Neuropsychologia 49 (2011) 2971–2984

Contents lists available at ScienceDirect

Neuropsychologia
journal homepage: www.elsevier.com/locate/neuropsychologia

Reviews and perspectives

Neuroanatomical and neurochemical bases of theory of mind

Ahmad Abu-Akel a,∗ , Simone Shamay-Tsoory b
a
Independent, Los Angeles, CA, USA
b
Department of Psychology, University of Haifa, Mount Carmel, Haifa 31905, Israel

a r t i c l e i n f o a b s t r a c t

Article history: This paper presents a novel neurobiological model of theory of mind (ToM) that incorporates both neu-
Received 10 December 2010 roanatomical and neurochemical levels of specificity. Within this model, cortical and subcortical regions
Received in revised form 14 July 2011 are functionally organized into networks that subserve the ability to represent cognitive and affective
Accepted 14 July 2011
mental states to both self and other. The model maintains that (1) cognitive and affective aspects of ToM
Available online 23 July 2011
are subserved by dissociable, yet interacting, prefrontal networks. The cognitive ToM network primarily
engages the dorsomedial prefrontal cortex, the dorsal anterior cingulate cortex and the dorsal striatum;
Keywords:
and the affective ToM network primarily engages the ventromedial and orbitofrontal cortices, the ventral
Cognitive theory of mind
Affective theory of mind
anterior cingulate cortex, the amygdala and the ventral striatum; (2) self and other mental-state repre-
Social cognition sentation is processed by distinct brain regions within the mentalizing network, and that the ability to
Dopamine distinguish between self and other mental states is modulated by a functionally interactive dorsal and
Serotonin ventral attention/selection systems at the temporoparietal junction and the anterior cingulate cortex;
Striatum and (3) ToM functioning is dependent on the integrity of the dopaminergic and serotonergic systems
Ventral and dorsal attention systems which are primarily engaged in the maintenance and application processes of represented mental states.
Self In addition to discussing the mechanisms involved in mentalizing in terms of its component processes, we
Other
discuss the model’s implications to pathologies that variably impact one’s ability to represent, attribute
Autism
and apply mental states.
Schizophrenia
Parkinson’s disease © 2011 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2971
2. The neuroanatomy of theory of mind: revisited. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2972
2.1. Cognitive and affective theory of mind: two dissociated circuits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2972
2.2. Neural bases of representing self and other mental states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2974
2.2.1. Mechanism underlying the distinction between self and other mental states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2975
3. Neurochemical bases of theory of mind . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2976
4. The integration: a neuroanatomical–neurochemical model of theory of mind . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2978
5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2980
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2981

1. Introduction eye-gaze, share attention, recognize emotion, and to distinguish

between self and other. These basic abilities are essentially neces-
Over the last two decades, isolating the neural basis of our abil- sary for mentalizing and thus can be considered essential parts of its
ity to represent and attribute affective and cognitive mental states process (Brothers, 1997; Flavell, 1999; Frith & Frith, 1999; Stone &
to self and other (i.e., theory of mind or mentalizing) has been Gerrans, 2006). With this ability, we create theories about others’
a main focus of cognitive and social neuroscience research. This beliefs, desires and emotions in order to understand and predict
ability is believed to be an outgrowth of pre-existing social intelli- their behavior.
gences such as the ability to detect another agent’s goal and follow Undoubtedly, at the core of ToM brain research is the for-
mulation of a predictive neurobiological model of our ability to
mentalize. A viable neurobiological model of ToM should mini-
∗ Corresponding author. mally explain three basic mentalizing processes which include the
E-mail address: abuakel@hotmail.com (A. Abu-Akel). ability to represent cognitive and affective mental states, attribute

0028-3932/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuropsychologia.2011.07.012
2972 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984
these mental states to self and other, and finally apply (or deploy)
these mental states in a manner that allows one to correctly under-
stand and predict behavior. According to Fuster (2001), two major
pitfalls must be avoided when formulating a neural basis of a com-
plex behavior or function: (1) to discuss this function in isolation
while neglecting others that complement it, and (2) to localize this
function within a discrete brain region. Accordingly, mapping a
neurobiological model to component processes of ToM will essen-
tially require a functionally interconnected brain network that
incorporates both neuroanatomical and neurochemical levels of
specificity. Based on emergent and longstanding evidence, we first
identify (in Section 2) brain regions that are engaged during ToM
processing, and describe, in Sections 2.1 and 2.2, how these var-
ious regions form, within the larger mentalizing network, neural
networks that subtend our ability to represent and apply cognitive
and affective mental states to self and other. Second, we introduce,
in Section 3, a candidate neurochemical system that is responsible
for the integrity of ToM functioning, and which we believe plays an
important role in the application and deployment of mental states.
In Section 4, we present a neuroanatomical–neurochemical model
of ToM, and discuss how this new integrative model can enhance
our understanding of aberrant mentalization processes in various
pathologies. Finally, we suggest, in Section 5, future research direc-
tions under the guidelines of the new model.
2. The neuroanatomy of theory of mind: revisited
With the availability of imaging techniques and lesion-based
approach studies, a concerted effort has emerged with the goal of
isolating the neural basis of ToM. Table 1 provides a summary of the
various regions that have been consistently associated with ToM
processing (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 a
network of functionally related regions (e.g., Gallagher & Frith,
2003; Saxe, 2006), and several accounts have been proposed to
determine 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 the
anterior paracingulate cortex is instead the key region, and that
other regions in the temporal lobes, the OFC and the amygdala
play secondary functions and are unlikely to be directly involved
in ToM. Later, Amodio and Frith (2006) extend this role to the
MPFC (in which they include the ACC). Contrary to these accounts,
Table 1
Theory of mind brain regions.
Brain region Brodmann’s area
Posterior regions
Temporo-parietal junction (including the Inferior 39/40
parietal lobe) (IPL/pSTS or TPJ)
Posterior cingulate/precuneus (PCC/PCun) 31/7
Superior temporal sulcus (STS) 21/22
Limbic–paralimbic regions
Orbitofrontal (OFC) 11/12/47
Ventral medial prefrontal cortex (vMPFC) 10/32
Anterior cingulate/paracingulate cortex (ACC/PrCC) 24/32
Temporal pole (TP) 38
Amygdala Subcortical
Striatum Subcortical
Frontal regions
Dorsal medial prefrontal cortex (dMPFC) 8/9
Dorsal lateral prefrontal cortex (DLPFC) 9/46
Inferior lateral frontal cortex (ILFC) 44/45/47
some researchers argue that mentalizing is subserved by posterior
regions. For example, Saxe (2006) suggests that the representation
of mental states, particularly false beliefs, is specifically subserved
by the right TPJ, and Samson, Apperly, Chiavarino, and Humphreys
(2004) show that the left TPJ (coupled with the frontal lobes) is
necessary for the representation of mental states. A slightly more
expansive network is proposed by Brunet-Gouet and Decety (2006)
which involves the MPFC, the amygdala and the IPL. However, little
work has been done to integrate these regions into a functionally
interconnected circuit (cf. Abu-Akel, 2003a). In the following sec-
tion we present a new model that situates these regions within
distinct neural networks that subserve the processing of affective
and cognitive ToM, and which is then extended, in Section 2.2, to
specify the networks and mechanism subserving the processing of
self 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, but
comprised 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 as
cold and hot aspects of ToM, where the cold or cognitive dimen-
sion pertains to inferences about knowledge and beliefs, and the
hot or affective dimension pertains to inferences about emotions.
Research has shown that affective and cognitive aspects of ToM are
behaviorally distinguishable, and could be mediated by dissociated
networks (e.g., Hynes, Baird, & Grafton, 2006; Shamay-Tsoory &
Aharon-Peretz, 2007; Shamay-Tsoory et al., 2006; Shamay-Tsoory,
Tomer, Berger, & Aharon-Peretz, 2005; Völlm et al., 2006). In this
section, we identify affective and cognitive ToM brain regions and
delineate the neural networks which they populate.
Numerous studies have investigated the role that various ToM
brain regions have in processing cognitive versus affective ToM by
examining 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, & O’Leary, 2008; Hooker, Verosky, Germinea,
Knight, & D’Esposito, 2008, 2010; Hynes et al., 2006; Russell et al.,
2000; Samson, Apperly, Kathirgamanathan, & Humphreys, 2005;
Schulte-Rüther, Markowitsch, Fink, & Piefke, 2007; Vogeley et al.,
2001) are involved in affective ToM processing, and that the dorsal
MPFC 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 ILFC
in the representation and regulation of socioemotional states and
their 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; Shaw et al., 2004; Stone,
Baron-Cohen, Calder, Keane, & Young, 2003), make these regions
suited for synthesizing the diverse range of information needed for
representing affective mental states (Beer, Shimamura, & Knight,
2004; Happaney, Zelazo, & Stuss, 2004). The involvement of the
dorsal MPFC and DLPFC in the processing of 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 or
brain 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 that
the ACC, the temporal pole and the striatum are likely to be differ-
entially involved in processing affective and cognitive ToM. With
 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984
respect to the ACC, many studies have shown that it responds to
a variety of cognitive and affective ToM tasks (Chiu et al., 2008;
Lombardo et al., 2009; Stuss et al., 2001; Völlm et al., 2006; Young,
Cushman, Hauser, & Saxe, 2007). However, there is evidence sug-
gesting that the ventral ACC (vACC) is involved in the emotional
aspects of self-reflection (Moran, Macrae, Heatherton, Wyland, &
Kelley, 2006; van der Meer, Costafreda, Aleman, & David, 2010),
and that the dorsal ACC (dACC) is preferentially involved in pro-
cessing cognitive ToM (Sommer et al., 2007). While there is a need
for research that specifically addresses, within a single paradigm,
the functional correlates of the dorsal and ventral ACC, it can
nonetheless be speculated that the ventral and dorsal aspects of
the ACC are respectively involved in the processing of affective and
cognitive ToM. The vACC constitutes the limbic region of the cingu-
late cortex and is associated with affective experiences, including
assigning emotional valence to external and internal stimuli, and is
directly engaged in autonomic regulation, through the direct pro-
jections of area 25 to the various brainstem autonomic nuclei as
well as the OFC and ventral MPFC (Barbas, 2007), regions that are
selectively involved in processing affective ToM. The dACC, on the
other hand, is associated with various cognitive functions such as
response selection (based on the motivational relevance of partic-
ular behaviors), attention-for-action, error detection, competition
monitoring, anticipation, and working memory (for reviews see
Bush, Luu, & Posner, 2000; Vogt, Hof, & Vogt, 2004). The dACC is also
strongly connected with the dorsal MPFC and the DLPFC, regions
that are selectively involved in processing cognitive ToM.
The temporal pole, which occupies the most rostral part of the
temporal lobe (BA 38) (Chabardès, Kahane, Minotti, Hoffmann, &
Benabid, 2002), is also considered a critical region for mentaliz-
ing (Frith & Frith, 2006; Olson, Plotzker, & Ezzyat, 2007; Ross &
Olson, 2010) that responds to both affective (e.g., Calabria, Cotelli,
Adenzato, Zanetti, & Miniussi, 2009; Kipps et al., 2009; Schulte-
Rüther et al., 2007; Völlm et al., 2006) and cognitive (e.g., Castelli,
Happé, Frith, & Frith, 2000; Lambon Ralph, Pobric, & Jefferies, 2009;
Ohnishi et al., 2004) ToM related tasks and functions. Similar to the
ACC, the TP is anatomically divided into dorsal and ventral parts
(Olson et al., 2007), which respectively have strong bidirectional
connections with the MPFC and the OFC (Kondo, Saleem, & Price,
2003). While there are no studies that specifically address the func-
tional correlates of the ventral and dorsal subregions with respect
to the processing of cognitive and affective ToM, the distinct pro-
jections of the ventral and dorsal subdivisions to the cognitive and
affective parts of the PFC, suggest that these subdivisions can be
selectively engaged in the processing of affective and cognitive
mental states.
The striatum is seldom discussed in the literature on the neural
basis of ToM, though several neuroimaging studies using differ-
ent tasks and stimuli, have noted the activity of this structure
during mentalizing (e.g., Baron-Cohen et al., 1999; Brüne et al.,
2008; Péron et al., 2010; Rilling, Sanfey, Aronson, Nystrom, &
Cohen, 2004a, 2004b; Sripada et al., 2009). Involvement of the
striatum in ToM processing is concordant with its role in facili-
tating the interface between cortical and subcortical information
(Simpson, Kellendonk, & Kandell, 2010), its involvement in goal
directed behavior (Goto & Grace, 2005), and the observation that
dopaminergic dysfunction within the striatum alone can lead to
frontal-like cognitive deficits (Frank & O’Reilly, 2006). In addi-
tion, the distinction between the dorsal striatum (i.e., the caudate
and the putamen), which is associated with motor and cognitive
functions, and the ventral striatum (i.e., the nucleus accumbens),
which is associated with affective functions (Dauer & Przedborski,
2003; Di Martino et al., 2008; Haber, Fudge, & McFarland, 2000;
Kish, Shannak, & Hornykiewicz, 1988; Owen, 2004), suggests that
these subsystems could be differentially involved in the processing
of cognitive and affective ToM. Parkinson’s disease (PD) provides
2973
probably the best evidence for the involvement of the striatum in
the processing of cognitive and affective ToM. In the early stages
of the disease, the dorsal striatum is more severely depleted than
the ventral striatum (Dauer & Przedborski, 2003; Kish et al., 1988;
Owen, 2004). During this stage, PD patients exhibit difficulties in
cognitive ToM only (Roca et al., 2010). As the disease progresses, the
ventral striatum is also impacted and, as a result, PD patients begin
to show impairments in both affective and cognitive ToM (Bodden,
Mollenhauer, et al., 2010). It is important to note that these
deficits were found to be largely independent from other cogni-
tive impairments, depressive symptoms and motor impairment in
these patients (Bodden, Mollenhauer, et al., 2010; Roca et al., 2010).
In all, there is considerable research supporting the functional
independence of affective and cognitive mental states, and this dis-
sociation appears to be supported by different regions within the
mentalizing network. Within this network, mental states are first
detected (represented) within the TPJ (Abu-Akel, 2003a; Aichhorn
et al., 2009; Samson et al., 2004; Saxe, 2006). It is important to
note that while we recognize that the TPJ consists of two anatom-
ically distinct regions including the IPL and caudal parts of the
superior temporal sulcus (pSTS) (Decety & Lamm, 2007; Zaitchik
et al., 2010), both are strongly recruited during the attribution of
beliefs (Zaitchik et al., 2010). Hence, the representation of mental
states within the TPJ is likely a functional outcome of these two
regions combined. Representations formed within the TPJ are then
relayed through the STS or the PCun/PCC to the limbic and paral-
imbic regions for emotional input and integration of this emotional
input with the incoming parasensory information. As will become
clear in Section 2.2 below, these posterior regions do not exhibit
preference for the processing of affective or cognitive mental states,
but play a major role in assigning agency to these mental states. As
can be seen from Fig. 1, the processing of affective ToM engages
the amygdala, ventral striatum, vTP, vACC, OFC, vMPFC and ILFC.
Conversely, the processing of cognitive ToM engages the dorsal
striatum, dTP, dACC, dMPFC and DLPFC. Given the role of the lateral
PFC in the application and execution of behavior, speech and rea-
soning (Fuster, 2001; Stuss & Benson, 1986), the DLPFC and the ILFC
respectively represent the execution and application nodes of the
cognitive and affective ToM networks. Indeed, neuropsychological
evidence shows that damage to these areas result in the inability
to carry out plans and actions (for reviews see Fuster, 2001; Miller
& Cohen, 2001).
Although both emotional and cognitive components of ToM
appear to trigger independent circuits within the larger men-
talizing network, they can be interacting functions of the brain
where affect and cognition can mutually affect each other (LeDoux,
1995; Shamay-Tsoory, 2010). Indeed, emotional representations
could influence cognitive processes by serving as biasing signals in
decision-making processes (Damasio, 1994; Etkin, Egner, & Kalisch,
2011) as well as indicators of mental states such as intentions
(Charlton & McClelland, 1999). This is suggested by the recipro-
cally interconnected limbic–paralimbic and neocortical areas of
the mentalizing network. The ACC is one candidate region where
processing of this interaction between cognitive and affective rep-
resentation takes place (Etkin et al., 2011). While, as noted above,
the ACC is anatomically divided into ventral and dorsal regions,
these regions are reciprocally connected with each other and
with cognitive and affective regions and their output counterparts
within the PFC. The assignment of cognitive or affective value to
mental states is likely achieved through the dense bidirectional
interactions of its limbic area (vACC) with the amygdala and the
posterior orbitofrontal cortex (Barbas, 2007). In addition, the ACC,
as mentioned above, is involved in response selection, emotional
control, attentional shifting, error detection, working memory
(Vogt, Finch, & Olson, 1992; Vogt et al., 2004), and self–other dis-
tinction (see Section 2.2.1 below). All these functions make the
2974 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984

Cognitive execution loop

DLPFC
(cognitive)

Limbic-Paralimbic
DMPFC
(cognitive)
dACC dTP/ PCun/PCC
(cognitive) Dorsal Striatum
(cognitive) TPJ
(IPL-pSTS)
Amygdala/ vTP/
Ventral Striatum STS
vACC
(affective)
OFC/ (affective)
vMPFC
(affective)

ILFC
(affective)

Affective execution loop

Fig. 1. Neural network for processing affective and cognitive mental states. The arrows are bidirectional. Represented mental states are formed at the temporoparietal
junction (TPJ) which is then relayed through the superior temporal sulcus (STS) or the precuneus/posterior cingulate complex (PCun/PCC) to limbic–paralimbic regions to
be assigned cognitive or affective values. Affective ToM (Hot-Red boxes) is mediated by a network that engages the ventral 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 the other hand, is mediated by a network that engages the dorsal striatum, dorsal temporal pole (dTP), dorsal anterior cingulate cortex (dACC), dorsal
medial prefrontal cortex (DMPFC), and dorsal lateral prefrontal cortex (DLPFC). The ILFC and the DLPFC represent the execution/application structures of their respective
affective and cognitive ToM networks. Interacting functions of the two networks could be mediated within the ACC. (For interpretation of the references to color in this figure
legend, the reader is referred to the web 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 and dorsal ACC are reciprocally
suppressed while processing affective or cognitive tasks, which
could reflect decision processes involved in assigning cognitive or
affective value to mental states.
2.2. Neural bases of representing self and other mental states
Mental states, whether cognitive or affective, are assigned
agency. While the relationship between self and other mentaliza-
tion is subject to debate (Carruthers, 2009), it can be characterized
by the presence of one metarepresentational mechanism with two
modes of access: a perception-based mode used for the represen-
tation of other mental states, and an introspective mode used to
represent self mental states (e.g., Carruthers, 2009; Frith & Happé,
1999; Happé, 2003; Williams, Lind, & Happé, 2009; Zinck, Lodahl,
& Frith, 2009). However, while representation of other mental
states can primarily be perception-based, i.e., relies on external
cues gleaned from the environment such as direction of eye gaze
and facial expressions, they can also be computed in consultation
with internally stored information such autobiographical memory
(van der Meer et al., 2010). Conversely, while representation of self
mental states can primarily be introspective-based, i.e., relies on
internal information such as autobiographical memory and emo-
tions (including interoception—i.e., awareness of bodily states),
external signals can be used to make appropriate inferences about
the 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 representing self mental states
(Brüne et al., 2008; Frith & Corcoran, 1996; Pickup & Frith, 2001).
Such dissociation has also been reported among individuals with
autism (Chiu et al., 2008; Williams & Happé, 2009). Accordingly, we
envision that self and other mentalizing is subserved by a shared
mentalizing network comprised of two interactive, yet dissociable,
subnetworks that represent self and other mental states.
Recent studies began uncovering the specific role various ToM
brain regions might have in processing self and other mental states.
Posterior regions within the mentalizing network (see Fig. 1) which
include the PCC/PCun, the TPJ and the STS appear to respond differ-
entially when processing self mental states. The TPJ has been seen
as 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 the
IPL) being differentially activated during the self-related attribu-
tions (Schulte-Rüther 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, the precuneus was
found to be functionally connected to the right IPL and the MPFC,
extending into the vMPFC during self-representation. Accordingly,
it is proposed that the precuneus is a nodal structure that subserves
self-representation. Indeed, a disruption of this region through the
application of TMS led to retrieval difficulties of previous judg-
ment of oneself compared with that of others. The left temporal
region (BA 21 or STS), on the other hand, was selectively active in
other-reference. Interestingly, the right IPL and the left STS were
correlated in such a way that activation increased in the STS and
decreased in the IPL with decreasing self-reference.
 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984
Differential activation between self- and other-reference was
also observed within the MPFC, where the vMPFC appears biased
towards self-mentalizing and the dMPFC is biased towards other-
mentalizing (D’Argembeau et al., 2007; Lombardo et al., 2010;
Mitchell, Macrae, & Banaji, 2006). It should be noted that in the
study by Mitchell et al. (2006), the activity of the vMPFC was asso-
ciated with self-referential processing including thinking about
similar others, and that the activity of the dMPFC in the study
by D’Argembeau et al. (2007), was associated with both self- and
other-referential processing. One can argue that the stated selec-
tivity of vMPFC for the processing of self mental states might be
undermined by the fact that it also responds to similar others.
However, it is important to emphasize that the response to similar
others could be due to simulation processes of likeness to oneself. If
you are thinking about the mental state of a person who is similar to
you, one cannot rule out that much of this inference is modeled after
one’s self. Alternatively, the response of the vMPFC to similar others
could be a function of the adjacent OFC, with which it is intimately
connected (Öngür, Ferry, & Price, 2003; Price, 2007), and which
itself has a prominent role in the social-perceptual aspect of ToM
(Bora, 2009; Lee, Farrow, Spence, & Woodruff, 2004), particularly in
processing 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 in
the decoding of mental states that principally rely on social infor-
mation from the environment such as eye gaze, the person’s actions,
tone of voice and facial expressions (Sabbagh, 2004). Accordingly,
we suggest that the vMPFC is selectively involved in self-reference
processes and in understanding the mental states of oneself or simi-
lar others. Our interpretation of this data is concordant with a recent
meta-analysis suggesting that “the vMPFC is specifically involved in
the processing of self-referential stimuli and not in the processing
of other-referential stimuli” (van der Meer et al., 2010, p. 941).
The selectivity of the dMPFC in the processing of other mental
states is not straightforward either, as there is evidence show-
ing that the dMPFC can be active during self referential tasks
as well (Gusnard, Akbudak, Shulman, & Raichle, 2001). In fact,
D’Argembeau et al. (2007) showed that within the dMPFC, the
dorsal anterior MPFC along with the precuneus was active dur-
ing self referential processing, whereas adopting the other person’s
perspective activated the posterior part of the dorsal MPFC. Such
response of the dMPFC during self and other-referential process-
ing is expected as this region appears to be selectively involved
in processing cognitive mental states, which can be of oneself or
another. Moreover, the meta-analysis by van der Meer et al. (2010)
also suggests that the dMPFC is not only involved in the processing
of self-relevant information, but also involved in the evaluation and
decision-making process of whether a certain stimulus is applicable
to the self or to another person.
Collectively, these studies suggest that the IPL, PCC/PCun, the
vMPFC, 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 posterior
dMPFC and the OFC, on the other hand, appear to be selec-
tively involved in the computation of other mental states. The
question then, what mechanism does the brain, within the gen-
eral mentalizing network, use to distinguish between self- and
other-mentalizing?
2.2.1. Mechanism underlying the distinction between self and
other mental states
Researchers argued that the distinction between self and other
mental 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
2975
activation of its executive functions of inhibition, planning and
coordination, which is required to suppress the prepotent self per-
spective in favor of another perspective. A similar network was
advanced 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 right
lateralized mirror neuron mechanism that occupies the IPL and the
inferior frontal gyrus (IFG). In this section, we elaborate on the role
of the fronto-parietal circuit in the distinction between self and
other, and propose that this distinction is mediated through com-
plementary attention systems that coexist within the mentalizing
network. These attention systems are generally known as the ven-
tral and dorsal attention systems. The ventral system is lateralized
to the right and is composed of the right TPJ and the IFG. This system
is an involuntary, bottom-up system that is involved in reorient-
ing attention in response to salient sensory stimuli or violation
of expectations (Corbetta & Shulman, 2002; Fox, Corbetta, Snyder,
Vincent, & Raichle, 2006), and it has been suggested that TPJ-IFG
co-activation may facilitate termination of ongoing activity and dis-
engagement of attention when shift cues are unexpected (Shulman
et al., 2009). Note that this ventral attention system greatly over-
laps with the right lateralized TPJ-ILFC network claimed by Uddin
and Decety and colleagues to underlie the mechanism for self and
other distinction. Complementing the ventral attention system, is
a bilateral dorsal attention system composed of the intraparietal
sulcus and the superior parietal lobe (BA 5 and 7) and the dorsal
frontal cortex, near or at the frontal eye field (∼BA 6 and 8). This
system is involved in voluntary, goal-driven, top-down orienting of
attention (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 or
stimuli, and the ventral system filters signals by monitoring can-
didate information for possible selection. Signals coming through
the ventral system disengage the dorsal system from its current
focus and reorient or refocus it towards behaviorally relevant stim-
uli. It has been suggested that the interaction between ventral
and 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 and
the precuneus provide one pathway through which these two
attentional systems interact (Lou et al., 2004). Recent evidence,
also suggests that interaction between these systems could occur
through 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 (ventral
attention system) (Beckmann, Johansen-Berg, & Rushworth, 2009;
Paus, 2001; Wang, Shima, Sawamura, & Tanji, 2001).
Obviously, there is a considerable anatomical overlap between
the mentalizing and attentional systems networks, specifically
within the TPJ and ACC regions. In addition, there is evidence sug-
gesting a functional overlap as well. With respect to the TPJ, a recent
meta-analysis showed substantial overlap of activation clusters
during agency, attentional reorienting and social cognition, which
suggests that “activation in the TPJ during social cognition may rely
on a lower-level computational mechanism involved in generating,
testing, and correcting internal predictions about external sensory
events” (Decety & Lamm, 2007, p. 583). Substantiating this con-
clusion, Mitchell (2008) provides evidence showing that the TPJ
is both active when participants perform attentional reorienting
tasks as well as false belief tasks. Accordingly, Mitchell proposes
that these two tasks are likely to draw on the same cognitive pro-
cess that may involve the suppression of salient stimuli in favor of
a less immediate alternative. While the degree of overlap between
attentional reorienting and ToM activation clusters within the TPJ
appears smaller than has been previously demonstrated (Scholz,
Triantafyllou, Whitfield-Gabrieli, Brown, & Saxe, 2009), it has been
2976 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984

suggested that attention signals in the TPJ may be important to
switch between internal, bodily, or self-perspective and exter-
nal, environmental, or other’s viewpoint during ToM processes
(Corbetta, Patel, & Shulman, 2008). This evidence, in our view, lends
support to the suggestion that the TPJ, which responds to both self
and other mental states, functions as a mediator between the self-
and other-perspective (Schulte-Rüther et al., 2007), and is the site
where 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 network
as a mediator between self- and other-perspective can be linked to
its anatomical characteristics. The TPJ is a heteromodal association
cortex that integrates inputs from the thalamus, the limbic system,
as well as from visual, auditory and somaesthetic areas, and is recip-
rocally connected with prefrontal and temporal cortices (Decety
& Lamm, 2007), which enables it to process information from the
external environment as well as from the internal-bodily environ-
ment. Perhaps the observed disruption of self–other discrimination
following rTMS over the right IPL (Uddin et al., 2006), is in fact a
disruption to the activity of the ventral attentional system. Similar
to the TPJ, there is also considerable functional overlap between
attentional and mentalization functions within the ACC. Based on
the well established role of the ACC in the representation of self and
other mental states and in directed attention, Gallagher and Frith
(2003) suggest that this region, and specifically the most anterior
section of it, might be specialized for directing attention to men-
tal states. We would also add that, due to its connections with the
ventral and dorsal attentional system, it is also involved in directing
attention to self versus other mental states (also see van der Meer
et al., 2010).
Accordingly, we propose that the role of the ventral and dor-
sal attention systems in attending to relevant internal and external
information is a mechanism that has been co-opted by the mental-
izing network, at the TPJ and ACC levels, to regulate the processing
of self and other mental states. Linking attentional and mentalizing
functions is consistent with studies showing that better atten-
tional inhibition processes explain performance differences in ToM
related tasks (Bialystok & Senman, 2004), and that infant attention
to 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 the
ACC levels. Fig. 2 presents a schematic representation of the pos-
tulated neural networks involved in the representation of self and
other mental states.
3. Neurochemical bases of theory of mind
Most available models map ToM processing at the gross neu-
roanatomical level. These models are limited in that they cannot
fully explain how various pathologies present with differing
neurobiological abnormalities exhibit similar ToM dysfunctions
such as in schizophrenia and autism, or how patients within a
single disorder such as in Parkinson’s disease and schizophre-

Cognitive execution loop

Dorsal attention system

dLPFC (includes FEF)
cognitive self & other

Limbic-Paralimbic
dMPFC (self & other)
(cognitive
self& other) dACC dTP/
(cognitive) Dorsal Striatum PCun/PCC
(cognitive) (self) TPJ
(IPL-pSTS)
(self-other)
Amygdala/ vTP/
Ventral Striatum STS
vACC (other)
(affective)
vMPFC/OFC (affective)
(affective
self & other)

ILFC
affective self & other
Ventral attention system

Affective execution loop

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 the
temporo-parietal junction (TPJ). Relevance of stimulus to self or other mental states is assigned through the ventral and dorsal attentional systems. If stimulus assigned
relevant to another person, this information is then sent back, through the posterior portion of the STS (pSTS) to the STS. If, on the other hand, stimulus is assigned relevant
to self, then this information is sent back, through the inferior parietal lobule (IPL) to the PCun/PCC. Signals from the limbic–paralimbic system (which involve the amygdala,
striatum, temporal pole (TP) and the anterior cingulate cortex (ACC)) determine whether representations are cognitive or affective. Within the ACC, attention to self-relevant
or other-relevant stimuli (and ultimately represented self or other mental states) is directed by engaging and disengaging the ventral and dorsal attentional systems. A dorsal
stream within the limbic–paralimbic system is dedicated to the processing of cognitive mental states, and a ventral stream is dedicated to the processing of affective mental
states. From there, self or other cognitive representations are sent through the dMPFC to DLPFC for execution/application decisions. In contrast, affective representations are
relayed from the ventral stream through vMPFC/OFC complex to the ILFC for execution/application decisions.
 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984
nia exhibit differing profiles of ToM impairment. It has been
suggested that understanding neurochemical processes chan-
neled along pathways from and to implicated regions within the
mentalizing network can provide a unifying framework where
such variation in ToM functioning within and across patholo-
gies can be explained (Abu-Akel, 2003b). In a step towards this
direction, it has been hypothesized that dopamine (DA) and sero-
tonin (5-hydroxytriptamine, 5-HT), collectively referred to as the
dopaminergic–serotonergic 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 the
following observations: (1) ToM dysfunctions are frequent conse-
quences of disorders that are associated with severe deficits in the
DS system such as autism and schizophrenia, (2) the DS system
innervates the PFC, the TPJ and the ACC, regions that are critical
for mentalizing, and (3) the DAergic system which is involved in
learning and signaling changes or errors in the predictions of future
salient and rewarding events (Schultz, Dayan, & Montague, 1997),
is a likely mechanism that enables us to predict the actions and
behaviors of others, and to use these prediction errors to mod-
ify our representations of the mental states. To this we add the
role of DAergic system in cognitive flexibility and stability which
is thought to be mediated by the tonic and phasic modes of DA
release—tonic DA is thought to be associated with the stabilization
and 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 that “social cognition may
be affected by dopaminergic levels, especially when mentalization
is performed” (p. 86), which they hypothesize could result from the
putative role of DAergic transmission in the updating of short-term
contextual representations by controlling the inflow of externally
or internally generated information. According to this hypothesis
it is predicted that disruption to the DA system itself or to neu-
rochemical processes that affect/modulate its functioning such as
the 5-HT system could lead to either a conceptual deficit of ToM
such as in autism, or to the generation of erroneous predictions
about the mental states of others, as is the case for patients with
schizophrenia.
Over the last few years, several lines of evidence have emerged
in support of the role of the DS system in the integrity of ToM
functioning. Though nascent, neurogenetic research that inves-
tigates the effect of genes with specific roles in neurochemical
signaling on cognitive functioning has provided important insights
to the roles of the DS system in ToM. For example, Bassett,
Caluseriu, Weksberg, Young, and Chow (2007) examined the role of
the 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 region
commonly deleted in 22q11DS, has been associated with high risk
for schizophrenia and is involved in DA metabolism (Akil et al.,
2003; Bearden et al., 2004; Egan et al., 2001). Comparisons between
22q11DS patients hemizygous for the COMT Met or Val alleles show
that patients carrying the COMT Met allele performed worse on
ToM tasks, communication and social functioning measures than
patients who carry the COMT Val allele. This difference remained
significant after controlling for a diagnosis of schizophrenia and
IQ. 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 children
was associated with the polymorphisms of the COMT gene and
the DA receptor D4 gene (DRD4) (Lackner, 2009), and spontaneous
eyeblink rates (Lackner, Bowmnan, & Sabbagh, 2010), which is a
functional marker of central DAergic function. Importantly, these
relationships were largely independent of the rather well estab-
lished link between DA and executive functioning skills. Drawing
2977
on the link between specific COMT alleles and DA activity in the
PFC, on the one hand, and ToM functioning, on the other, it is rea-
sonable to assume that a disruption of DA optimal levels within the
PFC could have direct consequences on our ability to mentalize.
The effect of the serotonergic system on ToM functioning has
also been reported. In this recent study, Bosia et al. (2010) inves-
tigated the effect of the −1019 C/G functional polymorphism of
serotonin 1A receptor (5-HT1A-R), which affects serotonin trans-
mission and dopamine release in the PFC, on ToM performance
among 118 patients with schizophrenia. They found significant
effect on ToM performance, with the CC genotype carriers per-
forming significantly better compared to the G allele carriers. It
is suggested that the underperformance of G allele carriers may be
attributable to the association of the G allele with 5-HT1A-R over-
expression which has been shown to disrupt the interaction of the
DAergic 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) decreasing
DA levels in the PFC by exerting inhibitory actions on pyrami-
dal glutamatergic cells. The finding suggests that the 5-HT1A-R
polymorphism, via its regulatory function of both the DAergic
and serotonergic systems in the PFC, might have a specific effect
on the integrity of ToM functioning. Moreover, Tylec, Kucharska-
Pietura, Jeleniewicz, Czernikiewicz, and Stryjecka-Zimmer (2010)
also found that the enzymatic activity of the monoamine oxidase
A (MAO-A), which reflects central serotonergic activity, predicted
mentalizing deficits in 100 patients with schizophrenia, partic-
ularly among 4/4 genotype carriers of the polymorphism VNTR
MAO-A.
These results support findings from imaging studies which
observed links between DAergic and serotonergic activities and
mentalizing abilities. In a single-photon emission computed
tomography study, Murphy et al. (2006) found that individuals
with Asperger’s syndrome had a significant reduction in cortical
5-HT2A receptor binding in the total, anterior, and posterior cin-
gulate, bilaterally in the frontal and superior temporal lobes, and
in the left parietal lobe. Reductions in 5-HT2A receptor binding in
the anterior and posterior cingulate and the right frontal cortex
were significantly correlated with increased qualitative abnormal-
ities in reciprocal social interactions which rely on ToM functioning.
In a more recent positron emission tomography study, Nakamura
et al. (2010) found that 5-HT transporter binding was significantly
lower throughout the brain in autistic individuals compared with
controls. In contrast, the DA transporter binding was significantly
higher in the orbitofrontal cortex of the autistic group, which was
inversely correlated with 5-HT transporter binding. Interestingly,
similar to the Murphy study, the reduction in 5-HT transporter
binding in the anterior and posterior cingulate cortices was associ-
ated with the impairment of social cognition in the autistic subjects,
as measured by the faux pas task which measures the integration
of both cognitive and affective ToM abilities. The inverse rela-
tionship between DA and 5-HT highlights the synergistic effects
both systems could have on mentalizing and social cognition
skills.
Psychopharmacological interventions, particularly those that
modify 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 patients
with schizophrenia compared to controls. Three groups were on
one of the following atypical antipsychotics: olanzapine, cloza-
pine or risperidone. The fourth group consisted of patients who
received typical antipsychotics such as fluphenazine, flupenthixol
and haloperidol. In the groups receiving olanzapine or clozap-
ine treatment, ToM functioning improved to levels comparable to
normal controls after at least 4 months, but not in those treated with
2978 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984
risperidone or typical antipsychotics. The lack of effect of risperi-
done on ToM functioning echoes the result reported by Mazza
et al. (2003) who found that ToM functioning of schizophrenic
patients receiving risperidone alone did not improve after 3 and
6 months of treatment. Interestingly, however, improvement in
ToM functioning was observed when risperidone was adminis-
tered together with donepezil, an anticholinesterasic drug. Mizrahi,
Korostil, Strakstein, Zipursky, and Kapur (2007) also examined
the effect of antipsychotic treatment on ToM functioning of 17
drug-free patients with first-episode psychosis over a period of
six weeks. Sixteen patients were treated with clozapine (n = 2),
olanzapine (n = 7) or risperidone (n = 7), and one with the typical
antipsychotic loxapine. While the relative contribution of these
drugs is not reported, significant improvement in ToM function-
ing was observed for the group as a whole, especially after the
first two weeks. Improvement in patients’ positive symptoms was
also observed, albeit independent of ToM. Given the evidence for
the lack of effect of risperidone on ToM functioning (Mazza et al.,
2003; Savina & Beninger, 2007), one can speculate that the observed
effect on ToM performance in this group is driven by the patients
receiving clozapine and olanzapine. In all, these studies suggest
that ToM functioning can improve after treatment with clozapine
or 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 on
ToM abnormalities is unknown. However, unlike typical antipsy-
chotics whose primary mode of action is the blockade of D2
receptors, these atypical antipsychotics are characterized by their
ability to bind to multiple DA and 5-HT receptors, and thus their
effect 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 (reviewed
in Meltzer, 2002). This, in turn, facilitates DA transmission in
this region which is necessary to carry out mentalizing activi-
ties (Savina & Beninger, 2007). When compared to clozapine or
olanzapine, the lack of a risperidone effect on ToM functioning
could be attributed to attenuated DA release within the mPFC
(Savina & Beninger, 2007), as well as to any number of factors
such as specific pharmacokinetic properties and ratio of affinity
to 5-HT versus DA receptors (Meltzer, 2002). The observed effect
on ToM functioning after risperidone was administered together
with donepezil (Mazza et al., 2003), can be attributed to the effect
of 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 functioning
in schizophrenia is achieved by stabilizing hyper DAergic activity
through inhibition of cholinergic input to DA neurons. Interest-
ingly, unlike clozapine and olanzapine, risperidone does not have
high affinity to cholinergic receptors (Horacek et al., 2006), which
suggests that modulation of cholinergic–DAergic interactions is an
important 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 ToM
functioning. Specifically, evidence shown here demonstrates not
only that ToM impairment is a frequent consequence in patholo-
gies that impact the integrity of DS system, but also that the DS
system could have a specific role in ToM processing. Drawing on
the 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 that
a disruption of DA/5-HT optimal levels within the PFC could have
direct consequences on our the ability to mentalize.
4. The integration: a neuroanatomical–neurochemical
model of theory of mind
In this section, we present an integrative
neuroanatomical–neurochemical model of ToM, which delin-
eates the neuroanatomical and neurochemical networks involved
in the representation of cognitive and affective mental states
to both self and other. As can be seen in Fig. 3, Panels A and
B respectively represent networks subtending cognitive and
affective ToM. These two networks form the larger mentalizing
network, and share the posterior regions, which include the TPJ,
STS, and PCC/PCun. These regions are involved in representing and
distinguishing self from other mental states whether cognitive or
affective. The process involved in the distinction between self or
other mental states is modulated by the reorienting functions of
the ventral and dorsal attentional systems (not shown here; but
see Section 2.2.1; Fig. 2).
Panel A, which represents the network for self–other cognitive
ToM, can be divided into three main components. The first is
the DS system, which is comprised of the nigrostriatal pathway
emanating from the substantia nigra pars compacta (SNc) and
the serotonergic pathway emanating from the dorsal raphe
nucleus. 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 regions
of the basal ganglia. The third part is comprised of paralimbic
and cortical regions, which is roughly divided into posterior and
anterior regions. Regions of interest within the posterior cortex
are the TPJ, STS, and the PCC/PCun. These posterior regions are
reciprocally connected with anterior regions of the network and
include the dTP, dACC, dMPFC and DLPFC. Within this cognitive
network the dorsal striatum receives inputs from cortical and
limbic–paralimbic regions, overlapping with input from the SNc
and 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 back
to paralimbic and cortical regions.
Panel B, on the other hand, which represents the network for
self–other affective ToM, is also comprised of three main compo-
nents. The first is the DS system, which involves the mesolimbic
and mesocortical pathways emanating from the ventral tegmen-
tal area (VTA), as well as the serotonergic pathways emanating
from the dorsal and medial raphe nuclei. The second is the ven-
tral striatum, which is comprised of the nucleus accumbens as
well as the limbic loop passing through the ventral pallidum and
the thalamus. The input of this system to the thalamus is modu-
lated by the direct and indirect pathways (not shown). The third
part is comprised of limbic–paralimbic and cortical regions. Here
the 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, vMPFC
and the ILFC. Within this affective network, the ventral striatum
receives inputs from cortical and limbic–paralimbic regions, over-
lapping with input from the VTA and the dorsal and medial raphe
nuclei. This information under the modulatory influence of DA and
5-HT is funneled through the limbic loop (or the ventral pallidal
system), through the thalamus, back to paralimbic and cortical
regions.
The function of the DS system within the ToM network is two-
fold: (1) to regulate the functionality of fronto-striatal circuits and
thus the representation of cognitive and affective mental states,
and (2) to maintain a fine balance between cognitive stability
and cognitive flexibility, and as such to monitor the maintenance
and updating of these mental representations. The spatiotempo-
 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984
Panel A: Self-Other Cognitive ToM
DLPFC
PCC/PCun
(self & other)
DMPFC (self)
TPJ
(self &
other) STS
(other)
dACC
dTP
Thalamus
GPe
Dorsal
Striatum
(Put/Caud)
S
T
N
SNc-A9 GPi
SNr
DRN
Serotonergic Projections
Fig. 3. Schematic representation of serotonin–dopamine interaction within the cognitive and affective mentalizing networks of self and other. ACC = anterior cingulate
cortex; DMPFC = dorsal medial prefrontal cortex; DRN = dorsal raphe nucleus; DLPFC = dorsolateral prefrontal cortex; GPi = globus pallidus interna; GPe = globus pallidus
externa; 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 Parkinson’s
disease (PD) (Poletti, Enrici, Bonuccelli, & Adenzato, 2011), can
be a viable framework to test how disruption of the DS system,
and particularly DA, affects the ability to represent cognitive and
affective mental states. In the early stages of PD, death of DAer-
gic neurons primarily in the substantia nigra causes disruptions
to the associative loop (PFC–head of the caudate–GPi/SNr–ventral
anterior thalamic nuclei–cortex) (Panel A in our model), which
is involved in executive, behavioral and cognitive functions (Di
Martino 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 involved
in cognitive functioning (Seamans & Yang, 2004), is less severely
affected in these early stages, but a rate of 50% depletion of DA
neurons has been reported in this system at later stages of the
disease (Owen, 2004). As the disease progresses, a 36–55% of
VTA 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 to
the limbic loop (medial prefrontal and orbitofrontal cortex–ventral
striatum–ventral pallidum–mediodorsal thalamic nuclei–cortex)
which is involved, among other things, in emotional, motivational
and reward seeking functions (Schultz, 2002).
As noted earlier, PD results in significant ToM deficits (for a
recent review see Poletti et al., 2011), with early-stage patients
performing poorly only on cognitive ToM (Péron et al., 2009; Roca
et al., 2010), and advance-stage patients performing poorly on both
cognitive and affective ToM (Bodden, Mollenhauer, et al., 2010).
2979
Panel B: Self-Other Affective ToM
ILFC
vMPFC/ PCC/PCun
(self & other)
OFC (self)
TPJ
(self &
other) STS
(other)
vACC/vTP
Amygdala
Thalamus
Ventral
Striatum
(NAc)
VP
VTA-
A10
DRN
MRN
Dopaminergic Projections
Accordingly, the disruption of the associative loop in the early
stages of the disease could account for the patients’ poor perfor-
mance in cognitive ToM, and a disruption of the mesocortical and
mesolimbic pathways at the more advance stages of the disease
could account for the poor performance in affective ToM (Bodden,
Dodel, & Kalbe, 2010). One could also predict that a disruption of
the mesocortical pathway at the later stages of the disease could
result in a more severe form of cognitive ToM functioning given
its 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 severe
ToM impairments in PD patients would provide strong evidence for
the 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-like
cognitive deficits or lesions (Frank & O’Reilly, 2006).
The DS system can also be utilized to understand abnormalities
associated with the application (or deployment) of mental states.
This execution/application component has been placed along a
continuum (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 patients
with Asperger’s syndrome (e.g., Bowler, 1992; Senju, Southgate,
White, & Frith, 2009), to a state where mental states are applied
uncontrollably, resulting in hypermentalism or overattribution of
mental 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-
2980 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984

Table 2 levels of cortical 5-HT2A receptors, including within the DLPFC, in

Pathologies and disorders that impact theory of mind functioning.
the pathological progression of schizophrenia (Dean, 2003), which
Pathologies and disorders Selected references as noted above is implicated in the application of represented men-
Psychiatric and personality disorders tal states.
Autism Baron-Cohen, Leslie, and On the other hand, overattribution of mental states in paranoid
Uta (1985) schizophrenia can result from either a system that makes errors of
Asperger’s syndrome Senju et al. (2009) commission because it does not work properly, or from a system
Anorexia Nervosa Russell, Schmidt, Doherty,
that makes errors of commission because it is over-active. Overat-
Young, and Tchanturia
(2009) tributions resulting from a system that does not work properly can
Bipolar Disorder Kerr, Dunbar, and Bentall be the result of a malfunction in DA signaling of prediction errors.
(2003) This is supported by evidence from an fMRI study showing that
Psychopathy and Antipersonality Disorders Shamay-Tsoory, Harari,
disruption of prediction-error signaling in the frontal cortex was
Aharon-Peretz, and
Levkovitz (2010) significantly related to the individual’s propensity to form delu-
Schizophrenia Corcoran, Mercer, and Frith sions (Corlett et al., 2007). Alternatively, it can be hypothesized
(1995), Brüne (2005) that overattributions can result from an overactive system char-
Social Anxiety Sripada et al. (2009) acterized by a decreased cortical tonic DA activity and increased
Basal ganglia disorders
striatal phasic DA activity. In this context, a hypofunction of PFC DA
Attention Deficit Hyperactivity Disorder Sodian, Hülsken, and
Thoermer (2003) would lead to the formation of unstable representations that are
Huntington’s Disease Snowden et al. (2003) open to interference by distracters, by inducing a state of hyper-
Parkinson’s disease Mengelberg and Siegert sensitivity of the DA system to the phasic release as well as by
(2003)
disinhibition of striatal DA (Bilder, Volavka, Lachman, & Grace,
Genetic disorders
22q11.2 deletion syndrome Bassett et al. (2007)
2004). Such disruption can increase the salience of internal and
Down’s Syndrome Cornish et al. (2005) external stimuli, making it difficult to control the formation of men-
Fragile X Syndrome (Martin-Bell Syndrome) Cornish et al. (2005) tal states. This in fact could explain the overactivity or lack of signal
Phenylketonuria (PKU) Dennis et al. (1999) drop in the paracingulate cortex (ParCC) and the TPJ which was
Prader–Willi Syndrome Koenig, Klin, and Schultz
associated with overattribution of mental states in patients with
(2004)
Sotos Syndrome (Cerebral Gigantism) Saddington, Oliver, Cole, paranoid schizophrenia (Walter et al., 2009). Studies that inves-
and Apperly (2010) tigate interindividual variation in the transporters and enzymes
Spinocerebellar Ataxia Garrard, Martin, Giunti, involved in the termination of DA release and activity could pro-
and Cipolotti (2008)
vide evidence for the effect of tonic and phasic modes of DA on one’s
Turner Syndrome (Ullrich-Turner Syndrome) Lawrence et al. (2007)
William’s Syndrome Tager-Flusberg and
ability to apply mental states (Yacubian & Büchel, 2009). The COMT
Sullivan (2000) gene and the relation of its polymorphisms to DA’s tonic and phasic
Neurological disorders modes of release in the PFC would be a profitable direction to pur-
Frontotemporal Dementia Snowden et al. (2003) sue in this regard (Bilder et al., 2004; Yavich, Forsberg, Karayiorgou,
Alzheimer’s Disease Zaitchik, Koff, Brownell,
Gogos, & Männistö, 2007).
Winner, and Albert (2004)
Multiple Sclerosis (MS) Banati et al. (2010)
Traumatic Brain Injury (TBI) Bibby and McDonald 5. Concluding remarks
(2005)
ToM functioning is compromised in a wide range of psychiatric,
neurological and genetic pathologies such as autism, schizophre-
ing mental states in patients with Asperger’s syndrome, on the nia and Parkinson’s disease. In fact, ToM impairment, of various
one hand, and the overattribution of mental states characteristic severities, and across the lifespan, has been linked to more than
of paranoid schizophrenia, on the other hand, can be explained in twenty pathologies (see Table 2). These pathologies can disrupt the
terms of the tonic and phasic mode of release of the DS system in mentalizing network at the neuroanatomical or neurochemical lev-
the PFC of these patients. Here we would predict that these patients els or at the genetic level, which could cause a malfunction in the
would exhibit diametrical profiles—Asperger’s patients would typ- DS system or compromise the development of neuroanatomical
ically have abnormally tonic PFC, and the paranoid patients with targets within the network. Though current mentalizing tests still
schizophrenia would have abnormally phasic PFC. Specifically, the promote a dichotomous stance of presence or absence of ToM abil-
application deficit in Asperger’s syndrome can be explained by ities, it is now widely accepted that ToM cannot be all-or-nothing
increased tonic and diminished phasic DA activity in the PFC of capacity (Abu-Akel & Bailey, 2000). Our model predicts that a dis-
these individuals, which would prevent them from updating and ruption within the network, at the neurochemical or anatomical
forming new representations in a fashion commensurate with real- levels, is more likely to lead to varying degrees of ToM impairment.
time interactions. It has been shown that 5-HT receptors affect tonic Damage to posterior regions and particularly the TPJ could lead to
and phasic release of DA (Remington, 2008), and there is strong a loss of one’s ability to represent mental states, and damage to
evidence that 5-HT2A receptors in the medial PFC potentiate meso- the ventral and dorsal attentional systems could lead to a malfunc-
cortical phasic DA release (Pehek, McFarlane, Maguschak, Price, & tion in one’s ability to distinguish between self and other mental
Pluto, 2001; Pehek, Nocjar, Roth, Byrd, & Mabrouk, 2006). Inter- states. Moreover, a disruption to lateral PFC structures within the
estingly, individuals with Asperger’s syndrome have a significant mentalizing network, and particularly to the mode of release of
reduction in cortical 5-HT2A receptor binding in the temporal, cin- both 5-HT and DA, could lead to a malfunction in the ability to
gulate and frontal cortices (Murphy et al., 2006). The diminished control the application of represented mental states. Accordingly,
levels of cortical 5-HT2A receptors in individuals with Asperger’s our model supports the evaluation of ToM functionality at three
syndrome could affect phasic DA activity, and consequently their levels of analyses which include the representation, attribution
ability to update and form new mental representation. We would and execution/application of mental states. The representational
expect a similar neurochemical profile in patients with negative aspect pertains to the individual’s ability to represent cognitive
schizophrenia who also suffer from an application deficit of ToM and affective ToM; the attributional or agentive aspect refers to the
(Bowler, 1992). Indeed, there is evidence implicating diminished individual’s ability to attribute mental states to self or other; and
 A. Abu-Akel, S. Shamay-Tsoory / Neuropsychologia 49 (2011) 2971–2984
the execution/application aspect refers to the manner in which the
individual applies mental states (e.g., overattribution).
By conceptualizing ToM in terms of its component processes and
brain circuitry, our neuroanatomical–neurochemical model, in its
current form, substantially improves current neurobiological mod-
els of ToM, in that it can account for a broader range of pathologies
affecting ToM processing, as well as the type of ToM impairments
present within and across pathologies. As such, it provides a suit-
able context where intra- and interindividual differences in ToM
abilities can be examined. Understanding the mechanisms govern-
ing DA and 5-HT modes of release is one crucial aspect that could
help explain intra- and inter-individual differences in represent-
ing and attributing mental states within and across pathologies.
Another profitable line of research would involve the effect of
certain genes on altering the functionality and connectivity of
neuroanatomical targets within the mentalizing network as has
been shown in healthy risk allele carriers of the polymorphism
rs1344706 in the gene ZNF804A (Walter et al., 2010). Moreover,
while our model largely reflects mentalizing networks in the adult
brain, it nonetheless provides a suitable framework for examin-
ing the development of ToM. Research that considers changes in
the functionality of the DS system and/or ToM neuronal structures
would greatly enhance our understanding of intraindividual differ-
ences in the functionality of ToM over the entire lifespan.
Moreover, the critical contribution of the DS system should
not obscure the role other transmitters could have in mediating
ToM functioning. A disruption to the DS system can be either pri-
mary or secondary. Therefore, there is an obvious need to study
the function of other neurotransmitters such as acetylcholine, glu-
tamate and GABA, as well as the role of neurohormones such as
oxytocin in ToM. Interestingly, it has recently been shown that
perspective-taking of mental states may be mediated by gluta-
matergic projections within the DLPFC (Montag, Schubert, Heinz,
& Gallinat, 2008), and that intranasal administration of oxytocin to
healthy controls improves their ability to infer the mental state of
others (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007). Ulti-
mately, we envision that the neurochemistry of ToM would involve
a number of transmitters that are inextricably linked, and uncov-
ering the cascading effects of these transmitters would be crucial
to understanding their role in mediating ToM functioning (Skuse &
Gallagher, 2009).
To conclude, we have presented a componential model that
involves a profuse network of functionally related cortical and sub-
cortical regions sustained by a complex interplay of DA and 5-HT
that subserves one’s ability to represent, attribute and apply men-
tal states. While the model will inevitably be revised with new
advances, the model, in its current form, provides a fertile ground
for research concerned with the neurobiological bases of ToM, as
well as with the understanding of pathologies that variably dis-
rupt one’s ability to represent, attribute and apply cognitive and
affective mental states.
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