Different functions in the cingulate cortex, a meta-analytic connectivity modeling study

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Different functions in the cingulate cortex, a meta-analytic connectivity modeling study

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DOI:10.1016/j.neuroimage.2011.03.066

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Different functions in the cingulate cortex, a meta-analytic connectivity

modeling study

D.M. Torta

, F. Cauda

^ Department of Psychology, University o f Turin, Turin, Italy CCS fMRI, Koelliker Hospital and University of Turin, Turin, Italy

A B S T R A C T

The cingulate cortex is a structurally heterogeneous brain region in v olve d in em otional, cogn itive and m otor tasl<s. W ith the aim o f iden tifyin g w hich behavioral domains are associated w ith the activation o f the cingulate cortex, w e perform ed a structure based-m eta-analysis using the activation IiI<eIihood estim ation (ALE), w hich assesses statistical significant convergence o f neuroim agin g studies using the BrainMap database. T o m ap the m eta-analytic coactivation maps o f the cingulate co rtex (M A C M ), w e subdivided the parenchym a along the rostro-caudal axis in 12 bilateral equispaced ROIs. ROIs w e re not chosen according to previou sly suggested subdivisions, as to obtain a co m p letely data-driven result. Studies w e re included w ith one or m ore activation coordinates in at least one o f the 12 pre-d efin ed ROIs. The m eta-analytic connectivity p rofile and behavioral dom ains profiles w ere iden tified for each ROI. Cluster analysis w as then perform ed on the M ACM and behavioral dom ains to group togeth er ROIs w ith similar profiles. The results sh ow ed that the cingulate cortex can be d iv id e d in three clusters according to the M ACM parcellation and in four according to the behavioral dom ain-based parcellation. In addition, a behavioral-dom ain based meta-analysis was conducted and the spatial consistency o f functional con n ectivity patterns across differen t dom ain-related ALE results w as evaluated b y com puting probabilistic maps. These maps iden tified some portions o f the cingulate co rtex as in v olve d in several tasks. Our results sh ow ed the existence o f a m ore specific functional characterization o f some portions o f the cingulate cortex but also a grea t m ultifunctionality o f others. By analyzing a large num ber o f studies, structure based meta-analysis can grea tly contribute to n e w insights in the functional significance o f brain activations and in the role o f specific brain areas in behavior.

Introduction

Ever since the v e r y first neu ropsychological studies, researchers have atte m p te d to relate b eh avioral functions to specific brain locations. O ver the last th ree decades, research has produ ced an enorm ou s am ou n t o f data loca lizin g p u tative brain underpinnings o f specific m ental operations. Thus, g iv e n the im p ressive b od y o f e vid en c e at our disposal, the need o f c o n v ergin g e vid en c e am on g studies w ith in a c oh e re n t th eoretica l fra m e w o rk is o f p rim ary interest.

The cingulate corte x is a particu larly in teresting area g iv e n the w id e v a rie ty o f tasks in w h ic h it is in volved . Im p ortan t in form ation regardin g th e structure o f this region and the functions it supports have b een m a in ly obtain ed fro m non-hum an prim ates (V o g t and Pandya, 1987; V o g t e t al., 1 9 8 7); but see (C o le e t al., 2 0 0 9 ) for a

Abbreviations: ROI, region of interest; ALE, Activation likelihood estimation; MACM,

Meta-analytic connectivity modeling.

* Corresponding author at: Department o f Psychology, Via Po 14,10123 Turin, Italy. Fax: + 3 9 0 11 8146231.

E-mail address: diana.torta@unito.it (D.M. Torta).

discussion o f the d ifferen c es b e tw e e n hum an and non human primates. D espite the hum an cingulate corte x has b een studied for o v e r a century, its structural and functional o rga n ization rem ain debated. Four sub-regions have b een p roposed to constitute the cingulate cortex: th e a n terior (24/32), m id (2 4 '/ 3 2 ') p osterior (23/31) and re tro s p le n ia l (2 3 '/ 3 1 ') c in gu late c o r te x (Fan e t al., 2008; Palom ero-G allagher e t al., 2008; Palom ero-G allagher e t al., 2009; Vogt, 2 0 0 5). Each o f these subdivisions is p roposed to d iffe r in term s o f cytoarchitecture, con n e ctivity and function. M oreover, considering the p lethora o f functions p erfo rm e d b y th e cingulate cortex, it is not surprising that functional resonance im a gin g (fM R I) studies are rep lete w ith activations o f this area.

Anatom ically, the an terior cingulate corte x is the m ore rostral part and the c o m p le x ity o f its functional con n e ctivity has been w e ll described (K osk i and Paus, 2000; M argu lies e t al., 200 7). The an terior cingulate corte x is central to a broad array o f cognitive, sensory- m otor, a ffective and visceral functions (D e vin s k y e t al., 1995; Dum and Strick, 1991; Shima and Tanji, 1998; V o g t e t al., 1995). For e xa m p le, th e a n te rio r cin g u la te c o r te x is in v o lv e d in c o n flic t m o n ito rin g (B o tv in ic k e t al., 2004; C arter e t al., 1 9 9 8), e rro r m on itorin g and d etection (G e h rin g and Fencsik, 2001; G ehring and

Knight, 2000; H olroyd e t al., 1998; Lorist e t al., 2 0 0 5), response selection (A w ii and Geiiring, 1999; Paus e t al., 1993) and attention control (C rotta z-H erb ette and M enon, 2006; Posner and Dehaene, 1994). This functional h e terog en e ity is also reflected at the anatom ical level, w h e re the an terior cingulate c orte x can be further su bdivided in several distinct subregions (D e vin s k y e t al., 1995; V o g t e t al., 1995). H o w e ve r, it is w o rth n otin g that factors such as stimulus presentation rate (B ench e t al., 1993), stimulus n o v e lty (P eters e n e t al., 1998) and practice e ffe c t (K e lly and Caravan, 2005; M ilha m e t al., 2 003), also influence the activation o f this p ortion o f the cingulate cortex. Several lines o f evid en c e fro m functional im agin g and lesion studies suggest a broad d ivision o f th e an terior cingulate corte x into dorsal and v en tral areas (Bush e t al., 2000; Koski and Paus, 2000; Yu cel e t al., 200 3). The dorsal p ortion o f th e an terior cingulate corte x has been found to be stron gly associated w ith m otor, attentional and cog n itive functions (M acD on ald e t al., 200 0), w h ereas th e v en tral portions o f such region (rostral, subcallosal and subgenual regio n s) seem to be in vo lv ed in em otions, m ood and au ton om ic functions (M a y b e r g e t al., 2002).

T h e dorsal m id -cin g u la te c o r te x is cen tral to s k e le to m o to r regulations (V o g t e t al., 1992), but its role in cog n itive tasks has also been found repeated ly. Such cog n itive tasks include: atten tion for action (B adgaiyan and Posner, 1998; Pardo e t al., 1990), response selection (C orb etta e t al., 1991; Paus e t al., 1993), error d etection and com p e tition m on itorin g (C arter e t al., 1998), an ticipation (M u rtha e t al., 1996) and w o rk in g m e m o ry (P e tit e t al., 1998).

T he p osterior cingulate corte x is th ou ght to p lay an im p orta nt role in tasks related to visuospatial orientation and navigation o f the b od y in e n v iron m en tal space (V o g t and Laureys, 200 5). Furtherm ore, its role has b een id en tifie d in tasks related to s e lf-re fle c tio n and au tobiographical m e m o ry (S pren g e t al., 2009).

Finally, th e retrosplenial cingulate corte x seem s to be in vo lv ed in m e m o ry and visuospatial functions (Burgess e t al., 2001; laria e t al., 2007; K eene and Bucci, 2008; Parker and Caffan, 1997; Vann e t al., 2009; V o g t and Laureys, 2005; V o g t and Pandya, 1987; V o g t e t al., 1987).

In th e p resent study, w e e m p lo y e d th e m eta-analytic c on n e ctivity m o d elin g (M A C M ) (R ob in son etal., 2 0 1 0 ) to in vestiga te the functional con n e ctivity and the b eh avioral dom ains w h e re in the cingulate cortex has been found active. T he M AC M is based on the assum ption that groups o f coordinates that co-activate across exp erim en ts can be p o o le d to id e n tify fu n ction a lly c on n ected n etw ork s. Like o th e r m ethods o f analysis o f functional con n ectivity, analyses carried ou t w h ich such a m eth od are based on the co-occu rren ce o f spatially separated n eu roph ysiological even ts (K oski and Paus, 2000; Postum a and Dagher, 2006; T oro e t al., 2 0 0 8). T he M AC M a llow s structure- based m eta-analyses, w h ich instead o f p oo lin g studies that share a com m on e xp erim en tal design, look for glob al c o-a ctiva tion patterns across a d iverse range o f tasks, thus resp on din g to the qu estion ‘for a giv en region w h a t tasks e licit a ctiva tion ?’ (Laird e t al., 2 009b).

T o re trie v e areas co-a ctiva ted b y d iffe re n t studies w e e m p lo y e d the BrainMap database (Laird e t al., 200 5). BrainMap is a c om m u n ity accessible database, w h ich archives peaks coordinates fro m published neu roim aging studies, alon g w ith the corresp on d in g m etadata that sum m arize the e xp erim en tal design. As suggested b y Price and Friston (P rice and Friston, 2 00 5) the relationship b e tw e e n a brain re gio n and a m ental function is n ot on e-to-on e . Instead, a single region can be in vo lv ed in m any c og n itive processes and single processes can activate m u ltip le regions. To map the specific M AC M o f each part o f the cingulate c orte x w e d efin ed tw e lv e 1 0 x 1 0 x 1 0 m m bilateral ROls alon g its rostral-cau d al axis and e xa m in ed the co-activations o f these areas w ith o th er areas in the brain, using an activation likelihood estim ation (ALE ) approach. Successively, w e id en tified the b ehavioral dom ains associated w ith each ROl. This subdivision in regions o f equal size enabled the d a ta -d riven clustering o f functional co-activations. A d ifferen t choice, such as a p rio ri d efin ed anatom ical subdivision w ou ld have p rev e n ted this d ata -driven o r b ottom -u p approach.

Methods

D efin ition o f the ROIs

The selection o f the ROls w as n ot based on p re-existing subdivisions (anatom ical, functional and histological) in ord er not to assume an a

p rio ri hypothesis; instead, our approach aim ed at obtaining data-driven

results. T h e re fo re w e s elected 12 c on secu tive b ilateral ROls o f 1 0 x 1 0 x 1 0 m m along the rostral-caudal axis o f the cingulate cortex (s e e Fig. 1 and Table 1 ). This choice w as also m otivated b y the technical constraints o f the M ACM for w hich: i) a consistent num ber o f foci is need ed for each subdivision, ii) a com parable num ber o f foci is n eeded in each voxel. The ratio b etw e en the m inim al dim ension o f voxels w e could select w ith such constraints and the d im ension o f the cingulate cortex led us to the identification o f 12 subdivision.

Structiire-based meta-analysis (M eta -a n a ly tic conn ectivity m odeling, M A C M )

M A C M o f re g io n a l co-a ctiva tio n s w a s d es ig n ed to establish con n e ctivity patterns for task-related increases for each o f the 12 ROls. To an alyze the w h o le -b ra in m eta-analytic con n e ctivity o f the cingulate cortex, for each ROl w e qu eried the BrainMap database for studies that included at least one o r m ore activation coordinates in that ROl. Searches w e r e conducted to find all exp erim en ts that reported activations in these regions d uring task conditions.

A ctiva tio n likelihood estim ation (A LE ) meta-analysis

The A ctiv a tio n lik elih ood estim ation (A LE ) analysis is a qu antita­ tiv e vox e l-b a se d m eta-analysis m eth od w h ic h can be used to estim ate consistent activation across d iffe re n t im a gin g studies (Laird e t al., 200 9a). ALE maps o f co-activations are d eriv e d on the basis o f foci o f interest, w h e re m u ltip le studies have rep orted statistically significant peaks activation. D iffe re n t form u la tion s o f th e ALE h ave been proposed, in this study w e used the E ickhoff and c olleagu es' (E ick h off e t al., 2 0 0 9 ) one.

In th e origin al form ulation (Turkeltau b e t al., 2 0 0 2), activation lik elih ood estim ates w e r e calculated for each v o x e l b y m o d elin g each coord in ate w ith an equal w e ig h tin g using a 3-D Gaussian p robability d en sity function. Successively, a perm u tation test w as carried ou t to d eterm in e the v o x e l-w is e significance o f the resu lting ALE values. The p erm u ta tio n te s tin g w a s im p le m e n te d using a n on -p a ra m e tric statistical approach (Turkeltau b e t al., 2 002), in w h ic h usually 5000 o r m ore perm utations w e r e gen era ted using the sam e num ber o f foci and Full W id th at H a lf M axim u m (F W H M ) alg orith m w a s used to gen era te the ALE map. As such, no assum ptions w e r e m ade w ith resp ect to the distribu tion or spatial separation o f these rand om foci (Laird e t al., 2005; Turkeltaub e t al., 200 2). Resulting statistical maps w e r e corrected for m u ltiple com parisons using false d isc ove ry rates (FD R ), and then th reshold ed at p <0.05 , corrected.

In th e revised a lg orith m (E ick h off e t al., 2 009), to lim it th e in te r­ subject and in te r-la b o ra to ry v a ria b ility typical o f n eu roim ag in g studies, an alg orith m w as im p lem en ted , w h ic h estim ates th e spatial u n certain ty o f each focus and takes in to accou nt the p ossible d ifferen ces am on g studies. This alg orith m w as p referred to a p re ­ specified F W H M as in the original ALE approach (Turkeltau b e t al., 2 00 2 ). The advantage o f the second alg orith m is that it allow s calculating the ab ove-chan ce clustering b e tw e e n exp erim en ts (i.e., rand om e ffects analysis, RFX), rather than b e tw e e n foci (fix e d effects analysis, FFX) (E ick h off e t al., 200 9). M oreo v er, fro m the origin al ALE m eth od (Turkeltau b e t al., 200 2), several o th er m od ification s have b een applied. A cluster analysis script w as ad d ed to id en tify areas o f high activation lik elih ood and return the cluster e x te n t ab ove a user- specified threshold (Lancaster e t al., 2 005). Laird and colleagues also ad d ed a correction for m u ltip le com parisons and a m eth od for

Fig. 1. In the left upper panel, the 12 bilateral ROIs are shown in a sagittal plan. ROIs were selected along the rostro-caudal axis of the cingulate cortex. In the left panel {lower), the

twelve bilateral ROIs are tridimensionally shown. In the right panel, upper and lower parts, coronal and transversal sections are shown. The selection of the ROIs was not based on pre­

existing subdivisions (anatomical, functional, histological) in order not to assume an a pnori hypothesis; instead, our approach aimed at obtaining data-driven results. The choice of 12 consecutive bilateral ROIs o f 1 0 x10 x10 mm along the rostral-caudal axis o f the cingulate cortex was also motivated by the technical constraints o f the MACM (see text for details).

com p u tin g statistical contrasts o f pairs o f ALE im ages (Laird e t aL, 200 9a). Indeed tiiese m od ification s w e r e aim ed to solve the several lim itations k n ow n to exist in the origin al im p lem en ta tion : 1) the alrea d y m en tion ed fixed -rath er than ra n d o m -e ffec t analysis, 2 ) the size o f the m o d ele d Gaussian that w a s specified b y th e user, and 3 ) the p erm u tation t-test that w as n ot an atom ically constrained. Recent advances in the techn iqu e have m od ified the u ser-specified Gaussian

Table 1

Coordinates o f the 12 ROIs.

ROI X Y Z Volume 1 7 / -8 26 - 6 10 x1 0 x1 0 mm 2 7 / -8 37 - 4 10 x1 0 x1 0 mm 3 7 / -8 39 8 10 x1 0 x1 0 mm 4 7 / -8 32 19 10 x1 0 x1 0 mm 5 7 / -8 22 28 10 x1 0 x1 0 mm 6 7 / -8 11 32 10 x1 0 x1 0 mm 7 7 / -8 0 37 10 x1 0 x1 0 mm 8 7 / -8 - 1 1 39 10 x1 0 x1 0 mm 9 7 / -8 - 2 2 38 10 x1 0 x1 0 mm 10 7 / -8 - 3 3 37 10 x1 0 x1 0 mm 11 7 / -8 - 4 3 29 10 x1 0 x1 0 mm 12 7 / -8 - 5 1 17 10 x1 0 x1 0 mm

m od el into an em p irica lly d eterm in e d qu an titative estim ate o f the b etw e en -s u b jec t and b e tw e e n -te m p la te variability. This correction m odels the spatial uncertainty o f each coord in ate b y w e ig h tin g each study b y the num ber o f included subjects. These m od ifications have added statistical p o w e r to the m eth od (E ick h off e t al., 2 00 9) and have elim in ated the p ossibility that ALE results m ay be d rive n b y the results o f a single study.

In our study, ALE maps w e r e created b y an alyzin g the pattern o f coactivations o f each o f the 12 ROl. A n ALE w as p erform e d for each ROl and associated coord in ates separately. To attribute each o f the ROIs to a functional netw ork , w e used a d ata -driven criterion o f parcellation that grou p ed data in clusters according to th eir functional sim ilarities (s e e n ext paragraph). ALE maps w e r e com p u ted at a False D iscovery Rate (F D R )-co rrec te d th reshold o f p < 0 .0 5 and v isu alized using M ricron ( w w w .m ric ro .c o m ) and B rainVoyager QX 2.0.

N etw ork labeling and M ACM -based parcellation

The labels for th e M AC M results sh ow n in Fig. 3 w e r e created as fo llo w s : 1) w e first aim ed to obtain a series o f tem p lates o f the principal n etw ork s found to be p resent in the resting (M a n tin i e t al., 2 0 0 7 ) and a ctive (S m ith e t al., 2 0 0 9 ) brain. T o do so, w e ap p lied an

In d ep en d en t C om p onen t Analysis (IC A ) d ec om p os ition on resting state datasets obtain ed fro m a grou p o f s even teen participants w h o took part in a previou s study (Cauda e t al., 2 0 1 0). This d ecom p osition w as d on e in accordance w ith M antini and colleagu es' procedu re (M a n tin i e t al., 2 0 0 7 ) and produ ced six IC A -d erived tem p lates (d efa u lt m o d e netw ork , attentional, sensorim otor, a n terior d efau lt m od e netw ork , u d itive and v is iv e ); and 2 ) b y p erfo rm in g a spatial correlation o f these tem p lates and each R O l-derived M AC M map, w e created a spatial correla tion profile for each o f th e ROIs, in w h ic h the spatial correlation coefficien ts b e tw e e n each ROI and each o f the six tem p lates w e r e stored. O nly tem p lates s h ow in g a significant (p < 0 .0 5 ) correlation w ith each ROI w e r e inclu ded in the spatial correlation profile. These profiles w e r e stored in th e ro w s o f Z, th e M A C M profile

m a tiix o f d im ensions Z x N v , w h e re N v is the num ber o f netw ork s

kept. To describe the d e g re e o f sim ilarity b e tw e e n profiles, w e com pu ted the fim ctio n a l sim ilarity m a tiix (S ) that is the cross­ correlation m a trix o f Z. T o cluster the ROIs in groups, w e used tw o d ifferen t clustering algorithm s: the K-m eans and the hierarchical clustering algorithm s. T he K -m eans a lg orith m is used to cluster n observations in k clusters in w h ic h each observa tion b elon gs to the cluster w ith the nearest mean. K initial m eans are ra n d om ly selected from th e dataset and k clusters are created b y associating e v e ry observa tion w ith the nearest mean. The cen troid o f each o f the K clusters b ecom es the n e w mean. This p rocedu re is then repeated until c on vergen ce is reached. In o rd er to e lim in ate subjective biases, in the selection o f the num ber o f groups, w e fo llo w e d the m e th o d o lo g y used b y Johansen-B erg and colle a g u e s (Johansen-B erg e t al., 2 0 0 4 ). Johansen-Berg and colleagues a p p lied a spectral re ord erin g a lgorith m onto a sim ilarity m atrix (o b ta in e d fro m probabilistic tractograph y data, but containing a sim ilarity in d ex as in our case) to find the re o rd erin g th at m in im izes the sum o f e le m e n t values m u ltip lied b y the squared distance o f that e le m e n t fro m the diagonal, hence forcing large values tow a rd s the diagonal. If the data contain clusters (re p res en tin g seed ROI w ith sim ilar c on n e ctivity), then these clusters w ill appear in the re o rd ered m atrix. Break points b e tw e e n clusters w ill represen t locations w h e re c on n e ctivity patterns change. N u m ber o f clusters w e re , on the basis o f this reord ered matrix, id en tified b y visual inspection as groups o f elem en ts that w e r e s tron gly correlated w ith each o th er and w e a k ly correla ted w ith the rest o f the matrix.

T o m in im ize the risk o f inconsistent results o btain ed for the initial random p lacem en t o f starting points, w e com pu ted the K-m eans clustering 256 tim es, as recom m en d ed b y N anetti and colleagues (N a n e tti e t al., 2 00 9). T he sam e clusters w e r e id en tified 211 ou t o f 256 times.

As w e w e r e in terested in an a lyzin g the hierarchical structure o f the clusters o f the cingulate cortex, w e p erfo rm e d a hierarchical clustering to m ap a d en d rogra m o f our R O l-w ise clustering results. W e used Cluster 3.0 ( http://bonsai.im s.u-tokyo.ac.jp/~m dehoon/ softw are/cluster/softw are.htm ) for the calculation and T re e V ie w ( http://jtreeview .sourceforge.net/) to map dendrogram s. T he sim i­ larity m atrix (S ) w as built using the Euclidean Distance and Centroid Linkage as clustering m ethod. In C entroid Linkage Clustering, a v e c to r is assigned to each pseu d o-item , and this v e c to r is used to com pu te the distances b e tw e e n this p seu d o-item and all rem aining item s o r pseu d o-item s using the sam e sim ilarity m etric that was e m p lo y e d to calculate th e initial sim ilarity m atrix. T he v e c to r is the average o f the vectors o f all actual item s contained w ith in the p seudo-item . Thus, w h e n a n e w branch o f the tree is form ed jo in in g to g e th e r a branch w ith n item s and an actual item , the n e w p seudo­ ite m is assigned a v e c to r that is the a v erage o f the n -I-1 vectors it contains, and n ot the a v erage o f the tw o jo in e d items.

Behavioral dom ain profiles and paradigm classes

Besides the functional con n ectivity o f d ifferen t portions o f the cingulate cortex, w e w e re interested in exam in in g w h ich m ental

processes are activated b y each ROI. In BrainMap, m etadata are orga n ized u nder p aradigm classes and b eh avioral dom ains. The ‘paradigm class’ is the exp erim ental task isolated by the contrast. For a given experim ent, m ultiple paradigm classes m ay apply. Paradigm classes include, am on g others, action observation, episodic recall, task sw itching etc. The ‘behavioral d om ain ’ describes the categories and subcategories o f m ental operations lik ely to be isolated b y the exp erim ental contrast. Behavioral dom ains are classified in six main categories: cognition, action, perception, em otion, interoception or pharm acology. The behavioral dom ains and paradigm classes are established b y the creators o f the database. A com p lete list o f BrainMap's behavioral dom ains can be accessed at http://brainmap.org/scribe/; description o f the classification o f behavioral dom ains and paradigm classes can be accessed at http://brainmap.org/scribe/index.html.

W e first included in th e analysis all b eh avioral dom ains and para digm classes in w h ich activations o f each ROI w e r e present. A fterw ard s, w e calculated the p ercentage o f occurrence o f each b eh avioral d om ain and paradigm class w ith resp ect to the num ber o f papers included in each ROI. O nly behavioral dom ains and p aradigm classes present in at least 5% o f the papers selected for each ROI w e re subm itted to the K -m eans clustering (s e e n ext paragraph).

B ehavioral dom ain-based pa rcellation

The b eh avioral d om ain clustering w as com pu ted using the same m ethods as for the M AC M -based clustering: R O l-related behavioral dom ain-based profiles w e r e clustered b y the K -m eans alg orith m and the o ptim al num ber o f clusters w as calculated using the sam e m eth od as fo r M A C M -b a se d n e tw o rk clu sterin g. S im ilarly, R O l-rela ted b eh avioral d om ain-based profiles w e r e subm itted to a hierarchical clustering using the Euclidean Distance and Centroid Linkage as clustering m ethod.

B ehavioral dom ain-based metaanalysis

To inspect i f an atom ically sim ilar regions o f the cingulate region sh o w d iffe re n t patterns o f co-activation, w e p erfo rm e d a separate m eta-analysis o n th e b eh avioral dom ains that w e r e p resent in at least 5% o f th e total num ber o f papers selected for each ROI: ‘e m o tio n ’, ‘atten tion ’, ‘pain’, ‘action e xe c u tio n ’, ‘m e m o ry ’ and ‘langu age’. For each d om ain w e p erfo rm e d a separate m eta-analysis using the BrainMap database (Laird e t al., 200 5). For the em otion a l d om ain the search lim its w e r e [Diagnosis = N orm als] A N D [Behavioral D om ain = E m o­ tion]. For the attentional d om ain the search lim its w e r e [D ia g n o­ sis = N orm als] A N D [Behavioral D om ain = C ogn ition ■ A tten tion ]. For the pain d om ain the search lim its w e r e [Diagnosis = N orm als] AN D [Behavioral D om ain = P erception ■ Som esthesis-P ain]. For the ac­ tion e xecu tion d om ain th e search lim its w e r e [Diagnosis = N o r­ m als] A N D [Behavioral D om ain = A ction ■ Execution]. For th e m e m o ry d om ain the search lim its w e r e [Diagnosis = N o r m a ls ] A N D [Behavioral D om ain = C ogn ition ■ M em o ry ]. For the language d om ain the search lim its w e r e [D ia g n osis = N o rm a ls ] A N D [B e h a v iora l D om ain = C ogn ition ■ Language].

Spatial proba bility maps

Spatial consistency o f functional c on n e ctivity patterns across d iffe re n t d om ain -related ALE results w a s evaluated b y com pu ting probabilistic maps. A t each spatial location, such maps represen t the relative num ber o f ALE values lead ing to significant results. The p rob a b ility map is calculated b y sum m ing v o x e l v alu e o f each d om ain -related ALE result and d iv id in g this valu e b y the num ber o f dom ains. ALE maps, b efo re the probability maps creation, w e re th reshold ed at a False D iscovery Rate (F D R )-corrected threshold o f p < 0 .0 5 and visu alized using M ricron ( w w w .m ric ro .c o m ) and Brain- V o y a g e r QX 2.0.

Results

A ctiva tio n likelihood estim ation (A LE ) m eta-analysis: maps o f coactivations (M A C M )

A total o f 1131 studies w e r e included in our m eta-analysis corresp on d in g to 1375 exp erim ents, lead ing to a total o f 18,976 foci. See Tabs S I - S I 2 o f the supporting on line m aterials for further d etails and for th e num ber o f studies included in each ROl.

Fig. 2 show s the ALE profiles o f each ROl.

ROl 1 w as found to be fu n ctionally c on n ected w ith the am ygdala, the orb itofron tal cortex, the v en trom ed ia l p refrontal cortex, the p osterior insular cortex, the nucleus accum bens and the precuneus. ROl 2 shared im p orta nt con n e ctivity sim ilarities w ith ROl 1, but it also s h ow ed stronger functional con n e ctivity w ith the p osterior cingulate corte x and w e a k e r w ith the p osterior insular cortex. ROl 3 besides som e co-activations in c om m o n w ith ROl 2, s h ow ed functional connections w ith th e an terior insular cortex, the striatum and the nucleus caudatus. ROl 4 s h ow ed co-activations w ith fronto-parietal areas. T he activation p rofile associated w ith ROl 4 w as characterized b y an increase in the c o-a ctiva tion o f ROl 4 and the dorsal anterior cingulate corte x and the absence o f the c o-a ctiva tion w ith the

am ygdala. ROl 5 w as found to be part o f a n etw o rk o f co-activations encom passing the an terior insular cortex, the thalam us and the m idbrain. N o m a jor functional d ifferen ces w e r e ob served b e tw e e n ROl 6 and ROl 5. ROl 7 s h ow ed co-activations w ith the parietal cortex, the intra parietal sulcus and the m id d le frontal gyrus. ROl 8 was fu n ctionally con n ected w ith sen sory-m otor areas. Similarly, ROl 9 s h ow ed connections w ith m otor cortices, but in addition, it sh ow ed increased co-activations w ith th e su p plem entary m o to r area and visual areas. ROl 10 w a s active to g e th e r w ith m o to r and visual areas, but lim b ic com pon en ts re-ap peared to g e th e r w ith strong functional connections w ith the m edial p refrontal corte x and the tem p oral parietal junction. ROl 11 w a s found to be part o f a m esial fro n to ­ parietal n etw o rk (p o s te rio r part o f the D M N see Raichle and Snyder, 2 0 0 7 ) and sh ow ed further coactivations w ith som e attentional- related areas such as th e d orsolateral p refron tal corte x (DLPFC) and the an terior insula. Co-activations o f ROl 12 w e r e su p er-im posable to those o f m esial fronto-pa rietal n etw o rk o f the D M N (R aichle and Snyder, 2007).

Fig. 3 show s that according to the M AC M -based parcellation, the cingulate corte x can be d ivid ed in th ree clusters: ROls 1, 2, 3 ,1 1 and 12 w e r e assigned to the first cluster, ROls 4, 5, 6 and 7 to the second, ROls 8, 9 and 10 to the third. Spatial distance b e tw e e n clusters in the

MACM- based parcellation

K-Means Clustering (K=3)

□ □ □ □ □ □ □ □ □ □ □ □

I3, % % % % % % % \ \ O O ^S- <s- "tì- < s ■<,

Hierarchical Clustering

Sensorim otor Anterior DMN ■Ì3-, -ij, I3, '{j <s

Behavioral domain-based parcellation

Hierarchical Clustering

K-Means Clustering (K=4)

□ □ □ □ □ □ □ □ □ □ □ □

'-S'

Fig. 3. In the upper panel the parcellation based on the MACM. Network labeling was done by correlating each ROI-derived MACM map to a template of the principal networl<s

identified in the resting and active brain: default mode network (DMN), attentional, sensorimotor, anterior default mode network (anterior-DMN), uditive, visive. In this way we produced a spatial correlation map for each of the ROl and each o f the template (see text for details). Only significant correlations were kept (default mode network, attentional, sensorimotor, anterior default mode network). The K-means clustering produced three subdivision o f the cingulate cortex. The K-means algorithm is used to cluster n observations in

k clusters in which each observation belongs to the cluster with the nearest mean. K initial means are randomly selected from the dataset and k clusters are created by associating

every observation with the nearest mean. In the dendrogram, near elements are more similar. The shades o f red represent how much each ROl can be considered as associated to a MACM profile. Brighter reds mean a greater association. In the lower panel the parcellation based on the behavioral profiles. Network labeling was done in accordance with the

BrainMap database. The K-means clustering was used to cluster the observations. Again, as in the MACM the distance between clusters represents their similarity (the closer, the more similar). The shades o f red represent how much each ROl can be considered as associated to a behavioral profile. Please see text for further details.

d en d rogram represents th eir d egree o f sim ilarity: the closer th e y are, the m ore th eir functional sim ilarity. In cluster 1, ROIs 2 and 3 w e re id en tified as m ore fu n ctionally sim ilar to each o th er than to ROl 1.

W ith in the sam e cluster, ROIs 11 and 12 form ed an oth er sub-cluster. In cluster 2, ROIs 5 and 6 w e r e m ore sim ilar to each o th er than to ROIs 4 and 7. In cluster 3, ROIs 8 and 9 w e r e m ore sim ilar to each o th er than

Fig. 4. ALE maps o f behavioral profiles.

to ROl 10. A d d ition ally, cluster 2 and 3 w e r e m o re sim ilar to each o th er than to cluster 1.

B ehavioral dom ain profiles

Six b eh avioral dom ains w e r e present in at least the 5% o f the papers selected for each ROl (s e e m ethods s ection ). T h e y w e r e labeled as follo w s: ‘e m o tio n ’, ‘a tten tion ’, ‘pain’, ‘action e xe c u tio n ’, ‘m e m o ry ’ and ‘langu age’. In this case, labeling w a s chosen in accordance w ith the labeling o f the BrainMap database. W e then id en tifie d the paradigm s that m ore often activated each ROl, using the same criterion as for the b eh avioral dom ains.

A c tiv ity in ROl 1 and 2 w as m ainly correlated w ith re w a rd -rela ted tasks, p ertaining to the em otion a l b eh avioral dom ain. ROl 3 w as found to be particu larly active for tasks related to the b eh avioral d om ain o f attention. A t the sam e tim e, it w as associated w ith pain discrim in ative paradigm s. ROl 4 s h ow ed a superim position o f a c tiv ity related to em otion a l and a tten tive tasks and w as related to rew a rd and pain d iscrim in ative paradigm s. ROl 5 w as activated b y various behavioral functions, such as attention, language and p erc e p tive som atic pain, but it w as particu larly a ctive in pain discrim ination paradigm s. ROl 6 s h ow ed a pattern sim ilar to that o f ROl 3. ROl 7 w a s specifically active for pain discrim ination paradigm s, d esp ite b ein g also part o f the n etw o rk underpinning o th er behavioral functions such as action e xecu tion and attention. ROl 8 sh ow ed a m otor pattern, thus b ein g active in action execu tion tasks and fin g er tapp in g paradigm s. ROl 9 w as m ore associated w ith m e m o ry and attentional tasks and activated b y paradigm s o f film v ie w in g and visual pursuit. ROl 10 s h ow ed a m o re ‘linguistic’ pattern o f activation, b ein g associated to linguistic functions, sem antic discrim ination and episodic recall paradigm s. ROl 11 w a s found to be in vo lv ed in several b eh avioral functions and active for rew a rd and langu age paradigm s. Finally, ROl 12 w as m ore

associated to m e m o ry abilities and rew a rd and w as active in n-back and face discrim ination tasks.

Fig. 3 show s h o w th e subdivision o f the cingulate c orte x according to th e b eh a v iora l d om a in y ie ld e d four clusters: cluster 1 w as constituted b y ROls 1, 2, 4 and 12, cluster 2 b y ROls 3,5 and 6, cluster 3 b y ROls 7 and 8 and cluster 4 b y ROls 9, 10 and 11. Alth ou gh pertaining to the sam e cluster, ROls 1 and 2 w e r e m ore sim ilar to each o th er than ROl 4 and ROl 12 form ed a separate sub-cluster. In cluster 2, ROls 3 and 6 w e r e m ore sim ilar to each o th er than ROl 5. In cluster 4, ROls 9 and 11 w e r e m ore sim ilar to each o th er than ROl 10. As a w h o le , clusters 1 and 4 w e r e m ore sim ilar to each o th er w h ereas cluster 3 rem ained a separate cluster.

Fig. 3 also depicts the functional c o m p le x ity o f som e o f th e ROls. Som e portions o f the cingulate c orte x w e r e in fact h igh ly correlated to specific b eh avioral dom ains (e.g. ROls 1 and 2, please re fe r to the legen d o f Fig. 3 for m ore d etails), w h ereas others activated for a plurality o f tasks and w e r e correlated to d ifferen t b ehavioral dom ains.

Behavioral dom ains meta-analysis

To further in vestigate the in v o lv e m e n t o f som e portions o f the cingulate c orte x in a plurality o f tasks, w e p erfo rm e d a separate m eta­ analysis for the six d om ains that w e r e m ore freq u en tly found present in th e cingulate c o rte x (an d id en tified as p reviou sly e xp la in e d ): attention, pain, language, action execution, em otion s and m e m o ry (s e e Tabs S13-S18 o f the su p plem entary o n line m aterial and Fig. 4 ).

The results o f the separate m eta-analysis for the six d om ains that w e r e m ore freq u e n tly found p resent in the cingulate c orte x led to the id en tification o f 314 papers using a total o f 5253 subjects in 2188 exp erim en ts id en tifyin g 17806 locations for th e attentional d om ain; o f 78 papers using a total o f 989 subjects in 250 exp erim en ts leading to 2276 locations for the pain d om ain; o f 455 papers using a total o f

7036 subjects in 1945 exp erim en ts lead ing to 16222 locations for the language dom ain, o f 94 papers using a total o f 1491 subjects in 117 exp erim en ts lead ing to 1772 locations for th e action execu tion d om ain; o f 314 papers using a total o f 5282 subjects in 1272 exp erim en ts lead ing to 8526 locations for the em o tio n d om ain; o f 388 papers using a total o f 7903 subjects in 1455 exp erim en ts lead ing to 12057 locations for the m e m o ry dom ain.

T o in vestiga te i f the sam e areas o f the cingulate corte x w e re recruited in various b eh avioral dom ains, w e calculated a probabilistic m ap con siderin g the p ercentage o f superim position o f the ALE- gen era ted m aps and the results o f the b eh avioral-d om ain based m eta­ analysis. The results o f this analysis sh ow ed that ROI 6 and 7 w e re v irtu a lly active for all the six b eh avioral dom ains (s e e Fig. 8 ). M ore specifically, the probabilistic m ap represen ted in Fig. 8 show s that in the region c ov e red b y ROI 7 and in m in or p ortion in ROI 6 there is a 100% superposition o f all six b eh avioral dom ains.

Discussion

T he aim o f the p resent study w as to picture the functional c o m p le x ity o f the cingulate corte x b y p oolin g to g e th e r activations extracted fro m o v e r 1000 studies in th e BrainMap database. The results indicate that the activations o f the cingulate corte x can be b road ly redu ced to th ree functional clusters and four behavioral dom ains (s e e Fig. 3 ). H o w e ve r, th e y also und erline the c o m p le x ity o f som e p ortions o f the cingulate area, w h ic h w e r e found to activate for a plurality o f b eh avioral dom ains.

T he discussion w ill fo llo w th ree m ain lines: w e w ill first discuss the c o-a ctiva tion profiles o f the ROIs and the functional clusters, then w e w ill a n alyze the b eh avioral dom ains (R O I p er ROI and as a cluster) and finally w e w ill discuss the in v o lv e m e n t o f som e portions o f the cingulate corte x in a plu rality o f tasks.

ALE profiles o f each ROI and fim c tio n a l clusters

ROIs 1 and 2 w e r e found to have im p orta nt coactivations w ith the am ygdala, th e orb ito fron ta l cortex, th e v en tro m e d ia l p refron ta l cortex, retrosplenial cortices and the nucleus accum bens (s e e also Beckmann e t al., 2009; Cauda e t al., in press-a; Yu e t al., 2 0 1 1). The functional sim ilarity found b e tw e e n ROIs 2 and 3 m a y in deed reside in th eir b ein g “transition re g io n s" w h e re in c og n itive and a ffective processes are in tegrated (D e vin s k y e t al., 1995; M argu lies e t al., 2 007). ROI 3 w as found to be coa ctive w ith the insular cortex. The jo in t activation o f the a n terior insular c o rte x and the an terior cingulate corte x is freq u en tly rep orted (Craig, 2009; M ed fo rd and Critchley, 201 0). This supports the idea that these tw o regions serve as com p le m e n ta ry lim b ic sensory and m o to r regions w o rk in g to ge th e r (Craig, 2 0 0 9 ), in v o lv e d in the p rodu ction o f in te ro ce p tio n and subjective feelings, coord in ating ap p ropriate responses to internal and externa l events. In particular, the an terior insular corte x is th ou ght to be in v o lv e d in the re-rep resen ta tion o f in terocep tive in form ation thus p articipating in b od ily aw areness (Craig, 2009).

ROIs 4 and 5 w e r e found to be part o f th e fronto-parietal netw ork s that have been p roposed to act to g e th e r for the selection o f w h e re and to w h a t allocate attention: the dorsal and v en tral fronto-parietal n etw ork s (s e e C orbetta e t al., 1991 ; Corbetta e t al., 2008; M en on and Uddin, 2010; S eeley e t al., 200 7). Furtherm ore, ROIs 5 -7 sh ow ed conju nct a c tiv ity w ith subcortical regions such as the thalamus and the m idbrain and w e r e also part o f a n etw o rk inclu ding the anterior insular corte x and the m edial thalamus. A ll these areas are som e o f the m ain constitu ent o f the so-called ‘Core System ’ (D osenbach e t al., 2006; M ed ford and Critchley, 2010; N elson e t al., 2 0 1 0 ) w h ic h is in vo lv ed in the im p lem en ta tion o f task-sets and sustained ‘set- m aintenance’ o v e r e n tire task epochs.

Functional links b e tw e e n the ven tral attentional n etw o rk and the norep h in ep h rin e a c tiv ity o f the locus coeruleus have b een ou tlined b y

neu rocom putational m od els (A ston -jon es, 2005; Bouret and Sara, 2005; Dayan and Yu, 2 0 0 6 ) and it has been sh ow n that subcortical regions like the superior colliculus are in vo lv ed in stim u lus-driven and g o a l-d riv en m echanism s o f a tten tion (B ell e t al., 2004; Fecteau e t al., 2004; Rafal e t al., 1988; Sapir e t al., 1999; T am ietto e t al., 201 0). M oreov er, the p ulvinar nucleus is in vo lv ed in the m od u lation o f the physical saliency o f a stimulus in b oth humans and non-hum ans prim ates (S n o w e t al., 2009; T am ietto and d e G elder, 2 0 1 0 ) and recruited for c ov e rt form s o f g o a l-d irected searches (Fairhall e t al., 200 9).

ROI 8 and 9 s h ow ed a m ore pronou nced pattern o f sen sorim otor con n ectivity. T h ree areas located in such regions, o ften described as cingulate m otor zone (Barbas, 2000; M ayka e t al., 2006; M orecraft e t al., 2007; M orecraft and Van Hoesen, 1998), have b een sh ow n to be in vo lv ed in m o to r control. These areas are situated w ith in the cingulate sulcus and consist in: ( i ) a rostral (C M A r) and ( i i ) ven tral (C M A v ) parts lyin g in the ven tral bank o f the cingulate sulcus. The third area, the dorsal cingulate m o to r area (C M A d ) is located in the dorsal bank o f the cingulate sulcus. Each o f such cingulate m o to r areas is characterized b y cytoarch itecton ic d ifferen ces (Cauda e t al., in press-b; Picard and Strick, 1996).

The pattern o f con n e ctivity o f ROI 10 com prised areas in v o lv e d in m e m o ry recall and attentional n etw ork s (B in d er e t al., 2 00 9). T he area activated b y the sem antic system in this study w a s located som e m illim eters m ore rostrally to that found b y o th e r studies. This region has b een linked to e p isod ic and visuospatial m e m o ry functions ( A g g le to n and Pearce, 2001 ; Epstein and Higgins, 2007 ; G ainotti e t al., 1998; Rudge and W arrin g ton , 1991; V in cen t e t al., 200 6), and has strong reciprocal connections w ith the h ippocam pal c o m p le x v ia the cingulum bundle (K obayashi and Am aral, 2003, 2007; M orris e t al., 1999). The m id/posterior cingulate c o rte x is affected e a rly in the course o f A lzh eim e r's disease (A D ), in w h ich the ep isod ic m e m o ry e n cod in g d eficit is often a m arker (D esgran ges e t al., 2002; N estor e t al., 200 3). P osterior ROIs s h ow ed a m ixed con n e ctivity w ith D M N and the attentional salience d etec tio n system . These areas have been re ce n tly associated to gain-sp ecific activation (in crea sed activation for increased gain, but no change in activation in relation to loss) (Fu jiw ara e t al., 2 00 9 ). The role in the evalu ation o f gain is w e ll exp ressed in th e pattern o f m eta-analytic con n ectivity. Indeed, the salience d e te c tio n system is stro n gly c on n ected to the v en tral striatum and shares several areas w ith the rew a rd system .

As far as the relationship b e tw e e n c o-a ctiva tion and functional con n e ctivity is concerned, it has b een show n that M A C M and resting state functional con n e ctivity m a y lead to sim ilar results (Cauda e t al., in press-a). Indeed, it is d ifficu lt to exp lain h o w such coactivations o f brain areas across d iffe re n t paradigm s and studies m a y e m e rg e in absence o f any functional con n e ctivity b e tw e e n these areas (as discussed in Koski and Paus, 2000; Laird e t al., 2009a; Postum a and Dagher, 2006; Sm ith e t al., 200 9). T he current op in ion (K oski and Paus, 2000; Laird e t al., 2009a; Postum a and Dagher, 2006; Smith e t al., 2 0 0 9 ) is to in terp ret the functional coactivations as a form o f functional c on n ectivity. F u rtherm ore th e m a pp in g o f functional con n e ctivity via coord in ate-b ased m eta-analysis has been valid ated b y com pa rin g the results o f M AC M to resting-state c on n ectivity (S m ith e t al., 200 9). Both approaches produ ced v e r y consistent results.

W h e n using a clustering procedure, all d iffe re n t patterns o f functional con n e ctivity w e r e grou p ed in th ree m ain clusters, that m a y be labeled as ‘self-re fe re n tia l’, ‘a tte n tiv e ’ and ‘sen s ory-m otor’. T he clustering p inp oin ted to a strict intercon n ection b e tw e e n anterior and p osterior parts o f the cingulate cortex, rep e a ted ly found in resting state functional con n ectivity. The clustering also su pported the existen ce o f a large in tercon n ected p ortion o f the cingulate cortex d e v o te d to s e lf referen tial functions; an an terior dorsal section d e v o te d to attentional functions and a p osterior area characterized b y sen sory-m otor functions and language. P alom ero-G allagher and

ROl

ROI 2

memorv V - - . > cognition

action execution■cution

V

perceptive somatic_pain passive listening

\ semantic

. - 'Y / d is c r im ir ia tio n

memory Cognition

Tfi

lanEuage

\

/ ' / V

action éxecution '^perceptive somatic

pain pain / d iscrim inationf^-fi \ semantic N , _ > -^ d iscrirrin a tio n

w

spatial face/m otor

discrtmination discrimination

ROI 3

ROl 4

episodic r e c a ll ( '^ '^ ^ , ^ iS ^ \ \ \ \ ' U,5 \ semantic / discrim inatior pain discrimination I a ngu a

\ Z

___________ \percep tlve somatic

Fig. 5. Shows the behavioral dom ains and paradigm classes for each ROl. Here, ROIs 1 - 4 are presented. Behavioral domains are on th e left-hand side, paradigm classes on the right-hand side. Please note th a t the dom ain ‘cognition’ w as never

considered in our analysis. Each vertex of the polygon represents a behavioral dom ain (left panel) or a paradigm class (right panel). The percentage of occurrence of each behavioral dom ain and paradigm class is show n on the radial axis of the polygon. Lower percentages of occurrence are closer to the center. Higher percentages of occurrence are closer to the vertexes.

ROl 5

ROl 6

cognition language attention perceptive somatic pain languag^V y \

\ y

perceptive somatic pain

ROl 7

cognition language

action execution ' Perceptive somatic

pain

ROI 8

V___V

action execution perceptive somatic

pain

face/motor discrimination

20.. T.

task sw itcliingf pain

/ discrimination

finger tapping

Fig. 6. Shows the behavioral domains and paradigm classes for each ROI. Here, ROIs 5 -8 are presented. Behavioral domains are on the left-hand side, paradigm classes on the right-hand side. Please note th a t the dom ain ‘cognition’ w as never

considered in our analysis. Each vertex of the polygon represents a behavioral dom ain (left panel) or a paradigm class (right panel). The percentage of occurrence of each behavioral dom ain and paradigm class is show n on the radial axis of the polygon. Lower percentages of occurrence are closer to the center. Higher percentages of occurrence are closer to the vertexes.

ROI 9

ROl 10

semantic

dis^ljimination discrimination semantic

20

-action execution T S ' p a l r

\\

l

J

visual pursuit/tracking

lem ory ^ \ C O g n iti(

10^

language ^ w attention

action execution perceptive somatic episodic recall pain discrimination

R O I 11 R O l 1 2

m emory p^^--^^_^>iCOgnition

X

language attention

action execution perceptive somatic _pain

cued e x p lic it ^ recognition

face/motor discrimination

episodic recall

Fig. 7. Shows the behavioral domains and paradigm classes for each ROl. Here, ROIs 9 -1 2 are presented. Behavioral domains are on the left-hand side, paradigm classes on the right-hand side. Please note th a t the dom ain ‘cognition’ was never

considered in our analysis. Each vertex of the polygon represents a behavioral dom ain (left panel) or a paradigm class (right panel). The percentage of occurrence of each behavioral dom ain and paradigm class is shown on th e radial axis of the polygon. Lower percentages of occurrence are closer to the center. Higher percentages of occurrence are closer to the vertexes.

Fig. 8. Shows the spatial probability maps o f each ROl. At each spatial location, such maps represent the relative number o f ALE values leading to significant results. The probability

map is calculated by summing voxel value o f each domain-related ALE result and dividing this value by the number o f domains. In ROls 6 and 7 there is a virtual overlap o f all behavioral domains.

colleagues (P alom ero-G a lla g h er e t al., 2 0 0 9 ) b y using a hierarchical clustering found support for the four, instead o f three, subregions m odels. Our M AC M data are m o re in favor o f a d ivision in three functional clusters. H o w e ve r, these results are o n ly in apparent contrast w ith Palom ero-G allagher's ones. Indeed, it has to be noted that th eir clustering w as based on the p os tm orte m analysis o f recep tor bind in g according to the d e g re e o f sim ilarity o f each area's recep tor architecture. In contrast, w e p ropose a th re e -reg ion sub­ d ivision o f the cingulate corte x based on functional con n e ctivity evidences.

Behavioral profiles and behavioral clusters

A ctivations in ROl 1 and 2 w e r e h igh ly correlated to the b ehavioral d om ain o f em o tio n and to rew a rd -rela ted tasks. A n terio r p ortions o f the cingulate corte x have b een rep orted rep e a ted ly as central to rew a rd -rela ted tasks (H a b e r and Knutson, 2 010). Indeed, recordings fro m neu rons in th e a n te rio r cin g u la te c o r te x (w h ic h re c e iv e im p orta nt d op a m in ergic projections, W illia m s and Goldm an-Rakic, 1998) d em on strated that such neurons en cod e rew a rd p rediction com b in in g in form ation about rew a rd m agn itu d e and rew a rd p roba­ b ility (A m ie z e t al., 2006; M atsu m oto e t al., 2003; R ushw orth and Behrens, 200 8). Similarly, an oth er area o f the frontal lobes, the orb itofron tal cortex, is in vo lv ed in elab oration o f rew a rd and in decision making, in particular o f the e xp e cted valu e o f a rew a rd (Sul e t al., 2 010). Lesion studies h o w e v e r suggest that the tw o areas cod e d ifferen t aspects o f rew a rd and rew a rd -rela ted behaviors. In humans and animals, lesions to the orb itofron tal corte x lead to the p referen ce o f sm all im m ed iate rew ards o v e r larger and d ela yed ones (K hera m in e t al., 200 2), but d o n ot im p air the a b ility o f eva lu atin g the e ffo rt that has to be m ade to obtain a rew ard. Conversely, lesions to the anterior

cingulate corte x d o n ot alter d elay-based decision tasks, but im pair the a b ility in e ffo rt based decision -m akin g tasks (R u d eb eck e t al., 2006; W a lto n e t al., 2003; W a lto n e t al., 2002).

Subgenual an terior cingulate corte x is th ou gh t to be im p licated in the regulation o f m ood. It has b een d em on strated that patients su fferin g fro m m a jor d ep re s s iv e d isord ers (M D D ) and b ip o la r d isorders have a redu ction in the m ean gra y m a tter v olu m e o f this areas irresp ective o f the m ood state (D re ve ts e t al., 1997; O ngur e t al., 1998). ROls 3 and 4 m ay in deed refle c t the area o f the cingulate cortex w h e r e th e d is tin c tio n a ffe c tiv e / c o g n itiv e starts to take p lace (D e vin s k y e t al., 1995). It has b een suggested that rather than look in g for a specific role o f the subregion o f th e cingulate corte x im plicated, it w o u ld be m ore useful to c on ceive that both kinds o f stim uli m ay share sim ilarities (e.g. th e y cause an avoidan ce reaction ) and th at it is this avoidan ce reaction w h ic h generates the response o f the cingulate cortex, and n ot em otion al o r painful stim uli p e r se (V o g t, 2 0 0 5). For instance, th e activation o f ROls 4 in tasks o f pain discrim ination, rew a rd and atten tion m ay reflect the p ro p e rty o f such areas, w o rk in g as saliency d etec to r and saliency m ap (Cauda e t al., 2011 ; Corbetta et al., 2008; Corbetta and Shulman, 2002).

ROl 3, 5 and 6 w e r e p red om in a n tly associated w ith the behavioral d om ains o f atten tion and activated b y pain related paradigm s. The in terp lay b e tw e e n atten tion and pain is a c om p le x and h ot area o f research (S e m in o w ic z and Davis, 2007a, b; W ie c h e t al., 200 8). A tte n tio n and its cou nterpart distraction h ave b een found to m odulate b oth the p ercep tion o f pain and the brain responses associated to it (Bantick e t al., 2002; P eyron e t al., 2000; R ainville e t al., 1997) but the characteristics o f the painful stimulus o f re ad ily grasping attention, seriou sly lim it the possibility o f studying th e interaction b e tw e e n atten tion and pain as it is d on e in o th er sensory dom ains (e.g. grading the cap ab ility o f a painful stimulus o f grasping attention, for a r e v ie w

on the caveats and possible con fou n din g aspects see (S e m in o w ic z and Davis, 2007b; W ie c h e t al., 2 0 0 8 )). It has also b een suggested that a gre a t part o f the response o f th e cingulate corte x to pain m ainly reflects the ac tiv ity o f a m u ltim od al saliency d etec to r system (D o w n a r e ta l.,2 0 0 0 ; lannetti and M ouraux, 2010; L e g ra in e ta l.,2 0 1 1 ; M ouraux e t al., 2011; V alen tin i e t al., in press).

In support o f the m u ltim od al and m ultifunctional p rofile o f the cingulate cortex, ROI 6 and 7 w e r e found to be virtu a lly active for all the b eh avioral dom ains, (s e e n ext paragraph).

Also, fro m Fig. 3 it can be noted that ROI 8 as w e ll w as in vo lv ed in a v a rie ty o f b eh avioral dom ains. Anatom ically, this p ortion o f the cingulate corte x has been id en tified as th e cingulate m o to r zone. The cingulate m otor zon e is p rev a le n tly in vo lv ed in action e xecu tion and m o to r paradigm s. Interestingly, this area is also in vo lv ed in pain discrim ination paradigm s as c on firm ed b y several fM RI and LEP studies (B e n tle y e t al., 2003; B entley e t al., 2001; B entley e t al., 200 2).

M o v in g caudally (R O I 8 to 9 ), an increase in the in v o lv e m e n t in sem antic as w e ll as atte n tiv e paradigm s is observable. The mid/ posterior cingulate corte x has b een found to be m a inly in vo lv ed in sem antic and langu age tasks. This ob serva tion is supported by findings (s e e Binder e t al., 2 0 0 9 ) w h ic h found the activation, am on g o th er areas, o f the p osterior cingulate corte x for the sem antic system (i.e. th e k n o w le d g e ab ou t p eop le, concepts, objects, s e lf etc.). A d d ition ally, activation o f p osterior portions o f the cingulate cortex has b een rep e a ted ly found in relation to m n em onic and em otion al tasks. Our results con firm previous findings o f functional c on n ectivity studies in humans (Cauda e t al., 2 01 0) and tracing e xp erim en ts in prim ates (P a rv izi e t al., 2 00 6) that s h ow ed selective in tercon n ectivity b e tw e e n the p osterior cingulate corte x and th e parahippocam pal form ation in subserving episodic m e m o ry retrieval. P osterior parts o f the cingulate c o rte x have b een re ce n tly associated to gain-sp ecific activations (Fu jiw ara e t al., 200 9). Several fM R I studies (D aselaar et al., 2004a; Daselaar e t al., 2004b; Kao e t al., 2005; M iller e t al., 2008; O tten and Rugg, 2001; Shrager e t al., 2008; W a g n e r and Davachi, 2 0 0 1 ) have sh ow n d ea ctiva tion in the p osterom ed ia l corte x e x te n d ­ ing into the p osterior cingulate corte x during m e m o ry encoding. These deactivation s have been in terp reted as the result o f the reallocation o f neuronal resources n eed ed for e fficie n t cog n itive processing. The p osterom ed ia l cortices have b een sh ow n to be in vo lv ed in self-referential and refle c tiv e ac tiv ity (A d d is e t al., 2004; Burianova e t al., 2010; Cauda e t al., 2010; Greicius e t al., 2003; Gusnard e t al., 2001; Johnson e t al., 2009; Johnson e t al., 2006; Svoboda e t al., 2 00 6 ). M oreov er, several studies have found a greater activation in the p osterom ed ia l cortices in p rop ortion to th e strength o r certain ty o f the m e m o ry decision, indicating that this region seem s to be specifically in vo lv ed in m e m o ry retrieval (Chua e t al., 2006; Svoboda e t al., 2006; W a g n e r e t al., 2005; W h e e le r and Buckner, 200 4). Indeed patients w ith focal lesions in this region suffer from am nestic syndrom es (G ain otti e t al., 1998; H eilm an e t al., 1990; Katai e t al., 1992; Rudge and W arrin gton , 1991; Takayam a e t al., 1991; Valenstein e t al., 1987). T he p osterior cingulate corte x has been described as in vo lv ed in the processing o f vale n c e and arousal o f a ffec tiv e pictures (N ie le n e t al., 2 009). A c tivation o f this area in em otion a l tasks m a y refle c t ep isod ic m e m o ry in v o lv e m e n t during evalu ation o f p os itiv e ly valen ce arousal.

Furtherm ore, these areas also s h ow ed an in v o lv e m e n t in saliency d etection w h ic h have been related to the ‘w a n tin g ’ c om p on en t o f rew a rd (B errid ge e t al., 2 00 9 ). Several human functional m agnetic reson an ce im a gin g (flVIRl) studies h ave c on firm e d this find in g sh ow in g an increased p osterior cingulate activation in relation to rew a rd (E rnst e t al., 2004; Izum a e t al., 2008; M arsh e t al., 2007; N ieu w en h u is e t al., 2005; O 'D oh erty e t al., 200 1).

The p arcellation o f the cingulate corte x based on ALE maps (M A C M ) p ro vid ed th ree functional clusters, w h ereas the parcellation based on the b eh avioral profiles p ro vid ed four clusters and a m ore precise p rofile (s e e Fig. 3 in w h ich the c olor o f the square represents

the d e g re e o f functional s im ilarity). The clustering based on the b eh avioral d om ains (s e e Figs. 3 and 5 - 7 ) d ivid ed the cingulate region in four portions, w h o s e p rofile is v e r y sim ilar to that o f the previous M AC M -based parcellation. H o w e ve r, the b eh avioral dom ain-based parcellation yield s to an ad ditional cluster in the m id cingu late cortex. This d ifferen ce w o u ld suggest that a parcellation o f th e cingulate corte x based on b eh avioral profiles can g iv e a m o re fine-grain ed picture o f the fu n ctionality o f this area.

Behavioral based metanalysis and spatial proba bility maps

To inspect if an atom ically sim ilar regions o f the cingulate region s h ow ed d ifferen t patterns o f co-activation, w e first p erform e d a separate m eta-analysis for the six d om ains that w e r e m ore present in th e c in g u la te c o r te x ; th e n w e c a lcu lated a p ro b a b ilis tic m ap con siderin g the p ercentage o f sup erim position o f the ALE -generated maps and the results o f the b eh avioral-d om ain based m eta-analysis. Indeed, in ROIs 6 and 7 th ere w as a virtu al o verla p o f all 6 b ehavioral dom ains. This supports the possibility that sim ilar portions o f the cingulate corte x m a y in deed activate for d iffe re n t b eh avioral dom ains. This in teresting find in g can be exp lain ed b y various possibilities: 1) som e p ortions o f the cingulate c o rte x m a y act as “ hub" areas in tercon n ecting d iffe re n t netw orks. R ecently He and colleagues (H e e t al., 2 0 0 9 ) suggested th at the w h o le brain w ork s in a m odular fashion, but specific m odules com m u n icate throu gh “ hub" areas. These hub areas w o u ld be high er o rd er associative areas able to link d iffe re n t sm aller netw orks. This possibility supports the suggestion proposed b y V o g t and colleagues (V o gt, 2 00 5) for w h ich it m ay be a m ore useful approach to consider that such portions o f the cingulate area, rather than b ein g p rim arily in vo lv ed in specific tasks, m a y be in vo lv ed in activities com m on to several tasks; 2 ) alternatively, these results m a y be exp lain ed b y lim itations in the current m e th o d o lo g y and future m o re fine grain ed results m ay p ro vid e m ore precise glim p ses o v e r th e functionality o f p ortions in vo lv ed in several tasks.

Conclusions

The cingulate corte x is a fascinating and c om p le x region func­ tio n a lly in vo lv ed in a broad v a rie ty o f tasks and richly interconnected w ith the rest o f the brain. Its structural and functional divisions are b ein g p rogressively u n veiled. H o w e ve r, to our k n o w led ge , this is the first study w h ich has system atically in vestigated the activations o f the cingulate c orte x inclu ding o v e r 1000 published neu roim aging studies. Our results s h o w th e e x is te n c e o f a m o re sp e cific fu n ctional characterization o f som e p ortions o f the cingulate cortex, but also a great m u ltifu n ctionality o f others. It rem ains an op e n qu estion as w h e th e r this is a p ecu liarity o f this “ hub" area o r the result o f the lim its o f the m e th o d o lo g y used.

Aclmowledgments

W e w o u ld like to thank Dr. M en g Liang and Dr. M arco T am ietto for th eir valu able com m en ts on an earlier v ersion o f this manuscript.

Appendix A. Supplementary data

S u p p lem en ta ry data to this a rticle can b e fou nd o n lin e at d o i: 10.1016/j.neuroim age.2011.03.066.

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