapted from those classically used in the visual modality, such asspatial exploration tasks. In a seminal study, De Renzi et al. (1970)examined the performance of RBD patients with visual field defects,other patients, and a group of healthy controls on a haptic versionof a maze exploration task. Participants were asked to find mar-bles placed at the extremity of one of the lateral arms of the maze,occluded from sight, by exploring it with their ipsilesional hand.RBD patients with visual field defects performed worse than anyother group when the marble was placed in the left half of themaze, taking longer, or even often failing, to find it. This behaviourwas interpreted as a tactile manifestation of impaired supramodalspatial representation. Several subsequent studies using varioushaptic spatial exploration paradigms confirmed that neglect-likebehaviours can be observed in such tasks (Beschin, Cazzani, Cubelli,Della Sala, & Spinazzola, 1996; although see Villardita, 1987 for con-flicting findings). For instance, neglect patients show a rightwardbias when exploring the space around them without visual feed-back in order to find soft target objects among rough distractors(Haeske-dewick, Canavan, & Hömberg, 1996), or to identify as manyitems as possible (Schindler, Clavagnier, Karnath, Derex, & Perenin,2006). On the other hand, it should be noted that several studieshave reported that visual neglect patients did not produce the clas-sical rightward bias when asked to haptically bisect rods, withoutvisual feedback (Chokron et al., 2002; Fujii, Fukatsu, Kimura, Saso,& Kogure, 1991; Hjaltason, Caneman, & Tegnér, 1993). This dis-crepancy between the results of haptic spatial exploration and rodbisection tasks might be due to the fact that these tasks rely on dif-ferent mechanisms (Halligan & Marshall, 1998; Karnath & Rorden,2012). Regardless of this, the evidence provided by haptic spatialexploration tasks should be considered with caution when used tosupport the existence of neglect symptoms in the tactile modal-
ity. Indeed, these tasks involve more than the mere detection ofcontralesional stimuli, and the rightward bias observed in neglectpatients may be confounded by several factors. In particular, perfor-mance on such tasks is likely to be sensitive to motor impairments
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hich are known to affect the initiation and execution of move-ents towards contralesional space in neglect patients (directional
ypokinesia; Mattingley, Bradshaw, & Phillips, 1992). Furthermore,t seems reasonable to assume that haptic spatial exploration relieseavily on visual imagery, known to be affected in some neglectatients (Guariglia et al., 1993; Palermo et al., 2009; Rode et al.,010). The rightward bias observed in such conditions may thus behe indirect consequence of the deficit in the visual modality.
More convincing evidence in support of the existence of neglectymptoms in the tactile domain comes from the frequent descrip-ion of tactile extinction in RBD patients. Patients with tactilextinction fail to detect the most contralesional of two simultane-us touches. This phenomenon has been described for stimulationspplied to homologous or non-homologous body parts on each sidef the body (Bender, 1952; Farnè, Demattè, & Làdavas, 2005), as wells for stimulations delivered on the two sides of the same body partLàdavas, Farnè, Carletti, & Zeloni, 1994; Moscovitch & Behrmann,994; Tinazzi, Ferrari, Zampini, & Aglioti, 2000). Tactile information
s coded according to different spatial frames of reference, repre-enting spatial location of touch in terms of its location on bodyarts or body sides (Tamè, Farnè, & Pavani, 2011), or in egocentricr allocentric representations of space (e.g. Tinazzi et al., 2000; foreview, see Medina & Coslett, 2010; Vallar, 1997). Accordingly, bothactile neglect and extinction may be modulated by body posturend the spatial location of stimuli in body-centred coordinates (lefts. right hemispace), or by the relative location of simultaneoustimulations in the case of tactile extinction. Touches deliveredo the contralesional left hand may thus be better detected if theeft hand lies in the spared right hemispace (Aglioti, Smania, &eru, 1999; Bartolomeo, Perri, & Gainotti, 2004; Moro, Zampini, &glioti, 2004; Mort et al., 2003; Smania & Aglioti, 1995). By contrast,timulations applied on the right hand may go undetected whenhe ipsilesional right hand is placed in the affected left hemispacend a simultaneous stimulation is delivered in the right hemispaceBartolomeo et al., 2004; Valenza, Seghier, Schwartz, Lazeyras, &uilleumier, 2004). Finally, some findings suggest that residual
mplicit processing of extinguished contralesional tactile events isreserved in some RBD patients with neglect and tactile extinction,onfirming that tactile deficits in neglect and extinction occur at aigh level of integration (Berti et al., 1999; Maravita, 1997).
In the auditory domain, RBD patients may also present signs ofpatial deficits, affecting either the localisation or the detection anddentification of sounds (for a detailed review, see Pavani, Husain,ádavas, & Driver, 2004). The first evidence for impairment in theerception of sound localisation in neglect patients was demon-trated by the presence of a systematic rightward bias in pointingesponses towards the perceived location of auditory stimuliBisiach, Cornacchia, Sterzi, & Vallar, 1984; Làdavas & Pavani, 1998;avani, Farnè, & Làdavas, 2005). In their seminal study, Bisiach et al.1984) attributed this deficit to a distortion of spatial representa-ion. However, such a bias in pointing responses may also be at leastn part explained by several non-auditory deficits documented ineglect patients (Pavani et al., 2004), such as impairment of move-ents directed towards the contralesional hemispace (Mattingley
t al., 1992), exacerbated influence of proprioceptive informationelative to the starting hand position (Làdavas & Pavani, 1998;avani, Farnè, et al., 2005), and automatic capture of attentiony ipsilesional visual stimuli (Gainotti, 2010; Pavani, Farnè, et al.,005; Soroker, Calamaro, Glicksohn, & Myslobodsky, 1997). Moreecent studies have, however, described disturbances in auditorypatial perception arising from an increased uncertainty regardingound localisation, rather than from an ipsilesional bias in spatial
epresentation. In these experiments, neglect patients had specificifficulties in judging whether pairs of consecutive auditory stim-li originated from the same or different spatial locations alonghe horizontal (Pavani, Meneghello, & Làdavas, 2001) or vertical
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(Pavani, Làdavas, & Driver, 2002, 2005) dimension. In addition todeficits in sound localisation, some neglect patients also exhibit arightward shift of the subjective auditory midline in tasks requir-ing them to indicate when sounds are perceived to be aligned withtheir mid-sagittal plane (Bisiach et al., 1984; Kerkhoff, Artinger, &Ziegler, 1999; Tanaka, Hachisuka, & Ogata, 1999; Vallar, Guariglia,Nico, & Bisiach, 1995). This type of impairment likely involves dif-ferent mechanisms from those of the rightward bias in pointingresponses to localise sounds, as suggested by their possible dou-ble dissociation (Bellmann, Meuli, & Clarke, 2001). This rightwarddeviation of the subjective auditory midline has been interpretedin terms of translation or rotation of an egocentric spatial frame ofreference (Bisiach et al., 1984; Kerkhoff, 1999; Tanaka et al., 1999;Vallar, Guariglia, Magnotti, & Pizzamiglio, 1995), a disorder that hasalso been proposed to explain similar phenomena in the visual (e.g.Karnath, 1997) and tactile (Karnath & Perenin, 1998) domains, andis considered by some authors as a core deficit in neglect (Karnath,1997; Ventre, Flandrin, & Jeannerod, 1984; although see Chokron& Bartolomeo, 1997; Farnè, Ponti, & Làdavas, 1998). Finally, evi-dence for an ipsilesional bias in auditory spatial localisation comesfrom a recent study by Eramudugolla and Mattingley (2008) whoreported a spatial bias in favour of ipsilesional space in a neglectpatient performing an auditory spatial search task in which the tar-get was a frequency-modulated tone amongst steady, non-spatiallyseparated, distractor tones.
While impaired detection of single sounds is rare in neglectpatients, unlike what is commonly seen in the visual modal-ity, auditory events may more often go undetected in situationsof simultaneous stimulations. Indeed, when neglect patients arepresented with at least two auditory stimuli, either in free-field(Deouell & Soroker, 2000; Soroker et al., 1997) or through head-phones (Bellmann et al., 2001; De Renzi, Gentilini, & Barbieri, 1989;Jacquin-Courtois et al., 2010; Spierer, Meuli, & Clarke, 2007), theyoften consistently fail to detect the contralesional stimulus. Therehas been some debate as to whether these impairments reflectgenuine spatial attention deficits, or mere perceptive extinction ofinformation entering the contralesional ear (Beaton & McCarthy,1995; Hugdahl & Wester, 1994; Hugdahl, Wester, & Asbjørnsen,1991). Recent evidence suggests that auditory detection and identi-fication deficits in neglect patients may in fact be due to spatial andattentional factors (Carlyon, Cusack, Foxton, & Robertson, 2001).For example, some neglect patients have impaired performancewhen asked to report the contralesional item of word pairs pre-sented diotically, i.e. binaurally with an inter-aural time differenceallowing for the lateralisation of one word to the ipsilesional andthe other to the contralesional side of space, but not when thesame stimuli were presented dichotically, i.e. each word to oneear only (Bellmann et al., 2001; Spierer et al., 2007). Further, ithas been reported that the presence of a fictitious source of soundin the ipsilesional visual hemifield improved the identification ofphonemes presented from the left side of space (Calamaro, Soroker,& Myslobodsky, 1995; Soroker, Calamaro, & Myslobodsky, 1995).This phenomenon was attributed to the so-called ventriloquisteffect, whereby the perceived location of an auditory stimulusdelivered simultaneously with a spatially incongruent visual stim-ulus is shifted towards the location the visual event. Indeed, onoccasions where this phenomenon occurred, patients reported per-ceiving the sound as coming from the right.
In view of the evidence reviewed so far it appears that in additionto vision, neglect can also affect the tactile and auditory modalities,although caution should be used when considering evidence fromcertain tasks, in particular those involving haptically-guided spatial
search or pointing responses to localise sounds. Other work sug-gests that neglect may also manifest in the chemical senses as wellas in the motor domain (e.g. Mattingley et al., 1992), and in theperception of thermal pain (Liu et al., 2011). These observations
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aturally raise the question of the multisensory nature of theeglect syndrome. If similar deficits observed in different sensoryodalities are indeed caused by a disruption of common processes,
hen manifestations of neglect in different senses should co-occurithin the same patients.
. Manifestations of neglect in multiple sensory modalities
High-order representation of space for guiding behaviour ischieved by the combination of perceptual information from sev-ral senses (Andersen, Snyder, Bradley, & Xing, 1997; Duhamel,olby, & Goldberg, 1998; Farnè, Brozzoli, Làdavas, & Ro, 2007; Farnèt al., 2005; Graziano & Gross, 1993, 1998; Jacobs, Brozzoli, Hadj-ouziane, Meunier, & Farnè, 2011; Rizzolatti, Fadiga, Fogassi, &allese, 1997). Despite the fact that its manifestations in the visualomain have attracted most of the attention of researchers and clin-
cians, neglect has long been considered a disorder of higher levelsf spatial representation and attention (Bisiach, Capitani, Luzzatti,
Perani, 1981). Accordingly, the first investigations of non-visualeglect-related deficits (Bisiach et al., 1984; De Renzi et al., 1970)ere prompted by the hypothesis that, if neglect is a higher-orderisorder of spatial cognition, it should be observable in non-visualpatial orientation tasks. These initial studies, as well as subsequenttudies on the topic, have thus documented the co-occurrencef visual and non-visual (i.e. tactile or auditory) neglect-relatedeficits, by comparing the performance of RBD patients with visualeglect to that of RBD patients without visual neglect and/or leftrain-damaged (LBD) patients and neurologically intact controls.verall, as detailed in the previous section, visual neglect patientsonsistently perform worse than any group of control patientsexcept in the case of haptic bisection of rods), and show an ipsile-ional bias reminiscent of the one classically observed in the visualodality, although dissociations between modalities have been
eported in rare individual cases (e.g. Beschin et al., 1996; Haeske-ewick et al., 1996; Hillis et al., 2006; Olson, Stark, & Chatterjee,003; Pavani, Ládavas, & Driver, 2003; Renzi, Gentilini, & Pattacini,984; Vallar et al., 1994; Vallar, Rusconi, Geminiani, Berti, & Cappa,991). In addition, neglect patients exhibit difficulties in localis-
ng contralesional sounds due to an uncertainty for sound positionlong the horizontal and vertical dimension (Pavani, Farnè, et al.,005; Pavani et al., 2002, 2001).
Although the association of tactile and visual deficits in neglectatients points to possible common underlying mechanisms, allhe above-mentioned studies compared groups of patients thatere constituted on the basis of cut-off scores on standard clinical
ests, which may create an artificially abrupt dichotomy betweeneglect and non-neglect patients. As Pavani et al. (2004) argued, thisight not be the most sensitive method to study the relationship
etween neglect-related deficits in different sensory modalities.nstead, correlation analyses between more continuous measuresf such deficits are probably better suited to this aim. Accord-ngly, a few authors have recently investigated the correlationetween the degree of impairment attributed to neglect in theifferent senses. Schindler et al. (2006) thus analysed the corre-
ation between performance on a visual and a haptic version of apatial search task. In line with previous reports, neglect patientsxhibited an ipsilesional bias for both visual and haptic search,hereas control RBD patients performed similarly to healthy con-
rol subjects. Crucially, the bias observed in the haptic version ofhe task, although less pronounced, was linearly correlated withhat in the visual modality. Schindler et al. proposed that their
ndings reflected damage either to a multimodal system, or to sep-rate modality-specific systems, coding the representation of spacen body-centred coordinates (Karnath, 1997; Vallar, 1998; Ventret al., 1984). However, as underlined previously, results from haptic
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spatial search tasks need to be considered with care, as their inter-pretation in terms of pure tactile manifestations of neglect is notunambiguous.
The relationship between neglect-related visual and hapticimpairments in the perception of spatial axes in the frontal andsagittal planes has also been explored. In addition to impairmentsin spatial orienting in the horizontal plane (classically described inthe literature), neglect patients have also long been known to showdisturbed perception of spatial axes in the frontal plane (Renzi,Faglioni, & Scotti, 1971; Vallar, Guariglia, Magnotti, et al., 1995).Perturbed spatial orientation judgments in neglect are thought toreflect impaired processing of gravitational input (Kerkhoff, 1999),due to damage to multisensory vestibular cortex which is fre-quently affected by lesions causing neglect (Karnath & Dieterich,2006). Kerkhoff and Zoelch (1998) systematically investigated thisaspect of visuospatial deficits in neglect and non-neglect patientsby asking them to align a luminous line with their subjective visualvertical and horizontal, and with an obliquely oriented referenceline. Only neglect patients performed poorly on this task, show-ing a consistent tilt of the perceived orientations away from theside of their lesion (i.e. clockwise and counter-clockwise tilt for LBDand RBD neglect patients, respectively). The link between neglectand impairment in visuospatial perception in the frontal planewas further confirmed by the strong correlation found betweena composite score of neglect severity and the amplitude of the tiltobserved in individual patients. Subsequent studies led by Kerkhoffet al. (Funk, Finke, Müller, Preger, & Kerkhoff, 2010; Funk, Finke,Müller, Utz, & Kerkhoff, 2010; Kerkhoff, 1999; Utz et al., 2011)demonstrated that neglect patients exhibit similar deficits whenperforming a haptic version of this task. A similar contraversive tiltwas observed when neglect patients had to align a bar, withoutthe aid of vision, with either the subjective vertical or horizontal,or with an obliquely oriented reference bar. In both modalities,neglect patients showed not only large constant errors, but alsoa high instability in their judgments, suggesting not only distor-tion, but also uncertainty in their representation of spatial axes inthe frontal plane (see also Pavani et al., 2002 for a similar obser-vation for sound localisation in contralesional space). According tothe authors, the interpretation of these results as a manifestationof a multimodal deficit is supported by two observations. First, tiltsobserved in the haptic version of the task were correlated withthose in the visual modality. Second, in two patients they observedthat a crossmodal version of the task, in which the orientation ofa visual stimulus had to be reproduced in the tactile domain, orvice-versa, also led to contraversive tilts of the three spatial axes inboth modalities, and was more pronounced in the visual-to-tactilecondition. Kerkhoff (1999) concluded that a common mechanism,i.e. a disturbed representation of gravity, was involved in bothtasks, but that this mechanism was not necessarily multisensorybecause visual and haptic tilts were similar in direction, but notin magnitude. Finally, Utz et al. (2011) recently reported a simi-lar deficit in neglect patients for the perception of the subjectivehaptic and visual vertical in the mid-sagittal plane, with constanterrors directed backwards. Again, the haptic backward tilt was pro-portional to that observed in the visual modality, and both werecorrelated with the deficits observed in the frontal plane, sug-gesting a common deficit affecting different sensory modalitiesand different spatial reference planes. However, the importanceof these findings for the investigation of tactile neglect should benuanced, for the same reasons discussed previously regarding hap-tic spatial search tasks. Indeed, even if the impact of contraslesionalhypokinesia is less critical in this case, haptic spatial orientation
judgment tasks could involve visual imagery, making it difficult toexplain haptic biases in terms of purely tactile deficits.
Correlational analyses of neglect-related visual and auditorydeficits provide more conclusive results. In a meta-analysis of their
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wn data Pavani et al. (2004, 2003) examined the relationshipetween the severity of visual neglect on standard cancellation and
ine bisection tests, and that of auditory deficits quantified on tasksuch as pointing to sounds, judging the spatial location of soundslong the horizontal or vertical dimension, and identifying wordsnder conditions of bilateral dichotic or diotic presentation. Despitehe fact that standard visual tests are probably much less sensitiveor detecting neglect than the complex auditory tasks used in thesetudies, performance on visual tests correlated significantly withuditory measures in most of the possible within-subject combi-ations of visual and auditory tasks. In fact, correlations betweenuditory measures and visual cancellation tasks were all signifi-ant (or approached significance for 2/14 comparisons, p < 0.08),nd the only two comparisons that failed to at least approach sig-ificance (p = 0.2) concerned line bisection tasks which are thoughto depend on different mechanisms (Fink et al., 2000; Halligan &
arshall, 1998). Pavani et al. (2004) therefore interpreted theseorrelations as strong support in favour of the existence of a mul-isensory disorder of spatial representation in neglect patients.
More recently, a few studies have sought to more system-tically explore the relationship between visual and auditoryeficits in neglect patients by using tasks in both modalitieshat were matched in terms of task demands and responseBarrett, Edmondson-Jones, & Hall, 2010; Eramudugolla, Irvine,
Mattingley, 2007; Sinnett, Juncadella, Rafal, Azanón, & Soto-araco, 2007). Eramudugolla et al. (2007) used a visual and anuditory extinction task in a sample of RBD patients, some of whomresented some signs of neglect. They observed no systematic asso-iation between visual and auditory extinction. In addition, theysed a visual and an auditory temporal order judgment (TOJ) task,here patients had to report which of the two stimuli presented
ilaterally occurred first. TOJ tasks are sometimes used to inves-igate spatial attention in neglect patients because, in addition tohe widely recognised spatial nature of their deficits, patients havelso been shown to exhibit difficulties in the temporal process-ng of contralesional stimuli (Husain, Shapiro, Martin, & Kennard,997; di Pellegrino, Basso, & Frassinetti, 1997; Rorden, Mattingley,arnath, & Driver, 1997). In particular, in the contralesional visualemifield neglect patients present with an abnormally long atten-ional dwell-time (i.e., the period during which the perception of
first attended stimulus interferes with that of a subsequent one),hich might contribute to their competitive bias in favour of ipsile-
ional stimuli in cases of sensory competition (Pellegrino, Basso, &rassinetti, 1998). In their visual and auditory version of the TOJaradigm, Eramudugolla et al. (2007) found a significant correla-ion between the severity of visual and auditory deficits. In sharpontrast, Sinnett et al. (2007) did not find any correlation betweenisual and auditory performance in their neglect patients. Theysed a TOJ paradigm similar to that used by Eramudugolla et al., but
n which auditory stimuli were presented in virtual auditory space,ather than under conditions of dichotic stimulation. Finally, Barrettt al. (2010) tested two neglect patients on visual and auditoryxtinction and TOJ tasks, using spatially and temporally matchedtimuli in both modalities. The first patient exhibited similar visualnd auditory extinction, was impaired for visual TOJ, but performedormally on auditory TOJ. The second patient, by contrast, showedo extinction, and was impaired for both visual and auditory TOJ.hese authors concluded that visual and auditory deficits may bessociated in neglect patients, but are not necessarily linked, andhat their manifestation may also depend on task demands. Furthertudies will be necessary to solve the issues raised by these dis-repant findings, in particular performance on visual and auditory
OJ tasks. The nature of auditory stimuli (e.g. noise vs. environ-ental sounds vs. verbal stimuli) might play an important role
n patients’ performance on these tasks and may explain somef the divergences reported above (see Eramudugolla et al., 2007
ia 50 (2012) 1029– 1044
for further discussion on this point). It should also be noted thatthese studies investigated the potential association between visualand auditory deficits on tasks that evaluate different aspects ofthe neglect syndrome from those reported by Pavani et al. in theirmeta-analysis (2004), which concerned almost exclusively visualcancellation and auditory spatial localisation tasks. There is someevidence suggesting that these different aspects of the syndromeinvolve separate mechanisms, and may even rely on different brainstructures (e.g. Karnath & Rorden, 2012). Furthermore, it is possi-ble that the association of deficits in different sensory modalitiesdepends on task demands, such as temporal perception and spatialorientation (see Barrett et al., 2010), whereby the greater the con-tribution of spatial information for resolving the task, the strongerthe association of deficits across senses.
Beyond the frequent co-occurrence and correlation in sever-ity of neglect symptoms in different sensory modalities, anotherargument in favour of the conception of neglect as a multisensorydisorder comes from bottom-up approaches to its rehabilitation.Indeed, sensory stimulation techniques, applied in the affectedhemifield, have been shown to improve performance beyond thesensory modality directly targeted by the intervention (Kerkhoff,2003). The rationale for these approaches is to activate the weak-ened representation of the contralesional hemispace in order torestore the balance between representations of both hemispaces.Since neglect affects spatial representations built on informationfrom multiple sensory channels, stimulation techniques have beenused to modulate sensory inputs in various modalities. While mostof the studies involving these methods have focused on the mod-ulation of visual symptoms of neglect, there is a growing bodyof evidence supporting the notion that manipulation of a givensensory input channel may improve performance in other sen-sory modalities. For example, caloric stimulation, which modulatesthe activity of the vestibular system, not only transiently relievesvisual symptoms of neglect (Rubens, 1985), but can also improvethe detection of contralesional tactile stimuli in RBD patients withapparent hemianaesthesia (Vallar et al., 1993; see also Rode et al.,1992). More recently, it was shown that galvanic vestibular stimu-lation durably improved tactile extinction in two patients (Kerkhoffet al., 2011). Another approach consists of activating contrale-sional space representation by proprioceptive input generated bymovements of the left limbs. Robertson and North (1992, 1993)showed that active left finger or leg movements in the left hemis-pace reduced the ipsilesional bias normally present during a visualletter cancellation task performed with the right hand. Left fin-ger movements in the right hemispace, or right finger movementsin either hemispace, had no effect. The effect was still observedif the left hand was occluded from sight, suggesting that propri-oceptive information was the critical factor. Furthermore, theseauthors suggested that movements had to be active to reducethe spatial bias, as they did not find any effect related to pas-sive left finger movements. However, Làdavas et al. later showedthat passive movements of the left upper limb are in fact suffi-cient to improve performance, provided that the task itself does notinvolve complex movements of the right upper limb (which wouldrecruit more mechanical receptors) (Frassinetti, Rossi, & Làdavas,2001; Làdavas, Berti, Ruozzi, & Barboni, 1997). Finally, prismaticadaptation, whereby patients adapt to the rightward optical devi-ation induced by prismatic lenses during manual pointing, affectsmost visual aspects of the neglect syndrome (Rossetti et al., 1998;review in Pisella, Rode, Farnè, Tilikete, & Rossetti, 2006; Rode, Klos,Courtois-Jacquin, Rossetti, & Pisella, 2006). Recent studies havedemonstrated that prismatic adaptation may also improve non-
visual components of neglect, such as postural (Tilikete et al., 2001)and haptic exploration deficits (McIntosh, Rossetti, & Milner, 2002),tactile extinction (Maravita et al., 2003), or auditory extinction dur-ing a dichotic listening test (Jacquin-Courtois et al., 2010).
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To summarise, the findings of the relatively small number oftudies devoted to the investigation of the association betweenon-visual (i.e. tactile or auditory) and visual neglect-relatedeficits tend to show that neglect manifests itself in several senses
n most patients. However, the significance of the ipsilesional biasn haptic spatial tasks needs to be disambiguated. The design ofetter experimental paradigms, devoid of potential confounds,
s necessary to further investigate spatial deficits in the tactileodality. Nonetheless, the available evidence suggests that within
given patient there is a correlation between the severity of neglectymptoms in different senses, although deficits are often moreronounced in the visual domain (e.g. Bisiach et al., 1984; Kerkhoff,999; Schindler et al., 2006; for detailed discussion, see Gainotti,010). Of interest with respect to the question of the multisensoryature of neglect is the fact that, in addition to affecting severalensory modalities, it also alters multisensory interactions. Indeed,mbalance in the representation of contralesional and ipsilesionalemispaces may bias crossmodal interactions known to occur
n neurologically intact individuals, resulting in abnormal (i.e.xacerbated or attenuated) modulation of one sensory modalityy another. The following section provides an overview of the
iterature dedicated to such effects in neglect patients.
. Neglect and multisensory interactions
One of the most obvious consequences of neglect on multisen-ory interactions is crossmodal extinction. Patients with extinctionay detect a single contralesional sensory event, but fail to do
o when it is presented simultaneously with an ipsilesional com-etitive stimulus (Bender, 1952). It is now well established thatuch a phenomenon can arise for two stimuli delivered withinhe same modality, but also between stimuli in different sensory
odalities (for review see Brozzoli et al., 2006; Farnè et al., 2007;acobs et al., 2011). For example, a patient may be able to detect
tactile stimulus applied on his contralesional, left hand, but mayiss the same stimulus if a visual stimulus is delivered simultane-
usly near his right hand (Mattingley, Driver, Beschin, & Robertson,997; di Pellegrino, Làdavas, & Farnè, 1997). Interestingly, visuotac-ile extinction is much weaker if the visual stimulus is applied inhe ipsilesional hemispace, but far from the hand, suggesting thatisuotactile interactions are strongest in the space immediatelyurrounding the body and thus occur at a high level of integrationf multisensory information. This was confirmed by di Pellegrino,àdavas, et al. (1997), who showed that when the ipsilesional visualtimulus was presented at the location where it previously inducedxtinction of a contralesional tactile stimulus, but with patientsolding their ipsilesional hand behind their back instead of closeo the visual stimulus, no extinction was observed. This findinguled out possible confounds linked to differences in retinotopic oreneral egocentric (i.e. trunk- or head-centred) localisation of theisual stimulus (see also Farnè, Demattè, & Làdavas, 2003). Similarbservations have been made for stimuli applied in the space sur-ounding the face (Làdavas, Zeloni, & Farnè, 1998). In this study, aisual stimulus applied near the right side of the face extinguished
tactile stimulation delivered on the left cheek. Again, visuotactilextinction was strongest for ipsilesional visual stimuli applied near,ather than far from, the body. These findings suggest that the spaceurrounding the body is not unitary, but rather consists of severalodules centred on different body parts. This was confirmed by
he demonstration that visuotactile extinction is strongest whenilateral concurrent stimuli are delivered to homologous, rather
han to non-homologous, body parts (Farnè et al., 2005). Similarnteractions have subsequently been described between tactile anduditory stimuli (Farnè & Làdavas, 2002; Làdavas, Pavani, & Farnè,001). Detection of single touches applied on the contralesional
ia 50 (2012) 1029– 1044 1035
side of the neck was prevented by ipsilesional white noise stim-uli delivered near the head. In line with what has been describedfor visuotactile interactions, audiotactile extinction was dramati-cally reduced when the auditory stimulus was delivered far fromthe head. Interestingly, audiotactile interactions showed anotherlevel of spatial selectivity: extinction of a contralesional tactilestimulus was strongest when the ipsilesional noise came from theback, rather than from the front, of the head. This suggests thatthe strength of multisensory interactions may depend on the func-tional relevance of a given sensory modality for a particular sectorof space (Farnè & Làdavas, 2002).
Multisensory extinction phenomena have been interpreted inthe context of an influential theoretical framework in which neglectis considered to be the consequence of a biased competitionbetween the representation of (or the ability to direct atten-tion towards) left and right hemispaces (Corbetta, Kincade, Lewis,Snyder, & Sapir, 2005; Duncan, 1996; Kinsbourne, 1987, 1993). Themultisensory representation of contralesional space is thus thoughtto be weak when compared with that of ipsilesional space, and thisimbalance leads to neglect or extinction of events occurring in con-tralesional space. Support for this interpretation comes from theobservation that a visual stimulus may improve performance if itis applied near the contralesional body part during simultaneousbilateral tactile stimulation (Làdavas, di Pellegrino, Farnè, & Zeloni,1998; Làdavas, Zeloni, et al., 1998). In this case, the visual stimulusenhances the activation of the weaker visuotactile representationof the space centred on the left body part, thereby allowing thedetection of a left tactile stimulus even when a concurrent stimulusis delivered to the right body part. Such multisensory competitiveinteractions can be further modulated by sensory input comingfrom other senses. For example, Kennett, Rorden, Husain, andDriver (2010) recently demonstrated that some postural manip-ulations may modulate visuotactile extinction. Their patient wastested for visual, tactile and visuotactile extinction in two differ-ent postures, (1) looking straight ahead at a fixation point betweenthe hands, or (2) with the head and eyes deviated 20◦ to the left.Her hands were occluded from sight. Visual stimuli were alwaysapplied at a constant retinotopic position (10◦ of eccentricity fromthe fixation point) and were therefore in register with the positionof the unseen hands in the straight-ahead condition, while in thedeviated condition, the right visual stimulus was delivered near theunseen left hand. Visual and tactile extinction were not affected bythe postural manipulation. By contrast, visuotactile extinction wasdramatically reduced in the deviated posture, when the left tactileand the right visual stimuli were delivered to the same spatial loca-tion. These results suggest that visuotactile interactions occurredin multisensory space centred on the unseen hands, reconstructedfrom proprioceptive information about the head/gaze posture.
By altering spatial representations based on visual, tactile, audi-tory and gravitational inputs, neglect may also induce pathologicalsensory interactions by conferring undue weight to more reliablesensory sources, such as proprioception. Such an effect has beendescribed in spatial orientation judgment tasks, in which neglectpatients show a systematic contraversive tilt of the subjective hor-izontal and vertical axes in the frontal plane, both in the visualand tactile modalities (Funk, Finke, Müller, Preger, et al., 2010;Kerkhoff, 1999; Utz et al., 2011). In a recent paper, Funk, Finke,Müller, Utz, et al. (2010) showed that manipulation of head posturemodulates performance in a similar manner in a visual and tactileversion of the task. While patients exhibited the usual counter-clockwise tilt in subjective orientations with their head upright, apassive rotation of the head in the same direction worsened the
contraversive tilt, whereas head rotation in the opposite direc-tion (clockwise) improved performance and nearly normalised it.Spatial orientation perception thus appears to rely on a mix of grav-itational and somatosensory (head and trunk position) information.
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unk et al. proposed that since neglect patients have impaired pro-essing of gravitational inputs (e.g. Pizzamiglio, Vallar, & Doricchi,995), they tend to rely more on proprioceptive information aboutead and trunk posture. As a consequence, their subjective ver-ical and horizontal axes are attracted towards their idiotropicector, formed by the body-and-head vertical axis, more so thann healthy individuals or non-neglect patients. Another examplef possible abnormal weight attributed to proprioceptive informa-ion in neglect patients comes from studies of pointing responses tonseen auditory targets, where the starting position of the ipsile-ional hand used to point was manipulated (Làdavas & Pavani,998; Pavani, Farnè, et al., 2005). Patients exhibited a systematicightward error when pointing to auditory targets presented inhe contralesional hemispace, and to a lesser degree when targetsere presented at fixation. Importantly, this rightward bias was
xacerbated when the initial position of the ipsilesional hand waso the right of the body midline, and reduced when it was in theeft hemispace. Healthy individuals have been reported to show
similar systematic effect of the initial position of the respondingand when pointing to remembered visual targets, although point-
ng responses remained accurate (Desmurget, Pélisson, Rossetti, Prablanc, 1998). Pavani, Farnè, et al. (2005) proposed that theffect of initial hand posture observed in neglect patients might be
pathological exacerbation of that existing in healthy individuals.eglect patients might rely more on proprioceptive informationbout the initial hand position for movement planning, due toathologically unstable auditory spatial representation and uncer-ainty in contralesional sound localisation (Pavani et al., 2002,001). An alternative interpretation, also interesting with respecto the impact of neglect on multisensory processing, would behat neglect patients are impaired for the complex multisensoryoordinate-transformations between different reference frameshat are necessary for planning hand pointing movements towardsuditory targets and are supported by the posterior parietal cortexe.g. Cohen & Andersen, 2002).
In contrast to the evidence reviewed so far in this section,ultisensory interactions biased by a weak representation of con-
ralesional events in neglect are not always deleterious, and mayn fact benefit patients’ performance. Multisensory stimulation,y taking advantage of sensory integration systems involved inpace representation (Farnè et al., 2007), might in fact be a promis-ng approach for the rehabilitation of neglect (Brozzoli et al.,006). Indeed, as the work by Làdavas and colleagues (Làdavas, diellegrino, et al., 1998; Làdavas, Zeloni, et al., 1998) on visuotactilextinction suggests, neglect patients may detect bimodal stimulietter than their unimodal components alone. In these studies, aisual stimulus presented near the contralesional hand or cheekmproved the detection of tactile stimuli applied to the same bodyart during tactile DSS. Recent work by Frassinetti and colleaguesurther addressed the question of the benefit of stimulus multi-
odality on neglect patients’ performance using an audiovisualaradigm (Frassinetti, Bolognini, Bottari, Bonora, & Làdavas, 2005;rassinetti, Pavani, & Làdavas, 2002). Neglect patients were bettert detecting contralesional flashes of light when they were accom-anied by a concurrent sound, but only if that sound was spatiallyoincident with the visual stimulus, or if it originated from a neigh-ouring location (at less than 16◦). In addition, this multisensoryain was inversely correlated with the detection of the correspond-ng single visual events, that is, the poorer the performance oningle stimuli, the greater the benefit from the congruent audi-ory stimulation. The multisensory enhancement effect observedere thus obeys two of the fundamental functional rules described
or multisensory neurons in the superior colliculus, namely thepatial rule, and the inverse effectiveness rule (Stein & Arigbede,972; for review, see Stein & Meredith, 1993). This observation
ed Frassinetti et al. to propose that such an effect was likely due
ia 50 (2012) 1029– 1044
to multisensory integration in this midbrain structure, which isspared by the lesions causing neglect. This interpretation was fur-ther supported by the demonstration that audiovisual integrationis subserved by the superior colliculus in humans. Indeed, whenspatial orientation is required by the task, audiovisual integrationoccurs only if visual stimuli are visible to the superior colliculus,i.e. not with purple stimuli (Leo, Bertini, di Pellegrino, & Làdavas,2008; Maravita, Bolognini, Bricolo, Marzi, & Savazzi, 2008).
Audiovisual enhancement has also been described in neglectpatients in the context of pointing responses to auditory stimuli(Passamonti, Frissen, & Làdavas, 2009). Patients were asked to pointto unimodal auditory stimuli before and after a period of adaptationto spatially congruent pairs of visual and auditory events. Presen-tation of spatially congruent visual stimuli is known to improveonline spatial localisation of sounds (Leo, Bolognini, Passamonti,Stein, & Làdavas, 2008; Stein, Huneycutt, & Meredith, 1988). In thisstudy, Passamonti and colleagues demonstrated that after-effectsdevelop after passive exposure to congruent audiovisual stimuli,as shown by an increased accuracy in auditory localisation afterthe adaptation period. Crucially, these after-effects, interpretedas a recalibration of the auditory space by visual stimulations,were observed not only when stimuli were delivered in the intacthemifield, but also when visual stimuli were delivered in the con-tralesional hemispace and were not consciously perceived. Thiseffect was observed mainly for the spatial locations trained duringthe adaptation period. The authors proposed that such cross-modalrecalibration might occur at the level of the inferior colliculus,where topographical maps of the auditory space are built and canbe recalibrated by visual information.
Another form of audiovisual interaction, known as the ven-triloquism effect, is also preserved in neglect patients and mightimprove performance in some conditions. The ventriloquism effectcorresponds to the recalibration of auditory space by incongruentvisual stimuli, whereby sound localisation is affected by the loca-tion of concurrent, spatially incongruent visual stimuli. This effecthas been shown to exist in neglect patients both online (Bertelson,Pavani, Ladavas, Vroomen, & de Gelder, 2000) or after a period ofpassive exposure (Passamonti et al., 2009), but not in hemianopicpatients, suggesting that the geniculostriate pathway, and the stri-ate cortex in particular, is necessary for recalibration of auditoryspace by incongruent visual stimuli (Passamonti et al., 2009). Again,visual stimuli that were not consciously detected biased localisa-tion of sounds in the contralesional hemispace. A somewhat similarphenomenon has been described by Soroker et al. (1995) whoshowed that patients with difficulties in identifying syllables pre-sented in the contralesional hemispace performed better when adummy loudspeaker was present in their right visual hemifield.However, as discussed by Bertelson et al. (2000), this effect likelyrelies on different mechanisms from those involved in the effectthey described in their study. Indeed, the dummy loudspeaker wasconstantly present, and the effect likely involved cognitive factorsrelated to the functional knowledge about loudspeakers, while thetraditional ventriloquism effect is automatic and depends on thesynchrony of brief visual and auditory events.
In sum, the literature reviewed in the last two sections providescompelling, although not unequivocal, evidence in favour of thehypothesis that a multisensory disorder of spatial representationand attention is at the core of the neglect syndrome. As pointedout by previous work (e.g. Karnath & Dieterich, 2006; Pavani et al.,2004), this conception fits well with the fact that areas usuallyaffected by lesions causing neglect are known to contain multi-sensory neurons responsible for the convergence and integration
of information coming from different senses to build multiple mul-tisensory representations of space. We turn now to a brief overviewof the current knowledge of the cerebral bases of neglect, and thendiscuss neuroanatomical, electrophysiological, and brain imaging
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tudies that have demonstrated the involvement of the relevanterebral areas in multisensory processing and integration.
. Multisensory role of areas involved in neglect
Overt clinical neglect is much more common after right than leftemisphere lesions (Heilman et al., 1993; Mesulam, 2000). The pre-ominance of right hemisphere lesions in the aetiology of neglect
s nowadays no longer disputed, although in the past it has beenrgued that it could in part reflect a sampling bias due to the apha-ia symptoms that commonly follow a left hemisphere stroke (e.g.eis et al., 2004). Indeed, attentional deficit and spatial represen-ation testing can be hampered by aphasic deficits. Nonetheless,arge-scale analyses confirmed a higher prevalence of neglect afteright-brain damage (Moscovitch & Behrmann, 1994). This lateral-sation supports the theory that has prevailed for a long period ofime in clinical neurology, claiming right hemisphere dominanceor spatial attention. Several theoretical frameworks have beenroposed to explain this hemispheric asymmetry. Although theroposed mechanism varied across theories, most of these inter-retations postulated a dominant role of the right hemisphere inepresenting and orienting attention to both sides of space, whilehe left hemisphere would only be concerned with the right con-ralateral hemispace (e.g. Bisiach, Pizzamiglio, Nico, & Antonucci,996; Heilman, Watson, & Valenstein, 1997; Jeannerod & Biguer,987; Posner et al., 1984). As a consequence, a lesion of the leftemisphere would impair only the representation of the rightemispace, and could be compensated for by the intact right hemi-phere; by contrast, a lesion of the right hemisphere would produce
massive bias in spatial representation between the two hemis-aces with a clear predominance of the right over the left side. Anlternative and currently quite influential account proposes insteadhat neglect results from a breakdown in the dynamic balancehat normally exists in the reciprocal inhibition between homol-gous areas of the two hemispheres that orient spatial attention inpposing, contralateral directions (Kinsbourne, 1977, 1987, 1993).ccording to this proposal, a lesion lateralised to one hemisphere
nduces not only its hypoactivity, but also hyperactivity in the otheremisphere due to the release of inhibition by the affected one. This
mbalance generates a general bias toward the ipsilesional side ofpace, which results in a biased competition between the repre-entations of both hemispaces (Driver et al., 1997; Duncan, 1996).he higher frequency of neglect following right than left brain dam-ge would be explained by the fact that the rightward orienting biasenerated by the left hemisphere is stronger than the opposing biasnduced by the right hemisphere.
Regardless of theoretical considerations, neglect has long beenttributed to lesions of the posterior portion of the right inferiorarietal lobule (IPL; Heilman et al., 1993; Vallar & Perani, 1986).owever, with the development of novel lesion localisation andverlapping methods, the precise neuroanatomical substrate ofeglect has been disputed, with some studies suggesting that theritical focus for neglect may in fact be more ventral and anterior, inhe superior temporal gyrus and adjacent insular cortex (Karnath,erber, & Himmelbach, 2001; Karnath, Fruhmann Berger, Küker, &orden, 2004). Most recent studies nonetheless seem to confirmhe crucial involvement of the IPL and the temporo-parietal junc-ion (TPJ; Buxbaum et al., 2004; Farnè et al., 2004; Halligan et al.,003; Mort et al., 2003). Discrepancies in lesion location acrosstudies may simply be due to differences in the tests used to diag-ose neglect (e.g. line bisection, cancellation tasks or extinction;
arnath & Rorden, 2012; Milner & McIntosh, 2005), or in the pro-le of impairment presented by the patients in the sample (e.g.otor vs. perceptual neglect; Buxbaum et al., 2004). Importantly,
he involvement of the posterior inferior parietal cortex in neglect
ia 50 (2012) 1029– 1044 1037
has been further supported by recent brain stimulation studiesshowing that interference with this region induces neglect-likeor extinction-like behaviours in healthy participants (Fierro et al.,2000; Meister et al., 2006; Oliveri & Caltagirone, 2006; Sparinget al., 2009). In addition to the IPL and TPJ, lesions to parieto-frontalconnections may also play a crucial role in the genesis of neglect(Doricchi, Thiebaut de Schotten, Tomaiuolo, & Bartolomeo, 2008;Doricchi & Tomaiuolo, 2003; de Schotten et al., 2005). Furthermore,other areas may be important, such as the intraparietal sulcus (IPS)and the prefrontal cortex. Indeed, although structurally intact inthe majority of neglect patients, IPS and prefrontal cortex can befunctionally impaired, especially but not exclusively, during theacute phase of neglect (Corbetta et al., 2005). Some authors havealso argued that the contribution of these regions to the neglectsyndrome might have been underestimated because of the intrin-sic limits of the lesion-overlap method (Ptak & Schnider, 2011;Vandenberghe & Gillebert, 2009).
Lesions to putative homologues of these areas in non-humanprimates induce abnormal behaviours reminiscent of what hasbeen described in neglect patients for the perception of visual(Denny-Brown & Chambers, 1958; Faugier-Grimaud, Frenois, &Stein, 1978; Heilman, Valenstein, Day, & Watson, 1995; Lynch &McLaren, 1989; Watson, Valenstein, Day, & Heilman, 1994) or tac-tile (Ettlinger & Kalsbeck, 1962) stimuli, or both tested separately(Matelli, Pavesi, & Rizzolatti, 1982; Rizzolatti, Matelli, & Pavesi,1983). However, more detailed structural comparisons betweenthe organisation of the parietal lobe in humans and non-humanprimates, which could increase our understanding of the neuralmechanisms underlying the functions subserved by these brainregions, are made difficult by evolutionary differences in pari-etal lobe parcellation. Anatomically, the human IPL consists of thesupramarginal gyrus (SMG, Brodmann’s area 40), an arched lobulesurrounding the end of the lateral fissure, and the angular gyrus(AG, Brodmann’s area 39), a lobule bypassing the ascending pos-terior segment (angular sulcus) of the parallel sulcus (Duvernoy,1999). The identification of putative homologues of these areas inmonkeys has been disputed in the past decades. Early investiga-tions first concluded that there are no homologues of these areasin monkeys (Roland, 1980). Other researchers, based on cytoarchi-tectonic studies, have proposed that human areas BA39 and BA40might in fact be an expansion of area 7, located in the superior pari-etal lobule in monkeys (Eidelberg & Galaburda, 1984). Finally, otherinvestigators proposed that the monkey homologues of humanareas BA39 and BA40 might also be found, at least in part, inthe superior temporal sulcus (STS; Mesulam, 1985; Watson et al.,1994). More recent cytoarchitectonic investigations in humansdelineated distinct areas within the IPL (Caspers et al., 2006, 2008),five of them in the lateral surface of the lobule and two in theconvexity of the sylvian fissure. Cytoarchitectonically, they can begrouped into a rostral and a caudal part, which roughly corre-sponds to the rostral and caudal parts of macaque IPL (Gregoriou,Borra, Matelli, & Luppino, 2006; Pandya & Seltzer, 1982). However,an intermediate region between the caudal and rostral parts inhumans does not have a corresponding structure in the parcella-tion of monkey IPL (Caspers et al., 2011; Mars et al., 2011). In sum,even though caution is always necessary when drawing homologiesbetween different species, neurophysiological and neuroanatom-ical data obtained in monkeys might help in understanding theresults of human studies at a different scale of analysis.
Homologies between IPL regions in monkeys and humans mightalso involve their connectivity. Tracer studies of axonal connectiv-ity in macaque monkeys reveal that the structural heterogeneity
of the IPL is accompanied by a differentiated connectivity of itssubregions, thereby supporting the idea of a differentiation in thefunctions the different partitions might serve. Rostral portions ofthe IPL show strong connectivity with premotor, somatosensory,
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nd SPL regions, whereas caudal portions are mainly connectedo occipital and inferior temporal areas (Gregoriou et al., 2006;etrides & Pandya, 2009). The connectivity of individual IPL areasn humans still remains largely unknown, even though the infor-
ation available from neuropsychological patients supports thedea of a similar connection pattern for humans and monkeys.ecently, diffusion tensor imaging (DTI) studies in healthy humansave started to reveal the differential connectivity of IPL regions.wo main fibre pathways connect the IPL with mainly frontalegions, namely the arcuate fascicle (AF) and the superior longi-udinal fascicle (SLF). It has been shown that both fibre tracts cane divided into different subcomponents extending from the rostralnd the caudal parts of the IPL, respectively (Catani, Jones, & ffytche,005; Makris et al., 2005). Using a connectivity-based parcellationypothesis, recent imaging findings showed that the rostral IPL isostly connected with the ventral premotor (PMv), IPS, and SPL
egions, whereas the most caudal part of IPL is more likely to con-ect with the temporal lobe (Caspers et al., 2011; Mars et al., 2011;ushworth, Behrens, & Johansen-Berg, 2006).
Neurophysiological investigations in non-human primates haveevealed the multisensory properties of neuron populations inhe IPL (for review, see e.g. Buneo & Andersen, 2006; Hyvärinen,982). In particular, many studies have described visuo-tactile cells,hich respond to both visual and tactile stimulations and demon-
trate multisensory integration at the single unit level (Hyvärinen,981; Hyvärinen & Poranen, 1974; Leinonen, Hyvärinen, Nyman,
Linnankoski, 1979; Mountcastle, Lynch, Georgopoulos, Sakata, &cuna, 1975; Robinson & Burton, 1980). The tactile receptive fieldsf these cells present a gross somatotopic organisation, represent-ng the hand, the arm or the face and head (Avillac, Deneve, Olivier,ouget, & Duhamel, 2005; Colby & Duhamel, 1991; Colby, Duhamel,
Goldberg, 1993; Duhamel et al., 1998; Hyvärinen, 1981; Robinson Burton, 1980). Importantly, the visual receptive field (RF) of theseells stays in register with their tactile RF, regardless of their posi-ion in space and their retinal location. Therefore, these bimodaleurons code space in body-part-centred coordinates. In addition,he visual RF extends only a few centimetres away from its corre-ponding tactile RF, thus integrating tactile information with visualtimuli located near the body. Bimodal neurons encoding visual anduditory information have also been described in the parietal cor-ex (e.g. Cohen & Andersen, 2002; Mazzoni, Bracewell, Barash, &ndersen, 1996; Schlack, Sterbing-D’Angelo, Hartung, Hoffmann,
Bremmer, 2005).In humans, the IPL, together with the most posterior regions of
he STG that are also thought to be involved in the neglect syndromeKarnath, 2001; Karnath et al., 2004), is part of the composite corti-al region commonly referred to as the Temporo-Parietal JunctionTPJ). Lesion studies and functional neuroimaging investigationsave shown that these regions are associated with attentional func-ions, in particular with the disengagement of attention and itse-orientation toward behaviourally relevant stimuli (Arrington,arr, Mayer, & Rao, 2000; Corbetta, Kincade, Ollinger, McAvoy, &hulman, 2000; Corbetta, Patel, & Shulman, 2008; Friedrich, Egly,afal, & Beck, 1998; Indovina & Macaluso, 2007; Kincade, Abrams,stafiev, Shulman, & Corbetta, 2005; Natale, Marzi, & Macaluso,010; Vossel, Thiel, & Fink, 2006). Their role in attention switching
s also accompanied by an involvement in less spatial aspects ofttention, such as maintaining alertness, sustained attention andetection of novelty (Downar, Crawley, Mikulis, & Davis, 2000;ingh-Curry & Husain, 2009) or breach of expectancy (Downar et al.,000; Downar, Crawley, Mikulis, & Davis, 2001). The ensemble ofata available on the attentional functions of the TPJ have resulted
n this brain region being considered as part of a circuit for nov-lty detection and a consequent re-allocation of attention towardsovel events. According to this point of view, the IPL would beart of a ventral attention network together with prefrontal areas
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(Corbetta & Shulman, 2002; Fink, Marshall, Weiss, & Zilles, 2001).Besides its involvement in attention, activity in IPL regions hasalso been claimed to be associated with magnitude perception andquantity judgement (for review, see Arsalidou & Taylor, 2011) notonly in a spatial dimension, but also in the temporal and numericaldomains (e.g. Maquet et al., 1996; for review, see Walsh, 2003).
The other main characteristic of IPL is its role in building amultisensory representation of space, evident during the localisa-tion of sensory targets in multiple sensory modalities (Bremmeret al., 2001; Bushara et al., 1999; Macaluso & Driver, 2001, 2005;Macaluso, Frith, & Driver, 2000). The first demonstrations ofmultimodal activity in the IPL using functional magnetic reso-nance imaging (fMRI) employed a conjunction analysis approach,whereby the authors considered that if one area is active duringthe presentation of stimuli in different sensory modalities, thisarea must contain bimodal neurons and/or intermingled unisen-sory populations of neurons each responding to one of the twomodalities. Bushara et al. (1999) employed a design that allowedthem to study the localisation of sounds in extrapersonal spaceusing the same frame of reference as for visual stimulations. Theyobserved modality specific activity in superior parietal areas duringthe localisation of visual or auditory stimuli. By contrast, activ-ity in an inferior parietal area remained unchanged during thelocalisation task, irrespective of the modality used, suggestingmultimodal activity within IPL. Similarly, Bremmer et al. (2001)have shown that a constellation of regions in the parietal lobeare responsive to more than one sensory modality (tactile, visual,and auditory modalities), including the IPL and its upper bound-aries in the IPS. Since these early neuroimaging studies otherapproaches have confirmed the multisensory nature of the activ-ity in IPL. Research investigating the coordination between visualand tactile spatial maps, for instance, confirmed the involve-ment of inferior portions of the parietal lobe in a multimodalrepresentation of space (Macaluso et al., 2000). In this study,participants received visual stimulation on the left or right side,together with tactile stimulation on the left or the right hand.These visuo-tactile stimulations could thus be spatially congru-ent (both on the same side) or incongruent (one on each side).Macaluso and colleagues observed a spatially specific interac-tion in early visual areas, that is, a modulation of brain activityassociated with spatially congruent visuo-tactile stimulation. Thisearly modulation presumably reflected the influence of higherorder, multisensory areas. In accordance with this hypothesis,the authors reported a strong correlation between the activ-ity in the right inferior parietal regions (the anterior portion ofthe SMG) and that in early visual areas, demonstrating a mod-ulation related to the spatial coincidence of tactile and visualinformation.
More recently, Gentile et al. (2011), using a very conserva-tive approach, showed multimodal activity in the inferior parietalregions (SMG) associated with tactile stimulation of the right handand visual stimulation close to that hand. These authors also testedfor the additivity and the superaddivity of the neural response tosensory stimulation, borrowing one of the criteria employed inelectrophysiology for studying the multisensory integrative prop-erties of neurons in the superior colliculus (Avillac, Ben Hamed,& Duhamel, 2007; Stein & Meredith, 1993). Given a multisensoryneuron, defined as a unit activated by either a visual stimulus ora tactile stimulus, or both presented simultaneously, three scenar-ios are possible: (1) the response of the neuron in case of bimodalstimulation is higher than the sum of the two responses in caseof visual or tactile stimulation (superadditivity); (2) the response
in case of bimodal stimulation is not different from the sum ofthe unimodal responses (additivity); (3) the bimodal response issignificantly lower than the sum of the two unimodal ones (subad-ditivity). The same approach has been applied to the blood oxygen
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evel dependent (BOLD) signal measured with fMRI, providing aery conservative criterion for investigating multisensory inte-ration in humans (Calvert, 2001). Gentile and colleagues wereble to identify additive responses in the contralateral SMG, anduperadditive responses in the IPS. Furthermore, a recent imagingnvestigation, using an fMRI-adaptation paradigm, showed that thePL is part of the network involved in the representation of visualnformation in the space near the hand (Brozzoli, Gentile, Petkova,
Ehrsson, 2011). Functional MRI adaptation relies on the repetitionuppression effect of the BOLD signal induced by the repetition oftimulations to which a given neural population is sensitive (Grill-pector, Henson, & Martin, 2006). In their study, Brozzoli et al.epeatedly presented an object close to or far from the right hand,hich was placed in front of the subject and visible to them. The
ationale was that all the areas that show a stronger adaptationffect for visual stimulations presented near rather than far fromhe hand may be considered as selectively encoding visual eventsocated near the hand. The SMG and IPS in IPL were part of the net-
ork of areas selective for the space near the hand (see also Makin,olmes, Brozzoli, Rossetti, & Farnè, 2009; Makin, Holmes, & Zohary,007).
To summarise, the areas that are most frequently damaged ineglect patients, in particular the IPL, show activity correlated witheveral attentional functions, as well as multisensory propertiesinked to the representation of space (preferably the space near theody). These main functions are intimately linked to each other: theepresentation of space is built by merging multisensory input, andttention can be enhanced or guided by the multisensory naturef external events (Talsma, Senkowski, Soto-Faraco, & Woldorff,010), especially when these events occur near the body (Brozzoli,akin, Cardinali, Holmes, & Farnè, 2011).
. Concluding remarks
Although researchers and clinicians have predominantlyttended to the visual symptoms of neglect, it is now clear thathis syndrome has an impact on non-visual sensory modalities asell. In particular, neglect-related symptoms have been described
n the haptic, tactile and auditory modalities, reminiscent of thosebserved in the visual domain, with impairment of the processingf contralesional stimuli and the presence of a bias in favour of thepsilesional side of space. Evidence gathered across different exper-mental paradigms, using different stimuli and measures, tends tohow that these impairments do not depend on low-level sensoryisturbances, but rather on high-order, spatial representationalr attentional deficits that may be multisensory in nature. Somereliminary support for this notion comes from the observationhat, in addition to co-occurring in most patients (when tested ineveral sensory modalities), the severity of visual and non-visualeglect symptoms are also often correlated. Furthermore, recentndings suggest that the effects of bottom-up, sensory stimulationehabilitative approaches, such as prismatic adaptation, propri-ceptive activation, or crossmodal stimulation, may spread andeneralise to sensory modalities that were not directly targetedy the intervention. Finally, neglect can bias normal multisensory
nteractions, either disrupting them, or exacerbating their effectn patients’ performance. When considered together with dataoncerning the multisensory properties and connectivity of thereas that are most frequently damaged in neglect patients andf their putative non-human primate homologues, the evidenceeem compelling, and the possibility that the neglect syndrome
ay involve the disruption of multisensory mechanisms of spatial
ttention and representation worth investigating further.The available data is not, however, unequivocal, and further
esearch is required to investigate several issues. In particular,
ia 50 (2012) 1029– 1044 1039
dissociations between visual and non-visual signs of neglect havebeen reported in some individual cases, as mentioned above.These results, as is traditionally the case in neuropsychology,have been interpreted as evidence for the existence of separateneural correlates for some aspects of spatial orientation and rep-resentation depending on the sensory modality. The associationof visual and non-visual neglect-related deficits would thus resultfrom joint damage to neighbouring unisensory areas involved inspatial representation. However, we think that clearly establishingdissociations, as well as associations, between neglect symptomsin different sensory modalities requires that the tasks used besimilar in terms of the physical quality of stimuli, difficulty, andtype of response. As argued by Bisiach et al. (1984), while tasksdeveloped to test spatial orientation capacities in the auditorydomain, for example, are quite complex, the visual symptoms ofneglect are usually measured in the same patients using muchsimpler standard clinical tests. The reported dissociations maythus reflect, at least to some extent, the different sensitivity ofthe tests used to evaluate neglect-related deficits in the differentsensory modalities. Furthermore, as argued by Pavani et al. (2004),the existence of dissociations in some individuals cannot ruleout the possible involvement of some common, multisensorymechanisms for spatial orientation and representation in the largeproportion of patients in whom neglect symptoms coexist acrosssensory modalities, and are often correlated in severity.
Another parameter that may appear to contradict the possi-ble multisensory nature of neglect is the observation that visualneglect largely dominates at the clinical level, and that visualsymptoms are often more pronounced than non-visual ones instudies that have analysed the manifestations of neglect in severalmodalities. Although some authors have interpreted this as evi-dence against a common, multimodal mechanism (e.g. Kerkhoff,1999), alternative interpretations exist. Indeed, it is possible thatthe same multisensory representation is disturbed in all cases, andthat some additional factors, inherent to the visual domain, aggra-vate the deficit in this modality. Along this line, Gainotti (2010;see also Schindler et al., 2006) recently proposed that the ipsile-sional attraction of attention in visual search (Gainotti et al., 1991;Mark et al., 1988) worsens visual symptoms of neglect. Anothercrucial parameter is the influence of concomitant primary sen-sory deficits. Indeed, the interaction of hemianopia and neglecthas been proven to aggravate visual symptoms of neglect (Doricchi& Angelelli, 1999; Doricchi et al., 2002; Ferber & Karnath, 2001;Gainotti et al., 2009), but the impact of such a phenomenon onnon-visual manifestations of neglect is currently unknown.
Finally, although the fact that the effects of bottom-up reha-bilitative procedures may generalise to other sensory modalitiesprovides compelling support for the notion of a multisensory originto the neglect syndrome, alternative interpretations are possible.Indeed, these techniques might in principle act on a more gen-eral process (e.g., egocentric reference frame, orienting of attention,interhemispheric competition) or even a combination of processes,which may in turn improve neglect in different sensory modal-ities. In other words, the crossmodal effects of prism adaptationand other techniques may relate more to the nature of the com-pensatory processes than to the pathophysiological mechanism ofneglect itself. Having said this, it might be more parsimonious atpresent to think of the generalised benefits emerging from sensorystimulation techniques as truly reflecting the multisensory natureof the deficit. Improving our understanding of the effects of sensorystimulation techniques on spatial cognition and neglect symptomswill surely be a fundamental axis for future research in order to
help resolve these issues.
To conclude, one of the challenges for future research on neglectwill be to try to reveal to what extent this syndrome affects themultisensory representation of space. One obvious approach to
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ddress this matter consists of systematically investigating theultisensory aspects of neglect in a large cohort of patients. A
rucial and non-trivial aspect of such an endeavour would be toevelop new standardised tests equated for their demands in theifferent sensory modalities. A first step would be to design tasks
nvolving simple detection or double simultaneous stimulations,lassically used to study extinction, using a performance-basedriterion to homogenise stimuli across sensory modalities (e.g.eeraerts, Michiels, Lafosse, Vandenbussche, & Verfaillie, 2005;
acobs et al., 2011). More elaborated tasks, designed to test othernown components of visual neglect, may also be developed so aso present similar demands and response modalities across senses.or example, a spatial search task should be designed so as to bedapted to the visual, tactile, and auditory domains, by presentingn each case an array of distracters within one target stimulus thateeds to be detected. In addition, this approach should be inte-rated with the previous recommendations regarding calibrationf the physical properties of the stimuli. In this case, the intensitynd/or duration of not only the stimulus, but also the distractors,hould be matched across modalities in terms of their detectabil-ty (for the target) and interfering effect (for the distractors). Theightward bias typical of neglect could then be further investigatedy varying the relative and absolute location of the target and dis-ractors across and within hemispaces. This approach would avoidhe possible confounds presented by tasks involving haptic spa-ial orientation or pointing responses to localise sounds, such ashose discussed previously. In addition, it will be necessary to sys-ematically take into account the co-occurrence of primary sensoryeficits, given their influence on the severity of neglect symptoms,t least in the visual domain.
Finally, an additional, potentially insightful perspective wouldonsist in testing the multisensory nature of neglect in the domainf non-spatially lateralised deficits. The importance of non-spatialeficits in the manifestation of neglect has been a relatively recent,nd quite revolutionary step forward in the testing and understand-ng of this syndrome (Buxbaum et al., 2004; Husain & Rorden, 2003).
e believe that this approach might have the advantage of iden-ifying crossmodal deficits without the potential confound of annderlying spatial representation deficit. These suggestions are ofourse not meant to be exhaustive, and should rather be considereds preliminary guidelines for answering the question of whethereglect is truly multisensory.
cknowledgments
The authors wish to thank the two anonymous reviewers forheir insightful comments and suggestions. Alessandro Farnè isupported by INSERM. This work was funded by the ANR grant no.PV08085CSA, the AVENIR grant no. R05265CS, and a scholar award
rom the James S. McDonnell Foundation.
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