(AR)Neuroanatomaical and Neurochemical Bases of Theory of Mind (2011)

7/26/2019 (AR)Neuroanatomaical and Neurochemical Bases of Theory of Mind (2011)

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http://localhost/var/www/apps/conversion/tmp/scratch_2/dx.doi.org/10.1016/j.neuropsychologia.2011.07.012mailto:[email protected]://www.elsevier.com/locate/neuropsychologiahttp://www.sciencedirect.com/science/journal/00283932http://localhost/var/www/apps/conversion/tmp/scratch_2/dx.doi.org/10.1016/j.neuropsychologia.2011.07.012


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2972 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 29712984

these mental states to self and other, and finally apply (or deploy)these mentalstates in a manner that allows one to correctlyunder-stand and predict behavior. According to Fuster (2001), two majorpitfalls must be avoided when formulating a neural basis of a com-plex behavior or function: (1) to discuss this function in isolationwhile neglecting others that complement it, and (2) to localize thisfunction within a discrete brain region. Accordingly, mapping aneurobiological model to component processes of ToM will essen-tially require a functionally interconnected brain network thatincorporates both neuroanatomical and neurochemical levels ofspecificity. Based on emergent and longstanding evidence, we firstidentify (in Section 2) brain regions that are engaged during ToMprocessing, and describe, in Sections 2.1 and 2.2, how these var-ious regions form, within the larger mentalizing network, neuralnetworks that subtend our ability to represent and apply cognitiveand affective mental states to self and other. Second, we introduce,in Section 3, a candidate neurochemical system that is responsiblefor the integrity of ToM functioning, andwhichwe believe plays animportant role in the application and deployment of mental states.In Section 4, we present a neuroanatomicalneurochemical modelof ToM, and discuss how this new integrative model can enhanceour understanding of aberrant mentalization processes in variouspathologies. Finally, we suggest, in Section 5, futureresearch direc-

tions under the guidelines of the new model.

2. The neuroanatomyof theory ofmind: revisited

With the availability of imaging techniques and lesion-basedapproach studies, a concerted effort has emerged with the goal ofisolatingthe neuralbasisof ToM. Table1 provides a summary of thevarious regions that have been consistently associated with ToMprocessing (for extensive reviews see Abu-Akel, 2003a; Brunet-Gouet & Decety, 2006; Carrington & Bailey, 2009; Frith & Frith,2006; Saxe, 2006; Van Overwalle & Baetens, 2009).

It is widely acknowledged that mentalizing is subserved by anetwork of functionally related regions (e.g., Gallagher & Frith,2003; Saxe, 2006), and several accounts have been proposed todetermine the particular roles these regions play during mental-izing (e.g., Abu-Akel, 2003a; Amodio & Frith, 2006; Brunet-Gouet& Decety, 2006; Gallagher & Frith, 2003; Saxe, 2006; Stone, 2000).For example, Stone (2000) argued that the OFC is the most cru-cial region for ToM. Gallagher and Frith (2003) proposed that theanterior paracingulate cortex is instead the key region, and thatother regions in the temporal lobes, the OFC and the amygdalaplay secondary functions and are unlikely to be directly involvedin ToM. Later, Amodio and Frith (2006) extend this role to theMPFC (in which they include the ACC). Contrary to these accounts,

Table 1

Theoryof mind brain regions.

Brain region Brodmanns area

Posterior regions

Temporo-parietal junction (including the Inferiorparietal lobe) (IPL/pSTSor TPJ)

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Posterior cingulate/precuneus (PCC/PCun) 31/7Superior temporal sulcus (STS) 21/22Limbicparalimbic regions

Orbitofrontal (OFC) 11/12/47Ventral medial prefrontal cortex (vMPFC) 10/32Anterior cingulate/paracingulatecortex (ACC/PrCC) 24/32Temporal pole (TP) 38Amygdala SubcorticalStriatum SubcorticalFrontal regions

Dorsal m edial p refrontal c ortex ( dMPFC) 8/9Dorsal lateral prefrontal cortex (DLPFC) 9/46Inferior lateral frontal cortex (ILFC) 44/45/47

some researchers argue that mentalizing is subserved by posteriorregions. For example, Saxe (2006) suggests that the representationof mental states, particularly false beliefs, is specifically subservedby the right TPJ, and Samson, Apperly, Chiavarino, and Humphreys(2004) show that the left TPJ (coupled with the frontal lobes) isnecessary for the representation of mental states. A slightly moreexpansivenetwork is proposed by Brunet-Gouet and Decety (2006)whichinvolvesthe MPFC, theamygdala and the IPL. However, littlework has been done to integrate these regions into a functionallyinterconnected circuit (cf. Abu-Akel, 2003a). In the following sec-tion we present a new model that situates these regions withindistinct neural networks that subserve the processing of affectiveand cognitive ToM, and which is then extended, in Section 2.2, tospecify the networks and mechanism subserving the processing ofself and other mental states.

2.1. Cognitive and affective theory of mind: two dissociated

circuits

It is widely accepted that ToM is not a monolithic process, butcomprised of cognitive as well as affective processing (Brothers& Ring, 1992; Shamay-Tsoory, Tibi-Elhanany, & Aharon-Peretz,2006). Brothers and Ring (1992) referred to these dimensions ascold and hotaspects of ToM, where the cold or cognitive dimen-sion pertains to inferences about knowledge and beliefs, and thehotor affective dimension pertains to inferences about emotions.Research has shown that affectiveand cognitive aspects of ToMarebehaviorally distinguishable, and could be mediated by dissociatednetworks (e.g., Hynes, Baird, & Grafton, 2006; Shamay-Tsoory &Aharon-Peretz, 2007; Shamay-Tsoory et al., 2006; Shamay-Tsoory,Tomer, Berger, & Aharon-Peretz, 2005; Vllm et al., 2006). In thissection, we identify affective and cognitive ToM brain regions anddelineate the neural networks which they populate.

Numerous studies have investigated the role that various ToMbrain regions have in processing cognitive versus affective ToM byexamining their activity in response to cognitive ToM tasks (e.g.,the false belief tasks) and affective ToM tasks (e.g., the faux pas

task). Available evidence suggests that within the PFC, the OFC(Hynes et al., 2006; Kipps & Hodges, 2006; Stone, Baron-Cohen,& Knight, 1998), vMPFC (Kipps & Hodges, 2006; Shamay-Tsoory &Aharon-Peretz, 2007; Shamay-Tsoory et al., 2006, 2005), and ILFC(Andreasen, Calage, & OLeary, 2008; Hooker, Verosky, Germinea,Knight, & DEsposito, 2008, 2010; Hynes et al., 2006; Russell et al.,2000; Samson, Apperly, Kathirgamanathan, & Humphreys, 2005;Schulte-Rther, Markowitsch, Fink, & Piefke, 2007; Vogeley et al.,2001) are involved in affective ToM processing, and that the dorsalMPFC and the DLPFC are uniquely involved in processing cogni-tive ToM (Kalbe et al., 2010; Sommer et al., 2007; Stuss, Gallup,& Alexander, 2001). The involvement of the vMPFC, OFC and ILFCin the representation and regulation of socioemotional states andtheir dense connections with the amygdala (Price, Carmichael,

& Drevets, 1996), which itself is strongly involved in process-ing affective ToM (Fine, Lumsden, & Blair, 2001; Kipps, Nestor,Acosta-Cabronero,Arnold,&Hodges,2009;Shawetal.,2004;Stone,Baron-Cohen, Calder, Keane, & Young, 2003), make these regionssuited for synthesizingthe diverse range of information needed forrepresenting affective mental states (Beer, Shimamura, & Knight,2004; Happaney, Zelazo, & Stuss, 2004). The involvement of thedorsal MPFCand DLPFC in theprocessingof cognitive mental states,on the other hand, is reasonable given that these regions have lit-tle or no direct anatomical connections with the limbic system orbrain centers involved in the processing of emotion states (Barbas& Pandya, 1989; Fuster, 1997; Ramnani & Owen, 2004).

Besides such dissociation within the PFC, there is evidence thatthe ACC, the temporal pole and the striatum are likely to be differ-

entially involved in processing affective and cognitive ToM. With


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PCun/PCC

Limbic-Paralimbic

OFC/

vMPFC(affective)

dTP/

Dorsal Striatum

(cognitive)

ILFC

(affective)

TPJ

(IPL-pSTS)

STS

DLPFC

(cognitive)

Affective execution loop

Cognitive execution loop

DMPFC

(cognitive)

vACC

(affective)

Amygdala/ vTP/

Ventral Striatum

(affective)

dACC

(cognitive)

Fig. 1. Neural network for processing affective and cognitive mental states. The arrows are bidirectional. Represented mental states are formed at the temporoparietaljunction (TPJ) which is then relayed through the superior temporal sulcus (STS) or the precuneus/posterior cingulate complex (PCun/PCC) to limbicparalimbic regions tobe assigned cognitive or affective values. Affective ToM (Hot-Red boxes)is mediated by a network that engages theventral striatum, amygdala, ventral temporal pole (vTP),ventral anterior cingulate cortex (vACC), the orbitofrontal cortex (OFC), the ventral medial prefrontal cortex (vMPFC), and inferolateral frontal cortex (ILFC). Cognitive ToM(Cold-Blue boxes), on theotherhand, is mediated by a network that engages the dorsal striatum, dorsal temporal pole (dTP),dorsal anterior cingulate cortex (dACC), dorsalmedial prefrontal cortex (DMPFC), and dorsal lateral prefrontal cortex (DLPFC). The ILFC and the DLPFC represent the execution/application structures of their respectiveaffective and cognitive ToM networks. Interacting functionsof the two networks could be mediatedwithinthe ACC. (For interpretationof thereferencesto colorin this figurelegend, the readeris referred to theweb version of the article.)

ACC an ideal infrastructure for synthesizing the diverse range of

information needed for a complex mental activity such as affec-tive and cognitive mentalizing. Interestingly, Drevets and Raichle(1998) have shown that the ventral anddorsal ACC are reciprocallysuppressed while processing affective or cognitive tasks, whichcould reflect decision processes involved in assigning cognitive oraffective value to mental states.

2.2. Neural bases of representing self and other mental states

Mental states, whether cognitive or affective, are assignedagency. While the relationship between self and other mentaliza-tion is subject to debate (Carruthers, 2009), it can be characterizedby the presence of one metarepresentational mechanism with twomodes of access: a perception-based mode used for the represen-

tation ofothermental states, and an introspective mode used torepresent selfmental states (e.g., Carruthers, 2009; Frith & Happ,1999; Happ, 2003; Williams, Lind, & Happ, 2009; Zinck, Lodahl,& Frith, 2009). However, while representation of other mentalstates can primarily be perception-based, i.e., relies on externalcues gleaned from the environment such as direction of eye gazeand facial expressions, they can also be computed in consultationwith internally stored information such autobiographical memory(van der Meer et al., 2010). Conversely, while representation of selfmental states can primarily be introspective-based, i.e., relies oninternal information such as autobiographical memory and emo-tions (including interoceptioni.e., awareness of bodily states),external signals can be used to make appropriate inferences aboutthe self. However, there is evidence which suggests that self- and

other-mentalizing can be dissociable. For example, schizophrenics

with passivity phenomena are unimpaired in attributing mental

states to others, but are impaired in representingself mental states(Brne et al., 2008; Frith & Corcoran, 1996; Pickup & Frith, 2001).Such dissociation has also been reported among individuals withautism(Chiu et al., 2008; Williams & Happ,2009). Accordingly,weenvision that self and other mentalizing is subserved by a sharedmentalizing network comprised of two interactive, yet dissociable,subnetworks that represent self and other mental states.

Recent studies began uncovering the specific role various ToMbrain regions might have in processing self andother mentalstates.Posterior regions within thementalizing network (see Fig.1) whichinclude the PCC/PCun,the TPJ andthe STS appearto respond differ-entially when processing self mental states. The TPJ has been seenas a mediator between self and other mental states. For example,a conjunction analysis of the self- and other-task showed pSTS/TPJ

activations, with the more posterior TPJ area (extending into theIPL) being differentially activated during the self-related attribu-tions (Schulte-Rther et al., 2007; Vogeley et al., 2001). Similarly,Lou et al. (2004) showed that the IPL and the PCC/PCun were selec-tively active in explicit self-reference.Moreover, theprecuneuswasfound to be functionally connected to the right IPL and the MPFC,extending into the vMPFC during self-representation. Accordingly,it is proposed that the precuneusis a nodal structurethat subservesself-representation. Indeed, a disruption of this region through theapplication of TMS led to retrieval difficulties of previous judg-ment ofoneself compared with that ofothers. The left temporalregion (BA 21 or STS), on the other hand, was selectively active inother-reference. Interestingly, the right IPL and the left STS werecorrelated in such a way that activation increased in the STS and

decreased in the IPL with decreasing self-reference.


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A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia49 (2011) 29712984 2975

Differential activation between self- and other-reference wasalso observed within the MPFC, where the vMPFC appears biasedtowards self-mentalizing and the dMPFC is biased towards other-mentalizing (DArgembeau et al., 2007; Lombardo et al., 2010;Mitchell, Macrae, & Banaji, 2006). It should be noted that in thestudy by Mitchell et al. (2006), the activity of the vMPFC was asso-ciated with self-referential processing including thinking aboutsimilar others, and that the activity of the dMPFC in the studyby DArgembeau et al. (2007), was associated with both self- andother-referential processing. One can argue that the stated selec-tivity of vMPFC for the processing of self mental states might beundermined by the fact that it also responds to similar others.However, it is important to emphasize that the response to similarotherscouldbe dueto simulation processes of likeness to oneself. Ifyouare thinkingabout the mentalstate of a personwho is similar toyou, one cannotruleoutthatmuchof this inferenceis modeled afterones self.Alternatively, theresponseof thevMPFC to similar otherscould be a function of the adjacent OFC, with which it is intimatelyconnected (ngr, Ferry, & Price, 2003; Price, 2007), and whichitself has a prominent role in the social-perceptual aspect of ToM(Bora, 2009;Lee, Farrow, Spence, & Woodruff,2004), particularly inprocessing of others emotional mental states (Hynes et al., 2006;Kana, Keller, Cherkassky, Minshew, & Just, 2009; Rowe, Bullock,

Polkey, & Morris, 2001; Stone et al., 1998; Stuss et al., 2001), and inthe decoding of mental states that principally rely on social infor-mationfromtheenvironmentsuchaseyegaze,thepersonsactions,tone of voice and facial expressions (Sabbagh, 2004). Accordingly,we suggest that the vMPFC is selectively involved in self-referenceprocessesand in understandingthe mental states of oneself or simi-larothers.Ourinterpretationofthisdataisconcordantwitharecentmeta-analysissuggestingthat thevMPFC is specificallyinvolved inthe processing of self-referential stimuli and not in the processingof other-referential stimuli (van der Meer et al., 2010, p. 941).

The selectivity of the dMPFC in the processing of other mentalstates is not straightforward either, as there is evidence show-ing that the dMPFC can be active during self referential tasksas well (Gusnard, Akbudak, Shulman, & Raichle, 2001). In fact,

DArgembeau et al. (2007) showed that within the dMPFC, thedorsal anterior MPFC along with the precuneus was active dur-ing self referential processing, whereas adopting the other personsperspective activated the posterior part of the dorsal MPFC. Suchresponse of the dMPFC during self and other-referential process-ing is expected as this region appears to be selectively involvedin processing cognitive mental states, which can be of oneself oranother. Moreover, the meta-analysis by van der Meer et al. (2010)also suggests that the dMPFC is not only involved in the processingof self-relevant information,but alsoinvolvedin theevaluation anddecision-making process of whether a certain stimulusis applicableto the self or to another person.

Collectively, these studies suggest that the IPL, PCC/PCun, thevMPFC, and possibly the anterior dMPFC form within the larger

mentalizing network, a sub-network that is involved in pro-cessing self mental states. The STS, and possibly the posteriordMPFC and the OFC, on the other hand, appear to be selec-tively involved in the computation of other mental states. Thequestion then, what mechanism does the brain, within the gen-eral mentalizing network, use to distinguish between self- andother-mentalizing?

2.2.1. Mechanism underlying the distinction between self and

other mental states

Researchers argued that the distinction between self and othermental states is subserved by a right fronto-parietal network.Decety and Sommerville (2003) proposed that the right lateral PFC

makes distinct self from other mental representations through the

activation of its executive functions of inhibition, planning andcoordination, which is required to suppress the prepotent self per-spective in favor of another perspective. A similar network wasadvanced by Uddin, Molnar-Szakacs, Zaidel, and Iacoboni (2006)and Uddin, Iacoboni, Lange, and Keenan (2007) but that such dis-tinction, they argue, could instead be implemented through a rightlateralized mirror neuronmechanism that occupies the IPL and theinferior frontal gyrus (IFG). In this section, we elaborate on the roleof the fronto-parietal circuit in the distinction between self andother, and propose that this distinction is mediated through com-plementary attention systems that coexist within the mentalizingnetwork. These attention systems are generally known as the ven-tral and dorsal attention systems. The ventral system is lateralizedtotherightandiscomposedoftherightTPJandtheIFG.Thissystemis an involuntary, bottom-up system that is involved in reorient-ing attention in response to salient sensory stimuli or violationof expectations (Corbetta & Shulman, 2002; Fox, Corbetta, Snyder,Vincent, & Raichle, 2006), and it has been suggested that TPJ-IFGco-activationmay facilitate termination of ongoingactivityand dis-engagement of attentionwhenshiftcues areunexpected (Shulmanet al., 2009). Note that this ventral attention system greatly over-laps with the right lateralized TPJ-ILFC network claimed by Uddinand Decety and colleagues to underlie the mechanism for self and

other distinction. Complementing the ventral attention system, isa bilateral dorsal attention system composed of the intraparietalsulcus and the superior parietal lobe (BA 5 and 7) and the dorsalfrontal cortex, near or at the frontal eye field (BA 6 and 8). Thissystem is involved in voluntary, goal-driven, top-downorienting ofattention (Corbetta & Shulman, 2002; Fox et al., 2006).

The ventral and dorsal systems are functionally interactive,where the dorsal system focuses attention on a specific goal orstimuli, and the ventral system filters signals by monitoring can-didate information for possible selection. Signals coming throughthe ventral system disengage the dorsal system from its currentfocus and reorient or refocus it towards behaviorally relevant stim-uli. It has been suggested that the interaction between ventraland dorsal attention systems occurs posteriorly in specific parietal

regions, which include the precuneus and the TPJ region (Corbetta& Shulman, 2002). The direct connections between the IPL andthe precuneus provide one pathway through which these twoattentional systems interact (Lou et al., 2004). Recent evidence,also suggests that interaction between these systems could occurthrough the middle frontal gyrus (Fox et al., 2006) and the ACC(Montoya, 2009) via their connections with the frontal eye field(dorsal attention network) and the inferior frontal gyrus (ventralattention system) (Beckmann, Johansen-Berg, & Rushworth, 2009;Paus, 2001; Wang, Shima, Sawamura, & Tanji, 2001).

Obviously, there is a considerable anatomical overlap betweenthe mentalizing and attentional systems networks, specificallywithin the TPJ and ACC regions. In addition, there is evidence sug-gesting a functional overlapas well.Withrespect tothe TPJ, a recent

meta-analysis showed substantial overlap of activation clustersduring agency, attentional reorienting and social cognition, whichsuggests that activation in the TPJduring socialcognition mayrelyon a lower-level computational mechanisminvolved in generating,testing, and correcting internal predictions about external sensoryevents (Decety & Lamm, 2007, p. 583). Substantiating this con-clusion, Mitchell (2008) provides evidence showing that the TPJis both active when participants perform attentional reorientingtasks as well as false belief tasks. Accordingly, Mitchell proposesthat these two tasks are likely to draw on the same cognitive pro-cess that may involve the suppression of salient stimuli in favor ofa less immediate alternative. While the degree of overlap betweenattentional reorienting and ToM activation clusters within the TPJappears smaller than has been previously demonstrated (Scholz,

Triantafyllou, Whitfield-Gabrieli, Brown, & Saxe, 2009), it has been


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suggested that attention signals in the TPJ may be important toswitch between internal, bodily, or self-perspective and exter-nal, environmental, or others viewpoint during ToM processes(Corbetta,Patel, & Shulman, 2008). This evidence,in ourview, lendssupport to the suggestion that the TPJ, which responds to both selfand other mental states, functions as a mediator between the self-and other-perspective (Schulte-Rther et al., 2007), and is the sitewhere the distinction between self and other takes place (Decety& Sommerville, 2003; Uddin, Kaplan, Molnar-Szakacs, Zaidel, &Iacoboni, 2005).

The positioning of TPJ within the general mentalizing networkas a mediator between self- and other-perspective can be linked toits anatomical characteristics. The TPJ is a heteromodal associationcortex that integrates inputs from the thalamus, the limbic system,aswellas from visual, auditoryand somaestheticareas,and isrecip-rocally connected with prefrontal and temporal cortices (Decety& Lamm, 2007), which enables it to process information from theexternal environment as well as from the internal-bodily environ-ment. Perhaps theobserved disruption of selfother discriminationfollowing rTMS over the right IPL (Uddin et al., 2006), is in fact adisruption to the activity of the ventral attentional system. Similarto the TPJ, there is also considerable functional overlap betweenattentional and mentalization functions within the ACC. Based on

the well established role of theACC in the representation of self andother mental states and in directed attention, Gallagher and Frith(2003) suggest that this region, and specifically the most anteriorsection of it, might be specialized for directing attention to men-tal states. We would also add that, due to its connections with theventral and dorsal attentional system, it is also involvedin directing

attention to self versus other mental states (also see van der Meeret al., 2010).

Accordingly, we propose that the role of the ventral and dor-sal attentionsystems in attendingto relevant internal and externalinformation is a mechanism that has been co-opted by the mental-izing network, at the TPJ and ACC levels, to regulate the processingof self and other mentalstates. Linking attentional andmentalizingfunctions is consistent with studies showing that better atten-tional inhibition processes explain performance differences in ToMrelated tasks (Bialystok & Senman, 2004), and that infant attentionto intentional actions significantly predicts later theory of mind(false-belief understanding), irrespective of IQ, verbal competence,and/or executive function (Wellman, Lopez-Duran, LaBounty, &Hamilton, 2008).

What emerges then is a mentalizing network composed of self-and other-mentalizing network which are modulated by a func-tionally interactive attention/selection system at the TPJ and theACC levels. Fig. 2 presents a schematic representation of the pos-tulated neural networks involved in the representation of self andother mental states.

3. Neurochemical bases of theory ofmind

Most available models map ToM processing at the gross neu-roanatomical level. These models are limited in that they cannotfully explain how various pathologies present with differingneurobiological abnormalities exhibit similar ToM dysfunctionssuch as in schizophrenia and autism, or how patients within asingle disorder such as in Parkinsons disease and schizophre-

PCun/PCC

(self)

Limbic-Paralimbic(self & other)

vMPFC/OFC

(affective

self & other)

dTP/

Dorsal Striatum

(cognitive) TPJ

(IPL-pSTS)

(self-other)

STS

(other)

Affective execution loop

Cognitive execution loop

dMPFC

(cognitive

self& other)

vACC

(affective)

Amygdala/ vTP/

Ventral Striatum

(affective)

dACC

(cognitive)

ILFC

affective self & other

dLPFC (includes FEF)

cognitive self & other

Dorsal attention system

Ventralattention system

Fig. 2. Neural network for processing self and other mental states. The arrows are bidirectional. The representation of self and other mental states is first processed in thetemporo-parietal junction (TPJ). Relevance of stimulus to self or other mental states is assigned through the ventral and dorsal attentional systems. If stimulus assignedrelevant to another person, this information is then sent back, through theposterior portion of theSTS (pSTS) to theSTS. If, on theotherhand, stimulus is assigned relevantto self, then this information is sent back, through theinferiorparietallobule(IPL) to thePCun/PCC. Signals from thelimbicparalimbic system(which involve theamygdala,striatum, temporal pole (TP)and the anterior cingulate cortex (ACC))determine whether representations are cognitive or affective.Within the ACC, attentionto self-relevantor other-relevantstimuli (and ultimatelyrepresentedself or other mental states) is directed by engaging and disengagingthe ventral and dorsal attentional systems.A dorsalstream withinthe limbicparalimbic systemis dedicatedto theprocessing of cognitivemental states, and a ventral streamis dedicatedto theprocessing of affective mentalstates. Fromthere, self or other cognitive representations are sent through the dMPFCto DLPFC for execution/application decisions. In contrast, affective representations are

relayed from theventral stream through vMPFC/OFC complex to the ILFC forexecution/application decisions.


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nia exhibit differing profiles of ToM impairment. It has beensuggested that understanding neurochemical processes chan-neled along pathways from and to implicated regions within thementalizing network can provide a unifying framework wheresuch variation in ToM functioning within and across patholo-gies can be explained (Abu-Akel, 2003b). In a step towards thisdirection, it has been hypothesized that dopamine (DA) and sero-tonin (5-hydroxytriptamine, 5-HT), collectively referred to as thedopaminergicserotonergic system (henceforth the DS system),mediate our ability to mentalize (Abu-Akel, 2003b). The hypoth-esized role of the DS system in ToM is primarily based on thefollowing observations: (1) ToM dysfunctions are frequent conse-quences of disorders that are associated with severe deficits in theDS system such as autism and schizophrenia, (2) the DS systeminnervates the PFC, the TPJ and the ACC, regions that are criticalfor mentalizing, and (3) the DAergic system which is involved inlearningand signaling changes or errorsin the predictions of futuresalient and rewarding events (Schultz, Dayan, & Montague, 1997),is a likely mechanism that enables us to predict the actions andbehaviors of others, and to use these prediction errors to mod-ify our representations of the mental states. To this we add therole of DAergic system in cognitive flexibility and stability whichis thought to be mediated by the tonic and phasic modes of DA

releasetonic DA is thought to be associated with the stabilizationand maintenance of PFC representations, and phasic DA is associ-ated with the updating of these representations (Grace, Floresco,Goto, & Lodge, 2007; Zweifel et al., 2009). In agreement with this,Brunet-Gouet and Decety (2006) suggest thatsocial cognitionmaybe affected by dopaminergic levels, especially when mentalizationis performed (p.86), whichthey hypothesize could resultfrom theputative role of DAergic transmissionin theupdating of short-termcontextual representations by controlling the inflow of externallyor internally generated information. According to this hypothesisit is predicted that disruption to the DA system itself or to neu-rochemical processes that affect/modulate its functioning such asthe 5-HT system could lead to either a conceptual deficit of ToMsuch as in autism, or to the generation of erroneous predictions

about the mental states of others, as is the case for patients withschizophrenia.

Over the last few years, several lines of evidence have emergedin support of the role of the DS system in the integrity of ToMfunctioning. Though nascent, neurogenetic research that inves-tigates the effect of genes with specific roles in neurochemicalsignaling on cognitive functioning has provided important insightsto the roles of the DS system in ToM. For example, Bassett,Caluseriu,Weksberg, Young, and Chow(2007)examined the role ofthe catechol-O-methyl transferase (COMT) gene in schizophrenia-related expression in 73 adults with 22q11 deletion syndrome(22q11DS). The COMT gene, which is located within the regioncommonly deleted in 22q11DS, has been associated with high riskfor schizophrenia and is involved in DA metabolism (Akil et al.,

2003;Bearden et al., 2004; Egan et al., 2001). Comparisonsbetween22q11DSpatientshemizygousfortheCOMTMet orValallelesshowthat patients carrying the COMT Met allele performed worse onToM tasks, communication and social functioning measures thanpatients who carry the COMT Val allele. This difference remainedsignificant after controlling for a diagnosis of schizophrenia andIQ. The link between variation in DAergic activity and ToM per-formance has also been observed in typically developing children.It was found that ToM performance in preschool aged childrenwas associated with the polymorphisms of the COMT gene andthe DA receptor D4gene (DRD4) (Lackner, 2009), and spontaneouseyeblink rates (Lackner, Bowmnan, & Sabbagh, 2010), which is afunctional marker of central DAergic function. Importantly, theserelationships were largely independent of the rather well estab-

lished link between DA and executive functioning skills. Drawing

on the link between specific COMT alleles and DA activity in thePFC, on the one hand, and ToM functioning, on the other, it is rea-sonable to assumethat a disruption of DA optimal levels withinthePFC could have direct consequences on our ability to mentalize.

The effect of the serotonergic system on ToM functioning hasalso been reported. In this recent study, Bosia et al. (2010) inves-tigated the effect of the 1019 C/G functional polymorphism ofserotonin 1A receptor (5-HT1A-R), which affects serotonin trans-mission and dopamine release in the PFC, on ToM performanceamong 118 patients with schizophrenia. They found significanteffect on ToM performance, with the CC genotype carriers per-forming significantly better compared to the G allele carriers. Itis suggested that the underperformance of G allele carriers may beattributable to the association of the G allele with 5-HT1A-R over-expression which has been shown to disrupt the interaction of theDAergic and serotonergic systems in the PFC. Such overexpression,the authors argue, may be due to (1) autorecptor desensitiza-tion and thus increased serotonin transmission and (2) decreasingDA levels in the PFC by exerting inhibitory actions on pyrami-dal glutamatergic cells. The finding suggests that the 5-HT1A-Rpolymorphism, via its regulatory function of both the DAergicand serotonergic systems in the PFC, might have a specific effecton the integrity of ToM functioning. Moreover, Tylec, Kucharska-

Pietura,Jeleniewicz, Czernikiewicz, and Stryjecka-Zimmer (2010)also found that the enzymatic activity of the monoamine oxidaseA (MAO-A), which reflects central serotonergic activity, predictedmentalizing deficits in 100 patients with schizophrenia, partic-ularly among 4/4 genotype carriers of the polymorphism VNTRMAO-A.

These results support findings from imaging studies whichobserved links between DAergic and serotonergic activities andmentalizing abilities. In a single-photon emission computedtomography study, Murphy et al. (2006) found that individualswith Aspergers syndrome had a significant reduction in cortical5-HT2A receptor binding in the total, anterior, and posterior cin-gulate, bilaterally in the frontal and superior temporal lobes, andin the left parietal lobe. Reductions in 5-HT2Areceptor binding in

the anterior and posterior cingulate and the right frontal cortexwere significantly correlated with increased qualitative abnormal-itiesin reciprocalsocial interactionswhich relyon ToMfunctioning.In a more recent positron emission tomography study, Nakamuraet al. (2010) found that 5-HT transporter binding was significantlylower throughout the brain in autistic individuals compared withcontrols. In contrast, the DA transporter binding was significantlyhigher in the orbitofrontal cortex of the autistic group, which wasinversely correlated with 5-HT transporter binding. Interestingly,similar to the Murphy study, the reduction in 5-HT transporterbinding in the anterior and posterior cingulate cortices was associ-atedwith theimpairment of social cognitionin theautisticsubjects,as measured by the faux pas task which measures the integrationof both cognitive and affective ToM abilities. The inverse rela-

tionship between DA and 5-HT highlights the synergistic effectsboth systems could have on mentalizing and social cognitionskills.

Psychopharmacological interventions, particularly those thatmodify the DS system, provide additional insight into the hypothe-sized role of the DS system in mentalizing. Savina and Beninger(2007) investigated the effect of typical and atypical antipsy-chotic drugs on ToM functioning in four groups of patientswith schizophrenia compared to controls. Three groups were onone of the following atypical antipsychotics: olanzapine, cloza-pine or risperidone. The fourth group consisted of patients whoreceived typical antipsychotics such as fluphenazine, flupenthixoland haloperidol. In the groups receiving olanzapine or clozap-ine treatment, ToM functioning improved to levels comparable to

normalcontrolsafteratleast4months,butnotinthosetreatedwith


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risperidone or typical antipsychotics. The lack of effect of risperi-done on ToM functioning echoes the result reported by Mazzaet al. (2003) who found that ToM functioning of schizophrenicpatients receiving risperidone alone did not improve after 3 and6 months of treatment. Interestingly, however, improvement inToM functioning was observed when risperidone was adminis-teredtogether withdonepezil, an anticholinesterasic drug. Mizrahi,Korostil, Strakstein, Zipursky, and Kapur (2007) also examinedthe effect of antipsychotic treatment on ToM functioning of 17drug-free patients with first-episode psychosis over a period ofsix weeks. Sixteen patients were treated with clozapine (n=2),olanzapine (n= 7) or risperidone (n=7), and one with the typicalantipsychotic loxapine. While the relative contribution of thesedrugs is not reported, significant improvement in ToM function-ing was observed for the group as a whole, especially after thefirst two weeks. Improvement in patients positive symptoms wasalso observed, albeit independent of ToM. Given the evidence forthe lack of effect of risperidone on ToM functioning (Mazza et al.,2003;Savina&Beninger,2007), onecanspeculatethattheobservedeffect on ToM performance in this group is driven by the patientsreceiving clozapine and olanzapine. In all, these studies suggestthat ToM functioning can improve after treatment with clozapineor olanzapine, but not with typical antipsychotics or risperidone

alone.The exact mechanism responsible for the observed therapeutic

effect of the atypical antipsychotics clozpaine and olanzapine onToM abnormalities is unknown. However, unlike typical antipsy-chotics whose primary mode of action is the blockade of D2receptors, these atypical antipsychotics are characterized by theirability to bind to multiple DA and 5-HT receptors, and thus theireffect on ToM functioning can be attributed to their synergis-tic effect on both the DAergic and serotonergic systems (Guillin,Abi-Dargham, & Laruelle, 2007). Moreover, their binding profile,which exerts potent antagonism to 5-HT2A relative to D2 recep-tors, preferentially increases DA efflux in the mPFC (reviewedin Meltzer, 2002). This, in turn, facilitates DA transmission inthis region which is necessary to carry out mentalizing activi-

ties (Savina & Beninger, 2007). When compared to clozapine orolanzapine, the lack of a risperidone effect on ToM functioningcould be attributed to attenuated DA release within the mPFC(Savina & Beninger, 2007), as well as to any number of factorssuch as specific pharmacokinetic properties and ratio of affinityto 5-HT versus DA receptors (Meltzer, 2002). The observed effecton ToM functioning after risperidone was administered togetherwith donepezil (Mazza et al., 2003), can be attributed to the effectof donepezil on cholinergic input to DA neurons. There is evi-dence that cholinergic input potentiates DAergic phasic activity(Grace et al., 2007; Lodge & Grace, 2006), and so it can be spec-ulated that the enhanced effect of donepezil on ToM functioningin schizophrenia is achieved by stabilizing hyper DAergic activitythrough inhibition of cholinergic input to DA neurons. Interest-

ingly, unlike clozapine and olanzapine, risperidone does not havehigh affinity to cholinergic receptors (Horacek et al., 2006), whichsuggests that modulation of cholinergicDAergic interactions is animportant property of antipsychotics that improve ToM function-ing.

Overall, evidence has accumulated in support of the hypoth-esized effect that the DS system has on the integrity of ToMfunctioning. Specifically, evidence shown here demonstrates notonly that ToM impairment is a frequent consequence in patholo-gies that impact the integrity of DS system, but also that the DSsystem could have a specific role in ToM processing. Drawing onthe link between 5-HT and DA activity in the PFC, on the one hand,and ToM functioning, on the other, it is reasonable to assume thata disruption of DA/5-HT optimal levels within the PFC could have

direct consequences on our the ability to mentalize.

4. The integration: a neuroanatomicalneurochemical

model of theory ofmind

In this section, we present an integrativeneuroanatomicalneurochemical model of ToM, which delin-eates the neuroanatomical and neurochemical networks involvedin the representation of cognitive and affective mental statesto both self and other. As can be seen in Fig. 3, Panels A andB respectively represent networks subtending cognitive andaffective ToM. These two networks form the larger mentalizingnetwork, and share the posterior regions, which include the TPJ,STS, and PCC/PCun. These regions are involved in representing anddistinguishing self from other mental states whether cognitive oraffective. The process involved in the distinction between self orother mental states is modulated by the reorienting functions ofthe ventral and dorsal attentional systems (not shown here; butsee Section 2.2.1; Fig. 2).

Panel A, which represents the network for selfother cognitiveToM, can be divided into three main components. The first isthe DS system, which is comprised of the nigrostriatal pathwayemanating from the substantia nigra pars compacta (SNc) andthe serotonergic pathway emanating from the dorsal raphenucleus. The second is the dorsal striatum and is comprised

of the caudate and the putamen as well as the direct (cor-tex+ striatum GPi thalamus+ cortex) and indirect (cor-tex+ striatum GPe STN+ GPi thalamus+ cortex)pathways, which, through the thalamus, form the output regionsof the basal ganglia. The third part is comprised of paralimbicand cortical regions, which is roughly divided into posterior andanterior regions. Regions of interest within the posterior cortexare the TPJ, STS, and the PCC/PCun. These posterior regions arereciprocally connected with anterior regions of the network andinclude the dTP, dACC, dMPFC and DLPFC. Within this cognitivenetwork the dorsal striatum receives inputs from cortical andlimbicparalimbic regions, overlapping with input from the SNcand the dorsal raphe nucleus. This information under the modula-tory influence of DA and 5-HT is funneled through the direct and

indirect pathway of the basal ganglia through the thalamus backto paralimbic and cortical regions.

Panel B, on the other hand, which represents the network forselfother affective ToM, is also comprised of three main compo-nents. The first is the DS system, which involves the mesolimbicand mesocortical pathways emanating from the ventral tegmen-tal area (VTA), as well as the serotonergic pathways emanatingfrom the dorsal and medial raphe nuclei. The second is the ven-tral striatum, which is comprised of the nucleus accumbens aswell as the limbic loop passing through the ventral pallidum andthe thalamus. The input of this system to the thalamus is modu-lated by the direct and indirect pathways (not shown). The thirdpart is comprised of limbicparalimbic and cortical regions. Herethe posterior cortical regions, which include the TPJ, STS, and the

PCC/PCun are reciprocally connected with limbic and frontal paral-imbic regions. These include the amygdala, vTP, vACC, OFC, vMPFCand the ILFC. Within this affective network, the ventral striatumreceives inputs from cortical and limbicparalimbic regions, over-lapping with input from the VTA and the dorsal and medial raphenuclei. This information under the modulatory influence of DA and5-HT is funneled through the limbic loop (or the ventral pallidalsystem), through the thalamus, back to paralimbic and corticalregions.

The function of the DS system within the ToM network is two-fold: (1) to regulate the functionality of fronto-striatal circuits andthus the representation of cognitive and affective mental states,and (2) to maintain a fine balance between cognitive stabilityand cognitive flexibility, and as such to monitor the maintenance

and updating of these mental representations. The spatiotempo-


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Panel A: Self-Other Cognitive ToM

DRN

MRN

VTA-

A10

vMPFC/

OFC

(self &

other)

vACC/vTP

Amygdala

Ventral

Striatum

(NAc)VP

Panel B: Self-Other Affective ToM

SNc-A9

SNr

STS

(other)

TPJ

(self&

other)PCC/PCun

(self)

DRN

DMPFC

(self &

other)

PCC/PCun

(self)

Dorsal

Striatum(Put/Caud)

Thalamus

GPi

GPe

S

T

N

dACC

dTP

STS

(other)

TPJ

self&

other

Serotonergic Projections

Dopaminergic Projections

ILFCDLPFC

Fig. 3. Schematic representation of serotonindopamine interaction within the cognitive and affective mentalizing networks of self and other. ACC= anterior cingulatecortex; DMPFC= dorsal medial prefrontal cortex; DRN= dorsal raphe nucleus; DLPFC= dorsolateral prefrontal cortex; GPi= globus pallidus interna; GPe=globus pallidusexterna; ILFC = inferolateral frontal cortex; MRN= media raphe nucleus; NAc= nucleus accumbens; OFC= orbitofrontal cortex; PCC/PCun= posterior cingulate/precuneus;STS =superior temporal cortex; SN= substantia nigra pars compacta; SNc= substantia nigra pars reticulata; STN= subthalamic nucleus; TPJ= temporoparietal junctions;vMPFC = ventral medial prefrontal cortex; VP= ventral pallidum; VTA= ventral tegmental area.

ral progression of DA depletion within the striatum in Parkinsonsdisease (PD) (Poletti, Enrici, Bonuccelli, & Adenzato, 2011), canbe a viable framework to test how disruption of the DS system,and particularly DA, affects the ability to represent cognitive andaffective mental states. In the early stages of PD, death of DAer-gic neurons primarily in the substantia nigra causes disruptionsto the associative loop (PFChead of the caudateGPi/SNrventralanterior thalamic nucleicortex) (Panel A in our model), whichis involved in executive, behavioral and cognitive functions (DiMartino et al., 2008; Haber et al., 2000; Lewis, Dove, Robbins,Barker, & Owen, 2003; Previc, 1999). A deterioration of the meso-cortical DA system (Panel B in our model) which is also involvedin cognitive functioning (Seamans & Yang, 2004), is less severely

affected in these early stages, but a rate of 50% depletion of DAneurons has been reported in this system at later stages of thedisease (Owen, 2004). As the disease progresses, a 3655% ofVTA neurons are depleted in these patients, causing a disrup-tion to the mesolimbic DA system (Panel B of our model) (Uhl,Hedreen, & Price, 1985). This in turn causes severe disruption tothe limbic loop (medial prefrontal and orbitofrontal cortexventralstriatumventral pallidummediodorsal thalamic nucleicortex)which is involved, among other things, in emotional, motivationaland reward seeking functions (Schultz, 2002).

As noted earlier, PD results in significant ToM deficits (for arecent review see Poletti et al., 2011), with early-stage patientsperforming poorly only on cognitive ToM (Pron et al., 2009; Rocaet al., 2010), and advance-stagepatients performing poorly on both

cognitive and affective ToM (Bodden, Mollenhauer, et al., 2010).

Accordingly, the disruption of the associative loop in the earlystages of the disease could account for the patients poor perfor-mance in cognitive ToM, and a disruption of the mesocortical andmesolimbic pathways at the more advance stages of the diseasecould account for the poor performance in affective ToM (Bodden,Dodel, & Kalbe, 2010). One could also predict that a disruption ofthe mesocortical pathway at the later stages of the disease couldresult in a more severe form of cognitive ToM functioning givenits projections to the cingulate and the DLPFC (Seamans & Yang,2004). Confirmation of the association of progressive DA deple-tion within the striatum (from dorsal to ventral) with more severeToM impairments in PD patients would provide strong evidence forthe dependence of ToM functioning on the integrity of the DAergic

system, and which would be consistent with the notion that DAer-gic dysfunction within the striatum alone can lead to frontal-likecognitive deficits or lesions (Frank & OReilly, 2006).

The DS system can also be utilized to understand abnormalitiesassociated with the application (or deployment) of mental states.This execution/application component has been placed along acontinuum (Abu-Akel & Bailey, 2000; Abu-Akel, 2008; Crespi &Badcock, 2008; Frith, 2004) ranging from a state where individ-uals suffer from an application deficit as is the case for patientswith Aspergers syndrome (e.g., Bowler, 1992; Senju, Southgate,White, & Frith, 2009), to a state where mental states are applieduncontrollably, resulting in hypermentalism or overattribution ofmental states as the case for patients with paranoid schizophre-nia (e.g., Bara, Ciaramidaro1, Walter, & Adenzato, 2011; Montag

et al., 2010; Walter et al., 2009). The lack of spontaneity in apply-


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Table 2

Pathologies and disordersthat impact theory of mind functioning.

Pathologies and disorders Selected references

Psychiatric and personalitydisorders

Autism Baron-Cohen, Leslie, andUta (1985)

Aspergers syndrome Senju et al. (2009)Anorexia Nervosa Russell, Schmidt, Doherty,

Young, and Tchanturia

(2009)Bipolar Disorder Kerr, Dunbar, and Bentall(2003)

Psychopathy and Antipersonality Disorders Shamay-Tsoory, Harari,Aharon-Peretz, andLevkovitz (2010)

Schizophrenia Corcoran, Mercer, and Frith(1995), Brne (2005)

Social Anxiety Sripada et al. (2009)Basal ganglia disorders

Attention Deficit Hyperactivity Disorder Sodian, Hlsken, andThoermer (2003)

Huntingtons Disease Snowden et al. (2003)Parkinsons disease Mengelberg and Siegert

(2003)Genetic disorders

22q11.2 deletion syndrome Bassett et al. (2007)Downs Syndrome Cornish et al. (2005)Fragile X Syndrome (Martin-Bell Syndrome) Cornish et al. (2005)Phenylketonuria (PKU) Dennis et al. (1999)PraderWilli Syndrome Koenig, Klin, and Schultz

(2004)Sotos Syndrome (Cerebral Gigantism) Saddington, Oliver, Cole,

and Apperly (2010)Spinocerebellar Ataxia Garrard, Martin, Giunti,

and Cipolotti (2008)Turner Syndrome (Ullrich-Turner Syndrome) Lawrence et al. (2007)Williams Syndrome Tager-Flusberg and

Sullivan (2000)Neurological disorders

Frontotemporal Dementia Snowden et al. (2003)Alzheimers Disease Zaitchik, Koff, Brownell,

Winner, and Albert(2004)Multiple Sclerosis (MS) Banati et al. (2010)Traumatic Brain Injury (TBI) Bibby and McDonald

(2005)

ing mental states in patients with Aspergers syndrome, on theone hand, and the overattribution of mental states characteristicof paranoid schizophrenia, on the other hand, can be explained interms of the tonic and phasic mode of release of the DS system inthe PFCof these patients.Here we would predict that these patientswould exhibit diametrical profilesAspergers patients would typ-ically have abnormally tonic PFC, and the paranoid patients withschizophrenia would have abnormally phasic PFC. Specifically, theapplication deficit in Aspergers syndrome can be explained byincreased tonic and diminished phasic DA activity in the PFC ofthese individuals, which would prevent them from updating and

forming new representations in a fashion commensurate withreal-timeinteractions. It hasbeen shown that5-HT receptorsaffect tonicand phasic release of DA (Remington, 2008), and there is strongevidence that 5-HT2Areceptors in the medial PFC potentiate meso-cortical phasic DA release (Pehek, McFarlane, Maguschak, Price, &Pluto, 2001; Pehek, Nocjar, Roth, Byrd, & Mabrouk, 2006). Inter-estingly, individuals with Aspergers syndrome have a significantreduction in cortical 5-HT2Areceptor binding in the temporal, cin-gulate and frontal cortices (Murphy et al., 2006). The diminishedlevels of cortical 5-HT2A receptors in individuals with Aspergerssyndrome could affect phasic DA activity, and consequently theirability to update and form new mental representation. We wouldexpect a similar neurochemical profile in patients with negativeschizophrenia who also suffer from an application deficit of ToM

(Bowler, 1992). Indeed, there is evidence implicating diminished

levels of cortical 5-HT2Areceptors, including within the DLPFC, inthe pathological progression of schizophrenia (Dean, 2003), whichas notedabove is implicated in the application of represented men-tal states.

On the other hand, overattribution of mental states in paranoidschizophrenia can result from either a system that makes errors ofcommission because it does not work properly, or from a systemthat makes errors of commission because it is over-active. Overat-tributions resultingfrom a system that does not work properly canbe the result of a malfunction in DA signaling of prediction errors.This is supported by evidence from an fMRI study showing thatdisruption of prediction-error signaling in the frontal cortex wassignificantly related to the individuals propensity to form delu-sions (Corlett et al., 2007). Alternatively, it can be hypothesizedthat overattributions can result from an overactive system char-acterized by a decreased cortical tonic DA activity and increasedstriatal phasic DA activity.In this context, a hypofunctionof PFC DAwould lead to the formation of unstable representations that areopen to interference by distracters, by inducing a state of hyper-sensitivity of the DA system to the phasic release as well as bydisinhibition of striatal DA (Bilder, Volavka, Lachman, & Grace,2004). Such disruption can increase the salience of internal andexternal stimuli, making it difficultto control theformation of men-

talstates. This in fact could explain the overactivityor lack of signaldrop in the paracingulate cortex (ParCC) and the TPJ which wasassociated with overattribution of mental states in patients withparanoid schizophrenia (Walter et al., 2009). Studies that inves-tigate interindividual variation in the transporters and enzymesinvolved in the termination of DA release and activity could pro-videevidencefortheeffectoftonicandphasicmodesofDAononesability to apply mentalstates (Yacubian & Bchel, 2009). The COMTgene andthe relation of itspolymorphisms to DAs tonic andphasicmodes of release in the PFC would be a profitable direction to pur-sue inthis regard(Bilder et al., 2004; Yavich, Forsberg, Karayiorgou,Gogos, & Mnnist, 2007).

5. Concluding remarks

ToM functioning is compromised in a wide range of psychiatric,neurological and genetic pathologies such as autism, schizophre-nia and Parkinsons disease. In fact, ToM impairment, of variousseverities, and across the lifespan, has been linked to more thantwenty pathologies (see Table 2). These pathologies can disrupt thementalizing network at theneuroanatomical or neurochemicallev-els or at the genetic level, which could cause a malfunction in theDS system or compromise the development of neuroanatomicaltargets within the network. Though current mentalizing tests stillpromote a dichotomous stance of presence or absence of ToM abil-ities, it is now widely accepted that ToM cannot be all-or-nothingcapacity (Abu-Akel & Bailey, 2000). Our model predicts that a dis-ruption within the network, at the neurochemical or anatomical

levels, is more likely to lead to varying degrees of ToMimpairment.Damage to posterior regions and particularly the TPJ could lead toa loss of ones ability to represent mental states, and damage tothe ventral and dorsal attentional systems could lead to a malfunc-tion in ones ability to distinguish between self and other mentalstates. Moreover, a disruption to lateral PFC structures within thementalizing network, and particularly to the mode of release ofboth 5-HT and DA, could lead to a malfunction in the ability tocontrol the application of represented mental states. Accordingly,our model supports the evaluation of ToM functionality at threelevels of analyses which include the representation, attributionand execution/application of mental states. The representationalaspect pertains to the individuals ability to represent cognitiveand affective ToM; theattributional or agentive aspect refers to the

individuals ability to attribute mental states to self or other; and


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Stone, V. E., Baron-Cohen, S., & Knight, R. T. (1998). Frontal lobe contributions toTheoryof Mind.Journal of Cognitive Neuroscience, 10, 640656.

Stone,V., & Gerrans, P. (2006). Whatsdomain-specificabout Theoryof Mind. SocialNeuroscience, 1, 309319.

Stuss,D. T., & Benson, F. D. (1986). The frontal lobes. New York: Raven Press.Stuss, D. T., Gallup, G. G., & Alexander, M. P. (2001). The frontal lobes are necessary

for Theory of Mind. Brain, 124, 279286.Tager-Flusberg, H., & Sullivan, K. (2000). A componential view of Theory of Mind:

Evidence from Williams syndrome. Cognition, 76, 5989.Tylec, A., Kucharska-Pietura, K., Jeleniewicz, W., Czernikiewicz, A., & Stryjecka-

Zimmer, M. (2010). Functional polymorphism of genes inactivating cate-

cholaminesand emotionaldeficitsin paranoid schizophrenia.PsychiatriaPolska,44, 207219.

Uddin, L. Q., Iacoboni, M., Lange, C., & Keenan, J. P. (2007). The self and social cog-nition: The role of cortical midline structures and mirror neurons. Trends inCognitive Sciences, 11, 153157.

Uddin, L. Q.,Kaplan, J. T.,Molnar-Szakacs, I.,Zaidel,E., & Iacoboni,M. (2005). Self-facerecognition activates a frontoparietal mirrornetworkin theright hemisphere:An event-related fMRI study. NeuroImage,25, 926935.

Uddin, L. Q., Molnar-Szakacs, I., Zaidel, E., & Iacoboni, M. (2006). rTMS to the rightinferior parietal lobule disrupts selfother discrimination. Social Cognitive andAffective Neuroscience, 1, 6571.

Uhl, G. R., Hedreen, J. C., & Price, D. L. (1985). Parkinsons disease: Loss of neuronsfrom the ventral tegmental area contralateral to therapeutic surgical lesions.Neurology,35, 12151218.

van der Meer, L., Costafreda, S., Aleman, A., & David, A. S. (2010). Self reflectionand thebrain: A theoretical review and meta-analysis of neuroimaging studieswith implications for schizophrenia.Neuroscience andBiobehavioral Reviews,34,935946.

Van Overwalle, F.,& Baetens, K. (2009). Understanding others actions and goals by

mirror and mentalizing systems: A metaanalysis. NeuroImage, 48, 564584.Vogeley, K., Bussfeld, P., Newen, A., Herrmann, S., Happ, F., Falkai, P., et al. (2001).

Mind reading: Neural mechanisms of Theory of Mind and self-perspective.Neu-roImage, 14, 170181.

Vogt, B. A., Finch, D. M., & Olson, C. R. (1992). Functional heterogeneity in cingulatecortex: The anterior executive and posterior evaluative regions.Cerebral Cortex,2, 435443.

Vogt, B.A., Hof,P. R., & Vogt, L.(2004). Cingulate gyrus.In G.Paxinos,& J.Mai (Eds.),The human nervous system2 (pp. 915945). San Diego: Elsevier.

Vllm, B. A., Taylor, A. N. W., Richardson, P., Corcoran, R., Stirling, J., McKie, J., et al.(2006). Neuronalcorrelates Theory of Mindand empathy:A functionalmagneticresonanceimaging study in a nonverbal task. NeuroImage, 29, 9098.

Walter, H., Ciaramidaro, A., Adenzato, M., Vasic, N., Ardito, R. B., Erk, S., et al.(2009). Dysfunction of the social brain in schizophrenia is modulated byintention type: An fMRI study. Social Affective and Cognitive Neuroscience, 4,166176.

Walter, H.,Schnell,K., Erk, S.,Arnold, C.,Kirsch, P.,Esslinger, C., et al. (2010). Effectsofa genome-wide supported psychosisrisk variant on neural activation duringa Theory of Mind task. Molecular Psychiatry, 19. doi:10.1038/mp.2010.18

Wang, Y., Shima, K., Sawamura, H., & Tanji, J. (2001). Spatial distribution of cin-gulate cells projecting to the primary, supplementary, and pre-supplementarymotor areas: A retrograde multiple labelling study in the macaque monkey.Neuroscience Research,39, 3949.

Wellman, H., Lopez-Duran, S., LaBounty,J., & Hamilton,B. (2008). Infant attentiontointentional actions predicts preschool Theory of Mind. Developmental Psychol-ogy, 44, 618623.

Williams, D. M., & Happ, F. (2009). What did I say? versus What did I think?:Attributingfalse beliefs to selfamongst children with and without autism.Jour-nal of autismand Developmental Disorders,39, 865873.

Williams, D. M., Lind, S. E.,& Happ,F. (2009). Metacognition maybe moreimpairedthan mindreading in autism. Behavioral and Brain Sciences,32, 162163.

Yacubian, J.,& Bchel, C. (2009). Thegeneticbasis of individualdifferencesin rewardprocessing and the link to addictive behavior and social cognition.Neuroscience,164, 5571.

Yavich, L., Forsberg, M. M., Karayiorgou, M., Gogos, J. A., & Mnnist, P. T.(2007). Site-specific role of catechol-O-methyltransferase in dopamine over-flow within prefrontal cortex and dorsal striatum.Journal of Neuroscience, 27,1019610209.

Young, L., Cushman, F., Hauser, M., & Saxe, R. (2007). The neural basis of the inter-actionbetween Theoryof Mind andmoraljudgment. Proceedingsof theNationalAcademy of Sciences, 104, 82358240.

Zaitchik, D., Koff, E., Brownell, H., Winner, E., & Albert, M. (2004). Inference of

mental states in patients with Alzheimers disease. Cognitive Neuropsychiatry,9, 301313.

Zaitchik, D., Walkerf, C., Millerg, S., LaVioletteh, P., Feczkoi, E., & Dickersonb,B. C. (2010). Mental state attribution and the temporoparietal junction: AnfMRI study comparing belief, emotion, and perception. Neuropsychologia, 48,25282536.

Zinck, A.,Lodahl, S.,& Frith,C. D. (2009). Making a case forintrospection.BehavioralandBrain Sciences,32, 163164.

Zweifel,L. S,Parkera, J. G., Lobbc, C. J., Rainwatera, A., Walla, V.Z., Fadoka, J.P., etal.(2009). Disruptionof NMDAR-dependentburst firingby dopamineneuronspro-videsselectiveassessmentof phasic dopamine-dependentbehavior.Proceedingsof theNational Academy of Sciences, 106, 72817288.

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