cortex 46 (2010) 769–780
available at www.sciencedirect.com
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Research report
Dissociating cognitive from affective theory of mind:
A TMS study
Elke Kalbea,b,*, Marius Schlegelb, Alexander T. Sackc, Dennis A. Nowaka,
Manuel Dafotakisa,b, Christopher Bangardd, Matthias Brande,f,
Simone Shamay-Tsooryg, Oezguer A. Onura,b and Josef Kesslerb
a
Institute of Neuroscience and Medicine (INM-3), Cognitive Neurology Section, Research Centre Juelich, Germany
Department of Neurology, University Hospital of Cologne, Germany
c
Department of Cognitive Neuroscience, Faculty of Psychology, Maastricht University, The Netherlands
d
Department of Radiology, University Hospital of Cologne, Germany
e
Department of General Psychology, Cognition, University of Duisburg-Essen, Germany
f
Erwin L. Hahn Institute for Magnetic Resonance Imaging, Essen, Germany
g
Department of Psychology and Brain and Behavior Center, University of Haifa, Israel
b
article info
abstract
Article history:
Introduction: ‘‘Theory of Mind’’ (ToM), i.e., the ability to infer other persons’ mental states, is
Received 5 September 2008
a key function of social cognition. It is increasingly recognized to form a multidimensional
Reviewed 9 December 2008
construct. One differentiation that has been proposed is that between cognitive and
Revised 6 April 2009
affective ToM, whose neural correlates remain to be identified. We aimed to ascertain the
Accepted 9 July 2009
possible role of the right dorsolateral prefrontal cortex (DLPFC) for cognitive ToM as
Action editor Elena Rusconi
opposed to affective ToM processes.
Published online 29 July 2009
Methods: 1 Hz repetitive transcranial magnetic stimulation (rTMS) was used to interfere
offline with cortical function of the right DLPFC in healthy male subjects who subsequently
Keywords:
had to perform a computerized task assessing cognitive and affective ToM.
Theory of Mind
Results: RTMS over the right DLPFC induced a selective effect on cognitive but not affective
Transcranial magnetic stimulation
ToM. More specifically, a significant acceleration of reaction times in cognitive ToM
Dorsolateral prefrontal cortex
compared to affective ToM and control items was observed in the experimental (right
5 cm rule
DLPFC) compared to the control (vertex) rTMS stimulation condition.
Conclusions: Our findings provide evidence for the functional independence of cognitive
from affective ToM. Furthermore, they point to an important role of the right DLPFC within
neural networks mediating cognitive ToM. Possible underlying mechanisms of the acceleration of cognitive ToM processing under rTMS are discussed.
ª 2009 Elsevier Srl. All rights reserved.
* Corresponding author. Institute of Neuroscience and Medicine (INM-3), Cognitive Neurology Section, Research Center Jülich,
Leo-Brandt-Str. 5, D-52425 Juelich, Germany.
E-mail address: [email protected] (E. Kalbe).
0010-9452/$ – see front matter ª 2009 Elsevier Srl. All rights reserved.
doi:10.1016/j.cortex.2009.07.010
770
1.
cortex 46 (2010) 769–780
Introduction
Theory of mind (ToM) is defined as the ability to attribute
mental states, such as desires, intentions and beliefs, to other
people in order to explain and predict their behavior (Frith and
Frith, 1999). It constitutes a central aspect of social cognition
which is regarded to be a highly specialized, human-specific
skill that forms a crucial prerequisite to function in social
groups (Adolphs, 2003a, 2003c; Herrmann et al., 2007). ToM is
commonly regarded to be mediated by a complex neural
network including the medial prefrontal cortex (mPFC), the
superior temporal sulcus region, the temporal pole (Frith and
Frith, 2003; Siegal and Varley, 2002), and the amygdalae
(Adolphs, 2003b). Many lesion studies (e.g., Eslinger et al.,
2007; Griffin et al., 2006; Happé et al., 1999; Siegal et al., 1996;
Stuss et al., 2001; Winner et al., 1998) and functional imaging
studies (e.g., Brunet et al., 2000; Gallagher et al., 2000; Sommer
et al., 2007; Vogeley et al., 2001) suggest that ToM and other
social cognitive functions are mediated predominantly by
a network lateralized to the right hemisphere, although
evidence for bilateral (e.g., Völlm et al., 2006; Hynes et al., 2006)
and left-sided involvement also exists (e.g., Baron-Cohen
et al., 1999; Calarge et al., 2003; Channon and Crawford, 2000;
Fletcher et al., 1995; Goel et al., 1995), probably depending on
task type and modality (Kobayashi et al., 2007).
Recent social cognitive neuroscience has begun to define
subcomponents of the complex concept we refer to as ToM.
One important differentiation is that of ‘affective’ versus
‘cognitive’ ToM, although different terms have been used for
these and related concepts (overview in Baron-Cohen and
Wheelwright, 2004; Kalbe et al., 2007). Whereas cognitive ToM,
for example assessed with so-called false belief tasks, is
thought to require cognitive understanding of the difference
between the speaker’s knowledge and that of the listener
(knowledge about beliefs), affective ToM, for example tested
with faux pas and irony tasks, is supposed to require in
addition an empathic appreciation of the listener’s emotional
state (knowledge about emotions) (Shamay-Tsoory et al.,
2006). Brothers (1995, 1997) had postulated a unitary social
‘editor’ which is specialized for processing others’
social intentions but which could not be dissociated into ‘hot’
social cognition (i.e., processing others’ emotional expressions) and ‘cold’ social cognition (i.e., attributing and processing cognitive mental states such as beliefs). However,
Eslinger et al. (1996) reported a dissociation between affective
and cognitive aspects of ‘empathy’ in brain damaged patients.
Furthermore, Blair (2005) and Blair and Cipolotti (2000) argued
that divergent results concerning ToM dysfunctions in sociopathy may be attributed to a selective deterioration of affective social cognition (‘emotional empathy’), while individuals
with autism show more difficulties with cognitive than with
emotional empathy. Recently, Shamay-Tsoory and colleagues
found selective deficits of affective as opposed to cognitive
ToM in various patients groups (Shamay-Tsoory and AharonPeretz, 2007; Shamay-Tsoory et al., 2006, 2005).
Already Eslinger (1998) suggested that different regions in
the prefrontal cortex may be relevant for these distinct functions, with a dorsolateral prefrontal cortex (DLPFC) system
mediating cognitive empathy and the orbitofrontal cortex
mediating affective empathy. Shamay-Tsoory et al. (2005)
confirmed the special role of the ventromedial prefrontal
cortex (VMPFC) in processing affective ToM and argued that
cognitive ToM may rather involve both the VMPFC and dorsal
parts of the prefrontal cortex (Shamay-Tsoory and AharonPeretz, 2007). Further confirmation for partially differential
mechanisms in processing affective and cognitive ToM was
recently provided by functional magnetic resonance imaging
(fMRI) studies (Hynes et al., 2006). These studies underline the
particular role of medial and orbital PFC for affective
perspective taking and show involvement of dorsolateral
prefrontal structures for cognitive ToM. Kobayashi et al. (2007)
and Sommer et al. (2007) found involvement especially of the
right-hemispheric DLPFC in false belief tasks (which can be
categorized as cognitive ToM tasks).
In summary, research so far (a) suggests a distinction
between affective and cognitive ToM functions and (b) point to
at least partly different neural correlates mediating these two
subcomponents. However, while the role of the VMPFC for
affective ToM is well documented, neural substrates of
cognitive ToM are less well defined but may include the
DLPFC.
On the basis of the aforementioned considerations, we
aimed to further examine the dissociation of cognitive and
affective ToM processes. We tried to elucidate neural
correlates of cognitive as opposed to affective ToM and,
more specifically, to investigate the functional relevance of
the DLPFC for cognitive ToM performance. For this purpose,
we applied 1-Hz repetitive transcranial magnetic stimulation (rTMS) to the DLPFC of 28 male right-handed healthy
subjects prior to the performance of a computer-based ToM
task that has previously been used to differentially assess
cognitive versus affective ToM (Shamay-Tsoory and
Aharon-Peretz, 2007). Although functional imaging studies
have shown somewhat contradictory results regarding laterality of ToM functions (see above) we decided to perform
rTMS over the right DLPFC for the following reasons: (i) We
used the ‘‘Yoni’’ paradigm introduced by Shamay-Tsoory
and Aharon-Peretz (2007) in which ToM has to be inferred
on the basis of eye gaze and facial expression. According to
Sabbagh (2004), a right-hemispheric mechanism mediates
the decoding of mental states based on immediate information, such as eye expression, while a left-hemispheric
network is responsible for complex reasoning about mental
states. It can be speculated that the right-hemispheric
decoding system is utilized when performing the Yoni task
(Shamay-Tsoory and Aharon-Peretz, 2007). (ii) Executive
functions have been conceptualized as a ‘‘co-opted’’ system
for ToM processing (Siegal and Varley, 2002), and recent
functional imaging research points to the central role of the
right DLPFC in executive working memory operations and
cognitive control functions (Lie et al., 2006).
TMS is a well-established tool for inducing transient
changes in brain activity non-invasively in conscious human
volunteers. Over the past couple of years, this ability of
actively interfering with neural processing during behavioral
performance has been increasingly used for the investigation
of causal brain-behavior relations in higher cognitive functions (Pascual-Leone et al., 2000; Sack and Linden, 2003). RTMS
has been applied to different areas within prefrontal cortex in
cortex 46 (2010) 769–780
order to successfully interfere with higher cognitive functions
such as visual (Mottaghy et al., 2002; Oliveri et al., 2001) and
spatial (Koch et al., 2005) working memory, verbal and
nonverbal memory encoding (Floel et al., 2004), divided
attention (Wagner et al., 2006), decision making (van’t Wout
et al., 2005), or the implementation of fairness-related
behavior (Knoch et al., 2006a, 2006b). RTMS has been used in
few studies to examine the sensorimotor side of empathy for
pain (Avenanti et al., 2005, 2009). Only one rTMS study
specifically addressed neural correlates of ToM using rTMS,
finding both dorsolateral and temporo-parietal involvement
(Costa et al., 2008). However, no differentiation was made
between cognitive and affective ToM.
For our study, we hypothesized dissociable effects of rTMS
over the right DLPFC on ToM. More specifically, on the basis of
the assumption that the DLPFC is involved in the neural
network which mediates cognitive but not affective ToM, we
expected a selective effect of rTMS over the right DLPFC on
cognitive but not affective ToM processes.
2.
Methods
2.1.
Sample
Twenty-eight male, right-handed subjects (mean age: 24.0,
standard deviation – SD: 2.7) without neurological or psychiatric history were included in the study. All subjects had
completed German high school with the highest degree (Abitur) and currently underwent higher university education in
various fields but not psychology. The study protocol was
approved by the local Ethics committee. All subjects signed
informed consent and underwent a medical safety screening
according to international safety guidelines for the use of TMS
(Wassermann, 1998). Cognitive dysfunction was excluded
with the cognitive screening instrument DemTect (Kalbe et al.,
2004; Kessler et al., 2000), subtest 4 (reasoning) of the German
intelligence test battery ‘‘Leistungsprüfsystem’’ (LPS 4, Horn,
1983), and the Trail Making Test A and B (TMT, Reitan, 1979;
Tombaugh, 2004). Mean group scores were 17.4 (SD: 1.1) out of
18 points in the DemTect, C-scores of 7.3 (SD: 1.5) for the LPS 4,
and percentiles of 4.4 (SD: 2.8) and 4.7 (SD: 2.9) for TMT
subtests A and B, respectively.
2.2.
ToM tasks
A German version of the ‘‘reading the mind in the eyes’’ test
(Baron-Cohen et al., 2001) was used as a general measure of
ToM abilities. To measure cognitive and affective ToM in the
TMS experiment we used a German modified version of the
‘‘Yoni’’ task introduced by Shamay-Tsoory et al. (2006). It is
based on a task previously described by Baron-Cohen and
Goodhart (1994) and involves the ability to judge mental states
via analysis of verbal cues, eye gaze, and facial expression. In
each of the 60 items presented on a computer screen, a face
named Yoni is shown in the middle with four coloured
pictures in the corners showing either faces or examples of
a semantic category (e.g., animals, fruits). An incomplete
sentence about what image Yoni is referring to is also presented, and the subject has to judge which of the four stimuli
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in the corners best fills the gap of the sentence. The items can
be subdivided into three types of categories with 20 items
each, that is (i) cognitive ToM (cog), (ii) affective ToM (aff), and
(iii) control physical condition (phy), with ten first order and
ten second order items in each category (Fig. 1). While answers
in the physical condition only require analysis of physical
attributes of the character, choices in the cognitive and
affective ToM items require mental inferences based on verbal
cues (contained in the sentences), eye gaze and/or facial
expression. More specifically, in the first order ToM stimuli
Yoni’s mental state about one of the four images in the
corners has to be inferred: Yoni is thinking of . (cog1, German:
Yoni denkt an.), or Yoni loves . (aff1, German: Yoni mag.),
while in the more complex second order ToM items the four
stimuli in the corners consist of faces, and an inference
regarding the interaction between Yoni’s and the other stimuli’s mental state is necessary. In the second order cognitive
items with the sentence Yoni is thinking of the . that . wants
(cog2, German: Yoni denkt an die., die . will ), both the verbal
and facial cues are neutral. In the second order affective items
with the sentence Yoni loves the . that . loves, (German: Yoni
mag die., die . mag) both cues are affective. The item sets of
all item subcategories are comparable with regard to sentence
complexity and visual complexity.
The task was programmed with the software PRESENTATION. The total task duration was 10 min and 30 sec. All items
were presented in randomized order for a maximum of 10 sec
during which the subjects had to answer by tapping a button
on the square number keyboard on the right side of the
console. The position of the answer buttons (1, 7, 9, 3) corresponded to the positions of the four stimuli in the corners of
the screen. As soon as subjects answered, a plain white screen
was shown until the end of the 10 sec time interval. Between
these fixed time intervals a black fixation cross on a white
screen was presented for .5 sec. In order to ensure comparability of reaction times (RTs), subjects always had to use the
same finger (right middle or index finger) to respond and
return to the starting position on button 5 in the middle of the
number keyboard after each item. For all items, RTs and
accuracy were registered.
Before rTMS stimulation and administration of the real
test, all subjects received an introduction to the Yoni task with
four explaining slides, and a training that resembled the test
but with only 21 items (7 cognitive, 7 affective, and 7 physical)
not included in the test.
2.3.
Magnetic resonance imaging (MRI) localisation of
rTMS target site
Each participant underwent a high resolution whole brain
anatomical MRI scan performed on a whole body 1.5 T
scanner (Achieva 1.5, Philips Medicine Systems, Best, the
Netherlands). This allowed for defining the rTMS target site
based on individual anatomical brain structure. To allow exact
positioning of rTMS over the DLPFC, nifedipine capsules were
sticky-taped over two frontal areas navigated prior to MRI
scanning by two common landmark procedures for the
DLPFC. The first of these two procedures determines DLPFC by
detecting the ‘‘motor hot spot’’ for the abductor pollicis brevis
muscle within the hand area of the primary motor cortex by
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cortex 46 (2010) 769–780
Fig. 1 – Item examples of the Yoni ToM task modified from Shamay-Tsoory et al. (2007) used in our TMS experiment.
single pulse TMS and then moving 5 cm anterior and in
parallel to the midsagital line (George et al., 1995). The second
approach uses the international 10–20 system to localize
DLPFC as corresponding to F4 (Herwig et al., 2003) (see Fig. 2).
The exact individual position of the DLPFC was determined at
the junction of BA 8 and BA 9 caudal to the medial section of
the medial frontal gyrus based on the anatomical brain scan of
each participant. This prefrontal section was used because the
dorsal part of the lateral prefrontal cortex is most clearly
related with complex executive functions (Lie et al., 2006;
Miller and Cohen, 2001; Petrides, 2005). Furthermore, this area
has been found to be active during false belief reasoning
which can be conceptualized as a cognitive ToM task (Sommer
et al., 2007).
Fig. 2 – a. Montreal Neurological Institute (MNI) headmesh showing the average locations of the two capsules in Talairach
coordinates. Capsule 1 indicates the stimulation site as determined by the 5 cm rule (x [ 51 ± 6, y [ 34 ± 11, z [ 53 ± 7).
Capsule 2 indicates F4, the stimulation site as determined by the 10–20 system (x [ 46 ± 4, y [ 49 ± 5, z [ 45 ± 6). b.
Anatomical regions shown on segmentations of the MNI template.
cortex 46 (2010) 769–780
In order to navigate the rTMS coil to the exact scalp position for stimulation of the DLPFC, the location of the DLPFC
was calculated in relation to the anatomical locations
proposed by each landmark procedure in three-dimensional
MRI reconstruction. The final actual rTMS could either be
based on one of the locations indicated by the two landmark
procedures or on a different location on the scalp when both
methods failed to overlie the intended cortical target site. The
advantage of this approach is two-fold: first it provides
a precise and individual determination of the MRI-guided
rTMS target site and second it offers an empirical assessment
of the accuracy and validity of the two most commonly used
standard anatomical landmark approaches for localizing BA 9.
2.4.
TMS protocol
A Magstim Rapid2 stimulator (Magstim company, Whitland,
UK), set at 100% of the individual resting motor threshold, and
a 70 mm figure of eight coil were used to deliver a 15 min
single train of 900 1 Hz rTMS at 100% of the motor threshold.
Stimulation parameters were chosen according to the 1 Hz
procedure described by Maeda et al. (2000) which has shown
to result in a 10–15 min reduction of cortical excitability of the
target area. For the detection of the resting motor threshold
the coil was placed tangentially over the right primary motor
cortex at the optimal site for the response of the left first
dorsal interosseus muscle. The resting motor threshold was
defined as the stimulator output intensity that evoked at least
5 out of 10 motor potentials of a minimum amplitude of 100 mV
from the contralateral first dorsal interosseus muscle (mean
was 58.4%, SD: 4%). Each subject received rTMS at two
different locations – one at the cortical target site of right BA9,
and one vertex (Cz) stimulation as control condition (Bestmann et al., 2002; Koch et al., 2006; Pascual-Leone et al., 1996).
Cz was localized according to the international 10–20 system
(Jasper, 1958). Concerning coil orientation, the figure eight coil
was held tangentially to subjects’ cortex in the angle of motor
spot localization. This corresponded roughly to an angle of 45
to midsagital line of the subject’s cortex. Holding the coil was
done manually with both hands during the entire stimulation.
2.5.
Procedure
The study was conducted as a within-subject design, where
half of the subjects were stimulated at the target area first, and
the other half was stimulated at the control site first. The
sequence of stimulation was randomly assigned to each
participant. Subsequently to the first stimulation the subject
was tested with the Yoni ToM task. After a 30 min interstimulation break the second stimulation was conducted after
which again the Yoni ToM task was administered. ToM testing
started immediately after stimulation. To ensure that subjects
were familiar with the task so that simple learning effects
during test administration under rTMS could be avoided, all
subjects received an introduction and training of the Yoni task
prior to the first stimulation. Furthermore, to ensure that
subjects did not occupy themselves with the experiment at
hand during the 30 min inter-stimulation break they had to
administer a filler task during that break. For this purpose,
a questionnaire (personality questionnaire NEO-FFI, Borkenau
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and Ostendorf, 1993) was chosen which was cognitively not
demanding, did not interfere with the experiment, and had an
administration time of approximately 30 min.
2.6.
Statistical analysis
All statistical analyses were carried out using the Statistical
Package for the Social Sciences (SPSS) version 15 for Windows
(Release 15.0.0, Chicago: SPSS Inc.). After checking for statistical normal distribution of the data with the Kolmogorov–
Smirnov-Test, a general linear model repeated measures
analysis on the factors ToM condition (cognitive ToM vs
affective ToM vs control physical items of the Yoni task) and
rTMS stimulation condition (experimental vs control) was
employed. For post-hoc testing paired samples t-tests with
corrected a were used.
3.
Results
3.1.
General ToM abilities
In the ‘reading the mind in the eyes’ task the group reached
a mean of 25.6 (SD ¼ 2.1) points (max. score ¼ 36) indicating
age- and gender-adequate ToM abilities according to the
normative data provided by Baron-Cohen et al. (2001).
3.2.
TMS adverse events
Side effects that occurred due to rTMS stimulation were mild
headache after stimulation in two subjects, eye or nose
twitching during stimulation in 16 subjects and jaw contractions during stimulation in one subject. One candidate subject
suffered a syncope during motor spot localization after
application of 15 single pulses at different output intensities
with a maximum of 70%. After an Electroencephalography
(EEG) recording with normal results the subject was excluded
from further participation.
3.3.
Experimental ToM task ‘‘Yoni’’: RTs
Mean RTs of the main Yoni ToM task categories for the
experimental and control stimulation conditions are indicated in Table 1. Control physical items were processed
significantly faster than cognitive (t ¼ 11.223, df ¼ 27, p < .001)
and affective (t ¼ 11.92, df ¼ 27, p < .001) items in the experimental as well as in the control stimulation condition
(t ¼ 9.987, df ¼ 27, p < .001 for cognitive and t ¼ 8.739, df ¼ 27,
p < .001 for affective items). Affective items were processed
significantly faster than cognitive items in the experimental
condition (t ¼ 11.920, df ¼ 27, p < .001) and in the control
condition (t ¼ 3.700, df ¼ 27, p < .001).
In a general linear model repeated measure analysis, the
factors stimulation site (two stages: experimental vs control)
and item type (three stages: cognitive vs affective vs control),
and the between-subject factor order of condition (experimental – control vs control – experimental) were used, the
latter of which is important to account for possible order
effects. In this analysis, there was a significant main effect for
stimulation site [Pillai’s Trace ¼ .262, F(1,27) ¼ 9.230, p ¼ .005]
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cortex 46 (2010) 769–780
Table 1 – Mean RTs in msec of answers to the categories of the Yoni ToM task in the two rTMS conditions.
Control stimulation
Cognitive items (total)
cog1
cog2
Affective items (total)
aff1
aff2
Physical items (total)
phy1
phy2
Experimental stimulation
Mean RT (ms)
(SD)
Mean RT (ms)
(SD)
2908
1989
3827
2658
2130
3187
1997
1707
2287
(629)
(445)
(936)
(580)
(530)
(699)
(406)
(368)
(486)
2625
1849
3402
2565
2032
3096
1881
1655
2107
(587)
(431)
(801)
(586)
(544)
687
(415)
(370)
(488)
p-value
.001*
.021
.004*
.199
.330
.167
.042
.248
.028
*p < .05
and item category [Pillai’s Trace ¼ .853, F(2,26) ¼ 72.603,
p < .001] and a significant interaction effect between the
factors item category and stimulation site [Pillai’s
Trace ¼ .258, F(2,26) ¼ 4.337, p ¼ .024]. However, neither the
interaction stimulation site with order of condition nor the
interaction item category with order of condition nor the three
way interaction stimulation site with item category with order
of condition were significant [Pillai’s Trace ¼ .128,
F(2,27) ¼ 3.802, p ¼ .062; Pillai’s Trace ¼ .036, F(2,26) ¼ .471,
p ¼ .630; and Pillai’s Trace ¼ .111, F(2,26) ¼ 1.558, p ¼ .230,
respectively]. Thus when stimulated experimentally
compared to control stimulation, subjects differed significantly in their RTs between categories, and order of stimulation did not influence this rTMS effect on ToM performance.
Post-hoc paired samples t-test, with a corrected a of .016
between experimental and control stimulation for the item
categories elicited that only RTs in the cognitive ToM category
differed significantly (t ¼ 3.618, df ¼ 27, p ¼ .001) (Fig. 3).
These significant differences corresponded to a fastening
of RTs in cognitive ToM items in the experimental stimulation
condition. The delta between the two conditions ranged from
23 to 287 msec across individuals. When subcategories were
analyzed (cog1, cog2, aff1, aff2, phy1, phy2, Table 1) with
paired samples t-test and a corrected a of .008 only RTs in the
cog2 category differed significantly (t ¼ 3.171, df ¼ 27,
p ¼ .004) (Fig. 4). For the cog1 category, p was .021.
To analyse whether RTs were stable over the duration of
the task for cognitive ToM items, paired samples t-tests of the
first versus the second half data were performed for each
condition. No significant differences were observed for cog1,
cog 2, and total cognitive ToM items indicating that there were
no learning effects.
Fig. 3 – Reaction time differences control minus
experimental condition for cognitive and affective ToM
items.
Fig. 4 – Reaction time differences control minus
experimental condition for subcategories of cognitive,
affective, and physical items.
3.4.
Experimental ToM task ‘‘Yoni’’: accuracy
There were no incorrect answers from any subject. The mean
number of misses (analyzed for all item categories) was 3.5
(SD ¼ 3.3) in the experimental and 2.8 (SD ¼ 2.9) in the control
condition. Only four out of 28 subjects (14.3%) had no misses
indicating that there was no ceiling effect in performance and
that task difficulty was adequate. A general linear model
repeated measures procedure for misses in the Yoni ToM task
using the factors also included in the RT analysis (i.e., ToM
condition and rTMS stimulation condition) showed no
significant results, even though there was a trend for interaction between the factors stimulation site and item category
[Pillai’s Trace ¼ .188, F(2,26) ¼ 3.009, p ¼ .067]. Remarkably,
within-group comparison of misses in the cog2 items in
cortex 46 (2010) 769–780
control versus experimental condition did not show a significant difference (Wilcoxon test, Z ¼ 1.447, p ¼ .148), indicating
that there was no specific effect in this item subcategory that
might be related to the results of the RT analysis.
4.
Conclusion
The main finding of our study is that rTMS over the right
DLPFC has a selective effect on cognitive but not affective ToM
performance. This result is in concordance with the recently
advanced view that these processes are subcomponents of the
complex concept we refer to as ToM and are at least partially
independent (Blair and Cipolotti, 2000; Eslinger, 1998; Eslinger
et al., 1996). Evidence for a functional dissociability of the
independence of cognitive and affective ToM also comes from
patient studies, which show selective deterioration of affective ToM in patients with ventromedial damage (ShamayTsoory and Aharon-Peretz, 2007; Shamay-Tsoory et al., 2005),
more pronounced dysfunction in affective than in cognitive
ToM in patients with schizophrenia (Shamay-Tsoory et al.,
2006), and also from psychophysiological findings (using skin
conductance responses) in healthy control subjects (Kalbe
et al., 2007). Furthermore, imaging studies have found
partially different networks mediating cognitive and affective
ToM (Hynes et al., 2006; Völlm et al., 2006). Although a side
result of our study, it should be noted in this context that we
found faster RTs for affective than for cognitive ToM items in
both conditions – a finding that is in concordance with ‘‘Yoni’’
results of Shamay-Tsoory and Aharon-Peretz (2007) and also
with behavioral results from a study that used cognitive and
emotional ToM short stories matched in word length (Hynes
et al., 2006). Albeit speculative at this point, the affective items
might be easier than the cognitive items in the Yoni task since
they involve an additional cue for making the decision: a smile
or a frown. This may enhance ToM processing. Alternatively,
the results could also reflect different mechanisms underlying
cognitive and affective ToM. Referring to the two fundamentally different mechanisms that have been proposed to
explain the process of mentalizing, ‘simulation theory’ posits
that other people’s mental states are represented by replicating or mimicking the mental life of the other person and
thus ‘slipping in the other person’s shoes’, while according to
the ‘theory theory’, others’ mental states are modelled rationally by a knowledge system that is independent from one’s
own mental states (Gallese and Goldman, 1998). Instead of
favouring one of these mechanisms, it has been hypothesized
that both of them exist and that cognitive ToM may primarily
represent a cognitive process which relies on ‘theories’ of
mind corresponding to the ‘theory theory’ while simulation
may rather be the underlying mechanism for affective ToM
(Adolphs, 2002; Adolphs et al., 2000; Heims et al., 2004; Kalbe
et al., 2007; Mitchell et al., 2005; Shamay-Tsoory and AharonPeretz, 2007). Shamay-Tsoory et al. (2005) suggest that simulation mechanism is essential at the beginning of the persons’
affective ToM process and is further used for making inferences regarding the other persońs affective mental states.
Affective ToM processing or ‘empathy’ is regarded to rely on
brain structures that develop early in ontogeny including the
limbic system and might thus be mediated by more automatic
775
and direct neural circuits as compared to cognitive mentalizing, that could pose more demands on cognitive resources
(Hynes et al., 2006; Mitchell et al., 2005; Satpute and
Lieberman, 2006; Singer, 2006) – and might thus be faster. In
this context it seems to be relevant to consider the connections
between limbic and prefrontal sections. The amygdala, which
is the key structure in evaluating emotional sensory stimuli
(e.g., Phelps, 2006; Phelps and LeDoux, 2005) is both directly
and indirectly connected with the orbitofrontal/ventromedial
part of the frontal lobe (e.g., Brand and Markowitsch, 2006). In
addition, the amygdala is linked to fast automatic responses
via its connections with hypothalamic nuclei and the brain
stem. Amygdala activation can therefore result in fast autonomic arousal (e.g., measured by skin conductance responses),
which is then perceived by somatosensory cortex. Information
about the emotionality of stimuli can significantly influence
evaluative processes, such as decision making, ToM, and other
complex function (Adolphs, 2001, 2003a, 2003b, 2003c; Bechara
et al., 2003; Brand et al., 2007; Damasio, 1994, 1996). This is
most likely the case due to the aforementioned connections
between amygdala and orbitofrontal cortex which has also
been named ‘‘expanded limbic system’’ (Nauta, 1979). It is
hypothesized that this limbic contribution to higher cognitive
functions, in particular within the field of social cognition and
those tasks that depend upon intuitive processes, is linked to
faster reactions, as the emotional system acts fast, parallel,
associative etc. (c.f.; Kahneman, 2003). This may – at least
partially – explain why we found faster reactions to affective
compared to cognitive ToM items. Taken together our results
corroborate the notion that cognitive and affective ToM are
functionally dissociable processes.
RTMS over the right DLPFC in our study induced an acceleration of RTs in cognitive ToM, not a decrease as might have
been expected. Certainty about the reliability of this finding
comes from the facts that (1) training effects can be excluded,
as all subjects received a training before test administration so
that they were customized to the task, and more importantly,
RTs for cognitive ToM items were stable over the duration of
the task (2) training or order effects on specific task trials or
items can be excluded, as the order of the items within the
Yoni task as well as the order of rTMS stimulation condition
were randomized across subjects, and also given the result
that there were no statistical effects for the factor order of
condition in the general linear model repeated measure
analysis (3) there was a statistically significant interaction
effect between the factors item category (cognitive vs affective
vs control items) and stimulation site (experimental vs
control). This latter effect stems from a significant difference
of RTs only in cognitive items between experimental and
control stimulation. One possible explanation for the fact that
processing of cognitive ToM items was faster after rTMS over
the DLPFC is that our control stimulation has led to decreased
RTs, not vice versa. However, this is unlikely, as rTMS stimulation over the vertex has been used as control stimulation in
numerous studies using a wide variety of paradigms, and to
the knowledge of the authors has not been shown to have any
specific effect on visual exploration (e.g., Nyffeler et al., 2008)
or other functions (Wiener et al., 2010; Viggiano et al., 2008).
Furthermore, a decrease of RTs after vertex stimulation would
not explain the differential effect on cognitive ToM as
776
cortex 46 (2010) 769–780
compared to the affective ToM and control items. Thus the
interpretation that RTs in response to cognitive ToM items
were fastened after rTMS over the right DLPFC seems valid.
One possible explanation for this result is that our stimulation
protocol could have had a facilitating effect when applied over
the right DLPFC and not an inhibitory one when applied over
the primary motor cortex (Maeda et al., 2000). For example,
Sack and Linden (2003) point out that one particular rTMS
protocol can have either inhibitory or facilitatory effects
depending on the cortical area where it is applied and the
behavioral task to be tested. In addition, stimulation characteristics, such as intensity, distribution, depth of penetration,
and accuracy, depend on factors such as scalp-cortex distance
or extent and conductivity of the stimulated tissue. In support
of these considerations, Dräger and co-workers found that
specific language (namely picture-word verification) function
was inhibited when a 1 Hz protocol with 600 pulses was conducted on Wernicke’s area and facilitated when it was used on
Broca’s area (Dräger et al., 2004). Despite these constraints,
Machii et al. (2006) in their recent review come to the
conclusion that deducing stimulation parameters which are
valid for motor areas and applying them to the study of
cognitive function is the standard procedure which has shown
to produce coherent results. Thus, although general questions
remain regarding the effect of our specific rTMS protocol, it is
definite that our stimulation protocol interfered with normal
processing of ToM in the DLPFC.
Assuming that our rTMS protocol inhibited excitability of
the right DLPFC, the fastening of RTs during the cognitive ToM
tasks suggest that normal functioning of the right DLPFC is
detrimental for performance in cognitive ToM processing.
Thus inhibition of the right DLPFC must have facilitated other
brain regions relevant for task performance, possibly by the
mechanism of ‘‘transcallosal inhibition’’. It is known that low
frequency rTMS has been shown to reduce transcallosal
inhibition within the motor system and may facilitate corticospinal excitability of the not stimulated motor cortex (Gilio
et al., 2003; Pal et al., 2005). 1 Hz rTMS over the primary motor
cortex facilitates function of the contralateral homologue by
reduction of transcallosal inhibition (Kobayashi et al., 2004;
Takeuchi et al., 2005). Comparable effects have also been
demonstrated for higher cortical functions. For example,
hampering function of the relevant left-hemispheric language
areas, either by stroke or after rTMS, causes enhanced neural
activation of the contralateral homotopic areas (Heiss et al.,
2002; Thiel et al., 2006). Also, the processing of specific
emotions such as anger or anxiety known to be lateralized can
be modulated by rTMS over the right PFC (van Honk et al.,
2002). Finally, low frequency rTMS stimulation of the right
frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex in patients with depression
(Isenberg et al., 2005).
In context of the task under discussion inhibition of the
right DLPFC by 1 Hz rTMS may have released left DLPFC from
transcallosal inhibition and resulted in enhanced function
within this area. This would point to a left rather than a righthemispheric DLPFC relevance for cognitive ToM. There is
evidence for involvement of the left PFC in ToM processing
(e.g., Baron-Cohen et al., 1999; Calarge et al., 2003; Channon
and Crawford, 2000; Fletcher et al., 1995; Gallagher et al., 2000;
Goel et al., 1995). Sabbagh (2004) suggested two anatomically
and functionally different ToM networks in the human cortex:
a right-hemispheric one, especially in the orbitofrontal and
medial temporal cortex, mediating ‘decoding mental states
from outside cues’, and a left-hemispheric network, especially
in the left medial frontal cortex, mediating ‘reasoning about
those mental states’. Left-sided cortical involvement in ToM
processing also includes lateral prefrontal structures (e.g.,
Baron-Cohen et al., 1999; Channon and Crawford, 2000; Shamay-Tsoory and Aharon-Peretz, 2007). In line with these
results, Satpute and Lieberman (2006) recently proposed the
framework of a ‘reflexive’ system for automatic social
perception (which relies on limbic/ventromedial and temporal
structures and is needed to code the trait and evaluative
implications of an observed behavior), as opposed to
a ‘reflective’ system for controlled social perception. The latter
system is supposed to be mediated, among other structures,
partly by the lateral prefrontal cortex, which is known to
mediate reasoning and logic, analogy, mathematical problemsolving as well as working memory and other executive
functions. Satpute and Lieberman (2006) propose that this
reflective system is involved when ‘symbolic computation’ is
necessary in a ToM task. More precisely, the system could
provide a corrective process of automatically generated
hypothesis about interpretations of behavior (mediated by
other structures), i.e., a ‘selection process’ (see also Leslie
et al., 2004, 2005), and is needed where multiple mental
perspectives have to be considered, self knowledge inhibited,
and beliefs considered in relation to subsequent mental states
(Bull et al., 2007).
In line with the aforementioned arguments one may
speculate that rTMS induced inhibition of right DLPFC functioning may cause stronger involvement of emotional reactions to cognitive tasks compared to intact right DLPFC
functions. The DLPFC is connected with other prefrontal areas
(ventrolateral and orbitofrontal sections) and basal ganglia,
via thalamic nuclei (Alexander and Crutcher, 1990; Alexander
et al., 1990; Barbas, 2000; Brand and Markowitsch, 2008) and
DLPFC functioning can inhibit orbitofrontal and limbic activation involved in social cognition and emotion processing
(for a discussion of disinhibition and prefrontal cortex see
Zamboni et al., 2008). Accordingly an inhibition of the right
DLPFC may result in a disinhibition of orbitofrontal functioning that then facilitates solving cognitive ToM items in
a more emotional and therefore faster way than usually done,
at least as long as the items are not too complex and do not
necessarily involve an executive component.
Although ToM and executive functions can be deteriorated
independently and thus seem dissociable (e.g., Fine et al.,
2001; Lough et al., 2001; Pickup, 2008; Rowe et al., 2001; Stone
et al., 1998), an association between the two has frequently
been shown (e.g., Channon and Crawford, 2000; Kobayashi
et al., 2007; Perner and Lang, 1999; Perner et al., 2002; Sabbagh
et al., 2006). It appears as if executive functions serve as a ‘coopted’ system (next to a ‘core’ ToM system), which is necessary to succeed at least in particular variants of ToM tasks
(Siegal and Varley, 2002). Cognitive ToM tasks which require
attributions about the propositional attitudes such as belief,
knowledge, intentions, are more likely to fall into this category
than affective ToM tasks that are associated with the ability to
cortex 46 (2010) 769–780
empathize (Shamay-Tsoory et al., 2002) and may involve
implicit affect sharing (Singer, 2006) through simulation processing (Mitchell et al., 2005). We thus conclude that the
DLPFC involvement in our study reflects contributions of
executive functions in solving cognitive ToM items as
assessed in the Yoni task. However, when right DLPFC functioning is reduced (via rTMS), integrity of the left DLPFC seems
to be sufficient to deal with the executive component of the
task. In addition, it might be that – in this case – an additional
contribution of limbic structures (i.e., the right orbitofrontal
section), which results from less inhibition by the right DLPFC,
may facilitate solving the cognitive ToM items.
In summary, our study provides empirical evidence for the
functional independence of cognitive and affective ToM.
Furthermore, it points to an important role of the DLPFC
within neural networks mediating cognitive ToM. However,
the exact role of this region within networks mediating ToM
needs to be specified. Future studies are warranted to assess
functional and effective brain connectivity between left and
right DLPFC during the execution of cognitive versus affective
ToM tasks. More concretely, fMRI connectivity studies (Friston
et al., 2003; Goebel et al., 2003) might reveal the exact neurocomputational mechanisms within bilateral DLPFC during
cognitive versus affective ToM, on the bases of which optimized rTMS protocols could be applied over left versus right
DLPFC in order to further elicit the relevance of this region for
cognitive ToM processes.
Acknowledgements
We thank Michelle Moerel, Faculty of Psychology, Maastricht
University, for support in graphical image processing, and
Ingo Meister and Mitra Ameli, Department of Neurology,
University of Cologne, for assistance in MRI and rTMS.
Furthermore, the work of the first author was funded in part
by the EC-FP6-project DiMI, LSHBCT-2005-512146.
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