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  • Neuropsychologia 50 (2012) 1471 1477

    Contents lists available at SciVerse ScienceDirect

    Neuropsychologia

    jo u rn al hom epa ge : www.elsev ier .com/ loca

    Disinhibited feedback as a cause of synesthesia: Econnec ete

    J. Neufeld richa Dept. of Psych nyb Center of Syst

    a r t i c l

    Article history:Received 24 NReceived in reAccepted 27 FAvailable onlin

    Keywords:SynesthesiaConnectivityAuditory-visualInferior parietalDisinhibited feedback

    sensoodelsulate

    tivatictivatnd th

    which may be located in the parietal cortex. This latter hypothesis is compatible with the disinhibitedfeedback model, which suggests unusual feedback from multimodal convergence areas as the cause ofsynesthesia. In this study, the relevance of these models was tested in a group (n = 14) of auditory-visualsynesthetes by performing a functional connectivity analysis on functional magnetic resonance imaging(fMRI) data. Different simple and complex sounds were used as stimuli, and functionally dened seedareas in the bilateral auditory cortex (AC) and the left inferior parietal cortex (IPC) were used for the con-

    1. Introdu

    In synesinducer, leainternally gMetzger, Focurrent. Indperiods (Simchological tactivation mfeedback mdisinhibitedcross activaof inducer back model

    Corresponapy, HannoverTel.: +49 511 5

    E-mail add1 These auth

    0028-3932/$ doi:10.1016/j.nectivity calculations. We found no differences in the connectivity of the AC and the visual areas betweensynesthetes and controls. The main nding of the study was stronger connectivity of the left IPC withthe left primary auditory and right primary visual cortex in the group of auditory-visual synesthetes.The results support the model of disinhibited feedback as a cause of synesthetic perception but do notsuggest direct cross-activation.

    2012 Elsevier Ltd. All rights reserved.

    ction

    thesia, the perception of a certain stimulus, called ands automatically and involuntarily to an additionalenerated sensation (Lupianez & Callejas, 2006; Mills,ster, Valentine-Gresko, & Ricketts, 2009), called a con-ucer-concurrent pairings remain stable over long timener & Logie, 2007). Three main classes of neuropsy-

    heories of synesthesia have been discussed: the crossodel (Ramachandran & Hubbard, 2001), the re-entrant

    odel (Smilek, Dixon, Cudahy, & Merikle, 2001), and the feedback model (Grossenbacher & Lovelace, 2001). Thetion model proposes a direct linkage between the areasand concurrent representation. The re-entrant feed-

    suggests crosstalk between the inducer and concurrent

    ding author at: Dept. of Psychiatry, Social Psychiatry and Psychother- Medical School, Carl-Neuberg-Strae 1, 30625 Hanover, Germany.32 9191; fax: +49 511 532 3187.ress: [email protected] (G.R. Szycik).ors contributed equally to this study.

    brain areas along with additional feedback from higher-level areas.The disinhibited feedback model proposes an unusual activationof the concurrent-related brain areas caused by the disinhibi-tion of feedback to these areas from a multisensory nexus area,e.g., the parietal cortex. Recently, new models of synesthesia havebeen introduced based on research on grapheme-color synesthetes.These models represent extensions of the cross activation theory inthe form of the so-called two-stage model (Hubbard, 2007) and thenew cascaded cross-tuning model of synesthesia (Hubbard, Brang,& Ramachandran, 2011).

    The majority of the knowledge about synesthesia comesfrom the most commonly investigated type, namely grapheme-color synesthesia (Simner et al., 2006). There is evidence thatthis type of synesthesia involves spatially adjacent brain areasresponsible for color processing (area V4) and grapheme rep-resentation (Brang, Hubbard, Coulson, Huang, & Ramachandran,2010; Hubbard, Arman, Ramachandran, & Boynton, 2005; Nunnet al., 2002), although a recent functional neuroimaging studyin which color processing centers were identied individually ineach participant challenges this view (Hupe, Bordier, & Dojat,2011). The spatial proximity of the two areas suggests directcross-activation as the mechanism responsible for grapheme-color

    see front matter 2012 Elsevier Ltd. All rights reserved.neuropsychologia.2012.02.032tivity study on auditory-visual synestha,b,1, C. Sinkea,b,1, M. Zedlera, W. Dilloa, H.M. Em

    iatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hanover, Germaems Neuroscience, Hanover, Germany

    e i n f o

    ovember 2011vised form 26 February 2012ebruary 2012e 6 March 2012

    a b s t r a c t

    In synesthesia, certain stimuli to onelated modality. In addition to other mwhich combines two previously formand hyperbinding. The direct cross-acspecic areas are responsible for co-asuggests that the inducing stimulus ate /neuropsychologia

    vidence from a functionalsa,b, S. Bleicha,b, G.R. Szycika,

    ry modality lead to sensory perception in another unstimu-, a two-stage model is discussed to explain this phenomenon,d hypotheses regarding synesthesia: direct cross-activation

    on model postulates that direct connections between sensory-ion and synesthetic perception. The hyperbinding hypothesise synesthetic sensation are coupled by a sensory nexus area,

  • 1472 J. Neufeld et al. / Neuropsychologia 50 (2012) 1471 1477

    synesthesia (Ramachandran & Hubbard, 2001). Evidence for thismodel has been provided by imaging research focusing on neu-roanatomical alterations (Jncke, Beeli, Eulig, & Hanggi, 2009)or effective connectivity analyses (van Leeuwen, den Ouden, &Hagoort, 20several neument of thLeeuwen, PZilles, & Finment of ththe only mof synesthebetween thin which accating thatcould be re2009). Currwith a pariIvry, & Robfor synesthactivation otion of areaand concurexperience (Hubbard, 2model of grporates botFurthermorfeatures of partial activcomes froming visual cletters (Jnctory, visual,was identiinterconnecaberrationscase study osia (Hanggigrapheme-city changesWotruba, &distributedcortex), as rfunctional agyrus can eing spatiallgrapheme-cties of cortithat synestnections becouplings. Fit is conceithat sound-ple, has a dwithin moFurthermorsynesthesiacoming from& Noesselt,

    Until nosynesthesiawithin moother formsstanding ofdue to the

    of the current study was to investigate the connectivity of a priorifunctionally dened brain regions in synesthesia. We decided touse a functional connectivity analysis of functional magnetic reso-nance imaging (fMRI) data from auditory-visual synesthetes and

    ls reuli

    esthestly . Wee conal aunallymodyed hEspoty ofs in ing

    d com to idhesiaour merebage m

    meden the vishe IPuld tivitentat

    ods

    rocedormed

    jects

    teen rt syn, handatz-Inmined

    music partit tonean, Kaed to ind wit matcked tons of d, gre

    itemd betponseesthetould bsia ints e

    uli an

    licit vg thents). nd puhe stimompoer blonter-s11). However, there is also growing evidence fromroimaging studies supporting the additional involve-e parietal cortex (Rouw & Scholte, 2007, 2010; vanetersson, & Hagoort, 2010; Weiss & Fink, 2009; Weiss,k, 2005) in grapheme-color synesthesia. This involve-e parietal cortex speaks against cross-activation asechanism in synesthesia. Furthermore, other formssia combine modalities with more spatial distancee involved brain areas, e.g., auditory-visual synesthesia,oustic stimulation leads to a visual experience, indi-

    additional mechanisms, apart from cross-activation,sponsible for this phenomenon (Goller, Otten, & Ward,ently, a combined model of cross-activation togetheretal hyperbinding mechanism (Esterman, Verstynen,ertson, 2006) is presented as an adequate explanationetic perception. This two-stage model proposes thatf concurrent areas is evoked directly by the activa-s that process the inducing stimuli, but the inducerrent sensations are bound together to form a holisticby parietal modulating mechanisms in a second step007). The recently introduced cascaded cross-tuning

    apheme-color synesthesia (Hubbard et al., 2011) incor-h early direct cross activation and top-down inuences.e, the model suggests that some of the form-relatedthe grapheme, rather than entire letters, may lead toation of color area V4. Support for the two-stage model

    a recent resting-state EEG study on subjects manifest-oncurrents evoked by auditorily presented words andke & Langer, 2011). In this study, in addition to the audi-

    frontal and limbic brain regions, the left parietal cortexed as a major hub region, which was more functionallyted in synesthetes than in non-synesthetes. Structural

    in brain connectivity have also been shown in a singlen a subject with tone-color and interval-taste synesthe-, Beeli, Oechslin, & Jancke, 2008) and in a group study onolor synesthetes, which indicated structural connectiv-

    in the fusiform gyrus and intraparietal sulcus (Hanggi, Jancke, 2011). These latter studies suggest a well-

    network, rather than only color-related areas (visualelevant for synesthetic color perception. The detectednd structural connectivity aberrations in the fusiformxplain the synesthetic perceptions for couplings affect-y adjacent inducer and concurrent brain areas (as inolor synesthesia) based on the small-world proper-cal connectivity (Bargary & Mitchell, 2008). It followshesia could be a result of direct, feedforward con-tween adjacent areas, especially for within-modalityor other kinds of synesthesia (e.g., between-modality),vable that the underlying mechanism is different andcolor (without speech relation) synesthesia, for exam-ifferent principal mechanism (e.g., disinhibition) thandality synesthesia (Cohen Kadosh & Walsh, 2008).e, many multisensory phenomena (also unrelated to) reect feedback inuences on sensory-specic areas

    spatial distant multimodal convergence zones (Driver 2008).w, knowledge regarding the perception processes in

    has been largely based on research regarding thedality grapheme-color synesthesia. Knowledge about

    of synesthesia, although important for a global under- perceptional processes, has been unfortunately sparserelatively small number of available subjects. The aim

    controby stimof synor (mo(Fig. 1)late thbilaterfunctiolinear emploand Dnectiviprocesexaminmethoabilitysynesteling, and thtwo-stsia wasbetwe(e.g., thfrom tity shoconnecrepres

    2. Meth

    All pgave infstudy.

    2.1. Sub

    Fournot repoage, sexWortschas deteryears of

    Eachdifferen(Eagleminstructments athat beswere assentatioRGB (refor eachcomparetheir resthe synthetes csynestheconcurre

    2.2. Stim

    To euli durinconcurrechords aorder. Tdesign cdition pand an icorded during the perception of synesthesia inducedunrelated to speech (tones and chords). In this formsia, hearing a sound leads to the perception of colorthree-dimensional) colored shapes moving in space

    focused the analysis on three seeds of interest to calcu-nectivity: the left inferior parietal cortex (IPC) and theditory cortex (AC). The areas of interest were dened

    in our previous study using a standard GLM (generalel) analysis (Neufeld et al., 2012). The analysis methodere was introduced previously by Rissman, Gazzaley,sito (2004) and allows analysis of the functional con-

    predened brain areas in relation to a specic cognitivethe whole brain. Thus, it is particularly suitable forthe two-stage synesthesia model. The advantage of thispared to resting-state connectivity analysis lies in theentify brain connectivity related to the perception of-inducing sounds. In contrast to dynamic causal mod-ethod is free of the necessity to predene networks

    y also has an explorative quality. With respect to theodel of synesthesia, we hypothesized that if synesthe-iated by direct cross-activation, increased connectivitye AC and at least one area of concurrent representationual cortex) would be expected. If disinhibited feedbackC leads to synesthesia, such an increased connectiv-

    not be found. In contrast, one would expect increasedy between the IPC and at least one area of concurrention and perhaps also to areas representing the inducer.

    ures were approved by the local Ethics Committee. The participants consent and received a minimal monetary compensation in this

    auditory-visual synesthetes and fourteen control subjects, who didesthesia, participated in the study. Participants were matched foredness (self-reported), IQ, as measured by the MWT-B (Mehrfach-telligenztest B) (Lehrl, Triebig, & Fischer, 1995) and musical expertise,

    by the Ollen Musical Sophistication Index (OMSI) (Ollen, 2006) and lessons (Table 1).cipant was subjected to a consistency test for synesthesia with 36s, which was a modied ofine version of the synesthesia batterygan, Nelson, Sagaram, & Sarma, 2007). In this test, the subjects werendicate a color related to the tones presented from different instru-th different pitches. The synesthetes were asked to choose the colorhed the synesthetic color induced by the tone; the non-synesthetes

    select the color that they believed t the tone best. After three pre-the stimuli in a randomized order, the geometric distance in theen, blue) color space of the color choices indicated by the subjects

    during the three runs was calculated. The mean values were thenween groups. The synesthetes were signicantly more consistent ins (Table 1). Furthermore, we conducted an intensive interview withes regarding the type of synesthetic perception. All of the synes-e identied as so-called associators, or subjects who experiencen their minds eye. In contrast, synesthesia projectors experiencexternally, colocalized with a presented inducer.

    d paradigm

    isual synesthetic perceptions, we presented different auditory stim- acquisition of the fMRI data (see Fig. 1 for examples of the inducedWe used 6 different sound classes (major, minor and dissonant pianore piano, sine and bassoon tones) presented in pseudo-randomizeduli were presented via pneumatic headphones in an event-related

    sed of three sessions and 48 stimuli per session (8 stimuli per con-ck; 24 stimuli per condition in total) with a stimulus duration of 2 stimulus interval of 13 s. Between the sessions, the participants had

  • J. Neufeld et al. / Neuropsychologia 50 (2012) 1471 1477 1473

    Fig. 1. Acoust iolin are shown exe the mmovement.

    an opportunitgeneral noise ldata acquisitiotic stimuli agaeach subject dthe sound leveand chords wening procedurby the stimuliperceived anyinduced by thsensations indsynesthetic separticipants hemeasurementto press the rigthe left one (winstructed to kAll synesthete

    2.3. Image acq

    Functionalzon; GE Medicfunctional scadimensional e26 axial slices,

    s = 5 m12 mind to a

    a ana

    werd the ares a

    igned l Neumalizm Gaufuncti

    Table 1Mean values, s

    N (male) Age (SD)MWT-Ba rigOMSIb probaYears of musYears of instHandednessDimensionle

    a Mehrfach b Ollen Musc Tone-colo** Signicantically induced synesthetic photisms. The photisms induced by single tones (sine, vmplarily. The photisms were perceived in 3D, and the forms changed according to

    y to relax to avoid tiring and attention diminishment. To reduce theoad on our subjects, all of the subjects used ear plugs during the fMRIn. Additionally, to achieve a better signal to noise ratio of the acous-inst the scanner noise, the sound level was adjusted individually foruring a test scan in which some of the stimuli were presented andl was adjusted until the stimuli were clearly audible and the tonesre clearly discriminable for the subject. Directly following the scan-e, we asked all participants about the synesthetic sensations induced

    and the scanner noise. All of the control participants denied having synesthetic sensations. All synesthetes reported strong synesthesiae stimuli. The majority of the synesthetes also reported synestheticuced by the scanner noise, which were of a different quality than thensations induced by the stimuli (e.g., more in the background). Allld a response device in their right hand and performed a task during

    to guarantee that they fully attended the stimuli. They were asked

    thicknessions of discarde

    2.4. Dat

    Datarealigneleast squThe realMontreaThe normaximu

    The ht button (with their right middle nger) when hearing a chord andith their right index nger) when hearing a tone. The subjects wereeep their eyes closed during the sessions to avoid visual deection.s reported that they perceive synesthesia with open and closed eyes.

    uisition

    images were acquired on a 1.5 T General Electric scanner (Signa Hori-al Systems, Milwaukee, WI) equipped with a standard head coil. T2*ns covering the whole brain were acquired using a multislice two-cho-planar imaging (EPI) sequence (acquisition matrix 64 64 pixels,

    TR = 3000 ms, echo-time (TE) = 40 ms, eld of view (FOV) = 26 cm, slice

    brain areas woThis approachwork, their actanalysis was imseparate covaeach separateeters were inceffect. For eaculus, parametand group-spean analysis of main effects: band within the

    tandard deviations (SD) and T-statistics of demographic data.

    Synaesthetes

    14 (5) 38.00 (13.77)

    ht aswers (SD) 30.79 (3.87) bility in % (SD) 43.45 (27.66) ic lessons (SD) 7.64 (5.92) rumental training (SD) 8.21 (10.53) : right (left) 13 (1) ss consistency scorec (SD) 1.26 (0.55)

    Wortschatz Test B according to Lehrl et al. (1995).ical Sophistication Index according to Ollen (2006).r consistency test: smaller scores indicate a higher tone-color consistency.

    at 0.01 level.and guitar) in A, which were painted by three different synesthetes,ounting and fading of the tone. The arrows indicate the direction of

    m, ip angle = 90). The measurements were acquired in three ses- each. Each fMRI time series consisted of 244 images; the rst 4 were

    llow the scanner to reach a steady state.

    lysis

    e analyzed with SPM5 (http://www.l.ion.ucl.ac.uk/spm). Weimages to the 1st volume to correct for inter-scan movements with approach and a rigid body spatial transformation to remove artifacts.images were normalized to the EPI-derived MNI template (ICBM 152,rological Institute), resulting in a voxel size of 2 mm 2 mm 2 mm.ed images were nally smoothed with an 8-mm full-width half-ssian kernel and ltered with a high-pass lter of 128 s.onal connectivity analysis was performed to examine how different

    rk together during the perception of auditory stimuli in synesthesia.

    was based on the hypothesis that if two regions interact within a net-ivity patterns should be strongly correlated (Rissman et al., 2004). Thisplemented on the basis of a specic general linear model (GLM) using

    riates to model the hemodynamic responses of each single trial (for stimulus and individual subject). The estimated movement param-orporated into the model to minimize the signal-correlated motionh participant in both experimental groups and each presented stim-er estimates (beta values) were extracted to form a set of condition-cic beta series. We functionally dened three seeds by calculatingvariance (ANOVA) model on spatially normalized data including twoetween the main effect group (2 levels, synesthetes and controls)

    main effect stimulation (6 levels, different sound conditions). This

    Controls Statistics

    14 (5)36.79 (12.64) t = 0.215; p = 0.83230.00 (4.13) t = 0.519; p = 0.60836.54 (26.76) t = 0.671; p = 0.5088.36 (8.85) t = 0.251; p = 0.8047.36 (9.46) t = 0.227; p = 0.822

    13 (1)1.85 (0.50) t = 2.981; p = 0.006**

  • 1474 J. Neufeld et al. / Neuropsychologia 50 (2012) 1471 1477

    Table 2Areas showing increased functional connectivity in synaesthetes compared to controls.

    Seed area Area showing increased connectivity MNI coordinates (xyz) Talairach coordinates (xyz) Cluster size

    Right A1 Left motor cortex (BA 6) 16, 4, 60 14, 1, 55 209Right motor cortex (BA 6) 26, 12, 56 26, 14, 51 68

    Left IPC Primary auditory cortex (BA 41) 40, 26, 8 40, 25, 9 113Primary visual cortex (BA 17) 12, 94, 6 12, 91, 1 53

    Areas showing signicantly increased functional connectivity to the investigated seed areas, their coordinates and their size (in voxels) are listed. The areas were identiedusing the Talairach demon tool.

    analysis revealed one signicant cluster in the inferior parietal cortex (IPC) for themain effect group (this area exhibited stronger activation for auditory stimulationin synesthetes compared to the controls) and two clusters in the right and left audi-tory cortex (AC) for the main effect stimulation. The results of this analysis arepresented and discussed extensively in Neufeld et al. (2012). The seed areas weredened for the whole group of subjects as a sphere with a 5 mm radius around thecenter of mass of the previously detected clusters: the left and right AC (lAC, xyz[50; 24; 2], rAC [58; 16; 4]) and the left IPC (xyz [46; 54; 58]). The betaseries of each seed were averaged across the voxels within the critical region andcorrelated with the beta series of every other voxel in the whole brain. For eachparticipant, maps of the correlation coefcients were calculated for each condition(rst level analysis) and normalized using an arc-hyperbolic tangent transform forfurther statistical inference.

    In the second step of the analysis, we focused on testing our hypothesesregarding the connectivity pattern underlying synesthesia. Thus, we conductedtwo-sample t tests to examine connectivity differences between the controls andsynesthetes during the perception of auditory stimulation. The resulting maps wereconsidered at p < 0.001 at the voxel level and p < 0.05 at the cluster level threshold.Here, we used a cluster level threshold correction technique based on permutationanalyses of sub-samples of a large dataset (Slotnick, Moo, Segal, & Hart, 2003). Thecluster threshold correction technique for multiple comparisons used here controlsfor false positives, with a relative sparing of statistical power (Forman et al., 1995;Thirion et al., 2007), and solves the problem of multiple comparisons with voxel-wise p-values in combination with a specic cluster size threshold. The identiedminimal clustethe brain sitesof the resultin1.7 (Eickhoff e

    3. Results

    No signiand control

    or reaction times (p = 0.793) in the tone-chord discrimination taskconducted during fMRI.

    No increased connectivity in the controls compared to thesynesthetes was found in any region for any of the seed areas.

    To test the direct cross-activation model of synesthesia, thefunctional connectivity of the bilateral auditory cortex (AC) forauditory stimulation was calculated. Based on this model, wehypothesized that there would be a stronger connectivity betweenthe AC and the visual cortex in the synesthesia group, but we did notobserve this effect. The right AC merely exhibited increased con-nectivity to areas in the left and right motor cortex in synesthetescompared to controls (Table 2). The left AC showed no differencesin connectivity between the groups.

    The main result of this study (Table 2, Fig. 2) is the ndingof a stronger connectivity of the left IPC to both the left primaryauditory cortex (BA 41, SPM Anatomy toolbox: probability of max-imum = 6090% of cluster in Te 1.1; 1060% of cluster in Te 1.0, 51%of cluster in Te 1.1; 13.3% of cluster in Te 1.0, 12.6% of cluster inOP 2, 11.3% of cluster in insula) and the right primary visual cortex(BA17, SPM Anatomy toolbox: probability of maximum = 70100%

    ter i 18)i in aution

    cussi

    maen th

    Fig. 2. Signicinferior parietMNI coordinat94, 6), idenr size calculated for our data amounts to 41 resampled voxels. All of meeting this criterion were considered. The anatomical identicationg brain sites was conducted using the SPM Anatomy toolbox versiont al., 2005).

    cant differences were found between the synesthetess in the number of correctly identied stimuli (p = 0.312)

    of clusin areastimulinterac

    4. Dis

    Thebetweant group differences in functional connectivity of the IPC. The connectivity analysis reveal cortex (IPC) in synesthetes compared to controls (p < 0.05, corrected for multiple comes xyz = 40, 26, 8), identied as the primary auditory cortex (BA 41) and (B) a cluster itied as the primary visual cortex (BA 17). p = posterior, a = anterior, r = right, l = left, colon area 17; 81.1% of cluster in area 17, 1.3% of cluster in the synesthetes. Thus, the processing of auditoryditory-visual synesthetes is accompanied by a stronger

    between these areas.

    on

    in nding of this study is the increased connectivitye left IPC and primary auditory (A1) and visual (V1)aled two brain areas exhibiting signicantly more connectivity to theparisons): (A) a cluster in the left temporal cortex (center of mass atn the left occipital cortex (center of mass at MNI coordinates xyz = 12,r bars indicate the strength of activation.

  • J. Neufeld et al. / Neuropsychologia 50 (2012) 1471 1477 1475

    areas in synesthesia. This nding supports the disinhibited feed-back model of synesthesia, which proposes increased feedbackprojections to the sensory areas in synesthetes from multimodal(e.g., parietal) brain sites (Grossenbacher & Lovelace, 2001). Inter-estingly, thand not secwe did not the investigconnectivit

    As a higa variety oimportanceGrafman, &Spence, & Dmore, it hasynesthetic2010; van L2005). Thusof synestheplay a crucsia and as tthe processway hierarcreceiving sistimuli entethe tempormodal area2006). Funcbeen reportmodeling (Cthetes, thesduring toneconnectionrent (primaconnectivitas revealedmorphomestudy, the city (suggaltered conmay be resrent to auddisinhibitedvergence arthe concurrthat the inited feedbaprocessing,port for lowstudy on auet al., 2009)early stagesfound. Mansia (Brang Ramachandusing audittied moreperception,increased fhave been may be exphere. It is lgrapheme-cone form otheir synesspatial loca

    involvement of different mechanisms in different types of synes-thetes has been found in synesthetes divided into projectors andassociators (van Leeuwen et al., 2011). Our results are in line withthe results of the study by van Leeuwen et al. because all our sub-

    uld eases beeme-ler-M, 20ht Alte, 2induon thf the2008

    as a stratcke icallyhesiaSteveolvestuded ghetesty, avel alor pion hatic s

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    the mbeerwormoron sh, 200gioniredlarlye target feedback regions are primary sensory areasondary or later sensory areas (e.g., V4). Furthermorend evidence to support the cross-activation model inated brain sites, as there was no increase in the directy between the auditory and visual brain areas.her-order cortical area, the left IPC plays a role inf cognitive functions. Recent research underlines the

    of this area in multimodal sensory perception (Bushara, Hallett, 2001; Calvert, 2001; Macaluso, George, Dolan,river, 2004; Szycik, Jansma, & Mnte, 2009). Further-s also been identied as a major hub for processing

    perception (Neufeld et al., 2012; Rouw & Scholte, 2007,eeuwen et al., 2010; Weiss & Fink, 2009; Weiss et al.,, in accordance with the disinhibited feedback modelsia (Grossenbacher & Lovelace, 2001), this area mayial role as a pathway convergence site in synesthe-he origin of the disinhibited feedback. In this model,ing of the inducing stimuli follows the inducer path-hically from the sensory-specic areas toward the areasgnals from multiple pathways. It is known that auditoryr the system in the sensory-specic auditory cortex of

    al lobe and, after some processing stations, reach multi-s in the parietal cortex (Campbell, 2008; Vigneau et al.,tional connections between A1 and the IPC have alsoed in a brain imaging study using structural equationaclin & Fonlupt, 2006). Our data indicate that in synes-e connections are stronger compared to the controls

    perception. However, our results also indicate that thes from the IPC to sensory-specic areas of the concur-ry visual cortex) are stronger in synesthetes. Structuraly changes to the IPC have recently been demonstrated,

    by the analysis of magnetic resonance surface-basedtry data (Hanggi et al., 2011). Although in this latterconnectivity differences exhibited only a low speci-esting global connectivity differences), this effect ofnectivity between the IPC and sensory-specic areasponsible for the synesthetic visual experience concur-itory stimulation. More precisely, as proposed by the

    feedback model, the information entering such a con-ea through the inducer pathway could propagate downent pathway. Furthermore, the current results suggestuence of the parietal cortex (for example, via disinhib-ck) impacts the sensory system at low-level stages of

    namely at the stage of the primary sensory areas. Sup--level effects in synesthesia comes from a recent EEGditory-visual synesthetes with tones as stimuli (Goller. In this study, effects on different EEG components at

    (approximately 100 ms after the stimulus onset) werey previous investigations of grapheme-color synesthe-et al., 2010; Hubbard et al., 2005; Nunn et al., 2002;ran & Hubbard, 2001) and auditory-visual synesthesiaory verbal stimuli (Beeli, Esslen, & Jancke, 2008) iden-

    associative visual areas as important for concurrent especially area V4 in the fusiform gyrus. Therefore,unctional connectivity between the IPC and V4 couldexpected. The lack of this nding in the current studylained by the different form of synesthesia analyzedikely that there are different mechanisms underlyingolor and auditory-visual synesthesia. Moreover, withinf synesthesia, individual synesthetes might perceivethetic sensations differently, for example, at differenttions (Dixon, Smilek, & Merikle, 2004). Evidence for the

    jects coIncr

    sia hagraphe(Gasch& Stirnthe rig& Schoto the study ment oet al., cortexdemonsis (Jnacoustsynest2001; the invgroup increassynestnectivilow-letion, coactivatchromZhang,1996).area, ain conc

    Onecalculaauditoareas, modelther exmay bcellatio2001; used intion ofinteressynestsynestcouplintional

    Thufeedbation ofow frrecentIPC to Athesia,and nu& ButtFurtheattentiDriversory reis requparticube identied as associators.d activation of the auditory cortex in synesthe-n observed previously in two studies investigating

    color synesthesia with acoustically induced stimuliarkefski et al., 2011; Sperling, Prvulovic, Linden, Singer,

    06). Furthermore, increased gray matter volumes in1 have been detected in projector synesthetes (Rouw010). Structural peculiarities in sensory areas relatedcer-concurrent coupling revealed by a single subjecte auditory-taste synesthete E.S. suggest the involve-

    auditory cortex in audition-related synesthesia (Hanggi). Furthermore the involvement of the right auditorystrong hub in auditory-visual synesthesia was recentlyed by means of resting state EEG connectivity analy-& Langer, 2011). In addition, V1 activation induced by

    presented inducers has been found in single cases of (Aleman, Rutten, Sitskoorn, Dautzenberg, & Ramsey,n, Hansen, & Blakemore, 2006), providing evidence forment of this area in synesthesia. Furthermore, recenties with grapheme-color synesthetes have revealedray matter volumes in low-level visual areas in projector

    (Rouw & Scholte, 2010) and increased structural con-s measured by Fractional Anisotropy, in synesthetes innd associative visual areas (Jncke et al., 2009). In addi-rocessing is not limited to V4: in non-synesthetes, V1as been observed to be most sensitive to isoluminanttimulation and red-green/blue-yellow stimuli (Engel,andell, 1997; Kleinschmidt, Lee, Requardt, & Frahm,efore, V1 might serve as a concurrent representationgh it does not appear to be the only visual area involvednt processing.ortant limitation of this study is the fact that we havehe connectivity of only one auditory area. The humanrtex can be divided into a considerable number of sub-

    a potential candidate as a seed for the cross activationnesthesia (Ramachandran & Hubbard, 2001). Thus, fur-ation of the connectivity over the entire auditory cortexuired, e.g., oriented on anatomical or functional par-rechmann, Baumgart, & Scheich, 2002; Morosan et al.,

    ya, 1995). Another important limitation of the method study is the lack of the ability to estimate the direc-observed connections. A directional analysis would be

    for example, in relation to the question of whether is uni- or bi-directional. In fact, there are descriptions of

    subjects with only unidirectional inducer-concurrentBeeli, Esslen, & Jancke, 2005) as well as with bidirec-lings (Goller et al., 2009).hough our data t well with the model of disinhibitedere is also another possible explanation for the induc-urrents in synesthesia. Alternatively to the information1 through the IPC toward V1, we can hypothesize from

    that there is increased concomitant feedback from thed V1. Besides its involvement in auditory-visual synes-IPC has proved to also be involved in grapheme-colorr-form synesthesia (Rouw & Scholte, 2010; Tang, Ward,rth, 2008; van Leeuwen et al., 2010; Weiss et al., 2005).e, this area plays an important role in the control ofifts to a certain sensory modality (Macaluso, Frith, &

    0). Thus, the IPC may inuence signal processing in sen-s by modulating attentional processes. Further research

    to elucidate the mechanisms underlying synesthesia, because there are earlier audiovisual convergence

  • 1476 J. Neufeld et al. / Neuropsychologia 50 (2012) 1471 1477

    sites than the IPC involved in multimodal processing, which mayalso serve as the origin of disinhibited feedback, e.g., the posteriorregion of the superior temporal sulcus area (Beauchamp, Argall,Bodurka, Duyn, & Martin, 2004; Reale et al., 2007; Szycik, Tausche,& Mnte, 2synesthesiainvestigatedalso did not

    5. Conclus

    In this stin combinamodels of ssuggest ansensory-specurrent (V1evidence fosynesthesiathan a direc

    Acknowled

    This worand Psychoparticipants

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    Disinhibited feedback as a cause of synesthesia: Evidence from a functional connectivity study on auditory-visual synesthetes1 Introduction2 Methods2.1 Subjects2.2 Stimuli and paradigm2.3 Image acquisition2.4 Data analysis

    3 Results4 Discussion5 ConclusionsAcknowledgementsReferences