Self Responses along Cingulate Cortex Reveal
Quantitative Neural Phenotype
for High-Functioning Autism
Pearl H. Chiu,1,2,3,5M. Amin Kayali,1,2,5Kenneth T. Kishida,1,2Damon Tomlin,2,6Laura G. Klinger,4Mark R. Klinger,4
and P. Read Montague1,2,3,*
1Computational Psychiatry Unit
2Department of Neuroscience
3Menninger Department of Psychiatry and Behavioral Sciences
Baylor College of Medicine, Houston, TX 77030, USA
4Department of Psychology, University of Alabama, Tuscaloosa, AL 35487, USA
5These authors contributed equally to this work.
6Present address: Center for the Study of Brain, Mind, and Behavior, Princeton University, Princeton, NJ 08544, USA.
to other agents is essential for all productive social
exchange. We approach this issue in high-functioning
males with autism spectrum disorder (ASD) using two
specific eigenvector (self eigenmode) associated with
imagining oneself executingaspecific motor act.Sec-
ond, we show that the same self eigenmode arises
during one’s own decision (the self phase) in an inter-
personal exchange game (iterated trust game). Third,
using this exchange game, we show that ASD males
exhibit a severely diminished cingulate self response
when playing the game with a human partner. This
diminishment covaries parametrically with their be-
haviorally assessed symptom severity, suggesting its
value as an objective endophenotype. These findings
may provide a quantitative assessment tool for high-
Reciprocal social interaction requires creatures to detect other
agents, sense the social signals they emit, and extract relevant
information carried by this important signal class. Social signals
are a broad and difficult cognitive domain to quantify in humans
due in part to the vast empirical and nonempirical literature
built around the idea of a social agent acting in the context of
others and the myriad of concepts surrounding the idea of the
‘‘self’’ (Decety and Sommerville, 2003; Dennett, 2001; Lieber-
man, 2007; Mitchell et al., 2006; Northoff et al., 2006; Ochsner
et al., 2005; Saxe et al., 2004; Uddin et al., 2007; Vogeley and
Fink, 2003). Nonetheless, some of the most important patholo-
gies of mental life revolve around perturbed function in the social
domain. One notable example is autism spectrum disorder
(ASD). Many symptoms characterize humans diagnosed on
this spectrum; however, one prominent feature is the perturbed
reaction to social signals emitted by other individuals (American
Psychiatric Association, 2000; Baron-Cohen, 2001; Frith, 2001,
2003; Klin et al., 2002; Lord et al., 2000a; Oberman and Rama-
games have added a new approach to assessing a subject’s
model of their partner and themselves during an active interper-
sonal exchange (Delgado et al., 2005; King-Casas et al., 2005;
Rilling et al., 2002, 2004; Sanfey et al., 2003; Singer et al.,
2006). Fairness games dominate these recent efforts because
they assess a subject’s internal norm for what is fair in an ex-
change, and they require that each subject models some aspect
of their partner’s mental state during the game (Camerer, 2003;
Camerer and Fehr, 2006; Kagel and Roth, 1997; Montague and
Lohrenz, 2007). Such simplified settings provide an excellent
starting point for quantitative descriptions of social signaling
and its pathologies because the parameter space is manage-
able, and reasonable normative solutions to these games exist
(Camerer, 2003; but see Greenwald and Jafari, 2003 for compli-
cations in solution concepts).
Recent work using the multiround trust game (Figure 1A; King-
Casas et al., 2005; Tomlin et al., 2006; also see Results and
Experimental Procedures) has identified activations along hu-
man cingulate cortex consistent with agent-specific response
patterns generated during interpersonal exchange with another
human. These patterns differentiate outcomes following revela-
tion of the partner’s decision (‘‘not self’’ or ‘‘other’’ response)
from those following submission of one’s own decision (‘‘self’’
response). Remarkably, the patterns are spatially complemen-
tary (Figure 1B, adapted from Tomlin et al., 2006), and almost
nomanipulation perturbsthemexceptone:the removalofthe in-
teractive partner (Tomlin et al., 2006). Removal of the social part-
ner causes the cingulate response patterns to disappear even
though the sensory, motor, and reward elements of the task
Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc. 463
remain intact (Figure 1B, adapted from Tomlin et al., 2006).
These results from the trust game are consistent with agent-
specific cingulate responses observed in a range of other exper-
iments. Anterior and posterior cingulate activation occurs in
response to the revelation of decisions of others in two-person
games like the Ultimatum and Prisoner’s Dilemma games (Rilling
et al., 2004). Furthermore, increased middle cingulate activation
or emotions (Jackson et al., 2006; Lamm et al., 2007; Singer
et al., 2004; Tomlin et al., 2006).
The consistency of these agent-specific cingulate response
patterns and their capacity to be estimated from single subjects
(see Supplementary Online Materials of Tomlin et al., 2006) sug-
gest their utility for understanding pathologies characterized by
impairments in the social domain. In this paper, we pursued
two goals. First, we sought to develop a standard basis set for
the cingulate response against which expressions of agency
might be compared quantitatively across groups. Second, we
sought to use this neural basis set to assess agent-specific
responses in a group specifically impaired in the social domain:
individuals with autism spectrum disorder.
The results fall into three domains, which we sketch here. First,
we report data from a visual imagery task used to validate our
designation of the ‘‘self’’ and ‘‘other’’ response patterns along
cingulate cortex (Rilling et al., 2004; Tomlin et al., 2006). The
imagery task has two important epochs: one where subjects
watch others performing specialized actions and another where
subjects imagine themselves performing the action. The imag-
ery experiment removes the complicating features present in
the trust game: playing another human, motor acts to report
decisions, gaining and losing money, and rounds preceding
and following each choice. Second, we use principal compo-
nent analysis of the cingulate responses during the ‘‘imagining
self’’ epoch to produce a neural basis set. This approach iden-
tifies a ‘‘self eigenmode’’ which differentiates ‘‘imagining self’’
from ‘‘watching others’’ and which also appears during the
‘‘self’’ phase of the trust game. Finally, we use the self eigen-
mode to quantify cingulate responses of high-functioning males
with autism playing the multiround trust game with a human
Figure 1. Schematic Representation of the Multiround Trust Game and Agent-Specific BOLD Responses along Cingulate Cortex
(A) Schematic representation of the multiround trust game. In each round, player 1, the ‘‘Investor,’’ is endowed with 20 monetary units. The Investor chooses to
sendsomeportionIofthisamounttoplayer2,the‘‘Trustee.’’Thisamountistripledto3Iandsent totheTrustee,whoreturnssomefractionfofthetripled amount.
The interaction continues for ten rounds, and the players maintain their respective roles throughout the game. For events labeled ‘‘ASD,’’ the Investor is a non-
psychiatric control participant, and the Trustee is a male with autism spectrum disorder or an age- and IQ-matched male control.
(B) Trust task events from which cingulate responses are taken. The base of the gray triangles identify the two 8 s epochs where the ‘‘other’’ and ‘‘self’’ responses
are defined, in both cases for the Trustee’s brain. The ‘‘other’’ response is taken as the peak BOLD response in the 8 s following the revelation of the Investor’s
decision averaged with its two flanking points, and the ‘‘self’’ response is taken as the peak response in the 8 s following submission of the Trustee decision
averaged with its two flanking points. The middle panel depicts the 11 regions of interest (ROIs) along the medial bank of cingulate cortex. The left panel shows
the average cingulate ‘‘other’’ response for each of the 11 domains from a database of 100 Trustees in this game. The right panel shows the cingulate ‘‘self’’
response from the same database. The lower panels show that these agent-specific response patterns disappear outside the context of social exchange
when the interactive partner is removed yet motor, monetary earnings, and visual aspects of the game remain constant (adapted from Tomlin et al., 2006);
n = 17 and 15 for sensory and motor controls, respectively. Maximum and minimum activations in the ‘‘other’’ response are 0.25% and ?0.10% change in
MR signal, and 0.30% and ?0.20% in the cingulate ‘‘self’’ response.
Diminished Cingulate ‘‘Self’’ Response in Autism
464 Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc.
Visual Imagery Task
Subjects watched short film clips depicting athletic actions (e.g.,
kicking a ball, dancing), then closed their eyes and imagined
themselves performing that act from a first-person ‘‘self’’ per-
spective (see Figure 2A and Experimental Procedures). The
task contains an epoch of watching others perform an action
and an epoch where the subjects imagine themselves perform-
ing the action. These distinct task demands respectively define
the ‘‘other’’ and ‘‘self’’ conditions in the visual imagery task.
Multiround Trust Game
The multiround trust game is an economic exchange game be-
tween two interacting players (Delgado et al., 2005; King-Casas
game to play and evokes parameterized social signals charac-
teristic of many reciprocal interactions. During each round, one
units) and chooses to send some portion of the endowment to
their partner, the ‘‘Trustee.’’ This chosen amount is tripled on
its way to the Trustee, and the Trustee decides what fraction of
the tripled amount to repay to the Investor (Figure 1A). This
pay-repay cycle and the two decisions within it (invest, repay)
the interacting partners for ten rounds. Players maintain their
respective roles for all ten rounds. The game engages basic
social exchange mechanisms since players must repeatedly
produce self-initiated actions and recognize their partner as
a separate receiving agent during the social interaction. The rev-
elation of a partner’s decision and the submission of a player’s
decision respectively define the ‘‘other’’ and ‘‘self’’ phases of
the trust game.
Agent-Specific Basis Sets in Cingulate Cortex
As outlined above, neural responses elicited in unselected con-
trol populations playing the multiround trust game are well char-
acterized (Delgadoetal.,2005; King-Casas etal.,2005;McCabe
Figure 2. Cingulate Self Response and Self Eigenmode Identified in Visual Imagery Task
(A) Schematic representation of the visual imagery task. In each trial, subjects were presented with a visual cue (2 s) indicating a target person to be presented in
an upcoming video. The subsequent video clip (4 s) depicted a specialized athletic act (e.g., kicking, throwing, dancing). Subjects were instructed to close their
eyesupon video offset,thenpresentedwithanauditorycuetoeither ‘‘watchit’’or‘‘doit.’’‘‘Watchit’’indicated thatsubjectsweretoimaginewatchingtheactions
in the video again, keeping the perspective of a spectator (third-person perspective). The ‘‘do it’’ cue indicated that subjects were to imagine the actions in the
video from the perspective of the target athlete (first-person perspective). A final auditory cue (‘‘stop’’) indicated the end of the trial, upon which subjects were to
open their eyes in preparation for the next trial. Maximum and minimum values in the mean cingulate ‘‘do it’’ BOLD response are 0.03% and ?0.12% change in
signal change extracted from ten equally sized spatial domains along the anterior-posterior axis of the medial cingulate cortex. The most posterior cingulate do-
the ‘‘self’’ response seen directly in the time series of the ‘‘self’’ phase of both the visual imagery task and the multiround trust game (Figures 1B and 2A).
visual imagery task are projected respectively onto the cingulate self-basis. The projection coefficients, plotted with SEM bars, of the BOLD responses on
principal component 2 (Figure 2B, dotted red circle) significantly differentiates the two experimental conditions (p = 1.87 3 10?15) and warrants the term ‘‘self
eigenmode’’ to describe this discriminating eigenvector.
Diminished Cingulate ‘‘Self’’ Response in Autism
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et al., 2001; Tomlin et al., 2006; Figure 1B). While the robust
cingulate activation patterns following the submission of one’s
‘‘own’’ decision and the observation of an ‘‘other’s’’ decision
are highly suggestive of distinct agent-specific hemodynamic
responses, the observed ‘‘self’’ and ‘‘other’’ response patterns
may be influenced by motor actions, responses to monetary
rewards, or reactions to one’s partner in the game. To reduce
cortex (Botvinick et al., 2001; Rushworth et al., 2007), we imple-
mented avisual imagerytaskthatrequired participants merelyto
imagine performing an act from the first-person (‘‘self’’) perspec-
tive (cf. K.T.K. et al., unpublished data). The peak hemodynamic
response during the self-imagery phase was extracted from
each of ten equally sized spatial domains along the anterior-pos-
terior axis of the cingulate cortex. As illustrated in Figure 2A, the
self phase of the visual imagery task elicits a hemodynamic
activation pattern along the anterior-posterior axis of the cingu-
late cortex identical to that seen in the self phase of the multi-
round trust game. Specifically, when simply imagining perform-
ing a motor act from the first-person perspective, subjects
(n = 81 controls) exhibit greater middle cingulate activation rela-
A neural basis set upon which the cingulate ‘‘self’’ response
could be further quantified was then defined using spatial princi-
pal components analyses (sPCA) of the peak BOLD responses
across the ten domains of cingulate tissue space extracted
from 81 subjects during the ‘‘self’’ phase of the visual imagery
data). The first three principal components resulting from this
sPCA account for 89.6% of the variance in the hemodynamic
response in the self phase of the imagery task (Figure 2B). These
eigenvectors thus comprise a neural ‘‘self basis’’ upon which
subjects’ hemodynamic responses in cingulate cortex was fur-
Visual Imagery Task Identifies Self Eigenmode
Projections of the self-phase cingulate BOLD response patterns
upon each principal component of the self basis further revealed
that only one eigenvector differentiated the video-watching
(‘‘other’’) and self-imagery (‘‘self’’) phases of the visual imagery
task (Figure 2C; see also Experimental Procedures and K.T.K.
et al., unpublished data). This eigenvector, principal component
We note that the shape of the self-eigenmode parallels that seen
in the hemodynamic ‘‘self’’ activation pattern across the cingu-
late cortex in both the multiround trust game and visual imagery
task: relatively greater activation in middle cingulate domains
and less activation in the anterior and posterior ends of the
cingulate cortex (compare the spatial distribution of PC2 in
Figure 2B to the cingulate BOLD response in Figure 2A).
Self Eigenmode Arises in Multiround Trust Game
Parallel analyses of hemodynamic responses in the ‘‘other’’ and
‘‘self’’ phases of the multiround trust game reveal patterns
remarkably similar to those seen in the visual imagery task along
the anterior-posterior axis of the cingulate cortex. That is, sPCA
of peak BOLD activations in the ‘‘self’’ phase of the trust game
yielded a neural basis whose first three components account
for 92.6% of the variance in cingulate hemodynamic response.
Moreover, the trust task self basis contains an eigenvector
(PC3 in Figure 3B) whose shape closely resembles both the
self eigenmode identified in the visual imagery task (PC2 in Fig-
ure 2B) and the BOLD response pattern in the self phase of the
trust game: greater amplitude in middle cingulate domains and
smaller response in the anterior and posterior ends of the cingu-
late cortex (compare PC3 in Figure 3B to the cingulate BOLD
response depicted directly above and to the self eigenmode in
Figure 2B). In contrast, sPCA of peak BOLD activations in the
‘‘other’’ phase of the trust game reveals a neural basis identical
to that seen in the ‘‘self’’ phase, except in one eigenvector
(PC3, red dotted circle, Figure 3A) that is exactly the shape of
an inverted self eigenmode. Expression of the self eigenmode
is near zero or negative ‘‘other’’ phase of the multiround trust
game (Figure 4A) and reaches maximal positive amplitude sub-
of the game.
Diminished ‘‘Self’’ Response in Autism
The presence of the self eigenmode in the trust game suggests
the utility of using this measure to characterize individuals with
specific impairments in the social domain that may be conferred
by deficits in agent-specific inferences. To this end, we detailed
theresponsepatternalong themedialbank ofcingulatecortex in
individuals with ASDwhile theyplayed the multiround trust game
(see Experimental Procedures for complete participant charac-
Behavioral Play of the ASD Group Does Not Differ
on the Multiround Trust Game
To first confirm basic cognitive understanding of the trust task
demands, we examined the behavioral strategies in the ASD
group as compared with both our large neurobehavioral data-
base in the trust game and also a group of age- and IQ-matched
controls. In addition, the 15 database pairs closest to the ASD
average behavioral vector comprised a ‘‘behavioral control
group’’ that was later used to test the possibility that play with
an individual with ASD somehow accounted for any observed
neural differences. As depicted in Figures 5A–5C, the behavioral
trajectories and game outcomes of the ASD group did not differ
from any of the three control groups, providing strong evidence
that in both the ASD group and adolescent controls, cognitive
understanding of the task was intact.
Diminished ‘‘Self’’ Response in BOLD Analysis
of Cingulate Cortex in ASD
cingulate response patterns of the ASD and the two unique
control groups emerged from time series analyses of the ‘‘self’’
and ‘‘other’’ phases of the trust game.The age- andIQ- matched
control group showed strong middle cingulate activation subse-
‘‘self’’ response patterns reported previously in both the trust
gameand perspective-taking tasks (Figures 1B and2B;Jackson
et al., 2006; Lamm et al., 2007; Singer et al., 2004; Tomlin et al.,
response pattern was absent in the ASD group (Figure 6A; third
row, white asterisk) and resembles that observed when controls
play the game in the absence of a social partner (Figure 1B and
Diminished Cingulate ‘‘Self’’ Response in Autism
466 Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc.
Tomlin et al.,2006). Equallyimportant,thereductioninthecingu-
late response was not all-or-none but correlated with symptom
Diagnostic Interview-Revised; Lord et al., 1994). Despite the di-
response pattern that was indistinguishable from the age- and
IQ- matched controls and exactly resembled the ‘‘other’’ re-
sponse reported previously to the revelation of the social deci-
sions of others (Figures 6A, 1B, and see Figure S1 available
online; Rilling et al., 2004; Tomlin et al., 2006).
Self Eigenmode Reduces Diminished ASD Self
Response to Single Projection Coefficient
Finally, we used the neural agent-specific basis sets identified
in the trust game and visual imagery tasks as normative stan-
dards against which the ASD cingulate ‘‘self’’ deficit could be
quantified. Specifically, we projected the cingulate responses
of the ASD group and the age- and IQ-matched controls onto
both the neural ‘‘self’’ and ‘‘other’’ bases of the trust task and
compared the projection coefficients across groups on each
principal component. The projections were not different except
in one principal component and one condition—the third princi-
pal component of the cingulate ‘‘self’’ basis, or the self eigen-
mode. In this projection, the ASD group-averaged coefficient
differed significantly from both the age- and IQ- controls and
behavior-matched controls (Figure 6C). Moreover, the ASD pro-
jection coefficient onto the self eigenmode (PC3) was not differ-
ent from zero (p = 0.19) while the coefficients of the adolescent
and behavior-matched controls were both significantly different
from zero (p = 0.000013 and p = 0.0000054, respectively; Fig-
ure 6C). As further detailed in the Supplemental Data (Figure S1),
the ASD and control groups did not differ on any projection co-
efficient onto any eigenmode identified in the ‘‘other’’ basis.
In two distinct large data sets and experimental tasks, we report
robust agent-specific hemodynamic response patterns along
the anterior-posterior axis of the cingulate cortex. Linear space
analyses of these response patterns defined agent-specific
cingulate basis sets containing a single eigenmode that differen-
tiates ‘‘self’’ from ‘‘other’’ task phases. Equally important, the re-
duction of agent-specific responses to a single discriminating
Figure 3. Trust Task Reveals Complementary Agent-Specific Cingulate Basis Sets and Self Eigenmode
peak % MR signal changes extracted from 11 distinct and equally sized spatial domains along the anterior-posterior axis of medial cingulate cortex; mean cin-
gulate BOLD responses reproduced from Figure 1B and Tomlin et al. (2006). The results of the sPCA on cingulate responses in the ‘‘other’’ and ‘‘self’’ phases of
the trust game are depicted here. Segment ‘‘p’’ refers to the most posterior cingulate domain; segment ‘‘a’’ refers to the most anterior cingulate domain.
(A)The‘‘other’’phaseof thetrustgameis depicted hereand references thetimepoints surrounding therevelation of theInvestor’s decision totheTrustee’s brain.
The spatial patterns of the first three principal components, accounting for 92.9% of the variance in cingulate activation, are illustrated here. Note that the spatial
pattern of principal component 3 (dotted red circle) resembles the normative ‘‘other’’ response observed in the time series data and is an inverted complement of
the self eigenmode.
(B) The ‘‘self’’ phase of the trust game is depicted here and references the time points surrounding the submission of the Trustee’s own decision in the game. The
spatial patterns of the first three principal components, accounting for 92.0% of the variance in cingulate ‘‘self’’ activation, are illustrated here. The spatial pattern
of principal component 3 (dotted red circle) closely resembles that of the self eigenmode and the normative ‘‘self’’ response reported directly from the time series
in the visual imagery task and multiround trust game (see Figure 1A and Tomlin et al., 2006).
Diminished Cingulate ‘‘Self’’ Response in Autism
Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc. 467
vector, the self eigenmode, allowed the detailed examination of
these patterns in individuals with ASD.
During the multiround trust game, high-functioning males with
ASD lack a neural activation pattern in cingulate regions previ-
ously shown to encode robust self-specific responses. In stark
normal response of the ASD cingulate cortex to the decision of
others highlights that the diminished self response is not a global
self phase of the trust game. The absent self response closely
resembles the lack of cingulate activation when healthy controls
perform the iterated trust game outside the context of a social
exchange and instead submit computer-guided responses in
the absence of a responsive social partner (Tomlin et al., 2006).
The reduced cingulate self response pattern (i.e., reduced self
eigenmode) and intact other response suggests that in the con-
text of the iterated trust game, individuals with ASD may be im-
paired in the capacity to represent the social intent of their own
behaviors, yet remain able to represent the actions of others.
That is, the capacity to represent simple social actions of others
may exist despite impoverished models of one’s own intentions.
In this case, the ‘‘other’’ response pattern may reflect cingulate
functions related less to intuiting others’ social intent than obser-
vations of others’ acts (e.g., Amodio and Frith, 2006; cf. K.T.K.
et al., unpublished data). In comparison, the reduced cingulate
self response pattern may reflect a diminished capacityto model
performance commonly seen in individuals with ASD on theory-
of-mind tasks. These tasks typically require a subject to put
himself ‘‘in another agent’s shoes’’ to infer the intentions of
that agent (Frith and Frith, 2006) and, by extension, individuals
lacking a capacity to delineate their own intentions are likely un-
able to attribute the social goals or intentions of others. Although
our data cannot distinguish among these hypotheses, the dimin-
ished self response in ASD supports a recent shift toward under-
standing autism in the context of dysfunctions in introspection or
self-referential processing (Baron-Cohen, 2001; Frith, 2001,
2003; Hill, and Frith, 2003; Iacoboni, 2006; Kennedy et al., 2006).
It should be emphasized that the precise cognitive processes
elicitedbythesubmission ofaplayer’sdecision andrevelationof
a partner’s decision in the iterated trust game are complex; con-
sequently, we use the terms ‘‘self’’ and ‘‘other’’ in the trust game
primarily to label the observed spatial patterns of response that
phases of the task: subsequent to a player’s own decision
(‘‘self’’) and subsequent to the revelation of the partner’s
decision (‘‘other’’). Both phases of the trust task are very likely
Figure 4. Expression of the Self Eigenmode during the Multiround Trust Game
Trustees’cingulate hemodynamic response patterns ateach TR(2 s)inthe ‘‘other’’and ‘‘self’’phases of the trust gamewere projected intothe three-dimensional
space whose axes comprise the first three eigenvectors of the neural self basis (projection coefficients at each TR indicated by red circles). In doing so, we
tracked the expression of the self eigenmode (PC3 in Figure 3B) across the course of the trust game. The coefficient of the self eigenmode is (A) near zero or
negative during the entire ‘‘other’’ phase of the trust game and (B) reaches maximal positive amplitude after the submission of players’ decisions.
Diminished Cingulate ‘‘Self’’ Response in Autism
468 Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc.
accompanied by a myriad of complex cognitive phenomena. For
example, in the ‘‘self’’ phase of the game, inferring the social
goals and intentions of others is expected for healthy individ-
uals—making a gesture in a social interaction should elicit com-
putations of how one’s actions influence the behavior of one’s
partner (Frith and Frith, 2006; King-Casas et al., 2005). Although
the current data cannot be definitive with regard to the function
of the cingulate cortex, the data from the visual imagery task
supports the designation of the ‘‘self’’ pattern in both tasks.
Moreover, while deficiencies in the social domain are specifically
implicated in autism (American Psychiatric Association, 2000;
Baron-Cohen, 2001; Frith, 2001, 2003; Klin et al., 2002; Lord
et al., 2000a; Oberman and Ramachandran, 2007), the degree
to which our data fit with existing theories about ASD remains
an intriguing avenue of future research.
The self eigenmode provides a useful quantitative measure for
differentiating the ‘‘other’’ condition from the ‘‘self’’ condition on
both the trust game and the imagery task. In the imagery task,
of subjects (n = 81; p =1.87 3 10?15; Figure 2). The negative pro-
jection coefficient means that the ‘‘watching others’’ condition
elicits a spatial pattern of response complementary to the self
eigenmode (Figure 2C) and exactly analogous to the response
whena partner’sdecision isrevealed inthe trust game (Figure3).
To reiterate, the peak response domain in the self eigenmode
(middle portions of the cingulate) lies precisely in the same
regions identified when subjects imagine emotions or actions
from a first-person perspective (Jackson et al., 2006; Lamm
et al., 2007; Singer et al., 2004).
Figure 5. Behavioral Characterization of ASD, Age- and IQ-Matched Control, and Behavior-Matched Control Pairs on the Iterated
(A) Dyadic behavioral trajectories do not differ among ASD, normative, and age- and IQ-matched controls. To characterize the behavioral exchange of each ex-
perimental pair, we formed vectors composed of the series of investment ratios (I=Investment=20) and fractions of Trustee repayments (R=repayment=3,I) over
the ten rounds of a dyad’s exchange. The behavioral vector for each pair p is denoted Up=ðI1;R1;I2;R2;.;I9;R9;I10;R10Þ, where Inrepresents the fraction in-
vested in round n and Rnrepresents the fraction repaid in round n. All Investors were adult controls; the indicated experimental groups are identified by the par-
ticipants in the Trustee role. The behavioral vectors for eachpair of eachexperimental group (ASD, ageand IQcontrol, behavioral control, databaseadult control)
are projected onto the plane defined by the first two principal components of the behavioral data from 100 iterated trust exchanges in our database of adult con-
trols. The projections of the 20-dimensional behavioral vectors onto this plane are identified as follows: blue circles = database adults, red squares = ASD, green
triangles = age and IQ-matched controls, blue circles with overlaid purple stars = behavioral controls. Open shapes represent the projections of the behavioral
vectors of each pair; solid black shapes represent the projections of the average behavioral vector of the indicated group. Behavioral controls are those 15 pairs
fromour normativedatabasewhosepattern ofplaymost closely resembledthatoftheASDpairs(seeExperimentalProceduresfor detaileddescription ofcontrol
(B) Round-by-round trustee repayment ratio and SEM for ASD and age- and IQ-matched control groups. Average trustee repayment ratio across the ten rounds
of the trust game do not differ between ASD and controls, supporting intact cognitive understanding of the basic elements of the task.
(C) Average Trusteeearnings and SEM for ASD and age- and IQ-matched controls. Average total earnings on the multiround trust game do not differ between the
ASD and control group.
Diminished Cingulate ‘‘Self’’ Response in Autism
Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc. 469
Future parametric experiments are required to make functional
tification of neural phenotypes using neural response basis sets
tool, identify subtypes of autism, or be used to seek covariates in
of complex phenotypes to single coefficients relative to normative
standards. In ASD, the present data suggest that a quantitative
may be of diagnostic and therapeutic utility. Indeed, the further
question emerges whether the cingulate ‘‘self’’ response and re-
lated capacity in ASD may be evoked with real-time feedback
or behavioral therapies dedicated to increasing individuals’ repre-
sentations of the self role in goal-directed social interactions.
Figure 6. Diminished Cingulate ‘‘Self’’ Response in Autism Spectrum Disorder
(A) Participants with ASD lack cingulate ‘‘self’’ response pattern. Cingulate responses to the revelation of a partner’s decision (‘‘other’’ response pattern) and
following the submission of one’s own decision (‘‘self’’ response pattern) are shown for the ASD group (n = 12), age- and IQ-matched controls (n = 18), and con-
partner’s decision elicits an unperturbed cingulate response pattern in the ASD and control groups (left column). In stark contrast, the activation following one’s
own decision is missing in the ASD group (white asterisk; p = 0.001 two-tailed for ASD versus age- and IQ-matched controls’ three middle cingulate segments;
p = 0.0004 for ASD versus behavior-matched controls). Maximum and minimum activations in the ‘‘other’’response are 0.25% and?0.10% change in MR signal,
and 0.30% and ?0.20% in the cingulate ‘‘self’’ response.
(B) Lack of cingulate ‘‘self’’ response pattern relates parametrically to ASD symptom severity. The reduction in the ‘‘self’’ response pattern in ASD participants
correlates with symptom severity on the Autism Diagnostic Interview-Revised. The ASD participants’ average cingulate response across the three middle seg-
ments and the fraction of maximum ADI subscale score are depicted: ADI total score (dark circles; r = ?0.73, p = 0.007), ADI social subscale (light circles;
r = ?0.70, p = 0.011), and ADI communication subscale (open circles; r = ?0.69, p = 0.012). No significant correlation was observed between the ADI repetitive
behavior subscale and cingulate ‘‘self’’ response (r = ?0.34, p = 0.28). Moreover, no significant correlations were observed between scores on any ADI symptom
domain and any cingulate region’s ‘‘other’’ response.
(C) Cingulate response basis set reduces diminished ASD ‘‘self’’ response to a single projection coefficient. To test for between-group differences in the ‘‘self’’
cingulateresponsepattern, two-tailedt testswereperformedonthe ASDand thetwocontrolgroups’expansioncoefficientsontoeachprincipal component (PC)
of the neural ‘‘self’’basis set. This analysis identified anattenuatedresponse inthe ASD group specifically along theself-eigenmode (PC3inFigure3B)compared
with both the age- and IQ-matched controls (p = 0.0036) and the behavior-matched controls (p = 0.00043; SEM is indicated; see Experimental Procedures for
control selection procedures). For all other comparisons between the ASD and control groups on the remaining PCs, p > 0.1. The diminished contribution of the
self eigenmode to the cingulate BOLD response in ASD is illustrated in the right panel.
Diminished Cingulate ‘‘Self’’ Response in Autism
470 Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc.
Multiround Trust Game with ASD
Participants comprised 16 high-functioning adolescent and young adults with
autism spectrum disorder (ASD) and 20 typically developing control adoles-
cents. All participants were male. Due to excessive motion during the experi-
ment, four ASD and two control individuals were excluded from analysis. This
brought the ASD group to 12 and the control group to 18 participants who
underwent analysis of BOLD responses. The ASD group was recruited from
the University of Alabama Autism Spectrum Disorders Research Clinic (L. Klin-
ger, Director). Age-, gender-, and IQ-matched control individuals with no
known psychiatric disorders were recruited from the Houston metropolitan
area by word of mouth and internet and poster advertisements. Following an
initial screening in which basic fMRI contraindications were assessed, qualify-
ing individuals were invited to the laboratory for diagnostic assessment and
of Medicine and the University of Alabama, Tuscaloosa, written informed
consent, or parental assent for participants under 18, was obtained at the first
Inclusion and exclusion criteria for the ASD group were assessed using the
Autism Diagnostic Interview-Revised (ADI-R; Lord et al., 1994) and the Autism
Diagnostic Observation Schedule (ADOS; Lord et al., 2000b), administered by
a PhD-level clinical psychologist or trained advanced doctoral students. Diag-
noses of ASD were subsequently made according to DSM-IV criteria for autis-
tic disorder, Asperger’s disorder, or PDD NOS. For all adolescents, IQ was
assessed with the Kaufman Brief Intelligence Test, Second Edition (K-BIT-2;
Kaufman and Kaufman, 2004). The following exclusion criteria were addition-
ally applied to all potential participants during recruitment: left-handedness,
history of seizures, head injuries resulting in more than 10 min of unconscious-
ness or with neurological sequelae. History of taking psychotropic medication
was a further exclusion criterion for the control group. The current psychotro-
pic medication use among participants with ASD was: sertraline (n = 1), atom-
oxetine (n = 1), sertraline and methylphenidate (n = 1).
The ASD and control groups did not differ on gender, age, or IQ measures.
Means and standard deviations of these measures are presented in Table 1.
Visual Imagery Task with Controls
A total of 81 subjects performed the visual imagery task. Individuals were
trained athletes recruited from local professional athletic teams and collegiate
institutions’ athletic departments (cf. K.T.K. et al., unpublished data). All
subjects provided written informed consent in accordance with Institutional
Review Board guidelines at Baylor College of Medicine.
Multiround Trust Game
The multiround trust game is an iterated economic exchange between two
players (King-Casas et al., 2005; Tomlin et al., 2006; Figure 1A). During each
round, one player (‘‘Investor’’) is endowed with a resource (here 20 monetary
units) and chooses to send some portion I to their partner the ‘‘Trustee.’’
This chosen amount is tripled to 3I, and the Trustee decides what fraction f
of the tripled amount to repay to the Investor (Figure 1A). This pay-repay cycle
constitutes a round of play, and the basic exchange is repeated within the
interacting partners for ten rounds. In the present version of the trust game,
players maintained their respective roles for all ten rounds and did not meet
before, during, or after the game. Players were not given any cues or sugges-
tions about strategy. The timeline of events is presented in Figure 1B; rounds
were separated by a variable 12 to 42 s intertrial interval.
Visual Imagery Task
Subjects were instructed that they would be viewing videos of individuals
performing specialized athletic acts and asked to imaginethese performances
from two different perspectives (Figure 2A). Each video clip in the imagery task
depicts athletes performing in the presence of other players. These athletes
include quarterbacksthrowingto other football players, soccer players kicking
the ball to teammates, and ballerinas dancing amidst a troupe. At the begin-
ning of each trial, subjects were cued to a target person. The video was then
presented (4 s) and on completion of the video, subjects were presented
with a brief auditory cue to ‘‘watch it’’ or ‘‘do it.’’ Subjects were instructed to
close their eyes subsequent to completion of the video, and prior to the audi-
tory cue (4.5 s window). On ‘‘watch it’’ trials, subjects were asked to imagine
watching the actions in the video again, from the spectator (third-person)
perspective. On ‘‘do it’’ trials, subjects were instructed to imagine performing
the actions from the perspective of target person in the video (first-person).
Subjects were given 6 s to visualize in the indicated perspective prior to an
auditory cue to ‘‘stop,’’ at which time the subjects were to open their eyes
and await the beginning of the next trial (intertrial interval = 8 s). The timeline
of events is presented in Figure 2A.
(sixfrom eachoffour sports)wereshown twicetoeachsubject,suchthat each
clip was imagined in both the first- and third-person perspective. The order of
presentation of the clips and the perspective instructions were random.
fMRI Data Acquisition and Reduction
All scans were performed on a Siemens 3.0 Tesla Allegra scanner. Initial high-
resolution T1-weighted scans were acquired using an MP-RAGE sequence
(Siemens). Continuous whole-brain imaging was performed as participants
engaged in the interpersonal exchange task. Functional run details were as
follows: echo-planar imaging, gradient recalled echo; repetition time (TR) =
slices acquired parallel to the anteroposterior commissural line for measure-
ment of the BOLD effect (Kwong et al., 1992; Ogawa et al., 1990a, 1990b).
Scanning yielded functional 3.3 mm 3 3.3 mm 3 4.0 mm voxels.
Data reduction was performed using SPM2 (http://fil.ion.ucl.ac.uk/spm;
Friston et al., 1995). Motion correction to the first functional scan was
performed using a six-parameter rigid-body transformation within subjects
tered to each individual’s structural MRI using a 12 parameter affine transfor-
mation. Slice timing artifact was corrected, and images were subsequently
spatially normalized to the MNI template by applying a 12 parameter affine
transformation, followed by a nonlinear warping using basis functions as rec-
ommended by Ashburner and Friston (1999). Images were resampled to 4 mm
3 4 mm 3 4 mm voxels during normalization. Finally, images were smoothed
with an 8 mm isotropic Gaussian kernel and high-pass filtered in the temporal
The cingulate cortex was examined using a detailed region-of-interest (ROI)
analysis identical to that described in Tomlin et al. (2006). First, the cingulate
Table 1. Demographic and Diagnostic Measures
Control Group (n = 18) ASD Group (n = 12)
Mean ± SDMean ± SD
14.9 ± 2.216.5 ± 3.3
Composite108 ± 13103 ± 18
Verbal108 ± 13101 ± 18
106 ± 15105 ± 15
Social interaction—17.9 ± 4.0
Communication—11.1 ± 4.3
Stereotyped behavior—6.2 ± 2.6
All between-group comparisons, p > 0.1.
Social interaction: qualitative abnormalities in reciprocal social interac-
Communication: qualitative abnormalities in communication.
Stereotyped behavior: restricted, repetitive, stereotyped patterns of
aAssessed with the Kauffman Brief Intelligence Test, Second Edition.
bAutism Diagnostic Interview-Revised.
Diminished Cingulate ‘‘Self’’ Response in Autism
Neuron 57, 463–473, February 7, 2008 ª2008 Elsevier Inc. 471
gyrus was outlined by hand using the canonical T1 image included with SPM 2
(resolution1.6mm 31.6mm31.5mm).After selection, structuralvoxelswere
converted into the analogous voxels for a functional image; any functional
voxel overlapping a designated structural voxel caused the functional voxel
to be included. The resulting mask comprised 398 voxels for the entire cingu-
In order to examine separate functional domains within the cingulate, the
mask was further divided into 11 nonoverlapping regions along the anterior-
posterior axis. Specifically, voxels were grouped according to their angle
relative to a point equidistant from the anterior and posterior extremes of the
cingulate mask (x = 0, y = ?3.5, z = 13) whose location along the dorsal-ventral
axis was aligned to the ventral edge of the posterior cingulate. The angular
boundaries for the zones were designated such that each area contained ap-
proximately the same number of voxels, and voxels across left- and right- cin-
gulatecortex werepooled foreach area. Eachdomain thusincluded36.2 ±2.1
voxels and extended 4 voxels bilaterally from the midline. Each domain was
then used as a separate mask for ROI analysis for which the raw MR response
To compute the magnitude of cingulate self responses, MR values were
averaged across the point of maximal activation and two adjacent flanking
points within 8 s following the submissions of one’s own decision (averaged
across the ten rounds of the multiround trust game) or subsequent to the au-
(‘‘other’’ response), MR values corresponding to the peak activity within 8 s
after screen onset activations were identified, averaged across rounds, and
compiled across the point of maximal activation and the two adjacent flanking
points. These analyses were performed for each cingulate domain and repre-
sent the responsiveness of each segment to the submission of one’s ‘‘own’’
decision and the revelation of a partner’s decision (‘‘other’’), respectively.
Principal Component Analyses
To examine differential spatial activation patterns in cingulate responses,
spatial principal component analysis (sPCA) was performed on (1) the cingu-
late responses of the 81 subjects in the visual imagery task and on (2) our trust
task database containing the cingulate responses of 100 unselected control
adults who played the Trustee role in the same multiround trust game played
round trust game, the PCA of the cingulate ‘‘self’’ and ‘‘other’’ responses was
thus performed on the dataset consisting of 100 11-dimensional vectors rep-
resenting each Trustee’s cingulate response following the submission of her
decision on the game (‘‘self’’ phase) or following the revelation of her partners’
decision (‘‘other’’ phase). The principal components were calculated as the
eigenvectors of the covariance matrix of the 11-dimensional dataset. Keeping
all the variance of the data, basis sets for the 11-dimensional cingulate space
in the ‘‘self’’ and ‘‘other’’ phases of the task were obtained.
The cingulate hemodynamic response data of the age- and IQ-control and
ASD groups were then projected onto this basis, yielding a projection matrix
upon which two sample t tests were performed to calculate the degree of sta-
tistical differences between the ASD and control groups along each principal
component. This analysis yielded a p value for each component as indicated
in Figures 6C and S1.
The spatial contribution of each of these components to the cingulate ‘‘self’’
response was obtained by keeping the projections along that component
unchangedwhilesetting allother projections tozeroand multiplying theresult-
cingulate basis. As illustrated in Figure 6C and Supplemental Data, ASD and
control populations differed only on one component in one phase of the
task, PC3 in the self phase whose shape resembles the normative ‘‘self’’
response seen directly in the time-series data.
Selection of Behavioral Control Pairs
It was possible that a perturbed pattern of monetary exchange with an ASD
trustee induced behavioral anomalies in the partner, thus inducing any ob-
served neuraldifferences.Totestthispossibility,we compared theASDneural
response patterns with a group of individuals from our normative database
whosepatternofplaymatchedthat oftheASDgroup. The‘‘behavioral-match’’
selection was as follows: We first formed behavioral vectors for each dyad to
characterize their behavioral exchange. Each vector was composed of the
series of investment ratios (I=Investment=20) and fractions of Trustee repay-
ments (R=repayment=3,I) over the ten rounds of a dyad’s exchange. These
vectors thus represent the monetary exchange pattern within a pair, and we
calculated the average such vector for pairs with an ASD trustee. From our
normative database, we then identified monetary exchange patterns that
matched the average ASD pattern of play. Specifically, the behavioral vector
foreachpairp wasdenotedUp=ðI1;R1;I2;R2;.;I9;R9;I10;R10Þ,andthe aver-
of control dyads ‘‘close’’ to this average was identified as those 15 normative
subject pairs whose pattern of exchange resembled the patterns for the ASD
subjects. The distance function that defined these pairs in 20-dimensional
behavioral space was as follows: dðp;UAÞ=P20
the projections of these 20-dimensional behavioral vectors onto the plane
defined by the first two principal components of the normative behavioral
data. The behavioral controls are indicated by stars overlaid on the blue circles
the average vector of the 12 ASD pairs, UA, is shown as a solid square and lies
well-within the space defined by normative monetary exchange.
jj. A threshold of
3.65 yielded 15 normative subject pairs. The points in Figure 5A represent
The Supplemental Data for this article can be found online at http://www.
This work was supported by The Kane Family Foundation (P.R.M.), The Dana
DA11723 to P.R.M.), National Institute of Neurological Disorders and Stroke
(R01 NS045790 to P.R.M.), The Angel Williamson Imaging Center, and the
American Psychological Association (T32 MH18882 to P.H.C.). We thank
M. Friedlander for establishing the collaboration between the BCM Computa-
tional Psychiatry Unit and the UA Autism Spectrum Disorders Research Clinic;
B. King-Casas (supported by the National Institute of Mental Health F32
MH078485) and T. Lohrenz for scientific discussion; the Hyperscan Develop-
image viewing software (http://people.hnl.bcm.tmc.edu/cuixu/xjView); and
P. Baldwin, C. Bracero, A. Harvey, C. Klein, J. McGee, S. Moore, K. Pfeiffer,
R. Pohlig, and J. Schwind for discussion and technical assistance.
Received: October 6, 2007
Revised: December 5, 2007
Accepted: December 11, 2007
Published: February 6, 2008
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