Sleeve Gastrectomy Recovering Disordered Brain Function in Subjects with Obesity: a Longitudinal fMRI Study

Abstract

Objective:
Bariatric surgery could recover regional dysfunction of cerebral cortex. However, it is unknown whether bariatric surgery could recover the global-level dysfunction in subjects with obesity. The aim of this study was to investigate the effect of bariatric surgery on global-level dysfunction in subjects with obesity by resting-state functional magnetic resonance imaging (fMRI).

Methods:
Resting-state fMRI was used to investigate dysfunction of whole-brain in 34 subjects with obesity and 34 age-and gender-matched normal-weight subjects, in which 17 subjects with obesity received sleeve gastrectomy. Fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC) among the whole brain were used to estimate the brain functional differences among the preoperative subjects, postoperative subjects, and the controls.

Results:
The preoperative subjects compared to controls had decreased resting-state activities in reward processing and cognitive control regions such as orbitofrontal cortex, middle frontal gyrus, superior frontal gyrus, and gyrus rectus. It was important that increased FC was also found in these regions. Correlation analysis showed that body mass index (BMI) was associated with these decreased activity and increased FC. More importantly, the dysfunction in these regions was recovered by the bariatric surgery.

Conclusions:
These results suggest that bariatric surgery-induced weight loss could reverse the global-level dysfunction in subjects with obesity. The dysfunction in these regions might play a key role in the development of obesity, which might serve as a biomarker in the treatment of obesity.

Full text

ORIGINAL CONTRIBUTIONS
Sleeve Gastrectomy Recovering Disordered Brain Function in Subjects
with Obesity: a Longitudinal fMRI Study
Panlong Li
1,2,3
&Han Shan
4
&Shengxiang Liang
1,2,3
&Binbin Nie
2,3
&Hua Liu
2,3
&Shaofeng Duan
2,3
&Qi Huang
2,3
&
Tianhao Zhang
2,3
&Guanglong Dong
5
&Yulin Guo
5
&Jin Du
6
&Hongkai Gao
7
&Lin Ma
4
&Demin Li
1
&Baoci Shan
2,3,8,9
#Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Objective Bariatric surgery could recover regional dysfunction of cerebral cortex. However, it is unknown whether bariatric
surgery could recover the global-level dysfunction in subjects with obesity. The aim of this study was to investigate the effect of
bariatric surgery on global-level dysfunction in subjects with obesity by resting-state functional magnetic resonance imaging
(fMRI).
Methods Resting-state fMRI was used to investigate dysfunction of whole-brain in 34 subjects with obesity and 34 age-and
gender-matched normal-weight subjects, in which 17 subjects with obesity received sleeve gastrectomy. Fractional amplitude of
low-frequency fluctuation (fALFF) and functional connectivity (FC) among the whole brain were used to estimate the brain
functional differences among the preoperative subjects, postoperative subjects, and the controls.
Results The preoperative subjects compared to controls had decreased resting-state activities in reward processing and cognitive
control regions such as orbitofrontal cortex, middle frontal gyrus, superior frontal gyrus, and gyrus rectus. It was important that
increased FC was also found inthese regions. Correlation analysis showed that body mass index (BMI) was associatedwith these
decreased activity and increased FC. More importantly, the dysfunction in these regions was recovered by the bariatric surgery.
Conclusions These results suggest that bariatric surgery-induced weight loss could reverse the global-level dysfunction in
subjects with obesity. The dysfunction in these regions might play a key role in the development of obesity, which might serve
as a biomarker in the treatment of obesity.
Keywords Magnetic resonance imaging .Obesity .Bariatric surgery .Functional connectivity .Brain
Panlong Li and Han Shan contributed equally to this work.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s11695-018-3178-z) contains supplementary
material, which is available to authorized users.
*Lin Ma
cjr.malin@vip.163.com
*Demin Li
lidm@zzu.edu.cn
*Baoci Shan
shanbc@mail.ihep.ac.cn
1
Department of Physics, Zhengzhou University,
Zhengzhou, Henan 450001, China
2
Division of Nuclear Technology and Applications, Institute of High
Energy Physics, Chinese Academy of Sciences, Beijing 100049,
China
3
Beijing Engineering Research Center of Radiographic Techniques
and Equipment, Beijing 100049, China
4
Department of Radiology, Chinese People’s Liberation Army
General Hospital, Beijing 100853, China
5
Department of General Surgery, Chinese People’s Liberation Army
General Hospital, Beijing, China
6
Department of Endocrinology, Chinese People’s Liberation Army
General Hospital, Beijing, China
7
Department of General Surgery, the General Hospital of Chinese
People’s Armed Police Forces, Beijing 100039, China
8
CAS Center for Excellence in Brain Science and Intelligence
Technology, Shanghai, China
9
Department of Physics, University of Chinese Academy of Sciences,
Beijing 100049, China
Obesity Surgery
https://doi.org/10.1007/s11695-018-3178-z

Introduction
Cross-sectional neuroimaging studies in humans have
shown that obesity is linked to disordered brain function
in brain areas governing reward processing, cognitive con-
trol, and feeding regulation [1–4]. These neuroimaging
studies remind us that the disordered brain function might
playaroleinobesity.
Relative to behavioral and pharmacological interventions,
surgical therapy is the most efficacy for weight loss in both a
short and long term. In recent years, great amount of re-
searchers have pointed out that the reduction in body weight
after bariatric surgery is likely due to physiological changes
more than purely restrictive gastric volume or malabsorption
[5,6]. There might be neural mechanisms underlying the bar-
iatric surgery. Therefore, great weight loss by bariatric surgery
provides an effective model to explore the neuromechanism
and treatment of obesity. Recent evidence has shown that the
bariatric surgery could change the neurocognitive and food
reward functions in subjects with obesity [7,8]. An fMRI
study found that the hypothalamic disordered functional con-
nectivity (FC) was recovered after the bariatric surgery in
people with obesity [9]. A somewhat similar study in females
found that stronger FC within the default mode network in
women with obesity was recovered by Roux-en Y gastric
bypass surgery [10]. A recent fMRI study reported that bariat-
ric surgery altered resting-state activity in the putamen, insula,
cingulate, thalamus, and frontal regions in females with obe-
sity [11]. Over all, these neuroimaging work has found the
reversibility of dysfunction in several regions which might
be associated with obesity.
Of note, FC of several region of interest (ROI) was chosen
to assess the effect of bariatric surgery. However, it was not
sure whether disordered FC existed in the residual regions
before the surgery, and the effect of bariatric surgery on the
FC of the residual regions was not sure. The whole-brain FC
analysis estimates the global-level FC which can provide more
comprehensive and identifiable information as it highlights
the irreducible nature of information integrated across the
whole brain [12–14]. Though some studies assessed the brain
activity alterations after bariatric surgery by fMRI, it was not
sure whether these regions with altered activity also had dis-
ordered FC. In addition, combining the results of whole-brain
FC analysis and activity analysis could achieve mutual cor-
roboration to afford reliable inference.
Hence, in the current study, two distinct analytic
methods: fractional amplitude of low-frequency fluctua-
tion (fALFF) and FC were used to evaluate the effect of
bariatric surgery on two aspects of brain function. First, we
predicted that subjects with obesity had dysfunction in
some brain areas. Second, we hypothesized that bariatric
surgery could recover some of the obesity-related dysfunc-
tion in some degree.
Methods
Standard Protocol Approvals and Participant
Consents
The protocol for this study was approved by the ethics com-
mittee of the Chinese People’s Liberation Army General
Hospital. All participants in this study were fully informed
of the study procedures and signed informed consent to par-
ticipate in the study.
Participants
We initially recruited 40 subjects with obesity from the
inpatient in Chinese People’s Liberation Army General
Hospital and Beijing Armed Police Corps Hospital, as well
as 36 healthy participants from four communities in
Beijing. The exclusion criteria for all participants included
any neurological or psychiatric disorders, smoking, sub-
stance abuse, as well as drugs acting on the central nervous
system by clinical interviews, medical history, and blood
testing. As the majority of participants seeking bariatric
surgeryintherecruitedBMIrange(30to56kg/m
2
)hada
history of diabetes, the subjects with obesity who had well-
controlled diabetes and were not taking insulin were includ-
ed in this research. One subject with obesity was excluded
from the study due to thyroid cancer, as revealed by
presurgical medical examination. Another one subject with
obesity was excluded from the study due to congenital ce-
rebrovascular malformations, as revealed by MRI.
Furthermore, one subject with obesity was excluded from
the study due to too much body fat that prevented him from
fitting into the magnetic resonance coil comfortably. In ad-
dition, two healthy and three subjects with obesity were
excluded from the study due to unqualified imaging
resulting from poor scanning compliance. Therefore, 34
participants with obesity (mean age = 27.8 years, range
from 17 to 42 years; mean BMI = 40.0 kg/m
2
, range from
30.3 to 55.4 kg/m
2
; 16 women) and 34 age -and sex -
matched normal-weight participants (mean age =
26.7years,rangefrom18to43years;meanBMI=
21.8 kg/m
2
, range from 18.5 to 25.0 kg/m
2
;15women)
were included in this study. Seventeen of them underwent
laparoscopic sleeve gastrectomy (LSG), and three of them
underwent gastric bypass (GB) at two surgical sites which
are Chinese People’s Liberation Army General Hospital
and Beijing Armed Police Corps Hospital. Fourteen of
them dropped out from the study prior to the postoperative
scan or did not undergo the surgery. To exclude the possible
confounding effects of different surgical technique, we only
included 17 postoperation subjects with LSG in this study.
The weight of the postoperative participants had a signifi-
cant loss about 4 months after the surgery (paired ttest
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showed the P< 0.0001). Postsurgical MRI scanning was
carried out about 4 months after the surgery. The sample
size in each step was given out in Fig. 1.Table1showed the
demographic information of participants.
MRI Data Acquisition
All MRI data were acquired on a 3 Tesla GE scanner
(DISCOVERY MR750) at the Chinese People’s Liberation
Army General Hospital. Participants were instructed to relax
but not fall asleep. During scanning, their eyes were kept
closed, and their ears were fitted with soft earplugs. After
the experiment, each participant was confirmed not having
fallen asleep during scanning. One hundred and eighty
resting-state volumes were collected using a multi-slice gradi-
ent-echo EPI sequence [echo time (TE), 30 ms; repetition time
(TR), 2000 ms; flip angle, 90°; slice thickness, 4 mm; number
of slices, 36; no slice gap, field of view (FOV), 240 mm ×
240 mm; matrix size, 64 × 64; voxel size, 3.75 × 3.75 ×
4mm
3
] covering the whole brain.
Data Preprocessing
All resting-state fMRI data were preprocessed using DPARSF
(Data Processing Assistant for Resting-State fMRI; http://
www.restfmri.net): A MATLAB toolbox for Bpipeline^data
analysis of resting-state fMRI. To avoid the non-equilibrium
effects of magnetization, the first ten volumes of the functional
scans were removed. The data preprocessing was referred to
previous research [15]. Specifically preprocessing steps in-
cluded (i) slice time correction; (ii) head motion correction
(if the head motion was larger than 1 mm and 1° in any direc-
tion, the data was discarded); (iii) normalizing to MNI
(Montreal Neurological Institute) space (voxel size 3 × 3 ×
3mm
3
); (iv) 6 mm full width at half-maximum (FWHM)
spatial smoothing; (v) linear detrending; (vi) band pass tem-
poral filtering (0.01–0.08 Hz); and (vii) regressing out nui-
sance covariates (6 head motion parameters, global mean sig-
nal, whiter matter signal, cerebrospinal fluid signal). The
preprocessed data were used to calculate the fALFF and FC
respectively.
FALFF Analysis
The fALFF is an improved approach to detect amplitude of
low-frequency fluctuation (ALFF) for resting state fMRI,
which reflects the intensity of regional spontaneous brain ac-
tivity [16]. The fALFF map of each participant was calculated
by REST software (http://www.restfmri.net). Two-sample t
test was performed by SPM12 software (http://www.fil.ion.
ucl.ac.uk/spm) to determine the fALFF differences within
the whole brain between the normal and preoperative
subjects as well as the normal and postoperative subjects. To
exclude the confounding effects of sample size different in
preoperative group and postoperative group, paired-sample t
test was performed to detect the fALFF differences between
the pre- and postsurgical status. Results were considered sig-
nificant at P< 0.05 (cluster size bigger than 50) after corrected
for multiple comparisons with the false discovery rate method
(FDR-corrected).
Functional Connectivity Analysis
Through fALFF analysis, we have detected altered activity in
the brain of subjects with obesity. But fALFF analysis only
gave out the activity of isolated region. We further used the
whole-brain FC analysis to indicate abnormal information in-
tegration between brain areas [9].
Fig. 1 Sample size in each step.
PC poor compliance, TC thyroid
cancer, CCM congenital
cerebrovascular malformations,
TMBF toomuchbodyfat
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Functional connectivity defines temporal correlation
between blood oxygen level-dependent (BOLD) signals
of distinct brain areas which reflect information integra-
tion between brain areas [17]. In this research, the
Anatomic-Automatic-Labeling (AAL) atlas [18] was used
to divide the whole brain into 90 regions [19,20]. Each
region’s time-course was extracted, and then the correla-
tions between the time-courses of each region were calcu-
lated. The correlations were used for further statistical
analysis.
As in the fALFF analysis, two-sample ttest was used to
calculate the differences in FC between the normal-weight
preoperative subjects as well as the normal-weight postoper-
ative subjects. Paired-sample ttest was applied to detect the
FC differences between pre- and postsurgical status. The sta-
tistical threshold was set at P<0.0005.
Correlation Analysis
To test whether these alterations were associated with obesity,
we also calculated the Pearson correlation coefficient between
BMI and fALFF and FC. The statistical threshold was set at
P<0.05.
Results
Two distinct analytic methods were used to evaluate the
impact of obesity and weight loss on the brain function in
subjects with obesity: fALFF and functional connectivity
MRI (fcMRI).
Decreased Brain Activity in Subjects with Obesity
Compared with normal-weight participants, the preoperative
subjects showed decreased fALFF in bilateral orbitofrontal
cortex (medial orbitofrontal cortex and superior orbitofrontal
cortex), superior frontal gyrus, and gyrus rectus (Fig. 2a). All
of these regions concentrated in the prefrontal cortex. No
increased fALFF region was found. It was noticeable that
subjects with obesity had significant weight loss (paired t
test showed the P< 0.0001) (Table 1), and the decreased
fALFF in those regions recovered to normal level (Fig. 2a)
about 4 months after the bariatric surgery. In addition, the
comparison between the post- and presurgical fALFF
shows great consistency in the location of areas (Fig. 2b).
See Supplementary Table 1fortheclustersize,MNIcoor-
dinates, and Tvalues for each area. Overall, these results
indicated decreased cerebral cortex activity in the preoper-
ative subjects in resting-state, and the reversibility of these
decreased cerebral cortex activity after weight loss was
caused by bariatric surgery.
Disordered Brain Functional Connectivity in Subjects
with Obesity
Two-sample ttest gave out the differences in functional con-
nectivity between preoperative subjects and normal-weight
participants (Fig. 3). In these results, right precentral cortex
had increased FC with bilateral superior frontal cortex, left
middle frontal cortex, and left medial superior frontal cortex;
right superior frontal cortex increased FC with bilateral
postcentral gyrus; right superior orbitofrontal cortex had in-
creased FC with left thalamus; left inferior frontal cortex had
Table 1 Demographic information of participants
Normal-weight subjects The preoperative obese The postoperative obese P1P2
N= 34, 15 females N= 34, 16 females
Mean SD Range Mean SD Range Mean SD Range
BMI (kg/m
2
) 21.8 1.8 18.5–25.0 40.0 6.5 30.3–55.4 34.4 5.9 27.47–42.93 *** ***
Age (years) 26.7 6.8 18–43 27.8 6.9 17–42 NS NS
SDP (mmHg) 123.7 7.8 110–150 142.9 15.5 125–170 127.1 14.2 112–165 *** NS
DBP (mmHg) 73.9 8.0 65–85 87.5 7.9 80–100 78.9 5.8 70–89 *** NS
FG (mmol/l) 4.48 0.56 3.64–5.30 5.95 1.82 4.05–8.31 5.11 1.52 3.67–7.94 ** NS
TC (mmol/l) 3.98 0.36 3.63–4.78 5.14 1.11 3.43–7.18 4.90 0.91 3.41–7.00 ** **
Triglyceride (mmol/l) 1.04 0.34 0.57–1.57 2.20 1.18 0.99–4.98 1.32 0.56 0.66–2.18 ** NS
HDL (mmol/l) 1.34 0.18 1.04–1.7 1.03 0.16 0.83–1.31 1.06 0.25 0.81–1.47 *** **
LDL (mmol/l) 2.29 0.49 1.64–2.98 3.27 0.58 2.26–4.33 3.21 0.52 2.68–4.16 *** ***
P1 P values of two-sample ttest between the preoperative obese and normal-weight participants, P2 P values of two-sample ttest between the
postoperative obese and normal-weight participants. NS no-significant, SBP systolic blood pressure, DBP diastolic blood pressure, FG fasting glucose,
TC total cholesterol, HDL high-density lipoprotein, LDL low-density lipoprotein
*P<0.05; **P< 0.01; ***P<0.001
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increased FC with postcingulum; left supplement motro area
had increased FC with middle cingulum; left medial
orbitofrontal cortex had increased FC with right postcentral
gyrus; and right inferior occipital gyrus had increased FC with
right calcarine, left lingual gyrus, and right inferior temporal
gyrus (Fig. 3a). After the surgery, most of these increased FCs
were recovered (Fig. 3bb). The results in comparison between
post-and presurgery were largely conserved (Fig. 3c).
Consistency was found after comparing the brain regions
found in FC and fALFF findings (Fig. 4). The prefrontal cor-
tex which had decreased fALFF had increased FC with other
regions.
Correlation Relationship
Significant correlations have been found between fALFF and
BMI (Supplementary Table 1)aswellasFCandBMI
(Supplementary Table 3). In general, the fALFF which was
decreased in the preoperative obese had negative correlations
(P< 0.05) with BMI, and the FC which was increased in the
preoperative subjects had positive correlations (P< 0.0001)
with BMI. These indicated that the disordered brain function
was associated with obesity.
Discussion
In this research, decreased cerebral cortex activity was found
mainly in the prefrontal cortex. These regions also had disor-
dered FC with other regions. After the bariatric surgery, the
decreased activity and disordered FC was recovered.
Compared to normal-weight participants, the subjects with
obesity had decreased fALFF in the orbitofrontal cortex,
superior frontal gyrus, and gyrus rectus. It was interesting that
these regions also had disordered FC. Besides, disordered FC
was found in thalamus and postcingulate gyrus in subjects
with obesity. The significant correlation between these disor-
dered brain function and BMI further indicated that the dys-
function in these regions was associated with obesity.
Previous studies also found that subjects with obesity had
decreased activity to food-related stimuli in superior frontal
gyrus [21–23], middle frontal gyrus [21–24], medial prefron-
tal cortex [23–25], and orbitofrontal cortex [23,24]. These
areas were executive components of the brain circuit implicat-
ed in cognitive control (including decision making and inhib-
itory control) and reward processing [26–29]. Disordered
brain activity and FC in these areas might indicate a weaker
cognitive control and reward processing system in subjects
with obesity [30]. Either disordered cognitive control or im-
paired reward processing system is substantially associated
with obesity. Several studies have shown that prefrontal cortex
transcranial direct current stimulation (tDCS) could reduce
food cravings and increase the self-reported ability to resist
food in adults [31,32]. The disordered cognitive control and
reward processing system made the subjects prone to take
more food ignoring self-status. The analysis above indicated
that obese-related disordered brain function might reflect an
obese-prone endophenotype, and the prefrontal cortex might
be a potential biomarker in the treatment of obesity.
Another remarkable finding was that the bariatric surgery
induced significant recovery of the disordered FC and brain
activity in subjects with obesity. Previous seed-based FC stud-
ies have reported that the bariatric surgery could partially re-
cover the hypothalamic dysfunction [9] and recover the disor-
dered FC within the default model network [10]insubjects
with obesity. Also, many studies support the notion of the
Fig. 2 Results of fALFF analysis. Color bar represents the tvalues. a
Group difference map illustrates clusters of significantly decreased
functional activity (red) in the subjects with obesity. bComparison
between post- and presurgical fAFLL. Clusters were threshold at
P< 0.05 after FDR correction, and cluster size threshold was bigger than
50
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recovery of obesity-associated brain activity [8–10,33,34]. In
this research, most of the disordered FC and all of the de-
creased activities were recovered by bariatric surgery. This
indicated that the bariatric surgery not only reduced the capac-
ity of stomach or restricted the absorption of nutrition but also
recovered the disordered obesity-related brain function. It is a
common feature that subjects with obesity have less cravings
for food after bariatric surgery [10,35].Therecoveryofthe
disordered reward processing and cognitive control system
might make them sense more satiety from food and perform
better self-management [10,36].
In this research, global-level recovery of obesity-related
dysfunction was first found in subjects with obesity. Before
the surgery, decreased activity was found mainly in the pre-
frontal cortex. FC analysis further revealed disordered FC in
these regions. Besides, FC analysis detected some other re-
gions such as thalamus, postcingulate gyrus, and striatum,
which also had disordered FC with these regions. This indi-
cated that a single analytical method might miss some impor-
tant information. After bariatric surgery, the decreased activity
in subjects with obesity recovered to normal level, while most
of the disordered FC recovered to normal level. This might
indicate that the recovery of FC was fall behind the activity.
Longer time follow-up studies need to be carried out to inves-
tigate whether the disordered FC would be recovered
completely. One weakness of the study is that we investigated
the brain dysfunction in subjects with obesity in resting state.
No stimulus was provided, such as glucose ingestion and food
images. Another limitation of our study is that the control
group was only tested once. Considering the neurological sta-
tus of the healthy group was almost unchanged within half a
year in which, we did not make the second scan for the control
group. Some operated patients, if achieving satisfactory clin-
ical outcome with substantial weight loss and no discomfort,
might not be compliant to the follow-up routine and thus
missed the second scan. For the same reason, it was also very
hard for the healthy volunteers to be scanned twice in such a
short time. In fact, we only investigated the effect of LSG not
BG on the brain function. The effect of other surgery protocol
such as BG should be carried out in the future studies.
In conclusion, the bariatric surgery in subjects with obesity
could recover the disordered brain function in areas governing
reward processing and cognitive control. These results sug-
gested that the obese-related brain dysfunction might indicate
an obese-prone endophenotype, and the recovery of the dis-
ordered reward processing and cognitive control system might
play a role in body mass reduction.
Acknowledgements The authors thank the patients and healthy volun-
teers who took part in this study.
Funding This work was supported by the National Natural Science
Foundation of China [grant numbers 81471741, 81471728, and
81671770].
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Ethical Statement All procedures performed in studies involving hu-
man participants were in accordance with the ethical standards of the
institutional and national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards.
Consent Statement Informed consent was obtained from all individual
participants included in the study.
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