Two Systems of Resting State Connectivity Between the Insula and Cingulate Cortex

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1 Human Bain Mapping 30: (2009) Two Systems of Resting State Connectivity Between the Insula and Cingulate Cotex Kei S. Taylo, 1,2 David A. Seminowicz, 1,2 and Kaen D. Davis 1,2,3 * 1 Division of Bain, Imaging and Behavio Systems Neuoscience, Toonto Westen Reseach Institute, Univesity Health Netwok, Toonto, Canada 2 Institute of Medical Science, Univesity of Toonto, Toonto, Canada 3 Depatment of Sugey, Univesity of Toonto, Toonto, Canada Abstact: The insula and cingulate cotices ae implicated in emotional, homeostatic/allostatic, sensoimoto, and cognitive functions. Non-human pimates have specific anatomical connections between sub-divisions of the insula and cingulate. Specifically, the anteio insula pojects to the pegenual anteio cingulate cotex (pacc) and the anteio and posteio mid-cingulate cotex (amcc and pmcc); the mid-posteio insula only pojects to the posteio MCC (pmcc). In humans, functional neuoimaging studies implicate the anteio insula and pe/subgenual ACC in emotional pocesses, the mid-posteio insula with awaeness and inteoception, and the MCC with envionmental monitoing, esponse selection, and skeletomoto body oientation. Hee, we tested the hypothesis that distinct esting state functional connectivity could be identified between (1) the anteio insula and pacc/amcc; and (2) the entie insula (anteio, middle, and posteio insula) and the pmcc. Functional connectivity was assessed fom esting state fmri scans in 19 healthy voluntees using seed egions of inteest in the anteio, middle, and posteio insula. Highly coelated, low-fequency oscillations (< 0.05 Hz) wee identified between specific insula and cingulate subdivisions. The anteio insula was shown to be functionally connected with the pacc/amcc and the pmcc, while the mid/posteio insula was only connected with the pmcc. These data povide evidence fo a esting state anteio insula pacc/ amcc cingulate system that may integate inteoceptive infomation with emotional salience to fom a subjective epesentation of the body; and anothe system that includes the entie insula and MCC, likely involved in envionmental monitoing, esponse selection, and skeletomoto body oientation. Hum Bain Mapp 30: , VC 2008 Wiley-Liss, Inc. Key wods: functional connectivity; fmri; esting state; salience; insula; cingulate INTRODUCTION Contact gant sponso: Canadian Institutes of Health Reseach. *Coespondence to: Kaen D. Davis, PhD, Division of Bain, Imaging and Behavio Systems Neuoscience, Toonto Westen Reseach Institute, Toonto Westen Hospital, Univesity Health Netwok, Room MP14-306, 399 Bathust Steet, Toonto, Ontaio, Canada M5T 2S8. kdavis@uhnes.utoonto.ca Received fo publication 5 Febuay 2008; Revised 16 Septembe 2008; Accepted 25 Octobe 2008 DOI: /hbm Published online 15 Decembe 2008 in Wiley InteScience (www. intescience.wiley.com). The insula and cingulate cotex play key oles in integating multimodal infomation impotant fo sensoimoto, emotional, allostatic/homeostatic, and cognitive functions (Caig, 2002; Citchley, 2004; Devinsky et al., 1995; Pollatos et al., 2007). Fo example, the dosal magin of the mid-posteio insula has been associated with inteoception because it eceives infomation egading the physiological condition of the body (Caig, 2004), including pain, tempeatue, sensual touch, itch, visceal sensations, thist, and hunge (Augustine, 1996; Books et al., 2005; Cole et al., 2006; Caig, 2003; Caig, 2004; Olausson et al., 2005; VC 2008 Wiley-Liss, Inc.

2 Taylo et al. Ostowsky et al., 2002; Schweinhadt et al., 2006). The anteio insula cotex is thought to fom a global epesentation of the bodily state, because it is situated to integate homeostatic affeent activity fom the dosal posteio insula with emotional salience (Caig, 2002). The insula cotex lies in the depths of the lateal sulcus coveed by the opecula of the fontal, paietal, and tempoal lobes (Tue et al., 1999) and contains ostovental aganula, middle dysganula, and posteio ganula egions (Augustine, 1985), each with connections to the fontal, paietal, and tempoal lobes (Mesulam and Mufson, 1982a; Mesulam and Mufson, 1982b; Mufson and Mesulam, 1982) and the cingulate gyus (Augustine, 1996). In the nonhuman pimate, the anteio insula is connected to the ostal extent of Bodmann aea 24 of the anteio cingulate cotex (ACC) and a dosal tansitional aea between aeas 24 and 6 (Mesulam and Mufson, 1982b; Vogt and Pandya, 1987). In contast, the mid and posteio pimate insula have connections with dosal cingulate aeas 23 and 24, and the uppe banks of the cingulate sulcus and pemoto cotex (Mesulam and Mufson, 1982b). The cingulate cotex has been divided into fou majo egions based on cytoachitectonics, electophysiology, imaging, and lesion studies (Vogt et al., 2005). These fou egions include the ACC, mid-cingulate cotex (MCC), posteio cingulate cotex (PCC), and etosplenial cotex (RSC). The ACC has been subdivided into subgenual (sacc) and pegenual ACC (pacc) egions, wheeas the MCC has been subdivided into anteio (amcc) and posteio mid-cingulate (pmcc) egions (Vogt et al., 2005; Vogt, 2005). The sacc and pacc ae pimaily concened with emotions and pain. The MCC includes egions involved in pain (Apkaian et al., 2005), and moto functions involved in esponse selection (amcc) and skeletomoto body oientation (pmcc) (Vogt, 2005). The MCC has also been implicated in cognitive pocesses including eo detection, salience, attention to behavioally elevant stimuli, anticipation, decision making, and task-set implementation (i.e., task initiation o task switching) (Bush et al., 2000; Davis et al., 1997; Davis et al., 2000; Dosenbach et al., 2006; Dosenbach et al., 2007; Dux et al., 2006; Fai et al., 2007; Rushwoth et al., 2007). To ou knowledge, infomation exchange between the insula and cingulate cotex has neve been diectly shown. Howeve, the distinct anatomical connections between these two bain egions identified in non-human pimates combined with the evidence fom numeous human functional imaging studies evealing coactivation within specific pats of the insula and cingulate cotex, suggests that multiple infomation pocessing pathways may exist between these two egions. Altenatively, these two bain egions could be pat of multiple netwoks with common inputs. Theefoe, the aim of this aticle was to examine functional connectivity between specific pats of the insula and subegions of the cingulate cotex. Functional connectivity has been opeationally defined to efe to tempoal coelations acoss cotical egions and can epesent an index of bain function (Fiston et al., 1993; Howitz, 2003). Seveal imaging modalities have been utilized to ecod indices of bain function, such as electoencephalogaphy (EEG), positon emission tomogaphy (PET), magnetoencephalogaphy (MEG), and functional magnetic esonance imaging (fmri). Resting state functional connectivity analysis is a technique that identifies cotical aeas that have stong tempoally-coelated low-fequency (< 0.1 Hz) activity in a non-task (i.e., est) state. Using this appoach the elationship between anatomically distinct, but functionally connected, bain egions can be investigated. It is thought that these lowfequency fluctuations ae functionally elevant indices of connectivity between bain egions subseving simila o elated bain functions (Bin, 2007). To date this appoach has identified multiple esting state netwoks, including the so called default mode o task-negative netwok, a netwok that is active duing est and is suppessed duing the pefomance of a task (Fox et al., 2005; Raichle et al., 2001), and the task-positive netwok, which pefoms attention oienting opeations (Fox et al., 2006). A ecent study by DeLuca et al. (2006) established that these esting state netwoks ae not atifacts poduced by aliasing of cadiac and espiatoy cycles, but ae localized to gay matte of the ceebal cotex and ae likely elated to ongoing neuonal activity (DeLuca et al., 2006). In addition, Damoiseaux et al. (2006) demonstated that these esting state netwoks display blood oxygen level dependent (BOLD) signal changes up to 3%, values that ae compaable with task-elated BOLD changes. Futhemoe, the authos demonstated that these netwoks wee consistent acoss individuals and stable acoss epeated sessions (Damoiseaux et al., 2006). Thus, in this study we used esting state functional connectivity analysis to detemine if BOLD fluctuations within the anteio, middle, and posteio insula coelate with specific subegions of the cingulate cotex. Based on pimate tacing studies and functional activation studies, we hypothesized that two distinct systems could be identified at est: (1) a system linking the anteio insula with pacc/amcc, potentially involved in integating inteoceptive infomation with emotional salience to fom a subjective bodily epesentation; (2) a system that links the entie insula with the MCC, potentially involved in geneal salience, esponse selection, and action. METHODS Subjects Nineteen ight-handed healthy subjects (11 male, 8 female; yeas old) with no histoy of neuological injuy, paticipated in the study. Handedness was detemined using the Edinbugh handedness inventoy (Oldfield, 1971). All subjects gave infomed witten consent to pocedues appoved by the Univesity Health Netwok Reseach Ethics Boad. 2732

3 Insula-Cingulate Resting State Connectivity TABLE I. Insula egions of inteest ROI cente of mass X Y Z ROI volume (mm 3 ), (mean 6 SD) R anteio insula (RaIC) , R middle insula (RmIC) , R posteio insula (RpIC) , L anteio insula (LaIC) , L middle insula (LmIC) , L posteio insula (LpIC) , Shown ae the coodinates (Talaiach space) and egion of inteest volumes fo each insula subegion used in the connectivity analysis. Data Acquisition All data wee obtained using a 3T GE MRI system fitted with an eight channel phased aay head coil. A theedimensional high esolution anatomical scan of the whole bain (124 sagittal slices, cm FOV, matix, mm voxels) was acquied with a T1- weighted 3D spoiled gadient echo (SPGR) sequence (flip angle 5 458, TE5 5 ms, TR 5 25 ms). Resting state fmri data was acquied using T2*-weighted echo plana imaging (EPI) (25 axial slices, FOV cm, matix, mm voxels, TE 5 40 ms, TR ms). The scan time was 5 minutes and 8 seconds (154 fames). Subjects wee instucted to elax, keep thei eyes closed, and think of nothing in paticula (Damoiseaux et al., 2006; Geicius et al., 2004). Geicius et al. (2003) investigated the default mode netwok duing esting state and duing a passive visual pocessing task (i.e., eyes open) and found almost identical pattens of activity, indicating that tasks that equie minimal cognitive pocessing do not disupt esting state netwoks (Geicius et al., 2003). Data Analysis Data wee pepocessed and analyzed using Bainvoyage QX v1.8 (Bain Innovation, Maasticht, Nethelands). Pepocessing included motion coection, slice timing coection, linea tend emoval, and spatial smoothing with a 6 mm FWHM Gaussian kenel. fmri datasets wee intepolated to mm voxels, egisteed to the high esolution anatomical image and nomalized to standad Talaiach space (Talaiach and Tounoux, 1988). Voxels ae epoted as mm. Pevious cytoachitechtonic studies pefomed in nonhuman pimates have identified thee distinct insula subegions which have diffeent anatomical connections with the est of the bain (ostovental aganula, middle dysganula, and posteio ganula egions [Augustine, 1985]). As ou main inteest was to examine the functional connectivity with these thee insula subegions and the cingulate cotex, six egions of inteest (ROIs) wee dawn fo each subject within the anteio, middle, and posteio insula (thee left and thee ight) based on pevious anatomical and MR imaging studies (Naidich et al., 2004; Tue et al., 1999; Vanavas and Gand, 1999) (Table I). Thus, the anteio insula included the anteio shot gyus, the midinsula included the middle and posteio shot gyus, and the posteio insula included the anteio long gyus (Books et al., 2002; Books et al., 2005; Schweinhadt et al., 2006). Because ou intention was to obtain an aveage time couse fo each majo egion of the insula that was as distinct as possible fom the adjacent aeas, each ROI was esticted to gay matte and caefully delineated to avoid ovelap with othe subegions (see Fig. 4A). The aveage time couse (aveaged acoss all voxels within each insula egion) was extacted fo each ROI on a single subject basis. Fequency peiodogams wee calculated sepaately fo each subject and ROI to ensue that the data wee in the typical esting state fequency ange (< 0.1 Hz). This was accomplished by pefoming Fouie tansfoms of the aveage time couse extacted fom each ROI using SPSS 12.0 (SPSS Inc., Chicago). Single subject aveage time couses wee then used as pedictos in a fixed effects multisubject geneal linea model (GLM). One multisubject GLM analysis was pefomed fo each ROI fo a total of six multisubject GLMs (i.e., anteio, mid, and posteio insula, bilateally). A conjunction analysis was pefomed to identify bain egions highly coelated with the insula ROIs in all 19 subjects. This was done by seaching acoss all subjects to identify the minimum statistical t-value fo each voxel. Once this minimum was identified, it was assigned as the voxel value. These maps wee then thesholded at a coected value of P < 0.05 (deived fom an uncoected P < and 120 mm 3 contiguous clustes as peviously epoted by Downa et al. [2003] and validated by a Monte Calo simulation implemented in the Analysis of Functional NeuoImages softwae with the AlphaSim application [ nimh.nih.gov/afni/doc/manual/alphasim]). To futhe identify the connectivity of each insula egion, unthesholded aveage t-scoes wee extacted fom 5 mm 3 cubes, which wee placed within each of the goup coelation maps, within fou bilateal bain egions: ACC, MCC, pimay (S1), and seconday (S2) somatosensoy 2733

4 Taylo et al. cotices centeed on the following x, y, z coodinates: pacc/amcc, 6 8, 38, 19; pmcc, 6 6, 9, 36; S1, 6 42, 222, 51; S2, 6 42, 222, 23. The stength of the esting state connectivity (i.e., the t-scoes) between each insula egion and the cingulate and somatosensoy egions wee then displayed visually as egional fingepints fom pola plots ceated with Sigma Plot 9.0. The somatosensoy cotices wee included in this analysis because anatomical pathways between the insula and somatosensoy egions have been identified in non-human pimates (Augustine, 1996), and because of ou inteest in nociception, duing which it is common to obseve activation within all fou of these bain egions. Random effects analyses wee also pefomed to ascetain if thee wee significant diffeences in spatial spead and stength of connectivity of the insula ROIs within cingulate cotex subegions. The models included all 19 subjects and thei pedictos, deived fom the anteio, middle, and posteio insula, fo the left and ight hemisphees sepaately. Six sets of contasts wee geneated: (1) left anteio insula vs. left posteio insula; (2) left anteio vs. left mid-insula; (3) left mid vs. left posteio insula; (4) ight anteio insula vs. ight posteio insula; (5) ight anteio vs. ight mid-insula; (6) ight mid vs. ight posteio insula. All statistical maps wee thesholded at a coected P < 0.05 (deived fom an uncoected P < and 120 mm 3 contiguous clustes). RESULTS The location and size of each insula ROI is shown in Table I. Single subject spectal analyses of the esting state BOLD activity within the insula ROIs identified lowfequency oscillations of Hz (mean 6 SE). Examples of these oscillations in an individual subject can be seen in Figues 1 3A,D. Resting state connectivity analysis based on seeds within the thee insula subdivisions evealed emakably simila (between subjects) low-fequency oscillations in specific cingulate subdivisions (see Figs. 1 3 B,E). The location of the cingulate subegions found to have tightly coelated esting state activity with the insula ROIs ae shown in Figues 1 3. Activity in both the left and ight anteio insula cotices was stongly coelated with the bilateal pacc/amcc and bilateal pmcc (Fig. 1C,F). Howeve, the fmri signal in the mid and posteio insula cotices wee stongly coelated with bilateal pmcc (Figs. 2 and 3, pats C,F), but not with the moe ostal pacc/amcc. A complete list of bain egions that displayed significant coelations with bilateal anteio, middle, o posteio insula in all 19 subjects is povided in Table II. Insula connectivity fingepints wee constucted to illustate pattens of connectivity of each insula subdivision with the cingulate cotex and also key somatosensoy egions. Figue 4 shows these fingepints as pola plots of the stength (aveage t-scoe) of coelated activity between the anteio, middle, and posteio insula and the cingulate, S1 and S2. The fingepints illustate that all insula ROIs, except the left posteio insula, had stongly coelated activity with pmcc, while only the anteio insula ROIs displayed significant coelations with pacc/ amcc. The left mid-insula and bilateal posteio insula wee significantly coelated with activity within S1 and S2. Howeve, thee wee no statistically significant coelations with S1 and S2 fo the ight middle insula and bilateal anteio insula (t < 4.0) (see Fig. 4). To detemine if the stength of the identified connectivity pattens wee significantly diffeent between the anteio, middle, and posteio insula, a andom effects goup analysis was pefomed. Connectivity with S1 and S2 was not found to diffe between sub-egions of the insula. Table III displays additional bain egions that demonstated significantly diffeent connectivity between insula subegions. Howeve, thee wee significant diffeences within the cingulate cotex fo the contasts: (1) anteio IC vs. posteio IC; (2) anteio IC vs. mid-ic; (3) mid-ic vs. posteio IC, and these ae highlighted in Figue 5. Inteestingly, the anteio insula bilateally showed stonge esting state connectivity with the pacc/amcc than eithe the middle o posteio insula (see Fig. 5, fist 2 columns). Howeve, the mid-insula was moe stongly connected with the pmcc than the posteio insula (Fig. 5, thid column). DISCUSSION We have used functional connectivity analysis to identify esting state systems between the insula and cingulate cotices. The anteio insula was shown to be functionally connected with the pacc/amcc and the pmcc, while the mid/posteio insula was only connected with the pmcc. We popose that the system linking the anteio insula with the pacc/amcc may be involved in emotional salience monitoing, while the system linking the entie insula with the pmcc could be a geneal salience and action system. The identification of a geneal salience system stems fom a lage body of conveging evidence, including Downa et al. (2000, 2002, 2003) who identified a set of bain egions, including the anteio insula and MCC, that detects salient envionmental changes egadless of the modality of the task employed (i.e., visual, auditoy, tactile, pain). Futhemoe, using single cell electophysiological ecodings in the human bain ou goup has identified neuons within the MCC that espond to pain (Hutchison et al., 1999) and neuons that espond to cognitivelydemanding tasks poposed to be involved in geneal salience detection (Davis et al., 2005). In contast, functional activation studies in healthy individuals and patients with abnomal emotional pocessing (e.g., depession) stongly implicate moe ostal aeas of the cingulate cotex (i.e., ACC) in emotional salience (Bush et al., 2000; Etkin et al., 2006; Maybeg et al., 2000; Phan et al., 2002). 2734

5 Insula-Cingulate Resting State Connectivity Whole bain multisubject conjunction analysis showing anteio insula connectivity with the cingulate cotex. The spectal analysis and ROI time couse fom a single subject is shown fo the Figue 1. left (A, B) and ight (D, E) anteio insula (aic). These egions had tight coelations of low-fequency oscillations (B, E) with the pegenual and mid-cingulate cotex (C, F). 2735

6 Taylo et al. Whole bain multisubject conjunction analysis showing midinsula connectivity with the cingulate cotex. The spectal analysis and ROI time couse fom a single subject is shown fo the Figue 2. left (A, B) and ight (D, E) mid-insula (mic). These egions had tight coelations of low fequency oscillations (B, E) with the mid-cingulate cotex (C, F). 2736

7 Insula-Cingulate Resting State Connectivity Whole bain multisubject conjunction analysis showing posteio insula connectivity with the cingulate cotex. The spectal analysis and ROI time couse fom a single subject is shown fo the Figue 3. left (A, B) and ight (D, E) posteio insula (pic). These egions had tight coelations of low fequency oscillations (B, E) with the mid-cingulate cotex (C, F). 2737

8 Taylo et al. TABLE II. Anatomical locations and cente of gavity coodinates (in Talaiach space) displayed fo bain egions that demonstated significant coelations with each of the six insula ROIs Talaiach coodinates ROI Anatomical location (cente of gavity) x y z Voxels LaIC Left insula ,023 Left cingulate gyus BA 24/32 (pacc/amcc) Left cingulate gyus/ba 24 (pmcc) ,419 Left ceebellum Left infeio fontal gyus/ba Right insula ,420 Right infeio paietal lobule/ba Right fusifom gyus/ba Right angula gyus/ba Right paacental/infeio paietal gyus/ba 2/ Right ceebellum Right cingulate gyus BA 24/32 (pacc/amcc) Right cingulate gyus/ba 24 (pmcc) Right cingulate gyus/ba31 (pmcc) LmIC Left insula ,545 Left postcental gyus/ba 2/BA 40 (S2) ,834 Left postcental gyus/ba 1, 2, 3 (S1) ,314 Left cingulate gyus/ba 24 (pmcc) ,479 Left pecental gyus/ba ,892 Left lingual gyus/ba Left middle fontal gyus/ba Right insula ,793 Right infeio paietal/postcental gyus/ba 40 (S2) ,033 Right postcental gyus/ba 2/ ,023 Right cingulate gyus/ba 24 (pmcc) Right pecental gyus/ba ,344 Right fusifom gyus/ba Right infeio fontal gyus/ba Right fusifom gyus/ba Right cuneus/ba LpIC Left insula ,422 Left infeio paietal gyus/ba 2/BA 40 (S2) ,257 Left medial fontal gyus/ba Left cingulate gyus/ba 31 (pmcc) Left pecuneus/ba Left cuneus/ba Left infeio paietal lobule/ba Left postcental gyus/ba ,240 Left pecental gyus/ba Left middle tempoal gyus/ba Right insula ,659 Right infeio paietal gyus/ba 2/BA 40 (S2) ,319 Right pecental gyus/ba 1, 2, 3 (S1) Right occipital lobe, sub-gyal, white matte Right cingulate gyus/ba 24 (pmcc) Right postcental gyus/ba 1, 2, 3 (S1) ,121 Right pecuneus/ba ,724 RaIC Right insula ,460 Right middle fontal gyus/ba Right/left cingulate gyus/ba 24/32 (pacc/amcc) ,118 Right cingulate gyus (GC)/BA 24 (pmcc) Left insula ,075 Left cingulate gyus/ba 24 (pacc/amcc) Left cingulate gyus/ba 24 (pmcc) RmIC Right insula ,546 Right postcental gyus/ba 1, 2, 3 (S1) Right pecental gyus/ba Right infeio fontal gyus/ba Right fusifom gyus/ba Right paahippocampal gyus/ba Right cuneus/ba 31/ Right cingulate gyus/ba 24 (pmcc)

9 Insula-Cingulate Resting State Connectivity TABLE II. (continued) Talaiach coodinates ROI Anatomical location (cente of gavity) x y z Voxels Left insula ,661 Left cingulated gyus/ba 24 (pmcc) Left cuneus/ba 31/ Left postcental gyus/ba 40/42 (S2) Left cuneus/ba RpIC Right insula ,701 Right postcental gyus/ba 40 (S2) Right pecental gyus/ba ,539 Right medial tempoal gyus/ba Left cuneus/ba ,776 Right postcental gyus/ba 1, 2, 3 (S1) Right cingulate gyus/ba 24/32 (pmcc) Left insula ,915 Left paacental/cingulate gyus/ba 24 (pmcc/apcc) ,371 Left supeio fontal gyus/ba Left cuneus/ba Left postcental gyus/ba 40 (S2) Bain aeas wee deived fom the multisubject conjunction analyses, thesholded at a coected P < Voxels ae epoted as mm 3. aic, anteio insula; mic, mid-insula; pic, posteio insula; pacc, pegenual anteio cingulate cotex; amcc, anteio mid-cingulate cotex; pmcc, posteio mid-cingulate cotex; S1, pimay somatosensoy cotex; S2, seconday somatosensoy cotex; R, ight; L, left. The insula and cingulate cotices have both been implicated in emotional, homeostatic/allostatic, sensoimoto, and cognitive functions (Caig, 2002; Caig, 2008; Citchley et al., 2003; Citchley, 2004; Citchley et al., 2005; Devinsky et al., 1995). Fo example, the anteio insula has been shown to be activated in studies of emotional aspects of pain (Rainville et al., 1997), empathy elating to pain (Singe et al., 2004), tempeatue (Caig et al., 2000; Davis et al., 2004; Olausson et al., 2005), emotion (Buchel et al., 1998; Phillips et al., 1998), salience (Downa et al., 2000; Downa et al., 2002; Downa et al., 2003), and duing subjective evaluation of autonomic function (i.e., heat beat detection) (Citchley et al., 2004). Inteestingly, the ight anteio insula is activated duing painful ectal distention in healthy individuals but not in patients with iitable bowel syndome (Kwan et al., 2005) and these patients also had cotical thinning of the anteio insula and pmcc (Davis et al., 2008). These findings suggest that the anteio insula nomally woks to monito intenal body functions. Accoding to Caig (2002), inteoceptive infomation egading the physiological condition of the entie body is eceived by the posteio insula which is then pojected to the anteio insula fo subjective evaluation of intenal conditions (Caig, 2002; Citchley et al., 2004). The sacc and pacc have also been implicated in autonomic and emotional pocessing, while the amcc and the pmcc have been implicated in cognitive and sensoimoto functions (Bush et al., 2000; Citchley, 2004; Devinsky et al., 1995; Vogt, 2005). The concept that at est, a netwok of cotical aeas exists with tightly coelated activity was intoduced by Biswal et al. (1995) who descibed a netwok of tempoally coelated moto-elated bain aeas. Functional connectivity analyses of esting state activity has identified low-fequency (< 0.1 Hz) fluctuations of BOLD fmri signals (Biswal et al., 1995; Fox et al., 2005; Raichle et al., 2001). Examination of low-fequency fluctuations has evealed spatiotempoal synchony (coelations) between distinct anatomical bain egions, which have been attibuted to spontaneous neuonal activity (Xiong et al., 1999). Using this technique, multiple netwoks of tempoally coelated bain egions have been identified that ae elated to specific types of sensoy, moto, and cognitive functions (DeLuca et al., 2006; Magulies et al., 2007; Seeley et al., 2007). Indeed, these intinsic netwoks include both the task negative netwok (i.e., the default mode esting state) that shows task-elated deactivations, and anticoelated task-positive netwoks (DeLuca et al., 2006; Fox et al., 2005; Fox et al., 2006) that ae activated duing specific tasks o by salient stimuli such as a painful event (Seminowicz and Davis, 2007). It has been poposed that the task-negative intinsic netwok acts to monito the envionment to pepae fo peception and/o action to salient infomation (Seminowicz and Davis, 2007). The intinsic task-positive netwok includes the dosolateal pefontal cotex, insula, supplementay moto aea, infeio paietal sulcus, and fontal eye fields (Fox et al., 2005). In a ecent functional connectivity study, Seeley et al. (2007) suggested that this task-positive netwok is actually composed of a salience netwok that includes dosal ACC, obitofontal-insula cotices, and subcotical limbic stuctues, and an executive-contol netwok, connecting the dosolateal fontal cotex with the paietal cotex. The authos popose that the salience netwok is esponding 2739

10 Taylo et al. Insula connectivity fingepints. (A) ROI s placed in the anteio (ed), mid (blue), and posteio (geen) insula ae shown fo a single subject. (B) Pola plots illustating pattens of connectivity of each insula subdivision with the cingulate cotex and also key somatosensoy bain aeas. These fingepints ae based on the coelations between pais of bain aeas. Concentic cicles Figue 4. epesent inceasing t-values of the coelation between esting activity of an insula ROI and the pegenual/anteio mid-cingulate (pacc/amcc), posteio mid-cingulate cotex (pmcc), pimay somatosensoy (S1), and seconday somatosensoy (S2) cotex. The lighte oute cicle denotes the egion of statistical significance at t > 4. R, ight; L, left. 2740

11 Insula-Cingulate Resting State Connectivity TABLE III. Contasts between insula sub-egions in a andom effects goup analysis of connectivity Talaiach coodinates Contast Anatomical location (cente of gavity) x y z voxels LaIC > Left anteio insula ,644 LpIC Left cingulate gyus/ba 32 (amcc) ,190 Left caudate Left middle fontal gyus/ba ,075 Right anteio insula ,063 Right middle fontal gyus/ba Right caudate ,132 LaIC > Left anteio insula ,501 LmIC Left medial fontal gyus/ba Left cingulate/medial fontal gyus/ba 32 (pacc/amcc) Left supeio fontal gyus/ba Left infeio fontal gyus/ba Right supeio fontal gyus/ba LmIC > Left mid posteio insula ,193 LaIC LmIC > Left mid-insula ,221 LpIC Left middle fontal gyus/ba Left supamaginal gyus/ba Left infeio fontal gyus/ba Right infeio paietal lobule/supamaginal gyus/ba ,730 Right infeio fontal gyus/ba 45/ ,981 Right infeio paietal gyus/ba Right fusifom/infeio tempoal gyus/ba Right pecental gyus/ba ,154 Right pecuneus/ba Right cingulate gyus/ba 32 (amcc/pmcc) ,872 RaIC > Right anteio insula/infeio fontal gyus/ba 45/ ,900 RpIC Right cingulate gyus/ba 32 (amcc) Right cingulate gyus/ba 24 (pacc) Left anteio insula ,627 Left supeio fontal gyus/ba Left middle fontal gyus/ba RaIC > Right infeio fontal gyus/ba RmIC RmIC > Right mid posteio insula ,069 RaIC Right paacental/cingulate gyus/ba 31 (pmcc/apcc) Left mid posteio insula ,872 Left paacental/cingulate gyus/ba 31(pMCC/aPCC) RmIC > Right anteio mid-insula ,219 RpIC Right middle fontal gyus/ba ,999 Right middle infeio tempoal gyus/ba 21/ ,589 Right supeio fontal gyus/ba Right cingulate gyus/ba 32/24 (amcc/pmcc) ,319 Left anteio mid-insula ,289 Left middle fontal gyus/ba 46/ ,001 Left infeio paietal lobule/ba ,589 Left infeio tempoal gyus/ba Anatomical locations and cente of gavity coodinates (in Talaiach space) ae povided fo the bain aeas whee the stength of connectivity was found to be significantly diffeent between insula sub-egions at P < 0.05 (coected). Voxels ae epoted as mm 3. aic, anteio insula; mic, mid-insula; pic, posteio insula; pacc, pegenual anteio cingulate cotex; amcc, anteio mid-cingulate cotex; pmcc, posteio mid-cingulate cotex; S2, seconday somatosensoy cotex; R, ight; L, left. to the amount of pesonal salience and not specifically to the stimuli s specific natue (i.e., homeostatic, emotional, o cognitive). Dosenbach et al. (2007) also sepaated this task-positive netwok into cingulo-opecula and fontopaietal components using esting state functional connectivity analysis. While these authos popose slightly diffeent functional oles fo these two netwoks, thei study also highlights the tight coupling of esting state activity between pats of the insula and cingulate cotex. Inteestingly, these netwoks wee epoted to be incomplete in childen (< 9 yeas) with stengthening and matuation of long ange connections occuing thoughout adolescence; a pocess that may be elated to inceased myelination o stengthening of connections though coactivation (Fai et al., 2007). 2741

12 Taylo et al. Random effects contast maps. All 19 subjects and thei insula ROIs wee included in the statistical model. Contasts wee made between: (1) bilateal anteio IC minus bilateal posteio (fist column); (2) bilateal anteio IC minus bilateal mid-ic (second column); (3) bilateal mid-ic minus bilateal posteio Figue 5. IC (thid column). Maps wee thesholded at coected P < Anteio insula demonstates stonge connectivity with the pacc/amcc than eithe the mid o posteio insula cotex. No significant diffeences wee identified fo the pmcc, S1 o S2. IC 5 insula cotex. Using an ROI appoach based on insula anatomy, we identified this anteio insula/pmcc o salience netwok and additionally found stong coelations between the mid/posteio insula and the MCC. If indeed this netwok is involved in geneal salience to intenal and extenally geneated stimuli, the involvement of a bain egion that has been temed the pimay inteoceptive cotex is not supising. Finally, ROIs placed in the mid/posteio insula also evealed stong coelations with the pimay and seconday somatosensoy cotices, suppoting ou hypothesis that this system may play a ole in skeletomoto body oientation and esponse selection. Although thee is a gowing body of evidence suppoting the existence of esting state functional connectivity netwoks, some studies have shown that in some situations, some of the low-fequency fluctuations ae due to non-neuonal physiological fluctuations, such as cadiac, espiatoy, and blood CO 2 fluctuations, o scanne instability (Bin et al., 2006; Bin et al., 2008a; Bin et al., 2008b; Fox and Raichle, 2007; Shmueli et al., 2007; Wise et al., 2004). Recent studies suggested that emoval of these atifacts (by ecoding these paametes at the time of scanning and including them as egessos in the statistical model) can clean the data and impove statistical significance (Bin et al., 2006; Shmueli et al., 2007). Hee, we did not collect these physiological paametes, and theefoe we cannot access the impact of these atifacts on ou data. Howeve, these potential souces of noise ae unlikely to have been a significant facto in ou study since the majo fequencies poduced though the cadiac and espiatoy pocesses ae in the ange of Hz and Hz, espectively (Codes et al., 2001) and most of ou data was in the Hz band. Howeve, it is also possible that high fequency data could be aliased into a lowe fequency ange. Futhemoe, although ou data may include some physiological noise, the use of seed egions that ae anatomically close, and theefoe likely to contain simila amounts of physiological noise, combined with the fact that distinct esting state netwoks wee still identified, leads us to believe that these noise souces wee not a majo facto. Tacing studies in the monkey delineate anteio insula connections with the ostal extent of ACC aea 24 and a dosal aea between aeas 24 and 6 (Mesulam and Mufson, 1982b; Vogt and Pandya, 1987); and mid and posteio insula connections with dosal aeas 23 and 24 (Mesulam 2742

13 Insula-Cingulate Resting State Connectivity and Mufson, 1982b). Although functional connectivity alone cannot demonstate diect monosynaptic connections, ou functional connectivity findings do suppot the anatomical evidence that in the human bain these aeas ae connected. Altenatively, sub-egions of the insula and cingulate could have common inputs diving the synchonous BOLD fluctuations. The thalamus is the most likely candidate as diect pojections fom the thalamus to the insula and cingulate have been demonstated in nonhuman pimates (Augustine, 1996; Caig, 2008; Hatanaka et al., 2003; Mufson and Mesulam, 1984; Vogt et al., 1979). Specifically, thalamic nuclei that poject to both the cingulate and the insula include the paafasciculais, submedial, euniens, limitans, and mediodosal nucleus (Hatanaka et al., 2003; Mufson and Mesulam, 1984; Vogt et al., 1979). In ou study, stong connectivity with the thalamus was not found in eithe the conjunction o the andom effect contast analyses, likely due to the stict statistical equiements combined with the minimum cluste size. We have identified two systems between the insula and cingulate cotices and used functional fingepints as a means to convey the connectivity of insula subegions with othe bain aeas. Pevious studies have used the concept of fingepints to display specific pattens of bain activity as pola plot displays of measues anging fom powe spectum peaks to desciptive measues of shape (DeMatino et al., 2007). In addition, Passingham et al. (2002) used fingepints to display cytoachetectonic and functional connectivity (Passingham et al., 2002). We now intoduce a new application of functional fingepinting to highlight the stength of esting state connectivity (i.e., coelation of oscillatoy activity) between bain aeas and conceptualize functional netwoks based on low-fequency esting state oscillations. Taken togethe, the known anatomical pojections in the pimate bain, combined with the functional connectivity analysis pefomed in ou study and pevious functional imaging data indicate two distinct systems between the insula and the cingulate in the adult human bain, fo which we suggest the following possible functions: (1) an emotional salience monitoing system linking the anteio insula with the pacc/amcc, a system esponsible fo integating inteoceptive infomation with emotional salience foming a subjective image of ou bodily state; and (2) a geneal salience and action system that links the entie insula and MCC, a system involved in envionmental monitoing, esponse selection and skeletomoto body oientation. 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