Recovery of empathetic function following resection of insular gliomas

Page 1

CLINICAL STUDY

Recovery of empathetic function following resection of insulargliomas

Xingchao Wang • Xiaosi Gu • Jin Fan •

Shiwei Wang • Fu Zhao • Patrick R. Hof •

Pinan Liu • Zhixian Gao

Received: 2 July 2013 / Accepted: 19 January 2014

� Springer Science+Business Media New York 2014

Abstract The insular cortex is located deep within the

Sylvian fissure between multi-functional and structurally-

compressed cerebral structures, and has been suggested to

play an important role in both basic sensorimotor and

complex social-emotional functions. Such structural and

functional complexity presents a challenge for neurosur-

geons to remove tumors within the insula safely. It has

therefore not yet been documented how neurosurgical

resection of insular gliomas would impact social-emotional

functions. In this study, we examined empathy, a high-level

social-emotional function, in four patients with localized

insular gliomas pre- and post-operatively. The patients

completed an empathy-for others pain task in which they

viewed another person’s hand or foot in painful or non-

painful situations and made judgments about either pain

(explicit empathy) or laterality of the hand or foot (implicit

empathy). They also completed questionnaires assessing

general emotional processing and personality. Deficits in

both explicit and implicit empathetic pain processing were

found in patients before the operations. However, the

operations significantly improved their empathetic ability

after surgery, accompanied by unchanged personality

traits. These results confirmed previous findings that the

insula plays a critical role for empathetic pain perception.

Importantly, the current results suggest that surgical

resection is not only a suitable treatment for insular glio-

mas for clinical consideration, but also effective in

improving high-level functions such as empathetic pain

perception.

Keywords Cognitive function � Empathic processing �Insular gliomas � Outcome � Surgery

Electronic supplementary material The online version of thisarticle (doi:10.1007/s11060-014-1380-y) contains supplementarymaterial, which is available to authorized users.

X. Wang � S. Wang � P. Liu (&) � Z. Gao (&)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital

Medical University, Beijing 100050, China

e-mail: [email protected]

Z. Gao

e-mail: [email protected]

X. Gu

Wellcome Trust Centre for Neuroimaging, University College

London, London WC1N 3BG, UK

X. Gu

Virginia Tech Carilion Research Institute, Roanoke, VA 24016,

USA

J. Fan

Department of Psychology, Queens College, The City University

of New York, Flushing, NY 11367, USA

J. Fan

Department of Psychiatry, Icahn School of Medicine at Mount

Sinai, New York, NY 10029, USA

J. Fan � P. R. Hof

Fishberg Department of Neuroscience, Icahn School of Medicine

at Mount Sinai, New York, NY 10029, USA

J. Fan � P. R. Hof

Friedman Brain Institute, Icahn School of Medicine at Mount

Sinai, New York, NY 10029, USA

F. Zhao � P. Liu

Department of Neural Reconstruction, Beijing Neurosurgery

Institute, Capital Medical University, Beijing 100050, China

123

J Neurooncol

DOI 10.1007/s11060-014-1380-y

Page 2

Introduction

The insular cortex is a complex structure located in the depth

of the Sylvian fissure at the junction of the frontal, parietal,

and temporal lobes, and has intricate connectivity with sur-

rounding cerebral structures [1, 2]. The insula participates in

many basic sensorimotor processes including gustation,

olfaction, motor integration, control of cardiovascular tone,

and speech [3]. The insula is also involved in high-level

social and emotional functions [4, 5] and has been proposed

to represent an important neural substrate for subjective

awareness [6, 7]. For instance, the insula is considered to be

critical for empathy, the ability to understand and share

others’ affective states [8, 9]. Previous studies using func-

tional magnetic resonance imaging (fMRI) and behavioral

tests have demonstrated that the insula, particularly the

anterior insular cortex (AIC), is activated when subjects

observe others in pain, suggesting that AIC is essential for

empathetic pain perception [10, 11].

The insula can be affected by various disease conditions,

of which gliomas are the most common [12, 13]. The

resection of insular gliomas remains a challenge for neu-

rosurgeons because of the region’s unique anatomical

location and difficulty of access [14]. Although successful

resection of insular tumors with minimal long-term mor-

bidity has been achieved with the development of advanced

surgical tools and skills over the past two decades, such

operations can affect multiple complex neurocognitive

functions, ranging from language to social-emotional pro-

cessing [15, 16]. On the other hand, cytoreduction of the

tumor surgically relieving the involvement of the sur-

rounding normal brain structure could alleviate associated

neurological deficits. However, due to the rarity of focal

surgical resection, only a handful of studies have explored

the impact of insula surgery on high-level functions and

behaviors [11]. Traditional clinical assessments using

structural brain imaging or surveys of quality of life do not

inform on a patient’s high-level functioning, especially

those functions dependent on the insula. Additionally,

patients with insular gliomas experience a prolonged and

slowly progressive clinical course compared to similar

tumors in other locations [17]. Insular gliomas are associ-

ated with longer periods of overall survival and progres-

sion-free survival [18]. It is therefore important to assess

changes in high-level functions in these patients to evaluate

long-term outcome of insular glioma operations.

Empathy is critical for effective social interactions and

has gained increasing interest in neuroscience [8, 19, 20].

The critical role of the insula in empathetic functions

makes empathy an important test case for high-level social-

emotional functions in insular glioma patients. To inves-

tigate the surgical impact on higher-level social-emotional

functions in patients with insular gliomas, we assessed

empathy pre- and post-operatively in four patients with

insular gliomas, in comparison to 18 matched normal

controls (NC), using the empathy for others pain (EOP)

task. The EOP provides a reliable assessment for empa-

thetic pain processing involving the insula [9]. We pre-

dicted that patients with insular gliomas would show

deficits in empathetic pain processing pre-operatively, and

that surgical reduction of the tumor mass with preserved

portions of functional insula, would at least partially restore

these functions.

Materials and methods

Participants

Insular glioma patients

Five insular patients met our inclusion criteria (see Supple-

mentary Materials for detailed information). However, one

patient presented dyskinesia for precise movement of the

right arm, and had to be excluded due to inability to operate a

computer mouse for task response selection 3 months post-

operatively (the incomplete dataset for this excluded patient

is provided in the Supplementary Materials). Consequently,

only results for the other four patients with unilateral insular

gliomas are reported (see Table 1 for all participants’ char-

acteristics). Among the four patients, three had right (P1, P2,

and P4) and one had left (P3) insular lesions, and all the

gliomas were Grade II or III pathologically (Table 1). Pre-

and postoperative head MRI scans of insular lesions are

shown in Fig. 1. Each patient was assessed pre-operatively

and 3 months postoperatively.

Normal controls

Eighteen neurologically intact individuals participated in

the study as NC. They were recruited from local commu-

nities in Beijing and were matched with the patients by age,

gender, education, and ethnicity (Table 1). They were

assessed twice, and the assessments were set 3 months

apart to match the time lag between testing sessions in the

patients. Then data from these two testing sessions were

compared with the patients’ pre- and postoperative results

separately.

Tasks and Assessments (see Supplementary Materials

for detailed information about these assessments).

Empathy for others pain (EOP)

Experimental stimuli and procedures were the same as

those described in a previous study [9] (also see Fig. 2).

Briefly, participants viewed color photographs on a

J Neurooncol

123

Page 3

computer screen showing another person’s left or right

hand or foot in painful or non-painful situations. There

were two types of tasks: in the task pain (TP) sessions, the

subjects were instructed to judge whether or not the person

in the photograph was suffering from pain; in the task

laterality (TL) sessions, they were instructed to judge the

laterality of the hand or foot (left or right). Accuracy and

reaction time (RT) were recorded.

General neurological evaluation

The Karnofsky performance score (KPS) and routine

neurological examination [21] were performed longitudi-

nally to provide a brief, but accurate report of the neuro-

logical status of a patient at a given time. Moreover, the

mini-mental state examination (MMSE) [22] and the short

form beck depression inventory (BDI-SF) [23, 24] were

used to assess the differences in general cognitive and

emotional abilities between the IC and NC groups.

Personality assessments

Davis [25] interpersonal reactivity index (IRI), the 20-item

Toronto Alexithymia Scale (TAS-20) [26] and the 30-Item

Short Version NEO-Five-Factor Inventory (NEO-FFI-30)

[27] were administered to assess general personality traits

in patients with insular gliomas pre- and postoperatively.

Data analysis

Accuracy and RT were analyzed for the four experimental

conditions (TP-pain, TP-no pain, TL-pain, TL-no pain) in

EOP. Participants’ sensitivity to pain and laterality was

measured by discrimination index d’ and decision bias was

measured by bias index b using signal detection theory

(SDT) [28]. SDT is a method to discern between signal and

noise, assuming the perceiver has an internal distribution of

signal and noise. In the context of TP, d’ is the distance

between the mean of the probability distribution for ‘‘pain’’

(target) and the mean of the probability distribution for ‘‘no

pain’’ (noise), measured in units of standard deviation. b,

which represents the position of the subject’s criterion, is

the ratio of the height of the ‘‘pain’’ (signal) distribution to

the ‘‘no pain’’ (noise) distribution for the value of thresh-

old. In TL, d’ is the distance between the mean of the

probability distribution for ‘‘left’’ (signal) and the mean of

the probability distribution for ‘‘right’’ (noise), measured in

units of standard deviation. b is the ratio of the height of

the ‘‘left’’ (signal) distribution to the ‘‘right’’ (noise) dis-

tribution for the value of threshold. For TL, d’ and b for

‘pain’ and ‘no pain’ conditions were calculated separately,

then the differences between conditions were tested.

Therefore, the d’ and b difference scores in TL representTa

ble

1P

arti

cip

ant

char

acte

rist

ics

Les

ion

late

rali

ty

Ch

ron

icit

y

(mo

nth

s)

Ag

e

(yea

rs)

Sex

Han

d-

nes

s

Ed

uca

tio

n

(yea

rs)

KP

Sp

re/

po

st

MM

SE

pre

/po

stB

DI

pre

/po

stH

isto

pat

ho

log

yM

edic

atio

ns

pre

/po

st

P1

R3

28

fR

99

0/9

02

6/2

54

/7A

stro

cyto

ma

no

/yes

P2

R3

28

fR

16

90

/10

02

7/2

90

/1A

stro

cyto

ma

no

/yes

P3

L3

48

fR

58

0/9

02

3/2

41

1/7

Oli

go

den

dro

gli

om

an

o/y

es

P4

R3

51

mR

15

90

/10

03

0/2

70

/1A

nap

last

ico

lig

od

end

rog

lio

ma

no

/yes

NC

N/A

N/A

43

±6

.61

0f/

8m

R1

2±

2.4

N/A

28

±1

.7/2

9±

1.4

2±

3.0

/2±

1.5

N/A

no

/no

pv

alu

eN

/AN

/A0

.30

00

.30

6N

/A0

.39

4N

/A0

.24

8/0

.06

10

.34

2/0

.14

8N

/AN

/A

Dat

aar

esh

ow

nas

mea

n±

stan

dar

dd

evia

tio

n.

All

pat

ien

tsu

nd

erw

ent

the

max

imal

safe

rese

ctio

no

fth

eir

insu

lar

gli

om

as(r

esec

tio

nv

olu

me[

95

%).

Th

ep

val

ue

isd

eriv

edfr

om

the

test

bet

wee

np

atie

nts

gro

up

san

dN

Cb

yn

on

par

amet

ric

bo

ots

trap

pin

gm

eth

od

Lle

ft,

Rri

gh

t,B

bil

ater

al,

ffe

mal

e,m

man

,P

1,

P2

,P

3an

dP

4ar

ep

atie

nts

wit

hin

sula

rg

lio

mas

,N

Cn

euro

log

ical

lyin

tact

con

tro

ls,

KP

SK

arn

ofs

ky

per

form

ance

sco

re,

ate

stto

qu

anti

fyca

nce

r

pat

ien

ts’

gen

eral

wel

l-b

ein

gan

dac

tiv

itie

so

fd

aily

life

[21],

MM

SE

min

i-m

enta

lst

atu

sex

amin

atio

n,a

test

for

cog

nit

ive

imp

airm

ent

[22

],B

DI

sho

rtfo

rmo

fth

eB

DI,

am

easu

reo

fb

asel

ine

mo

od

[24

],C

hro

nic

ity

the

tim

ele

ng

thb

etw

een

the

last

inte

rven

tio

nd

ate

and

test

ing

dat

e,A

ge

the

age

atth

efi

rst

test

ing

dat

e,P

re/P

ost

the

resu

lts

of

firs

tan

dse

con

das

sess

men

tsfo

rN

C,

and

pre

-/

po

sto

per

ativ

ere

sult

sfo

rth

ep

atie

nts

,M

edic

ati

on

sit

incl

ud

esan

ti-e

pil

epti

cd

rug

s(D

epak

in,

20

0m

gT

idp

.o.,

con

tin

uo

us

for

2w

eek

s,n

ose

izu

res,

sto

pp

ing

trea

tmen

tg

rad

ual

lyan

dle

avin

ga

med

icat

ion

-fre

ep

erio

do

f2

mo

nth

sb

efo

rep

ost

op

erat

ive

asse

ssm

ent)

and

sho

rtte

rmtr

eatm

ent

usi

ng

low

-do

sed

exam

eth

aso

ne

afte

rsu

rger

yte

mp

ora

rily

for

pre

ven

tin

gb

rain

edem

a(1

0m

g,B

id,

i.v

.fo

r2

day

s,5

mg

,B

id,

i.v

.fo

r2

day

s,5

mg

,Q

d,

i.v

.fo

r2

day

san

d0

.75

mg

,T

id,

p.o

.fo

r3

day

s)

J Neurooncol

123

Page 4

the interference effect of pain on laterality judgment. The

mean RT under TP [(RTTP-pain ? RTTP-no pain)/2] and TL

[(RTTL-pain ? RTTL-no pain)/2] and cost of pain in RT

(additional time-consuming for processing the pain

information) under TP (RTTP-pain - RTTP-no pain) and TL

(RTTL-pain - RTTL-no pain) were calculated as well.

The nonparametric bootstrapping method was used to

assess the probability of observing a difference between

Fig. 1 Lesion imaging. Five axial slices of the insular lesions of four patients are shown preoperative (above line) and postoperative (below line)

in T1 3.0 T MRI images. The focal high signal in P2 lesion was due to hemostasis control

J Neurooncol

123

Page 5

insular and control groups [29, 30] (see Supplementary

Materials for detailed information about these procedures),

due to the small sample size of the patient group, and the

fact that our dataset does not meet the assumptions required

to perform parametric tests.

Results

Clinical assessments

The pre- and postoperative MMSE scores of the patients

were similar to the NC (Table 1). The NC showed stable

BDI scores without depression, and the BDI of patients

showed mild, non-significant increase postoperatively.

Patients showed moderate improvement in KPS scores

after surgery. Only P3 had speech deficits and contralateral

hemiparesis identified during routine neurological exami-

nation immediately after surgery and these symptoms

improved substantially 3 months postoperatively. The

other patients did not show any neurological dysfunction

postoperatively.

Preoperative deficits and postoperative improvement

in explicit empathetic pain processing associated

with insular gliomas

For explicit empathetic pain processing under TP, preoper-

ative insular glioma patients showed a significantly smaller

d0 than NC (p = 0.044; Fig. 3a), indicating diminished

ability to discriminate painful from non-painful stimuli.

Postoperatively, the reassessed d’ of patients did not show

significant difference compared to results of the second

testing session of NC (p = 0.161; Fig. 3a), indicating sig-

nificant improvement in sensitivity to others’ pain.

However, there was no significant dissimilarity between

patients and controls in b during pain judgment preopera-

tively (p = 0.221; Fig. 3b). Although there were some

fluctuations among individual patients’ b scores, the post-

operative group difference between patients and NC for pain

judgment was again not significant (p = 0.138; Fig. 3b).

The response speed of patients during explicit empathetic

pain judgment did not show significant differences either in

mean RT [(RTTP-pain ? RTTP-no pain)/2] (p = 0.185; Fig. 3c)

or cost of pain RT (RTTL-pain - RTTL-no pain) (p = 0.307;

Fig. 3d) compared to NC preoperatively. Postoperatively,

group differences in cost of pain RT (p = 0.265; Fig. 3d)

and overall RT (p = 0.184; Fig. 3c) under TP between

patients and NC were also not significant. Our results

demonstrate significant post-operative improvement in dis-

crimination accuracy of others’ pain (indexed by d’), and no

significant change in other behavioral indices during explicit

empathetic processing in insular patients.

Preoperative deficits and postoperative improvement

in implicit empathetic pain processing associated

with insular gliomas

Implicit empathetic processing was examined by assessing

the interference effect of empathetic pain on laterality

Rig

htLe

ft

Painful Non-painfulFig. 2 Sample stimuli of the

experimental stimulus set.

Participants were instructed to

choose between ‘‘non-painful’’

and ‘‘painful’’ for the TP, and

‘‘left’’ and ‘‘right’’ for the TL

through button press within a

time window of 4,000 ms

(2,500 ms of stimulus display

and 1,500 ms of fixation)

J Neurooncol

123

Page 6

judgment (d0TL-painful - d0TL-non-painful). The negative

scores of NC subjects (Fig. 4a) suggest that they performed

worse on the TL-painful than on the TL-non-painful con-

dition and that pain interfered with laterality judgment.

However, preoperative patients had significant greater

positive d’ difference scores compared to NC (p = 0.004;

Fig. 4a), indicating that empathetic pain did not interfere

with laterality judgment, and they performed better on the

TL-painful than on the TL-non-painful condition. These

results suggest that insular gliomas disrupted not only

explicit but also implicit processing of empathetic pain

preoperatively. When the interference effect of empathetic

pain on laterality judgment was reassessed postoperatively,

NC scores remained negative. Interestingly, the difference

in d’ scores of patients changed from positive preopera-

tively to negative postoperatively, indicating a typical

normal interference effect of pain on laterality judgment

after surgery (p = 0.385 compared to NC; Fig. 4a). These

results suggest that implicit sensitivity to others’ pain was

restored in insular patients postoperatively.

In addition, there were no significant preoperative

(p = 0.324; Fig. 4b) and postoperative (p = 0.335; Fig. 4b)

differences in interference effect of empathy for pain

on decision bias compared to NC. Neither preoperative

nor postoperative mean RT [(RTTL-pain ? RTTL-no pain)/2]

(preoperative p = 0.351 and postoperative p = 0.247;

Fig. 4c) and RT cost of pain (RTTL-pain-RTTL-no pain; pre-

operative p = 0.161 and postoperative p = 0.196; Fig. 4d)

during laterality judgment differed significantly from

controls.

Personality assessments

General personality traits were examined pre- and post-

operatively using three questionnaires (i.e. IRI, TAS-20,

NEO-FFI-30). Only the Neuroticism (N) subscale of NEO-

FFI-30 revealed a significant difference in patients com-

pared to NC in both examinations, indicating that the

patients were more neurotic (preoperative p = 0.030 and

postoperative p = 0.026; Fig. S1).

Discussion

Preoperative functional impairment in patients

with insular gliomas

The impaired sensitivity in empathetic pain processing

observed in insular glioma patients preoperatively support

the notion that insular tumors affect high-level functions

0.0

0.5

1.0

1.5

2.0

2.5

3.0

NC P1 P2 P3 P40.0

1.0

2.0

3.0

4.0

NC P1 P2 P3 P4

0.0

200.0

400.0

600.0

800.0

1000.0

1200.0

1400.0

NC P1 P2 P3 P4

mea

n R

T(m

s)

-400.0

-350.0

-300.0

-250.0

-200.0

-150.0

-100.0

-50.0

0.0

50.0

100.0

150.0

NC P1 P2 P3 P4co

st o

f pai

n in

RT

(m

s)

5.0

6.0 (the second time)

Patient (after surgery)

(the first time)

before surgery)

NC

Patient (

NCa b

c d

Fig. 3 Behavioral performance

on TP. a Presurgically, insular

glioma patients had significantly

smaller d’ (p = 0.044)

compared with NC, indicating

reduced discrimination accuracy

in empathetic pain processing.

After surgery, there was no

significant difference

(p = 0.161) between the

patients’ and retested NC

results. b For the patients group,

neither preoperative

(p = 0.221) nor postoperative

(p = 0.138) decision bias

indexed by b showed significant

alteration during TP compared

to NC. c Neither patients’

preoperative (p = 0.185) nor

postoperative (p = 0.184) mean

RT showed significant

difference compared to NC.

d RT cost of pain did not show

significant differences pre-

(p = 0.307) and postoperatively

(p = 0.265) between patients

and NC. Error bars represent

95 % CI

J Neurooncol

123

Page 7

and that the insula plays an important role in empathetic

abilities. Studies have shown that both low- and high-grade

gliomas can cause neurocognitive impairments in memory,

attention, and executive function [31, 32], and that these

disturbances might be attributed to both tumor and treat-

ment side effects [33–35]. In addition, tumor location may

impact cognitive functions in different ways. For instance,

frontal and temporal lobe lesions impair social behavior

[36], but in the case of insular tumors, deficits in empathy

were evident preoperatively in our patients.

The insula serves a major role in emotional awareness

[6]. Deficits in explicit and implicit empathetic pain pro-

cessing have been associated with focal AIC lesions as

shown in our previous study [11]. Because insular gliomas

not only damage normal insular structure but also affect

surrounding brain regions [37], we propose that the com-

bination of the tumor itself and tumor-related increase in

intracranial pressure have a critical impact on AIC func-

tion, resulting in empathetic processing deficits. Further-

more, this behavioral deficit observed in preoperative

insular glioma patients may be due to the failure of

the insula to integrate sensory information with abstract

representation of subjective feelings and emotional

awareness [11].

Mechanisms underlying postoperative recovery

of empathetic function

The pre- and postoperative comparisons demonstrated that

empathy could be improved by surgery in insular glioma

patients. The restoration of empathy in these four patients

can be attributed to the reduction of the tumor mass with

proper protection of the normal surrounding tissue. Per-

ilesional plasticity is an important compensatory mecha-

nism in glioma patients for postoperative improvement of

cognitive deficits [38, 39]. In this study, however, because

of the AIC is an important structure for empathy [2, 40],

plasticity in perilesional tissues might have been insuffi-

cient to maintain normal empathetic function, but preser-

vation of parts of the AIC could explain the recovery of

empathy for pain. It is also important to note that although

the patients took anti-epileptic medications and steroids

right after their surgeries, they were reassessed 3 months

postoperatively, long after they had stopped taking these

medications. Therefore, we believe that these drugs had no

direct influence on the outcome of our study.

It is also noteworthy that there are individual differences

in empathetic processing pre- and postoperatively. Youn-

ger age and smaller tumor size may indicate a relatively

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

1.0

NC P1 P2 P3 P4 -8.0

-6.0

-4.0

-2.0

0.0

2.0

4.0

6.0

8.0

10.0

NC P1 P2 P3 P4

0.0

200.0

400.0

600.0

800.0

1000.0

1200.0

1400.0

1600.0

NC P1 P2 P3 P4

mea

n R

T (

ms)

0.0

20.0

40.0

60.0

80.0

100.0

120.0

140.0

NC P1 P2 P3 P4co

st o

f pai

n in

RT

(m

s)

(the second time)

Patient (after surgery)

(the first time)

(before surgery)

NC

Patient

NC

a b

c d

Fig. 4 Behavioral performance

on TL. a Insular glioma patients

group had greater scores of d’

difference on TL task

preoperatively (p = 0.004), but

not postoperatively (p = 0.385).

b Patients showed no significant

difference in interference effect

of pain on TL decision bias pre-

(p = 0.324) and postoperatively

(p = 0.335). c Patients showed

no significant difference

compared to NC in mean RT

during laterality judgment pre-

(p = 0.351) and postoperatively

(p = 0.247). d Neither

preoperative (p = 0.161) nor

postoperative (p = 0.196) RT

cost of pain during TL showed

significant alteration between

patients group and results from

both NC assessments. Error

bars represents 95 % CI

J Neurooncol

123

Page 8

stable neurocognitive status and a significant postoperative

improvement of the cognitive deficits, as seen in P1. With

the same young age but a much larger glioma, however, P2

still showed the best empathetic performance (highest d’

and the d’ difference closest to NC). P2’s tumor expansion

did not invade the whole insula, and the preserved portions

of the AIC may have helped to maintain P2’s normal

functional state. Owing to the older age of P3, the large

tumor size, its extensive invasion of the AIC, and its

location in the dominant (left) hemisphere, P3 had the most

severe empathetic deficits (the smallest d’ and difference in

d’ compared to NCs). This is not surprising and is con-

sistent with our understanding of the characteristics of

glioma prognosis. Although P4 suffered from a small

tumor in the AIC, the older age and higher grade of the

glioma may have caused a more destructive progression

[32] and contribute to greater preoperative empathetic

deficits with only moderate recovery.

Clinical considerations

Neurocognitive function outcomes in brain surgery patients

have become an important consideration for neurosurgeons.

Assessments and reassessments of high-level neurocognitive

functions may inform surgeons about the changes in those

functions longitudinally and help guiding clinical manage-

ment [41–43]. Previous clinical studies have revealed that

the most common functional alterations in insular gliomas

patients after surgery were transient deficits in speech and

motor functions [17, 38]. It was concluded that insula

patients were not preferentially vulnerable to neurocognitive

decline after surgery compared to patients with lesions in

neighboring brain regions [44]. Our study provides longi-

tudinal evidence supporting the sensitivity of high level

insular functions to surgical impact. We demonstrate that

insular gliomas are associated with empathy deficits and that

appropriate surgical procedures may help mitigate these

deficits. Moreover, surgeries do not necessarily lead to

additional cognitive disability, supporting the safety and

efficacy of such insular glioma surgeries.

In the current study, we did not use awake craniotomy

and cortical mapping during surgery. Experience with

topographic anatomy and surgery can also ensure the out-

come and safety of surgery. Our protocols suggest that

determining the boundary of tumor accurately to protect

surrounding healthy brain tissues is crucial for operative

outcome. Ultimately, our findings suggest it is important to

assess the neurocognitive status of glioma patients using

sophisticated neuropsychological examinations, especially

for cortical regions like the insula. We show that technical

and anatomical challenges are always the most critical

factors for insular surgery outcomes. To date, surgical

treatment remains the most effective method for insular

patients not only for maximal cytoreduction and accurate

diagnosis, but also for the protection of social-emotional

functions.

Acknowledgments This research was supported by National Sci-

ence and Technology Support Program of the 12th 5-year of China

(Grant Number: 2012BAI12B03) to P. L, by Natural Science Foun-

dation of Beijing (Grant Number: 7112049) to P. L and by National

Science Foundation of China (Grant Number: 81328008) to J. F and

Z. G. J. F was supported by National Institute of Health (NIH) Grants

R21MH083164. P. R. H was supported by The James S. McDonnell

Foundation (Grant 22002078).

Conflict of interest The authors declare they have no conflict of

interest.

References

1. Naidich TP, Kang E, Fatterpekar GM, Delman BN, Gultekin SH,

Wolfe D, Ortiz O, Yousry I, Weismann M, Yousry TA (2004)

The insula: anatomic study and MR imaging display at 1.5 T.

AJNR 25:222–232

2. Gu X, Hof PR, Friston KJ, Fan J (2013) Anterior insular cortex

and emotional awareness. J Comp Neurol 521:3371–3388.

doi:10.1002/cne.23368

3. Stephani C, Fernandez-Baca Vaca G, Maciunas R, Koubeissi M,

Luders HO (2011) Functional neuroanatomy of the insular lobe.

Brain Struct Funct 216:137–149. doi:10.1007/s00429-010-0296-3

4. Butti C, Hof PR (2010) The insular cortex: a comparative per-

spective. Brain Struct Funct 214:477–493. doi:10.1007/s00429-

010-0264-y

5. Menon V, Uddin LQ (2010) Saliency, switching, attention and

control: a network model of insula function. Brain Struct Funct

214:655–667. doi:10.1007/s00429-010-0262-0

6. Craig AD (2009) How do you feel–now? The anterior insula and

human awareness. Nat Rev Neurosci 10:59–70. doi:10.1038/

nrn2555

7. Craig AD (2010) The sentient self. Brain Struct Funct

214:563–577. doi:10.1007/s00429-010-0248-y

8. Singer T, Seymour B, O’Doherty J, Kaube H, Dolan RJ, Frith CD

(2004) Empathy for pain involves the affective but not sensory

components of pain. Science 303:1157–1162. doi:10.1126/sci

ence.1093535

9. Gu X, Liu X, Guise KG, Naidich TP, Hof PR, Fan J (2010)

Functional dissociation of the frontoinsular and anterior cingulate

cortices in empathy for pain. J Neurosci 30:3739–3744. doi:10.

1523/JNEUROSCI.4844-09.2010

10. Singer T, Lamm C (2009) The social neuroscience of empathy.

Ann NY Acad Sci 1156:81–96. doi:10.1111/j.1749-6632.2009.

04418.x

11. Gu X, Gao Z, Wang X, Liu X, Knight RT, Hof PR, Fan J (2012)

Anterior insular cortex is necessary for empathetic pain percep-

tion. Brain 135:2726–2735. doi:10.1093/brain/aws199

12. Hentschel SJ, Lang FF (2005) Surgical resection of intrinsic

insular tumors. Neurosurgery 57:176–183

13. Signorelli F, Guyotat J, Elisevich K, Barbagallo GM (2010)

Review of current microsurgical management of insular gliomas.

Acta Neurochir (Wien) 152:19–26. doi:10.1007/s00701-009-

0450-y

14. Yasargil MG, von Ammon K, Cavazos E, Doczi T, Reeves JD,

Roth P (1992) Tumours of the limbic and paralimbic systems.

Acta Neurochir (Wien) 118:40–52

J Neurooncol

123

Page 9

15. Jones CL, Ward J, Critchley HD (2010) The neuropsychological

impact of insular cortex lesions. J Neurol Neurosurg Psychiatry

81:611–618. doi:10.1136/jnnp.2009.193672

16. Xie C, Bai F, Yu H, Shi Y, Yuan Y, Chen G, Li W, Chen G,

Zhang Z, Li SJ (2012) Abnormal insula functional network is

associated with episodic memory decline in amnestic mild cog-

nitive impairment. Neuroimage 63:320–327. doi:10.1016/j.neu

roimage.2012.06.062

17. Sanai N, Polley MY, Berger MS (2010) Insular glioma resection:

assessment of patient morbidity, survival, and tumor progression.

J Neurosurg 112:1–9. doi:10.3171/2009.6.JNS0952

18. Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha

S, Tihan T, Vandenberg S, McDermott MW, Berger MS (2008)

Role of extent of resection in the long-term outcome of low-grade

hemispheric gliomas. J Clin Oncol 26:1338–1345. doi:10.1200/

JCO.2007.13.9337

19. Preston SD, de Waal FB (2002) Empathy: its ultimate and

proximate bases. Behav Brain Sci 25:1–20

20. Caruana F, Jezzini A, Sbriscia-Fioretti B, Rizzolatti G, Gallese V

(2011) Emotional and social behaviors elicited by electrical

stimulation of the insula in the macaque monkey. Current Biol

21:195–199. doi:10.1016/j.cub.2010.12.042

21. Yates JW, Chalmer B, McKegney FP (1980) Evaluation of

patients with advanced cancer using the Karnofsky performance

status. Cancer 45:2220–2224

22. Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state.

A practical method for grading the cognitive state of patients for

the clinician. J Psychiatr Res 12:189–198

23. Vath R, Miranda M, Becker J, Gibson S (1972) Attempted val-

idation of a pragmatic classification of depression. Psychol Rep

30:287–290

24. Knight RG (1984) Some general population norms for the short

form beck depression inventory. J Clin Psychol 40:751–753

25. Davis MH (1983) Measuring individual differences in empathy:

evidence for a multidimensional approach. J Pers Soc Psychol

44:113–126

26. Bagby RM, Taylor GJ, Parker JD (1994) The Twenty-item Tor-

onto Alexithymia Scale–II. Convergent, discriminant, and con-

current validity. J Psychosom Res 38:33–40

27. Korner A, Geyer M, Roth M, Drapeau M, Schmutzer G, Albani

C, Schumann S, Brahler E (2008) Personality assessment with the

NEO-Five-Factor Inventory: the 30-Item-Short-Version (NEO-

FFI-30). Psychother Psychosom Med Psychol 58:238–245.

doi:10.1055/s-2007-986199

28. Stanislaw H, Todorov N (1999) Calculation of signal detection

theory measures. Behav Res Methods Instrum Comput 31:137–149

29. Hasson U, Avidan G, Deouell LY, Bentin S, Malach R (2003)

Face-selective activation in a congenital prosopagnosic subject.

J Cogn Neurosci 15:419–431. doi:10.1162/089892903321593135

30. Mooney CZ, Duval RD (1993) Bootstrapping: a nonparametric

approach to statistical inference. Sage, Newbury Park

31. Olson JD, Riedel E, DeAngelis LM (2000) Long-term outcome of

low-grade oligodendroglioma and mixed glioma. Neurology

54:1442–1448

32. Bosma I, Vos MJ, Heimans JJ, Taphoorn MJ, Aaronson NK,

Postma TJ, van der Ploeg HM, Muller M, Vandertop WP, Slot-

man BJ, Klein M (2007) The course of neurocognitive func-

tioning in high-grade glioma patients. Neuro-oncology 9:53–62.

doi:10.1215/15228517-2006-012

33. Tucha O, Smely C, Preier M, Lange KW (2000) Cognitive def-

icits before treatment among patients with brain tumors. Neuro-

surgery 47:324–333

34. Klein M, Heimans JJ, Aaronson NK, van der Ploeg HM, Grit J,

Muller M, Postma TJ, Mooij JJ, Boerman RH, Beute GN, Os-

senkoppele GJ, van Imhoff GW, Dekker AW, Jolles J, Slotman

BJ, Struikmans H, Taphoorn MJ (2002) Effect of radiotherapy

and other treatment-related factors on mid-term to long-term

cognitive sequelae in low-grade gliomas: a comparative study.

Lancet 360:1361–1368

35. Douw L, Klein M, Fagel SS, van den Heuvel J, Taphoorn MJ,

Aaronson NK, Postma TJ, Vandertop WP, Mooij JJ, Boerman

RH, Beute GN, Sluimer JD, Slotman BJ, Reijneveld JC, Heimans

JJ (2009) Cognitive and radiological effects of radiotherapy in

patients with low-grade glioma: long-term follow-up. Lancet

Neurol 8:810–818. doi:10.1016/S1474-4422(09)70204-2

36. Gallagher HL, Happe F, Brunswick N, Fletcher PC, Frith U, Frith

CD (2000) Reading the mind in cartoons and stories: an fMRI

study of ‘theory of mind’ in verbal and nonverbal tasks. Neuro-

psychologia 38:11–21

37. Kahana MJ (2006) The cognitive correlates of human brain

oscillations. J Neurosci 26:1669–1672. doi:10.1523/JNEUR

OSCI.3737-05c.2006

38. Duffau H, Taillandier L, Gatignol P, Capelle L (2006) The insular

lobe and brain plasticity: lessons from tumor surgery. Clin Neurol

Neurosurg 108:543–548. doi:10.1016/j.clineuro.2005.09.004

39. Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P, Lopes M,

Mitchell MC, Sichez JP, Van Effenterre R (2003) Functional

recovery after surgical resection of low grade gliomas in eloquent

brain: hypothesis of brain compensation. J Neurol Neurosurg

Psychiatry 74:901–907

40. Sterzer P, Kleinschmidt A (2010) Anterior insula activations

in perceptual paradigms: often observed but barely under-

stood. Brain Struct Funct 214:611–622. doi:10.1007/s00429-

010-0252-2

41. Meyers CA, Hess KR, Yung WK, Levin VA (2000) Cognitive

function as a predictor of survival in patients with recurrent

malignant glioma. J Clin Oncol 18:646–650

42. Armstrong CL, Goldstein B, Shera D, Ledakis GE, Tallent EM

(2003) The predictive value of longitudinal neuropsychologic

assessment in the early detection of brain tumor recurrence.

Cancer 97:649–656. doi:10.1002/cncr.11099

43. Giovagnoli AR (2012) Investigation of cognitive impairments in

people with brain tumors. J Neurooncol 108:277–283. doi:10.

1007/s11060-012-0815-6

44. Wu AS, Witgert ME, Lang FF, Xiao L, Bekele BN, Meyers CA,

Ferson D, Wefel JS (2011) Neurocognitive function before and

after surgery for insular gliomas. J Neurosurg 115:1115–1125.

doi:10.3171/2011.8.JNS11488

J Neurooncol

123