Neurocase

The Neural Basis of Cognition

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Stroke of bad luck?

Eun Hye Kim, Jui-Hong Chien, Chang-Chia Liu, Kumiko Oishi, Kenichi Oishi,
Rajani Sebastian, Cornelia Demsky, Frederick Lenz & Argye E. Hillis

To cite this article: Eun Hye Kim, Jui-Hong Chien, Chang-Chia Liu, Kumiko Oishi, Kenichi Oishi,
Rajani Sebastian, Cornelia Demsky, Frederick Lenz & Argye E. Hillis (2017) Stroke of bad luck?,
Neurocase, 23:1, 70-78, DOI: 10.1080/13554794.2017.1296578

To link to this article: http://dx.doi.org/10.1080/13554794.2017.1296578

Published online: 05 Apr 2017.

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NEUROCASE, 2017
VOL. 23, NO. 1, 7078
http://dx.doi.org/10.1080/13554794.2017.1296578

Stroke of bad luck?

Eun Hye Kima, Jui-Hong Chienb, Chang-Chia Liub, Kumiko Oishic, Kenichi Oishid, Rajani Sebastiana, Cornelia Demskya,
Frederick Lenzb and Argye E. Hillisa,e,f
a
Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; bDepartments of Neurosurgery, Johns Hopkins
University School of Medicine, Baltimore, MD, USA; cWhiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; dDepartments
of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; eDepartments of Physical Medicine & Rehabilitation, Johns
Hopkins University School of Medicine, Baltimore, MD, USA; fDepartment of Cognitive Science, Johns Hopkins University, Baltimore, MD, USA

ABSTRACT ARTICLE HISTORY

We hypothesized that distinct acute right hemisphere lesions disrupt separate components of valuation Received 19 September
and emotional response to winning and losing money and of emotional empathy in observing a 2016
partner win or lose money. We measured skin conductance response (SCR) and ratings of emotions Accepted 13 February 2017
when acute right hemisphere stroke patients or healthy controls won or lost money in roulette, or when KEYWORDS
they watched a partner win or lose. Our results showed that percentage of damage after stroke to right Empathy; autonomic
anterior insula and frontal operculum negatively correlated with both SCR to winning and losing and nervous system; emotions;
difference between rating wins versus losses. social cognition; stroke

Introduction prefrontal cortex, and anterior insula (Croxson, Walton,

OReilly, Behrens, & Rushworth, 2009; ODoherty, Kringelbach,
Can a stroke make you a good loser but a poor friend? Right
Rolls, Hornak, & Andrews, 2001; Rushworth, Noonan, Boorman,
hemisphere stroke survivors often have blunted emotional
Walton, & Behrens, 2011; Tom, Fox, Trepel, & Poldrack, 2007),
response and less empathy for their partners pain and dis-
whereas the effort involved in this valuation depends on at
tress. Extensive research has led to an understanding of emo-
least anterior cingulate cortex and ventral striatum (Croxson
tional empathy as consisting of both emotional contagion
et al., 2009; Kurniawan, Guitart-Masip, Dayan, & Dolan, 2013).
(sharing anothers emotion) and affective perspective-taking
Functional neuroimaging studies have also revealed that
(making inferences about the emotional state of others)
the brain regions involved in reward networks are also
(Decety & Jackson, 2004; Preston & De Waal, 2002).
engaged in various aspects of emotional empathy. Most stu-
Observing another person experiencing a state elicits compar-
dies show activation in anterior cingulate and anterior insula
able states in the observer through activation of the brain
while observing others experiencing pain or having negative
circuitry that represents interoceptive or emotional states
emotions (e.g., Gu et al., 2012). In an Activation Likelihood
(emotional contagion). The second component of emotional
Estimation (ALE) meta-analysis of 112 functional magnetic
empathy is often considered to be a higher order cognitive
resonance imaging (fMRI) studies of empathy, significant acti-
function, because it requires interpretation of the perceived
vation was associated with the empathy tasks across studies in
emotional state and attribution to the other person (affective
bilateral dorsomedial prefrontal cortex, right more than left
perspective-taking) (Jabbi, Swart, & Keysers, 2007). Affective
inferior frontal cortex, bilateral anterior insula, anterior and
perspective-taking is one type of cognitive perspective-taking
posterior cingulate, bilateral temporoparietal junction, and
or theory of mind (understanding what another person is
right amygdala (Bzdok et al., 2012). In nine independent fMRI
thinking or feeling). Emotional contagion develops earlier, e.g.,
studies of empathy for pain and an ALE meta-analysis of 32
babies cry when their mothers are upset, but only later in
studies of empathy for pain, neural activation was identified
development do children attribute their own emotional
within bilateral anterior insula, anterior cingulate, precuneus,
response to the parent.
and thalamus across studies (Lamm, Decety, & Singer, 2011).
Affective perspective-taking requires that a person infers
However, these studies did not identify distinctive roles for
how they would feel in a given situation, and then attribute
each node in the identified brain network during various
that feeling to the other person. Inferring how one would feel
cognitive processes that underlie empathy or empathy for
in a given situation depends on a valuation system a cere-
pain.
bral network that encodes a value signal and represents
A resting state fMRI study revealed that dominance of
rewards of various natures on a common scale (Levy &
emotional empathy in healthy controls was associated with
Glimcher, 2012; Sugrue, Corrado, & Newsome, 2005).
increased functional connectivity among the ventral anterior
Functional neuroimaging studies have indicated that the
insula, orbitofrontal cortex, amygdala, and anterior cingulate
human valuation system depends on a cerebral network that
(Cox et al., 2012). Dominance of cognitive empathy was asso-
includes at least orbitofrontal cortex, medial and lateral
ciated with functional connectivity between parts of the

CONTACT Argye E. Hillis argye@jhmi.edu

2017 Informa UK Limited, trading as Taylor & Francis Group

brainstem, superior temporal sulcus, and ventral anterior
insula. Finally, many fMRI studies have demonstrated activa-
tion in temporoparietal junction in association with empathy
tasks (Saxe & Kanwisher, 2003). But when emotional perspec-
tive-taking was compared to third-person visuospatial judg-
ments, greater activation in temporoparietal junction was
associated with third-person visuospatial judgments (Schnell,
Bluschke, Konradt, & Walter, 2011). This finding indicates that
temporoparietal junction may have a general role in assign-
ment of agency or mentalizing, rather than a specific role in
emotional empathy (Decety & Lamm, 2007).
However, it is widely recognized that functional imaging
studies reveal correlations between areas of activation and
performance of a task so that they can only reveal brain
areas engaged in a task, rather than areas of the brain that
are critical for the task (Fellows et al., 2005; Squire, Wixted, &
Clark, 2007). Lesion studies are useful in providing a comple-
mentary approach for testing whether specific regions acti-
vated during a task, such as a measure of cognitive or affective
perspective-taking, are indeed necessary for that function.
Impairments in empathy have been studied in a number of
neurological conditions, but primarily in neurological disease
states with fairly diffuse, bilateral damage, or dysfunction, such
as frontotemporal dementia (P. J. Eslinger et al., 2005; P. J.
Eslinger, Moore, Anderson, & Grossman, 2011; Rankin, Kramer,
& Miller, 2005), autism (Baron-Cohen, Jolliffe, Mortimore, &
Robertson, 1997; Dziobek et al., 2008), schizophrenia (Hooker,
Bruce, Lincoln, Fisher, & Vinogradov, 2011; Lee, Zaki, Harvey,
Ochsner, & Green, 2011), and head injury (McDonald &
Flanagan, 2004; Neumann et al., 2012). In these diseases, it is
difficult to attribute the deficits to specific lesions in the brain.
There have been a few studies of impaired empathy after
stroke and other focal brain injury, and these have had each
reported one or a few patients with impaired empathy due to
lesions in prefrontal cortex (Bramham, Morris, Hornak, Bullock,
& Polkey, 2009) (Spikman, Timmerman, Milders, Veenstra, &
Van Der Naalt, 2012), inferior frontal gyrus (Samson et al.,
2005), amygdala (Hurlemann et al., 2010; Stone, Baron-
Cohen, Calder, Keane, & Young, 2003) Hurlemann et al.,
2010), anterior insula (Gu et al., 2012), anterior cingulate (Gu
et al., 2012), or temporal pole (Narvid et al., 2009). Some group
studies of highly heterogeneous lesions (meningioma, head
injury, etc.) and/or heterogeneous time post-onset find similar
lesion sites (S. Shamay-Tsoory, Tomer, Berger, & Aharon-Peretz,
2003; S. G. Shamay-Tsoory, Tomer, Berger, Goldsher, & Aharon-
Peretz, 2005; S. G. Shamay-Tsoory, Aharon-Peretz, & Perry,
2009; S. Shamay-Tsoory, Tomer, Goldsher, Berger, & Aharon-
Peretz, 2004; S. G. Shamay-Tsoory & Aharon-Peretz, 2007).
Many of these patient studies have reported double dissocia-
tions between abnormal scores on emotional contagion and
perspective-taking, relative to healthy controls on the
Interpersonal Reactivity Index (Davis, 1983) or other self-report
measures (P. J. Eslinger, Parkinson, & Shamay, 2002; P. J.
Eslinger et al., 2011; P. Eslinger, Satish, & Grattan, 1996; S. G.
Shamay-Tsoory et al., 2009).
Most studies have indicated that emotional empathy is
more impaired after right hemisphere lesions, compared to
left hemisphere lesions. For example, studies have reported
more severe impairment of emotional empathy in patients
NEUROCASE 71
with right hemisphere than left hemisphere atrophy in fronto-
temporal dementia (P. J. Eslinger et al., 2011; Rankin et al.,
2006) and more common deficits in emotional empathy after
right hemisphere than left hemisphere focal lesions (S.
Shamay-Tsoory et al., 2003; S. G. Shamay-Tsoory et al., 2005;
S. Shamay-Tsoory et al., 2004). One previous study confirmed
that acute stroke involving right medial prefrontal cortex,
anterior cingulate, anterior insula, temporal pole, amygdala,
orbitofrontal cortex, or inferior frontal cortex resulted in
impaired affective perspective-taking, evaluated by asking par-
ticipants to make judgments of emotions about others from
stories or videos (Leigh et al., 2013). However, it was not
possible to determine from that study whether emotional
contagion and/or valuation were impaired. Instead, it was
noted that participants were impaired in some component
of affective perspective-taking (making inferences about the
emotions of another). Affective valuation and emotional con-
tagion are often measured by an observer rating the emo-
tional response (Adolphs, 2003) or by self-rating scales such as
the Interpersonal Reactivity Index (Davis, 1983). However, in
right hemisphere stroke patients, outward expression of emo-
tion and self-rating scales do not provide reliable measures,
because right hemisphere stroke often leads to deficits in
facial expression, prosody (tone of voice), and interospection
(Barrett et al., 2006; Blake, Frymark, & Venedictov, 2013; Ferre,
Ska, Lajoie, Bleau, & Joanette, 2011) that would compromise
these measures. However, emotional responsiveness and con-
tagion can be objectively and sensitively measured with skin
conductance response (SCR) in individuals without autonomic
neuropathy (Tranel, 2000).
We sought to determine whether components of the
empathy network identified by functional imaging studies
are critical for emotional contagion and/or valuation of reward
or cost (aspects of perspective-taking). We tested the hypoth-
esis that strokes in specific right frontal, temporal, insular, or
cingulate cortical regions impair emotional responsiveness
and emotional contagion, and/or valuation in a simple task
that reliably generates positive and negative states in healthy
controls (winning and losing money). We tested this hypoth-
esis in individuals with acute ischemic right hemisphere
stroke, because acute stroke offers the opportunity to test
the effects of lesions before reorganization or recovery, in
previously neurologically normal individuals.
Materials and methods
Participants
We studied nine right-handed patients with acute right hemi-
sphere stroke (within 1 week of stroke onset) and nine right-
handed, age-matched healthy controls. Inclusion criteria for
stroke patients were as follows: right hemisphere ischemic
stroke within the past week, competency in English, ability
to provide informed consent, and comprehension of the task
and the Likert scale (assessed by answering questions about
the task and scale). Participants with any of the following
conditions were excluded from the study: stroke restricted to
the brainstem or cerebellum decreased mental status or
ongoing sedation, substance use or withdrawal, previous
72 E. H. KIM ET AL.

neurological disease affecting the brain, intracerebral hemor- SCR. Baseline SCR was defined as the average of the SCR values
rhage or edema on initial MRI scan, and peripheral or auto- during a 2-s interval before the roulette outcome time.
nomic neuropathy by clinical examination or history. Controls
were right handed without neurological deficits. All partici-
Imaging
pants provided informed consent for the study.
Given the small patient sample (and low power), we did not
use a whole brain voxel-based lesion-deficit-mapping
Assessment of emotional response approach. Rather, because there is a large literature on brain
regions involved in the neural circuits supporting empathy, we
Each player had five rounds total; one player finished all five
used a region of interest (ROI) approach to identify which of
rounds before the other player started. The order of the
these areas are critical to valuation and emotional contagion.
players (participant first or partner first) was randomized to
The 12 ROIs were selected on the basis of functional imaging
avoid an order effect.
studies and lesion studies providing evidence for the neural
The roulette wheel had eight red numbers and eight black
network underlying empathy (Bzdok et al., 2012; Gu et al.,
numbers. Only black numbers were used. The player chose
2012; Lamm et al., 2011; Rankin et al., 2005; S. G. Shamay-
numbers as the winning numbers, and the remaining numbers
Tsoory, 2011) or autonomic function (Beissner, Meissner, Bar, &
became the losing numbers. For each round, the player
Napadow, 2013): orbitofrontal cortex; medial prefrontal cortex;
received 10 chips to bet either to place on winning numbers
inferior frontal gyrus pars operularis, pars triangularis, and pars
or to set aside. If the ball landed on one of the winning numbers,
orbicularis; uncinate fasciculus; anterior insula; middle and
the player won the same amount of chips he or she placed on
superior temporal pole; amygdala; and dorsal and the sub-
that number. If the ball landed on one of the losing numbers, the
genual anterior cingulate gyrus. An investigator (KO) masked
player lost all the chips on the table. However, the player could
to behavioral responses, and SCR results measured the per-
still keep the chips that were set aside. The roulette wheel also
centage of damage to the 12 ROIs on MRI diffusion-weighted
included a green zero; if the ball landed on that number, the
imaging (DWI) sequences, which are the sequences most sen-
player got an extra round, thus an additional 10 chips to bet.
sitive to acute infarct. First, the boundaries of the acute stroke
After each round, the participant was asked how he or she felt
lesion(s) were identified, using a threshold of >30% intensity
by being asked to point to the corresponding face expressing
increase from the unaffected area in the DWI, and then the
emotions from happy to sad on a vertical Likert scale (1 = happy
boundaries were manually modified to avoid false-positive
to 7 = sad, with numeric labels and emoticon faces, arranged
and false-negative areas (Oishi et al., 2009) using RoiEditor
vertically to avoid left neglect). Likert scales were presented in
(www.MRIstudio.org) to create the lesion map. Then, the DWI
vertical arrays so that hemispatial neglect would not influence
b0 sequence was transformed to the JHU-MNI-b0 atlas using
responses. All responses were also given verbally. When the
affine transformation and large deformation diffeomorphic
partner was playing, the patient was asked how the partner
metric mapping. These matrices were applied to the lesion
would feel after each round, using the same mechanisms. At
map for registration. The JHU-MNI Brain Parcellation Map
the end of the game, the total number of chips was counted and
(cmrm.med.jhmi.edu) was then overlaid on the registered
rounded to the nearest 10; for every 10 chips, the participant
lesion map to determine the percentage of volume of each
won $1.00. By the end of the game, they could win up to $5.00
of the12 ROIs infarcted in each case using DiffeoMap (www.
(but could not lose more than they started with).
MRIstudio.org).

Measurement of SCR Analysis/Calculation

SCR (reported in microsiemens or S) was measured through an
isolated skin conductance coupler (Model V71-23, Coulbourn
Instruments, Allentown, PA) with three electrodes
(Compumedisc USA Inc., Charlotte USA) on the ventral distal
phalanges of index, middle, and ring fingers of the left hand.
The coupler delivered low distortion sine wave excitation vol-
tage of 0.5 V (mean square root) at 100 Hz across the skin and
measured the resulting current flow as the SCR. The measured
current was further processed by the coupler into an output
voltage signal for recording. The SCR was alternating current
coupled with 5 s time constant before recording. The recording
module was Neuro Omega (Alpha Omega, Nazareth, Israel) with
sampling rate set at 1 kHz. The recorded SCR was downsampled
to 50 Hz prior to the subsequent analysis.
Roulette outcome time was identified when the dealer
announced the roulette outcome as a win or a loss. Response
magnitude was defined as the maximum SCR during the 6-s
interval after the roulette outcome time minus the baseline
Using STATA version 14, we evaluated differences between
groups with Wilcoxon MannWhitney tests or KruskalWallis
tests (for more than two groups) and differences between
ratings of emotions (on the continuum from happy to sad)
for wins versus losses (as well as ratings and SCR for observer
vs. player) with Wilcoxon signed-rank tests. We evaluated
correlations between percent damage to each ROI and (1)
SCR to winning or losing and (2) difference between ratings
of emotions for winning versus losing, using Spearman corre-
lations. We used an alpha level of p < 0.05.
Results
All stroke patients were alert and oriented in all spheres with
normal language comprehension. They all had right middle
cerebral artery (MCA) distribution strokes, except for one
whose stroke involved both MCA and posterior cerebral artery
distributions. They all had fluent, grammatical speech. None
 NEUROCASE 73

was below normal for their age on forward or backward digit
span. All patients but one had either left hemispatial neglect
(on a gap-detection task that evaluates for both viewer-cen-
tered and object-centered neglect) (Ota, Fujii, Suzuki, Fukatsu, &
Yamadori, 2001) or line bisection in various positions with
respect to the trunk or impairment on a test of affective pro-
sody recognition (Ross & Monnot, 2008) (see Tables 14 for
demographics and scores on neglect and prosody tests). Note
that only three patients had testing of affective prosody. For all
tests, they each used their right, dominant (non-paretic) hand
to respond. Figure 1 shows the lesion overlap of the nine
patients. The crosshairs show the area of greatest overlap.
Skin conductance response (SCR)
Table 2. Gray and white matter structures (parcels on the JHU-MNI Brain
Parcellation Map; cmrm.med.jhmi.edu) in the right hemisphere where at least
10% of the parcel was lesioned.
Experimental ID
CES5849: SFG (posterior segment and prefrontal cortex), MFG (posterior
segment and dorsal prefrontal cortex), IFG (pars opercularis, pars orbitralis,
pars triangularis), LOFG, PreCG, SPG, SMG, AG, PC, STG (posterior and pole),
MTG (posterior), IOG, dACC, anterior insula, posterior insula,amygdala,
supCR, bCC, postIC, EC, cingulum, SFOF, SLF,uncinate fasciculus
DSY2473: SFG (posterior segment and pole), MFG (posterior segment), postCR
HBD1527: dACC, anterior and posterior insula, amygdala, SCR, pIC, bCC, EC,
cingulum,SFOF, SLF, uncinate fasciculus
JFN0433: ITG, PHG, FG, MOG, IOG, cuneus, lingual gyrus, PCC, hippocampus,
cingulum, fornix, PTR, SS
PMN3796: postCG, preCG, SMG, STG (posterior),anterior insula, EC, SFOF (<10% of
IFG opercularis)
PSN9712: supCR, postCR, PTR, SLF (<10% of IFG orbitalis and anterior insula)

The magnitude of SCR was no different for wins versus RGR6308: postCG, SMG, anterior insula, posterior insula, supCR, postCR, EC,SLF
(<10% of IFG opercularis)
losses for either stroke patients (mean 4.42 vs. 4.09;
z = 0.90; p = 0.37) or controls (mean 50.5 vs. 53.9; TDN5381: gyrus rectus, rACC. dACC, subgenual and subcallosal ACC, anterior
insula,posterior insula, nucleus innominata of Mynert, nucleus accumbens,
z = 1.02; p = 0.31). This result is consistent with previous genu of corpus callosum, bCC, cingulum, IFO, SLF, uncinate fasciculus,
studies showing SCR in response to both positive and olfactory radiation(<10% of IFG opercularis)
negative stimuli (Haney & Euse, 1976; but see Sokol- VET6413: MFG (posterior segment), IFG (opercularis, orbitalis, and triangularis),
Hessner et al., 2009, discussed later). The SCR was also preCG, postCG, SMG, STG (posterior and pole), MTG (posterior), IOG,
no different in response to observing another win or lose anterior insula, posterior insula, caudate, putamen, antiCR, postCR and
superior corona radiata, tapatum, anterior, posterior, and retrolenticular IC,
versus in response to themselves winning or losing, for either EC, IFO, PTR, SFO, SLF, uncinate fasciculus
stroke patients (mean 4.48 vs. 3.72; z = 1.12; p = 0.26) or SFG: Superior frontal gyrus; IFG: inferior frontal gyrus; IFG: inferior frontal gyrus;
healthy controls (mean 55.2 vs. 49.2; z = 0.42; p = 0.68). LOFG: lateral orbitofrontal gyrus; PreCG: precentral gyrus; SPG: superior parietal
This result is consistent with functional imaging studies gyrus; SMG: supramarginal gyrus; AG: angular gyrus; PC: pre-cuneus;
STG: superior temporal gyrus; MTG: middle temporal gyrus; IOG: inferior occipi-
that show a substantial overlap in brain regions activated tal gyrus; dACC: dorsal anterior cingulate cortex; supCR: superior corona radiata;
in individuals when they watch another experiencing pain bCC: body of corpus callosum; postIC: posterior limb of internal capsule;
or pleasure as when they themselves experience the same EC: external capsule; SFOF: superior fronto-occipital fasciculus; SLF: superior
longitudinal fasciculus; postCR: posterior corona radiate;
pain or pleasure (Lamm et al., 2011). In this respect, the PHG: parahippocampal gyrus; FG: fusiform gyrus; MOG: middle occipital gyrus;
autonomic response seems to parallel the neural response. IOG: inferior occipital gyrus; PCC: posterior cingulate gyrus; PTR: posterior
Because of the lack of differences across these conditions, thalamic radiation; SS: sagittal stratum; postCG: post-central gyrus.
hereafter SCR is not reported separately for wins versus
losses or conditions (self vs. partner), except in the figures. Table 3. Performance on neglect tests: given in percent error/percent deviation
SCR to winning or losing negatively correlated only with to right (for line bisection).
percent damage to right anterior insula (rho = 0.56; Leftright Leftright
p = 0.015), right medial prefrontal cortex (rho = 0.54; gap circle
detection detection Line Line Line
p = 0.022), and right frontal operculum (rho = 0.48; (object- (viewer- bisection bisection bisection
p = 0.045). SCR magnitude was lower in response to wins Experimental centered centered right of center of left of
and losses in patients with right anterior insula, compared to ID neglect) neglect) trunk trunk trunk
controls and stroke patients without these lesions (z = 6.30; CES5849 12.50 8013.3
DSY2473 00 00 8.9 8.2 0.74
p < 0.00001; Figure 2). SCR magnitude was also lower in HBD1527 00 600 15.6 14.8 5.9
response to wins and losses in patients with right medial JFN0433 00 10060 49.6 79.3 100
prefrontal lesions, compared to controls and patients without PMN3796 00 00 9.6 12.6 8.15
PSN9717 55.63.3 17.423.3 7.4 0.7 51.2
these lesions (z = 5.36; p < 0.00001). Similarly, SCR magnitude RGR6308 00 00 2.2 8.3 17.2
TDN5381 00 86.716.6 1.2 14.8 33.0
VET6413 00 10043 34.8 43.7 25.2
Table 1. Demographics.
Abnormal scores are in bold.
Experimental Education in NIHSS Infarct volume
ID Age Sex years score (mm3)
CES5849 23 Female 12 17 286,381 Table 4. Recognition of affective prosody: given in percent error.
DSY2473 58 Male 12 3 9358.6
HBD1527 70 Female 12 2 2669.1 Recognition of emotional Recognition of
JFN0433 62 Female 12 4 54,197.2 Experimental prosody in neutral content Recognition sincere
PMN3796 55 Female 11 7 21,553.8 ID sentences of sarcasm sentences
PSN9712 76 Male 10 4 17,091.3 HBD1527 62.5 80 15
RGR6308 85 Male 12 13 19,785.4 PMN3796 81.7
TDN5381 38 Female 16 11 45,426.5 PSN9712 75 25 80
VET6413 81 Female 16 13 123,688 Abnormal scores are in bold.
74 E. H. KIM ET AL.

right anterior insula or frontal operculum showed a dimin-

ished difference between their ratings of how happy or sad
they or their partner was when they won or lost, compared to
healthy controls. That is, controls and patients without ante-
rior insula or frontal operculum lesions rated partners and
themselves as significantly happier when they won versus
lost (z = 3.06; p = 0.002) on a 7-point scale; but patients
with anterior insular and frontal opercular lesions showed no
difference in ratings for wins versus losses (z = 1.57; p = 0.12).
The difference between ratings for wins compared to losses
was lower patients with right anterior insular and frontal oper-
cular lesions, compared to controls or stroke patients without
these lesions (Figure 3); the difference across groups was
significant (2 (1) = 7.65; df1; p = 0.0057) by KruskalWallis.
Moreover, the difference between ratings for wins versus
losses negatively correlated with percent damage to right
anterior insula (rho = 0.62; p = 0.006) and frontal opercular
Figure 1. Overlap of lesions of all nine right hemisphere stroke patients. The
(rho = 0.72; p = 0.0007) but not total infarct volume
crosshairs show the point of maximal overlap.
(rho = 0.46; ns) or percent damage to other ROIs.

was lower in response to wins and losses in patients with right

frontal operculum lesions, compared to controls and stroke
patients without these lesions (z = 2.71; p = 0.0067).
Emotional ratings
Ratings of emotions on a 7-point scale from happy to sad were
not significantly different for the participants themselves versus
for the partner they observed for stroke patients (wins: 1.5 vs.
2.2; p = 1.0; or losses: 5.0 vs. 6.0; p = 0.1) or controls (2.0 vs. 1.7;
p = 0.1; losses: 5.0 vs. 6.3; p = 0.1). Only patients with lesions in
Discussion
We hypothesized that specific acute right hemisphere lesions
would disrupt separate components of valuation and emo-
tional response to winning and losing money and components
of emotional empathy in observing a partner win or lose
money. However, we found that lesions disrupted valuation
and perception of emotion in both self and others. That is, we
thought that some lesions would spare emotional response to
egocentric winning and losing but would impair response to
others winning and losing. In contrast to this hypothesis, the

Figure 2. SCR to winning or losing for participants with and without anterior insula and frontal operculum lesions in each condition.
Panel A: Mean SCR to winning or losing for patients with right anterior insula lesions versus controls and patients without anterior insula lesions; Panel B: mean SCR
to winning or losing for patients with right frontal operculum lesions versus controls and patients without right frontal operculum lesions; Panel C: mean SCR to
watching the partner win or lose for patients with right medial prefrontal lesions versus controls and patients without medial prefrontal lesions; and Panel D: mean
SCR to watching the partner win or lose for patients with right frontal operculum lesions versus controls and patients without right frontal operculum lesions.
Error bars show the standard error of the mean. Data are shown separately for trials in which the participant played themselves (Panels A and B) and when they
observed a partner play (Panels C and D).

Figure 3. Ratings of wins versus losses for patients with anterior insula lesions,
right opercular lesions, and controls or patients with right hemisphere lesions
not including the anterior insula or right operculum.
critical lesions we identified were associated with generally
impaired valuation of reward (which seemed to blunt the
patients response to winning and losing themselves, as well
their response to others winning and losing). This blunting of
emotional responsiveness and perception did undermine
emotional empathy but was not specific to empathy.
More specifically, several results from this study converge
in support of the hypothesis that acute lesions of right anterior
insula and frontal operculum undermine emotional perception
and emotional contagion (autonomic response both to win-
ning and losing money oneself and to observing another win
or lose) as well as one aspect of affective perspective-taking
(ability to rate anothers emotional response to winning or
losing). Not only were lesions associated with inability to rate
anothers emotional response but also inability to rate their
own emotional response. This impaired valuation may under-
lie both deficits in emotional contagion and affective perspec-
tive-taking (components of emotional empathy) in some
individuals with right insular and opercular lesions. However,
it is unclear from our results whether failure to recognize or
code an event as reward or cost leads diminished autonomic
response to the event, or whether diminished autonomic
response contributes to impaired recognition of the reward/
cost. We identified a single dissociation: patients with right
medial prefrontal lesions showed diminished SCR but not
diminished rating of emotional response to winning and los-
ing. No patients in this study had impaired rating of emotions
(on the happy to sad scale) but intact SCR. In our very simple
task of roulette, rating of emotion showed a narrower range
of performance than the SCR, and rating may have been
relatively insensitive to deficits compared to SCR.
Functional imaging studies of healthy controls also show
that anterior insula and frontal operculum are engaged in
emotional empathy (Jabbi & Keysers, 2008; Jabbi et al.,
2007). One study showed that anterior insulafrontal opercu-
lum activation in response to observing others engaged in
both negative and positive gustatory behavior (drinking dis-
gusting, neutral, or pleasant drinks) correlated with self-rating
scores on an empathy scale (Jabbi et al., 2007). The authors
proposed that anterior insulafrontal operculum activation
represented transformation of observed states into emotional
NEUROCASE 75
states. This proposal was based on (1) converging evidence
from functional imaging studies demonstrating the role of
these brain areas in processing empathy for pain (Singer
et al., 2004) and perceiving ones own visceral state and (2)
the anatomical connections with anterior insula and frontal
operculum, which are needed for such transformations
(Mesulam & Mufson, 1982). A previous study showed that
right anterior insula lesions are associated with impairments
of perspective-taking (Leigh et al., 2013). However, emotional
contagion was not studied. Our study provides the first evi-
dence that unilateral (right) lesions in anterior insula or frontal
operculum can cause impairments in emotional responsive-
ness and emotional contagion as well as valuation or ratings
of emotions in oneself and others.
Lesions in right medial prefrontal cortex were not only
associated with impairments in autonomic response to winning
or losing (emotional responsiveness and emotional contagion),
but also they were not associated with impairments of valua-
tion in this study. We assessed valuation by asking the partici-
pant to rate how happy their partner was when they won or
lost (and how happy they themselves were when they them-
selves won or lost). One limitation of our study was that rating
of the partners emotion might have been based on either (1)
assessment of the partners emotional facial expression and
tone of voice or (2) judgment of whether the partner should
be happy or sad because they won or lost (based on how they
themselves would feel in the same situation). Participants with
right anterior insula or frontal opercular lesions failed to rate
the emotions in the same manner as controls, regardless of
which strategy they used. The participants with right medial
prefrontal lesions did rate emotions similarly to controls but it is
unclear which strategy they used. While valuation is one com-
ponent of affective perspective-taking (i.e., it is critical to under-
stand how one would feel in order to make inferences about
how another would feel in the same situation); affective per-
spective-taking also requires attribution and mental flexibility
(Rankin et al., 2005). Previous studies have reported that
patients with acute right medial prefrontal lesions are impaired
in affective perspective-taking, when the task requires making a
judgment of emotions of others from stories read to them or
from videos (Leigh et al., 2013). Chronic right medial prefrontal
lesions have also been associated with impaired affective per-
spective-taking (S. G. Shamay-Tsoory & Aharon-Peretz, 2007).
In our study, the SCR was not significantly different for wins
versus losses in patients or controls. In contrast, Sokol-Hessner
et al. (2009) reported that, on average, healthy participants
showed a greater SCR to losses versus gains per dollar lost or
won. However, the greater average SCR for losses versus gains
was observed only in a condition in which they were asked to
consider each trial as a single event and not when they were
asked to consider all of the trials in context, as though they
were building a portfolio. Furthermore, there were substantial
differences across individuals in both conditions; some
showed lower SCR to losses versus wins and many showed
no difference. Additionally, the extent to which the SCR was
greater for losses correlated with loss aversion in making
decisions. In our paradigm, individuals were not instructed to
take a particular perspective with regard to single trials versus
the whole game. Moreover, those with loss aversion could
76 E. H. KIM ET AL.
avoid substantial loss by only putting a small amount of their
cash at risk with each trial. Finally, the amount of money lost
or won in each trial was relatively small (up to $5.00).
Together, our results and previous results show that SCR to
winning or losing depends on both the individual and the
context.
A limitation of this study is that the small number of
patients and variety of lesion sites did not allow us to evaluate
the role of all regions likely to be critical components of the
neural networks underlying reward and emotional empathy.
For example, other studies have shown that SCR correlates
with activation not only in anterior insula but also in amygda-
lae, orbitofrontal gyrus, and cingulate cortex during emotional
states, such as fear (Mriau et al., 2009; Piche, Arsenault, &
Rainville, 2010). Only three of our patients had amygdala
damage. In our study, patients with damage involving right
amygdala, anterior cingulate cortex, temporal pole, and orbi-
tofrontal gyrus also had reduced SCR compared to healthy
controls, but they did not have reduced SCR compared to
patients without such lesions. Furthermore, the percent
damage to these structures did not correlate with the SCR or
with the difference in emotional rating for wins versus losses
(a measure of perspective-taking). These areas may also be
critical to one or both components of empathy (Chakrabarti,
Bullmore, & Baron-Cohen, 2006; P. Eslinger et al., 1996; Gu
et al., 2012; Olson, Plotzker, & Ezzyat, 2007; Rankin et al.,
2005; S. G. Shamay-Tsoory, 2011). However, we may have
had inadequate power to demonstrate their role. We did
show that acute lesions of right anterior insula or frontal
operculum have a detrimental effect on SCR as well as on
rating of emotions of others, relative to healthy controls. But
larger studies are needed to identify all of the areas critical for
these components of valuation and emotional empathy.
Another limitation of our study is that we did not include
patients with similar size acute lesions that include left anterior
insula, medial prefrontal cortex, and/or frontal operculum. We
have attempted to test such patients, but their testing was
complicated by language deficits that interfered with their
understanding of the game and/or rating procedure. Patients
with isolated lesions to these structures should have adequate
comprehension for the task, and future studies will evaluate
whether acute lesions to left anterior insula, medial prefrontal
cortex, and/or frontal operculum cause similar impairments.
It is possible that the deficits in emotional contagion and
understanding of positive and negative emotions of self and
others become mitigated over time; other neural regions may
be able to assume the role of damaged right anterior insula
and frontal operculum during recovery. However, persistently
impaired emotional empathy (with inability to experience or
express emotions or to use emotional processing to relate to
others) has been reported after a right MCA stroke that
included anterior insula and operculum, as well as anterior
temporal cortex (P. J. Eslinger & Geder, 2000). In our study, one
patient who was retested 1 month later showed an increase in
SCR to wins and losses (from mean 4.1 to 8.6 S above base-
line; median 3.57.7 S above baseline), but not to the level of
normal controls. She continued to show no difference (<1 on a
Likert scale) between ratings of wins versus losses (her own or
partners). She had a second stroke prior to her planned
testing at 6 months poststroke. Future studies will evaluate
which areas are critical to recovery of distinct components of
empathy.
Our results show that acute right anterior insula or frontal
operculum stroke can cause impaired autonomic response
and impaired perception of the emotional state of oneself
and others, perhaps due to impaired transformation of experi-
enced and observed states into emotional states (Jabbi et al.,
2007). These deficits are manifest as a blunted emotional
responsiveness (being a good loser or at least unperturbed
by losing) and a loss of emotional empathy (being a poor
friend).
Acknowledgments
This work was supported by the National Institutes of Health (National
Institute of Neurological Disorders and Stroke) under grants R01NS47691,
R01DC05375 (to AEH) and R01NS38493 (to FAL); National Institute on
Deafness and Communication Disorders under grant R01DC05375 and
NICHD under grant R01 HD065955. The content is solely the responsibility
of the authors and does not necessarily represent the views the National
Institutes of Health.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the National Institutes of Health (National
Institute of Neurological Disorders and Stroke) under grants R01NS47691,
R01DC05375 (to AEH) and R01NS38493 (to FAL); National Institute on
Deafness and Communication Disorders under grant R01DC05375 and
NICHD under grant R01 HD065955.
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