, 806 (2008);
et al.Brooks King-Casas,
Borderline Personality Disorder
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The Rupture and Repair
of Cooperation in Borderline
Brooks King-Casas,1,2Carla Sharp,2Laura Lomax-Bream,2Terry Lohrenz,1
Peter Fonagy,2,3,4P. Read Montague1,2*
To sustain or repair cooperation during a social exchange, adaptive creatures must
understand social gestures and the consequences when shared expectations about fair
exchange are violated by accident or intent. We recruited 55 individuals afflicted with
borderline personality disorder (BPD) to play a multiround economic exchange game with
healthy partners. Behaviorally, individuals with BPD showed a profound incapacity to maintain
cooperation, and were impaired in their ability to repair broken cooperation on the basis of a
quantitative measure of coaxing. Neurally, activity in the anterior insula, a region known to
respond to norm violations across affective, interoceptive, economic, and social dimensions,
strongly differentiated healthy participants from individuals with BPD. Healthy subjects
showed a strong linear relation between anterior insula response and both magnitude of
monetary offer received from their partner (input) and the amount of money repaid to their
partner (output). In stark contrast, activity in the anterior insula of BPD participants was
related only to the magnitude of repayment sent back to their partner (output), not to the
magnitude of offers received (input). These neural and behavioral data suggest that norms
used in perception of social gestures are pathologically perturbed or missing altogether
among individuals with BPD. This game-theoretic approach to psychopathology may open
doors to new ways of characterizing and studying a range of mental illnesses.
tive mathematical setting for understanding
social exchange (1–5). This same game-theoretic
framework has exposed some of the basic
computations underlying social interaction and
identified neural correlates of cooperation, rec-
iprocity, and social signaling (6–14). Collective-
ly, this work raises the possibility of a new
approach to characterizing and understanding
psychopathology from a normative perspec-
tive. In conditions ranging from psychosis to
developmental and personality disorders, af-
flicted individuals often display a dramatically
perturbed capacity to model others and to sense
and respond appropriately to the social signals
they emit (15–17). Consequently, using norma-
tive game-theoretic probes of social signaling in
identified psychopathologies offers the oppor-
tunity to understand some of the components
of these disorders in terms of malfunctioning
computations (18, 19).
heoretical and empirical work on coop-
eration has made tremendous strides by
using game theory to provide a norma-
We examined two groups of individuals
that vary in their capacity to maintain stable in-
terpersonal relationships and used a multiround
economic exchange game (Fig. 1) (20) to probe
two fundamental components underlying the ca-
pacity to sustain a successful social exchange:
cooperation and its repair. Specifically, we studied
a group of control individuals and a second group
of individuals diagnosed with borderline per-
sonality disorder (BPD), a psychiatric disorder
characterized by unstable relationships, affec-
tive dysregulation, and a broad incapacity to
trust appropriately the actions and (possible)
motives of others (21–23).
Successful cooperation between two agents
requires a range of intact computations includ-
ing the capacity to sense, value, and respond to
social gestures exchanged with one’s partner
(24–26). However, cooperative exchange is frag-
ile and can easily be ruptured by accident (e.g.,
through impoverished models of social partners)
or intent (27). The successful repair of broken
cooperation in an iterated exchange requires the
capacity to coax one’s partner back into coop-
eration through the medium of generous gestures
(28–32). In an economic exchange game, such
gestures are encoded as money units, which
exposes their immediate cost to each subject.
However, for such gestures to be meaningful,
cooperating individuals must possess norms
that accurately encode what is expected of
themselves and their partners, and they must
sense when these norms have been significantly
violated (33). We pursued the hypothesis that
social exchange norms of subjects with BPD are
either pathologically perturbed or missing alto-
gether, preventing sustained cooperation or the
repair of cooperation after it breaks down.
Before scanning, all participants (healthy sub-
ject group and BPD group) underwent diagnos-
tic and symptom assessment and were matched
on demographic variables including sex, age,
education, and verbal IQ (see table S1) (20).
Within each trust exchange, cooperation occurs
when an investor and trustee act in a manner
that mutually benefits both players. For exam-
ple, if an investor sends $20 to a trustee, and the
trustee splits the tripled investment ($60) with
the investor, both the investor and trustee profit.
The investor earns $10 more, and the trustee
earns $30 more, than if the investor had sent
1Computational Psychiatry Unit and Department of Neuro-
science, Baylor College of Medicine, 1 Baylor Plaza, Houston,
TX 77030, USA.2Menninger Department of Psychiatry and
Behavioral Sciences, Baylor College of Medicine, 1 Baylor
Plaza, Houston, TX 77030, USA.3Research Department of Clin-
ical, Educational, and Health Psychology, University College
London, Gower Street, London WC1E 6BT, UK.4Anna Freud
Centre, London NW3 5SD, UK.
*To whom correspondence should be addressed. E-mail:
Fig. 1. Cooperation fails across rounds when individuals with BPD engage in a repeated exchange of
trust. Among 38 healthy investors (gray) paired with healthy trustees (gray), investments were large and
sustained across early (1 to 5) rounds and late (6 to 10) rounds of the game. However, among 55
healthy investors (gray) paired with 55 trustees with BPD (red), a decrease in investment level from
early to late rounds of the game indicates a failure in cooperation across the iterated exchange. Mean
percent invested and SEM are plotted.
8 AUGUST 2008VOL 321
on August 11, 2008
nothing. However, if a trustee does not repay at
least the amount invested, the investor accrues
no benefit from the exchange, likely triggering
smaller subsequent investments. Thus, increased
cooperation is seen with increased money ex-
changed across the course of the 10-round game.
In the current study, subjects diagnosed with
BPD played the trustee role against a healthy
investor; as expected, each game began normally
with the healthy investor showing a level of trust
comparable to that of healthy investors playing
healthy trustees (Fig. 1).
BPD subjects send signals that break co-
operation. In early rounds of this multiround
game, investment levels did not differ between
subjects partnered with BPD trustees and sub-
jects partnered with healthy trustees. However,
in late rounds of the game, investments were
significantly lower for dyads with a BPD trustee
relative to control dyads with a healthy trustee
(Fig. 1). This definitive downward shift in in-
vestment levels for dyads with BPD trustees
reflects a break in cooperation [see figs. S2 to
S4 and (34) for additional detailed analyses].
We strongly suspected that this breakdown was
caused by the social signals emitted by the BPD
trustee and were not due to a sampling of healthy
investors that happened to be uncooperative. To
test this claim empirically, we recruited an ad-
ditional cohort of 68 healthy investors to play an
adaptive computer agent designed to play as
either a BPD trustee or a healthy trustee. A sig-
nificant within-subject effect confirmed that BPD
trustee behavior alone elicits a breakdown in co-
operation (see fig. S5) (20).
Coaxing pays into the future. Although the
BPD subjects showed a consistent tendency
to rupture cooperation with their healthy part-
ners, the issue of broken cooperation arises dur-
ing all interpersonal exchange. Individuals bring
to any two-party interaction variability in their
expectations of partner behavior, variable sen-
sitivities to deviations from these norms, and
variable responses to these deviations. These
issues highlight a feature that plagues all social
exchange—breakdowns in cooperation are com-
mon, and successful social agents must sense
(or even anticipate) these failures and select ac-
tions to repair them (28–32). Consequently, we
specifically sought to identify strategic responses
to cooperation breakdowns that allow healthy
trustees to maintain high levels of cooperation
into the later rounds of the exchange. We fo-
cused on rounds in which cooperation was low,
that is, rounds in which investments of $5 or less
were made. Low investments act as a viable proxy
for broken cooperation because in this eco-
nomic exchange game and other related games
(7, 9, 10, 35), opening investments to a responder
(here the trustee) are typically large. For invest-
ments to become small, a responder has to
“prove” that they are not worthy of a large in-
vestment by acting in an untrustworthy man-
ner. Such ruptures of cooperation, nevertheless,
provide the trustee an opportunity to repair the
broken cooperation. If trustees repay a large
fraction of the tripled investment, they signal
their trustworthiness in the presence of low of-
fers and may garner greater investments on sub-
sequent rounds (Fig. 2A). We term this behavior
“coaxing” and show in Fig. 2B that coaxing
pays dividends for four rounds into the future.
In this same figure, we summarize the results for
low offers when the trustees do not coax—trust
and cooperation remain broken. So in the context
of this multiround game, coaxing repairs coop-
eration and pays off generously for the coaxer.
Remarkably, comparison of healthy trustees to
BPD trustees found healthy players to be al-
most twice as likely as BPD players to coax in
the presence of low offers (i.e., repay a third or
more of the investment) (Fig. 2C and fig. S3).
BPD subjects have perturbed norm devia-
tion responses in insular cortex. These behav-
ioral data with humans and computer agents
suggest strongly that BPD subjects are likely to
emit responses that cause cooperation to rupture,
and, once ruptured, they show substantially di-
minished rates of coaxing (generous gestures) to
repair the break (Fig. 2C). A question naturally
arises about whether there is a comprehensible
and consistent neural correlate of the rupture
in cooperation that serves to cue the repair (or
not) of cooperation. To investigate the possi-
ble neural origins of failures in cooperation and
the lack of coaxing, we first sought between-
group differences in the sensitivity of trustee
brains to the revelation of small relative to large
investments. A general linear model (GLM) anal-
ysis identified several regions that significant-
ly differentiated the controls from the BPD
individuals, including bilateral anterior insula,
along with frontal and parietal areas (Fig. 3, top
left; also see table S3 and fig. S6). Subsequent
within-subject analyses identified only a single
region in controls with greater response to small,
relative to large investments—bilateral anterior
insula. In particular, both a GLM analysis (Fig. 3,
top middle; also see table S4) and region-of-
interest (ROI) analysis of voxels identified in
the between-group comparison show a strong
Fig. 2. (A) Coaxing by
trustees engenders trust from
investors. Cooperation with-
in the iterated trust game is
expressed as high levels of
investment combined with
equitable sharing of invest-
ment returns (see fig. S2 for
normative behavior). When
cooperation falters (i.e., when
investments are low), trustees
can rebuild trust and cooper-
ation by coaxing back higher
and higher investment levels.
In this schematic represen-
tation, the investor entrusts
only a small portion of their
to their partner. The $15 re-
ceived by the trustee is far
less than the$60 that would
have been received if the
investor had sent the entire
endowment. Thus, in order to maximize their gains, a trustee must induce cooperation in a repeated
exchange. The trustee can coax back trust from their partner by repaying a large proportion of the tripled
investment–signaling their own trustworthiness and, thus, eliciting larger subsequent investments.
Conversely, if the trustee does not coax and instead keeps a large proportion of the tripled
investment, the investor is likely to invest less on subsequent rounds and cooperation will continue to
devolve. (B) Coaxing pays off. The effect of such coaxing is summarized in the effect of repayment on
investments in subsequent rounds among healthy subjects. This analysis is restricted to low
investments (all rounds with investments <$5). Blue bars depict mean T SE investment level
following small repayments (repayment less than one-third of the tripled investment; “no coax”
condition); green bars depict investment level following large repayments (more than or equal to
one-third; “coax” condition). The analysis indicates that coaxing elicits larger investments in rounds
following coaxing behavior (green) than for rounds following no coaxing (blue). Note that the
coaxing-related increase in investment persists across rounds, such that a large repayment in the
current round earns larger investment up to four rounds into the future. (C) BPD subjects coax less.
Healthy trustees are twice as likely as BPD trustees to coax when cooperation between players is low.
Specifically, healthy trustees are more likely to make a large repayment (≥ investment amount) after
having received a small investment (≤$5). Conversely, BPD trustees are more likely to make a small
repayment (< investment amount) after receiving a small investment. The y axis indicates the
proportion of exchanges that trustees repay more than or equal to the investment amount after
receiving a small investment (≤$5).
VOL 3218 AUGUST 2008
on August 11, 2008
negative relation between bilateral anterior in-
sula activity and investment level (Fig. 3, bot-
tom middle). In stark contrast, in BPD subjects
comparable GLM and ROI analyses (Fig. 3,
top right and bottom right, respectively; also
see table S5) showed no systematic relation of
insula response and investment level. Addi-
tional ROI analyses of medicated and unmed-
icated BPD participants (Fig. 4, left and middle),
and BPD participants matched on income level
(Fig. 4, right) to healthy trustees confirm that the
diminished response cannot be attributed to
group differences in sex, age, verbal IQ, edu-
cation, income level, or medication status.
Repayment-related insula activity intact in
BPD subjects. In earlier work using this same
multiround trust game (35) and single-shot
ultimatum games (12), small offers increase
the probability of defection in the partner, and
such behavior is preceded by increased activ-
ity in the anterior insular cortex [also see (36)
for review]. Consequently, we pursued an ad-
ditional region-of-interest analysis of the anterior
insular cortex to examine whether activity in
this region predicts small repayments by trustees
(Fig. 5). Using the same voxels originally iden-
tified in the group by investment-level GLM,
we found that both healthy and BPD trustees
show a negative relation between insula activ-
ity and repayment level during trustee deci-
sions. That is, despite the diminished insula
response exhibited by BPD trustees during the
receipt of small offers (input), a robust insula
response in this group is observed preceding
decisions to repay small amounts (output). Thus,
healthy subjects show a strong linear relation
between anterior insula response and both the
monetary offer sent from their partner [input
(Fig. 3)] and their monetary response back to
their partner [output (Fig. 5)], whereas BPD
subjects’ insula yielded a linear relationship
only to their response back to their partner [out-
put (Fig. 5)], but showed no differential activity
upon receipt of offers from their partner (Fig. 3).
Moreover, the BPD insula response, on receipt
of offers from the investor, showed the same
average level of activity across all investment
levels, a fact true for both medicated and un-
medicated subjects (Fig. 4).
Although the insular cortex has traditionally
been associated with pain perception, represen-
tation, and interoception (37, 38), responses in
the anterior insula have recently been identified
in social interactions where norms are violated
(12, 14, 39, 40). In an ultimatum game, in which
one player offers to split an endowment with a
second player, small offers are perceived as
unfair and typically refused (41–43). In such
instances, anterior insula activity both scales
negatively with offer size and predicts whether
the offer is subsequently rejected (12). In a re-
lated finding, anterior insula activity of observ-
ers is greater when a punishment is applied to
players perceived as fair relative to players per-
ceived as unfair (13). In nonsocial tasks, activity
in the anterior insula has been found to encode
representations of risk and uncertainty about de-
cision outcomes (44–50). The association of the
insula with a representation of outcome variance
suggests that the insula may encode the distribu-
tion of likely outcomes in social interactions; that
is, responses in the anterior insula may indicate
social norm violations within interpersonal con-
texts. Furthermore, violations of such norms could
serve as control signals that update expectations
about social partners or at least inform learning
about a subset of parameters associated with one’s
partner. This possibility is supported by the work
of Preuschoff and Bossaerts, who have recently
reported prediction errors of risk to evoke strong
responses in the bilateral anterior insula, consistent
with this speculation (49–51). Taken together,
these data suggest that the strong negative
relation between offer size and activity in the
anterior insula seen in healthy trustees reflects
the perceived violation of social norms in the
two-party trust exchange.
Moreover, in BPD, the robust insula response
preceding one’s own repayments is discordant
with the absent insula relation to the investments
Fig. 3. Response of 38 healthy trustee brains and 55 BPD trustee brains
to level of cooperation. (Top) Results of both between- and within-group
GLM analyses identified cortical regions with greater response to small
investments (I ≤ $5) relative to large investments (I > $10). All sig-
nificant voxels are conservatively corrected using false-discovery rate
procedures to the P < 0.05 level in yellow; P < 0.10 in orange (see
tables S3 to S5). (Bottom) Percent change in hemodynamic signal was
averaged from the 115 most significant voxels identified in the group-
level GLM (top left and table S3) during the 4- to 8-s period following
the revelation of investment. The means T SE of the resulting signal are
plotted in $4 bins. Responses in bilateral anterior insula in healthy trustees
scale strongly and negatively with the size of investment (r = –0.97; bottom
middle). In contrast, similar analyses in individuals with BPD showed no such
8 AUGUST 2008VOL 321
on August 11, 2008
of others and highlights the specificity of the
observed deficit in BPD. That is, in BPD, the
apparent insensitivity of the insula only to offer
level size, and not their own repayment, suggests
two possibilities: (i) Monetary reward is not re-
inforcing to individuals with BPD; or, (ii) low
offers are not perceived to be a violation of social
norms to individuals with BPD. Previous work
has shown monetary reward to be a potent re-
inforcer in natural and laboratory settings in this
group (52), which makes the former less likely.
Furthermore, studies of interpersonal and emo-
tional processing in BPD suggest that this group
holds negative expectations of social partners and
exhibits negative evaluative biases (53, 54), con-
sistent with the presence of atypical social norms.
Economic probe corresponds with self-report
measure of trust. To compare social norms of
healthy trustees to BPD trustees within the current
study, we also implemented a self-report measure
of trust (55) that gauges expectations across a
variety of social situations and with a variety of
social agents. Individuals with BPD expressed
significantly lower levels of self-reported trust
relative to healthy controls [P < 0.005 (Fig. 6)],
a finding that agrees with the diminished trust
exhibited by this group in the economic ex-
change. Together, these results suggest that the
diminished insula response to low offers does
indeed reflect atypical social norms in this group.
Put another way, the low offers from social part-
ners do not violate the social expectations of
individuals with BPD, which accounts for the
diminished insula response in the BPD group.
The atypical social norms of individuals with
BPD have considerable implications for both
partners in a repeated cooperative exchange.
Specifically, the incapacity of individuals with
BPD to recognize norm violations as such and
to respond so as to signal trustworthiness to their
partner can result in an inability of both indi-
viduals to effectively model the intentions of one
another. For example, an investor might send a
small amount to a trustee to signal lack of trust
and may do so with the expectation that the
trustee will, in turn, signal a desire to cooperate
through a large repayment (coaxing). However,
the lack of expected response (failure to coax)
may inadvertently signal additional lack of co-
operation, regardless of the trustee’s intent. In
short, the atypical social norms of a single partner
can have deleterious effects on the ability of both
players to model and predict the actions of social
partners and, thus, to inhibit both players’ ability
to mutually benefit from cooperative exchange.
A number of studies have utilized resting-state
and emotional challenge paradigms to investi-
gate personality disorders; however, the current
study is the first large-scale investigation of in-
terpersonal behavior among individuals diag-
nosed with a personality disorder (Axis-II) (22)
using a normative economic exchange game.
The critical role that interpersonal deficits play
across a variety of such disorders, along with
the substantive contribution that neuroimaging
studies have made in elucidating the etiology of
Axis-I clinical disorders, recommend the future
use of game-theoretic probes of interpersonal in-
teraction to uncover the neural processes under-
lying social pathologies (18, 19, 56).
References and Notes
1. R. Axelrod, W. D. Hamilton, Science 211, 1390
2. H. Gintis, Game Theory Evolving (Princeton Univ. Press,
Princeton, NJ, 2000).
3. M. A. Nowak, Evolutionary Dynamics: Exploring the
Equations of Life (Harvard Univ. Press, Cambridge, MA,
4. R. L. Trivers, Q. Rev. Biol. 46, 35 (1971).
Fig. 4. Diminished relation
of insula activity to invest-
ment level is not attributa-
ble to medication status or
income level in BPD trustees.
ROI analyses within subsam-
ples of BPD trustees were
performed as described in
Fig. 3. The systematic neg-
ative relation of investment
level to bilateral anterior in-
sula activity seen in healthy
controls is absent in both
medicated and unmedicated
BPD trustees, as well as in BPD trustees matched to the income level of the control group.
Fig. 5. Both healthy and
BPD trustees exhibit a sys-
tematic negative relation
of repayment level and bi-
lateral anterior insula ac-
tivity during their decision
performed using bilater-
al anterior insula voxels
identified in the between-
group analysis illustrated
in Fig. 3 and used in the
ROI analyses of Figs. 3
and 4. To investigate whether the insula activity also scales with trustee responses to norm
violations, insula activity during trustee decisions is plotted by repayment level. Both healthy and
BPD trustees show a strong negative relation between activity and repayment level. As trustees
repaid more than 60% of the tripled investment in only ~ 7% of rounds, high repayment rounds
are excluded from this analysis.
Fig. 6. Behavioral and self-report
levels of trust indicate perturbed
social norms among individuals with
BPD. (Left) Individuals with BPD re-
port lower trait levels of trust using a
self-report measure [Interpersonal
Trust Scale (55)]. (Right) Individuals
with BPD repay less than the healthy
group, which indicate lower levels of
trust within the exchange game (also
see fig. S2).
VOL 3218 AUGUST 2008
on August 11, 2008
5. J. von Neumann, O. Morgenstern, Theory of Games and Download full-text
Economic Behavior (Princeton Univ. Press, Princeton, NJ,
ed. 2, 1947).
6. D. J. de Quervain et al., Science 305, 1254 (2004).
7. M. R. Delgado, R. H. Frank, E. A. Phelps, Nat. Neurosci.
8, 1611 (2005).
8. D. Knoch, A. Pascual-Leone, K. Meyer, V. Treyer, E. Fehr,
Science 314, 829 (2006).
9. K. McCabe, D. Houser, L. Ryan, V. Smith, T. Trouard,
Proc. Natl. Acad. Sci. U.S.A. 98, 11832 (2001).
10. F. Krueger et al., Proc. Natl. Acad. Sci. U.S.A. 104,
11. J. Rilling et al., Neuron 35, 395 (2002).
12. A. G. Sanfey, J. K. Rilling, J. A. Aronson, L. E. Nystrom,
J. D. Cohen, Science 300, 1755 (2003).
13. T. Singer et al., Nature 439, 466 (2006).
14. M. Spitzer, U. Fischbacher, B. Herrnberger, G. Grön,
E. Fehr, Neuron 56, 185 (2007).
15. M. Sprong, P. Schothorst, E. Vos, J. Hox, H. Van
Engeland, Br. J. Psychiatry 191, 5 (2007).
16. M. Brüne, U. Brüne-Cohrs, Neurosci. Biobehav. Rev. 30,
17. J. Rogers, E. Viding, R. J. Blair, U. Frith, F. Happé,
Psychol. Med. 36, 1789 (2006).
18. P. H. Chiu et al., Neuron 57, 463 (2008).
19. J. K. Rilling et al., Biol. Psychiatry 61, 1260 (2007).
20. Materials and methods are available as supporting
material on Science Online.
21. K. Lieb, M. C. Zanarini, C. Schmahl, M. M. Linehan,
M. Bohus, Lancet 364, 453 (2004).
22. American Psychiatric Association, Diagnostic and
Statistical Manual of Mental Disorders: DSM-IV-TR
(American Psychiatric Association, Washington, DC, ed. 4,
text revised, 2000).
23. P. Fonagy, A. W. Bateman, J. Clin. Psychol. 62, 411 (2006).
24. C. D. Frith, U. Frith, Brain Res. 1079, 36 (2006).
25. T. Singer, Neurosci. Biobehav. Rev. 30, 855 (2006).
26. A. G. Sanfey, G. Loewenstein, S. M. McClure, J. D. Cohen,
Trends Cogn. Sci. 10, 108 (2006).
27. R. Axelrod, D. Dion, Science 242, 1385 (1988).
28. J. Bendor, R. M. Kramer, S. Stout, J. Conflict Resolut. 35,
29. D. Fudenberg, E. Maskin, Am. Econ. Rev. 80, 274 (1990).
30. J. Wu, R. Axelrod, J. Conflict Resolut. 39, 183 (1995).
31. M. A. Nowak, K. Sigmund, Nature 355, 250 (1992).
32. C. Wedekind, M. Milinski, Proc. Natl. Acad. Sci. U.S.A.
93, 2686 (1996).
33. E. Fehr, C. F. Camerer, Trends Cogn. Sci. 11, 419 (2007).
34. To explore whether lower levels of tit-for-tat reciprocity
may have contributed to such failures of cooperation,
linear regressions of behavior between partners were
carried out. Consistent with previous work, reciprocity was
found to be a strong predictor of subsequent increase or
decreases in amount of money sent (table S2). Reciprocity
is defined as the fractional change in money sent across
rounds by one player in response to the fractional change
in money sent across rounds by their partner. Thus,
investor reciprocity on round j was calculated as ∆Ij– ∆Rj–
1, where ∆Ijindicates the fractional change in investment
from round j – 1 to round j and ∆Rj–1indicates the
fractional change in repayment from round j – 2 to round j
– 1. Although deviation in perfect tit-for-tat behavior was
a significant predictor of change in partner behavior
across groups, the strength of this relation did not differ
between pairs that included healthy trustees and pairs that
included BPD trustees (table S2), which suggests sensitiv-
ity and responsivity to tit-for-tat behavior is intact among
individuals with BPD.
35. B. King-Casas et al., Science 308, 78 (2005).
36. B. Seymour, T. Singer, R. Dolan, Nat. Rev. Neurosci. 8,
37. A. D. Craig, Curr. Opin. Neurobiol. 13, 500 (2003).
38. A. D. Craig, Annu. Rev. Neurosci. 26, 1 (2003).
39. P. R. Montague, T. Lohrenz, Neuron 56, 14 (2007).
40. M. P. Paulus, Science 318, 602 (2007).
41. C. Camerer, Behavioral Game Theory: Experiments on
Strategic Interaction (Princeton Univ. Press, Princeton,
42. E. Fehr, K. M. Schmidt, Q. J. Econ. 114, 817 (1999).
43. W. Güth, R. Schmittberger, B. Schwarze, J. Econ.
Behav. Organ. 3, 367 (1982).
44. G. S. Berns et al., Science 312, 754 (2006).
45. H. D. Critchley, C. J. Mathias, R. J. Dolan, Neuron 29, 537
46. S. A. Huettel, C. J. Stowe, E. M. Gordon, B. T. Warner,
M. L. Platt, Neuron 49, 765 (2006).
47. A. Simmons, S. C. Matthews, M. P. Paulus, M. B. Stein,
Neurosci. Lett. 430, 92 (2008).
48. M. P. Paulus, C. Rogalsky, A. Simmons, J. S. Feinstein,
M. B. Stein, Neuroimage 19, 1439 (2003).
49. K. Preuschoff, P. Bossaerts, S. R. Quartz, Neuron 51, 381
50. K. Preuschoff, P. Bossaerts, Ann. N. Y. Acad. Sci. 1104,
51. K. Preuschoff, S. Quartz, P. Bossaerts, J. Neurosci. 28,
52. D. M. Dougherty, J. M. Bjork, H. C. G. Huckabee, F. G. Moeller,
A. C. Swann, Psychiatry Res. 85, 315 (1999).
53. K. M. Putnam, K. R. Silk, Dev. Psychopathol. 17, 899
54. S. Sieswerda, A. Arntz, M. Wolfis, J. Behav. Ther. Exp.
Psychiatry 36, 209 (2005).
55. J. B. Rotter, J. Pers. 35, 651 (1967).
56. A. Todorov, L. T. Harris, S. T. Fiske, Brain Res. 1079, 76
57. This work was supported by the Child and Family Program at
the Menninger Clinic, E. Bleiberg, Director (P.F., L.L., C.S),
National Institute of Mental Health (NIMH) grant
MH078485 (B.K.); NIMH grant MH52797 (P.R.M.); National
Institute of Neurological Disorders and Stroke grant
NS045790 (P.R.M.); and National Institute on Drug Abuse
grant DA11723 (P.R.M). We thank P. Chiu for comments
on this manuscript. We also thank R. Bhimani,
C. Bracero, C. Ha, A. Jarman, O. Mosko, and technical
staff of the Human Neuroimaging Laboratory at Baylor
College of Medicine. We thank referring clinicians
affiliated with the Menninger Department of Psychiatry at
Baylor College of Medicine for assistance in recruitment,
including E. Bleiberg, G. Gabbard, S. Twemlow,
and E. Weinberg.
Supporting Online Material
Materials and Methods
Figs. S1 and S6
Tables S1 to 5
25 February 2008; accepted 30 June 2008
The Crystal Structure of a Sodium
Galactose Transporter Reveals
Mechanistic Insights into
Salem Faham,1Akira Watanabe,1Gabriel Mercado Besserer,1Duilio Cascio,2Alexandre Specht,3
Bruce A. Hirayama,1Ernest M. Wright,1* Jeff Abramson1*
Membrane transporters that use energy stored in sodium gradients to drive nutrients into cells
constitute a major class of proteins. We report the crystal structure of a member of the solute sodium
symporters (SSS), the Vibrio parahaemolyticus sodium/galactose symporter (vSGLT). The ~3.0 angstrom
structure contains 14 transmembrane (TM) helices in an inward-facing conformation with a core
structure of inverted repeats of 5 TM helices (TM2 to TM6 and TM7 to TM11). Galactose is bound in
the center of the core, occluded from the outside solutions by hydrophobic residues. Surprisingly, the
architecture of the core is similar to that of the leucine transporter (LeuT) from a different gene family.
Modeling the outward-facing conformation based on the LeuT structure, in conjunction with
biophysical data, provides insight into structural rearrangements for active transport.
proposed that energy was obtained from the
inward Na+gradient, that is, Na+/glucose co-
is harnessed to do work. For the active
transport (symport) (1). This hypothesis has been
extensively tested, refined, and expanded to in-
clude the active transport of solutes and ions in
virtually all cell types (2). It is now established
the active pumping of Na+out of the cell. This
brane potential, drives the transport of substrates
into cells. Despite this paradigm, the structural
basis for Na+solute symport is unknown.
with sugars, amino acids, inorganic ions, or vita-
human physiology and disease where mutations
oral rehydration therapy, and SGLTs are currently
being targeted in drug trials for type II diabetes.
The first member of the SSS family to be
cloned was the intestinal Na+/glucose symporter
1Department of Physiology, David Geffen School of Medi-
cine, University of California, Los Angeles, CA 90095–1751,
USA.2UCLA–Department of Energy Institute of Genomics
and Proteomics, University of California, Los Angeles, CA
90095, USA.3Laboratoire de Chimie Bioorganique, Uni-
versité Louis Pasteur, CNRS UMR 7175 LC01, Faculté de
Pharmacie, 74 Route du Rhin, 67401 Illkirch, France.
*To whom correspondence should be addressed. E-mail:
firstname.lastname@example.org (E.M.W.); jabramson@mednet.
8 AUGUST 2008 VOL 321
on August 11, 2008