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Comparing prefrontal cognitive control
over interference by food images in
binge-eating disorder and bulimia
nervosa
Jung Eun Lee
Department of Medicine
The Graduate School, Yonsei University
[UCI]I804:11046-000000514586[UCI]I804:11046-000000514586
Comparing prefrontal cognitive control
over interference by food images in
binge-eating disorder and bulimia
nervosa
Directed by Professor Young-Chul Jung
The Doctoral Dissertation
submitted to the Department of Medicine
the Graduate School of Yonsei University
in partial fulfillment of the requirements for the degree
of Doctor of Philosophy
Jung Eun Lee
December 2017
This certifies that the Doctoral Dissertation
of Jung Eun Lee is approved.
------------------------------------ Thesis Supervisor : Young-Chul Jung
------------------------------------ Thesis Committee Member#1 : Suk Kyoon An
------------------------------------ Thesis Committee Member#2 : Jeong-Hoon Kim
------------------------------------ Thesis Committee Member#3: Changsoo Kim
------------------------------------ Thesis Committee Member#4: Soo-Hee Choi
The Graduate School
Yonsei University
December 2017
ACKNOWLEDGEMENTS
First of all, I would like to express my sincere gratitude to my thesis
supervisor, professor Young-Chul Jung. I was fortunate that I could have the
opportunity to learn not only his keen insight but also his thoughtful consideration
and finish my degree with his support.
I am sincerely thankful to Professor Suk Kyoon An, Jeong-Hoon Kim,
Changsoo Kim and Soo-Hee Choi for their valuable comments and suggestions
on my thesis. I also appreciate Minji Bang and my colleagues in FIND
(Functional Imaging in Neuropsychiatric Disorders) who helped me in every
aspect.
I take this chance to thank my beloved family: my father, my mother,
my sister and my brother. My parents gave me immeasurable support and
encouragement through my whole life. Thanks to my sister and my brother for
being who they are.
Especially, I would like to express my deep gratitude and love to my
husband who always has been best for me and my daughter who is giving
priceless happiness to my life.
<TABLE OF CONTENTS>
ABSTRACT ····································································· 1
I. INTRODUCTION ···························································· 3
II. MATERIALS AND METHODS ··········································· 6
1. Participants ································································· 6
2. Procedure and stimuli ···················································· 7
A. Stroop match-to-sample task using craving-specific food stimuli
··················································································· 7
3. Image acquisition ························································· 10
4. Preprocessing and fMRI contrast analysis ···························· 11
5. Statistical analysis ························································ 12
III. RESULTS ···································································· 13
1. Participants characteristics ············································· 13
2. Behavioral performance: accuracy and reaction time ·············· 16
3. Cerebral activation associated with food stimuli ···················· 18
IV. DISCUSSION ······························································ 22
V. CONCLUSION ····························································· 27
REFERENCES ································································· 28
ABSTRACT(IN KOREAN) ················································· 36
PUBLICATION LIST ························································ 38
LIST OF FIGURES
Figure 1. Stroop match-to-sample task ·························· 9
Figure 2. Brain activation associated with food stimuli ······· 21
LIST OF TABLES
Table 1. Demographic and clinical characteristics of subjects
······································································ 14
Table 2. Behavioral performance results ························· 17
Table 3. Between-group comparisons of significant activation
in response to food stimuli ······································ 19
1
ABSTRACT
Comparing prefrontal cognitive control over interference by food images
in binge-eating disorder and bulimia nervosa
Jung Eun Lee
Department of Medicine
The Graduate School, Yonsei University
(Directed by Professor Young-Chul Jung)
Binge-eating disorder (BED), which is characterized by recurrent
episodes of binge-eating without inappropriate compensatory behavior, was
approved as an official diagnosis in DSM-5. However, the neural bases that
differentiate BED from other eating disorders, especially bulimia nervosa (BN),
are still under debate. Thirty-nine participants (healthy controls, n = 14; BN, n =
13; BED, n = 12) underwent functional magnetic resonance imaging while
performing a Stroop-Match-to-Sample task. We investigated how food images
interfered with the behavioral performance and blood-oxygenation-level-
dependent neuronal activity. Women with BED and BN showed lower accuracy
compared to the healthy controls, which indicates impaired prefrontal cognitive
control over interference by food images. Women with BED demonstrated
2
stronger activation in the ventral striatum toward food images compared to
healthy controls, which is critical for processing reward-related cues. By contrast,
women with BN exhibited stronger activation in the premotor cortex and the
dorsal striatum which is associated with habit formation. We did not detect
differential activation in the medial prefrontal cortex or the anterior cingulate
cortex, instead the dorsolateral prefrontal cortex, the associative visual cortex,
and the temporoparietal junction were involved. This result may indicate the
attempt of compensating for inappropriate top-down cognitive control in
response to disease-salient stimuli in BN. These aberrant ventral and dorsal
frontostriatal activations toward food images should be associated with increased
reward sensitivity and habitual binge-eating/purging behaviors in BED and BN.
----------------------------------------------------------------------------------------
Key words: binge-eating disorder, bulimia nervosa, reward sensitivity, habit
formation, stroop task, fMRI
3
Comparing prefrontal cognitive control over interference by food
images in binge-eating disorder and bulimia nervosa
Jung Eun Lee
Department of Medicine
The Graduate School, Yonsei University
(Directed by Professor Young-Chul Jung)
I. INTRODUCTION
Binge-eating disorder (BED) is a diagnosis in the fifth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) that has a
clinical profile distinct from other eating disorders 1. It is characterized by
recurring episodes of binge-eating to which reward sensitivity and rash-
spontaneous impulsiveness contribute2 but differs from bulimia nervosa (BN) by
the lack of inappropriate compensatory behaviors to prevent weight gain 3.
Despite this difference, it remains unclear whether BED represents a true
independent diagnosis rather than a variant of BN 4, as both of these disorders
exhibit increased food-related impulsivity 1,5 and encompass comparable levels
of dysfunctional cognitive bias, such as body dissatisfaction 6.
Eating disorders develop and are maintained by dysfunctional attitudes
4
towards food and the body resulting from biased information processing 7.
Individuals with BN show a greater cognitive bias towards eating disorder-related
words in the Stroop task 8 and significantly slower reaction times to food-related
stimuli than the healthy control (HC) group 9,10, indicating that their increased
attention requires greater processing capacity and thus prolongs performance
time 11. BED patients also show decreased performance during food-specific task
12. It was postulated that neurobiological vulnerabilities might drive these
cognitive biases towards food stimuli in eating disorder patients 8.
Brain imaging has been used to investigate the neuronal circuits related
to behaviors in and the pathophysiology of eating disorders 13-16. In response to
food stimuli, individuals with BN exhibit exaggerated activity in the visual cortex,
the dorsolateral prefrontal cortex, the insula, and the ventral striatum 17,18. Overall,
accumulating evidence indicates that impairments of the frontostriatal
components of the cortico-striato-thalamo-cortical circuits supporting self-
regulatory control and reward-based learning contribute to the development and
maintenance of BN 16,19,20. Several studies report that BED patients have
increased activity in reward-related areas, such as the ventral striatum, and a
diminished ability to recruit impulse control-related brain regions such as the
ventromedial prefrontal cortex and the inferior frontal gyrus in response to food
stimuli than do HC 21,22. A positron emission tomography study revealed that
dopamine release in the caudate and putamen significantly increased by the food
stimuli in binge eaters relative to obese subjects without binge eating disorder,
and dopamine release correlated with binge eating scores 22.
However, only a few brain imaging studies focused on the differences
5
between BED and BN. Schienle et al. 23 found increased orbitofrontal cortex
activity in patients with BED, whereas Weygandt et al. 4 reported that individuals
with BN showed stronger responses in the left ventral striatum and the anterior
cingulate cortex. Nevertheless, both BED and BN patients exhibit abnormal
activation of the reward system to food-related cues, yet it is supposed that BN
patients have more intense top-down control regarding their conflict about
“pleasant” but “forbidden” food 23. The difference between them remains unclear
due to the limited understanding of contributing neurobiological factors.
To investigate the differences in prefrontal cognitive control over
disease-salient stimuli, we tested BN and BED patients using the Stroop match-
to-sample task 24 while performing functional magnetic resonance imaging
(fMRI). During this task, the subject’s attention is controlled by an interaction
between bottom-up processing initiated by sensory stimuli and top-down
cognitive processing driven mainly by the prefrontal cortex 25,26. The initiation of
the bottom-up signal by food-related stimuli is mediated by reward-related areas,
which interfere with the top-down control of attention 27. We postulate that
women with BED and BN experience increased interference toward food images,
which impairs their prefrontal cognitive top-down control and behavioral
performance. We assumed that slower response time and lower accuracy rate in
the Stroop match-to-sample task would be identified in BN compared to BED.
We hypothesize that this increased interference is associated with increased
activation in the reward system in both BED and BN, while BN would show
stronger activation in the top-down control related region such as anterior
cingulate cortex and medial prefrontal cortex.
6
II. MATERIALS AND METHODS
1. Participants
The participants in this study were 39 right-handed, female adults (HC,
n = 14; BN, n = 13; BED, n = 12) between 20 and 30 years of age that were
recruited through an internet advertisement. All participants reported their height
and weight and completed the Korean version of the Eating attitudes test-26
(EAT-26) 28 for screening of eating disorders. Participants who scored below 21
points on the EAT-26 and had no history of axis I disorders were classified as the
HC group. Formal diagnoses of eating disorders were established according to
the DSM-5 through clinical interviews conducted by a psychiatrist. The presence
of comorbid psychiatric disorders, medical history and surgical history was
assessed using a structural clinical interview for DSM disorders 29. Participants
with a body mass index (BMI) lower than 17.5 kg/m2, had current or past
psychiatric disorders, had current or past use of psychiatric or herbal medications,
had traumatic brain injury, neurological illness, relevant visual defects, or any
radiological contraindications for MRI were excluded. All participants answered
a set of questionnaires after screening of eating disorders, including the Korean
version of the Eating disorder examination questionnaire (EDE-Q) 30, Binge-
eating scale (BES) 31, Beck depression inventory (BDI) 32, Beck anxiety inventory
(BAI) 33, Barratt impulsiveness scale (BIS) 34, and the revised Questionnaire on
eating and weight patterns (QEWP-R) 35. Eating disorder symptoms were
evaluated using the EDE-Q, BES, and QEWP-R, and impulsiveness was assessed
with the BIS. Verbal intelligence quotient (IQ) scores were determined using the
7
Wechsler adult intelligence scale-IV 36. This study was carried out under the
guidelines for the use of human participants established by the institutional
review board at Yonsei University. Written informed consent was obtained from
all participants after they were provided with a complete description of the scope
of the study.
2. Procedure and stimuli
Participants were asked to abstain from eating for at least 6 hours before
an fMRI session, which was performed between 6 pm and 8 pm. Before the fMRI
experiment, each participant rated the feeling of hunger on a 7-point Likert scale
(“not hungry” to “very hungry”) and underwent a blood glucose test to confirm
the fasting status.
A. Stroop match-to-sample task using craving-specific food stimuli
To test the interference from food stimuli on cognitive control, we
modified the Stroop match-to-sample task 24 using two different conditions, the
food stimuli condition and the neutral stimuli condition (Fig. 1, top panel). We
chose food pictures for the interference stimuli as this is a symptom-specific
stimulus with a high possibility of stimulating the targeted neural circuits 37. As
craving-specific changes in fMRI signals have been reported 38 and there are
individual preferences for types of food that may affect craving, we applied an
individualized Stroop task. All the participants were shown 60 pictures (54 food
pictures and 6 neutral pictures) and instructed to rate their level of craving after
seeing each image. Food stimuli included Korean-specific food as well as
8
Western food considering a culture-bound effect. The six food pictures with the
highest craving scores were selected as the interference stimuli. In the food
stimuli condition, these six food pictures were presented between the cue and the
target word for each individual, whereas six neutral pictures selected from the
International affective picture system 39 were presented in the neutral condition.
Stimuli were created using E-prime software (Psychology Software Tools, Inc.)
and presented through nonmagnetic goggles. Subjects matched the color of a cue
(“XXX”) displayed for 500 ms in the center of the screen to the color of a target
Stroop word, which appeared for 1000 ms after an interference stimuli interval of
2700 ms. The intertrial fixation interval was 2400 ms. The total duration of each
trial was 6.6 s.
9
Figure 1. Stroop match-to-sample task. The top panel depicts examples for
food and neutral stimuli presentations. The bottom panel depicts examples of the
experimental paradigm.
10
For these experiments, there were 2 runs, run 1 and run 2 (Fig. 1, bottom
panel), for which the order was randomized to minimize the learning effect. Run
1 was a match-to-color task and run 2 was a match-to-letter task. In run 1, the
participants were instructed to match the color of the cue to the written color of
the Stroop word (e.g., the word “YELLOW” written in red font is regarded as
red). In run 2, the participants were instructed to match the color of the cue to the
color that the Stroop word means (e.g., the word “YELLOW” written in red font
is regarded as yellow). The colors of the cue and target word were red, yellow, or
blue. Subjects were instructed to press a red key when the cue and the target
matched and a green key for nonmatches using their right hand, yielding accuracy
and reaction time measures. Each run had eight blocks (four with food stimuli
and four with neutral stimuli) comprising six trials. The total duration of each run
was 323.4 s. The subjects performed a practice session before entering the scanner.
3. Image acquisition
MRI was conducted on a 3T Siemens Magnetom MRI scanner (Siemens
AG, Erlangen, Germany) equipped with an eight-channel head coil. Whole-brain
fMRI data were acquired during the Stroop task with a T2-weighted gradient
echo-planar pulse sequence (TE = 30 ms, TR = 2200 ms, flip angle = 90, field
of view = 240 mm, matrix = 64 64, slice thickness = 4 mm). High-resolution
anatomical images were acquired with a T1-weighted spoiled gradient echo
sequence (TE = 2.19 ms, TR = 1780ms, flip angle = 9, field of view = 256mm,
matrix = 256x256, slice thickness = 1mm) to underlay the fMRI data. Participants’
motions were minimized in accordance with the best practice for head fixation,
11
and structural image series were inspected for residual motion.
4. Preprocessing and fMRI contrast analysis
Spatial preprocessing and statistical analyses of functional images were
performed using SPM8 (Statistical Parametric Mapping, Wellcome Trust Centre
for Neuroimaging; www.fil.ion.ucl.ac.uk/spm). Motion artifacts of individual
subjects were assessed by visually inspecting realignment parameter estimations
to confirm there were no abrupt head motions and the maximum head motion in
each axis was <4 mm. The anatomical volume was segmented into gray matter,
white matter, and cerebrospinal fluid. The gray matter image was used for
determining the parameters of normalization on the standard Montreal
Neurological Institute gray matter template. The spatial parameters were then
applied to the realigned and unwarped functional volumes that were ultimately
resampled to voxels of 2 × 2 × 2 mm and smoothed with an 8-mm full-width at
half maximum kernel.
Individual statistics were computed using a general linear model
approach as implemented in SPM8. To obtain the blood-oxygenation-level-
dependent(BOLD) response related to food stimuli, individual contrast was
generated by contrasting “food stimuli” blocks with “neutral stimuli” blocks at
the first-level analysis. The resulting set of contrast images were then entered into
second-level analysis using a full factorial model. To compare the contrasts
between groups, exclusive masks were created for each group with SPM maps
with a threshold at P < 0.05. Statistical interferences were thresholded using an
uncorrected P < 0.001, kE ≥ 5 voxels for the whole brain.
12
5. Statistical analysis
Statistical analyses were conducted using the Statistical Package for the
Social Sciences (SPSS 18.0). Two-tailed one-way analyses of variance
(ANOVAs) were used to compare the demographic and clinical characteristics
and repeated-measures ANOVAs were used to compare behavior performances
between groups with significance considered at P < 0.05.
13
III. RESULTS
1. Participants characteristics
Individuals with eating disorders (BED and BN groups) scored higher
on the EAT-26, EDE-Q, and BES than the HC group, which corresponded with
the diagnoses (Table 1). No significant differences were observed in verbal IQ
and hunger scale values among the three groups. Individuals in each of the groups
had blood glucose levels below 110 mg/dL before scanning.
14
Tab
le 1
. D
emogra
ph
ic a
nd
cli
nic
al
cha
ract
eris
tics
of
sub
ject
s
Char
acte
rist
ic
Stu
dy g
roup
S
tati
stic
al r
esult
s
HC
(n
= 1
4)
BE
D (
n =
12)
BN
(n =
13)
F
P v
alue
Gro
up
dif
fere
nce
*
Age
(yr)
2
3.3
± 2
.2
23.6
± 2
.6
23.7
± 2
.2
0.6
33
0.5
37
—
Dura
tio
n o
f il
lnes
s (y
r)
—
5.0
± 3
.4
7.5
± 4
.0
21.9
41
<0.0
01
HC
<B
ED
, B
N
BM
I (kg/m
2)
2
0.4
± 2
.6
25.6
± 3
.8
21.5
± 2
.2
11.5
21
<0.0
01
HC
, B
N<
BE
D
Ver
bal
IQ
1
10
2.8
6 ±
8.7
104.2
3 ±
11.9
96.2
5 ±
12.1
1.8
97
0.1
65
—
EA
T-2
62
4.6
4 ±
6.8
21.8
5 ±
12.9
34.3
3 ±
7.9
31.8
65
<0.0
01
HC
<B
ED
< B
N
ED
E-Q
2
12
.36
± 9
.2
45.3
8 ±
22.9
55.9
1 ±
18.6
22.0
87
<0.0
01
HC
<B
ED
, B
N
BE
S
9.2
1 ±
5.3
21.7
7 ±
5.9
26.1
7 ±
7.3
26.9
40
<0.0
01
HC
<B
ED
, B
N
BD
I
5.4
3 ±
5.5
14.6
9 ±
8.6
20.4
2 ±
7.4
14.3
00
<0.0
01
HC
<B
ED
, B
N
BA
I
4.5
0 ±
5.2
12.3
8 ±
6.6
19.9
1 ±
9.6
14.7
4
<0.0
01
HC
<B
ED
<B
N
BIS
49.0
7 ±
7.5
5
8.0
0 ±
6.8
5
4.3
3 ±
8.5
4.6
82
0.0
16
HC
<B
ED
Hunger
Sca
le
2.4
3±
0.8
2.4
6±
1.5
2.9
2±
1.1
0.7
35
0.4
87
—
15
Val
ues
are
ex
pre
ssed
as
mea
n (
SD
). B
AI,
Bec
k a
nxie
ty i
nven
tory
, B
DI,
Bec
k d
epre
ssio
n i
nven
tory
; B
ED
, b
inge-
eati
ng d
iso
rder
; B
ES
, B
inge-
eati
ng s
cale
; B
IS,
Bar
ratt
im
puls
iven
ess
scal
e; B
MI,
body m
ass
ind
ex;
BN
, b
uli
mia
ner
vo
sa,
EA
T-2
6,
Eat
ing
atti
tudes
te
st-2
6;
ED
E-Q
, E
atin
g
dis
ord
er
exam
inat
ion
ques
tio
nn
aire
; H
C,
hea
lth
y
con
tro
ls;
IQ, in
tell
igen
ce q
uo
tien
t.
*B
on
ferr
oni
corr
ecte
d,
P <
0.0
5.
1W
ech
sler
ad
ult
inte
llig
ence
sca
le-I
V.
2K
ore
an v
ersi
on
16
2. Behavioral performance: accuracy and reaction time
There was significant difference in accuracy among the three groups
(Table 2). Accuracy scores decreased from the HC group to the BED group
followed by the BN group, but only the difference between the HC and BN groups
was statistically significant after Bonferroni correction (P = 0.011). Reaction
times increased from the HC group to the BED group followed by the BN group,
but the differences were not statistically significant. A repeated-measures
ANOVA revealed no significant effects of condition (food vs. neutral stimuli) on
accuracy (F[1,36] = 0.004, P = 0.952) or reaction time (F[1,36] = 0.563, P =
0.458). There were no significant interactions between group and condition in
accuracy (F[2,36] = 0.353, P = 0.705) or reaction time (F [2,36] = 2.075, P =
0.140).
17
Tab
le 2
. B
eha
vio
ral
per
form
an
ce r
esu
lts
Cat
ego
ry
Stu
dy g
roup
S
tati
stic
al r
esult
s
HC
B
ED
B
N
F
P v
alue
Gro
up
dif
fere
nce
*
Acc
ura
cy (
%)
Fo
od
sti
mu
li
96
.27
±4
.4
93.7
1±
6.8
90.0
6±
10.4
4.6
01
0.0
13
HC
> B
N
Neu
tral
sti
mu
li
95
.53
±5
.7
94.2
3±
5.1
90.8
6±
6.3
4.7
04
0.0
12
HC
> B
N
Rea
ctio
n t
ime
(ms)
Food s
tim
uli
549.8
4±
73
.1
55
9.3
5±
55.5
585.1
0±
12
0.7
1.1
63
0.3
18
—
Neu
tral
sti
mu
li
54
9.5
7±
81.0
565.9
9±
76.3
566.4
2±
124.1
0.2
74
0.7
61
—
BE
D, b
inge-
eati
ng d
iso
rder
; B
N,
buli
mia
ner
vosa
; H
C, hea
lthy c
ontr
ols
.
* B
onfe
rroni
corr
ecte
d, P
< 0
.05
.
18
3. Cerebral activation associated with food stimuli
The eating disorder group showed greater activation in the dorsolateral
prefrontal cortex (x,y,z:-18,44,48; BA 9; P < 0.001), the orbitofrontal cortex
(x,y,z: -24,20,-8; BA 11), the premotor cortex (x,y,z: -42,8,54; BA 6), and the
ventral striatum (x,y,z: 18,16,-4, x,y,z: 6,6,2) compared to the HC group. The
BED group demonstrated stronger activation of the ventral striatum (x,y,z: 6,6,2)
in response to food stimuli compared to that in the HC group (Table 3, Fig. 2.).
The BN group showed stronger BOLD responses in the dorsal striatum (x,y,z:
8,14,8), the premotor cortex (x,y,z: -42,8,54; BA 6), the dorsolateral prefrontal
cortex (x,y,z: 20,44,48; BA 9, x,y,z:-16,34,58; BA 8), the associative visual
cortex (x,y,z: 26,-70,2; BA 19, x,y,z:-34,-72,34; BA 19), and the
temporoparietal junction (x,y,z: -48,-44,-4; BA 21) compared to the HC group.
There were no brain regions in the HC group with significantly stronger
activation than in the eating disorder group. However, the BN group showed
greater activation than the BED group in the dorsal striatum (x,y,z: 6,14,10),
the premotor cortex (x,y,z: -40,8,52; BA 6), the dorsolateral prefrontal cortex
(x,y,z: 20,44,48; BA 9, x,y,z:-16,34,58; BA 8), the associative visual cortex
cortex (x,y,z: 26,-70,2; BA 19, x,y,z:-34,-72,34; BA 19), and the
temporoparietal junction (x,y,z: -48,-44,-4; BA 21), whereas the BED group
showed greater activation than the BN group in the associative visual cortex
(x,y,z: -28,-86,0; BA 18), and the postcentral cortex (x,y,z: 60,0,28; BA 43).
19
Table 3. Between-group comparisons of significant activation in response to
food stimuli＊
Region BA kE Tmax x y z
ED (BN+BED) > HC
Dorsolateral prefrontal cortex L 9 21 3.65 -18 44 48
Orbitofrontal cortex L 11 13 4.24 -24 20 -8
Premotor cortex L 6 51 4.71 -42 8 54
Ventral striatum R 7 3.66 18 16 -4
R 35 4.91 6 6 2
Postcentral cortex R 43 12 3.95 60 0 26
Associative visual cortex R 18 24 3.99 16 -92 -4
BN > HC
Dorsolateral prefrontal cortex R 9 5 3.54 20 44 48
L 8 61 4.58 -16 34 58
Dorsal striatum R 26 3.79 8 14 8
Premotor cortex L 6 61 4.32 -42 8 54
Temporoparietal junction R 21 13 4.18 -48 -44 -4
Associative visual cortex R 19 116 4.29 26 -70 2
L 19 60 3.83 -34 -72 34
BED > HC
Ventral striatum R 6 3.89 6 6 2
Postcentral cortex R 43 21 4.39 60 0 28
20
BN > BED
Dorsolateral prefrontal cortex R 9 5 3.54 20 44 48
L 8 60 4.58 -16 34 58
Dorsal striatum R 34 3.79 6 14 10
Premotor cortex L 6 21 4.06 -40 8 52
Temporoparietal junction R 21 13 4.18 -48 -44 -4
Associative visual cortex R 19 116 4.29 26 -70 2
L 19 60 3.83 -34 -72 34
BN < BED
Postcentral cortex R 43 20 4.39 60 0 28
Associative visual cortex L 18 5 3.57 -28 -86 0
＊Exclusive masks were created for each group with SPM maps with a threshold
at P < 0.05. Statistical inferences were thresholded using an uncorrected P <
0.001, kE ≥ 5 voxels for the whole brain.
L, Left; R, Right; BA, Brodmann’s area; BED, binge-eating disorder; BN,
bulimia nervosa; HC, healthy controls; ED, eating disorder.
21
Figure 2. Brain activation associated with food stimuli. Red indicates areas
where activation was stronger in the bulimia nervosa group than the healthy
control group. Green indicates areas where activation was stronger in the binge-
eating disorder group than the healthy control group. Cyan indicates areas where
activation was stronger in the bulimia nervosa group than the binge-eating
disorder group.
22
IV. DISCUSSION
This study investigated the effect of food stimuli on prefrontal cognitive
control in individuals with BED and BN. In particular, BN participants
demonstrated poorer performance on the Stroop task than the HC group,
indicating that they are more affected by interference from food stimuli (bottom-
up processing) during a task evaluating the top-down control of attention. This
behavior data grossly correlated with the fMRI findings.
The eating disorder group showed increased activation in the ventral
striatum and orbitofrontal cortex which is associated with the reward circuit 23. It
can be assumed that the food stimuli, disease-salient to eating disorder patients,
elicited the food reward which can trigger food consumption 4.
As hypothesized, participants with BED showed stronger activation in
the ventral striatum, an area that is critical for processing incentive salience of
stimuli and reward-related cues 40. These data support the notion that disease-
salient stimuli elicit bottom-up processing that impinges on top-down attention
control 25. Thus, BED patients exhibit increased reward sensitivity without
inhibitory control. Our findings are consistent with previous studies 23,41,42 and are
also in line with the definition of BED, which is characterized by a loss of control
over food without compensatory behaviors. We did not observe differential
activation of other brain reward regions, such as the orbitofrontal cortex. This
might be due to the difference of this task design from previous studies which
involved passive viewing of food pictures, as the orbitofrontal cortex is associated
with calculating the reward value and further decision-making processes 43.
23
BED participants showed neural responses that differed from those with
BN, who had higher activation in the dorsal striatum and the premotor cortex.
These regions are a part of the cortico-basal ganglia network, which plays a
crucial role in habit formation 44. Substantial research has made a consensus that
human instrumental behaviors are controlled by action-outcome(A-O) system
and stimulus-response(S-R) system which are controlled by the cortico-basal
ganglia network 45. If the behavior is overtrained or the reward response is
repeated after it is acquired by A-O learning, the behavior will become insensitive
to the reward and proceed automatically(S-R learning) 44,46. This shift from A-O
system to S-R system is called habit formation.
According to this principle, the binge-eating and purging behaviors that
characterize BN may initially begin as goal-directed actions, which then become
habitual after they are repeated persistently. BN patients typically binge on highly
palatable foods that activate the reward circuit 47,48. In addition, the purging
behavior to prevent weight gain and relieve stress is also rewarding 4,49. The
binge-eating and purging behavior itself acts as conditioned reinforcement. This
is consistent with the clinical features of BN who have suffered from the illness
for a substantial period of time; they report that they binge and purge habitually
without evaluating the consequences, even though it is not as rewarding as it was
before. Our data are largely compatible with a previous findings of greater dorsal
striatum grey matter volume in BN compared to BED 50 and abnormally increased
dorsal striatum activity during habit learning in BN 51. Moreover, recent
preclinical data suggest that rats habitually binge-eat seems to fail to update new
response-outcome information and demonstrated increased dorsal striatum
24
activity 52,53. Together with the behavior data (lower accuracy), our result
indicates inappropriate top-down control of the frontostriatal circuit in response
to disease-salient stimuli, thereby promoting the gradual change from voluntary
to habitual actions in BN 19.
However, there was no differential neural activation of the ventral
striatum in the BN group, perhaps due the protracted illness duration in the
participants of this study. The median illness duration was 7.5 years, perhaps
reflecting the habitual nature of the behavior and reduced ventral striatum
activation.
We did not detect differential activation in the medial prefrontal cortex
or the anterior cingulate cortex, instead the dorsolateral prefrontal cortex was
involved 54,55. The anterior cingulate cortex and the medial prefrontal cortex is
critical in controlling top-down cognitive control process to adjust behavior and
guide performance 56,57 during the Stroop task, while the dorsolateral prefrontal
cortex is associated with executing attention 58. Moreover, the BN group showed
increased activation of the associative visual cortex and the temporoparietal
junction compared to not only the BED group but also the HC group. The
dorsolateral prefrontal cortex and the associative visual cortex is part of the dorsal
attention network which is recruited for top-down control of attention and is
thought to generate and maintain endogenous signals based on current tasks 25,59.
On the other hand, the ventral attention network represents the exogenous
orienting system which detects behaviorally salient stimuli and acts as a “circuit
breaker” of the dorsal attention network 25. The temporoparietal junction region
is suggested to be associated with the interaction between ventral and dorsal
25
attention network 25. This result, the involvement of the dorsolateral prefrontal
cortex, the associative visual cortex, and the temporoparietal junction, may
indicate the attempt of compensating for inappropriate top-down control in
response to disease-salient stimuli in BN.
According to the normal motivated learning theory, the dopamine
transmission from the ventral striatum is critical in acquisition of the motivational
memory and is necessary in facilitation of learning 60. The cortico-striatal
glutamate circuit plays a dominant role in the development of habit memory
which proceed without ongoing decision-making and in the engagement of well-
learned behavior 60,61. Furthermore, the role of glutamate transmission involving
the dorsal striatum becomes more important than corticofugal glutamate
projection, as a behavior evolve into a habitual behavior utilizing working
memory circuitry 61,62. From this point of view, the eating behavior of BED
showing stronger activation of the ventral striatum can be regarded as a reward-
seeking impulsive behavior which is not yet consolidated, while BN who showed
stronger activation of the dorsal striatum can be considered as a habitual eating
disorder. Although more research is needed, our finding may imply the serial
relationship of BED and BN in a perspective of a pathology of normal learning.
There are several limitations of this study to be acknowledged. The
sample size was not large enough to obtain a statistically significant difference in
the behavior data between BED and HC groups. We used the uncorrected P value
due to the small sample size. The behavior data did not differ between food and
neutral stimuli even though the IQ difference was not significant. This might be
due to the residual interference from food stimuli on neutral stimuli conditions
26
considering the relatively short block time. Also, we only included female
participants between 20 and 30. Finally, the differences in BDI and BAI scores
between eating disorder and HC groups may have influenced their responses,
though participants with comorbid psychiatric disorders were excluded from the
study.
27
V. CONCLUSION
Women with BN and BED exhibited increased interference toward food
images, which impaired their prefrontal cognitive top-down control and
behavioral performance. Women with BED demonstrated stronger activation of
the ventral striatum, whereas women with BN exhibited stronger activation of the
premotor cortex and the dorsal striatum. Our findings suggest that women with
eating disorders have dysfunctional ventral and dorsal frontostriatal circuits,
which mediate the reward sensitivity and habitual binge-eating/purging behaviors
in eating disorders.
28
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36
ABSTRACT(IN KOREAN)
신경성 폭식증과 폭식 장애 여성에서 음식자극 간섭이 전전두엽
인지조절에 미치는 영향 비교
<지도교수 정 영 철 >
연세대학교 대학원 의학과
이 정 은
폭식 장애는 보상행동을 동반하지 않는 반복적인 폭식을
특징으로 하며 최근 정신질환의 진단 및 통계 편람(Diagnostic and
Statistical Manual of Mental Disorders, fifth edition)에서 공식
진단명으로 인정받았다. 하지만 폭식 장애를 다른 식이 장애, 특히
신경성 폭식증과 구분 짓는 신경인지적 특성에 대해서는 논란이 있다.
이 연구에서는 폭식 장애와 신경성 폭식증 환자에서 나타나는
전전두엽 인지 조절(prefrontal cognitive control)의 차이를
알아보기 위해 총 39명(정상군 14명, 신경성 폭식증 13명, 폭식 장애
12명)의 피험자를 대상으로 음식 자극을 이용한 스트룹 검사
(Stroop-Match-to-Sample task)를 시행하며 기능적 뇌자기공명영상을
촬영하였다. 이를 통하여 식이 장애 환자에게 질병 특이
자극(disease-salient stimuli)인 음식 자극이 과제 수행 반응과
혈중 산소치 의존 신경 활성도(blood-oxygen-level-dependent
neuronal activity)에 주는 영향에 대해 살펴보았다. 폭식 장애
환자군과 신경성 폭식증 환자군이 스트룹 검사에서 정상군보다 낮은
정확도를 보였고, 이는 음식 자극의 간섭으로 인하여 저하된 인지
37
조절 능력을 반영한다고 볼 수 있겠다. 폭식 장애 환자군은 정상군과
비교했을 때 음식 자극 상황에서 배쪽 줄무늬체(ventral striatum)의
활성도가 높았으나, 신경성 폭식증 환자군에서는 등쪽
줄무늬체(dorsal striatum)와 운동앞겉질(premotor cortex)의
활성도가 높게 측정되었다. 배쪽 줄무늬체는 보상 회로(reward
circuit)에서 핵심적인 역할을 하는 영역이며, 등쪽 줄무늬체와
운동앞겉질은 이마엽줄무늬체 회로(frontostriatal circuit)에
포함된 영역으로 습관 형성(habit formation)에 관여한다. 이와 같은
음식 자극에 대한 뇌영역 활성도의 차이가 폭식 장애와 신경성
폭식증 환자에서 나타나는 식이 행동의 차이와 연관이 있는 것으로
생각된다.
----------------------------------------------------------------
핵심되는 말: 폭식 장애, 신경성 폭식증, 보상 감도, 습관 형성, 스
트룹 검사, 기능적 뇌자기공명영상
38
PUBLICATION LIST
Jung Eun Lee, Kee Namkoong, Young-Chul Jung. Impaired prefrontal cognitive
control over interference by food images in binge-eating disorder and bulimia
nervosa. Neuroscience Letters 2017;651: 95-101.
