Integration of Visual and Tactile Signals From the Hand in ... · Giovanni Gentile, Valeria I....

doi:10.1152/jn.00840.2010 105:910-922, 2011. First published 8 December 2010;J NeurophysiolGiovanni Gentile, Valeria I. Petkova and H. Henrik EhrssonHand in the Human Brain: An fMRI StudyIntegration of Visual and Tactile Signals From the

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Integration of Visual and Tactile Signals From the Hand in the Human Brain:An fMRI Study

Giovanni Gentile, Valeria I. Petkova, and H. Henrik EhrssonBrain, Body and Self Laboratory, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

Submitted 5 October 2010; accepted in final form 7 December 2010

Gentile G, Petkova VI, Ehrsson HH. Integration of visual and tactilesignals from the hand in the human brain: an fMRI study. J Neuro-physiol 105: 910–922, 2011. First published December 8, 2010;doi:10.1152/jn.00840.2010. In the non-human primate brain, a num-ber of multisensory areas have been described where individualneurons respond to visual, tactile and bimodal visuotactile stimulationof the upper limb. It has been shown that such bimodal neurons canintegrate sensory inputs in a linear or nonlinear fashion. In humans,activity in a similar set of brain regions has been associated withvisuotactile stimulation of the hand. However, little is known abouthow these areas integrate visual and tactile information. In thisfunctional magnetic resonance imaging experiment, we employedtactile, visual, and visuotactile stimulation of the right hand in anecologically valid setup where participants were looking directly attheir upper limb. We identified brain regions that were activated byboth visual and tactile stimuli as well as areas exhibiting greateractivity in the visuotactile condition than in both unisensory ones. Theposterior and inferior parietal, dorsal, and ventral premotor cortices, aswell as the cerebellum, all showed evidence of multisensory linear(additive) responses. Nonlinear, superadditive responses were ob-served in the cortex lining the left anterior intraparietal sulcus, theinsula, dorsal premotor cortex, and, subcortically, the putamen. Theseresults identify a set of candidate frontal, parietal and subcorticalregions that integrate visual and tactile information for the multisen-sory perception of one’s own hand.

I N T R O D U C T I O N

The human brain receives information through multiplesensory channels, the inputs of which can be optimally com-bined to form a coherent percept of the world surrounding usfor the facilitation of adaptive behavior (Ernst and Bülthoff2004; Stein and Stanford 2008). Similarly, to maintain acoherent representation of the body to enable interactions totake place with external objects, the brain needs to integratevisual and somatosensory signals (e.g., Graziano and Botvinick2002). An extensive body of evidence supports the notion thatindividual neurons in the non-human primate brain dischargewhen a specific body part is stimulated across somatic andvisual modalities. Over the past few decades, such multisen-sory, visuotactile neurons have been identified in a set ofcortical and subcortical regions of the macaque brain. Neuronswith visuotactile properties have been found in area 7b in theinferior posterior parietal lobe (Hyvärinen 1981; Hyvärinenand Poranen 1974), the ventral intraparietal area (VIP) in thefundus of the intraparietal sulcus (Avillac et al. 2005; Colbyand Duhamel 1991; Colby et al. 1993; Duhamel et al. 1998),the premotor cortex in the frontal lobe (Graziano and Gandhi

2000; Graziano et al. 1997; Rizzolatti et al. 1981), the upperbank of the superior temporal sulcus (Bruce et al. 1981), and,subcortically, the superior colliculus (Stein and Meredith 1993;Wallace and Stein 2001; Wallace et al. 1996) and putamen(Graziano and Gross 1993). A densely interconnected subset ofthese visuotactile areas, consisting of parietal and premotorregions, as well as the putamen, is thought to play a funda-mental role in the multisensory representation of the space inthe immediate vicinity of the body (Graziano and Botvinick2002). The properties of the visuotactile receptive fields ofthese neurons, centered around different body parts and re-stricted to the space immediately surrounding them, the so-called “peripersonal space” (Rizzolatti et al. 1981, 1997), makethis set of multisensory regions an ideal candidate for hostingthe mechanisms necessary to enable one to interact with theexternal world (Graziano and Botvinick 2002; Rizzolatti et al.1987), defend the body from potential threats (Cooke andGraziano 2004; Cooke et al. 2003; Graziano et al. 2002), andidentify one’s own limbs (Ehrsson et al. 2004, 2005, 2007).

Seminal studies on the superior colliculus of the cat (Steinand Meredith 1993; Stein and Stanford 2008) showed thatindividual cells not only respond to multiple sensory modalitiesbut integrate their signals to produce a combined, multisensoryresponse the magnitude of which reflects a linear or nonlinearcomputation performed on the unisensory inputs. Avillac andcolleagues (2007) were the first to show that individual neuronsin an intraparietal node (area VIP) of the macaque multisensorynetwork described above integrate visual and tactile signals ina fashion that obeys the computational principles described inthe superior colliculus (Stein and Meredith 1993; Stein andStanford 2008).

A growing body of evidence from recent neuroimagingstudies in healthy humans suggests that a similar set of regionsexists in the human brain where visual and tactile signalsconverge (Banati et al. 2000; Bremmer et al. 2001; Driver andNoesselt 2008; Hadjikhani and Roland 1998; Lloyd et al. 2003;Makin et al. 2007; Pasalar et al. 2010; Sereno and Huang 2006;Tal and Amedi 2009). Visual unisensory stimulation near thehand and tactile unisensory stimulation on the hand activate theanterior part of the intraparietal cortex (Makin et al. 2007).Lloyd and colleagues described how visuotactile stimulation ofthe hand activates premotor and intraparietal areas, but they didnot compare these responses to unisensory conditions (Lloyd etal. 2003). Studies on the rubber hand illusion, a multisensoryillusion where participants experience a referral of touch fromtheir hidden real hand to a rubber hand touched in full view,have related activation of premotor and intraparietal areas tothis visuotactile perceptual phenomenon (Ehrsson et al. 2004,2007). However, the rubber hand illusion is also associated

Address for reprint requests and other correspondence: G. Gentile, Dept. ofNeuroscience, Retzius väg 8, 17177 Stockholm, Sweden (E-mail [email protected]).

J Neurophysiol 105: 910–922, 2011.First published December 8, 2010; doi:10.1152/jn.00840.2010.

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with the resolution of multisensory conflict and recalibration ofposition sense of the hand; in light of this, it cannot beexcluded that these processes also contribute to the observedfrontoparietal activations. Thus what is missing from the hu-man neuroimaging literature available to date is an experimentthat uses natural stimuli to compare unisensory and visuotactilestimulation of the hand directly to identify the hypothesizedmultisensory responses in the key candidate areas defined innon-human primates.

In this functional magnetic resonance imaging (fMRI)study, we investigated the multisensory integrative proper-ties of regions in the human brain that are sensitive to visualand tactile stimulation of one’s own real hand. Specifically,the aim was to classify such regions in terms of the changesmeasured at the level of the blood-oxygen-level-dependent(BOLD) signal when comparing unisensory and multisen-sory stimulation of the hand in humans. In particular, wetested our prediction that some of these areas would displayadditive and, crucially, superadditive multisensory re-sponses during bisensory visuotactile stimulation. Such afinding would support the hypothesis that a set of visuotac-tile regions exists in the human brain, similar to thosepreviously identified in non-human primates, where visualand tactile signals are integrated to attain a coherent multi-sensory perception of the body.

M E T H O D S

Participants

Twenty-four healthy right-handed subjects [5 females, 25 ! 4(SD) yr] without a history of neurological or psychiatric disordersparticipated in the experiment. Handedness was self-reported bythe participants in a questionnaire before the experiment. We onlyrecruited subjects who were !175 cm tall to ensure that their handwas accessible for direct tactile stimulation in the constrainedspace of the scanner environment. All subjects gave their writteninformed consent before taking part in the study, which wasapproved by the local ethical committee at the Karolinska Institu-tet.

Experimental setup

During scanning, the participant lay comfortably in a supine posi-tion on the bed of the MR scanner. To ensure that multisensorystimulation of the hand was as natural as possible, we used a setup thatgave the subjects direct view of their hand and that employed tactilestimulation conducted with real objects (Fig. 1, left).

This was achieved by tilting the participant’s head downward andplacing his or her right hand on a custom-made support positionedabove the waist. The required tilt of the head was achieved by slantingthe head coil with the help of a custom-made wooden wedge (throughan angle of "11°). In addition, the participant’s head was tilted byanother 20° using pillows and foam pads. The participant woreMR-compatible headphones to dampen the scanner noise as well as toreceive the appropriate set of instructions throughout the acquisitionsessions (see following text). The resting left hand was placed in acomfortable position alongside the participant’s body. Instructionswere transmitted to the experimenter and the participant via a com-puter running Presentation 14.1 (Neurobehavioral Systems, Albany,CA) and connected to an MR-compatible sound delivery system(Nordic Neuro Lab, Bergen, Norway).

Experimental design

A 2 # 2 factorial design was used, with the sensory modality ofstimulation (visual, tactile) and presence thereof (present, absent) asthe experimental factors (Fig. 1, right). A block design was used tomaximize the efficiency of the experimental design (Friston et al.1999). Each stimulation or baseline epoch lasted 16 s and wasfollowed by a 3 s intertrial interval during which both experimenterand participant received a brief audio instruction. The latter identifiedthe upcoming stimulation epoch for the experimenter and cued theparticipant as to whether keep his or her eyes open or closed. Twobaseline conditions were included, with eyes open and closed, respec-tively. This made it possible to use separate baselines for the visualand tactile unisensory conditions, thereby ensuring that the conjunc-tion analysis was based on orthogonal contrasts (Beauchamp et al.2008; Bremmer et al. 2001; Friston et al. 2005; Nichols et al. 2005;Price and Friston 1997). The participant was instructed to keep his orher eyes closed during purely tactile stimulation and during thecorresponding baseline or open during all visual conditions includingthe relative baseline. During all epochs involving visual (-tactile)stimulation, the participant was further instructed to fixate on a point"2 cm above his or her right hand. The fixation point was marked andvisible during all conditions carried out with the participant’s eyesopen. All stimulations were delivered using a spherical object made ofa soft material attached to a 50-cm-long stick, which allowed theexperimenter to hide his hand from the participant’s view while stillpermitting carefully controlled stimulation. We used real physicalobjects rather than computer generated stimuli because the former areknown to be more potent in activating multisensory neurons inexperiments in non-human primates (Graziano and Gandhi 2000).During tactile stimulation, the participant’s right index finger wastouched by the same object used in the visual condition. A trainedexperimenter moved the ball on the skin from the distal to theproximal phalanx, yielding a discrete number of events in the 16-s-long epoch. In total, 10 brush strokes were applied to the index finger

Tac!le s!mula!on

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FIG. 1. Experimental setup and design.Photograph of the experimental setup anddiagram of the experimental design. The par-ticipant’s head was tilted to provide directvision of the right hand, which was placed onan angled support. Inset: how the handlooked from the participant’s perspective andillustrates the approximate position of thefixation point, above the right hand. Theexperimental design was a 2 # 2 factorial,manipulating the modality of stimulation andthe presence thereof. RestEC, rest conditionwith eyes closed. T, tactile; V, visual; VT,visuotactile.

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during each tactile or visuotactile stimulation epoch. To ensure thatthe same number of stimuli was presented during each epoch, theexperimenter followed a prerecorded metronome. Visual stimulationclose to the hand was delivered by moving the object at !2 cm fromthe participant’s right index finger following a sequence of eventsidentical to the one applied during the tactile epochs. During bisensory(visuotactile) stimulation, the experimenter repeated the tactile stim-ulation pattern while the subject fixed his or her gaze just above his orher own right hand. All participants underwent three sessions offunctional acquisition, each composed of five blocks in which allepochs (including the baselines) were repeated once. The baselinecondition made with eyes closed always followed the tactile epoch,while the baseline condition made with eyes open always followed thelast of the visual epochs, the order of which was randomized acrosssessions.

fMRI acquisition

fMRI acquisition was performed using a Siemens TIM Trio 3Tscanner equipped with a 12-channel head coil (Siemens, Erlangen,Germany). We acquired gradient echo T2*-weighted echo-planarimages with blood-oxygenation-level-dependent (BOLD) contrast asan index of brain activity (Logothetis et al. 2001). A functional imagevolume comprised 47 continuous near-axial slices of 3-mm thickness(with a 0.3-mm interslice gap), which ensured that the whole brainwas within the field of view (58 " 76 matrix, 3.0 " 3.0 mm in-planeresolution, TE # 40 ms). One complete volume was collected every3 s (TR # 3,000 ms). A total of 513 functional volumes werecollected for each participant (171 in each run). In each run, an initialbaseline of 18 s and a final baseline of 20 s were included. To facilitateanatomical localization of statistically significant activations, a high-resolution structural image was acquired for each participant at thebeginning of the experiment (3D MPRAGE sequence, voxel size 1 "1 " 1 mm, FOV 250 " 250 mm, 176 slices, TR # 1,900 ms, TE #2.27 ms, flip angle # 9°).

Data analysis

The fMRI data were analyzed using the Statistical ParametricMapping software package, version 8 (SPM8; http//:www.fil.ion.ucl.ac.uk/spm; Wellcome Department of Cognitive Neurology, Lon-don, UK). The first three volumes were discarded from furtheranalysis due to non-steady-state magnetization. The functional imageswere realigned to correct for head movements and co-registered witheach participant’s high resolution structural scan. The anatomicalimage was then segmented into white matter, gray matter, and cere-brospinal fluid partitions and normalized to the Montréal NeurologicalInstitute (MNI) standard brain. The same transformation was thenapplied to all functional volumes, which were resliced to a 2.0 " 2.0 "2.0 mm voxel size. The functional images were then spatiallysmoothed with an 8-mm full-width-at-half-maximum (FWHM) iso-tropic Gaussian kernel. For each individual subject’s dataset, we fitteda linear regression model (a general linear model) to the data (in the1st level analysis). For each of the experimental conditions describedin the preceding text, we defined a boxcar function time-locked to theonset of the corresponding epoch, which was then convolved with thecanonical hemodynamic response function implemented in SPM8.The realignment parameters were included in the model as regressorsof no interest to account for residual head motion effects. We thendefined linear contrasts within the general linear model (see followingtext). To accommodate intersubject variability, the contrast images forthe comparisons of interest from all participants were entered into arandom effect group analysis (2nd level analysis). To account for theproblem of multiple comparisons in the statistical analysis of whole-brain data, we only report peaks of activation surviving a significancethreshold of P $ 0.05, corrected using topological peak-false discov-ery rate (FDR) as implemented in SPM8 (Chumbley et al. 2010). In

addition, given the strong a priori hypotheses on the anatomicallocalization of visuotactile multisensory regions in the human brain(see INTRODUCTION), a significance level of 0.05 was used with smallvolume corrections centered around relevant coordinates from aprevious study (Ehrsson et al. 2004).

Crucially, to obtain a direct comparison between the multisensorystimulation and the unisensory conditions, we employed a 2 " 2factorial analysis taking the modality of stimulation (tactile or visual)and the presence thereof (present, absent) as factors (Fig. 1, right). Inthe following, T stands for the tactile only condition, V for the visualonly condition, VT for the visuotactile condition, and RestEC/RestEO

for the baseline condition with eyes closed/open, respectively. Re-gions displaying superadditive responses were identified by examin-ing the positive interaction contrast, defined as [(VT % V) % (T %RestEC)], which is equivalent to (VT %RestEC) & [(V % RestEC) '(T % RestEC)]. This contrast reveals the voxels where visuotactilestimulation of the hand produces a response that is significantly higherthan the sum of the two unisensory stimuli presented in isolation. Apotential concern with the latter contrast is that it can also includevoxels where the positive interaction is driven by deactivations duringunisensory conditions (negative BOLD-signal with respect to thebaseline) (e.g., Kawashima et al. 1995), thereby yielding unwantedfalse positives (Calvert 2001). Therefore we excluded from the anal-ysis all those voxels that exhibited a significant deactivation (negativeBOLD-response relative to the baseline, P $ 0.01 uncorrected) for atleast one of the sensory modalities of interest. Because the participantshad their eyes closed in the tactile condition, we included the restcondition where the participant’s eyes were closed to ensure that theeffects of eyes-closed/eyes-open were matched in the analysis of thefactorial design. This choice of rest condition assured that the keycontrast, the interaction term, was well-balanced and not biased by acomparison of tactile responses with baseline intervals carried outwith the participant’s eyes open.

In the factorial design, one can also examine the main effect oftactile stimulation, defined as [(T ' VT) % (V ' RestEC)], and themain effect of visual stimulation corresponding to the contrast [(V 'VT) % (T ' RestEC)]. A conjunction analysis of the main effects wasthen carried out to identify the brain regions performing multisensoryintegration in an additive fashion in which the response to visuotactilestimulation does not exceed the algebraic sum of the responses tounisensory visual and tactile stimulation.

Finally, we also tested for possible subadditive effects by applyingthe negative interaction contrast [(T % RestEC) % (VT % V)], whichis equivalent to (VT % RestEC) $ [(V % RestEC) ' (T % RestEC)].

As complementary analysis, to identify areas showing evidence ofmultisensory convergence, we performed a conjunction analysis at thegroup level (Friston et al. 2005; Nichols et al. 2005; Price and Friston1997) of the unisensory activation maps (T % RestEC) and (V %RestEO) where RestEC and RestEO stand for the baseline with eyesclosed and open, respectively. Such analysis identifies brain regionsresponding significantly to both unisensory visual and tactile stimuli.

Visualization of the effect size of each contrast was achieved bygenerating plots by extracting the contrast estimates (the beta param-eters of the general linear model) for the visuotactile, visual, andtactile conditions, all relative to the mean across the experimentalsession. FreeSurfer (Athinoula A. Martinos Center for BiomedicalImaging, Massachusetts General Hospital, Boston, MA) was used todisplay significant activations on a reconstructed canonical corticalsurface. Significant activations were anatomically localized by super-imposing the activation maps onto the average normalized high-resolution MRI image and labeled using the nomenclature from ahuman brain atlas (Duvernoy 1999). To support localization withrespect to cytoarchitectonically defined areas, we used the Anatomytoolbox for SPM (Eickhoff et al. 2005).

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R E S U L T S

Multisensory integration: factorial analysis

The factorial analysis we describe here allowed for theidentification of those voxels showing evidence of multisen-sory integration when comparing bisensory and unisensoryconditions using the 2 ! 2 factorial design.

Table 1 and Fig. 2 contain a summary of the key findings,highlighting areas providing evidence of superadditive andadditive multisensory responses.

First, we sought to identify and localize active clustersshowing nonlinear superadditive responses by examining thepositive interaction contrast, defined as [(VT "V) " (T "RestEC)]. Clusters obtained from such a contrast contain voxelswhere the BOLD signal measured from epochs of visuotactilestimulation is significantly greater than the sum of the re-sponses registered during the two unisensory conditions. Wefound significant activations (Fig. 3; Table 1) in the leftanterior intraparietal sulcus ("32,-46,62; P # 0.013 cor-rected), left insular cortex ("32,-26,16; P # 0.004 corrected),left dorsal premotor cortex ("34,-16,62; P # 0.015 corrected),and left putamen ("24,4,8; P # 0.011 corrected). At a lowerthreshold, activations were also observed in the right parietaloperculum (52, "22, 18; P $ 0.001 uncorrected) and rightcerebellum (16, "62, "46; P $ 0.001 uncorrected).

Next we looked at the contrast examining the additive multi-sensory responses by performing a conjunction analysis of the twomain effects, defined as [(T % VT) " (V % RestEC)] ! [(V %VT) " (T % RestEC)] (Fig. 4; Table 1). In the parietal lobe,such responses were located in a cluster spanning the leftpostcentral sulcus, the superior parietal gyrus and the anterior

intraparietal sulcus (with the peak at "38, "38, 62; P $ 0.001corrected), in the left supramarginal gyrus ("56, "26, 22; P $0.001 corrected) and in the left parietal operculum/insula (-"0,"30, 20; P $ 0.001 corrected). Significant clusters were alsodetected in the right parietal operculum and in the cortexadjacent to the posterior segment of the right lateral fissure (46,"32, 24; P # 0.017 corrected). In the frontal lobe, clustersshowing additive responses were located in the dorsal and inthe ventral parts of the premotor cortex (at "38, "12, 64 withP # 0.009 and at "58, 2, 36 with P # 0.041 corrected,respectively). Subcortically, clusters of active voxels display-ing additive multisensory responses were found in the rightcerebellum (lobule VIII, 20, "60, "46; P $ 0.001 corrected)and in the left thalamus ("16, "22,4; P # 0.017 corrected).

Finally, we probed for subadditive responses by examiningthe negative interaction contrast, defined as [(T " RestEC) "(VT-V)]. No significant effects were found for this contrast,and, therefore no visuotactile brain regions were classified assubadditive in this study.

Multisensory convergence: conjunction analysis

As a complementary analysis, a conjunction analysis of thetwo unisensory activation maps was performed to identifyareas of convergence, i.e., to identify all the voxels onto whichresponses to both sensory modalities mapped significantly (T-RestEC ! V - RestEO, Fig. 5; Table 2).

The cortex lining the left postcentral sulcus (x # "36, y #"38, z # 60; P # 0.002, part of a cluster extending into themost superior portion of the anterior intraparietal sulcus; allreported coordinates are in MNI space), the left parietal oper-

TABLE 1. Superadditive and additive BOLD responses

Anatomical location

MNI coordinates

Peak t-Value Peak P Cluster Sizex y z

Superadditive responses (VT " V) & (T " RestEC)Left anterior intraparietal sulcus "32 "46 62 4.58 0.005* 108Left putamen "24 4 8 4.19 0.011* 25Left precentral gyrus (PMd) "34 "16 62 3.50 0.015* 45Left insula "32 "26 16 3.49 0.015* 51Right parietal operculum 52 "22 18 3.01 $0.001† 36Right cerebellum 16 "62 "46 3.37 $0.001† 87

Additive responses [(T % VT) " (V % RestEC)] ![(VT " V) " (T % RestEC)]

Left parietal operculum "50 "30 20 11.61 $0.001 531Left postcentral sulcus "38 "38 62 10.12 $0.001 395Left supramarginal gyrus "56 "26 22 9.45 $0.001 531Right cerebellum (lobule VIIIb) 20 "60 "46 8.84 $0.001 79Left postcentral sulcus "56 "26 44 8.55 $0.001 531Left supramarginal gyrus "56 "22 30 7.55 $0.001 531Left precentral gyrus (PMd) "38 "12 64 6.36 0.009 117Right cerebellum (lobule VIIIa) 14 "68 "44 6.00 0.015 79Right lateral fissure, posterior segment 46 "32 24 5.87 0.017 336Left ventrolateral thalamus "16 "22 4 5.85 0.017 96Right parietal operculum 54 "28 24 5.45 0.033 336Left precentral gyrus (PMv) "58 2 36 4.07 0.041(*) 32

Significant additive responses were obtained from the conjunction analysis of the two main effects, defined as [(T % VT) " (V % RestEC)] ! [(VT % V) "(T % RestEC)]; superadditive responses were obtained from the interaction contrast (VT " V) & (T " RestEC) masked exclusively with negativeblood-oxygen-level-dependent (BOLD) responses following one or both unisensory conditions (P $ 0.01 uncorrected). The MNI coordinates, t-values, P values,and cluster sizes of the activation maximum in each of the corresponding anatomical regions are reported. In this case, peaks sharing the same cluster size arepart of the same activation cluster. The t-value threshold corresponding to the whole-brain FDR-threshold of 0.05 was 4.63. P $ 0.05 after correction for multiplecomparisons in the whole brain using topological FDR for peak height. *P $ 0.05 after small volume correction based on a priori hypotheses. †P $ 0.001uncorrected.




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culum and insular cortex (SII, !48, !34, 20; P " 0.007) andthe left dorsal (!40, !10, 62; P " 0.021) and ventral (! 60,2, 32; P " 0.028) premotor cortices all exhibited significantBOLD responses to both tactile and visual unisensory stimu-lation. At a lower threshold this contrast revealed additionalactive areas in the left supramarginal gyrus (!56, !26, 42;P # 0.001 uncorrected), right parietal operculum (SII, 48,!28, 24; P # 0.001 uncorrected), right cerebellum (lobule VI,32, !60, !20; P # 0.001 uncorrected) and left putamen (!22,2, !4; P # 0.001 uncorrected).

To rule out the possibility that the identification of areasshowing convergence and revealing integration of hand-related visual and tactile signals was the result of theintersubject averaging performed in group analyses of fMRIdata, we carefully checked the key contrasts in our analysis(see preceding text) for all participants individually. Thisanalysis showed a remarkable consistency across partici-pants for the contrasts described in the preceding text, asexemplified in Fig. 6 for four representative subjects.

D I S C U S S I O N

This fMRI study has identified candidate brain sites associ-ated with the convergence and integration of visual and so-matic signals from the hand in premotor, parietal, and subcor-tical regions. To our knowledge, this is the first direct com-parison of unisensory and multisensory visuotactile stimulationconditions of the hand conducted with the intention of charac-terizing multisensory integrative effects in analogy with the

literature on multisensory integration in non-human primates(Avillac et al. 2007). We found enhanced BOLD responses tomultisensory stimuli in the left (contralateral) ventral anddorsal premotor cortex, left anterior part of the intraparietalsulcus, left inferior parietal cortex (supramarginal gyrus), leftpostcentral sulcus, left insula, and bilateral parietal operculum.Subcortically, multisensory integrative effects were detected inthe left putamen, left thalamus, and right cerebellum. Theseregions are anatomically interconnected and are known tocontain neurons that integrate visual and somatic signals innonhuman primates (as discussed in greater detail in thefollowing text). Additionally, the sensorimotor properties ofthese regions are known to be fundamental for sensory guid-ance of arm and hand actions (Andersen et al. 1997; Rizzolattiet al. 1998). The localization and specificity of the fMRIactivations described here to sets of brain regions that areknown to be anatomically interconnected suggest that theperceptual binding of vision and touch arises as the integrationof signals across interconnected brain regions. This is consis-tent with the literature on audiovisual perceptual binding inhumans, that has shown the importance of interconnected brainregions for the fusion of auditory and visual cues (Bushara etal. 2003).

Our results are important because they provide robust evi-dence that these circuits are functionally relevant for multisen-sory perception of the hand in space. Further, they providecompelling support for the hypothesis that, in man, as in thenon-human primate (Graziano and Botvinick 2002), visual,tactile, and proprioceptive signals from the upper limb con-verge onto multisensory neuronal populations in specific pre-motor, parietal, and subcortical structures that represent thespace near the body in a common hand-centered referenceframe.

Additive and superadditive responses

At the level of a single neuron, the firing rates induced byuni- and multisensory stimuli can be directly compared andclassified into additive and sub- and superadditive (Stein andStanford 2008; Wallace et al. 1996). All three types of inter-action are known to contribute to behavior and perception(Stanford and Stein 2007). In fact, linear, additive responsesare the most common mode of response of individual multi-sensory neurons to non near-threshold stimuli (Stanford andStein 2007; Stanford et al. 2005). Therefore in the presentstudy, we interpret both linear and nonlinear responses in thehypothesized areas as reflecting biologically meaningful mul-tisensory integration.

This approach calls for some further critical discussion whenemployed with BOLD-based fMRI as this neuroimaging tech-nique measures signals from a large population of (possiblyheterogeneous) neurons within a voxel (Logothetis 2008;Logothetis et al. 2001). In other words, a voxel could containboth uni- and multisensory neuronal populations. This hassparked an important discussion in the field of multisensorybrain imaging concerning which criteria should be used toidentify multisensory responses. One highly influential studyargued that superadditivity should be taken as the “goldenstandard” (Calvert 2001). More recent reviews have, however,challenged this claim and have suggested that other types ofresponse should also be carefully investigated (Goebel and van

PoCSVT = T + V

VT > T + V

PMd aIPS

VT > T + V

PMvSMG

SII / ins

FIG. 2. Illustration of the superadditive and additive responses. Activationmaps corresponding to additive (red) and superadditive (blue) responses tomultisensory stimulation, displayed on an inflated average cortical surface ofthe left hemisphere. For display purposes only, the statistical thresholds werechosen to be P # 0.005 for both contrasts. A black star in the vicinity of a bluecolor-coded cluster indicates superadditive responses that are significant aftercorrection for multiple comparisons (P # 0.05 corrected); these are located inthe insular region, premotor cortex and anterior intraparietal cortex. All redcolor-coded clusters contained statistically significant (P # 0.05 corrected)local maxima, reported in Table 1. PMv, ventral premotor cortex; PMd, dorsalpremotor cortex; PoCS, postcentral sulcus; aIPS, anterior intraparietal sulcus;SMG, supramarginal gyrus; SII/ins, secondary somatosensory cortex / insularregion. The data corresponding to this figure are reported in Table 1.




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Atteveldt 2009; Laurienti et al. 2005; Stein et al. 2009). Thecentral point in this discussion is that fMRI studies cannotdirectly discriminate between areal and neuronal convergence(Calvert 2001; Goebel and van Atteveldt 2009; Stevenson et al.2007). In principle, a linear BOLD response could be producedby two separate populations of unisensory cells co-existingwithin the same voxel. The other side of this coin, though, isthat a nonlinear, superadditive response at the voxel levelcannot be simply explained away as convergence of sensoryinputs onto different, noninteracting neuronal populations(Calvert 2001; Goebel and van Atteveldt 2009; Laurienti et al.2005; Stevenson et al. 2007). Thus a superadditive BOLDresponse must reflect a neuronal interaction of some sort, be itexpressed at the level of discharge rates or local field potentials(Logothetis et al. 2001). It is important to note that there areseveral arguments that can be called on to explain why thesuperadditive criterion may turn out to be too conservative, twosuch being: the tendency of neurons to respond nonlinearlyonly for weak, near-threshold stimuli (Laurienti et al. 2005;Stanford et al. 2005; Stevenson et al. 2007) and vascularceiling effects for the BOLD response (Buxton et al. 2004),which might prevent detection of nonlinear interactions (Cal-vert 2001; Goebel and van Atteveldt 2009; Stevenson et al.2007). In light of this, the linear responses we observed in theleft ventral premotor cortex and the left supramarginal gyrus,where we had particularly strong a priori anatomo-functionalhypotheses (see INTRODUCTION), most likely reflect biologically

relevant evidence of the occurrence of multisensory integrationin these areas.

Posterior parietal cortex

The posterior parietal cortex is generally considered to be akey region for the fusion of signals from different sensorymodalities. In our study, we have found clear evidence for theconvergence of visual and somatic signals on and their inte-gration in several key areas in this part of the brain. Theanatomical locations of these response patterns in the parietallobe fit well with earlier electrophysiological studies on non-human primates (Avillac et al. 2005; Colby and Duhamel1991; Colby et al. 1993; Duhamel et al. 1998; Hyvärinen 1981;Hyvärinen and Poranen 1974), as will be discussed in somedetail in this section.

It is particularly important that we were able to detect a zoneof convergence of visual and tactile signals on and theirintegration in the anterior part of the intraparietal sulcus. Thisactivation exhibited a superadditive response profile and waslocated on the medial bank of the anterior segment of theintraparietal sulcus, close to the junction with the postcentralsulcus; the cluster of active voxels extended into the superiorparietal gyrus as well. The overlap between the active clusterobtained in the conjunction analysis of the two unisensoryconditions and the cluster identified by the positive interactioncontrast in the factorial analysis was highly convincing. Thelocation of these activations on the medial bank of the intra-

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FIG. 3. Superadditive responses to multisensorystimulation. Parameter estimates (!SE) for uni- andmultisensory stimuli in a set of regions where su-peradditive responses were found (P " 0.05 cor-rected for multiple comparisons). Each plot is pairedwith 2 anatomical sections of a standard brain dis-playing the localization of the superadditive re-sponses. Coordinates in MNI space. TPar op, pari-etal operculum. Cer, cerebellum.




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parietal sulcus fits very well with the activations reported inthis region during the rubber hand illusion (Ehrsson et al.2004). This illusion is associated with perceptual binding oftactile and visual stimuli, consistent with the evidence pre-sented here that this area is a site of visuotactile convergenceand integration. Furthermore, our results confirm and go be-yond the data presented by Makin and colleagues (2007),showing evidence not only of multisensory convergence, butalso of integration of visual and tactile hand-related signals inthe anterior intraparietal area.

It is not straightforward to relate the anatomical location ofthe activated areas directly to specific functional regions de-fined in and around the intraparietal sulcus in the macaquebrain, as homological relations have not been fully established(Culham et al. 2006; Grefkes and Fink 2005). In the monkeybrain, the anterior intraparietal area (AIP) lays on the lateral bankof the sulcus, while areas VIP (ventral intraparietal area) and MIP(medial intraparietal area) are found on the medial bank (Grefkesand Fink 2005). Thus it is possible that the activation underdiscussion was driven by active neurons in the two latter areas

rather than in the former. Taken together, the results presentedhere provide compelling support for the notion that the anteriorintraparietal cortex contributes to the multisensory representationof the arm in space (Makin et al. 2007, 2008), in addition to itswell-established role in the sensory guidance of grasp-relatedaction (Binkofski et al. 1998; Culham et al. 2003, 2006; Ehrssonet al. 2000, 2001).

Anterior to the intraparietal sulcus, we observed multisen-sory responses in the form of distinct peaks of activation in thecortex lining the postcentral sulcus. The anterior bank of thissulcus corresponds to area 2 of the primary somatosensorycortex, the posterior bank being associated with area 5 of theposterior parietal cortex instead. Area 2, although traditionallyconsidered part of the primary somatosensory cortex, isthought to be involved in higher order somatosensory process-ing (Bodegård et al. 2001; Iwamura 1998; Roland et al. 1998),with an emphasis on proprioceptive signals (Naito et al. 2005).Area 5 is generally considered to be a somatosensory associ-ation area (Bodegård et al. 2000; Duffy and Burchfiel 1971;Mountcastle et al. 1975; Sakata et al. 1973; Taoka et al. 2000).

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FIG. 4. Additive responses to multisensory stim-ulation. Parameters estimates (!SE) for uni- andmultisensory stimuli in a set of regions (see text forclarification) where additive responses were found(P " 0.05 corrected for multiple comparisons). Eachplot is paired with 2 anatomical sections of a stan-dard brain displaying the localization of the additiveresponses. All reported coordinates are in MNIspace. Supramarg, supramarginal.




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Based on research on nonhuman primates, areas 2 and 5 are nottaken to be the primary candidate sites for visuotactile integra-tion in the parietal lobe (the intraparietal and inferior posteriorparietal cortex being stronger candidates; see INTRODUCTION).However, in area 5 of the monkey brain, neurons with bothvisual and tactile receptive fields have been described (Gra-ziano et al. 2000; Iriki et al. 1996; Sakata et al. 1973). Grazianoand colleagues showed how these cells integrate visual andsomatic information for the representation of arm position inspace (Graziano et al. 2000), although the greatest proportionof cells of this type was observed in the part of area 5 locatedin the medial bank of the intraparietal sulcus (MIP) (Grazianoand Botvinick 2000). Nevertheless, our human data support theexisting evidence in non-human primates that the cortex liningthe postcentral sulcus is involved in the integration of visualand somatic information from the hand. Anatomically, area 5receives prominent inputs from the primary somatosensorycortex, and in particular from area 2 (Pandya and Kuypers1969; Pearson and Powell 1985). Additionally, area 5 is alsoconnected to the primary motor cortex and premotor areas andis involved in reaching movements (Andersen et al. 1997;Johnson et al. 1996; Mountcastle et al. 1975; Scott et al. 1997).Therefore it is possible that the activations observed in passive

participants under discussion here reflect a multisensory mech-anism for the localization of the arm in space, a prerequisite forpotential hand-object interactions.

The inferior posterior parietal cortex was also identified as asite of multisensory convergence and visuotactile integration inthe present study. The corresponding activation was located inthe left supramarginal gyrus. Although the precise homologybetween cytoarchitectonical areas of human and monkey infe-rior parietal lobes is not fully known (Eidelberg and Galaburda1984), it has been suggested that the inferior parietal cortex inmonkeys (area 7b/PF) likely corresponds to the supramarginalgyrus in the human brain (Krams et al. 1998). In monkeys, thisregion has anatomical connections to areas 2, 4, 5, and 45, theparietal operculum (Hyvärinen 1982; Neal et al. 1987 1990b),ventral premotor cortex (Ghosh and Gattera 1995; Godschalket al. 1984; Neal et al. 1990a), and insula (Neal 1990; Neal etal. 1987), all of which are areas that displayed evidence ofmultisensory integration in the present study. Neurons withbimodal visuotactile responses have been found in this region(Hyvärinen 1981; Hyvärinen and Poranen 1974; Ishida et al.2010). The inferior parietal cortex is an important node in thefronto-parietal circuits involved in sensory-guided hand actions(Luppino and Rizzolatti 2000); in human neuroimaging stud-ies, it is consistently activated during hand-object interactions(Binkofski et al. 1998; Ehrsson et al. 2000, 2001; Kuhtz-Buschbeck et al. 2001). The supramarginal gyrus is alsoactivated by proprioceptive stimulation inducing sensations oflimb movement (Naito et al. 2005), demonstrating that thisregion receives significant proprioceptive inputs. The datareported here are interesting in this respect as they show thatthe involvement of this region in the sensory representation ofthe hand is fundamentally multisensory in nature, continuouslycombining visual and somatic data from the hand in space.

Parietal operculum and insula

We also found superadditive responses in clusters located inthe contralateral (left) insula and in the right parietal opercu-lum; the left parietal operculum exhibited additive multisen-sory responses. The parietal operculum is part of the secondarysomatosensory area (SII) in humans, a relatively early process-ing node in the somatosensory system (Eickhoff et al. 2006). In

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FIG. 5. Conjunction analysis of unisensory responses. Conjunction analysisof the 2 unisensory activation maps, showing clusters activated by both tactileand visual stimuli, displayed on an inflated canonical cortical surface. Voxel-wise threshold: P ! 0.005 uncorrected, for illustration purposes only. SII/ins,secondary somatosensory cortex and insula. See Table 2 for additionalinformation.

TABLE 2. Conjunction analysis of unisensory responses

Anatomical Location

MNI Coordinates

Peak t-Value Peak P Cluster Sizex y z

Conjunction of unisensory responses (T " RestEC)! (V " RestEO)

Left postcentral sulcus* "36 "38 60 6.27 0.002 76Left parietal operculum "48 "34 20 5.53 0.007 340Left precentral gyrus (PMd) "40 "10 62 4.99 0.021 135Left precentral gyrus (PMv) "60 2 32 3.18 0.028† 17Left supramarginal gyrus "56 "26 42 4.15 !0.001† 340Left putamen "22 2 "4 4.14 !0.001† 9Right parietal operculum 48 "28 24 4.25 !0.001‡ 220Right cerebellum (Lobule VI) 32 "60 "20 3.02 !0.001‡ 8

Significant activations from a conjunction analysis performed on the two unisensory activation maps. The MNI coordinates, t-values, P values, and cluster sizesfor the maximum activation in each of the corresponding anatomical regions are reported. The t-value threshold corresponding to the whole-brain FDR-thresholdof 0.05 was 4.78. In this case, peaks sharing the same cluster size are part of the same activation cluster. P ! 0.05 after correction for multiple comparisons inthe whole brain using topological FDR for peak height. *Part of a cluster extending into the anterior section of the intraparietal sulcus (IPS) and superior parietalgyrus. †P ! 0.05 after small volume correction based on a priori hypotheses. ‡P ! 0.001 uncorrected.




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human brain imaging studies, it is consistently activated by awide range of somatic stimuli (Banati et al. 2000; Bodegård etal. 2000; Ledberg et al. 1995; Naito et al. 1999; O’Sullivan etal. 1994; Roland et al. 1998). Furthermore, activations in theparietal operculum are induced by passive movements (Weilleret al. 1996) and illusory arm movements elicited by tendonvibration (Naito et al. 2005). In monkeys, the parietal opercu-lum receives prominent tactile and deep receptor inputs (Rob-inson and Burton 1980) and is anatomically connected to theinferior posterior parietal cortex (Disbrow et al. 2003) and tothe ventral premotor cortex (Cipolloni and Pandya 1999; Dis-brow et al. 2003; Ghosh and Gattera 1995; Godschalk et al.1984; Matelli et al. 1986) and thus probably works in concertwith these areas to represent the spatial location of the arm andan object touching it in space. Moreover, a recent study offeredfurther evidence that regions within the human parietal oper-culum are anatomically connected with key multisensory areasin the frontal and parietal lobes (Eickhoff et al. 2010). In thelight of this, the parietal operculum could be an importantprocessing node in the network involved in the multisensoryperception of the hand in space as suggested by our results.

In addition, we observed multisensory effects in the leftinsular cortex. The insula, together with the adjacent claus-trum, has been suggested to be an important cortical site formultisensory integration (Bushara et al. 2001a; Hadjikhani andRoland 1998; Naghavi et al. 2007). In particular, the insula/claustrum region has been associated with cross-modal visuot-actile processing for recognition (Banati et al. 2000) anddiscrimination (Hadjikhani and Roland 1998) tasks. The find-ing that we report here provide new evidence that the basicintegration of visual and somatic signals from a static hand andan object touching it is performed in this multisensory area.

Frontal responses

The premotor cortex is a site of convergence of visual,tactile, and proprioceptive information (Rizzolatti et al. 1981;

Graziano et al. 1997). It is also involved in the control ofgoal-directed hand actions (Rizzolatti et al. 1998) and defen-sive movements (Graziano et al. 2002). In the present study,we found clear evidence in the left (contralateral) premotorcortex for the convergence of visual and somatic signals fromthe hand as well as of integration of these signals within thisarea. In the ventral premotor cortex, multisensory enhancementwas additive; in addition to this, in the dorsal part of thepremotor cortex, we found evidence for superadditive effects.These results fit well with electrophysiological studies onnonhuman primates, which have stressed the importance of thepremotor cortex in processing visual and tactile sensory signalsfrom the body and its surrounding space.

Bimodal visuotactile neurons have been described in theventral premotor cortex of the macaque (Graziano and Gandhi2000; Graziano et al. 1997; Rizzolatti et al. 1981) with over-lapping tactile and visual receptive fields anchored to specificbody parts. In particular, Graziano and colleagues describedbisensory neurons that are sensitive to somatosensory andvisual stimulation of the monkey’s hand (Graziano and Bot-vinick 2002; Graziano and Gandhi 2000; Graziano et al. 1997).These responses are also present in anesthetized monkeys(Graziano and Gandhi 2000), which suggests that premotorneurons perform multisensory integration even when the mon-key is not planning or performing an action. In the presentstudy, participants held their arm still and did not perform anymotor tasks, so the measured premotor responses most likelyreflect basic visuotactile integration mechanisms. This inter-pretation fits with earlier fMRI studies that reported premotoractivations during visuotactile stimulation of the arm in passivesubjects (Ehrsson et al. 2004; Lloyd et al. 2003).

Besides the ventral premotor cortex, we also found evidenceof visuotactile integration in the dorsal premotor cortex. Al-though this region of the premotor cortex has not been asextensively characterized as its ventral neighbor in terms of itsmultisensory properties, visuotactile neurons have been de-

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FIG. 6. Consistent activations across individualparticipants. Convergence of unisensory tactile andvisual responses in 4 individual participants, labeledA–D. Middle: active clusters in the cortex within andaround the intraparietal sulcus outlined by greensquares. Top: an enlarged view of the area withineach square; for ease of anatomical localization, asegment of the intraparietal sulcus is outlined. Bot-tom: active clusters in the ventral premotor cortex(inferior part of the precentral gyrus and sulcus),highlighted by green arrows. All activation mapswere thresholded at P ! 0.001, uncorrected fordisplay purposes only.




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scribed in the caudal part of this area (Fogassi et al. 1999;Graziano and Gandhi 2000). The convergence of propriocep-tive, tactile, and visual information, as well as its connectivitypattern with several regions in the posterior parietal lobe, inparticular area 5 (Rizzolatti et al. 1998), has led scientists toassign to the dorsal premotor cortex an important role inmonitoring and controlling arm and hand movements in space(Rizzolatti et al. 1998; Scott et al. 1997). Integration of visual,tactile, and proprioceptive information in the dorsal premotorcortex might therefore be important for calibrating the repre-sentation of limb position (Ehrsson et al. 2004) as part of acircuit devoted to the control of arm and hand movements(Kertzman et al. 1997).

Putamen

The evidence provided here for visuotactile integration inthe human putamen was particularly noteworthy. In the ma-caque putamen, bisensory, visuotactile neurons with body-centered receptive fields, similar to those found in frontal andparietal regions, were identified in a classic paper by Grazianoand Gross (1993). In this report, the authors described howneurons with tactile receptive fields organized somatotopicallyinto arm, hand, and face regions were also responsive to visualstimulation and in particular visual stimuli originating from thespace close to the body (Graziano and Gross 1993). Given thetight anatomical connections with multisensory frontal andparietal regions (Cavada and Goldman-Rakic 1991; Grazianoand Gross 1993; Künzle 1978; Parthasarathy et al. 1992;Weber and Yin 1984), the putamen is considered part of thevisuotactile network responsible for motor interactions withenvironmental objects (Graziano and Gross 1993). To the bestof our knowledge, the evidence we have found of superadditiveBOLD responses in the contralateral (left) putamen providesthe most conclusive evidence today that the human putamenperforms integration of visual and somatic signals from thehand, possibly in hand-centered reference frames. The previ-ously mentioned fMRI studies, which included unisensoryvisual and tactile stimulation conditions (Makin et al. 2007)and bisensory stimulation (Ehrsson et al. 2004; Lloyd et al.2003), failed to identify consistent activation in the putamen.Our stimulation paradigm using robust natural bisensory stim-ulation of the hand and functional imaging at a higher fieldstrength of 3T, rather than the 1.5T in the reported studies, aremost likely responsible for the increase in sensitivity thatallowed us to describe activations in this small subcorticalstructure.

Cerebellum

In the study being presented here, the cerebellum displayedevidence of convergence of visual and tactile hand-relatedsignals as well as of multisensory integration of both theadditive and superadditive type. All activations were localizedin the ipsilateral (right) cerebellum. Although the cerebellumhas long been considered to be primarily involved in thecontrol of action, recent developments have suggested that thisstructure also plays an important role in perceptual and cogni-tive functions (Gao et al. 1996; Ramnani 2006; Schmahmannand Sherman 1998; Strick et al. 2009). The possibility thatthere is convergence of signals from different sensory modal-

ities in cerebellar regions is supported by extensive knowledgeof the functional connectivity of this structure in nonhumanprimates. Visual (Glickstein et al. 1994; Sultan and Glickstein2007), tactile (Bloedel 1973; Bushara et al. 2001b; Snider andStowell 1944), and kinesthetic (Murphy et al. 1973; van Kan etal. 1993) information is conveyed to the cerebellum eitherdirectly or indirectly, reinforcing the notion that this structurecould be an important node in cortico-cerebellar networks forthe processing of multisensory information. In humans, neu-roimaging studies have demonstrated the involvement of thecerebellum in multisensory processing (Bushara et al. 2001a;Hagura et al. 2009; Kavounoudias et al. 2008; Naumer et al.2010; Stevenson et al. 2009) as well as cerebellar activationfollowing tactile stimulation of the hand in passive participants(Bushara et al. 2001b; Fox et al. 1985), which is consistentwith our results. This accumulating body of evidence suggeststhat the cerebellum may play a role in the multisensory net-work devoted to the representation of the limb across sensorymodalities, although the present data cannot substantiate anyspeculation on the functional nature of such involvement.

Multisensory circuit for body ownership

Our results are also relevant for studies of body ownership,where the integration of vision and touch is assumed to be thefundamental mechanism behind the self-attribution of limbs(Ehrsson et al. 2004, 2005, 2007; Makin et al. 2008) and entirebodies (Petkova and Ehrsson 2008). Crucial fMRI evidence forthis idea came from the observation that touches sensed on anowned rubber hand were associated with activations in theventral premotor and intraparietal cortices (Ehrsson et al.2004). However, in this earlier study and similar ones con-ducted subsequently, the authors did not include a conditionwhere the real hand was stimulated to demonstrate that theseareas are robustly activated when one’s own real hand isstimulated naturally in full view (Ehrsson et al. 2004, 2005,2007). In light of this, the present findings that tactile stimu-lation of a real hand being watched by its “owner” activates theventral premotor and intraparietal cortices, regions recognizedto be sites of convergence and integration of visual and tactilesignals, provide an important validation of the multisensoryhypothesis of body ownership (Ehrsson et al. 2004; Makin etal. 2008; Petkova and Ehrsson 2008; Tsakiris 2010).

Conclusions

In this fMRI study, we manipulated the contribution ofvision and touch to passive, ecologically valid stimulation ofthe hand in humans to characterize cortical and subcorticalregions in terms of their multisensory, visuotactile responses.Adopting a methodology originated in electrophysiologicalstudies in animals (Stein and Stanford 2008; Wallace et al.1996) and introduced in the human brain imaging literature(Calvert 2001) to assess multisensory integration, we describedlinear and nonlinear BOLD responses to visuotactile stimula-tion in a set of premotor, posterior parietal, and subcorticalregions matching the neurophysiological literature on multi-sensory areas in nonhuman primates and humans well. Theseresults provide compelling support for the role of these areas inintegrating visual and tactile information to build a cross-modal representation of hand-related sensory signals.




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A C K N O W L E D G M E N T S

The authors thank U. Keiller, T. Jonsson, and T.-Q. Li for help with thesetup. The authors also thank three anonymous reviewers, whose commentshelped improve this manuscript.

G R A N T S

This study was funded by the European Research Council, the SwedishFoundation for Strategic Research, the Human Frontier Science Program, andStockholm Brain Institute. All scans were performed at the MR-Centre at theKarolinska University Hospital in Huddinge, Sweden.

D I S C L O S U R E S

No conflicts of interest, financial or otherwise, are declared by the author(s).

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