A Cross-Modal System Linking Primary Auditory and Visual Cortices: Evidence From Intrinsic fmri Connectivity Analysis

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1 Human Bain Mapping 29: (2008) A Coss-Modal System Linking Pimay Auditoy and Visual Cotices: Evidence Fom Intinsic fmri Connectivity Analysis Mak A. Ecket, 1 * Niav V. Kamda, 2 Catheine E. Chang, 3 Chistian F. Beckmann, 4 Michael D. Geicius, 2,5 and Vinod Menon 2,6 1 Depatment of Otolayngology, Medical Univesity of South Caolina, Chaleston, South Caolina 2 Depatment of Psychiaty, Stanfod Univesity Medical Cente, Stanfod, Califonia 3 Depatment of Electical Engineeing, Stanfod Univesity Medical Cente, Stanfod, Califonia 4 Oxfod Cente fo Functional Magnetic Resonance Imaging of the Bain (FMRIB), Univesity of Oxfod, Oxfod, United Kingdom 5 Depatment of Neuology and Neuological Sciences, Stanfod Univesity Medical Cente, Stanfod, Califonia 6 Neuosciences Pogam, Stanfod Univesity Medical Cente, Stanfod, Califonia Abstact: Recent anatomical and electophysiological evidence in pimates indicates the pesence of diect connections between pimay auditoy and pimay visual cotex that constitute coss-modal systems. We examined the intinsic functional connectivity (fcmri) of putative pimay auditoy cotex in 32 young adults duing esting state scanning. We found that the medial Heschl s gyus was stongly coupled, in paticula, to visual cotex along the anteio banks of the calcaine fissue. This obsevation was confimed using novel goup-level, tenso-based independent components analysis. fcmri analysis evealed that although oveall coupling between the auditoy and visual cotex was significantly educed when subjects pefomed a visual peception task, coupling between the anteio calcaine cotex and auditoy cotex was not disupted. These esults suggest that pimay auditoy cotex has a functionally distinct elationship with the anteio visual cotex, which is known to epesent the peipheal visual field. Ou study povides novel, fcmri-based, suppot fo a neual system involving low-level auditoy and visual cotices. Hum Bain Mapp 29: , VC 2008 Wiley-Liss, Inc. Key wods: functional connectivity; coss-modal; multisensoy; pimay auditoy cotex; pimay visual cotex This aticle contains supplementay mateial available via the Intenet at suppmat Contact gant sponso: National Institutes of Health; Contact gant numbes: MH19938, MH01142, HD31715, HD40761, NS048302, MH62430, HD33113, HD047520, NS058899; Contact gant sponso: National Cente fo Reseach Resouces; Contact gant numbe: C06 RR014516; Contact gant sponso: National Science Foundation; Contact gant numbe: BCS , BCS ; Contact gant sponsos: Alzheime s Association, Sinclai Fund. *Coespondence to: Mak A. Ecket, Depatment of Otolayngology/Reseach, Medical Univesity of South Caolina, 135 Rutledge Avenue, P.O. Box 550, Chaleston, SC ecket@musc.edu Received fo publication 13 July 2007; Accepted 1 Febuay 2008 DOI: /hbm Published online 15 Apil 2008 in Wiley InteScience (www. intescience.wiley.com). VC 2008 Wiley-Liss, Inc.

2 APimay Auditoy-Visual System INTRODUCTION Histoically, sensoy cotex has been chaacteized as hieachical with association cotex poviding the linkage between sensoy systems [Todd, 1912]. Moe ecently thee is tact tacing, electophysiology, and neuoimaging evidence fo diect connections between low-level sensoy cotex [Bosch et al., 2005; Cappe and Baone, 2005; Clavagnie et al., 2004; Falchie et al., 2002; Foxe et al., 2002; Ghazanfa et al., 2005; Johnson and Zatoe, 2006; Kayse et al., 2005; Lauienti et al., 2002; Lehmann et al., 2006; Matuzzi et al., 2007; Ni et al., 2006; Rockland and Ojima, 2003; Rockland and Van Hoesen, 1994; Schoede and Foxe, 2005; Tanabe et al., 2005; Watkins et al., 2006]. The coss-modal esults acoss neuoimaging expeiments geneally fall into two classes in which low level sensoy inteactions can be attibuted to (1) indiect inteactions because of the influence of association cotex and (2) diect connections between sensoy cotices. The majoity of neuoimaging studies involving multisensoy expeiments demonstate that association cotex dives the inteactions between sensoy cotex. Posteio association and fontal lobe cotex appea to influence low-level multisensoy pocessing in functional imaging studies equiing attention to a sensoy stimulus [Calvet et al., 2000; Macaluso et al., 2000] and high cognitive load [Cottaz-Hebette et al., 2004; Johnson and Zatoe, 2007], espectively. Fo example, Macaluso et al. [2000] demonstated that activity in multisensoy paietal lobe cotex was selectively coelated with activity in occipital cotex when tactile stimuli wee obseved to elicit inceased occipital esponses to a visual stimulus, suggesting that paietal lobe cotex was esponsible fo the occipital cotex esponses to tactile stimuli. In addition, coss-modal inhibition between sensoy cotices has been obseved when the cognitive load is high (e.g., a two-back woking memoy task), suggesting the occuence of top-down inhibitoy contol by executive function systems [Cottaz-Hebette et al., 2004]. Evidence that association cotex and pefontal cotex dive low-level multisensoy inteactions does not peclude, howeve, that thee ae diect inteactions between low-level sensoy cotex. Evidence fo diect connections between low-level sensoy cotices has been epoted in anatomical tacing and electophysiological studies. Anatomical tace studies of nonhuman pimates demonstate the existence of diect pathways between pimay sensoy aeas [Cappe and Baone, 2005; Clavagnie et al., 2004; Falchie et al., 2002; Rockland and Ojima, 2003; Rockland and Van Hoesen, 1994]. Fo example, neuons in nonhuman pimate auditoy cotex have pojections that teminate in the anteio but not posteio egions of pimay visual cotex [Falchie et al., 2002; Rockland and Ojima, 2003]. In addition, electophysiological studies demonstate coss-modal pocessing in low-level sensoy cotex at time peiods well befoe association cotex could possibly espond to a stimulus and dive the esponse [Giad and Peonnet, 1999]. Togethe, the findings fom functional and anatomical studies of coss-modal connections suggest thee ae locally specific egions of low-level sensoy cotex that engages in coss-modal pocessing though diect connections with othe low-level sensoy egions, as well as influences though association cotex. In paticula, the tact tacing studies suggest that functional connectivity should be most pominent between medial Heschl s gyus and anteio calcaine egions. fcmri is a functional-imaging method that can be used to examine the stength of functional connectivity between two anatomical egions duing tasks and when subjects ae not given a specific task o when thee is not attention demanding task. fcmri has been used to examine tonically active sensoy, moto, and cognitive netwoks obseved in esting state data [Biswal et al., 1997; Geicius et al., 2003]. These studies have highlighted obust coupling between homologous egions acoss the ceebal hemisphees [Salvado et al., 2005]. Fo example, left and ight hemisphee auditoy cotices demonstate highly coelated pattens of activity [van de Ven et al., 2004]. In this fcmri study we used egions-of-inteest (ROIs), defined by each individual s unique anatomy, to identify the functional pathways associated with lowlevel pimay auditoy cotex duing the esting state. In addition to chaacteizing auditoy pathways in esting state data, we asked whethe auditoy and visual cotex would exhibit positively coelated activity when thee was no specific task, and whethe these egions would exhibit negatively coelated activity when subjects wee engaged in a visual task. MATERIALS AND METHODS Paticipants Thity-two Stanfod Univesity students (17 female) wee ecuited fo functional imaging tasks ove a 4-yea peiod (mean age 21.12, yeas). Fouteen of these paticipants also pefomed a visual peception task. These studies wee appoved by the Stanfod Univesity Institutional Review Boad and these tasks wee undetaken with the undestanding and witten assent and/o consent of each subject. fmri Paadigms Duing a esting state scan paticipants wee instucted to lay quietly with thei eyes closed. The length of the scan was 4 min. The visual pocessing task consisted of the pesentation of a static black-and-white adial checkeboad patten and a flashing checkeboad, in which the white and black pattens wee inveted with an 8 Hz fequency. The visual stimulus angle subtended by the checkeboad was Pesentation of the static and flashing stimuli altenated evey 20 s fo six cycles. In both conditions, subjects wee instucted to passively 849

3 Ecket et al. view the checkeboad. The total length of the task was 4 min. Image Acquisition Functional images of the adults wee acquied on a 3T Geneal Electic Signa scanne by using a standad Geneal Electic whole-head coil. The scanne uns on an LX platfom, with gadients in minicrm configuation (35 mt/ m, SR 190 mt pe m/s) and has a Magnex (Concod, CA) 3-T 80-cm magnet. The adults wee scanned with the following spial pulse sequence: epeat time 5 2,000 ms; echo time 5 30 ms; flip angle 808; field of view mm 2 ; and a matix size of [Glove and Lai, 1998]. Twenty-eight axial slices (4-mm thick, 0.5-mm skip) paallel to the anteio commisue-posteio commisue line wee acquied. To educe bluing and signal loss aising fom field inhomogeneities, an automated high-ode shimming method based on spial acquisitions was used befoe acquiing functional MRI data [Kim et al., 2002]. To aid in the localization of functional data, high-esolution T1-weighted spoiled gass gadient ecalled 3D MRI images wee collected on a 1.5-T o a 3T Geneal Electic Signa scanne with the following sequence paametes: 124 coonal slices, 1.5-mm thickness; no skip; epeat time, 11 ms; echo time, 2 ms; and flip angle, 158. The images wee econstucted as a matix with a 1.5-, 0.9-, 0.9-mm spatial esolution. Image and fcmri Analyses SPM2 ( was used fo image pepocessing. Images wee coected fo movement using least-squae minimization without highe-ode coections fo spin histoy and nomalized to MNI coodinate space. Images wee then esampled to 2 mm isotopic esolution using sinc intepolation and smoothed with a 4-mm Gaussian kenel to decease spatial noise. Pio to data analysis, scaling and filteing steps wee pefomed acoss all bain voxels. The scaled wavefom of each bain voxel was then filteed by using a bandpass filte (0.0083/s < f < 0.15/s) to educe the effect of low-fequency dift and high-fequency noise. To pefom the fcmri analyses, time seies data wee extacted fom each voxel within stuctual ROIs epesenting putative pimay auditoy and visual cotex. The intensity of all the voxels within an ROI wee then aveaged at each time point to ceate a single time seies ove the couse of the esting state scan. The esulting time seies, epesenting the aveage intensity of all voxels in the ROI, was then used as a covaiate of inteest in a wholebain egession analysis. Whole-bain gay matte and white matte aveage time seies wee included as covaiates to identify bain egions that exhibited coelated activity that was independent of global fluctuations in signal. Contast images coesponding to the ROI egesso wee detemined individually fo each subject and enteed into a second-level, single-sample t-test analysis (height theshold of FDR P < 0.05 and an extent theshold of P < 0.01) to detemine the bain aeas that showed significant functional connectivity acoss subjects. Anatomical Regions of Inteest To maintain a consistent coodinate space fo the stuctual and functional MRI datasets, the stuctual MRI scans wee nomalized to the MNI template using affine and nonlinea tansfomations in SPM2. ROIs epesenting the left and ight putative pimay auditoy cotex (A1) wee ceated based on anatomical landmaks fom each paticipant s nomalized stuctual MRI. The tem putative is used in descibing these ROIs because we do not have histological confimation that the ROIs cove o ae limited to koniocotex. The fist medial appeaance of Heschl s gyus was used to define the medial bounday of the A1 anatomical ROI. The lateal bounday was defined by the most lateal position of Heschl s gyus as it is viewed in the coonal plane of section whee thee is a clea distinction between the insula and Heschl s gyus. MRIco was used to demacate Heschl s gyus in the sagittal plane of section [Roden and Bett, 2000]. When a sulcus intemedius indented the cown of Heschl s gyus and ceated two gyi, both gyi wee included in the ROI. Complete duplications of Heschl s gyus (sepaate exta gyus) wee not included in the ROI. Supplementay mateials Figue 1 shows that the A1 masks coespond to the Te1.0 and Te1.1 egions [Moosan et al., 2005]. ROIs fo the putative left and ight V1 also wee ceated based on anatomical landmaks fo each paticipant. Hee again, the tem putative is used to denote that we did not have histological confimation of the boundaies fo pimay visual cotex. MRIco was used to demacate the uppe and lowe bank of the calcaine fissue in sagittal plane of section. The lateal bounday was defined by the sagittal section in which the calcaine fissue was no longe continuous fom its anteio to posteio end. Supplementay mateials Figue 1 shows that that the V1 ROI coespond to 60% pobability maps of Bodmann aea 17 ( [Amunts et al., 2000]. The cytoachitectonic pobability maps wee not used because the pobability maps extended into nonauditoy cotex among individual subjects, pesumably because of the high degee of sulcal/gyal vaiability in this egion. High pobability masks (e.g., 90%), which wee moe constained to the sulcal/gyal featues of auditoy and visual cotex wee composed of too few voxels to have confidence that a eliable esting state fmri signal could be obtained. Steps also wee taken to educe the potentially confounding BOLD signal fom white matte. The nomalized stuctual images wee segmented using the MNI a pioi gay, white and CSF images in SPM2. Each nomalized gay matte image was then multiplied by the anatomical 850

4 APimay Auditoy-Visual System Functional connectivity esults-left hemisphee. (a) Activity coelated with A1: Voxels in the anatomically defined left A1 ROI demonstated significant coelated activity with the MGN, contalateal HG and STG, anteio calcaine, and MT1 while subjects wee exposed to scanne noise and ested with thei eyes closed. (b) Activity coelated with V1: Voxels fom the anatomically defined left V1 ROI exhibited significant coelated activity Figue 1. thoughout the visual system and with the left medial Heschl s gyus. The sagittal sections displayed in (a) and (b) ae fom the left hemisphee. FDR P < 0.05, cluste extent P < The colo scale epesents the t-scoes. A1 5 putative pimay auditoy cotex/heschl s gyus; STG, supeio tempoal gyus; MGN, medial geniculate nucleus. ROI to ceate a gay matte-specific ROI fo the left and ight putative A1 and V1 egions. The esulting left and ight A1 ROIs exhibited a left geate than ight stuctual asymmety that is consistent with pevious obsevations of stuctual asymmeties in Heschl s gyus (Left A1 ROI: cc, sd ; Right A1 ROI: cc, sd ; paied t-test t , P < 0.001) [Leonad et al., 1998; Penhune et al., 1996]. Thee was no hemispheic diffeence in left and ight V1 ROI volumes (Left V1 ROI: cc, sd ; Right V1 ROI: cc, sd ; paied t-test t , ns). Individual vaiation in these anatomical ROIs did not significantly pedict individual vaiation in the stength of auditoy and visual associations (cluste t-scoes) that ae pesented late. Tenso-ICA Replication Tenso-ICA was pefomed to examine pattens of tempoally coelated activity acoss subjects [Beckmann and Smith, 2005]. Taditional ICA is used to chaacteize unique pattens of vaiance o stuctue in data without dependence on an explicit geneative model. Tenso-ICA is simila but is extended to a goup analysis. Unlike the pevious appoach, tenso-ica does not depend on a specific seed point o ROI and epesents latent signals in the data as the oute poduct of matices that chaacteizes these signals in the spatial, tempoal, and subjects domain. The final ICA egession coefficients in the spatial domain ae escaled in units of voxel-wise esidual noise vaiance, so that these maps can be undestood as Z-statistics which 851

5 Ecket et al. TABLE I. Anatomical egions significantly coelated with activity in the left A1 ROI duing the esting state task Anatomical egions Peak coodinate Cluste extent Maximum Z-scoe (L) Heschl s gyus, STG, Insula, IFG, globus pallidus, putamen, caudate 240, 222, 8 4, (R) Heschl s gyus, STG, Insula, IFG 40, 226, 14 2, (R) Putamen/globus pallidus 28, 212, (L) and (R) Posteio thalamus, MGN 218, 222, , 220, (L) and (R) Peipheal V1 26, 266, , 266, (L) MT1 250, 268, (L) Left hemishpee; (R) ight hemisphee; STG, supeio tempoal gyus; IFG, infeio fontal gyus; MGN, medial geniculate nucleus. expess the voxel-wise signal-to-noise atio o the numbe of standad deviations the egession coefficient is fom the backgound noise. These Z-statistic images ae then thesholded using an altenative hypothesis testing appoach by fitting a Gaussian/Gamma mixtue model to the histogam of Z values. Voxel-wise posteio pobabilities ae evaluated to detemine whethe the data fit a Gamma distibution o Gaussian distibuted backgound noise. A voxel is consideed as a significant membe of an independent component when it exceeds the pobability of belonging to the Gaussian backgound noise class (P > 0.5). Please see Beckman and Smith [2004] fo additional details. RESULTS Intinsic Auditoy Cotex Connectivity As shown in Figue 1a and Table I, the left A1 ROI exhibited significant coelated activity with the left and ight supeio tempoal gyus and the medial geniculate nucleus (MGN) [Devlin et al., 2006] (FDR < 0.05, cluste extent < 0.01). In addition, significantly coelated activity was also detected in cotex dosal to the left and ight anteio calcaine fissue, posteio thalamic nuclei (distinct fom the medial geniculate nucleus), and lateal occipitotempoal cotex coesponding to aea MT1 [Huk et al., 2002]. The ight A1 ROI showed a simila connectivity patten, as shown in Supplementay mateials Figue 2a and Supplementay mateials Table I. To cooboate ou findings of auditoy-visual cotex coupling, time seies data wee aveaged fom an anatomically defined V1 ROI and used as the seed in a paallel fcmri analysis. As shown in Figue 1b and Table II, the left V1 ROI exhibited significant coelated activity with the left medial Heschl s gyus (FDR < 0.05, cluste extent < 0.01). Significant coelated activity also was obseved in aea MT1, a lateal geniculate nucleus, and the hippocampus. The ight V1 RO1 showed a simila connectivity patten, as shown in Supplementay mateials Figue 2b and Supplementay mateials Table II. fcmri maps fom the left A1 ROI and left V1 ROI analyses showed ovelap within putative pimay auditoy and Figue 2. Tenso-ICA maps demonstate tempoally coelated activity between auditoy and visual cotex. Significant auditoy to anteio calcaine connectivity was pesent bilateally. Note the common pattens of connectivity acoss the tenso-ica and fcmri maps pesented in Figue 1 and Supplementay Figue 2. The colo ba epesents the pobabilities of coelated activity between 0.5 and

6 APimay Auditoy-Visual System TABLE II. Anatomical egions significantly coelated with activity in the left V1 ROI duing the esting state task Anatomical egions Peak coodinate Cluste extent Maximum Z-scoe (L) and (R) visual cotex, aea MT1/lateal occipitotempoal cotex, paahippocampal gyus, hippocampus, posteio thalamus, LGN 24, 284, 8 15, Medial fontal cotex 0, 58, (L) Heschl s gyus 240, 222, (L) Left hemishpee; (R) ight hemisphee. visual cotex. Specifically, egions in the medial Heschl s gyus and cotex just dosal to the anteio calcaine fissue exhibited significant coelated activity acoss the two analyses. Tenso-ICA Replication Tenso-ICA was pefomed to confim the findings fom the fcmri analyses. Thity independent components wee computed, fom which we identified a component with stong coupling within the auditoy cotex. As shown in Figue 2, this component eflects tempoally coelated pattens of activity in the auditoy cotex and includes the anteio calcaine cotex, thus confiming findings fom the ROI analyses. Coss-Modal Connectivity Duing the Visual Peception Task Time seies data fom the flashing checkeboad task wee used to test the pediction that auditoy and visual cotex would be uncoupled when subjects wee engaged in a visual task. Figue 3a,b shows a significant attenuation of coelated activity between auditoy and visual cotex when the entie V1 ROI was used to define the visual cotex (left: t , P < 0.005; ight t , P < 0.01), but not when the compaisons wee based on activity in the A1 ROI and the anteio calcaine cluste that was coupled with A1 duing the esting state (left: t , ns; ight t , ns). The anteio calcaine cluste exhibited positively coelated activity with auditoy cotex duing the checkeboad task, in contast to posteio calcaine egions. Figue 3c shows that the attenuation in coelated activity between the A1 ROI and the V1 ROI (including the anteio calcaine egions coelated with A1 duing the esting state) was most pominent in the middle and posteio egions of calcaine cotex. DISCUSSION Both ROI-based fcmri analysis and tenso-ica of esting state data identified a coss-modal netwok that includes low-level auditoy and low-level visual cotices. Ou analyses futhe indicate (1) that functional connectivity of low-level auditoy and visual cotex is influenced by peceptual conditions and (2) that auditoy cotex exhibits diffeent pattens of coupled activity with anteio and posteio calcaine cotex. Ou findings ae consistent with anatomical evidence fom nonhuman pimate tacing studies fo a coss-modal system linking low-level auditoy cotex with the anteio potion of stiate cotex. One stength of ou study was the use of anatomically defined ROIs as seeds in the fcmri analyses. These ROIs wee demacated on nomalized stuctual images that wee coegisteed with the nomalized functional images. Supplementay Figue 1 shows that these anatomical ROI exhibited a high degee of ovelap with the cytoachitectonic pobability maps fo these aeas [Amunts et al., 2000; Moosan et al., 2005], but had the additional advantage of constaining the analyses to each individual s unique anatomy. The caeful delineation of auditoy cotex anatomy yielded functional pathways that have not been epoted in pio intinsic functional connectivity studies [Beckmann and Smith, 2005; Damoiseaux et al., 2006; Salvado et al., 2005; van de Ven et al., 2004]. This pecision may have allowed us to identify, fo the fist time, functional connectivity between putative pimay auditoy cotex and its thalamic gateway, the MGN. The tenso ICA esults confimed coelated activity between auditoy and visual cotex. The tenso ICA appoach did not, howeve, captue the thalamic associations seen with the ROI analyses. This may eflect the lack of unique independent components in the MGN. The anteio calcaine cotex is a temination site fo pimay auditoy cotex fibes in nonhuman pimate fibe tacing studies [Clavagnie et al., 2004; Falchie et al., 2002; Rockland and Ojima, 2003; Rockland and Van Hoesen, 1994]. As shown in Figues 1 and 2 and Supplementay Figue 2, medial Heschl s gyus exhibits significant coelated activity with anteio calcaine cotex. Ou functional connectivity esults suppot the pemise that a simila auditoy visual pathway exists in humans. Futhe suppot fo this pemise comes fom obsevations of (1) diect fibe connections between auditoy and visual cotex noted ealie; (2) educed functional connectivity of homologous cotical aeas in individuals with callosal agenesis [Achad et al., 2006; Quigley et al., 2003]; (3) disupted auditoy 853

7 Ecket et al. Diect compaisons of coelated activity between auditoy and visual cotex duing the esting state as compaed with the checkeboad tasks. (a) Coelated activity between auditoy cotex and the entie V1 ROI: t-scoes in the putative pimay auditoy cotex wee deived fom the functional connectivity esults with the V1 ROI. Coelated activity was significantly educed when subjects viewed the flashing checkeboad as compaed with the esting-state task. (b) Coelated activity between auditoy cotex and the anteio calcaine egion identified in the esting-state analysis: t-scoes in the peipheal V1 wee extacted fom the functional connectivity esults with the Heschl s gyus ROI. Thee was no significant diffeence between the two tasks in this case. (c) The t-scoe map epesenting the coelation between the A1 ROI and visual cotex duing the Figue 3. esting state task was subtacted fom the t-scoe map epesenting the coelation between the A1 ROI and visual cotex duing the visual task. This compaison was limited to the V1 ROI, as well as the anteio calcaine egion significantly coelated with the A1 ROI duing the esting state task. The bluegeen egions ae aeas that showed deceases in coelated activity with the pesentation of visual stimuli when compaed with the esting state task (thesholded fo t , which epesents P < 0.05 fo a one-tailed t-test involving 14 subjects). Results fo the left and ight hemisphee A1 ROI analyses ae pesented togethe. Please note the elative decease in t-scoe in posteio and middle calcaine egions in compaison with the anteio calcaine egions. localization when visual cotex eceives tanscanial magnetic stimulation [Lewald et al., 2004]; (4) auditoy cotex activity duing silent lip eading [Calvet et al., 1997]; and (5) auditoy visual inteactions that have been obseved in low-level visual cotex within 70 ms of stimulus pesentation [Giad and Peonnet, 1999]. 854

8 APimay Auditoy-Visual System Ou esults point to distinct pattens of coss-modal oganization within pimay visual cotex. Compaison of functional connectivity duing the visual peception and esting state tasks evealed that coelated activity between auditoy and anteio calcaine cotices was not significantly affected by the checke boad stimuli. In contast, coelated activity between the auditoy and posteio calcaine cotex was significantly educed. Futhemoe, duing the visual peception task, these egions wee invesely coelated, wheeas auditoy cotex was positively coelated with anteio calcaine cotex. One explanation fo these findings is that cotex epesenting peipheal visual space (at least 308 fom the midline) may not have been engaged by ou checkeboad stimuli (visual angle of 18.98), and fo this eason did not exhibit a significant decease in coelated activity with auditoy cotex duing the visual task. An eyes-open condition o a condition that diected attention to peipheal space may have significantly educed the stength of coelated activity between auditoy and anteio calcaine cotex. Although additional expeiments ae necessay to test the hypothesis that anteio and posteio calcaine cotex have distinct functional elationships with low-level auditoy cotex, the distinct pattens of coelated esting state activity between anteio and posteio calcaine cotex suppots the pemise that cotex in the medial Heschl s gyus and anteio calcaine cotex constitute a coss-modal system fo stimulus pocessing; whethe this is accomplished though diect o indiect connections emains an open question. Ou data povide novel evidence that the degee of functional connectivity between putative pimay sensoy egions can be selectively alteed duing peception, and point to functional heteeogeneity within the putative pimay visual cotex with espect to coss-modal integation. The behavioal significance of this diffeential patten of coupled netwok activity involving the medial Heschl s gyus and anteio calcaine cotex emains to be investigated. Futhe eseach is needed to caefully delineate inteactions between the pimay and auditoy cotices in elation to stimuli pesented in the peipheal and foveal visual fields. The diffeential pattens of coelated activity between auditoy cotex with anteio calcaine vesus posteio calcaine egions, as well as the animal tacing studies demonstating connections between auditoy cotex and anteio calcaine cotex, suggests some intiguing hypotheses. In paticula, we hypothesize that the cossmodal netwok obseved in ou study eflects a system that facilitates the identification of stimuli in peipheal space. Based on ou findings, we pedict that auditoy stimuli pesented to peipheal space will elicit coelated activity in the anteio calcaine cotex. At pesent it is not clea whethe the obseved functional connectivity between low-level auditoy and visual cotices eflect diect connections between these egions. It is possible that inteactions between these sensoy egions eflect top down modulation fom associations aeas such as V5/MT [Beauchamp, 2005] o highe ode cotical egions such as the ACC [Cottaz-Hebette and Menon, 2006]. Multisensoy and/o coss-modal neuons ae most fequently obseved in association cotex. One explanation fo coelated activity between low-level sensoy systems is that bidiectional [Peltie et al., 2007] o feedback connections fom association cotex mediate this inteaction [Calvet et al., 2000; Macaluso et al., 2000, 2005; Schlack et al., 2005]. One candidate association cotex egion is V5/MT1, which appeas to povide feedback infomation between auditoy and visual cotex. Fo example, Calvet et al. [1999] demonstated inceased activity in low-level auditoy cotex and V5/MT1 when people listened to speech and viewed the speake s face compaed to when people head only the speech o viewed only the speake s face. In ou study, V5/MT1 was the only association cotex egion that was pat of the low-level multisensoy fcmri netwok. We hypothesize that V5/MT1 is capable of modulating signaling between low-level auditoy and visual cotices. Using TMS, a V5/MT1 to V1 feedback pathway has been obseved in the pimate that is impotant fo visual awaeness [Pascual-Leone and Walsh, 2001]. Whethe this feedback pathway enhances the signaling of the low-level auditoy and visual egions when vision is limited o degaded emains to be examined [Weeks et al., 2000]. Ou findings, nevetheless, suggest that TMS studies of aea V5/MT1 when combined with fcmri studies of esting state data can help to shed light on this impotant question. 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